Tuesday, April 2, 2013
Magnesium
Magnesium
Magnesium is the eleventh most abundant element by mass in the human body. The adult body content is 25 g distributed in the skeleton and soft tissues. The chemical is essential in manipulating important biological polyphosphate such as ATP, DNA, and RNA and in functionming enzymes(a).
A. Magnesium and hypertension
B. Magnesium sulphate
C. Magnesium deficiency complications
D. Magnesium and Asthma
Magnesium and Type II diabetes
1. High dietary magnesium intake is associated with low insulin resistance in the Newfoundland population
In the study to investigate the association between magnesium intake and IR in normal-weight (NW), overweight (OW) and obese (OB) along with pre- and post- menopausal women, showed that subjects with the highest intakes of dietary magnesium had the lowest levels of circulating insulin, HOMA-IR, and HOMA-ß and subjects with the lowest intake of dietary magnesium had the highest levels of these measures, suggesting a dose effect. Multiple regression analysis revealed a strong inverse association between dietary magnesium with IR. In addition, adiposity and menopausal status were found to be critical factors revealing that the association between dietary magnesium and IR was stronger in OW and OB along with Pre-menopausal women(1).
2. Magnesium intake and risk of type 2 diabetes
In the study to assess the association between magnesium intake and risk of type 2 diabetes with retrieved studies published in any language by systematically searching MEDLINE from 1966 to February 2007 and by manually examining the references of the original articles, found that magnesium intake was inversely associated with incidence of type 2 diabetes. This finding suggests that increased consumption of magnesium-rich foods such as whole grains, beans, nuts, and green leafy vegetables may reduce the risk of type 2 diabetes(2).
3. Fiber and magnesium intake and incidence of type 2 diabetes
In the study to examine associations between fiber and magnesium intake and risk of type 2 diabetes and summarized existing prospective studies by meta-analysis, found that during 176 117 person-years of follow-up, we observed 844 incident cases of type 2 diabetes in the European Prospective Investigation Into Cancer and Nutrition-Potsdam. Higher cereal fiber intake was inversely associated with diabetes risk (RR for extreme quintiles, 0.72 [95% confidence interval [CI], 0.56-0.93]), while fruit fiber (0.89 [95% CI, 0.70-1.13]) and vegetable fiber (0.93 [95% CI, 0.74-1.17]) were not significantly associated. Meta-analyses showed a reduced diabetes risk with higher cereal fiber intake (RR for extreme categories, 0.67 [95% CI, 0.62-0.72]), but no significant associations for fruit (0.96 [95% CI, 0.88-1.04]) and vegetable fiber (1.04 [95% CI, 0.94-1.15]). Magnesium intake was not related to diabetes risk in the European Prospective Investigation Into Cancer and Nutrition-Potsdam (RR for extreme quintiles, 0.99 [95% CI, 0.78-1.26]); however, meta-analysis showed a significant inverse association (RR for extreme categories, 0.77 [95% CI, 0.72-0.84])(3).
4. Dietary calcium and magnesium, major food sources, and risk of type 2 diabetes in U.S. black women
In a a prospective cohort study including 41,186 participants of the Black Women's Health Study without a history of diabetes who completed validated food frequency questionnaires at baseline, during 8 years of follow-up (1995-2003), we documented 1,964 newly diagnosed cases of type 2 diabetes, showed that
a diet high in magnesium-rich foods, particularly whole grains, is associated with a substantially lower risk of type 2 diabetes in U.S. black women(4).
5. Serum and dietary magnesium and the risk for type 2 diabetes mellitus
In the study to assess the risk for type 2 diabetes associated with low serum magnesium level and low dietary magnesium intake in a cohort of nondiabetic middle-aged adults (N = 12,128) from the Atherosclerosis Risk in Communities Study during 6 years of follow-up, found that aassessed the risk for type 2 diabetes associated with low serum magnesium level and low dietary magnesium intake in a cohort of nondiabetic middle-aged adults (N = 12,128) from the Atherosclerosis Risk in Communities Study during 6 years of follow-up(5).
6. Associations of serum and urinary magnesium with the pre-diabetes, diabetes and diabetic complications in the Chinese Northeast population
In the study to investigate the association of Mg level in the serum or urine of the patients, lived in the Northeast areas of China, with either pre-diabetes or diabetes with and without complications, from January 2010 to October 2011, patients with type 1 diabetes (T1D, n = 25), type 2 diabetes (T2D, n = 137), impaired fasting glucose (IFG, n = 12) or impaired glucose tolerance (IGT, n = 15), and age/gender matched control (n = 50) enrolled in the First Hospital of Jilin University, showed that serum Mg levels in the patients with IGT, IFG, T2D, and T1D were significantly lower than that of control. The urinary Mg levels were significantly increased only in T2D and T1D patients compared to control. There was no difference for these two changes among T2D with and without complications; In addition, there was a significantly positive correlation of serum Mg levels with serum Ca levels only in T2D patients, and also a significantly positive correlation of urinary Mg levels with urinary Ca levels in control, IGT patients, and T2D patients. Simvastatin treatment in T2D patients selectively reduced serum Ca levels and urinary Mg levels(6).
7. Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes
In the study to evaluate the efficacy and safety of oral magnesium supplementation, with magnesium chloride (MgCl2), in the treatment of newly diagnosed depression in the elderly with type 2 diabetes and hypomagnesemia, found that at baseline, there were no differences by age (69 +/- 5.9 and 66.4 +/- 6.1 years, p = 0.39), duration of diabetes (11.8 +/- 7.9 and 8.6 +/- 5.7 years, p = 0.33), serum magnesium levels (1.3 +/- 0.04 and 1.4 +/- 0.04 mg/dL, p = 0.09), and Yasavage and Brink Score (17.9 +/- 3.9 and 16.1 +/- 4.5 point, p = 0.34) in the groups with MgCl2 and imipramine, respectively. At end of follow-up, there were no significant differences in the Yasavage and Brink score (11.4 +/- 3.8 and 10.9 +/- 4.3, p = 0.27) between the groups in study; whereas serum magnesium levels were significantly higher in the group with MgCl2 (2.1 +/- 0.08 mg/dL) than in the subjects with imipramine (1.5 +/- 0.07 mg/dL), p < 0.0005. In conclusion, MgCl2 is as effective in the treatment of depressed elderly type 2 diabetics with hypomagnesemia as imipramine 50 mg daily(7).
8. The effect of magnesium supplementation on primary insomnia in elderly
In a double-blind randomized clinical trial conducted in 46 elderly subjects, randomly allocated into the magnesium or the placebo group and received 500 mg magnesium or placebo daily for 8 weeks with Questionnaires of insomnia severity index (ISI), physical activity, and sleep log completed at baseline and after the intervention period, showed that no significant differences were observed in assessed variables between the two groups at the baseline. As compared to the placebo group, in the experimental group, dietary magnesium supplementation brought about statistically significant increases in sleep time (P = 0.002), sleep efficiency (P = 0.03), concentration of serum renin (P < 0.001), and melatonin (P = 0.007), and also resulted in significant decrease of ISI score (P = 0.006), sleep onset latency (P = 0.02) and serum cortisol concentration (P = 0.008). Supplementation also resulted in marginally between-group significant reduction in early morning awakening (P = 0.08) and serum magnesium concentration (P = 0.06). Although total sleep time (P = 0.37) did not show any significant between-group differences(8).
9. Correlation of magnesium intake with metabolic parameters, depression and physical activity in elderly type 2 diabetes patients
In a cross-sectional study involved 210 type 2 diabetes patients aged 65 years and above with participants were interviewed to obtain information on lifestyle and 24-hour dietary recall. Assessment of depression was based on DSM-IV criteria, showed that among all patients, 88.6% had magnesium intake which was less than the dietary reference intake, and 37.1% had hypomagnesaemia. Metabolic syndromes and depression were associated with lower magnesium intake (p < 0.05). A positive relationship was found between magnesium intake and HDL-cholesterol (p = 0.005). Magnesium intake was inversely correlated with triglyceride, waist circumference, body fat percent and body mass index (p < 0.005). After controlling confounding factor, HDL-cholesterol was significantly higher with increasing quartile of magnesium intake (p for trend = 0005). Waist circumference, body fat percentage, and body mass index were significantly lower with increase quartile of magnesium intake (p for trend < 0.001). The odds of depression, central obesity, high body fat percentage, and high body mass index were significantly lower with increasing quartile of magnesium intake (p for trend < 0.05). In addition, magnesium intake was related to high physical activity level and demonstrated lower serum magnesium levels. Serum magnesium was not significantly associated with metabolic parameters(9).
10. Depressive symptoms and hypomagnesemia in older diabetic subjects
In the study to to assess the hypothesis that hypomagnesemia is associated with depressive symptoms in older people with diabetes, showed that serum magnesium levels were significantly lower among depressive than control diabetic subjects (0.74 +/- 0.25 vs. 0.86 +/- 0.29 mmol/L, p = 0.02). Twenty four (43.6%) and 7 (12.7%) individuals in the case and control group exhibited low serum magnesium levels (p = 0.0006). The adjusted logistic regression analysis showed an independent association between hypomagnesemia and depressive symptoms (OR 1.79; CI(95%) 1.1-6.9, p = 0.03)(10).
Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/23472169
(2) http://www.ncbi.nlm.nih.gov/pubmed/17645588
(3) http://www.ncbi.nlm.nih.gov/pubmed/17502538
(4) http://www.ncbi.nlm.nih.gov/pubmed/17003299
(5) http://www.ncbi.nlm.nih.gov/pubmed/10527292
(6) http://www.ncbi.nlm.nih.gov/pubmed/23418599
(7) http://www.ncbi.nlm.nih.gov/pubmed/19271419
(8) http://www.ncbi.nlm.nih.gov/pubmed/23853635
(9) http://www.ncbi.nlm.nih.gov/pubmed/22695027
(10) http://www.ncbi.nlm.nih.gov/pubmed/17845894
Magnesium and Muscles
1. Magnesium for skeletal muscle cramps
Skeletal muscle cramps are common and often presented to physicians in association with pregnancy, advanced age, exercise or disorders of the motor neuron (such as amyotrophic lateral sclerosis). In a andomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp) and to considere comparisons of magnesium with no treatment, placebo control, or other therapy, found that it is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this patient population is needed. We found no randomized controlled trials evaluating magnesium for exercise-associated muscle cramps or disease state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease)(1).
2. Clinical aspects and treatment of calf muscle cramps during pregnancy
According to the study by Riss P, Bartl W, and Jelincic D., muscle cramps were noticed most often in the second half of pregnancy. Gravidae with muscle cramps were on the average older and of higher parity; there was no relationship between muscle cramps and complications during pregnancy or unfavorable fetal outcome. In an uncontrolled therapeutic trial 21 women with muscle cramps received 1,8 g monomagnesium-aspartate twice daily per mouth for 4 weeks. 21 women with muscle cramps had no therapy. 4 weeks after the initiation of magnesium therapy 19/21 women were free of symptoms, compared to only 7/21 patients in the control group. Muscle cramps during pregnancy do not have to be considered a risk factor; they can be significantly improved by the administration of oral magnesium(2).
3. The effect of oral magnesium substitution on pregnancy-induced leg cramps
In the study to to determine whether women with pregnancy-related leg cramps would benefit from oral magnesium supplementation, indicated that serum magnesium levels in these patients were at or below the lower reference limit, as is also often the case in healthy pregnant patients. Oral magnesium substitution decreased leg cramp distress (p < 0.05 compared with the placebo group, p < 0.001 compared with initial complaints), but did not significantly increase serum magnesium levels, excess magnesium being excreted as measured by an increase in urinary magnesium levels (p < 0.002). Oral magnesium supplementation seems to be a valuable therapeutic tool in the treatment of pregnancy-related leg cramps(3).
4. Pathophysiology and therapy of magnesium deficiency in pregnancy
In the study to determine serum magnesium(Mg)-levels in 67 pregnant women in late pregnancy. 42 gravidae complained of nightly muscle cramps; 21 of them received 1.8 g monomagnesiumaspartate twice daily per mouth for 4 weeks, found that serum Mg-levels were lower in pregnant women as compared to a control group of non pregnant women. Gravidae complaining of muscle cramps had significantly lower serum Mg-levels than women without muscle cramps. The administration of Mg was associated with a significant rise in serum Mg-levels as early as 2 weeks after the initiation of therapy.The Our study indicates that nightly muscle cramps during pregnancy might be a sign of a latent magnesium deficiency which can be influenced by oral magnesium(4).
5. Serum magnesium level in preterm labour
Preterm labour, (PTL) defined as labour after 28 weeks but before 37 completed week of gestation, is an ill omen for our country as the incidence is 5-10% leading to 70-80% of perinatal deaths. According to the study by the Indira Gandhi Institute of Medical Sciences, varied hypomagnesemia was observed in Preterm labour cases (1.47 mg/dl +/- 0.22 S.D.), normal value of serum magnesium was found in normal non-pregnant ladies and slightly low value were observed in pregnant ladies of same gestational age. Age and parity had no significant effect on serum magnesium level in our study. As far as socio-economic study is concerned, it was found to be higher in high socio-economic group and low in lower group. Thus from this study it can be concluded that estimation of serum magnesium in pregnancy may prove to be a valuable tool in predicting preterm onset of labour(5).
6. Relationship between hypermagnesaemia in preterm labour and adverse health outcomes in babies
In the study of the Magnesium and Neurologic Endpoints Trial (the so-called MagNET Trial) undertaken to establish whether the antenatal usage of magnesium sulphate could protect neonates from having adverse neurologic outcomes, showed that unfortunately, the trial was suspended after 15 months of enrolment because of excess total paediatric mortality among those exposed to magnesium sulphate. Following our original report and contrary to the original hypotheses, additional analyses of our data have actually shown a statistically significant increase in the risk of neonatal intraventricular hemorrhage, as well as total adverse paediatric outcomes, among those with higher levels of ionized magnesium at delivery. Nonetheless, it has been postulated, but not established, that anions of magnesium other than sulphate could have a more benign, or even beneficial, effect on health outcomes in the neonate(6).
7. Nocturnal leg cramps
Up to 60 percent of adults report that they have had nocturnal leg cramps. The recurrent, painful tightening usually occurs in the calf muscles and can cause severe insomnia. According to the study by the St. Mark's Family Medicine Residency, nocturnal leg cramps are associated with vascular disease, lumbar canal stenosis, cirrhosis, hemodialysis, pregnancy, and other medical conditions. Medications that are strongly associated with leg cramps include intravenous iron sucrose, conjugated estrogens, raloxifene, naproxen, and teriparatide. A history and physical examination are usually sufficient to differentiate nocturnal leg cramps from other conditions, such as restless legs syndrome, claudication, myositis, and peripheral neuropathy. Laboratory evaluation and specialized testing usually are unnecessary to confirm the diagnosis. Limited evidence supports treating nocturnal leg cramps with exercise and stretching, or with medications such as magnesium, calcium channel blockers, carisoprodol, or vitamin B(12). Quinine is no longer recommended to treat leg cramps(7).
8. Stretching before sleep reduces the frequency and severity of nocturnal leg cramps in older adults
According to the study by the Hanze University of Applied Sciences, in the study of nighty adults aged over 55 years with nocturnal leg cramps who were not being treated with quinine, with the experimental group performed stretches of the calf and hamstring muscles nightly, immediately before going to sleep, for six weeks. The control group performed no specific stretching exercises. Both groups continued other usual activities, showed that nightly stretching before going to sleep reduces the frequency and severity of nocturnal leg cramps in older adults(8).
9. The effect of magnesium infusion on rest cramps
Rest cramps (also known as nocturnal leg cramps) are very common in a geriatric population. In a double blind, placebo controlled randomized controlled trial conducted on 46 community-dwelling older adult (69.3 ± 7.7 years) rest cramp sufferers to determine whether 5 consecutive days infusion of 20-mmol (5 g) magnesium sulfate would reduce the frequency of leg cramps per week in the 30 days immediately pre and post infusions and whether the response to treatment varied with the extent to which infused magnesium was retained (as measured by 24-hour urinary magnesium excretion), found that intravenous magnesium infusion did not reduce the frequency of leg cramps in a group of older adult rest cramp sufferers regardless of the extent to which infused magnesium was retained. Although oral magnesium is widely marketed to older adults for the prophylaxis of leg cramps, our data suggest that magnesium therapy is not indicated for the treatment of rest cramps in a geriatric population(9).
10. Muscle cramps--differential diagnosis and therapy
Calf cramps are sudden, involuntary, painful contractions of part of or the entire calf muscle that are visible, persist for seconds to minutes and then spontaneously resolve. According to the study by Kompetenzzentrum für Bewegungsstörungen, Paracelsusklinik Zwickau, Muscle cramps can occur with no identifiable cause, and are then referred to as common calf cramps. They may also be symptoms associated with diseases of the peripheral and central nervous system and muscle diseases. They also occur in association with metabolic disorders. In such cases the cramps are more extensive, intense and persist for longer. Cramp-fasciculation-myalgia syndrome additionally involves paresthesias and other signs of hyperexcitability of peripheral nerves. The recommended treatment for patients with frequent calf cramps causing significant impairment of well-being is oral administration of quinidine and/or botulinum toxin treatment of the calf muscles. During pregnancy both products are contraindicated, while probatory administration of magnesium is indicated(10).
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(1) http://www.ncbi.nlm.nih.gov/pubmed/22972143
(2) http://www.ncbi.nlm.nih.gov/pubmed/6553557
(3) http://www.ncbi.nlm.nih.gov/pubmed/7631676
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(8) http://www.ncbi.nlm.nih.gov/pubmed/22341378
(9) http://www.ncbi.nlm.nih.gov/pubmed/21289017
(10) http://www.ncbi.nlm.nih.gov/pubmed/19402333
Magnesium deficiency
1. Magnesium metabolism and its disorders
Magnesium is the fourth most abundant cation in the body and plays an important physiological role in many of its functions. Magnesium balance is maintained by renal regulation of magnesium reabsorption. According to the study by the Department of Chemical Pathology, St Thomas' Hospital, magnesium deficiency and hypomagnesaemia can result from a variety of causes including gastrointestinal and renal losses. Magnesium deficiency can cause a wide variety of features including hypocalcaemia, hypokalaemia and cardiac and neurological manifestations. Chronic low magnesium state has been associated with a number of chronic diseases including diabetes, hypertension, coronary heart disease, and osteoporosis. The use of magnesium as a therapeutic agent in asthma, myocardial infarction, and pre-eclampsia is also discussed. Hypermagnesaemia is less frequent than hypomagnesaemia and results from failure of excretion or increased intake. Hypermagnesaemia can lead to hypotension and other cardiovascular effects as well as neuromuscular manifestations(1).
2. Implications of magnesium deficiency in type 2 diabetes
Magnesium is the fourth most abundant cation in the body and plays an important physiological role in many of its functions. It plays a fundamental role as a cofactor in various enzymatic reactions involving energy metabolism. According to the study by the Punjab Agricultural University, magnesium is a cofactor of various enzymes in carbohydrate oxidation and plays an important role in glucose transporting mechanism of the cell membrane. It is also involved in insulin secretion, binding, and activity. Magnesium deficiency and hypomagnesemia can result from a wide variety of causes, including deficient magnesium intake, gastrointestinal, and renal losses. Chronic magnesium deficiency has been associated with the development of insulin resistance. The present review discusses the implications of magnesium deficiency in type 2 diabetes(2).
3. Magnesium (Mg) status in patients with cardiovascular diseases
Mg is an important cofactor for many enzymes especially those involved in phosphate transfer reactions. Mg is therefore essential in the regulation of the metabolism of other ions and cellular functionsé According to the study by the, deficiency has been shown to be associated with fatal cardiovascular diseases such as cardiac arrhythmias and coronary heart disease, as well as with risk factors for these diseases, such as hypertension, and diabetes mellitus. Our findings showed that serum total Mg was similar in all groups, but patients with arrhythmias and diabetes mellitus revealed lower levels of serum ionized Mg. On the other hand, patients with essential hypertension exhibited higher intraerythrocyte Mg concentrations than healthy controls(3).
4. Hypokalemia and hypomagnesemia in a cirrhotic patient. Correction of metabolic disorders by magnesium
According to the study by Bletry O, Certin M, Herreman G, Wechsler B, and Godeau P., there is a report of a case of a cirrhotic with severe hypokalemia (2 mEq/l) responding incompletely to attempts at correction by classical treatments. The findings of a serum and red cell magnesium deficiency led to administration of this electrolyte which proved efficacous. They then recall the mechanism of hypokalemia and hypomagnesemia in alcoholics, study the possible relationship between these abnormalities, their noxious effects and suggest a treatment(4).
5. Symptomatic hypomagnesemia in children
Hypocalcemia and hyperphosphatemia suggesting impaired parathyroid function were the most common electrolyte disorders. Hypokalemia was also frequently noted. The related symptoms including seizure, tetany, and weakness were common. According to the National Taiwan University Hospital, hypocalcemia and hyperphosphatemia suggesting impaired parathyroid function were the most common electrolyte disorders. Hypokalemia was also frequently noted. The related symptoms including seizure, tetany, and weakness were common. Drug-induced renal magnesium wasting was the most common cause of symptomatic hypomagnesemia, and tended to occur in older children using aminoglycoside, furosemide, and amphotericin-B. The associated gastrointestinal causes might add a minor contribution to the development of hypomagnesemia. Analyses of PTH levels in 13 children suggested that inhibition of PTH synthesis or secretion was responsible for hypomagnesemic hypocalcemia in most patients. However, peripheral PTH resistance might also account for the mechanism in a few patients. In most patients, symptomatic hypomagnesemia was transient, and improved after magnesium provision. Only one child with congenital renal magnesium wasting and two with primary hypomagnesemia needed long-term magnesium treatment(5).
