Evaluation of T cell stimulation by thyrotropin-receptor epitopes in Graves' disease.

In Graves' disease (GD) immunized T cells reactive to TSH-receptor epitopes contribute to pathogenesis through B cell help, and cytotoxicity. We evaluated T cell responses to synthetic TSH-receptor epitopes in hyperthyroid patients with GD prior to therapy, at 6-8 weeks after radioactive iodine (RAI) administration, or 6-8 months later when euthyroid, and in control subjects. All T cell responses were relatively low as generally found in human autoimmune diseases. Responses in hyperthyroid GD patients were significantly greater than among controls, were augmented 6-8 weeks after RAI treatment, were still present after patients became euthyroid, and did not differ between DR3+ and non-DR3+ patients. Patient's T cells reacted to multiple different epitopes, and reactivity differed depending on the course of the disease and treatment.While certain epitopes most commonly cause T cell reactivity, we did not find evidence for a single or few "dominant" epitopes.

Prevalence and risk factors for female sexual dysfunction in women attending a medical clinic in south India.

BACKGROUND: Reports from India on the prevalence and determinants of female sexual dysfunction (FSD) are scant. AIMS: To determine the prevalence and risk factors for FSD. SETTINGS AND DESIGN: A cross-sectional survey in a medical outpatient clinic of a tertiary care hospital. MATERIALS AND METHODS: We administered a Tamil version of the Female Sexual Function Index (FSFI) to 149 married women. We evaluated putative risk factors for FSD. We elicited participant's attributions for their sexual difficulties. STATISTICAL ANALYSIS: We estimated the prevalence of possible FSD and sexual difficulties from published FSFI total and domain cut-off scores. We used logistic regression to identify risk factors for possible FSD. RESULTS: FSFI total scores suggested FSD in two-thirds of the 149 women (73.2%; 95% confidence intervals [CI] 65.5% to 79.6%). FSFI domain scores suggested difficulties with desire in 77.2%; arousal in 91.3%; lubrication in 96.6%; orgasm in 86.6%, satisfaction in 81.2%, and pain in 64.4%. Age above 40 years (odds ratios [OR] 11.7; 95% CI 3.4 to 40.1) and fewer years of education (OR 1.2; 95% CI 1.0 to 1.3) were identified by logistic regression as contributory. Women attributed FSD to physical illness in participant or partner, relationship problems, and cultural taboos but none had sought professional help. CONCLUSIONS: Sexual problems suggestive of dysfunction, as suggested by FSFI total and domain scores, are highly prevalent in the clinic setting, particularly among women above 40 and those less educated, but confirmation using locally validated cut-off scores of the FSFI is needed.

Feasibility of yoga as a complementary therapy for patients with type 2 diabetes: The Healthy Active and in Control (HA1C) study.

OBJECTIVES: This study:Healthy Active and in Control (HA1C), examined the feasibility and acceptability of yoga as a complementary therapy for adults with Type-2 Diabetes (T2DM). DESIGN: A 2-arm randomized clinical trial comparing Iyengar yoga with a supervised walking program. SETTING: Hospital based gym-type facility and conference rooms. INTERVENTIONS: Participants were randomized to a 12-week program of either; (1) a twice weekly Iyengar yoga, or (2) a twice-weekly program of standard exercise (SE). MAIN OUTCOME MEASURES: Primary outcomes assessed feasibility and acceptability, including enrollment rates, attendance, study completion, and participant satisfaction. Secondary outcomes included HbA1c, physical activity, and measures of diabetes-related emotional distress, self-care and quality of life (QOL). Assessments were conducted at baseline, end of treatment, 6-months and 9-months post-enrollment. RESULTS: Of 175 adults screened for eligibility, 48 (30 women, 18 men) were eligible and enrolled. The most common reasons for ineligibility were orthopedic restrictions, HbA1c levels <6.5 and BMI > 42. Session attendance was high (82% of sessions attended), as was follow-up completion rates (92%). Program satisfaction rated on a 5-point scale, was high among both Yoga (M = 4.63, SD = 0.57) and SE (M = 4.77, SD = 0.52) participants. Overall 44 adverse events (26 Yoga, 18 SE) were reported. Of these, six were deemed "possibly related" (e.g., neck strain, back pain), and 1 "probably related" (ankle pain after treadmill) to the study. Yoga produced significant reductions in HbA1c. Median HbA1c at 6 months was 1.25 units lower for Yoga compared to SE (95% CI: -2.54 -0.04). Greater improvements in diabetes self-care, quality of life, and emotional distress were seen among Yoga participants than among SE participants. Increases in mindfulness were seen in Yoga but not in SE. CONCLUSIONS: The yoga intervention was highly feasible and acceptable, and produced improvements in blood glucose and psychosocial measures of diabetes management.

