Rationale, study design and methodology of the LANDMARC trial: a 3-year, pan-India, prospective, longitudinal study to assess management and real-world outcomes of diabetes mellitus.

AIM: India contributes towards a large part of the worldwide epidemic of diabetes and its associated complications. However, there are limited longitudinal studies available in India to understand the occurrence of diabetes complications over time. This pan-India longitudinal study was initiated to assess the real-world outcomes of diabetes across the country. METHODS: The LANDMARC study is the first prospective, multicentre, longitudinal, observational study investigating a large cohort of people with type 2 diabetes mellitus across India over a period of 3 years. The primary objective of this ongoing study is to determine the proportion of people developing macrovascular diabetes complications over the duration of the study (36 months ± 45 days) distributed over seven visits; the secondary objective is to evaluate microvascular diabetes complications, glycaemic control and time-to-treatment adaptation or intensification. Overall, 6300 participants (aged 25-60 years) diagnosed with type 2 diabetes for at least 2 years will be included from 450 centres across India. Data will be recorded for baseline demographics, comorbidities, glycaemic measurements, use of anti-hyperglycaemic medications and any cardiovascular or other diabetes-related events occurring during the observational study period. CONCLUSIONS: The LANDMARC study is expected to reveal the trends in complications associated with diabetes, treatment strategies used by physicians, and correlation among treatment, control and complications of diabetes within the Indian context. The findings of this study will help to identify the disease burden, emergence of early-onset complications and dose titration patterns, and eventually develop person-centred care and facilitate public health agencies to invest appropriate resources in the management of diabetes. (Trial Registration No: CTRI/2017/05/008452).

Stability of 27 biochemistry analytes in storage at a range of temperatures after centrifugation.

Knowledge of factors affecting sample integrity is vital to make informed judgements on the validity of results. However, the information available for sample stability is incomplete, confusing and conflicting, particularly post-centrifugation. This study aims to investigate the effects of storage conditions on biochemical analytes. As part of this study, a new method has been developed, based on the manufacturer's stated analytical precision for the methodology. Ten adult volunteers were recruited into the study. Blood was collected into serum-separating tubes, and allowed to clot at room temperature for 30 minutes. After centrifugation, serum samples were stored frozen, refrigerated or at ambient temperature for between two hours and three months. After the allotted time had elapsed, designated serum aliquots were stored at -80 degrees C, before batch analysis for 27 biochemical analytes. Twenty-three out of the 27 analytes remained stable until the last time-point tested at all temperature conditions. Alanine aminotransferase (ALT), lactate dehydrogenase (LD-P), potassium and uric acid showed reduced stability with at least one of the storage conditions tested. The method developed provided robust sample stability data within the inherent imprecision of the assay(s) used. The results generated can be used to create an evidence-based policy recommending sample handling and transportation practices that will ensure optimal sample integrity, and permit informed judgements to be made on results of stored samples. Minimal effects on sample stability were noted for the majority of analytes using the storage conditions tested in this study.

Stability of haematology parameters on the LH750: comparison of Sarstedt Monovettes and BD Vacutainers.

Haematological analysis of white blood cells, red blood cells and platelets is used to aid diagnosis and treatment. Although most laboratories aim to analyse haematology samples on the day of collection, this is not always possible, particularly when the laboratory is remote from the patient. The integrity of a haematological sample is known to depend on time and temperature: measurement technique has already been found to have an impact on stability. This study aims to evaluate whether or not the type of EDTA specimen tube affects the stability, and the effect on stability using two commonly used blood collection systems (Becton Dickinson Vacutainers and Sarstedt Monovettes). Blood was drawn from 20 volunteers and stored refrigerated. Haematological analysis was conducted on a Beckman Coulter LH750 haematology analyser at multiple time points up to 72 h. The results were examined using analysis of variance (ANOVA), to look for imprecision both within-run and between run. Stability assessment was performed using an in-house method based on the manufacturer's stated precision limits. An analyte was classed as unstable when the cumulative SD/CV exceeded the precision limits of that assay. The method used to assess stability was found to provide robust stability information that matched data provided by the manufacturer and other researchers. Accurate full blood count results can be obtained on samples up to 48 h, provided that the samples are stored in a refrigerator. The tube type was found to have minimal impact on the stability of haematological samples.

Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. METHODS: This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA(1c) 7.5-10%) and combination therapy (7.0-10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA(1c). Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times. RESULTS: The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA(1c) significantly vs glargine (1.33% vs 1.09%; -0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (-1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference -1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference -3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide reduced systolic BP (-4.0 mmHg) vs glargine (+0.5 mmHg; -4.5 mmHg difference, 95% CI 6.8, -2.2; p = 0.0001) but not vs placebo (p = 0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies. CONCLUSIONS/INTERPRETATION: Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA(1c) was within the predefined non-inferiority margin. TRIAL REGISTRATION: ClinicalTrials.gov NCT00331851. FUNDING: The study was funded by Novo Nordisk A/S.