6. Hypomagnesemia: an evidence-based approach to clinical cases
Hypomagnesemia is defined as a serum magnesium level less than 1.8 mg/dL (< 0.74 mmol/L). Hypomagnesemia may result from inadequate magnesium intake, increased gastrointestinal or renal losses, or redistribution from extracellular to intracellular space. Increased renal magnesium loss can result from genetic or acquired renal disorders. According to the Rush University Medical Center, Chicago, most patients with hypomagnesemia are asymptomatic and symptoms usually do not arise until the serum magnesium concentration falls below 1.2 mg/dL. One of the most life-threatening effects of hypomagnesemia is ventricular arrhythmia. The first step to determine the likely cause of the hypomagnesemia is to measure fractional excretion of magnesium and urinary calcium-creatinine ratio. The renal response to magnesium deficiency due to increased gastrointestinal loss is to lower fractional excretion of magnesium to less than 2%. A fractional excretion above 2% in a subject with normal kidney function indicates renal magnesium wasting. Barter syndrome and loop diuretics which inhibit sodium chloride transport in the ascending loop of Henle are associated with hypokalemia, metabolic alkalosis, renal magnesium wasting, hypomagnesemia, and hypercalciuria. Gitelman syndrome and thiazide diuretics which inhibit sodium chloride cotransporter in the distal convoluted tubule are associated with hypokalemia, metabolic alkalosis, renal magnesium wasting, hypomagnesemia, and hypocalciuria. Familial renal magnesium wasting is associated with hypercalciuria, nephrocalcinosis, and nephrolithiasis. Asymptomatic patients should be treated with oral magnesium supplements. Parenteral magnesium should be reserved for symptomatic patients with severe magnesium deficiency (< 1.2 mg/dL). Establishment of adequate renal function is required before administering any magnesium supplementation(6).
7. Abnormal renal magnesium handling
The normal fractional urinary excretion of filtered magnesium is about 5%. In magnesium deficiency in man, the kidneys can normally reduce the 24-hour urinary magnesium excretion to less than 1 mmol (24 mg) via unknown mechanisms, and initially without a fall in plasma magnesium concentration. According to the University of British Columbia, congenital renal magnesium wasting occurs in several syndromes including Bartter's syndrome in which it is associated with hypercalciuria, and the defect may be in the thick ascending limb of Henle's loop, and Gitelman's syndrome in which there is hypocalciuria, and the defect may be in the distal convoluted tubule. Other causes of renal magnesium wasting include diabetes mellitus, hypercalcemia and diuretics. Magnesium wasting may also result from various toxicities including those of cis-platinum, in which the biochemical features resemble Gitelman's syndrome, and those of aminoglycosides, pentamidine and cyclosporin. Calcitriol deficiency may also contribute to renal magnesium wasting in some circumstances. Mild hypermagnesemia may occur in familial hypocalciuric hypercalcemia and may reflect abnormal sensitivity of the loop of Henle to calcium and magnesium ions. By contrast, the hypermagnesemia that occurs in chronic renal failure results from the reduced glomerular filtration of magnesium(7).
8. Hypomagnesemia: renal magnesium handling
Magnesium is an important constituent of the intracellular space that affects a number of intracellular and whole body functions. Magnesium balance depends on intake and renal excretion, which is regulated mainly in the thick ascending limb of the loop of Henle. According to the University of Pennsylvania School of Medicine, hypomagnesemia may result from gastrointestinal losses or renal losses, the latter due to primary renal magnesium wasting or in association with sodium loss. Hypomagnesemia may arise together with and contribute to the persistence of hypokalemia and hypocalcemia. The major direct toxicity of hypomagnesemia is cardiovascular. When urgent correction of hypomagnesemia is required, as with myocardial ischemia, post cardiopulmonary bypass, and torsades de pointes, intravenous or intramuscular magnesium sulfate should be used. Oral magnesium preparations are available for chronic use(8).
9. Magnesium metabolism in health and disease
Magnesium (Mg) is the main intracellular divalent cation, and under basal conditions the small intestine absorbs 30-50% of its intake. Normal serum Mg ranges between 1.7-2.3 mg/dl (0.75-0.95 mmol/l), at any age. According to the study by Hospital Italiano de Buenos Aires, eEven though eighty percent of serum Mg is filtered at the glomerulus, only 3% of it is finally excreted in the urine. Altered magnesium balance can be found in diabetes mellitus, chronic renal failure, nephrolithiasis, osteoporosis, aplastic osteopathy, and heart and vascular disease. Three physiopathologic mechanisms can induce Mg deficiency: reduced intestinal absorption, increased urinary losses, or intracellular shift of this cation. Intravenous or oral Mg repletion is the main treatment, and potassium-sparing diuretics may also induce renal Mg saving. Because the kidney has a very large capacity for Mg excretion, hypermagnesemia usually occurs in the setting of renal insufficiency and excessive Mg intake. Body excretion of Mg can be enhanced by use of saline diuresis, furosemide, or dialysis depending on the clinical situation(9).
10. Magnesium deficiency: pathogenesis, prevalence, and clinical implications
Hypomagnesemia is probably the most underdiagnosed electrolyte deficiency in current medical practice. Patients with cardiovascular disease who are at greatest risk for the development of magnesium deficiency are those treated with diuretics or digitalis. According to the study by the, both potassium and magnesium deficiencies are associated with increased ventricular ectopy and may increase the risk of sudden unexpected death. Refractory potassium repletion can be caused by concomitant magnesium depletion, and can be corrected with magnesium supplementation. Routine serum magnesium determination is recommended whenever the testing of electrolyte levels is required, especially in patients taking diuretic drugs or digitalis. Because hypomagnesemia is not necessarily present in a magnesium-deficient state, it is recommended that both potassium and magnesium be repleted in patients with hypokalemia. Potassium-/magnesium-sparing diuretics may be helpful in the prevention of these electrolyte deficiencies(10).
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Magnesium and heart failure
1. Significance of magnesium in congestive heart failure
Electrolyte balance has been regarded as a factor important to cardiovascular stability, particularly in congestive heart failure. According to the study by the Irvine Medical Center,, magnesium is important as a cofactor in several enzymatic reactions contributing to stable cardiovascular hemodynamics and electrophysiologic functioning. Its deficiency is common and can be associated with risk factors and complications of heart failure. Typical therapy for heart failure (digoxin, diuretic agents, and ACE inhibitors) are influenced by or associated with significant alteration in magnesium balance. Magnesium therapy, both for deficiency replacement and in higher pharmacologic doses, has been beneficial in improving hemodynamics and in treating arrhythmias. Magnesium toxicity rarely occurs except in patients with renal dysfunction(1).
2. Magnesium in congestive heart failure, acute myocardial infarction and dysrhythmias
Magnesium plays an important role in the functioning of the cardiovascular system. According to the study by the Hackettstown Community Hospital, a decrease in magnesium has been linked with tachydysrhythmias, increased mortality in patients with congestive heart failure, and increased mortality after an acute myocardial infarction. The research shows that the use of magnesium supplements in these situations may be beneficial for treating and preventing life-threatening conditions. Magnesium supplements can be administered safely either orally or parenterally depending on the situation(2).
3. Potassium and magnesium depletions in congestive heart failure--pathophysiology, consequences and replenishment
Congestive heart failure (CHF) is becoming more frequent worldwide. According to the study by the Volgograd State Medical University, both potassium (K) and magnesium (Mg) deficiencies are common and can be associated with risk factors and complications of heart failure (HF). The major causes of K and Mg depletions are the effects of compensatory neuroendocrine mechanisms (activation of the renin-angiotensin-aldosterone and sympathoadrenergic systems), digoxin therapy, and administration of thiazide or loop diuretic therapy in CHF. Particular attention should be paid to K and Mg restoration in CHF, because of the consequences of both deficiencies (increased arrhythmic risk, vasoconstriction), and the co-supplementation of both ions is necessary in order to achieve K repletion. Mg and K should be employed as first-line therapy in digitalis intoxication and drug-related arrhythmias, and should be considered an important adjuvant therapy in diuretic treated patients with CHF. Another possibility to restore normal K and Mg status is usage of a K, Mg sparing diuretics(3).
4. Calcium, magnesium and potassium intake and mortality in women with heart failure
In the study of the 161 808 participants in the Women's Health Initiative (WHI), we studied 3340 who experienced a HF hospitalisation to hypothesised that Ca, Mg and K would be inversely associated with mortality in people with HF, showed that intake was assessed using questionnaires on food and supplement intake. Hazard ratios (HR) and 95 % CI were calculated using Cox proportional hazards models adjusted for demographics, physical function, co-morbidities and dietary covariates. Over a median of 4·6 years of follow-up, 1433 (42·9 %) of the women died. HR across quartiles of dietary Ca intake were 1·00 (referent), 0·86 (95 % CI 0·73, 1·00), 0·88 (95 % CI 0·75, 1·04) and 0·92 (95 % CI 0·76, 1·11) (P for trend = 0·63). Corresponding HR were 1·00 (referent), 0·86 (95 % CI 0·71, 1·04), 0·88 (95 % CI 0·69, 1·11) and 0·84 (95 % CI 0·63, 1·12) (P for trend = 0·29), across quartiles of dietary Mg intake, and 1·00 (referent), 1·20 (95 % CI 1·01, 1·43), 1·06 (95 % CI 0·86, 1·32) and 1·16 (95 % CI 0·90, 1·51) (P for trend = 0·35), across quartiles of dietary K intake(4).
5. Functional reserves of the heart under conditions of alimentary magnesium deficit
In the study to assess functional reserves of myocardium in animals with deficit of magnesium during stress tests with magnesium deficit was modeled by 10 week long magnesium deficient diet, showed that
in animals with magnesium deficit we noted smaller increases of left ventricular pressure, myocardial contraction and relaxation rates under conditions of all functional tests, and of systolic arterial pressure during loading with volume and adrenaline. Lowering of myocardial reactivity under conditions of volume and adrenaline loading as well as isometric work load could constitute a basis of genesis of heart failure in magnesium deficit(5).
6. Complications of association magnesium sulfate with nicardipine during preeclampsia
There is a report of a heart failure and a collapse following concurrently administration of nicardipine and magnesium sulfate. These two drugs have potential negative inotropic effect and decrease systemic vascular resistance. Magnesium sulfate is the first-line treatment for the prevention of primary and recurrent eclamptic seizures. Combination with calcium channel blockers should be used cautiously, according to Service de gynécologie-obstétrique, centre hospitalier Franck-Joly(6).
7. Magnesium deficiency in heart failure patients with diabetes mellitus
In the study to assess the serum magnesium level in heart failure patients with diabetes mellitus conducted at Basic Medical Sciences Institute (BMSI), Jinnah Postgraduate Medical Centre (JPMC), Karachi, in collaboration with National Institute of Cardiovascular Diseases (NICVD), Karachi, from April 2003 to December 2003, showed that out of 45 cases of heart failure, 15 were diabetic. Of these, eleven (73.3%) had low serum magnesium (<1.8 mg/dl), one (6.7%) was within normal range (1.8-2.0 mg/dl) and three (20%) were in the high level range(>2.0 mg/dl). Low serum magnesium level in heart failure patients with diabetes mellitus(7).
8. Associations of dietary magnesium intake with mortality from cardiovascular disease
In the study to to investigate the relationship between dietary magnesium intake and mortality from cardiovascular disease in a population-based sample of Asian adults, based on dietary magnesium intake in 58,615 healthy Japanese aged 40-79 years, in the Japan Collaborative Cohort (JACC) Study, found that
dietary magnesium intake was inversely associated with mortality from hemorrhagic stroke in men and with mortality from total and ischemic strokes, coronary heart disease, heart failure and total cardiovascular disease in women. The multivariable hazard ratio (95% CI) for the highest vs. the lowest quintiles of magnesium intake after adjustment for cardiovascular risk factor and sodium intake was 0.49 (0.26-0.95), P for trend = 0.074 for hemorrhagic stroke in men, 0.68 (0.48-0.96), P for trend = 0.010 for total stroke, 0.47 (0.29-0.77), P for trend < 0.001 for ischemic stroke, 0.50 (0.30-0.84), P for trend = 0.005 for coronary heart disease, 0.50 (0.28-0.87), P for trend = 0.002 for heart failure and 0.64 (0.51-0.80), P for trend < 0.001 for total cardiovascular disease in women. The adjustment for calcium and potassium intakes attenuated these associations(8).
9. Parameters of mineral metabolism predict midterm clinical outcome in end-stage heart failure patients
In the study to investigate to which extent disturbances in mineral metabolism predict 90-day clinical outcome in end-stage heart failure patients, found that of the study cohort, 33.4% reached the primary endpoint. In detail, 19% were transplanted (the vast majority was listed "high urgent"), 8.8% died and 5.6% received MCS implants. As determined by logistic regression analysis, all aforementioned biochemical parameters were independently related to the primary endpoint. Results did not change substantially when transplanted patients were censored. A risk score (0-5 points) was developed. Of the patients who scored 5 points 89.5% reached the primary endpoint whereas of the patients with a zero score only 3.8% reached the primary endpoint. The data demonstrate that in addition to the well-known predictive value of disturbed sodium metabolism, derangements in calcium, phosphate, and magnesium metabolism also predict midterm clinical outcome in end-stage heart failure patients(9).
10. Magnesium and anabolic hormones in older men
Optimal nutritional and hormonal statuses are determinants of successful ageing. The age associated decline in anabolic hormones such as testosterone and insulin-like growth factor 1 (IGF-1) is a strong predictor of metabolic syndrome, diabetes and mortality in older men. Studies have shown that magnesium intake affects the secretion of total IGF-1 and increase testosterone bioactivity. In the study to evaluate of 399 ≥65-year-old men of CHIANTI, a study population representative of two municipalities of Tuscany (Italy) with complete data on testosterone, total IGF-1, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and serum magnesium levels, showed that
after adjusting for age, magnesium was positively associated with total testosterone (β ± SE, 34.9 ± 10.3; p = 0.001) and with total IGF-1 (β ± SE, 15.9 ± 4.8; p = 0.001). After further adjustment for body mass index (BMI), log (IL-6), log (DHEAS), log (SHBG), log (insulin), total IGF-1, grip strength, Parkinson's disease and chronic heart failure, the relationship between magnesium and total testosterone remained strong and highly significant (β ± SE, 48.72 ± 12.61; p = 0.001). In the multivariate analysis adjusted for age, BMI, log (IL-6), liver function, energy intake, log (insulin), log (DHEAS), selenium, magnesium levels were also still significantly associated with IGF-1 (β ± SE, 16.43 ± 4.90; p = 0.001) and remained significant after adjusting for total testosterone (β ± SE, 14.4 ± 4.9; p = 0.01). In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1.© 2011 The Authors. International Journal of Andrology © 2011 European Academy of Androlo(10).
Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/8800040
(2) http://www.ncbi.nlm.nih.gov/pubmed/8106895
(3) http://www.ncbi.nlm.nih.gov/pubmed/16272623
(4) http://www.ncbi.nlm.nih.gov/pubmed/23199414
(5) http://www.ncbi.nlm.nih.gov/pubmed/23098349
(6) http://www.ncbi.nlm.nih.gov/pubmed/22981126
(7) http://www.ncbi.nlm.nih.gov/pubmed/22360033
(8) http://www.ncbi.nlm.nih.gov/pubmed/22341866
(9) http://www.ncbi.nlm.nih.gov/pubmed/21905973
(10) http://www.ncbi.nlm.nih.gov/pubmed/21675994
Magnesium and Bone health
1. Nutrition and bone health. Magnesium and bone
Magnesium is related to a number of biological enzymatic reactions such as catalytic role for the reaction of kinases in ATP production. On the other hand, magnesium is one of the essential minerals for bone formation. According to the study by the National Institute of Health and Nutrition., in the magnesium-deficient rats, apparent bone loss caused by increase in bone resorption and decrease in bone formation was observed. Although, epidemiological studies suggest that magnesium deficiency is one of the risk factor for osteoporosis, a relationship between magnesium intake and bone mineral density is not clear. This may be due to the differences in the population, decrease in sex hormone secretion, and the possibility that magnesium-deficiency is also accompanied with another nutrient insufficiency, e.g., calcium(1).
2. Skeletal and hormonal effects of magnesium deficiency
Magnesium (Mg) is the second most abundant intracellular cation where it plays an important role in enzyme function and trans-membrane ion transport. Mg deficiency has been associated with a number of clinical disorders including osteoporosis. Osteoporosis is common problem accounting for 2 million fractures per year in the United States at a cost of over $17 billion dollars. The average dietary Mg intake in women is 68% of the RDA, indicating that a large proportion of our population has substantial dietary Mg deficits. In the study to review the evidence for Mg deficiency-induced osteoporosis and potential reasons why this occurs, including a cumulative review of work in our laboratories and well as a review of other published studies linking Mg deficiency to osteoporosis, showed that pidemiological studies have linked dietary Mg deficiency to osteoporosis. As diets deficient in Mg are also deficient in other nutrients that may affect bone, studies have been carried out with select dietary Mg depletion in animal models. Severe Mg deficiency in the rat (Mg at <0.0002% of total diet; normal = 0.05%) causes impaired bone growth, osteopenia and skeletal fragility. This degree of Mg deficiency probably does not commonly exist in the human population. We have therefore induced dietary Mg deprivation in the rat at 10%, 25% and 50% of recommended nutrient requirement. We observed bone loss, decrease in osteoblasts, and an increase in osteoclasts by histomorphometry. Such reduced Mg intake levels are present in our population(2).
3. Magnesium deficiency and osteoporosis: animal and human observations
Although osteoporosis is a major health concern for our growing population of the elderly, there continues to be a need for well-designed clinical and animal studies on the link between dietary magnesium (Mg) intake and osteoporosis. According to the study by the University of Southern California and The Orthopaedic Hospital, Los Angeles, relatively few animal studies have assessed the skeletal and hormonal impact of long-term low Mg intake; however, these studies have demonstrated that Mg deficiency results in bone loss. Potential mechanisms include a substance P-induced release of inflammatory cytokines as well as impaired production of parathyroid hormone and 1,25-dihydroxyvitamin D. Abnormal mineralization of bones may also contribute to skeletal fragility. Clinical studies have often varied greatly in study design, subject age, menopausal status and outcome variables that were assessed. Most studies focused on female subjects, thus pointing to the great need for studies on aging males. According to the U.S. Department of Agriculture, the mean Mg intake for males and females is 323 and 228 mg/day, respectively. These intake levels suggest that a substantial number of people may be at risk for Mg deficiency, especially if concomitant disorders and/or medications place the individual at further risk for Mg depletion(3).
4. Nutrition and bone health. Magnesium-rich foods and bone health
According to the study by the Kagawa Nutrition University, about 60% of magnesium in human body is present in the skeleton. Various foods are containing magnesium. The major sources are foods of plant origin like grain, vegetable and pulse. EAR (estimated average requirement) and RDA (recommended dietary allowance) are set for age 1 year or over in Japan. There may be a large number of people who have inadequate intake of magnesium judging by the results of the national nutrition survey. Adequate intakes of magnesium and also other nutrients related bone health are desired(4).
5. Magnesium and osteoporosis: current state of knowledge and future research directions
According to the study by the University of Milan,, a tight control of magnesium homeostasis seems to be crucial for bone health. On the basis of experimental and epidemiological studies, both low and high magnesium have harmful effects on the bones. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting on the secretion and the activity of parathyroid hormone and by promoting low grade inflammation. Less is known about the mechanisms responsible for the mineralization defects observed when magnesium is elevated. Overall, controlling and maintaining magnesium homeostasis represents a helpful intervention to maintain bone integrity(5).
6. Magnesium metabolism in 4 to 8 year old children
Magnesium (Mg) is a key factor in bone health, but few studies have evaluated Mg intake or absorption and their relationship with bone mineral content (BMC) or bone mineral density (BMD) in children. In the study to measure Mg intake, absorption, and urinary excretion in a group of children 4 to 8 yrs of age, found that a small, but significantly greater Mg absorption efficiency (percentage absorption) in males than females (67 ± 12% vs 60 ± 8%, p = 0.02) but no difference in estimated net Mg retention (average of 37 mg/day in both males and females). Relating dietary Mg intake to estimated Mg retention showed that an intake of 133 mg/day, slightly above the current Estimated Average Requirement (EAR) of 110 mg/day led to a net average retention of 10 mg/day, the likely minimum growth-related need for this age group. Covariate analysis showed that Mg intake and total Mg absorption, but not calcium intake or total absorption were significantly associated with both total body BMC and BMD. These results suggest that usual Mg intakes in small children in the United States meet dietary requirements in most but not all children. Within the usual range of children's diets in the United States, dietary Mg intake and absorption may be important, relatively unrecognized factors in bone health(6).