Maternal nutrient restriction in early pregnancy programs hepatic mRNA expression of growth-related genes and liver size in adult male sheep.

The liver is a major metabolic and endocrine organ of critical importance in the regulation of growth and metabolism. Its function is determined by a complex interaction of nutritionally regulated counter-regulatory hormones. The extent to which hepatic endocrine sensitivity can be programed in utero and whether the resultant adaptations persist into adulthood is unknown and was therefore the subject of this study. Young adult male sheep born to mothers that were fed either a control diet (i.e.100% of total live weight-maintenance requirements) throughout gestation or 50% of that intake (i.e. nutrient restricted (NR)) from 0 to 95 days gestation and thereafter 100% of requirements (taking into account increasing fetal mass) were entered into the study. All mothers gave birth normally at term, the singleton offspring were weaned at 16 weeks, and then reared at pasture until 3 years of age when their livers were sampled. NR offspring were of similar birth and body weights at 3 years of age when they had disproportionately smaller livers than controls. The abundance of mRNA for GH, prolactin, and IGF-II receptors, plus hepatocyte growth factor and suppressor of cytokine signaling-3 were all lower in livers of NR offspring. In contrast, the abundance of the mitochondrial protein voltage-dependent anion channel and the pro-apoptotic factor Bax were up regulated relative to controls. In conclusion, maternal nutrient restriction in early gestation results in adult offspring with smaller livers. This may be mediated by alterations in both hepatic mitogenic and apoptotic factors.

Lipid Microdomains in Synapse Formation.

Membrane lipid rafts (i.e., cholesterol/sphingolipids domains) exhibit functional roles in both healthy and pathological states of the nervous system. However, due to their highly dynamic nature, it remains a challenge to characterize the fundamental aspects of lipid rafts that are important for specific neuronal processes. An experimental approach is presented here that allows for the interfacing of living neurons with an experimentally accessible model membrane where lipid order in cellular rafts can be reproducibly mimicked. It is demonstrated that coexisting lipid microdomains in model membranes can regulate axonal guidance and establish stable presynaptic contacts when interfaced with neurons in vitro. Experimental evidence is provided where specific functional groups and lateral organizations are favored by neurons in establishing synaptic connections. The model membrane platform presented in this work provides an accessible and direct means to investigate how lipid rafts regulate synapse formation. This experimental platform can similarly be extended to explore a variety of other cellular events where lipid lateral organization is believed to be important.

HIV in couples in South India; implications for prevention.

We studied HIV prevalence in couples in Chennai, India. In 56% both partners were infected. Among discordant couples, 35 men and seven women were infected. Heterosexual intercourse is the primary risk factor. Concordance was related to sex with commercial sex workers for men and to genital ulcer disease for women. Median CD4 count was 97 cells/mm(3) among concordant men, 222 cells/mm(3) among discordant men. Condom use increased, and frequency of sexual intercourse decreased, among all couples after HIV diagnosis.

Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development.