Efficacy of teriparatide in increasing bone mineral density in postmenopausal women with osteoporosis--an Indian experience.

BACKGROUND AND OBJECTIVE: Osteoporosis is emerging as a leading cause of substantial morbidity in India, particularly in postmenopausal women. Teriparatide (recombinant human parathyroid hormone [1-34]) increases bone formation and improves bone microarchitecture, thereby reducing the risk of fractures. This study was conducted to evaluate the efficacy of teriparatide in increasing bone mineral density (BMD) in postmenopausal women with osteoporosis. MATERIAL AND METHODS: A randomised, prospective, multicentre, open-label, controlled study was conducted on 82 postmenopausal women with established osteoporosis. Patients were randomly divided into control and teriparatide groups, each group consisting of 41 patients. All the patients were supplemented with 1000 mg of elemental calcium and 500 IU of vitamin D throughout the study period of 180 days. Besides, teriparatide group patients were administered teriparatide 20 microg daily subcutaneously. Lumbar spine, femoral neck and total hip BMD, bone mineral content (BMC) and bone area were measured by dual energy x-ray absorptiometry (DXA) at baseline and at the end of 6 months of treatment. Bone biomarkers, such as serum bone specific alkaline phosphatase (BSAP) and serum osteocalcin (OC), representing bone formation, and urinary deoxypyridinoline (DPD), representing bone resorption were assessed at baseline, and at 3 and 6 months of treatment. RESULTS: During the study period, 9 patients (11%) were lost to follow-up--6 in control group (7.3%) and 3 in teriparatide group (3.7%). There was an excellent compliance to both oral and injectable medication. The investigational product teriparatide was well tolerated and there were no serious adverse events. In addition, there were no significant differences between the groups in the incidence of adverse events. The percentage of increase in lumbar spine BMD, which is the primary endpoint, was significantly (P < 0.001) higher in teriparatide group compared to that in control group (6.58% vs. 1.06%). Further, teriparatide significantly increased percentage of change in lumbar spine T-score (P < 0.001), BMC (P < 0.001) and bone area (P < 0.028) compared to control group at 6 months. Administration of teriparatide resulted in a significant percentage of increase in all the bone biomarkers in teriparatide group compared to control group patients at 3 and 6 months over baseline, thereby showing that there was a significant increase in bone turnover in teriparatide group of patients. CONCLUSION: These results show that teriparatide is an effective and safe drug in increasing the BMD and therefore, teriparatide provides yet another new therapeutic option for reducing the risk management of osteoporosis in postmenopausal women (clinicaltrials.gov number, NCT00500409).

Variation of pKa in the N-terminal tyrosine side chain in octapeptide analogs of tendamistat influences alpha-amylase inhibition.

Peptide analogs of tendamistat were synthesized and analyzed for alpha-amylase inhibitory activity. The pK(a) of the N-terminal tyrosine was modified by incorporation of ring-substituted analogs, which alters hydrogen bonding capacity. K(i) values ranging from 70 to 524 microM generally increased with increasing pK(a), indicating a necessity for H-bond donor ability.

Microbial cellulases - Diversity & biotechnology with reference to mangrove environment: A review.

Cellulose is an abundant natural biopolymer on earth, found as a major constituent of plant cell wall in lignocellulosic form. Unlike other compounds cellulose is not easily soluble in water hence enzymatic conversion of cellulose has become a key technology for biodegradation of lignocellulosic materials. Microorganisms such as aerobic bacteria, fungi, yeast and actinomycetes produce cellulase that degrade cellulose by hydrolysing the ß-1, 4-glycosidic linkages of cellulose. In contrast to aerobic bacteria, anaerobic bacteria lack the ability to effectively penetrate into the cellulosic material which leads to the development of complexed cellulase systems called cellulosome. Among the different environments, the sediments of mangrove forests are suitable for exploring cellulose degrading microorganisms because of continuous input of cellulosic carbon in the form of litter which then acts as a substrate for decomposition by microbe. Understanding the importance of cellulase, the present article overviews the diversity of cellulolytic microbes from different mangrove environments around the world. The molecular mechanism related to cellulase gene regulation, expression and various biotechnological application of cellulase is also discussed.

Phosphate solubilization and acid phosphatase activity of Serratia sp. isolated from mangrove soil of Mahanadi river delta, Odisha, India.