7. Maternal first-trimester diet and childhood bone mass
In the study to assess the association of maternal first-trimester dietary intake during pregnancy with childhood bone mass, showed that higher first-trimester maternal protein, calcium, and phosphorus intakes and vitamin B-12 concentrations were associated with higher childhood bone mass, whereas carbohydrate intake and homocysteine concentrations were associated with lower childhood bone mass (all P-trend < 0.01). Maternal fat, magnesium intake, and folate concentrations were not associated with childhood bone mass. In the fully adjusted regression model that included all dietary factors significantly associated with childhood bone mass, maternal phosphorus intake and homocysteine concentrations most-strongly predicted childhood bone mineral content (BMC) [β = 2.8 (95% CI: 1.1, 4.5) and β = -1.8 (95% CI: -3.6, 0.1) g per SD increase, respectively], whereas maternal protein intake and vitamin B-12 concentrations most strongly predicted BMC adjusted for bone area [β = 2.1 (95% CI: 0.7, 3.5) and β = 1.8 (95% CI: 0.4, 3.2) g per SD increase, respectively(7).
8. Magnesium intake mediates the association between bone mineral density and lean soft tissue in elite swimmers
In the study to o understand if Mg intake mediates the association between bone mineral density (BMD) and lean soft tissue (LST) in elite swimmers, showed that males presented lower values than the normative data for BMD. Mg, phosphorus (P) and vitamin D intake were significantly lower than the recommended daily allowance. A linear regression model demonstrated a significant association between LST and BMD. When Mg intake was included, we observed that this was a significant, independent predictor of BMD, with a significant increase of 24% in the R(2) of the initial predictive model. When adjusted for energy, vitamin D, calcium, and P intake, Mg remained a significant predictor of BMD. In conclusion, young athletes engaged in low impact sports, should pay special attention to Mg intake, given its potential role in bone mineral mass acquisition during growth(8).
9. Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density
In a cross-sectional study of 136 healthy Caucasian, postmenopausal women, free of medications known to affect bone, with bone mineral density (BMD) and body composition (lean and fat tissue) were measured by dual X-ray absorptiometry using specialized software for different skeletal sites, showed that independent influence of calcium, energy, and protein, examined separately and in multiple regression models on BMD of several skeletal sites. Magnesium, zinc and vitamin C were significantly related to BMD of several skeletal sites in multiple regression models (controlled for age, fat and lean tissue, physical activity and energy intake), each contributing more than 1% of variance. Serum PTH and 25(OH)D did not show significant association with bone mass(9).
10. Evaluation of magnesium intake and its relation with bone quality in healthy young Korean women
In a study to evaluate Mg intake in healthy adults and its relation with bone quality of a total of 484 healthy young women in their early 20s, with anthropometric measurements, dietary intake survey using 3-day dietary records, and the bone quality of the calcaneus using quantitative ultrasounds were obtained and analyzed and average age, height, and weight of the subjects were respectively 20.20 years, 161.37 cm, and 54.09 kg, respectively, showed that the subject's average intake of energy was 1,543.19 kcal, and the average Mg intake was 185.87 mg/day. Mg intake per 1,000 kcal of consumed energy in our subjects was 119.85 mg. Subjects consumed 63.11% of the recommended intake for Mg. Food groups consumed with high Mg content in our subjects included cereals (38.62 mg), vegetables (36.97 mg), milk (16.82 mg), legumes (16.72 mg), and fish (16.50 mg). The level of Mg intake per 1,000 kcal showed significant correlation to the SOS in the calcaneus (r = 0.110, p < 0.05) after adjustment for age, BMI, and percent body fat. In addition, the intakes of Mg from potatoes (p < 0.001), legumes (p < 0.05), and fungi and mushrooms (p < 0.05) positively correlated with the SOS of the calcaneus. Tthe magnesium intake status of young Korean women aged 19-25 years is unsatisfactory. Improving dietary intake of Mg may positively impact bone quality in this population(10).
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Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/20445288
(2) http://www.ncbi.nlm.nih.gov/pubmed/19828898
(3) http://www.ncbi.nlm.nih.gov/pubmed/15607643
(4) http://www.ncbi.nlm.nih.gov/pubmed/20445289
(5) http://www.ncbi.nlm.nih.gov/pubmed/23912329
(6) http://www.ncbi.nlm.nih.gov/pubmed/23787702
(7) http://www.ncbi.nlm.nih.gov/pubmed/23719545
(8) http://www.ncbi.nlm.nih.gov/pubmed/23015157
(9) http://www.ncbi.nlm.nih.gov/pubmed/12700617
(10) http://www.ncbi.nlm.nih.gov/pubmed/21465282
Thursday, March 21, 2013
Dietary Mineral Cobalt
Cobalt is one of many essential mineral needed by our body in very small amounts to enhance productions of red blood cell and the formation of myelin nerve coverings It also is vital as a necessary cofactor for making the thyroid hormone thyroxine and stored in the red blood cells, the plasma, liver, kidney, spleen, pancreas, etc.
1. Dietary cobalt and Cobalt whole blood concentrations in healthy adult male
Recently, there has been an increase in the marketing and sales of dietary supplements, energy drinks, and other consumer products that may contain relatively high concentrations of essential elements. According to the study of assessement of Co whole blood concentrations in four healthy adult male volunteers who ingested a commercially available Co supplement (0.4mg Co/day) for 15 or 16days by ChemRisk, LLC, indicated that the mean whole blood Co concentration in the volunteers after 15 or 16days of dosing was 3.6μg Co/L and ranged from 1.8 to 5.1μg Co/L. The mean observed concentration in the study group was approximately 9-36 times greater than background concentrations. Further studies of Co whole blood concentrations following supplementation over longer time periods with additional monitoring of physiological parameters may provide useful information for evaluating the health of persons who take various doses of Co(1).
2. Cobalamin absorption: Mammalian physiology and acquired and inherited disorders
Vitamin B12 (cobalamin) is a cobalt-containing compound synthesized by bacteria and an essential nutrient in mammals, which take it up from diet. mIn the review to summarize the causes leading to vitamin B12 deficiency including decreased intake, impaired absorption and increased requirements, found that under physiological conditions, vitamin B12 bound to the gastric intrinsic factor is internalized in the ileum by a highly specific receptor complex composed by Cubilin (Cubn) and Amnionless (Amn). Following exit of vitamin B12 from the ileum, general cellular uptake from the circulation requires the transcobalamin receptor CD320 whereas kidney reabsorption of cobalamin depends on Megalin (Lrp2). Whereas malabsorption of vitamin B12 is most commonly seen in the elderly, selective pediatric, nondietary-induced B12 deficiency is generally due to inherited disorders including the Imerslund-Gräsbeck syndrome and the much rarer intrinsic factor deficiency. Biochemical, clinical and genetic research on these disorders considerably improved our knowledge of vitamin B12 absorption. This review describes basic and recent findings on the intestinal handling of vitamin B12 and its importance in health and disease(2).
3. Cobalamin deficiency and spina bifida and other neural tube defects
Cobalamin deficiency in the newborn usually results from cobalamin deficiency in the mother. Megaloblastic anaemia, pancytopenia and failure to thrive can be present, accompanied by neurological deficits if the diagnosis is delayed. According to the study by the the McGill University-Montreal Montreal Children's Hospital Research Institute of the McGill University Health Center, most cases of spina bifida and other neural tube defects result from maternal folate and/or cobalamin insufficiency in the periconceptual period. Polymorphisms in a number of genes involved in folate and cobalamin metabolism exacerbate the risk. Inborn errors of cobalamin metabolism affect its absorption, (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and transport (transcobalamin deficiency) as well as its intracellular metabolism affecting adenosylcobalamin synthesis (cblA and cblB), methionine synthase function (cblE and cblG) or both (cblC, cblD and cblF). Inborn errors of folate metabolism include congenital folate malabsorption, severe methylenetetrahydrofolate reductase deficiency and formiminotransferase deficiency(3).
4. Inherited cobalamin malabsorption and Gene involved
Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. According to the study by the Ohio State University, in the revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved(4).
5. Cobalamin) deficiency and complications
Vitamin B12 (or cobalamin) deficiency is well known in geriatric patients, but not in those with spinal cord injury (SCI). According to the study by the Veterans Affairs Puget Sound Health Care System, Cobalamin deficiet SCI patients presented with depression and fatigue, 2 had worsening pain, 2 had worsening upper limb weakness, and 2 had memory decline. Of the 12 patients with subnormal serum vitamin B12 levels, 6 were asymptomatic. Classic laboratory findings of low serum vitamin B12, macrocytic red blood cell indices, and megaloblastic anemia were not always present. Anemia was identified in 7 of the 16 patients and macrocytic red blood cells were found in 3 of the 16 patients. Only 1 of the 16 SCI patients had a clear pathophysiologic mechanism to explain the vitamin B12 deficiency (ie, partial gastrectomy); none of the patients were vegetarian. Twelve of the SCI patients appeared to experience clinical benefits from cyanocobalamin replacement (some patients experienced more than 1 benefit), including reversal of anemia (5 patients), improved gait (4 patients), improved mood (3 patients), improved memory (2 patients), reduced pain (2 patients), strength gain (1 patient), and reduced numbness (1 patient)(5).
6. Psychiatric manifestations of vitamin B12 deficiency
There is a report of a case of a patient with vitamin B12 deficiency, who has presented severe depression with delusion and Capgras' syndrome, delusion with lability of mood and hypomania successively, during a period of two Months. Case report - Mme V., a 64-Year-old woman, was admitted to the hospital because of confusion. She had no history of psychiatric problems. She had history of diabetes, hypertension and femoral prosthesis. The red blood count revealed a normocytosis with anemia (hemoglobin=11,4 g/dl). At admission she was uncooperative, disoriented in time and presented memory and attention impairment and sleep disorders. She seemed sad and older than her real age. Facial expression and spontaneous movements were reduced, her speech and movements were very slow. She had depressed mood, guilt complex, incurability and devaluation impressions. She had a Capgras' syndrome and delusion of persecution. Her neurologic examination, cerebral scanner and EEG were postponed because of uncooperation. Further investigations confirmed anemia (hemoglobin=11,4 g/dl) and revealed vitamin B12 deficiency (52 pmol/l) and normal folate level. Antibodies to parietal cells were positive in the serum and antibodies to intrinsic factor were negative. An iron deficiency was associated (serum iron=7 micromol/l; serum ferritin concentration=24 mg/l; serum transferrin concentration=3,16 g/l). This association explained normocytocis anemia(6).
7. Effect of dietary organic supplementation on milk production, follicular growth, embryo quality, and tissue mineral concentrations in dairy cows
In the study to evaluate the potential effects of organic trace mineral supplementation on reproductive measures in lactating dairy cows, Cows were blocked by breed and randomly assigned at dry-off to receive inorganic trace mineral supplementation (control; n = 32) or to have a portion of supplemental inorganic Zn, Cu, Mn, and Co replaced with an equivalent amount of the organic forms of these minerals (treatment; n = 31), found that replacing a portion of inorganic supplemental trace minerals with an equivalent amount of these organic trace minerals (Zn, Mn, Cu, and Co) increased milk production in mid-lactation, but did not affect postpartum follicular dynamics, embryo quality, or liver and luteal trace mineral concentrations(7).
8. zinc-nickel-cobalt solution (ZnNiCo) and inflammation in adipose tissue
In the study to test the effect of a zinc-nickel-cobalt solution (ZnNiCo) on adipocyte function and to identify potential health effects of this solution in the context of obesity and associated disorders, indicated that the trace elements present in ZnNiCo are able to modulate the expression level of several inflammation related transcripts in adipocytes. These studies suggest that ZnNiCo could play a role in the prevention of inflammation in adipose tissue in obesity(8).
9. Cobalt-containing supplements
Cobalt-containing supplements are readily available in the U.S. and have been marketed to consumers as energy enhancers. However, little information is available regarding cobalt (Co) body burden and steady-state blood concentrations following the intake of Co dietary supplements. According to the study by the ChemRisk, LLC, 4840 Pearl East Circle, Boulder, CO 80301, United States, Pre-supplementation blood Co concentrations were less than the reporting limit of 0.5μg/L, consistent with background concentrations reported to range between 0.1 and 0.4μg/L. The mean whole blood Co concentration in the volunteers after 15 or 16days of dosing was 3.6μg Co/L and ranged from 1.8 to 5.1μg Co/L. The mean observed concentration in the study group was approximately 9-36 times greater than background concentrations. Further studies of Co whole blood concentrations following supplementation over longer time periods with additional monitoring of physiological parameters may provide useful information for evaluating the health of persons who take various doses of Co(9).
10. Vitamin B12 malabsorption: Mammalian physiology and acquired and inherited disorders
Vitamin B12 (cobalamin) is a cobalt-containing compound synthesized by bacteria and an essential nutrient in mammals. According to the study by the Hospitalier National d'Ophtalmologie des Quinze-Vingts, malabsorption of vitamin B12 is most commonly seen in the elderly, selective pediatric, nondietary-induced B12 deficiency is generally due to inherited disorders including the Imerslund-Gräsbeck syndrome and the much rarer intrinsic factor deficiency. Biochemical, clinical and genetic research on these disorders considerably improved our knowledge of vitamin B12 absorption(10).
11. The effects of Co on FA composition in blood
In the study to examine the amount of Co needed to obtain this effect. High-yielding dairy cows (n 4), equipped with ruminal cannulas, used in a 4 × 4 Latin square design, found that there was a linear effect of increasing the level of Co on milk FA composition. The effects of Co on FA composition in blood were insignificant compared with the effects on milk. In milk fat, the concentration of cis-9-18 : 1 was reduced by as much as 38 % on T4 compared with T1. Feed intake and milk yield were negatively affected by increasing the Co level(11).
12. For more information of Cobalamin (Vitamin B12), please visit Vitamin B12 in vitamins and minerals section
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Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/23207477
(2) http://www.ncbi.nlm.nih.gov/pubmed/23178706
(3) http://www.ncbi.nlm.nih.gov/pubmed/16846473
(4) http://www.ncbi.nlm.nih.gov/pubmed/22929189
(5) http://www.ncbi.nlm.nih.gov/pubmed/12828286
(6) http://www.ncbi.nlm.nih.gov/pubmed/15029091
(7) http://www.ncbi.nlm.nih.gov/pubmed/20817861
(8) http://www.ncbi.nlm.nih.gov/pubmed/23503329
(9) http://www.ncbi.nlm.nih.gov/pubmed/23207477
(10) http://www.ncbi.nlm.nih.gov/pubmed/23178706
(11) http://www.ncbi.nlm.nih.gov/pubmed/22682538
1. Dietary cobalt and Cobalt whole blood concentrations in healthy adult male
Recently, there has been an increase in the marketing and sales of dietary supplements, energy drinks, and other consumer products that may contain relatively high concentrations of essential elements. According to the study of assessement of Co whole blood concentrations in four healthy adult male volunteers who ingested a commercially available Co supplement (0.4mg Co/day) for 15 or 16days by ChemRisk, LLC, indicated that the mean whole blood Co concentration in the volunteers after 15 or 16days of dosing was 3.6μg Co/L and ranged from 1.8 to 5.1μg Co/L. The mean observed concentration in the study group was approximately 9-36 times greater than background concentrations. Further studies of Co whole blood concentrations following supplementation over longer time periods with additional monitoring of physiological parameters may provide useful information for evaluating the health of persons who take various doses of Co(1).
2. Cobalamin absorption: Mammalian physiology and acquired and inherited disorders
Vitamin B12 (cobalamin) is a cobalt-containing compound synthesized by bacteria and an essential nutrient in mammals, which take it up from diet. mIn the review to summarize the causes leading to vitamin B12 deficiency including decreased intake, impaired absorption and increased requirements, found that under physiological conditions, vitamin B12 bound to the gastric intrinsic factor is internalized in the ileum by a highly specific receptor complex composed by Cubilin (Cubn) and Amnionless (Amn). Following exit of vitamin B12 from the ileum, general cellular uptake from the circulation requires the transcobalamin receptor CD320 whereas kidney reabsorption of cobalamin depends on Megalin (Lrp2). Whereas malabsorption of vitamin B12 is most commonly seen in the elderly, selective pediatric, nondietary-induced B12 deficiency is generally due to inherited disorders including the Imerslund-Gräsbeck syndrome and the much rarer intrinsic factor deficiency. Biochemical, clinical and genetic research on these disorders considerably improved our knowledge of vitamin B12 absorption. This review describes basic and recent findings on the intestinal handling of vitamin B12 and its importance in health and disease(2).
3. Cobalamin deficiency and spina bifida and other neural tube defects
Cobalamin deficiency in the newborn usually results from cobalamin deficiency in the mother. Megaloblastic anaemia, pancytopenia and failure to thrive can be present, accompanied by neurological deficits if the diagnosis is delayed. According to the study by the the McGill University-Montreal Montreal Children's Hospital Research Institute of the McGill University Health Center, most cases of spina bifida and other neural tube defects result from maternal folate and/or cobalamin insufficiency in the periconceptual period. Polymorphisms in a number of genes involved in folate and cobalamin metabolism exacerbate the risk. Inborn errors of cobalamin metabolism affect its absorption, (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and transport (transcobalamin deficiency) as well as its intracellular metabolism affecting adenosylcobalamin synthesis (cblA and cblB), methionine synthase function (cblE and cblG) or both (cblC, cblD and cblF). Inborn errors of folate metabolism include congenital folate malabsorption, severe methylenetetrahydrofolate reductase deficiency and formiminotransferase deficiency(3).
4. Inherited cobalamin malabsorption and Gene involved
Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. According to the study by the Ohio State University, in the revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved(4).
5. Cobalamin) deficiency and complications
Vitamin B12 (or cobalamin) deficiency is well known in geriatric patients, but not in those with spinal cord injury (SCI). According to the study by the Veterans Affairs Puget Sound Health Care System, Cobalamin deficiet SCI patients presented with depression and fatigue, 2 had worsening pain, 2 had worsening upper limb weakness, and 2 had memory decline. Of the 12 patients with subnormal serum vitamin B12 levels, 6 were asymptomatic. Classic laboratory findings of low serum vitamin B12, macrocytic red blood cell indices, and megaloblastic anemia were not always present. Anemia was identified in 7 of the 16 patients and macrocytic red blood cells were found in 3 of the 16 patients. Only 1 of the 16 SCI patients had a clear pathophysiologic mechanism to explain the vitamin B12 deficiency (ie, partial gastrectomy); none of the patients were vegetarian. Twelve of the SCI patients appeared to experience clinical benefits from cyanocobalamin replacement (some patients experienced more than 1 benefit), including reversal of anemia (5 patients), improved gait (4 patients), improved mood (3 patients), improved memory (2 patients), reduced pain (2 patients), strength gain (1 patient), and reduced numbness (1 patient)(5).
6. Psychiatric manifestations of vitamin B12 deficiency
There is a report of a case of a patient with vitamin B12 deficiency, who has presented severe depression with delusion and Capgras' syndrome, delusion with lability of mood and hypomania successively, during a period of two Months. Case report - Mme V., a 64-Year-old woman, was admitted to the hospital because of confusion. She had no history of psychiatric problems. She had history of diabetes, hypertension and femoral prosthesis. The red blood count revealed a normocytosis with anemia (hemoglobin=11,4 g/dl). At admission she was uncooperative, disoriented in time and presented memory and attention impairment and sleep disorders. She seemed sad and older than her real age. Facial expression and spontaneous movements were reduced, her speech and movements were very slow. She had depressed mood, guilt complex, incurability and devaluation impressions. She had a Capgras' syndrome and delusion of persecution. Her neurologic examination, cerebral scanner and EEG were postponed because of uncooperation. Further investigations confirmed anemia (hemoglobin=11,4 g/dl) and revealed vitamin B12 deficiency (52 pmol/l) and normal folate level. Antibodies to parietal cells were positive in the serum and antibodies to intrinsic factor were negative. An iron deficiency was associated (serum iron=7 micromol/l; serum ferritin concentration=24 mg/l; serum transferrin concentration=3,16 g/l). This association explained normocytocis anemia(6).
7. Effect of dietary organic supplementation on milk production, follicular growth, embryo quality, and tissue mineral concentrations in dairy cows
In the study to evaluate the potential effects of organic trace mineral supplementation on reproductive measures in lactating dairy cows, Cows were blocked by breed and randomly assigned at dry-off to receive inorganic trace mineral supplementation (control; n = 32) or to have a portion of supplemental inorganic Zn, Cu, Mn, and Co replaced with an equivalent amount of the organic forms of these minerals (treatment; n = 31), found that replacing a portion of inorganic supplemental trace minerals with an equivalent amount of these organic trace minerals (Zn, Mn, Cu, and Co) increased milk production in mid-lactation, but did not affect postpartum follicular dynamics, embryo quality, or liver and luteal trace mineral concentrations(7).
8. zinc-nickel-cobalt solution (ZnNiCo) and inflammation in adipose tissue
In the study to test the effect of a zinc-nickel-cobalt solution (ZnNiCo) on adipocyte function and to identify potential health effects of this solution in the context of obesity and associated disorders, indicated that the trace elements present in ZnNiCo are able to modulate the expression level of several inflammation related transcripts in adipocytes. These studies suggest that ZnNiCo could play a role in the prevention of inflammation in adipose tissue in obesity(8).
