The Optimal Parathyroid Hormone Cut-Off Threshold for Early and Safe Management of Hypocalcemia After Total Thyroidectomy.

OBJECTIVE: To define optimal intact parathyroid hormone (iPTH) cut-off threshold predictive of hypocalcemia after total thyroidectomy for safe and effective postoperative management. METHODS: This prospective single center study was done in 2 phases. In phase I, predictors of symptomatic hypocalcemia were analyzed and the receiver operating characteristic curve was used to define the optimal iPTH cut-off threshold predictive of hypocalcemia. Phase II studied giving prompt prophylactic supplemental calcium and vitamin D to all patients who had iPTH levels below the calculated threshold, while phase I patients were given prompt selective supplementation if they had postoperative hypocalcemia or symptoms. RESULTS: Univariate analysis of patients in phase I showed that postoperative iPTH was the only significant variable that can predict symptomatic hypocalcemia. Using receiver operating characteristic curve and Youden index, the confirmed optimal cut-off threshold predictive of hypocalcemia was iPTH 19.95 pg/mL, with area under the curve of 0.903, 100% sensitivity, negative predictive value, and highest Youden index, while iPTH 15 pg/mL and iPTH 10 pg/mL were less optimal. Symptomatic hypocalcemia occurred in 30% of the phase I cohort who received selective supplementation versus 3% of those in the phase II cohort who received prophylactic supplementation. Return to emergency department and need for intravenous calcium were also significantly better in phase II. CONCLUSION: iPTH cut-off for post-thyroidectomy hypocalcemia was 19.95 pg/mL. Low-risk patients were discharged with no supplementation while all high-risk patients received prompt calcium and vitamin D supplementation, which led to effective hypocalcemia management and safe 24-hour discharge.

Benefits of Zubex beyond glycemic control: Evidence of the antiatherogenic effect.

OBJECTIVE: To determine the effect of Zubex (aqueous extract of Curcuma longa linn, Iron murakab, Eugenia jambolana, Lin seed or flflax seed, processed egg shell calcium and Asphaltum) on plasma sialic acid (PSA) along with cardiovascular (CV) risk factors in streptozotocin-induced diabetic rats. METHODS: Thirty male albino rats were divided into groups (1-6) with 5 rats in each group. Group 1 and 2 served as normal control (NC) and diabetic control (DC), respectively, and were given normal saline only. Groups 3-5 were given Zubex in different doses 100-400 mg/(kg day). Group 6 received glibenclamide 600 µg/(kg day) orally as a reference drug. Fasting plasma glucose (FPG) and PSA levels were determined at baseline after every 2 weeks for 10 weeks. The other parameters including blood lipids and hepatic enzymes were determined at baseline and at the end of the study. Finally, the liver was subjected to histological examination. RESULTS: Compared with DC group, Zubex treated groups showed signifificant decline in FPG levels (P<0.05). At the endpoint, the decrease in PSA concentration was significant (P<0.05) from baseline at the doses of 200 and 400 mg/(kg day) only and insignifificant at the dose of 100 mg/ (kg day). Statistically signifificant improvements were observed in blood lipids at the doses of 200 and 400 mg/kg (P<0.05) compared with DC; but, the improvement was insignifificant in low density lipoprotein-cholesterol and high density lipoprotein-cholesterol at the dose of 100 mg/ (kg day). Signifificant decreases were also found in hepatic enzyme levels at all the doses of Zubex (P<0.05). Histological examination showed marked improvement in streptozotocin induced liver injury after treatment of all the 3 doses of Zubex. CONCLUSION: Zubex could ameliorate PSA and other diabetic complications effectively and may be a useful alternative/adjuvant in diabetes treatment.

Lower hypoglycemic but higher antiatherogenic effects of bitter melon than glibenclamide in type 2 diabetic patients.

OBJECTIVE: Since antiquity bitter melon has been in use for treating diabetes but clinical trials show conflicting results about its usefulness. The present study aims to asses and compare the hypoglycemic and antiatherogenic effects as well as the safety of two different doses of bitter melon with glibenclamide. METHODS: A total of 95 participants were randomized into 3 groups; group I and group II received bitter melon (2 g/day and 4 g/day respectively) and group III received glibenclamide (5 mg/day) for 10 weeks. Glycemic control and antiatherogenic effects were determined by assessing glycohemoglobin (HbA1-c), fasting plasma glucose (FPG), 2 hour oral glucose tolerance test (OGTT), plasma sialic acid (PSA), systolic blood pressure (SBP), blood lipids and atherogenic index at different time periods. RESULTS: Compared to baseline, mean reduction in HbA1-c at the endpoint was significant among patients of group I, group II and group III (p ≤ 0.05, p ≤ 0.02 and p < 0.005 respectively) and same was the case for FPG (p ≤ 0.05, p < 0.04, p < 0.003 respectively), but the improvement in 2 hour OGTT was significant only in group III (p < 0.03). The decrease in PSA was observed only among group I and group II with the later showing significant reduction from baseline (p < 0.01). In group III, the level slightly increased. Parameters including blood lipids, atherogenic index, body weight and SBP improved among patients of group I and group II but deteriorated among group III patients. CONCLUSIONS: Our study concludes that bitter melon has a weaker hypoglycemic effect but ameliorates the diabetes associated cardiovascular (CV) risk factors more effectively than glibenclamide. TRIAL REGISTRATION: The trial was registered with Naseer Teaching Hospital Clinical Trials Registry number GU2014492233.

Molecular characterization of farnesyl pyrophosphate synthase from Bacopa monniera by comparative modeling and docking studies.