Maternal nutrient restriction at specific stages of gestation has differential effects on fetal development such that the offspring are programmed to be at increased risk of adult disease. We investigated the effect of gestational age and maternal nutrition on the maternal plasma concentration of leptin and cortisol together with effects on fetal adipose tissue deposition plus leptin, IGF-I, IGF-II ligand, and receptor mRNA abundance near to term. Singleton bearing ewes were either nutrient restricted (NR; consuming 3.2-3.8 MJ/d of metabolizable energy) or fed to appetite (consuming 8.7-9.9 MJ/d) over the period of maximal placental growth, i.e. between 28 and 80 d gestation. After 80 d gestation, ewes were either fed to calculated requirements, consuming 6.7-7.5 MJ/d, or were fed to appetite and consumed 8.0-10.9 MJ/d. Pregnancy resulted in a rise in plasma leptin concentration by 28 d gestation, which continued up to 80 d gestation when fed to appetite but not with nutrient restriction. Plasma cortisol was also lower in NR ewes up to 80 d gestation, a difference no longer apparent when food intake was increased. At term, irrespective of maternal nutrition in late gestation, fetuses sampled from ewes NR in early gestation possessed more adipose tissue, whereas when ewes were fed to appetite throughout gestation, fetal adipose tissue deposition and leptin mRNA abundance were both reduced. These changes may result in the offspring of NR mothers being at increased risk of obesity in later life.

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12.

A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods. Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals. The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed.

Photooxidation of cedrelone, a tetranortriterpenoid from Toona ciliata.

Cedrelone, a tetranortriterpenoid on photolysis by UV light yields a true photooxidation product 3 [14 beta,15beta,22beta,23beta-diepoxy-6-hydroxy-1,5, 20(22)-meliatriene-2,7,21-trione] whose structure is well established by NMR studies and confirmed by X-ray crystallography, along with product 4 [14 beta,15beta-epoxy-6,23-dihydroxy-1,5,20(22)-meliatriene-2,7, 21-trione]. Addition of rose bengal increases the rate of photooxidation whereas DABCO decreases rate of photolysis proving the involvement of singlet oxygen in the photooxygenation. Both the photoproducts exhibited antifeedant activity.

Correlation of serum prostate specific antigen levels and bone scintigraphy in carcinoma prostate.

Serum prostate specific antigen (PSA) has been suggested as an accurate means of monitoring prostate cancer. An analysis of PSA levels and bone scan findings was carried out in a heterogeneous group of patients with a view to determine whether PSA can accurately predict bone metastases in carcinoma prostate. Of the 48 patients studied, all 10 untreated cases had elevated PSA levels, eight having bone metastases. In 29 cases on follow-up after treatment of the primary, 10 out of 11 cases with normal PSA had a negative bone scan. In the nine who received hormonal therapy, the PSA levels were generally lower than others in the study group. Two out of four with normal PSA had bone metastases. In 26 cases with positive bone scans, 23 had elevated PSA levels (mean 109.9 ng ml-1). Among 22 patients who had normal bone scans, all 10 with high PSA were found to have soft tissue disease which could explain the elevated PSA. In those with normal PSA, 12 out of 15 patients had negative scans. PSA has fairly high sensitivity (86.5%) and negative predictive value (80%). But it suffers from low specificity (54.5%) and low positive predictive value (69.7%) for bone metastases. In an untreated patient with elevated PSA, a bone scan may be required to exclude bone metastases, whereas during follow-up after treatment, a normal PSA level may obviate a "routine" bone scan.

Supracostal approach in percutaneous nephrolithotomy: experience with 102 cases.

PURPOSE: To assess retrospectively the safety and efficacy of the supracostal approach in percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: Among 862 patients who underwent PCNL between April 1986 and December 1999, supracostal puncture was performed in 102. Their stones were either solitary (66.5%), multiple (15.7%), or staghorn (19.6%). Upper ureteral calculi were the commonest indication (32.4%). The interspace between the 11th and 12th ribs was used in all cases. After tract dilatation with telescopic metal dilators, pneumatic or ultrasound lithotripsy was used for fragmentation. RESULTS: Complete clearance was achieved in 79.5%. Ten patients (9.8%) had pleural violation in the form of hydrothorax, pneumothorax, or hydropneumothorax. All of these patients were managed successfully by intercostal chest tube drainage. CONCLUSION: Supracostal puncture in a safe and effective approach with acceptable morbidity in selected cases of staghorn, upper ureteral, and upper caliceal calculi.