9. Cobalt-containing supplements
Cobalt-containing supplements are readily available in the U.S. and have been marketed to consumers as energy enhancers. However, little information is available regarding cobalt (Co) body burden and steady-state blood concentrations following the intake of Co dietary supplements. According to the study by the ChemRisk, LLC, 4840 Pearl East Circle, Boulder, CO 80301, United States, Pre-supplementation blood Co concentrations were less than the reporting limit of 0.5μg/L, consistent with background concentrations reported to range between 0.1 and 0.4μg/L. The mean whole blood Co concentration in the volunteers after 15 or 16days of dosing was 3.6μg Co/L and ranged from 1.8 to 5.1μg Co/L. The mean observed concentration in the study group was approximately 9-36 times greater than background concentrations. Further studies of Co whole blood concentrations following supplementation over longer time periods with additional monitoring of physiological parameters may provide useful information for evaluating the health of persons who take various doses of Co(9).
10. Vitamin B12 malabsorption: Mammalian physiology and acquired and inherited disorders
Vitamin B12 (cobalamin) is a cobalt-containing compound synthesized by bacteria and an essential nutrient in mammals. According to the study by the Hospitalier National d'Ophtalmologie des Quinze-Vingts, malabsorption of vitamin B12 is most commonly seen in the elderly, selective pediatric, nondietary-induced B12 deficiency is generally due to inherited disorders including the Imerslund-Gräsbeck syndrome and the much rarer intrinsic factor deficiency. Biochemical, clinical and genetic research on these disorders considerably improved our knowledge of vitamin B12 absorption(10).
11. The effects of Co on FA composition in blood
In the study to examine the amount of Co needed to obtain this effect. High-yielding dairy cows (n 4), equipped with ruminal cannulas, used in a 4 × 4 Latin square design, found that there was a linear effect of increasing the level of Co on milk FA composition. The effects of Co on FA composition in blood were insignificant compared with the effects on milk. In milk fat, the concentration of cis-9-18 : 1 was reduced by as much as 38 % on T4 compared with T1. Feed intake and milk yield were negatively affected by increasing the Co level(11).
12. For more information of Cobalamin (Vitamin B12), please visit Vitamin B12 in vitamins and minerals section
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Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/23207477
(2) http://www.ncbi.nlm.nih.gov/pubmed/23178706
(3) http://www.ncbi.nlm.nih.gov/pubmed/16846473
(4) http://www.ncbi.nlm.nih.gov/pubmed/22929189
(5) http://www.ncbi.nlm.nih.gov/pubmed/12828286
(6) http://www.ncbi.nlm.nih.gov/pubmed/15029091
(7) http://www.ncbi.nlm.nih.gov/pubmed/20817861
(8) http://www.ncbi.nlm.nih.gov/pubmed/23503329
(9) http://www.ncbi.nlm.nih.gov/pubmed/23207477
(10) http://www.ncbi.nlm.nih.gov/pubmed/23178706
(11) http://www.ncbi.nlm.nih.gov/pubmed/22682538
Wednesday, March 20, 2013
Proctitis
Proctitis is is defined as a condition of inflammation of the anus and the lining of the rectum (i.e., the distal 10–12 cm) of that can lead to bowl discomfort, bleeding, a discharge of mucus or pus, etc.
I. Causes and Risk factors
A. Types of Cause of Proctitis
Types of Proctitis are depending to the underlined causes of the diseases
1. Radiation proctitis
The condition is the result of exposure to x-rays or other ionizing radiation
2. Ischemic proctitis
According to the study by the University of Illinois at Chicago/Metropolitan Group Hospitals-St. Francis Hospital, Ischemic injury to the rectum is rare owing to its rich vascular supply, and is seldom seen in clinical practice(1). There is a report of Six patients with acute ischemic proctitis; four cases occurred after direct arterial interruption, one after accidental embolization of the blood supply to the rectum, and one from tumor edema. Bloody diarrhea was the most common symptom. Loss of anal sphincter tone was also an early sign in three patients(2).
3. Ulcerative proctitis
Epidemiological studies have shown that ulcerative proctitis represents 25-55% of ulcerative colitis. In western countries, the incidence of ulcerative proctitis has been increased, while the incidence of more extensive colitis remained unchanged. Ulcerative proctitis has shown to be a benign disease, with a prevalence of local symptoms, less systemic and extraintestinal manifestations, and low endoscopic grades of activity(3).
4. Sexually transmitted proctitis
Gastrointestinal manifestations of sexually transmitted infections (STI) are common. Proctitis, or inflammation of the rectum, has several infectious and non‐infectious causes, the infectious pathogens typically being sexually acquired. Chlamydia, gonorrhoea, herpes simplex virus and syphilis are among the STI that can cause anorectal disease, and more recently outbreaks of less common infections such as lymphogranuloma venereum (LGV)(4).
5. Autoimmune disease
Systemic lupus erythematosus (SLE) is an autoimmune disease, due to the body's immune system mistakenly attacks healthy tissue. Ischaemic colitis is relatively uncommon in systemic lupus erythematosus (SLE). There is a report of a a 38-year-old woman, who presented with haematochezia which subsequently proved to be due to ischaemic proctitis with a large rectal ulcer in a case that was subsequently diagnosed as SLE, according to the study by the Nil Ratan Sircar Medical College(4a).
6. Non-sexually transmitted infection
The classical example of non-sexually transmitted infection occurs in children and is caused by the same bacteria that cause strep throat(4b).
B. Rick factors
1. Low abdominal pain, high inflammatory lesions and an family history
According to the study by Hôpital Pontchaillou, of the Endoscopic information obtained for 52 patients with ulcerative proctitis (23 F, 29 H) seen during a ten-year period. The median follow-up was 68 +/- 8 months, showed that low abdominal pain, an family history of ulcerative colitis, and high inflammatory lesions at referral were significantly associated with a higher risk of extension(5).
2. Young age of onset of symptoms, smoking and appendectomy
According to the study of "Course and natural history of idiopathic ulcerative proctitis in adults" by Università degli Studi di Brescia Cattedra di Chirurgia Generale, Young age of onset of symptoms, smoking and appendectomy are associated with an increased risk of extension of the disease(6).
3. Sexual behavior(7)
a. Men having sex with men (MSM)
Sexually transmitted infection (STI) screening programmes are implemented in many countries to decrease burden of STI and to improve sexual health. In a study of a total of 1455 consultations in MSM showed that the prevalence of C. trachomatis and N. gonorrhoeae per anatomic site was: urethral infection 4.0% respectively and 2.8%, oropharynx 1.5% and 4.2%, and anorectum 8.2% and 6.0%. The majority of chlamydia cases (72%) involved a single anatomic site, which was especially manifest for anorectal infections (79%), while 42% of gonorrhoea cases were single site. Twenty-six percent of MSM with anorectal chlamydia and 17% with anorectal gonorrhoea reported symptoms of proctitis; none of the oropharyngeal infections were symptomatic. Most cases of anorectal infection (83%) and oropharyngeal infection (100%) would have remained undiagnosed with a symptom-based protocol.
b. Others
If you have multiple partners, , don't use condoms and have sex with a partner who has an STI, you are as an increased risk to develop proctitis.
4. Inflammatory bowel diseases
Risk of proctitis is increased with patient with IBD. In the study of a total of 1,255 filled questionnaires received with 96 were rejected and 1,159 (92.3 %), this comprised data on 745 (64.3 %) patients with UC, 409 (35.3 %) with CD, and 5 with indeterminate colitis. The median duration of illness was longer in patients with CD (48 months) compared to those with UC (24 months) (p = 0.002), found that more than one half of patients (UC 51.6 %, CD 56.9 %) had one or more extraintestinal symptoms. A definite family history of IBD was present in 2.9 % (UC 2.3 % and CD 4.6 %; p = 0.12). The extent of disease in UC was pancolitis 42.8 %, left-sided colitis 38.8 %, and proctitis alone in 18.3 %(8).
5. Cancer radiation therapy
According to the study by the University of Minnesota Hospital and Clinics, a high posterior rectal dose (> 5,000 cGy) is associated with increased prevalence of proctitis after radiation therapy(9).
6. Socioeconomic factors, dietary and other personal habits, and medical history
In the study of the risk factors for extensive ulcerative colitis and ulcerative proctitis of a total of 167 (98%) of all prevalent cases of ulcerative colitis diagnosed in Uppsala county from 1945 to 1964 and 167 age and sex matched population, showed that ulcerative colitis patients were less likely than controls to be current cigarette, pipe, or cigar smokers (odds ratio (OR) = 0.44; 95% confidence limits (CL) = 0.25-0.78), but more likely to have symptoms induced by drinking milk (OR = 4.63; 95% CL = 2.15-9.93). Patients with ulcerative colitis do not differ in most of the socioeconomic, dietary and personal habits compared with the background population(10).
7. Frequent fecal impactions
Frequent fecal impactions without proper treatment are associated toincreased risk of proctitis, according to the study by the Ohio University(10a).
II. Symptoms
1. Rectal bleeding and anal discomfort
There is a report of a A 45-year-old man was referred to our surgical clinic for investigation of rectal bleeding and anal discomfort. is a sexually transmitted infection caused by Chlamydia trachomatis. There are few reports describing rectal stricture as a late complication of chronic proctitis associated with lymphogranuloma venereum (LGV) infection. Lymphogranuloma venereum (LGV)proctitis is often mild, but chronic cases can be associated with serious complications. If LGV is misdiagnosed or partially treated, the natural history of chronic long-lasting inflammation of the rectum may include the development of fissures, perianal abscess and strictures of the rectum(11).
2. Change of Singapore General Hospital
According to the Singapore General Hospital study of review, 77 patients were admitted for the treatment of radiation proctitis, with a median follow-up period of 14 (range 1-61) months. There were 23 male and 54 female patients, with a median age of 63.9 (range 37-89) years, the most common presenting symptom was bleeding per rectum (89.6 percent), with a change in bowel habits a distant second (10.4 percent)(12).
2. Constipation
There is a report of a 72-year-old white woman presenting with a large abdominal mass, who had at least 4 episodes of radiographically demonstrated fecal impaction over the previous year without adequate treatment. The patient required hospitalization for a bleeding rectal ulcer during the second episode of fecal impaction. Computed tomography (CT) scans on this admission revealed a dilated colon up to 16 x 14 cm in maximal dimensions extending over 30 cm, filled with massive fecal material, according to the study by the College of Osteopathic Medicine, Ohio University, Athens(13).
3. Urgency, diarrhea, and tenesmus
According to the study of 50 patients to compare colonic irrigation and oral antibiotics (irrigation group) versus 4% formalin application (formalin group) for treatment of hemorrhagic radiation proctitis by Chulalongkorn University, Bangkok, showed that treatment with daily self-administered colonic irrigation with 1 L of tap water and a 1-week period of oral antibiotics (ciprofloxacin and metronidazole) indicated a a significant improvement in rectal bleeding and bowel frequency in both treatment groups, but significant improvement in urgency, diarrhea, and tenesmus was demonstrated only in the irrigation group(15).
4. Anorectal pain, discharge and change in stool frequency
The University Hospital, Zurich, Switzerland report a study since 2003, there are twelve cases of proctitis, all in men having sex with men (MSM), caused by the LGV serovar L2 C. In the observation of trachomatis, of the overall 11 patients the majority were HIV positive and only 2 were HIV negative. Only one patient reported previous sexual contacts outside Europe (Thailand) as the likely place of infection. The clinical presentation was characterised by anorectal pain, discharge, tenesmus and change in stool frequency(16).
5. Blood in stool
In most cases, blood in stool is presented for patient with ulcerative proctitis.
6. Ulcers, and occasionally lymphadenopathy and fever
Symptoms of infectious proctitis can include rectal blood and mucous discharge, anorectal pain, ulcers, and occasionally lymphadenopathy and fever, according to the study by the University of Chicago Medical Center(14)
IV. Complications and diseases associated with Proctitis
A. Complications
A.1. Diseases complications
1. Intractable bleeding, intestinal obstruction or intra-abdominal sepsis
In the review of 77 patients admitted for the treatment of radiation proctitis, with a median follow-up period of 14 (range 1-61) months. There were 23 male and 54 female patients, with a median age of 63.9 (range 37-89) years.the majority of the patients (72.5 percent) received non-surgical treatment, most commonly using topical 4 percent formalin solution to arrest the bleeding, with more than half the patients requiring repeat treatments. 14 (18.2 percent) patients required colorectal resections for intractable bleeding, intestinal obstruction or intra-abdominal sepsis(17).
2. Syphilis
There is a first report of a case of with simultaneous manifestations of proctitis, gastritis, and hepatitis. The diagnosis of syphilitic proctitis and gastritis was established by the demonstration of spirochetes with anti-Treponema pallidum antibody staining in biopsy specimens. Unusual manifestations of secondary syphilis completely resolved after 4 weeks of antibiotic therapy(18).
3. Bleeding areas in the rectum, internal and/or external hemorrhoids
According to the study by, Surgeons are appropriately concerned about using conventional methods of treatment in patients with radiation proctitis, such as cautery for complications of bleeding areas in the rectum, rubber band ligation, or excision of internal and/or external hemorrhoids, for fear of poor healing and possible exacerbation of the original problem(19).
4. Comstipation
According to the study by University La Sapienza, constipation in ulcerative proctitis (UP), may be correlated with rectal fibrosis, which reduces the transit of stools from the left colon. The concomitance of asymptomatic anorectal organic or functional alteration may contribute to worsen constipation(20).
5. Increased irritation to the anal and rectal area in patients with proctitis.
6. Etc.
A.2. Complications after treatment
1. Formalin installation treatment
Inn the study to evaluate the results of formalin installation treatment in terms of outcome and complications with a solution of 4% formalin was introduced in aliquots of 50 ml kept in contact with the mucosa for 30 s and then cleared away using saline irrigation; five to six aliquots were used in each session, showed that in a mean follow-up of 18 months (range 6-26), two patients had repeat episodes of bleeding, one underwent successful repeat irrigation, and the other refused further treatment. One patient suffered from severe anococcygeal pain and worsening of incontinence after the procedure. The pain was treated with lidocaine ointment and sitz baths with partial success. Another patient developed severe formalin-induced colitis 5 days after the procedure, which required intravenous antibiotics and hydration. Formalin installation may be effective in controlling refractory bleeding due to radiation induced proctitis(21).
2. Systemic isotretinoin therapy
Isotretinoin's best-known and most dangerous side effect is birth defects due to in utero exposure. There is a report of complications of anal fissure, rectal bleeding and proctitis with the systemic isotretinoin therapy(22).
3. Etc.
B. Diseases associated with Proctitis
1. Inflammatory bowel diseases (IBD) and sexual transmitted infections
Proctitis is a common problem and is most frequently associated with inflammatory bowel diseases (IBD). However, in the last ten years the incidence of infectious proctitis appears to be rising, especially in men who have sex with men. This may be due to the rise of people participating in receptive anal sex as well as the increase in sexually transmitted infections, such as those from Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex virus and Treponema pallidum. Recent outbreaks of lymphogranuloma venereum among homosexual men throughout Europe highlight the need to consider sexually transmitted infections in the differential diagnosis of proctitis, according to the study by the University of Florence(23).
2. Procitis associated with chlamydial infection
According to the University of Sydney, New South Wales. an aged koala presented for euthanasia was found to have asymptomatic chronic proctitis, cystitis, prostatitis, urethritis and conjunctivitis associated with chlamydial infection. Inflammation was severe in the terminal rectum and extended into the proximal common vestibule. Chlamydial organisms were visualised in the rectal surface epithelium using Giminez' stain and an immunoperoxidase staining method. Organisms were also detected in the epithelium of the bladder, prostate and urethra(24). Other in the study to investigate the prevalence and genotype distribution of Chlamydia trachomatis infection among men who have sex with men (MSM), 145 MSM from two sauna settings in Shenzhen, China were invited to participate in this study during September 2008 and May 2009, showed that the prevalence of anorectal chlamydial infection was 24% in the study population and was significantly associated with proctitis symptoms(25).
3. Human immunodeficiency virus infection
There is a report of a of published cases and a recently managed patient is presented, which describes the clinical features of cytomegalovirus proctitis. About half of the reports describe sexually transmitted cytomegalovirus proctitis following anal intercourse, which typically presents with rectal bleeding and a mononucleosis-like syndrome. This condition resolves spontaneously and may be associated with human immunodeficiency virus infection(26).
4. Immune-mediated diseases
In the study to to evaluate the prevalence of pANCA expression and its association with clinical findings and disease course in Korean patients with UC, included 484 patients with UC who were diagnosed and treated between 1990 and 2006 at Severance Hospital, Yonsei University, Seoul, Korea, showed that the prevalence of pANCA expression in Korean patients with UC was relatively low compared to that in Western countries. Although UC patients with pANCA expression had more severe clinical findings at diagnosis and higher cumulative relapse rates in our study, further prospective studies are warranted to clarify whether pANCA positivity influences the initial clinical presentation or disease aggressiveness(27).
5. Hermansky Pudlak syndrome
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder consisting of oculocutaneous albinism, platelet dysfunction and systemic complications associated with lipofuscin deposition in the reticuloendothelial system. According to Auxilio Mutuo Hospital, Rio Piedras, there is a report of a series of two patients with HPS treated in Puerto Rico, and the results from medical and surgical intervention for gastrointestinal disease. Our experience with HPS patients has shown the difficult management of perineal disease similar in the management of Crohn's. However, complications from the bleeding diathesis necessitate caution during surgery and potential anesthesia complications(28).
6. Crohn's disease
There is a report of four patients with Crohn's disease who underwent fecal diversion with an in situ rectum were observed in whom sigmoidoscopy was initially normal at the time of the diversion, became distinctly abnormal during the year after the diversion, and then returned to normal within 3 mo following reestablishment of intestinal continuity. The entity of nonspecific diversion proctitis might account for this phenomenon independently or by accelerating the Crohn's disease process, according to the study(29).
7. Etc.
V. Misdiagnosis and Diagnosis
A. Misdiagnosis
1. Hirschsprung's disease
Allergic proctitis and abdominal distention mimicking Hirschsprung's disease in infants.In the study to determine the incidence and clinical aspects of allergic proctitis (AP) in infants with symptoms that mimic Hirschsprung's disease (HD), found that in the infants with severe abdominal distention, the incidence of AP mimicking HD was relatively high. Therefore, consideration of AP should be part of the differential diagnosis in infants with severe abdominal distention or findings that mimic HD. For differentiation of these disorders, a rectal suction biopsy is very useful.In the infants with severe abdominal distention, the incidence of AP mimicking HD was relatively high. Therefore, consideration of AP should be part of the differential diagnosis in infants with severe abdominal distention or findings that mimic HD. For differentiation of these disorders, a rectal suction biopsy is very useful(30).
2. Diffuse cavernous haemangioma of the rectum (DCHR)g masquerading
Diffuse cavernous haemangioma of the rectum (DCHR) is a rare benign vascular neoplasm that affects mainly young adults and can present with rectal bleeding or massive haemorrhage. There is a report of a case of DCHR masquerading as proctitis which was diagnosed many years ago following colonoscopy, according to St. George's Hospital NHS Trust, London(31).
3. Colitis cystica profunda and solitary rectal ulcer syndrome-polyoid variant
Colitis cystica profunda and solitary rectal ulcer syndrome-polyoid variant are related chronic benign disorders with characteristic histological features. There is a report of a case of colitis cystica profunda and solitary rectal ulcer syndrome-polypoid variant that was misdiagnosed initially as an ulcerative proctitis, according to the study by Ben-Gurion University of the Negev, Beer-Sheva, Israel(32).
4. Rectal strictures
Rectal strictures are uncommon in young patients without a history of malignancy, inflammatory bowel disease or previous surgery. It presents with nonspecific symptoms, rectal ulcer, proctitis, anal fissures, abscesses and rectal strictures. Clinical and endoscopic findings as well as histology resemble Crohn's disease, which may be misdiagnosed/ According to the study by King's College Hospital, rectal lymphogranuloma venereum is a rare cause of rectal strictures but surgeons should be aware of its existence and include it in the differential diagnosis of unexplained strictures in high-risk patients(33).
5. Etc.
B. Diagnosis
1. Stool sample
The aim of the stool examination is to find out types of bacterial causes of infection.
Unfornunately, Non-invasive diagnostic tools to evaluate the severity of acute, radiation-induced proctitis are not readily available, but faecal calprotectin and lactoferrin concentrations could be markers of acute, radiation-induced proctitis(34).
2. Blood test
The aim of the blood test is also to determine the types of infection as well as blood loss
3. Proctoscopy
Proctoscopy procedure in which yuor doctor insert a thin tube containing a camera and a light to visually inspect to look for sign of proctitis. In a prospective study of 130 patients who underwent external radiation therapy (RT) for stage T1 to T4 prostate cancer between 1997 and 2008, to determine the Role of Early Proctoscopy in Predicting Late Symptomatic Proctitis After External Radiation Therapy for Prostate Carcinoma, Proctoscopy showed that In patients with acute endoscopic proctitis (AEP) and Acute clinical proctitis (ACP), the risk of late clinical proctitis (LCP) was more than 5-fold increased compared to those who were asymptomatic, while a much smaller increase in risk occurred in patients with ACP only. Early proctoscopy can provide valuable information regarding the likelihood of late(35).