UNLABELLED: Farnesyl pyrophosphate synthase (FPS; EC 2.5.1.10) is a key enzyme in isoprenoid biosynthetic pathway and provides precursors for the biosynthesis of various pharmaceutically important metabolites. It catalyzes head to tail condensation of two isopentenyl pyrophosphate molecules with dimethylallyl pyrophosphate to form C15 compound farnesyl pyrophosphate. Recent studies have confirmed FPS as a molecular target of bisphosphonates for drug development against bone diseases as well as pathogens. Although large numbers of FPSs from different sources are known, very few protein structures have been reported till date. In the present study, FPS gene from medicinal plant Bacopa monniera (BmFPS) was characterized by comparative modeling and docking. Multiple sequence alignment showed two highly conserved aspartate rich motifs FARM and SARM (DDXXD). The 3-D model of BmFPS was generated based on structurally resolved FPS crystal information of Gallus gallus. The generated models were validated by various bioinformatics tools and the final model contained only α-helices and coils. Further, docking studies of modeled BmFPS with substrates and inhibitors were performed to understand the protein ligand interactions. The two Asp residues from FARM (Asp100 and Asp104) as well as Asp171, Lys197 and Lys262 were found to be important for catalytic activity. Interaction of nitrogen containing bisphosphonates (risedronate, alendronate, zoledronate and pamidronate) with modeled BmFPS showed competitive inhibition; where, apart from Asp (100, 104 and 171), Thr175 played an important role. The results presented here could be useful for designing of mutants for isoprenoid biosynthetic pathway engineering well as more effective drugs against osteoporosis and human pathogens. ABBREVIATIONS: IPP - Isopentenyl Pyrophosphate, DMAPP - Dimethylallyl Pyrophosphate, GPP - Geranyl Pyrophosphate, FPP - FPPFarnesyl Pyrophosphate, DOPE - Discrete Optimized Protein Energy, BmFPS - Bacopa monniera Farnesyl Pyrophosphate Synthase, RMSD - Root Mean square Deviation, OPLS-AA - Optimized Potentials for Liquid Simulations- All Atom, FARM - First Aspartate Rich Motif, SARM - Second Aspartate Rich Motif.

Structural characterization of a flavonoid glycosyltransferase from Withania somnifera.

UNLABELLED: Medicinal plants are extensively utilized in traditional and herbal medicines, both in India and around the world due to the presence of diverse low molecular weight natural products such as flavonoids, alkaloids, terpenoids and sterols. Flavonoids which have health benefits for humans are the large class of phenylpropanoid-derived secondary metabolites and are mostly glycosylated by UDP-glycosyltransferases (UGTs). Although large numbers of different UGTs are known from higher plants, very few protein structures have been reported till now. In the present study, the three-dimensional model of flavonoid specific glycosyltransferases (WsFGT) from Withania somnifera was constructed based on the crystal structure of plant UGTs. The resulted model was assessed by various tools and the final refined model revealed GT-B type fold. Further, to understand the sugar donors and acceptors interactions with the active site of WsFGT, docking studies were performed. The amino acids from conserved PSPG box were interacted with sugar donor while His18, Asp110, Trp352 and Asn353 were important for catalytic function. This structural and docking information will be useful to understand the glycosylation mechanism of flavonoid glucosides. ABBREVIATIONS: DOPE - Discrete Optimized Potential Energy, PDB - Protein Data Bank, PSPG - Plant Secondary Product Glycosyltransferase, RMSD - Root Mean Squared Deviation, UDP - Uridine diphosphate, UGT - UDP-glycosyltransferases.

Serum sialic acid changes in non-insulin-dependant diabetes mellitus (NIDDM) patients following bitter melon (Momordica charantia) and rosiglitazone (Avandia) treatment.

Diabetes mellitus is associated with an increase in sialic acid concentration along with other complications. Sialic acid changes in NIDDM patients were investigated following bitter melon (55 ml/24h) and rosiglitazone (4 mg/24h) treatment. A total of 25 patients of both sexes were used in each experimental group. Patients following bitter melon treatment showed no significant difference of serum sialic acid (57.95+/-4.90 vs. 57.6+/-5.56 mg/dl, p=0.17) and serum glucose concentration (93.7+/-9.63 vs. 88.35+/-6.31 mg/dl, p=0.78) as compared to control subjects. However, the concentration of total cholesterol was significantly high in these patients as compared to control subjects (192+/-14.23 vs. 170.6+/-15.1mg/dl, p<0.03) but within normal range (160-200mg/dl), suggesting the significant hypoglycemic and lipid-lowering properties of bitter melon. The patients following rosiglitazone treatment showed a significant increase of serum sialic acid concentration (60.2+/-5.80 vs. 57.6+/-5.56 mg/dl, p=0.01) along with glucose (112+/-6.2 vs. 88.35+/-6.31 mg/dl, p<0.04) and total cholesterol concentration (216.45+/-20.2 vs. 170.6+/-15.1mg/dl, p<0.01) as compared to control subjects. In addition six of the patients had retinopathy, two of whom were suffering also from myocardial infarction and they still had a higher serum sialic acid (61.05+/-1.20mg/dl), glucose (187+/-2.11 mg/dl), total cholesterol (239.10+/-5.04 mg/dl) and triglyceride (183+/-4.14 mg/dl) concentration, indicating a poor response of these patients to rosiglitazone. Comparison of serum sialic acid concentration of patients, following bitter melon and rosiglitazone treatment revealed no significant difference but the study showed that bitter melon could be more effective in the management of diabetes and its related complications as compared to rosiglitazone.