Phosphorus is an essential element for all life forms. Phosphate solubilizing bacteria are capable of converting phosphate into a bioavailable form through solubilization and mineralization processes. Hence in the present study a phosphate solubilizing bacterium, PSB-37, was isolated from mangrove soil of the Mahanadi river delta using NBRIP-agar and NBRIP-BPB broth containing tricalcium phosphate as the phosphate source. Based on phenotypic and molecular characterization, the strain was identified as Serratia sp. The maximum phosphate solubilizing activity of the strain was determined to be 44.84 µg/ml, accompanied by a decrease in pH of the growth medium from 7.0 to 3.15. During phosphate solubilization, various organic acids, such as malic acid (237 mg/l), lactic acid (599.5 mg/l) and acetic acid (5.0 mg/l) were also detected in the broth culture through HPLC analysis. Acid phosphatase activity was determined by performing p-nitrophenyl phosphate assay (pNPP) of the bacterial broth culture. Optimum acid phosphatase activity was observed at 48 h of incubation (76.808 U/ml), temperature of 45 °C (77.87 U/ml), an agitation rate of 100 rpm (80.40 U/ml), pH 5.0 (80.66 U/ml) and with glucose as a original carbon source (80.6 U/ml) and ammonium sulphate as a original nitrogen source (80.92 U/ml). Characterization of the partially purified acid phosphatase showed maximum activity at pH 5.0 (85.6 U/ml), temperature of 45 °C (97.87 U/ml) and substrate concentration of 2.5 mg/ml (92.7 U/ml). Hence the present phosphate solubilizing and acid phosphatase production activity of the bacterium may have probable use for future industrial, agricultural and biotechnological application.

Short-term naloxone administration in schizophrenic and manic patients. A World Health Organization Collaborative Study.

A double-blind study of the behavioral effects of short-term naloxone hydrochloride administration was performed in 32 schizophrenic and 26 manic patients in a World Health Organization collaborative project. There was a significant naloxone-associated reduction in overall physician-rated symptoms in schizophrenic patients concurrently treated with neuroleptic medication (N = 19) but not in medication-free schizophrenics (N = 13). Physician rating of auditory hallucinations showed significant naloxone-associated improvement for the total schizophrenic population, while self-ratings of auditory hallucinations showed improvement only in neuroleptic-treated schizophrenics. While further studies are needed to delineate these effects as to clinical significance, they may bear etiological implications for the psychobiology of schizophrenia, including the possibility of synergistic effects of dopamine and endorphin blockade. Naloxone produced no significant behavioral effects in manic patients. These findings are discussed with relationship to the hypotheses of endorphin involvement in schizophrenia and mania.

Antianxiety effect of cannabis: involvement of central benzodiazepine receptors.

The present work, involving clinical, behavioral, and biochemical studies, was undertaken to elucidate the probable mechanism of the observed antianxiety effects of cannabis. The population for the clinical study consisted of 50 male chronic cannabis users who were otherwise healthy and 50 matched controls. When evaluated on Taylor's Manifest Anxiety Scale (TMA), these subjects had low anxiety scores as compared with the controls. To explore the possible interaction of cannabis with the benzodiazepine receptors, behavioral and biochemical studies in mice were devised, involving acute and chronic cannabis administration. Behavioral study revealed that mice under chronic cannabis treatment scored significantly higher on foot shock-induced aggression, but this was significantly blocked by benzodiazepine receptor antagonist. Furthermore, chronic cannabis treatment significantly (p less than 0.001) increased the frequency of licking response periodically punished by shocks. This confirms the antianxiety effect of cannabis, which also appears to be mediated through a benzodiazepine receptor, as it was reduced significantly (p less than 0.001) by a benzodiazepine receptor blocker. Specific 3H-diazepam binding was carried out in frontal cortex to assess both the population and affinity of benzodiazepine receptors. Our results indicate that acute cannabis treatment has no significant effect, whereas chronic cannabis treatment significantly increased 3H-diazepam binding as compared with controls. Scatchard analysis further reveals that increased affinity is responsible for increased binding to these receptors. It is therefore our contention that the antianxiety effect of cannabis is mediated through central benzodiazepine receptors.

Repeated naloxone administration in schizophrenia: a phase II World Health Organization Study.

In the context of a previous WHO collaborative study, six research centers reported that naloxone (0.3 mg/kg) produced significant improvement in symptomatology in neuroleptic-treated patients. In the current Phase II WHO study, repeated (4 days) naloxone (0.3 mg/kg) administration was performed in schizophrenic patients (n = 43) from five WHO collaborating centers using a double-blind, placebo-controlled design. Both naloxone and placebo administrations were associated with significant reductions in symptoms. Naloxone, however, was not superior to placebo. These data are discussed in relation to endorphin hypotheses of schizophrenia.