4. Rectal culture
Rectal culture is the laboratory test of normally involves a swab of patients rectum with an aim to determine types of bacterial causes of proctitis.
5. Rectal microscopy
The Microstructure imaging of human rectal mucosa may be helpful in determination the causes of the disease. According to the study by the Urinary Medicine, Mortimer Market Centre, in all, 134/136 had rectal microscopy of whom, 47/134 (35%) were smear-positive for Rectal gonorrhoea (GC) . Of the 136 cases, 90 received antibiotics for GC at their first presentation. Twenty-four of 90 (27%) would not have been treated until culture results were available, if rectal microscopy had not been performed. The results suggest that rectal microscopy remains an important tool and increases the proportion of men treated for GC at their first attendance(36).
6. Sigmoidoscopy
Sigmoidoscopy is a procedure of using a flexible tube called a sigmoidoscope with a small camera attached to the end placed through the anus and gently moved into your colon for examination of up to the sigmoid. Dr. McMillan A. in the study to to assess the value of sigmoidoscopy in the routine investigation of homosexual men, this procedure was undertaken on 1118 men who attended a sexually transmitted diseases clinic as "new" or "return new" patients, indicated that Serious rectal disease was not identified in any of the 557 men who were symptomless at the initial attendance. Though the extent of the proctitis diagnosed in 166 men would not have been defined, 99% (465) of 470 anorectal lesions would have been identified if proctoscopy alone had been performed. It is concluded that sigmoidoscopy does not have a role in the routine investigation of homosexual men(37).
VI. Preventions
A. Diet to prevent Proctitis
1. Black and green tea
Gallocatechin, containing catechin is phytochemicals of Flavan-3-ols, in the group of Flavonoids (polyphenols), found abundantly in green and black tea. In the evaluation of the anti-inflammatory and antimicrobial effect of nanocatechin on CBP and plasma concentration of catechins in an animal model, found that the use of ciprofloxacin, catechin, and nanocatechin showed statistically significant decrease in bacterial growth and improvement in prostatic inflammation compared with the control group. The nanocatechin group showed statistically significant decrease in bacterial growth and improvement in prostatic inflammation compared with the catechin group. Plasma concentrations of epicatechin, gallocatechin gallate, and epigallocatechin gallate were significantly higher in the nanocatechin group than those in the catechin group. These results suggest that nanocatechin has better antimicrobial and anti-inflammatory effects on rat CBP than catechin due to higher absorption into the body, according to "Anti-inflammatory and antimicrobial effects of nanocatechin in a chronic bacterial prostatitis rat model" by Yoon BI, Ha US, Sohn DW, Lee SJ, Kim HW, Han CH, Lee CB, Cho YH(38).
Other In the identification of tea polyphenols were evaluated for their ability to inhibit enterovirus 71 (EV71) replication in Vero cell culture, found that The viral inhibitory effect correlated well with the antioxidant capacity of polyphenol. Mechanistically, EV71 infection led to increased oxidative stress, as shown by increased dichlorofluorescein and MitoSOX Red fluorescence. Upon EGCG treatment, reactive oxygen species (ROS) generation was significantly reduced. Consistent with this, EV71 replication was enhanced in glucose-6-phosphate dehydrogenase deficient cells, and such enhancement was largely reversed by EGCG, according to "Antiviral effect of epigallocatechin gallate on enterovirus 71" by Ho HY, Cheng ML, Weng SF, Leu YL, Chiu DT(39).
2. Apple skin
Quercetin is a member of flavonoids, found abundantly in apple skin It is also one of antioxidants with property of protecting our body in fighting against forming of free radicals cause of mutation of cells`DNA. According to the study of `Antimicrobial and cytotoxic activities of leaves, twigs and stem bark of Scutia buxifolia Reissek.`by Boligon AA, Janovik V, Frohlich JK, Spader TB, Forbrig Froeder AL, Alves SH, Athayde ML. (Source from a Phytochemical Research Laboratory, Department of Industrial Pharmacy , Federal University of Santa Maria , Build 26, room 1115 , Santa Maria , CEP 97105-900 , Brazil.), posted in PubMed, researchers found that quercitrin, isoquercitrin and rutin were identified by HPLC and may be partially responsible for the antimicrobial activities observed. This study reports for the first time the antimicrobial and cytotoxic activities of S. buxifolia leaves, twigs and stem bark.
Also according to the study of `Antioxidant and Anti-Inflammatory Activities of Quercetin 7-O-β-D-Glucopyranoside from the Leaves of Brasenia schreberi.`by Legault J, Perron T, Mshvildadze V, Girard-Lalancette K, Perron S, Laprise C, Sirois P, Pichette A. (Source from Laboratory for Analysis and Separation of Plant Species (LASEVE), Université du Québec à Chicoutimi , Chicoutimi, Québec, Canada.), posted in PubMed, researchers found that some flavonoids have been reported to possess beneficial effects in cardiovascular and chronic inflammatory diseases associated with overproduction of nitric oxide. Quercetin-7-O-β-D-glucopyranoside possesses anti-inflammatory activity, inhibiting expression of inducible nitric oxide synthase and release of nitric oxide by lipopolysaccharide-stimulated RAW 264.7 macrophages in a dose-dependent manner. Quercetin-7-O-β-D-glucopyranoside also inhibited overexpression of cyclooxygenase-2 and granulocyte macrophage-colony-stimulating factor.
3. Tomatoes
Tomato is a red, edible fruit, genus Solanum, belongs to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose
and often in green house. Tomato is considered as antiseptic natural foods including natural antiseptic agent ascorbic acid that helps to enhance the immune system in guarding our body against the possibility of infection, sepsis, or putrefaction, according to the article of "The 7 Benefits Of Drinking Lemon Water" posted in Simple Health Cures. Other study indicated that Lycopene, one of the powerful antioxidant in tomatoes, not only helps the immune system in neutralizing the forming of free radicals in the body and according to Harvard investigation as it found that men who ate more than 10 servings tomato-based foods daily (like cooked tomatoes and tomato sauce,) had a 35 percent lower risk of developing prostate cancer than those who ate the least amount of these foods. The benefits of lycopene was more pronounced with advanced stages of prostate cancer. Also according to the study of "Chemoprevention of prostate cancer with lycopene in the TRAMP model" by Konijeti R, Henning S, Moro A, Sheikh A, Elashoff D, Shapiro A, Ku M, Said JW, Heber D, Cohen P, Aronson WJ., posted in PubMed(40)
4. Fennel
Fennel is a species of Foeniculum Vulgare, belong to the family Apiaceae (Umbelliferae), and native to to the shores of the Mediterranean. It is now widely cultivated all around the globe to use as food and herb. In the determination of the chemical compositions of the essential oil and hexane extract isolated from the inflorescence, leaf stems, and aerial parts of Florence fennel found that the essential oil, anethole, and hexane extract were effective against most of the foodborne pathogenic, saprophytic, probiotic, and mycotoxigenic microorganisms tested. The results of the present study revealed that (E)-anethole, the main component of Florence fennel essential oil, is responsible for the antimicrobial activity , according to "Antimicrobial activities of essential oil and hexane extract of Florence fennel [Foeniculum vulgare var. azoricum (Mill.) Thell.] against foodborne microorganisms" by Cetin B, Ozer H, Cakir A, Polat T, Dursun A, Mete E, Oztürk E, Ekinci M(41).
Other In the study of fennel honey, ethanol, and aqueous propolis extracts orally and theirs effect on immune defense found that all tested previously bee product-immunized rats could significantly challenge the induced S. aureus infection (P < .01). The effects were more pronounced in rats that had received fennel honey solution, according to "Immune defense of rats immunized with fennel honey, propolis, and bee venom against induced staphylococcal infection" by Sayed SM, Abou El-Ella GA, Wahba NM, El Nisr NA, Raddad K, Abd El Rahman MF, Abd El Hafeez MM, Abd El Fattah Aamer A(42).
B. Phytochemicals and antioxidants to prevent Proctitis
1. Theaflavin-3-gallate
Theaflavin-3-gallate, a theaflavin derivative, is phytochemicals of Flavan-3-ols, in the group of Flavonoids (polyphenols) found abundantly in black tea. In the comparison of TF derivatives (theaflavin (TF(1)), theaflavin-3-gallate (TF(2)A), theaflavin-3'-gallate (TF(2)B), and theaflavin-3,3'-digallate (TF(3))) in scavenging reactive oxygen species (ROS) in vitro, indicated that positive antioxidant capacities of TF(2)B on singlet oxygen, hydrogen peroxide, hydroxyl radical, and the hydroxyl radical-induced DNA damage in vitro were found, according to "Evaluation of the antioxidant effects of four main theaflavin derivatives through chemiluminescence and DNA damage analyses" by Wu YY, Li W, Xu Y, Jin EH, Tu Y(43).
Other In the evaluation of the antimicrobial activities of seven green tea catechins and four black tea theaflavins, found that (-)-gallocatechin-3-gallate, (-)-epigallocatechin-3-gallate, (-)-catechin-3-gallate, (-)-epicatechin-3-gallate, theaflavin-3, 3'-digallate, theaflavin-3'-gallate, and theaflavin-3-gallate showed antimicrobial activities at nanomolar levels; (ii) most compounds were more active than were medicinal antibiotics, such as tetracycline or vancomycin, at comparable concentrations; (iii) the bactericidal activities of the teas could be accounted for by the levels of catechins and theaflavins as determined by high-pressure liquid chromatography; (iv) freshly prepared tea infusions were more active than day-old teas; and (v) tea catechins without gallate side chains, gallic acid and the alkaloids caffeine and theobromine also present in teas, and herbal (chamomile and peppermint) teas that contain no flavonoids are all inactive, according to "Antimicrobial activities of tea catechins and theaflavins and tea extracts against Bacillus cereus" by Friedman M, Henika PR, Levin CE, Mandrell RE, Kozukue N(44).
2. Allyl sulfides
Garlic has been used in traditional Chinese and herbal medicine over thousands of year as antibacterial, antiviral, and antifungal agent and in treating other conditions such as parasites, respiratory problems, poor digestion, low energy, etc. In many studies, researchers found that Allyl sulfides, a phytochemical in garlic has been demonstrated effectively in treating certain diseases.
According to the article of "GARLICTHE BOUNTIFUL BULB" by Carmia Borek, Ph.D. posted in Life extension magazine, the author indicated that human studies confirm immune stimulation by garlic. Subjects receiving aged garlic extract at 1800 mg a day for three weeks showed a 155.5% increase in natural killer immune cell activity that kills invaders and cancer cells. Other subjects receiving large amounts of fresh garlic of 35g a day, equivalent to 10 cloves, showed an increase of 139.9%. In six weeks, patients with AIDS receiving aged garlic extract showed an enhancement of natural killer cells from a seriously low level to a normal level.
3. Piperine
Piperine is a phytochemical alkaloid in the class of organosulfur compound, found abundantly in white and black pepper, long pepper, etc. In the valuation of novel synthetic analogues of piperine as inhibitors of multidrug efflux pump NorA of Staphylococcus aureus, showed that a newly identified class of compounds derived from a natural amide, piperine, is more potent than the parent molecule in potentiating the activity of ciprofloxacin through the inhibition of the NorA efflux pump. These molecules may prove useful in augmenting the antibacterial activities of fluoroquinolones in a clinical setting, according to "Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus" by Ashwani Kumar, Inshad Ali Khan, Surrinder Koul, Jawahir Lal Koul, Subhash Chandra Taneja, Intzar Ali, Furqan Ali, Sandeep Sharma, Zahid Mehmood Mirza, Manoj Kumar, Pyare Lal Sangwan, Pankaj Gupta, Niranjan Thota and Ghulam Nabi Qazi(45)
Other In the investigation of investigate the anti-inflammatory effect of piperine against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis and compared it with that of the non-steroidal anti-inflammatory drug indomethacin, found that Histopathological analysis of joints also revealed that synovial hyperplasia and mononuclear infiltration observed in arthritic rats were alleviated by piperine. Thus, the present study clearly indicated that piperine possesses promising anti-inflammatory effect against adjuvant-induced arthritis by suppressing inflammation and cartilage destruction, according to "Anti-inflammatory Effect of Piperine in Adjuvant-Induced Arthritic Rats-a Biochemical Approach" by Murunikkara V, Pragasam SJ, Kodandaraman G, Sabina EP, Rasool M(46).
4. Sinigrin
Sinigrin is a phytochemical glucosinolate, belongs to the family of glucosides found abundantly in Brussels sprouts, broccoli, the seeds of black mustard, etc. In the investigation of Allyl isothiocyanate (AIT) derived from the glucosinolate sinigrin found in plants of the family Brassicaceae and its antimicrobial agent against a variety of organisms, including foodborne pathogens such as Escherichia coli O157:H7, found that it can be postulated that: 1) AIT is a more effective antimicrobial at low pH values and its degradation reduces this activity; 2) decomposition products in water might not participate in the antimicrobial action of AIT; and 3) AIT seems to have a multi-targeted mechanism of action, perhaps inhibiting several metabolic pathways and damaging cellular structures, according to "Enzymatic inhibition by allyl isothiocyanate and factors affecting its antimicrobial action against Escherichia coli O157:H7" by Luciano FB, Holley RA(47).
Other In the examination of the effect of an aqueous extract of cooked Brussels sprouts on formation of 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in calf thymus DNA in vitro, found that Sinigrin, a glucosinolate abundant in Brussels sprouts, co-eluted with the most effective fraction and had DNA protective effects. In comparison with other antioxidants the patterns of effect of the extract in the five damage systems were more similar to that of sodium azide than to those of dimethylsulfoxide and vitamin C, according to "Inhibition of oxidative DNA damage in vitro by extracts of brussels sprouts" by Zhu C, Poulsen HE, Loft S(48).
VI. Treatments
A. In conventional medicine perspective
Medical treatment of proctitis depends on the etiology
A.1. Radiation proctitis
A.1.1. Acute radiation proctitis
Acute radiation proctitis usually does not require treatment as the diseases can resolve after several months. Topical mesalazine is contraindicated during radiotherapy. Hydrocortisone enema is not superior to sucralfate in preventing acute rectal toxicity.. According to the study to assess whether the topical use of steroids or 5-aminosalicylic acid (5-ASA) is superior to sucralfate in preventing acute rectal toxicity during three-dimensional conformal radiotherapy (3DCRT) to 76 Gy(63),
A.1.2. Chronic radiation proctitis
Chronic radiation proctitis is the result of damage to the blood vessels which supply the colon due to radiotherapy.
1. Non surgical interventions
Chronic radiation proctitis (inflammation of the rectum) may develop after the completion of pelvic radiotherapy. In Studies (preferentially randomised controlled trials) of interventions for the non-surgical management of late radiation proctitis in patients who have undergone pelvic radiotherapy as part of their cancer treatment, indicated that Late radiation complications are a relatively rare manifestation, with many potential carers and poor diagnostic criteria. Although certain interventions look promising and may be effective (such as rectal sucralfate, adding metronidazole to the anti-inflammatory regime and heater probes), single small studies (even if well conducted) provide insufficient evidence(64).
2. Surgical interventions
a. Cryospray Ablation
Radiation proctitis, a common condition associated with radiotherapy for the treatment of pelvic cancers, is characterized by difficult to manage rectal pain and bleeding. According to the study by the Uniformed Services University of the Health Sciences, Cryotherapy is an effective method in the management of chronic radiation proctitis with minimal complications(65).
b. Radio frequency ablation (RFA)
Radiation proctitis is a frequent complication of pelvic radiation for cancer. There is a report of a case of refractory radiation proctitis, with suboptimal response to other therapies, treated successfully with a novel method, radiofrequency ablation(66).
A.2. Ischemic proctitis
A.2.1. Acute ischemic proctitis
1. Non surgical interventions, include
a. Superficial mucosal ischemia
Superficial mucosal ischemia was treated without surgery, but deeper levels of necrosis required laparotomy and Hartmann's resection. Rectal excision was not necessary. Four patients survived the ischemic event(67).
b. Formalin instillation
Topical (4 percent) formalin is safe and effective in treatment of radiation-induced hemorrhagic proctitis. A single treatment will stop bleeding in 75 percent of patients(68). Other study also indicated that there is a case of an elderly male with multiple medical problems and hemorrhagic, ischemic proctitis is presented. The proctitis was refractory to all other medical options but responded to topical instillation of 4 percent formalin(69).
2. Surgical interventions include
a. Proctectomy
There is a report of four cases of acute ischemic proctitis that required complete proctectomy. All patients had large vessel atherosclerosis with rectal bleeding and sepsis as the presenting signs and symptoms. Three of four patients underwent complete proctectomy as the initial procedure. The fourth patient underwent complete proctectomy five days after the initial intervention. Two of four patients survived and were ultimately discharged from the hospital. A third patient recovered from surgery but ultimately died of respiratory complications. Only the patient who was initially treated by subtotal proctectomy died as the result of the disease. Although ischemic necrosis of the rectum is rare, complete proctectomy may be necessary to save the patient's life(70).
b. Transcatheter embolization
In the study of treatment of lower gastrointestinal bleeding was attempted in 13 patients by selective embolization of branches of the mesenteric arteries with Gelfoam, showed that One patient improved after embolization but bleeding recurred within 24 hours and in another patient the catheterization was unsuccessful. Five patients with diverticular hemorrhage were embolized in the right colic artery four times, and once in the middle colic artery. Three patients had embolization of the ileocolic artery because of hemorrhage from cecal angiodysplasia, post appendectomy, and leukemia infiltration. Three patients had the superior hemorrhoidal artery embolized because of bleeding from unspecific proctitis, infiltration of the rectum from a carcinoma of the bladder, and transendoscopic polypectomy(71).
A.2.2. Chronic ischemic proctitis
1. Non surgical treatments
In the study to identify the various non-surgical treatment options for the management of late chronic radiation proctitis and evaluate the evidence for their efficacy, showed that Sixty-three studies met the inclusion criteria, including six randomised controlled trials that described the effects of anti-inflammatory agents in combination, rectal steroids alone, rectal sucralfate, short chain fatty acid enemas and different types of thermal therapy(72).
2. Surgical interventions include
1. Laparoscopic colorectal surgery
In the study to assess the outcome of laparoscopic colorectal surgery in patients >60 years of age and compare it to a younger group of patients who underwent similar procedures, indicated that here were no statistically significant differences between the younger and older groups relative to the incidence of complications (11 vs 14%, respectively) and conversion (8 vs 11%, respectively) or the length of ileus (2.8 vs 4.2 days, respectively) or hospitalization (5.2 vs 6.5 days, respectively) (P = NS for all). There was no mortality in either group. The outcome of laparoscopic colorectal surgery in older patients is similar to that noted in younger patients. Advanced age should not be a contraindication to laparoscopic colorectal surgery(73).
2. Laparoscopic or laparoscopic-assisted colorectal operations
There were 140 laparoscopic and laparoscopic-assisted procedures performed between May 1991 and January 1995. The mean patient age was 48 (range 12-88) years; there were 78 males and 62 females. Indications for surgery included inflammatory bowel disease in 47, colorectal carcinoma in 19, diverticular disease in 17, polyps in 16, familial polyposis in 7, colonic inertia in 7, fecal incontinence in 11, sigmoidocele in 3, irradiation proctitis in 3, rectal prolapse in 2, intestinal lymphoma in 2, and miscellaneous conditions in 6. The procedures included 38 total abdominal colectomies (TAC) (ileoanal reservoir 28, ileorectal anastomosis 8 and end ileostomy 2); 70 segmental resections of the colon, small bowel, and rectum(74)
A.1.3. Ulcerative proctitis
1. Non surgical treatments
Ulcerative proctitis is an important and increasingly common subcategory of ulcerative colitis (UC) in which inflammation is limited to the rectum. According to the study by the McGill University Health Centre, treatment options include the oral and/or rectal 5-aminosalicylate (5-ASA) preparations. Rectal therapy delivering higher concentrations of active medication (5-ASA or glucocorticoids) directly to the inflamed mucosa while minimizing systemic absorption provides a highly effective and safe treatment. Oral glucocorticoids are indicated in patients who are resistant to or intolerant of 5-ASA therapy. Immunomodulators have an important role in individuals with glucocorticoid dependent or glucocorticoid refractory disease(75).
2. Surgical treatments
In case of severity, surgery may be necessary. According to the study by the, Severe UC is defined as more than 6 bloody stools per day and signs of systemic involvement (fever, tachycardia, anemia). These patients should be hospitalized for intensive treatment and surveillance (ECCO EL 5, RG D) as the development of a toxic megacolon and perforation is a potentially life-threatening condition. Intravenous steroids (e.g. methylprednisolone 60 mg/d or hydrocortisone 400 mg/d) remain the mainstay of conventional therapy to induce remission (ECCO EL 1b, RG D; DGVS C). Patients refractory to maximal oral treatment with prednisolone and 5-ASA can be given the tumor necrosis factor (TNF)-α blocker IFX at 5 mg/kg (ACG EL A). Nevertheless, colectomy rates are as high as 29% in patients with severe UC and who need intravenous corticosteroids. They should therefore be presented to the colorectal surgeon on the day of admission. It is crucial that gastroenterologists and surgeons provide joint daily care in order to avoid delaying the necessary surgical therapy(76).