Does failure to visualize the ureter distal to an impacted calculus constitute an impediment to successful lithotripsy?

BACKGROUND: A severe degree of ureteral obstruction is viewed as a predictor of poor outcome in shockwave lithotripsy (SWL). Impacted stones are often considered a contraindication to in-situ SWL. PATIENTS AND METHODS: Impaction in our study was defined as failure to visualize the ureter distal to the calculus with proximal hold-up of contrast for as long as 3 hours on an intravenous urogram (IVU). We evaluated 30 patients with impacted ureteral calculi, who were compared with a second unimpacted group matched for stone size and stone location. The calculi were reorganized into < or =10-mm and >10-mm groups. The results were compared in terms of clearance rates, number of shockwaves, number of sessions, and number of days between the start of SWL and clearance. RESULTS: Between January 1998 and December 2001, 30 impacted stones were treated with lithotripsy. Complete clearance rates in the impacted as well as the non-impacted group were 76.7%. There was no statistical difference in the number of shockwaves, sessions, or time to clearance. The results were poorer in lower-ureteral than upper-ureteral calculi, but this difference did not reach statistical significance. However, the differences between the < or =10-mm and >10-mm stones were statistically significant. CONCLUSION: Impaction on an IVU does not affect the results of lithotripsy.

Maternal nutrient restriction during placental growth, programming of fetal adiposity and juvenile blood pressure control.

Epidemiological and experimental studies have demonstrated that maternal undernutrition during pregnancy is associated with abnormal placental growth. In sheep, maternal nutrient restriction over the period of rapid placental growth (30-80 days) restricts placentome growth. Then following adequate nutrition up to term (147 days), placental mass is greater in association with a higher total abundance of the predominant placental glucose transporter-1. The resulting lambs are larger at birth, have heavier kidneys with an increased expression of the glucocorticoid-responsive type 1 angiotensin II receptor. Near to term, these fetuses possess more adipose tissue, the endocrine sensitivity of which is markedly enhanced. For example, the abundance of mRNA for 11beta-hydroxysteroid dehydrogenase type 1, which catalyses the conversion of cortisone to bio-active cortisol is increased. This is associated with a higher abundance of both leptin and glucocorticoid receptor mRNA. At 6 months of age, the juvenile offspring of nutrient restricted ewes have lower resting blood pressure that was positively correlated with plasma cortisol concentration, suggesting their blood pressure could be more strongly driven by circulating cortisol. These offspring also exhibited a greater pressor response to vasoconstrictor challenges, but showed no difference in vasodilatory response. At this age, the kidney weight was similar between groups, but the abundance of cytochrome c in kidney mitochondria was enhanced in lambs born to nutrient restricted ewes that could indicate increased mitochondrial activity. Reduced maternal nutrition during the period of rapid placental growth may therefore contribute to hypertension in later life through physiological and vascular adaptations during fetal life.

Paediatric renal transplantation--a 15 year experience.

OBJECTIVE: To review the outcome of paediatric renal transplantation over a period of 15 years in a developing country. METHODS: This is a retrospective study of 63 children, less than 15 years of age, who underwent living-related renal transplantation in Christian Medical College and Hospital Vellore between 1984 and 1996. RESULTS: The records of 12 patients were not adequate for detailed analysis. Parents were the donors for these children in 84.3% of cases. The most common known cause of end-stage renal disease in these children was reflux nephropathy. Combinations of cyclosporine, azathioprine and prednisolone were used as immunosuppressive drugs. Complications occurred in 16 patients. During the follow-up period, eight patients died and two returned to receiving haemodialysis. Patient survival was 92% at the end of 1 year and 90% at the end of 3 years. Graft survival was 88% and 86% at 1 and 3 years, respectively. CONCLUSION: Our study validates the concept of renal transplantation as optimal therapy with adequate medical, social and functional rehabilitation for children with end-stage renal disease. Our study also indicates that vesicoureteric reflux appears to be underdiagnosed and should be actively pursued to prevent complications.