Markers in psychoses: studies from India.

Genetic considerations are important in studying the pathogenesis of the psychoses. There are few reports from India, however, which have pursued a "biological marker" approach to functional illness of this type. A review of such few studies as do exist is presented to add to contemporary knowledge in the area. Recommendations are also made for evolving newer research strategies.

Propranolol in schizophrenia.

1. 15 schizophrenic patients diagnosed according to criteria of I.C.D.-9 were treated with d1-propranolol in a 4 week open study. 2. A fixed dose schedule was followed and a maximum dose of 1920 mg/day was reached by day 17. 3. Results revealed a significant reduction in core schizophrenic symptoms of CPRS & BPRS starting between 1st and second weeks of therapy. Higher doses were well tolerated and serious bradycardia occurred only in 3 patients. 4. The implications of these results are discussed.

Circulating testosterone in pure motor stroke.

Serum LH, FSH and testosterone were quantitated in 9 patients with pure motor stroke within 24-48 h of its reported onset. High circulating LH with normal or low testosterone was noted in 8 of them. In response to an intravenous bolus of GnRH, the LH responses were exaggerated in all, but the FSH responses in 7 of them were comparable to those in eugonadal age matched controls. The rise in testosterone following 2000U hCG daily for 3 consecutive days was insignificant in the patients group compared to the controls. The data suggest normally operative pituitary testicular feed-back but decreased Leydig cell response in pure motor stroke.

Social factors and mental illness: an analysis of first admissions to a psychiatric hospital.

The authors have investigated all first admissions to a psychiatric hospital during a five year period (1972-1976) to determine the diagnostic socio-economic and demographic variables among these patients. Variables of age, sex, religion, education, occupation, income, domicile, family structure and size, and sibling position have been studied. A comparison of these variables has been made between neuroses and psychoses; and between schizophrenia and affective disorders. The significant variables are discussed in the context of socio-cultural practices in India.

Depressive disorders in the developing world.

In order to find out whether the finding of different prevalence rates for depression in rural and urban areas of India is supported by a difference in symptomatology as well, 30 rural and 42 urban hospitalized MDP-Depressed patients were compared on Hamilton Depression Scale and Schedule for Standardized Assessment of Patients with Depressive Disorders. Symptoms of guilt, loss of concentration and memory were significantly more in urban patients whereas gastrointestinal somatic symptoms were significantly higher in rural subjects. The difference is probably due to urban subjects being more sophisticated, expressive and familiar with mental disorders as compared to rural patients who being more familiar with somatic illnesses tend to somatize their psychic distress.

Effect of sulphonylurea therapy on insulin sensitivity in non insulin dependent diabetics.

Insulin tolerance test was done to assess the insulin sensitivity in a group of untreated non insulin dependent diabetic subjects before and after sulfonylurea (tolbutamide, glibenclamide, glipizide) therapy. The parameters studied were KITT, slope of the blood glucose fall, summation values, and area under the curve of glucose response. All the three commonly used sulphonylurea drugs improved insulin sensitivity after 4 weeks of therapy.

Aetiologic factors in male infertility: clinical, microbiological and hormonal evaluation.

Seventy two infertile men were studied. History of small pox and mumps infection was noted in 4 and 3 patients respectively. Seven patients had varicocele (9.2%), and small atrophic testes were found in 9 (12.5%). Azoospermia was reported in 41 (58.3%) and oligospermia in 17 (23.6%), and 14 patients (19.4%) had normal sperm counts. Mycoplasma were grown from urethral swabs in 25 (35%) patients. Mean LH and FSH were elevated in azoospermics (p less than 0.001), E2-17B in oligospermics (p less than 0.001) and FSH in normospermic (p less than 0.01) patients. Hypergonadotropism suggestive of primary testicular failure was recorded in 43 (59.7%) patients. Hypogonadotropism was noted in 3 (4%) and hyperprolactinemia due to pituitary microadenoma induced infertility in only one patient. No aetiology could be determined in 11 (16%) patients.

Hysteria in India: clinical aspects.

Two hundred fifteen cases (38 males, 177 females) of hysteria were studied, while the investigators kept in view the cultural factors affecting clinical presentations and influencing etiological aspects of emotional disorders. India hysterics of either sex presented with multiple symptoms, usually combinations of physical and psychogenic manifestations. There was no significant difference between clinical presentations as observed in the two sexes. Sensory disturbances, paraplegias, monoplegias were in low frequency. Although a wide range of premorbid personality patterns could be identified in the present study, the most frequently occurring personality in females was hysterical and in males antisocial. Family history and parental deprivation did not appear to offer any relationship towards the occurrence of hysteria.