A.1.4. Sexually transmitted proctitis
1. Non surgical interventions(77)
Treatment can be started empirically while awaiting the microbiological results, thus reducing inflammation, infection duration and hence infectivity of the patient. The appropriate treatment of sexually transmitted proctitis has important implications in the control of HIV by reducing both HIV transmission and susceptibility.
a. Azithromycin (1 g as a single dose) or doxycycline (100 mg twice daily for a week) is an effective treatment for chlamydia.
b. HIV‐positive men with proctitis should be treated for LGV in the first instance. The preferred treatment is doxycycline 100 mg twice daily for 3 weeks; erythromycin may be used as an alternative.
c. Homosexual men with symptomatic rectal chlamydia should be given LGV treatment until the serovar is determined.
d. The treatment of gonorrhoea depends on local guidelines, based on surveillance of resistance patterns of the organism. A minimum criterion is that at least 95% of gonorrhoea prevalent in a population should be susceptible to the antibiotic used
e. Patients with recurrent symptoms of HSV may benefit from long‐term suppressive treatment. Early syphilis is treated with intramuscular procaine penicillin (10 days) or benzathine penicillin (2.4 g as a single dose). Doxycycline can be used in patients allergic to penicillin (100 mg twice daily for 2 weeks). Longer courses of antibiotics are used for latent syphilis.
2. Surgical interventions include Appendicectomy
In the report of a prospective case series of 30 adult patients (median age 35 years, range 17-70 years; male/female: 11/19) with ulcerative proctitis (median duration of symptoms 5 years, range 8 months to 30 years; median Simple Clinical Colitis Activity Index score 9, range 7-12), who underwent appendicectomy in the absence of any history suggestive of previous appendicitis, showed that the report so far provides rationale for controlled trials to properly evaluate the possible role of appendicectomy in the treatment of ulcerative proctitis(78).
A.1.5. Autoimmune disease
Non surgical and surgical interventions
The development of ischemic colitis in patients with SLE is an uncommon complication. But widespread fibrinoid vasculitis, typical of SLE, is thought to be a likely predisposing factor. If this vasculitis involves the colon, ischemic colitis occurs. Gastrointestinal vasculitis is one of the most serious complications of SLE, even though the occurrence of colonic lesions is rare (0.2%). The gastrointestinal vasculitis of SLE is consequence of tissue damage from vasculopathy mediated by immune complexes, and has been associated with SLE activity. There are no pathognomic and histopathologic findings in SLE; however, pathologic changes associated with gastrointestinal vasculitis occur in the small vessels of the intestinal wall rather than in medium-sized mesenteric arteries. Ischemic colitis in patients with SLE is caused by decreased blood perfusion of mesenteric vasculatures. The predisposing factors are embolism, thrombosis, vasospasm, drugs (steroids and immunosuppressive agents), vasculitis, performed colonoscopy, and enema. Management of abdominal manifestations of SLE, in the absence of compelling radiographic or clinical findings suggestive of infarction or perforation, are steroid, antibiotics, and fluid therapy, According to the study by the The Catholic University of Korea(79).
B. In Herbal medicine perspective
The aim of herbal treatment is strenghten the immune sytem of the body to fight off the invasion of bacterial causes of the diseases
1. Echinacea, Ashwagandha and Brahmi
Herbs, as food or medicine, can strengthen the body and increase its resistance to illnesses by acting on various components of the immune system. In the study to compare the efficacy of Echinacea, Ashwagandha and Brahmi in strenghten the immune system, showed that Herbal remedies based on Echinacea, Brahmi, or Ashwagandha can enhance immune function by increasing immunoglobulin production. Furthermore, these herbal medicines might regulate antibody production by augmenting both Th1 and Th2 cytokine production(49).
2. Cinnamon
In administration of popular herb used in traditional medicine to treat various disorders such as chronic gastric symptoms, arthritis, and the common cold and its immunomodulatory effect found that observations provided evidence that CWE was able to down-regulate IFN-γ expression in activated T cells without altering IL-2 production, involving inhibition of p38, JNK, ERK1/2, and STAT4, according to the study of "Immunomodulatory effect of water extract of cinnamon on anti-CD3-induced cytokine responses and p38, JNK, ERK1/2, and STAT4 activation" by Lee BJ, Kim YJ, Cho DH, Sohn NW, Kang H. (50)
. Other in the observation of three natural essential oils (i.e., clove bud oil, cinnamon oil, and star anise oil) and their antimicrobal effects found that the cinnamon oil-chitosan film had also better antimicrobial activity than the clove bud oil-chitosan film. The results also showed that the compatibility of cinnamon oil with chitosan in film formation was better than that of the clove bud oil with chitosan, according to the study of "Synergistic Antimicrobial Activities of Natural Essential Oils with Chitosan Films" by Wang L, Liu F, Jiang Y, Chai Z, Li P, Cheng Y, Jing H, Leng X.(51)
3. Green Tea
In the assessment of unregulated activity of these receptors could lead to autoimmune diseases and the effects of green tea catechin, epigallocatechin gallate of the study of "Green tea catechin, epigallocatechin gallate, suppresses signaling by the dsRNA innate immune receptor RIG-I." by Ranjith-Kumar CT, Lai Y, Sarisky RT, Cheng Kao C., researchers found that EGCG and its derivatives could have potential therapeutic use as a modulator of RIG-I mediated immune responses by binding RIG-I and inhibits its signaling at low micromolar concentrations in HEK293T cells(52)
Other In the observation of green tea and rosemary leaf powders on the growth of microorganisms of the study of "Inhibitory effect of commercial green tea and rosemary leaf powders on the growth of foodborne pathogens in laboratory media and oriental-style rice cakes' by Lee SY, Gwon SY, Kim SJ, Moon BK.[13c], researchers indicated that 1 or 3% green tea or rosemary to rice cakes did not significantly reduce total aerobic counts; however, levels of B. cereus and S. aureus were significantly reduced in rice cakes stored for 3 days at room temperature (22 degrees C) and that suggested the use of natural plant materials such as green tea and rosemary could improve the microbial quality of foods in addition to their functional properties(53).
4. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in trditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
In the explore more systematically in various diseases of curcumin's therapeutic promise,
indicated that curcumin may be particularly suited to be developed to treat gastrointestinal diseases. This review summarizes some of the current literature of curcumin's anti-inflammatory, anti-oxidant and anti-cancer potential in inflammatory bowel diseases, hepatic fibrosis and gastrointestinal cancers, according to "Therapeutic potential of curcumin in gastrointestinal diseases" by Rajasekaran SA(54).
Other In the research of a literature search (PubMed) of almost 1500 papers dealing with curcumin, most from recent years, with ll available abstracts were read and pproximately 300 full papers were reviewed, found that curcumin, a component of turmeric, has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NFkappaB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS). Significant preventive and/or curative effects have been observed in experimental animal models of a number of diseases, including arteriosclerosis, cancer, diabetes, respiratory, hepatic, pancreatic, intestinal and gastric diseases, neurodegenerative and eye diseases, "Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases" by Bengmark S(55).
C. In traditional Chinese medicine perspective
1. Xilei-san
Xilei-san is a traditional Chinese herbal medicine that has proven to be of possible use in the treatment of ulcerative proctitis. In the study to compare the efficacy of Xilei-san with dexamethasone enemas in subjects with mild-to-moderate active UP, showed that Xilei-san enemas are comparable to dexamethasone enemas in this study. This medicine is safe, well accepted, and may be an alternative drug in the treatment of mild-to-moderate active UP(56).
2. The Erkang capsule
Shi-Quan-Da-Bu-Tang is a traditional Chinese herbal medicine formula used to increase vital energy, and strengthen health and immunity. The Erkang capsule is a modified formula of Shi-Quan-Da-Bu-Tang, with the addition of four other herbs to increase the adaptogen effects and ergogenic properties. In mice study, the Erkang treated group had significant differences in mortality, body weight change, fatigue, cold temperature endurance, and immune function related organ weight change, compared to the control animals(57).
3. Lingzhi
Reishi mushroom or Lingzhi is a fungal species in the genus Ganoderma, belonging to the family Ganodermataceae, native to Asia. The herb has been use in traditional medicine as anti-caners and anti inflammatory, antioxdant agent and to enhance immune function, treat hepatitis B virus, protect against neuron degeneration, etc. In the demonstration of Ganoderma lucidum, a medicinal fungus is thought to possess and enhance a variety of human immune functions, found that Our current results of analyzing rLZ-8-mediated signal transduction in T cells might provide a potential application for rLZ-8 as a pharmacological immune-modulating agent, according to "Reishi immuno-modulation protein induces interleukin-2 expression via protein kinase-dependent signaling pathways within human T cells" by Hsu HY, Hua KF, Wu WC, Hsu J, Weng ST, Lin TL, Liu CY, Hseu RS, Huang CT(58). Other In the investigation of the water-soluble, polysaccharide components of Reishi (designated as MAK) in murine colitis induced by trinitrobenzene sulphonic acid (TNBS), found that MAK-stimulated PMs produced GM-CSF in a dose-dependent manner. Intestinal inflammation by TNBS was improved by feeding with MAK. MLNs of mice treated with TNBS produced IFN-γ, which was inhibited by feeding with MAK. In contrast, MLNs of mice treated with TNBS inhibited GM-CSF production, which was induced by feeding with MAK and conculded that that the induction of GM-CSF by MAK may provide the anti-inflammatory effect, according to "The water-soluble extract from cultured medium of Ganoderma lucidum (Reishi) mycelia (Designated as MAK) ameliorates murine colitis induced by trinitrobenzene sulphonic acid" by Hanaoka R, Ueno Y, Tanaka S, Nagai K, Onitake T, Yoshioka K, Chayama K(59).
4. Ren Shen
Ren Shen is also known as Gingshen. The smells aromatic, tastes sweet and slightly warm herbs had been used in TCM as improved immune system, Anti Cancer, Anti aging, Anti stress, etc. agent and to generates fluids and reduce thirst, for xinqixu (heart qi deficient) palpitations with instant sweating and anxiety, insomnia, dizziness/headache, forgetfulness, impotence, diabetes, bleeding in the vagina not during period, seizures in children, chronic weakness, etc. as it strongly tonifies Original Qi, tonifies the Spleen and the Lungs, promotes generation of Body Fluids, calms thirs and the Mind, etc. by enhancing the functions of spleen and lung. In the study of Water-soluble ginseng oligosaccharides (designated as WGOS) with a degree of polymerization ranging from 2 to 10 were obtained from warm-water extract of Panax ginseng roots, found that WGOS were potent B and T-cell stimulators and WGOS-1 has the highest immunostimulating effect on lymphocyte proliferation among those purified fractions. It is hoped that the WGOS will be developed into functional food or medicine, according to "Structural characterization and immunological activities of the water-soluble oligosaccharides isolated from the Panax ginseng roots" by Wan D, Jiao L, Yang H, Liu S(60). Other In the evaluation of the extraction conditions of polysaccharides from the rhizomes of Panax japonicus C.A. Meyer and its antioxidant effect found that antioxidant activity exhibited Panax japonicus polysaccharides (PJP) had a good potential for antioxidant, according to "Optimization of polysaccharides from Panax japonicus C.A. Meyer by RSM and its anti-oxidant activity" by Wang R, Chen P, Jia F, Tang J, Ma F(61).
5. Qingre Buyi Decoction
In the study to investigate the efficiency, safety, and possible mechanisms of Qingre Buyi Decoction (QBD) in the treatment of acute radiation proctitis (ARP), showed that Addition of QBD to the conventional treatment can effectively alleviate the damage of intestinal mucosal barrier function and improve all main clinical symptoms and signs of the ARP. The combination of conventional treatment with Chinese herbal medicine QBD is effective and safe for ARP.(62).
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I. Causes and Risk factors
A. Types of Cause of Proctitis
Types of Proctitis are depending to the underlined causes of the diseases
1. Radiation proctitis
The condition is the result of exposure to x-rays or other ionizing radiation
2. Ischemic proctitis
According to the study by the University of Illinois at Chicago/Metropolitan Group Hospitals-St. Francis Hospital, Ischemic injury to the rectum is rare owing to its rich vascular supply, and is seldom seen in clinical practice(1). There is a report of Six patients with acute ischemic proctitis; four cases occurred after direct arterial interruption, one after accidental embolization of the blood supply to the rectum, and one from tumor edema. Bloody diarrhea was the most common symptom. Loss of anal sphincter tone was also an early sign in three patients(2).
3. Ulcerative proctitis
Epidemiological studies have shown that ulcerative proctitis represents 25-55% of ulcerative colitis. In western countries, the incidence of ulcerative proctitis has been increased, while the incidence of more extensive colitis remained unchanged. Ulcerative proctitis has shown to be a benign disease, with a prevalence of local symptoms, less systemic and extraintestinal manifestations, and low endoscopic grades of activity(3).
4. Sexually transmitted proctitis
Gastrointestinal manifestations of sexually transmitted infections (STI) are common. Proctitis, or inflammation of the rectum, has several infectious and non‐infectious causes, the infectious pathogens typically being sexually acquired. Chlamydia, gonorrhoea, herpes simplex virus and syphilis are among the STI that can cause anorectal disease, and more recently outbreaks of less common infections such as lymphogranuloma venereum (LGV)(4).
5. Autoimmune disease
Systemic lupus erythematosus (SLE) is an autoimmune disease, due to the body's immune system mistakenly attacks healthy tissue. Ischaemic colitis is relatively uncommon in systemic lupus erythematosus (SLE). There is a report of a a 38-year-old woman, who presented with haematochezia which subsequently proved to be due to ischaemic proctitis with a large rectal ulcer in a case that was subsequently diagnosed as SLE, according to the study by the Nil Ratan Sircar Medical College(4a).
6. Non-sexually transmitted infection
The classical example of non-sexually transmitted infection occurs in children and is caused by the same bacteria that cause strep throat(4b).
B. Rick factors
1. Low abdominal pain, high inflammatory lesions and an family history
According to the study by Hôpital Pontchaillou, of the Endoscopic information obtained for 52 patients with ulcerative proctitis (23 F, 29 H) seen during a ten-year period. The median follow-up was 68 +/- 8 months, showed that low abdominal pain, an family history of ulcerative colitis, and high inflammatory lesions at referral were significantly associated with a higher risk of extension(5).
2. Young age of onset of symptoms, smoking and appendectomy
According to the study of "Course and natural history of idiopathic ulcerative proctitis in adults" by Università degli Studi di Brescia Cattedra di Chirurgia Generale, Young age of onset of symptoms, smoking and appendectomy are associated with an increased risk of extension of the disease(6).
3. Sexual behavior(7)
a. Men having sex with men (MSM)
Sexually transmitted infection (STI) screening programmes are implemented in many countries to decrease burden of STI and to improve sexual health. In a study of a total of 1455 consultations in MSM showed that the prevalence of C. trachomatis and N. gonorrhoeae per anatomic site was: urethral infection 4.0% respectively and 2.8%, oropharynx 1.5% and 4.2%, and anorectum 8.2% and 6.0%. The majority of chlamydia cases (72%) involved a single anatomic site, which was especially manifest for anorectal infections (79%), while 42% of gonorrhoea cases were single site. Twenty-six percent of MSM with anorectal chlamydia and 17% with anorectal gonorrhoea reported symptoms of proctitis; none of the oropharyngeal infections were symptomatic. Most cases of anorectal infection (83%) and oropharyngeal infection (100%) would have remained undiagnosed with a symptom-based protocol.
b. Others
If you have multiple partners, , don't use condoms and have sex with a partner who has an STI, you are as an increased risk to develop proctitis.
4. Inflammatory bowel diseases
Risk of proctitis is increased with patient with IBD. In the study of a total of 1,255 filled questionnaires received with 96 were rejected and 1,159 (92.3 %), this comprised data on 745 (64.3 %) patients with UC, 409 (35.3 %) with CD, and 5 with indeterminate colitis. The median duration of illness was longer in patients with CD (48 months) compared to those with UC (24 months) (p = 0.002), found that more than one half of patients (UC 51.6 %, CD 56.9 %) had one or more extraintestinal symptoms. A definite family history of IBD was present in 2.9 % (UC 2.3 % and CD 4.6 %; p = 0.12). The extent of disease in UC was pancolitis 42.8 %, left-sided colitis 38.8 %, and proctitis alone in 18.3 %(8).
5. Cancer radiation therapy
According to the study by the University of Minnesota Hospital and Clinics, a high posterior rectal dose (> 5,000 cGy) is associated with increased prevalence of proctitis after radiation therapy(9).
6. Socioeconomic factors, dietary and other personal habits, and medical history
In the study of the risk factors for extensive ulcerative colitis and ulcerative proctitis of a total of 167 (98%) of all prevalent cases of ulcerative colitis diagnosed in Uppsala county from 1945 to 1964 and 167 age and sex matched population, showed that ulcerative colitis patients were less likely than controls to be current cigarette, pipe, or cigar smokers (odds ratio (OR) = 0.44; 95% confidence limits (CL) = 0.25-0.78), but more likely to have symptoms induced by drinking milk (OR = 4.63; 95% CL = 2.15-9.93). Patients with ulcerative colitis do not differ in most of the socioeconomic, dietary and personal habits compared with the background population(10).
7. Frequent fecal impactions
Frequent fecal impactions without proper treatment are associated toincreased risk of proctitis, according to the study by the Ohio University(10a).
II. Symptoms
1. Rectal bleeding and anal discomfort
There is a report of a A 45-year-old man was referred to our surgical clinic for investigation of rectal bleeding and anal discomfort. is a sexually transmitted infection caused by Chlamydia trachomatis. There are few reports describing rectal stricture as a late complication of chronic proctitis associated with lymphogranuloma venereum (LGV) infection. Lymphogranuloma venereum (LGV)proctitis is often mild, but chronic cases can be associated with serious complications. If LGV is misdiagnosed or partially treated, the natural history of chronic long-lasting inflammation of the rectum may include the development of fissures, perianal abscess and strictures of the rectum(11).
2. Change of Singapore General Hospital
According to the Singapore General Hospital study of review, 77 patients were admitted for the treatment of radiation proctitis, with a median follow-up period of 14 (range 1-61) months. There were 23 male and 54 female patients, with a median age of 63.9 (range 37-89) years, the most common presenting symptom was bleeding per rectum (89.6 percent), with a change in bowel habits a distant second (10.4 percent)(12).
2. Constipation
There is a report of a 72-year-old white woman presenting with a large abdominal mass, who had at least 4 episodes of radiographically demonstrated fecal impaction over the previous year without adequate treatment. The patient required hospitalization for a bleeding rectal ulcer during the second episode of fecal impaction. Computed tomography (CT) scans on this admission revealed a dilated colon up to 16 x 14 cm in maximal dimensions extending over 30 cm, filled with massive fecal material, according to the study by the College of Osteopathic Medicine, Ohio University, Athens(13).
3. Urgency, diarrhea, and tenesmus
According to the study of 50 patients to compare colonic irrigation and oral antibiotics (irrigation group) versus 4% formalin application (formalin group) for treatment of hemorrhagic radiation proctitis by Chulalongkorn University, Bangkok, showed that treatment with daily self-administered colonic irrigation with 1 L of tap water and a 1-week period of oral antibiotics (ciprofloxacin and metronidazole) indicated a a significant improvement in rectal bleeding and bowel frequency in both treatment groups, but significant improvement in urgency, diarrhea, and tenesmus was demonstrated only in the irrigation group(15).
4. Anorectal pain, discharge and change in stool frequency
The University Hospital, Zurich, Switzerland report a study since 2003, there are twelve cases of proctitis, all in men having sex with men (MSM), caused by the LGV serovar L2 C. In the observation of trachomatis, of the overall 11 patients the majority were HIV positive and only 2 were HIV negative. Only one patient reported previous sexual contacts outside Europe (Thailand) as the likely place of infection. The clinical presentation was characterised by anorectal pain, discharge, tenesmus and change in stool frequency(16).
5. Blood in stool
In most cases, blood in stool is presented for patient with ulcerative proctitis.
6. Ulcers, and occasionally lymphadenopathy and fever
Symptoms of infectious proctitis can include rectal blood and mucous discharge, anorectal pain, ulcers, and occasionally lymphadenopathy and fever, according to the study by the University of Chicago Medical Center(14)
IV. Complications and diseases associated with Proctitis
A. Complications
A.1. Diseases complications
1. Intractable bleeding, intestinal obstruction or intra-abdominal sepsis
In the review of 77 patients admitted for the treatment of radiation proctitis, with a median follow-up period of 14 (range 1-61) months. There were 23 male and 54 female patients, with a median age of 63.9 (range 37-89) years.the majority of the patients (72.5 percent) received non-surgical treatment, most commonly using topical 4 percent formalin solution to arrest the bleeding, with more than half the patients requiring repeat treatments. 14 (18.2 percent) patients required colorectal resections for intractable bleeding, intestinal obstruction or intra-abdominal sepsis(17).