Mucocutaneous exposure to body fluids during digestive endoscopy: the need for universal precautions.

BACKGROUND: Endoscopy personnel are at high risk of exposure to infectious body fluids during endoscopy. There are no studies documenting the frequency of such exposure. AIM: To determine the frequency of exposure to body fluids, and factors that may modify the risk of exposure during digestive endoscopy. METHODS: During a 10-month period, 948 endoscopy procedures done by two endoscopists were assessed for the occurrence of splashes to uncovered parts of the body. Odds ratio was used to determine any change in the exposure risk with different risk factors. RESULTS: The overall frequency of splash to any part of the body was 13.2% (95% CI 10.8-15.9). Common sites of exposure were the eyes, face, forearms and feet. Splash to the skin of the face, forearms and feet occurred in 9.5% (95% CI 7.5-11.8). The risk remained unchanged during therapeutic endoscopy, assisted endoscopy, or endoscopy with biopsy or cytology. Using video endoscopy led to significant reduction in splashes on the skin. Overall splash rate to the eyes was 4.1% (95% CI 2.9-5.6). This remained unchanged during therapeutic endoscopy, assisted endoscopy, and endoscopic biopsy or cytology sampling. The risk was not reduced during video endoscopy. CONCLUSIONS: Endoscopy results in muco-cutaneous exposure to potentially infectious body fluids in 13% or more procedures. The risk of exposure is not reduced by video endoscopy, or by avoiding instrumentation of the biopsy channel. We recommend that all endoscopists and endoscopy assistants must follow universal precautions.

Removal of impacted basket during endoscopic papillotomy: a novel method using precut papillotome.

Basket impaction is a rare problem during endoscopic papillotomy and stone extraction for the bile duct. Mechanical lithotriptor is usually employed to break the stone, but a few patients may require surgery. We describe a patient in whom a precut papillotome was used to break the stone and remove the impacted basket.

Endoscopic palliation of malignant obstructive jaundice using resterilized accessories: an audit of success, complications, mortality and cost.

OBJECTIVE: To assess the success, complications and cost of endoscopic endoprosthesis placement for palliation of obstructive jaundice caused by malignancy. METHODS: Four hundred and two consecutive patients with obstructive jaundice due to nonresectable malignancy undergoing endoscopic stenting were studied. Commercial or home-made 7F or 10F endoprostheses were placed using minor modifications of the standard technique. The accessories were sterilized and reused. RESULTS: Endoprosthesis placement was successful in 291 patients (72.4%, 95% CI 67.7-76.7)-241 in one attempt, 49 in two attempts, and one in three attempts. Fifty nine patients (14.6%, 95% CI 11.4-18.6) had procedure-related complications, including cholangitis (30), pancreatitis (15), perforation (3) and bleeding (11). The incidence of cholangitis was significantly higher in bifurcation blocks than in other lesions (17.6% vs 4.7%, p = 0.0005). The success rate did not differ between distal and proximal lesions (68.1% vs 72.9%). The procedural cost per patient could be reduced from Rs 14,850 to Rs 6565 by reusing accessories after sterilization, and using home-made stents. CONCLUSIONS: Endoscopic endoprosthesis placement is a safe and effective method for palliation of malignant obstructive jaundice. Preparation of indigenous stents and reuse of accessories can reduce the cost of the procedure by over 50%.

Two novel xanthones from Garcinia mangostana.

The isolation of two novel xanthones isolated from the fruit hulls of Garcinia mangostana is reported. The structures were elucidated by means of spectroscopic analysis.

Antifungal activity of some tetranortriterpenoids.

Natural tetranortriterpenoids such as cedrelone from Toona ciliata, azadiradione from Azadirachta indica, limonin, limonol and nomilinic acid from Citrus medica, along with some cedrelone derivatives were tested for their antifungal activity against Puccinia arachidis, a groundnut rust pathogen. Results show that cedrelone was the most effective in reducing rust pustule emergence. Replacement of functional groups or modification of the A or the B ring in cedrelone reduced the effectiveness indicating the importance of specific structural features for activity.