2. Syphilis
There is a first report of a case of with simultaneous manifestations of proctitis, gastritis, and hepatitis. The diagnosis of syphilitic proctitis and gastritis was established by the demonstration of spirochetes with anti-Treponema pallidum antibody staining in biopsy specimens. Unusual manifestations of secondary syphilis completely resolved after 4 weeks of antibiotic therapy(18).
3. Bleeding areas in the rectum, internal and/or external hemorrhoids
According to the study by, Surgeons are appropriately concerned about using conventional methods of treatment in patients with radiation proctitis, such as cautery for complications of bleeding areas in the rectum, rubber band ligation, or excision of internal and/or external hemorrhoids, for fear of poor healing and possible exacerbation of the original problem(19).
4. Comstipation
According to the study by University La Sapienza, constipation in ulcerative proctitis (UP), may be correlated with rectal fibrosis, which reduces the transit of stools from the left colon. The concomitance of asymptomatic anorectal organic or functional alteration may contribute to worsen constipation(20).
5. Increased irritation to the anal and rectal area in patients with proctitis.
6. Etc.
A.2. Complications after treatment
1. Formalin installation treatment
Inn the study to evaluate the results of formalin installation treatment in terms of outcome and complications with a solution of 4% formalin was introduced in aliquots of 50 ml kept in contact with the mucosa for 30 s and then cleared away using saline irrigation; five to six aliquots were used in each session, showed that in a mean follow-up of 18 months (range 6-26), two patients had repeat episodes of bleeding, one underwent successful repeat irrigation, and the other refused further treatment. One patient suffered from severe anococcygeal pain and worsening of incontinence after the procedure. The pain was treated with lidocaine ointment and sitz baths with partial success. Another patient developed severe formalin-induced colitis 5 days after the procedure, which required intravenous antibiotics and hydration. Formalin installation may be effective in controlling refractory bleeding due to radiation induced proctitis(21).
2. Systemic isotretinoin therapy
Isotretinoin's best-known and most dangerous side effect is birth defects due to in utero exposure. There is a report of complications of anal fissure, rectal bleeding and proctitis with the systemic isotretinoin therapy(22).
3. Etc.
B. Diseases associated with Proctitis
1. Inflammatory bowel diseases (IBD) and sexual transmitted infections
Proctitis is a common problem and is most frequently associated with inflammatory bowel diseases (IBD). However, in the last ten years the incidence of infectious proctitis appears to be rising, especially in men who have sex with men. This may be due to the rise of people participating in receptive anal sex as well as the increase in sexually transmitted infections, such as those from Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex virus and Treponema pallidum. Recent outbreaks of lymphogranuloma venereum among homosexual men throughout Europe highlight the need to consider sexually transmitted infections in the differential diagnosis of proctitis, according to the study by the University of Florence(23).
2. Procitis associated with chlamydial infection
According to the University of Sydney, New South Wales. an aged koala presented for euthanasia was found to have asymptomatic chronic proctitis, cystitis, prostatitis, urethritis and conjunctivitis associated with chlamydial infection. Inflammation was severe in the terminal rectum and extended into the proximal common vestibule. Chlamydial organisms were visualised in the rectal surface epithelium using Giminez' stain and an immunoperoxidase staining method. Organisms were also detected in the epithelium of the bladder, prostate and urethra(24). Other in the study to investigate the prevalence and genotype distribution of Chlamydia trachomatis infection among men who have sex with men (MSM), 145 MSM from two sauna settings in Shenzhen, China were invited to participate in this study during September 2008 and May 2009, showed that the prevalence of anorectal chlamydial infection was 24% in the study population and was significantly associated with proctitis symptoms(25).
3. Human immunodeficiency virus infection
There is a report of a of published cases and a recently managed patient is presented, which describes the clinical features of cytomegalovirus proctitis. About half of the reports describe sexually transmitted cytomegalovirus proctitis following anal intercourse, which typically presents with rectal bleeding and a mononucleosis-like syndrome. This condition resolves spontaneously and may be associated with human immunodeficiency virus infection(26).
4. Immune-mediated diseases
In the study to to evaluate the prevalence of pANCA expression and its association with clinical findings and disease course in Korean patients with UC, included 484 patients with UC who were diagnosed and treated between 1990 and 2006 at Severance Hospital, Yonsei University, Seoul, Korea, showed that the prevalence of pANCA expression in Korean patients with UC was relatively low compared to that in Western countries. Although UC patients with pANCA expression had more severe clinical findings at diagnosis and higher cumulative relapse rates in our study, further prospective studies are warranted to clarify whether pANCA positivity influences the initial clinical presentation or disease aggressiveness(27).
5. Hermansky Pudlak syndrome
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder consisting of oculocutaneous albinism, platelet dysfunction and systemic complications associated with lipofuscin deposition in the reticuloendothelial system. According to Auxilio Mutuo Hospital, Rio Piedras, there is a report of a series of two patients with HPS treated in Puerto Rico, and the results from medical and surgical intervention for gastrointestinal disease. Our experience with HPS patients has shown the difficult management of perineal disease similar in the management of Crohn's. However, complications from the bleeding diathesis necessitate caution during surgery and potential anesthesia complications(28).
6. Crohn's disease
There is a report of four patients with Crohn's disease who underwent fecal diversion with an in situ rectum were observed in whom sigmoidoscopy was initially normal at the time of the diversion, became distinctly abnormal during the year after the diversion, and then returned to normal within 3 mo following reestablishment of intestinal continuity. The entity of nonspecific diversion proctitis might account for this phenomenon independently or by accelerating the Crohn's disease process, according to the study(29).
7. Etc.
V. Misdiagnosis and Diagnosis
A. Misdiagnosis
1. Hirschsprung's disease
Allergic proctitis and abdominal distention mimicking Hirschsprung's disease in infants.In the study to determine the incidence and clinical aspects of allergic proctitis (AP) in infants with symptoms that mimic Hirschsprung's disease (HD), found that in the infants with severe abdominal distention, the incidence of AP mimicking HD was relatively high. Therefore, consideration of AP should be part of the differential diagnosis in infants with severe abdominal distention or findings that mimic HD. For differentiation of these disorders, a rectal suction biopsy is very useful.In the infants with severe abdominal distention, the incidence of AP mimicking HD was relatively high. Therefore, consideration of AP should be part of the differential diagnosis in infants with severe abdominal distention or findings that mimic HD. For differentiation of these disorders, a rectal suction biopsy is very useful(30).
2. Diffuse cavernous haemangioma of the rectum (DCHR)g masquerading
Diffuse cavernous haemangioma of the rectum (DCHR) is a rare benign vascular neoplasm that affects mainly young adults and can present with rectal bleeding or massive haemorrhage. There is a report of a case of DCHR masquerading as proctitis which was diagnosed many years ago following colonoscopy, according to St. George's Hospital NHS Trust, London(31).
3. Colitis cystica profunda and solitary rectal ulcer syndrome-polyoid variant
Colitis cystica profunda and solitary rectal ulcer syndrome-polyoid variant are related chronic benign disorders with characteristic histological features. There is a report of a case of colitis cystica profunda and solitary rectal ulcer syndrome-polypoid variant that was misdiagnosed initially as an ulcerative proctitis, according to the study by Ben-Gurion University of the Negev, Beer-Sheva, Israel(32).
4. Rectal strictures
Rectal strictures are uncommon in young patients without a history of malignancy, inflammatory bowel disease or previous surgery. It presents with nonspecific symptoms, rectal ulcer, proctitis, anal fissures, abscesses and rectal strictures. Clinical and endoscopic findings as well as histology resemble Crohn's disease, which may be misdiagnosed/ According to the study by King's College Hospital, rectal lymphogranuloma venereum is a rare cause of rectal strictures but surgeons should be aware of its existence and include it in the differential diagnosis of unexplained strictures in high-risk patients(33).
5. Etc.
B. Diagnosis
1. Stool sample
The aim of the stool examination is to find out types of bacterial causes of infection.
Unfornunately, Non-invasive diagnostic tools to evaluate the severity of acute, radiation-induced proctitis are not readily available, but faecal calprotectin and lactoferrin concentrations could be markers of acute, radiation-induced proctitis(34).
2. Blood test
The aim of the blood test is also to determine the types of infection as well as blood loss
3. Proctoscopy
Proctoscopy procedure in which yuor doctor insert a thin tube containing a camera and a light to visually inspect to look for sign of proctitis. In a prospective study of 130 patients who underwent external radiation therapy (RT) for stage T1 to T4 prostate cancer between 1997 and 2008, to determine the Role of Early Proctoscopy in Predicting Late Symptomatic Proctitis After External Radiation Therapy for Prostate Carcinoma, Proctoscopy showed that In patients with acute endoscopic proctitis (AEP) and Acute clinical proctitis (ACP), the risk of late clinical proctitis (LCP) was more than 5-fold increased compared to those who were asymptomatic, while a much smaller increase in risk occurred in patients with ACP only. Early proctoscopy can provide valuable information regarding the likelihood of late(35).
4. Rectal culture
Rectal culture is the laboratory test of normally involves a swab of patients rectum with an aim to determine types of bacterial causes of proctitis.
5. Rectal microscopy
The Microstructure imaging of human rectal mucosa may be helpful in determination the causes of the disease. According to the study by the Urinary Medicine, Mortimer Market Centre, in all, 134/136 had rectal microscopy of whom, 47/134 (35%) were smear-positive for Rectal gonorrhoea (GC) . Of the 136 cases, 90 received antibiotics for GC at their first presentation. Twenty-four of 90 (27%) would not have been treated until culture results were available, if rectal microscopy had not been performed. The results suggest that rectal microscopy remains an important tool and increases the proportion of men treated for GC at their first attendance(36).
6. Sigmoidoscopy
Sigmoidoscopy is a procedure of using a flexible tube called a sigmoidoscope with a small camera attached to the end placed through the anus and gently moved into your colon for examination of up to the sigmoid. Dr. McMillan A. in the study to to assess the value of sigmoidoscopy in the routine investigation of homosexual men, this procedure was undertaken on 1118 men who attended a sexually transmitted diseases clinic as "new" or "return new" patients, indicated that Serious rectal disease was not identified in any of the 557 men who were symptomless at the initial attendance. Though the extent of the proctitis diagnosed in 166 men would not have been defined, 99% (465) of 470 anorectal lesions would have been identified if proctoscopy alone had been performed. It is concluded that sigmoidoscopy does not have a role in the routine investigation of homosexual men(37).
VI. Preventions
A. Diet to prevent Proctitis
1. Black and green tea
Gallocatechin, containing catechin is phytochemicals of Flavan-3-ols, in the group of Flavonoids (polyphenols), found abundantly in green and black tea. In the evaluation of the anti-inflammatory and antimicrobial effect of nanocatechin on CBP and plasma concentration of catechins in an animal model, found that the use of ciprofloxacin, catechin, and nanocatechin showed statistically significant decrease in bacterial growth and improvement in prostatic inflammation compared with the control group. The nanocatechin group showed statistically significant decrease in bacterial growth and improvement in prostatic inflammation compared with the catechin group. Plasma concentrations of epicatechin, gallocatechin gallate, and epigallocatechin gallate were significantly higher in the nanocatechin group than those in the catechin group. These results suggest that nanocatechin has better antimicrobial and anti-inflammatory effects on rat CBP than catechin due to higher absorption into the body, according to "Anti-inflammatory and antimicrobial effects of nanocatechin in a chronic bacterial prostatitis rat model" by Yoon BI, Ha US, Sohn DW, Lee SJ, Kim HW, Han CH, Lee CB, Cho YH(38).
Other In the identification of tea polyphenols were evaluated for their ability to inhibit enterovirus 71 (EV71) replication in Vero cell culture, found that The viral inhibitory effect correlated well with the antioxidant capacity of polyphenol. Mechanistically, EV71 infection led to increased oxidative stress, as shown by increased dichlorofluorescein and MitoSOX Red fluorescence. Upon EGCG treatment, reactive oxygen species (ROS) generation was significantly reduced. Consistent with this, EV71 replication was enhanced in glucose-6-phosphate dehydrogenase deficient cells, and such enhancement was largely reversed by EGCG, according to "Antiviral effect of epigallocatechin gallate on enterovirus 71" by Ho HY, Cheng ML, Weng SF, Leu YL, Chiu DT(39).
2. Apple skin
Quercetin is a member of flavonoids, found abundantly in apple skin It is also one of antioxidants with property of protecting our body in fighting against forming of free radicals cause of mutation of cells`DNA. According to the study of `Antimicrobial and cytotoxic activities of leaves, twigs and stem bark of Scutia buxifolia Reissek.`by Boligon AA, Janovik V, Frohlich JK, Spader TB, Forbrig Froeder AL, Alves SH, Athayde ML. (Source from a Phytochemical Research Laboratory, Department of Industrial Pharmacy , Federal University of Santa Maria , Build 26, room 1115 , Santa Maria , CEP 97105-900 , Brazil.), posted in PubMed, researchers found that quercitrin, isoquercitrin and rutin were identified by HPLC and may be partially responsible for the antimicrobial activities observed. This study reports for the first time the antimicrobial and cytotoxic activities of S. buxifolia leaves, twigs and stem bark.
Also according to the study of `Antioxidant and Anti-Inflammatory Activities of Quercetin 7-O-β-D-Glucopyranoside from the Leaves of Brasenia schreberi.`by Legault J, Perron T, Mshvildadze V, Girard-Lalancette K, Perron S, Laprise C, Sirois P, Pichette A. (Source from Laboratory for Analysis and Separation of Plant Species (LASEVE), Université du Québec à Chicoutimi , Chicoutimi, Québec, Canada.), posted in PubMed, researchers found that some flavonoids have been reported to possess beneficial effects in cardiovascular and chronic inflammatory diseases associated with overproduction of nitric oxide. Quercetin-7-O-β-D-glucopyranoside possesses anti-inflammatory activity, inhibiting expression of inducible nitric oxide synthase and release of nitric oxide by lipopolysaccharide-stimulated RAW 264.7 macrophages in a dose-dependent manner. Quercetin-7-O-β-D-glucopyranoside also inhibited overexpression of cyclooxygenase-2 and granulocyte macrophage-colony-stimulating factor.
3. Tomatoes
Tomato is a red, edible fruit, genus Solanum, belongs to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose
and often in green house. Tomato is considered as antiseptic natural foods including natural antiseptic agent ascorbic acid that helps to enhance the immune system in guarding our body against the possibility of infection, sepsis, or putrefaction, according to the article of "The 7 Benefits Of Drinking Lemon Water" posted in Simple Health Cures. Other study indicated that Lycopene, one of the powerful antioxidant in tomatoes, not only helps the immune system in neutralizing the forming of free radicals in the body and according to Harvard investigation as it found that men who ate more than 10 servings tomato-based foods daily (like cooked tomatoes and tomato sauce,) had a 35 percent lower risk of developing prostate cancer than those who ate the least amount of these foods. The benefits of lycopene was more pronounced with advanced stages of prostate cancer. Also according to the study of "Chemoprevention of prostate cancer with lycopene in the TRAMP model" by Konijeti R, Henning S, Moro A, Sheikh A, Elashoff D, Shapiro A, Ku M, Said JW, Heber D, Cohen P, Aronson WJ., posted in PubMed(40)
4. Fennel
Fennel is a species of Foeniculum Vulgare, belong to the family Apiaceae (Umbelliferae), and native to to the shores of the Mediterranean. It is now widely cultivated all around the globe to use as food and herb. In the determination of the chemical compositions of the essential oil and hexane extract isolated from the inflorescence, leaf stems, and aerial parts of Florence fennel found that the essential oil, anethole, and hexane extract were effective against most of the foodborne pathogenic, saprophytic, probiotic, and mycotoxigenic microorganisms tested. The results of the present study revealed that (E)-anethole, the main component of Florence fennel essential oil, is responsible for the antimicrobial activity , according to "Antimicrobial activities of essential oil and hexane extract of Florence fennel [Foeniculum vulgare var. azoricum (Mill.) Thell.] against foodborne microorganisms" by Cetin B, Ozer H, Cakir A, Polat T, Dursun A, Mete E, Oztürk E, Ekinci M(41).
Other In the study of fennel honey, ethanol, and aqueous propolis extracts orally and theirs effect on immune defense found that all tested previously bee product-immunized rats could significantly challenge the induced S. aureus infection (P < .01). The effects were more pronounced in rats that had received fennel honey solution, according to "Immune defense of rats immunized with fennel honey, propolis, and bee venom against induced staphylococcal infection" by Sayed SM, Abou El-Ella GA, Wahba NM, El Nisr NA, Raddad K, Abd El Rahman MF, Abd El Hafeez MM, Abd El Fattah Aamer A(42).
B. Phytochemicals and antioxidants to prevent Proctitis
1. Theaflavin-3-gallate
Theaflavin-3-gallate, a theaflavin derivative, is phytochemicals of Flavan-3-ols, in the group of Flavonoids (polyphenols) found abundantly in black tea. In the comparison of TF derivatives (theaflavin (TF(1)), theaflavin-3-gallate (TF(2)A), theaflavin-3'-gallate (TF(2)B), and theaflavin-3,3'-digallate (TF(3))) in scavenging reactive oxygen species (ROS) in vitro, indicated that positive antioxidant capacities of TF(2)B on singlet oxygen, hydrogen peroxide, hydroxyl radical, and the hydroxyl radical-induced DNA damage in vitro were found, according to "Evaluation of the antioxidant effects of four main theaflavin derivatives through chemiluminescence and DNA damage analyses" by Wu YY, Li W, Xu Y, Jin EH, Tu Y(43).
Other In the evaluation of the antimicrobial activities of seven green tea catechins and four black tea theaflavins, found that (-)-gallocatechin-3-gallate, (-)-epigallocatechin-3-gallate, (-)-catechin-3-gallate, (-)-epicatechin-3-gallate, theaflavin-3, 3'-digallate, theaflavin-3'-gallate, and theaflavin-3-gallate showed antimicrobial activities at nanomolar levels; (ii) most compounds were more active than were medicinal antibiotics, such as tetracycline or vancomycin, at comparable concentrations; (iii) the bactericidal activities of the teas could be accounted for by the levels of catechins and theaflavins as determined by high-pressure liquid chromatography; (iv) freshly prepared tea infusions were more active than day-old teas; and (v) tea catechins without gallate side chains, gallic acid and the alkaloids caffeine and theobromine also present in teas, and herbal (chamomile and peppermint) teas that contain no flavonoids are all inactive, according to "Antimicrobial activities of tea catechins and theaflavins and tea extracts against Bacillus cereus" by Friedman M, Henika PR, Levin CE, Mandrell RE, Kozukue N(44).
2. Allyl sulfides
Garlic has been used in traditional Chinese and herbal medicine over thousands of year as antibacterial, antiviral, and antifungal agent and in treating other conditions such as parasites, respiratory problems, poor digestion, low energy, etc. In many studies, researchers found that Allyl sulfides, a phytochemical in garlic has been demonstrated effectively in treating certain diseases.
According to the article of "GARLICTHE BOUNTIFUL BULB" by Carmia Borek, Ph.D. posted in Life extension magazine, the author indicated that human studies confirm immune stimulation by garlic. Subjects receiving aged garlic extract at 1800 mg a day for three weeks showed a 155.5% increase in natural killer immune cell activity that kills invaders and cancer cells. Other subjects receiving large amounts of fresh garlic of 35g a day, equivalent to 10 cloves, showed an increase of 139.9%. In six weeks, patients with AIDS receiving aged garlic extract showed an enhancement of natural killer cells from a seriously low level to a normal level.
3. Piperine
Piperine is a phytochemical alkaloid in the class of organosulfur compound, found abundantly in white and black pepper, long pepper, etc. In the valuation of novel synthetic analogues of piperine as inhibitors of multidrug efflux pump NorA of Staphylococcus aureus, showed that a newly identified class of compounds derived from a natural amide, piperine, is more potent than the parent molecule in potentiating the activity of ciprofloxacin through the inhibition of the NorA efflux pump. These molecules may prove useful in augmenting the antibacterial activities of fluoroquinolones in a clinical setting, according to "Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus" by Ashwani Kumar, Inshad Ali Khan, Surrinder Koul, Jawahir Lal Koul, Subhash Chandra Taneja, Intzar Ali, Furqan Ali, Sandeep Sharma, Zahid Mehmood Mirza, Manoj Kumar, Pyare Lal Sangwan, Pankaj Gupta, Niranjan Thota and Ghulam Nabi Qazi(45)
Other In the investigation of investigate the anti-inflammatory effect of piperine against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis and compared it with that of the non-steroidal anti-inflammatory drug indomethacin, found that Histopathological analysis of joints also revealed that synovial hyperplasia and mononuclear infiltration observed in arthritic rats were alleviated by piperine. Thus, the present study clearly indicated that piperine possesses promising anti-inflammatory effect against adjuvant-induced arthritis by suppressing inflammation and cartilage destruction, according to "Anti-inflammatory Effect of Piperine in Adjuvant-Induced Arthritic Rats-a Biochemical Approach" by Murunikkara V, Pragasam SJ, Kodandaraman G, Sabina EP, Rasool M(46).
4. Sinigrin
Sinigrin is a phytochemical glucosinolate, belongs to the family of glucosides found abundantly in Brussels sprouts, broccoli, the seeds of black mustard, etc. In the investigation of Allyl isothiocyanate (AIT) derived from the glucosinolate sinigrin found in plants of the family Brassicaceae and its antimicrobial agent against a variety of organisms, including foodborne pathogens such as Escherichia coli O157:H7, found that it can be postulated that: 1) AIT is a more effective antimicrobial at low pH values and its degradation reduces this activity; 2) decomposition products in water might not participate in the antimicrobial action of AIT; and 3) AIT seems to have a multi-targeted mechanism of action, perhaps inhibiting several metabolic pathways and damaging cellular structures, according to "Enzymatic inhibition by allyl isothiocyanate and factors affecting its antimicrobial action against Escherichia coli O157:H7" by Luciano FB, Holley RA(47).
Other In the examination of the effect of an aqueous extract of cooked Brussels sprouts on formation of 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in calf thymus DNA in vitro, found that Sinigrin, a glucosinolate abundant in Brussels sprouts, co-eluted with the most effective fraction and had DNA protective effects. In comparison with other antioxidants the patterns of effect of the extract in the five damage systems were more similar to that of sodium azide than to those of dimethylsulfoxide and vitamin C, according to "Inhibition of oxidative DNA damage in vitro by extracts of brussels sprouts" by Zhu C, Poulsen HE, Loft S(48).
VI. Treatments
A. In conventional medicine perspective
Medical treatment of proctitis depends on the etiology
A.1. Radiation proctitis
A.1.1. Acute radiation proctitis
Acute radiation proctitis usually does not require treatment as the diseases can resolve after several months. Topical mesalazine is contraindicated during radiotherapy. Hydrocortisone enema is not superior to sucralfate in preventing acute rectal toxicity.. According to the study to assess whether the topical use of steroids or 5-aminosalicylic acid (5-ASA) is superior to sucralfate in preventing acute rectal toxicity during three-dimensional conformal radiotherapy (3DCRT) to 76 Gy(63),
A.1.2. Chronic radiation proctitis
Chronic radiation proctitis is the result of damage to the blood vessels which supply the colon due to radiotherapy.
1. Non surgical interventions
Chronic radiation proctitis (inflammation of the rectum) may develop after the completion of pelvic radiotherapy. In Studies (preferentially randomised controlled trials) of interventions for the non-surgical management of late radiation proctitis in patients who have undergone pelvic radiotherapy as part of their cancer treatment, indicated that Late radiation complications are a relatively rare manifestation, with many potential carers and poor diagnostic criteria. Although certain interventions look promising and may be effective (such as rectal sucralfate, adding metronidazole to the anti-inflammatory regime and heater probes), single small studies (even if well conducted) provide insufficient evidence(64).
2. Surgical interventions
a. Cryospray Ablation
Radiation proctitis, a common condition associated with radiotherapy for the treatment of pelvic cancers, is characterized by difficult to manage rectal pain and bleeding. According to the study by the Uniformed Services University of the Health Sciences, Cryotherapy is an effective method in the management of chronic radiation proctitis with minimal complications(65).
b. Radio frequency ablation (RFA)
Radiation proctitis is a frequent complication of pelvic radiation for cancer. There is a report of a case of refractory radiation proctitis, with suboptimal response to other therapies, treated successfully with a novel method, radiofrequency ablation(66).
A.2. Ischemic proctitis
A.2.1. Acute ischemic proctitis
1. Non surgical interventions, include
a. Superficial mucosal ischemia
Superficial mucosal ischemia was treated without surgery, but deeper levels of necrosis required laparotomy and Hartmann's resection. Rectal excision was not necessary. Four patients survived the ischemic event(67).
b. Formalin instillation
Topical (4 percent) formalin is safe and effective in treatment of radiation-induced hemorrhagic proctitis. A single treatment will stop bleeding in 75 percent of patients(68). Other study also indicated that there is a case of an elderly male with multiple medical problems and hemorrhagic, ischemic proctitis is presented. The proctitis was refractory to all other medical options but responded to topical instillation of 4 percent formalin(69).
2. Surgical interventions include
a. Proctectomy
There is a report of four cases of acute ischemic proctitis that required complete proctectomy. All patients had large vessel atherosclerosis with rectal bleeding and sepsis as the presenting signs and symptoms. Three of four patients underwent complete proctectomy as the initial procedure. The fourth patient underwent complete proctectomy five days after the initial intervention. Two of four patients survived and were ultimately discharged from the hospital. A third patient recovered from surgery but ultimately died of respiratory complications. Only the patient who was initially treated by subtotal proctectomy died as the result of the disease. Although ischemic necrosis of the rectum is rare, complete proctectomy may be necessary to save the patient's life(70).
b. Transcatheter embolization
In the study of treatment of lower gastrointestinal bleeding was attempted in 13 patients by selective embolization of branches of the mesenteric arteries with Gelfoam, showed that One patient improved after embolization but bleeding recurred within 24 hours and in another patient the catheterization was unsuccessful. Five patients with diverticular hemorrhage were embolized in the right colic artery four times, and once in the middle colic artery. Three patients had embolization of the ileocolic artery because of hemorrhage from cecal angiodysplasia, post appendectomy, and leukemia infiltration. Three patients had the superior hemorrhoidal artery embolized because of bleeding from unspecific proctitis, infiltration of the rectum from a carcinoma of the bladder, and transendoscopic polypectomy(71).
A.2.2. Chronic ischemic proctitis
1. Non surgical treatments
In the study to identify the various non-surgical treatment options for the management of late chronic radiation proctitis and evaluate the evidence for their efficacy, showed that Sixty-three studies met the inclusion criteria, including six randomised controlled trials that described the effects of anti-inflammatory agents in combination, rectal steroids alone, rectal sucralfate, short chain fatty acid enemas and different types of thermal therapy(72).
2. Surgical interventions include
1. Laparoscopic colorectal surgery
In the study to assess the outcome of laparoscopic colorectal surgery in patients >60 years of age and compare it to a younger group of patients who underwent similar procedures, indicated that here were no statistically significant differences between the younger and older groups relative to the incidence of complications (11 vs 14%, respectively) and conversion (8 vs 11%, respectively) or the length of ileus (2.8 vs 4.2 days, respectively) or hospitalization (5.2 vs 6.5 days, respectively) (P = NS for all). There was no mortality in either group. The outcome of laparoscopic colorectal surgery in older patients is similar to that noted in younger patients. Advanced age should not be a contraindication to laparoscopic colorectal surgery(73).
2. Laparoscopic or laparoscopic-assisted colorectal operations
There were 140 laparoscopic and laparoscopic-assisted procedures performed between May 1991 and January 1995. The mean patient age was 48 (range 12-88) years; there were 78 males and 62 females. Indications for surgery included inflammatory bowel disease in 47, colorectal carcinoma in 19, diverticular disease in 17, polyps in 16, familial polyposis in 7, colonic inertia in 7, fecal incontinence in 11, sigmoidocele in 3, irradiation proctitis in 3, rectal prolapse in 2, intestinal lymphoma in 2, and miscellaneous conditions in 6. The procedures included 38 total abdominal colectomies (TAC) (ileoanal reservoir 28, ileorectal anastomosis 8 and end ileostomy 2); 70 segmental resections of the colon, small bowel, and rectum(74)
A.1.3. Ulcerative proctitis
1. Non surgical treatments
Ulcerative proctitis is an important and increasingly common subcategory of ulcerative colitis (UC) in which inflammation is limited to the rectum. According to the study by the McGill University Health Centre, treatment options include the oral and/or rectal 5-aminosalicylate (5-ASA) preparations. Rectal therapy delivering higher concentrations of active medication (5-ASA or glucocorticoids) directly to the inflamed mucosa while minimizing systemic absorption provides a highly effective and safe treatment. Oral glucocorticoids are indicated in patients who are resistant to or intolerant of 5-ASA therapy. Immunomodulators have an important role in individuals with glucocorticoid dependent or glucocorticoid refractory disease(75).
2. Surgical treatments
In case of severity, surgery may be necessary. According to the study by the, Severe UC is defined as more than 6 bloody stools per day and signs of systemic involvement (fever, tachycardia, anemia). These patients should be hospitalized for intensive treatment and surveillance (ECCO EL 5, RG D) as the development of a toxic megacolon and perforation is a potentially life-threatening condition. Intravenous steroids (e.g. methylprednisolone 60 mg/d or hydrocortisone 400 mg/d) remain the mainstay of conventional therapy to induce remission (ECCO EL 1b, RG D; DGVS C). Patients refractory to maximal oral treatment with prednisolone and 5-ASA can be given the tumor necrosis factor (TNF)-α blocker IFX at 5 mg/kg (ACG EL A). Nevertheless, colectomy rates are as high as 29% in patients with severe UC and who need intravenous corticosteroids. They should therefore be presented to the colorectal surgeon on the day of admission. It is crucial that gastroenterologists and surgeons provide joint daily care in order to avoid delaying the necessary surgical therapy(76).
A.1.4. Sexually transmitted proctitis
1. Non surgical interventions(77)
Treatment can be started empirically while awaiting the microbiological results, thus reducing inflammation, infection duration and hence infectivity of the patient. The appropriate treatment of sexually transmitted proctitis has important implications in the control of HIV by reducing both HIV transmission and susceptibility.
a. Azithromycin (1 g as a single dose) or doxycycline (100 mg twice daily for a week) is an effective treatment for chlamydia.
b. HIV‐positive men with proctitis should be treated for LGV in the first instance. The preferred treatment is doxycycline 100 mg twice daily for 3 weeks; erythromycin may be used as an alternative.
c. Homosexual men with symptomatic rectal chlamydia should be given LGV treatment until the serovar is determined.
d. The treatment of gonorrhoea depends on local guidelines, based on surveillance of resistance patterns of the organism. A minimum criterion is that at least 95% of gonorrhoea prevalent in a population should be susceptible to the antibiotic used
e. Patients with recurrent symptoms of HSV may benefit from long‐term suppressive treatment. Early syphilis is treated with intramuscular procaine penicillin (10 days) or benzathine penicillin (2.4 g as a single dose). Doxycycline can be used in patients allergic to penicillin (100 mg twice daily for 2 weeks). Longer courses of antibiotics are used for latent syphilis.
2. Surgical interventions include Appendicectomy
In the report of a prospective case series of 30 adult patients (median age 35 years, range 17-70 years; male/female: 11/19) with ulcerative proctitis (median duration of symptoms 5 years, range 8 months to 30 years; median Simple Clinical Colitis Activity Index score 9, range 7-12), who underwent appendicectomy in the absence of any history suggestive of previous appendicitis, showed that the report so far provides rationale for controlled trials to properly evaluate the possible role of appendicectomy in the treatment of ulcerative proctitis(78).
A.1.5. Autoimmune disease
Non surgical and surgical interventions
The development of ischemic colitis in patients with SLE is an uncommon complication. But widespread fibrinoid vasculitis, typical of SLE, is thought to be a likely predisposing factor. If this vasculitis involves the colon, ischemic colitis occurs. Gastrointestinal vasculitis is one of the most serious complications of SLE, even though the occurrence of colonic lesions is rare (0.2%). The gastrointestinal vasculitis of SLE is consequence of tissue damage from vasculopathy mediated by immune complexes, and has been associated with SLE activity. There are no pathognomic and histopathologic findings in SLE; however, pathologic changes associated with gastrointestinal vasculitis occur in the small vessels of the intestinal wall rather than in medium-sized mesenteric arteries. Ischemic colitis in patients with SLE is caused by decreased blood perfusion of mesenteric vasculatures. The predisposing factors are embolism, thrombosis, vasospasm, drugs (steroids and immunosuppressive agents), vasculitis, performed colonoscopy, and enema. Management of abdominal manifestations of SLE, in the absence of compelling radiographic or clinical findings suggestive of infarction or perforation, are steroid, antibiotics, and fluid therapy, According to the study by the The Catholic University of Korea(79).
B. In Herbal medicine perspective
The aim of herbal treatment is strenghten the immune sytem of the body to fight off the invasion of bacterial causes of the diseases
1. Echinacea, Ashwagandha and Brahmi
Herbs, as food or medicine, can strengthen the body and increase its resistance to illnesses by acting on various components of the immune system. In the study to compare the efficacy of Echinacea, Ashwagandha and Brahmi in strenghten the immune system, showed that Herbal remedies based on Echinacea, Brahmi, or Ashwagandha can enhance immune function by increasing immunoglobulin production. Furthermore, these herbal medicines might regulate antibody production by augmenting both Th1 and Th2 cytokine production(49).
2. Cinnamon
In administration of popular herb used in traditional medicine to treat various disorders such as chronic gastric symptoms, arthritis, and the common cold and its immunomodulatory effect found that observations provided evidence that CWE was able to down-regulate IFN-γ expression in activated T cells without altering IL-2 production, involving inhibition of p38, JNK, ERK1/2, and STAT4, according to the study of "Immunomodulatory effect of water extract of cinnamon on anti-CD3-induced cytokine responses and p38, JNK, ERK1/2, and STAT4 activation" by Lee BJ, Kim YJ, Cho DH, Sohn NW, Kang H. (50)
. Other in the observation of three natural essential oils (i.e., clove bud oil, cinnamon oil, and star anise oil) and their antimicrobal effects found that the cinnamon oil-chitosan film had also better antimicrobial activity than the clove bud oil-chitosan film. The results also showed that the compatibility of cinnamon oil with chitosan in film formation was better than that of the clove bud oil with chitosan, according to the study of "Synergistic Antimicrobial Activities of Natural Essential Oils with Chitosan Films" by Wang L, Liu F, Jiang Y, Chai Z, Li P, Cheng Y, Jing H, Leng X.(51)
3. Green Tea
In the assessment of unregulated activity of these receptors could lead to autoimmune diseases and the effects of green tea catechin, epigallocatechin gallate of the study of "Green tea catechin, epigallocatechin gallate, suppresses signaling by the dsRNA innate immune receptor RIG-I." by Ranjith-Kumar CT, Lai Y, Sarisky RT, Cheng Kao C., researchers found that EGCG and its derivatives could have potential therapeutic use as a modulator of RIG-I mediated immune responses by binding RIG-I and inhibits its signaling at low micromolar concentrations in HEK293T cells(52)
Other In the observation of green tea and rosemary leaf powders on the growth of microorganisms of the study of "Inhibitory effect of commercial green tea and rosemary leaf powders on the growth of foodborne pathogens in laboratory media and oriental-style rice cakes' by Lee SY, Gwon SY, Kim SJ, Moon BK.[13c], researchers indicated that 1 or 3% green tea or rosemary to rice cakes did not significantly reduce total aerobic counts; however, levels of B. cereus and S. aureus were significantly reduced in rice cakes stored for 3 days at room temperature (22 degrees C) and that suggested the use of natural plant materials such as green tea and rosemary could improve the microbial quality of foods in addition to their functional properties(53).
4. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in trditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
In the explore more systematically in various diseases of curcumin's therapeutic promise,
indicated that curcumin may be particularly suited to be developed to treat gastrointestinal diseases. This review summarizes some of the current literature of curcumin's anti-inflammatory, anti-oxidant and anti-cancer potential in inflammatory bowel diseases, hepatic fibrosis and gastrointestinal cancers, according to "Therapeutic potential of curcumin in gastrointestinal diseases" by Rajasekaran SA(54).
Other In the research of a literature search (PubMed) of almost 1500 papers dealing with curcumin, most from recent years, with ll available abstracts were read and pproximately 300 full papers were reviewed, found that curcumin, a component of turmeric, has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NFkappaB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS). Significant preventive and/or curative effects have been observed in experimental animal models of a number of diseases, including arteriosclerosis, cancer, diabetes, respiratory, hepatic, pancreatic, intestinal and gastric diseases, neurodegenerative and eye diseases, "Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases" by Bengmark S(55).
C. In traditional Chinese medicine perspective
1. Xilei-san
Xilei-san is a traditional Chinese herbal medicine that has proven to be of possible use in the treatment of ulcerative proctitis. In the study to compare the efficacy of Xilei-san with dexamethasone enemas in subjects with mild-to-moderate active UP, showed that Xilei-san enemas are comparable to dexamethasone enemas in this study. This medicine is safe, well accepted, and may be an alternative drug in the treatment of mild-to-moderate active UP(56).
2. The Erkang capsule
Shi-Quan-Da-Bu-Tang is a traditional Chinese herbal medicine formula used to increase vital energy, and strengthen health and immunity. The Erkang capsule is a modified formula of Shi-Quan-Da-Bu-Tang, with the addition of four other herbs to increase the adaptogen effects and ergogenic properties. In mice study, the Erkang treated group had significant differences in mortality, body weight change, fatigue, cold temperature endurance, and immune function related organ weight change, compared to the control animals(57).
3. Lingzhi
Reishi mushroom or Lingzhi is a fungal species in the genus Ganoderma, belonging to the family Ganodermataceae, native to Asia. The herb has been use in traditional medicine as anti-caners and anti inflammatory, antioxdant agent and to enhance immune function, treat hepatitis B virus, protect against neuron degeneration, etc. In the demonstration of Ganoderma lucidum, a medicinal fungus is thought to possess and enhance a variety of human immune functions, found that Our current results of analyzing rLZ-8-mediated signal transduction in T cells might provide a potential application for rLZ-8 as a pharmacological immune-modulating agent, according to "Reishi immuno-modulation protein induces interleukin-2 expression via protein kinase-dependent signaling pathways within human T cells" by Hsu HY, Hua KF, Wu WC, Hsu J, Weng ST, Lin TL, Liu CY, Hseu RS, Huang CT(58). Other In the investigation of the water-soluble, polysaccharide components of Reishi (designated as MAK) in murine colitis induced by trinitrobenzene sulphonic acid (TNBS), found that MAK-stimulated PMs produced GM-CSF in a dose-dependent manner. Intestinal inflammation by TNBS was improved by feeding with MAK. MLNs of mice treated with TNBS produced IFN-γ, which was inhibited by feeding with MAK. In contrast, MLNs of mice treated with TNBS inhibited GM-CSF production, which was induced by feeding with MAK and conculded that that the induction of GM-CSF by MAK may provide the anti-inflammatory effect, according to "The water-soluble extract from cultured medium of Ganoderma lucidum (Reishi) mycelia (Designated as MAK) ameliorates murine colitis induced by trinitrobenzene sulphonic acid" by Hanaoka R, Ueno Y, Tanaka S, Nagai K, Onitake T, Yoshioka K, Chayama K(59).
4. Ren Shen
Ren Shen is also known as Gingshen. The smells aromatic, tastes sweet and slightly warm herbs had been used in TCM as improved immune system, Anti Cancer, Anti aging, Anti stress, etc. agent and to generates fluids and reduce thirst, for xinqixu (heart qi deficient) palpitations with instant sweating and anxiety, insomnia, dizziness/headache, forgetfulness, impotence, diabetes, bleeding in the vagina not during period, seizures in children, chronic weakness, etc. as it strongly tonifies Original Qi, tonifies the Spleen and the Lungs, promotes generation of Body Fluids, calms thirs and the Mind, etc. by enhancing the functions of spleen and lung. In the study of Water-soluble ginseng oligosaccharides (designated as WGOS) with a degree of polymerization ranging from 2 to 10 were obtained from warm-water extract of Panax ginseng roots, found that WGOS were potent B and T-cell stimulators and WGOS-1 has the highest immunostimulating effect on lymphocyte proliferation among those purified fractions. It is hoped that the WGOS will be developed into functional food or medicine, according to "Structural characterization and immunological activities of the water-soluble oligosaccharides isolated from the Panax ginseng roots" by Wan D, Jiao L, Yang H, Liu S(60). Other In the evaluation of the extraction conditions of polysaccharides from the rhizomes of Panax japonicus C.A. Meyer and its antioxidant effect found that antioxidant activity exhibited Panax japonicus polysaccharides (PJP) had a good potential for antioxidant, according to "Optimization of polysaccharides from Panax japonicus C.A. Meyer by RSM and its anti-oxidant activity" by Wang R, Chen P, Jia F, Tang J, Ma F(61).
5. Qingre Buyi Decoction
In the study to investigate the efficiency, safety, and possible mechanisms of Qingre Buyi Decoction (QBD) in the treatment of acute radiation proctitis (ARP), showed that Addition of QBD to the conventional treatment can effectively alleviate the damage of intestinal mucosal barrier function and improve all main clinical symptoms and signs of the ARP. The combination of conventional treatment with Chinese herbal medicine QBD is effective and safe for ARP.(62).
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(67) http://www.ncbi.nlm.nih.gov/pubmed/1582361
(68) http://www.ncbi.nlm.nih.gov/pubmed/8620787
(69) http://www.ncbi.nlm.nih.gov/pubmed/10696902
(70) http://www.ncbi.nlm.nih.gov/pubmed/17160570
(71) http://www.ncbi.nlm.nih.gov/pubmed/2958057
(72) http://www.ncbi.nlm.nih.gov/pubmed/12107832
(73) http://www.ncbi.nlm.nih.gov/pubmed/8955249
(74) http://www.ncbi.nlm.nih.gov/pubmed/8932614
(75) http://www.ncbi.nlm.nih.gov/pubmed/11726080
(76) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158396/
(77) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2660501/
(78) http://www.ncbi.nlm.nih.gov/pubmed/19584834
(79) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716627/
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