Vitamin D supplementation and adverse skeletal and non-skeletal outcomes in individuals at increased cardiovascular risk: Results from the International Polycap Study (TIPS)-3 randomized controlled trial.

BACKGROUND AND AIMS: Vitamin D has mostly been tested in Western populations. We examined the effect of high dose vitamin D in a population drawn predominantly from outside of Western countries. METHODS AND RESULTS: This randomized trial tested vitamin D 60,000 IU monthly in 5670 participants without vascular disease but at increased CV risk. The primary outcome was fracture. The secondary outcome was the composite of CV death, myocardial infarction stroke, cancer, fracture or fall. Death was a pre-specified outcome. Mean age was 63.9 years, and 3005 (53.0%) were female. 3034 (53.5%) participants resided in South Asia, 1904 (33.6%) in South East Asia, 480 (8.5%) in South America, and 252 (4.4%) in other regions. Mean follow-up was 4.6 years. A fracture occurred in 20 participants (0.2 per 100 person years) assigned to vitamin D, and 19 (0.1 per 100 person years) assigned to placebo (HR 1.06, 95% CI 0.57-1.99, p-value = 0.86). The secondary outcome occurred in 222 participants (1.8 per 100 person years) assigned to vitamin D, and 198 (1.6 per 100 person years) assigned to placebo (HR 1.13, 95% CI 0.93-1.37, p = 0.22). 172 (1.3 per 100 person years) participants assigned to vitamin D died, compared with 135 (1.0 per 100 person years) assigned to placebo (HR 1.29, 95% CI 1.03-1.61, p = 0.03). CONCLUSION: In a population predominantly from South Asia, South East Asia and South America, high-dose vitamin D did not reduce adverse skeletal or non-skeletal outcomes. Higher mortality was observed in the vitamin D group. REGISTRATION NUMBER: NCT01646437.

Changing the paradigm in postherpetic neuralgia treatment: lidocaine 700 mg medicated plaster.

OBJECTIVE: Chronic pain is currently considered a disease state with biopsychosocial consequences and a negative impact on patients' quality of life (QoL). Pain from postherpetic neuralgia (PHN) can persist for months or years and is a prototypical example of chronic pain. We analyzed PHN as a model of chronic pain, including its effects on QoL and clinical aspects. We explored treatment options, focusing on the topical treatment with lidocaine 700 mg medicated plaster (LMP) and how this impacts PHN management. MATERIALS AND METHODS: This article is a narrative review of published studies. Preclinical and clinical studies were retrieved from literature through a search performed in PubMed/MEDLINE. RESULTS: To choose the appropriate treatment for chronic pains, such as PHN, not only efficacy but also tolerability, manageability, practicality, and compliance are important factors, especially in the long term. It is also important to set treatment expectations with the patients as total suppression of pain may be unrealistic, and a balance needs to be found between pain control and the minimization of adverse events. In this respect, LMP may be the best currently available treatment: it is easy to use, has low systemic absorption and thus a low risk for pharmacological interactions. Therefore, treatments can be personalized, and concomitant medications can be added, if needed. Recent data from a real-world study support this view by showing that LMP has superior effectiveness in reducing pain and improving the QoL compared to other commonly used systemic treatments and confirming its good tolerability profile that is mainly characterized by localized skin reactions. CONCLUSIONS: LMP is one of the best currently available treatment options for PHN patients balancing good efficacy with an excellent tolerability profile and can therefore be considered for use as a first-line treatment for PHN.

Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial.

BACKGROUND: The combination of three blood-pressure-lowering drugs at low doses, with a statin, aspirin, and folic acid (the polypill), could reduce cardiovascular events by more than 80% in healthy individuals. We examined the effect of the Polycap on blood pressure, lipids, heart rate, and urinary thromboxane B2, and assessed its tolerability. METHODS: In a double-blind trial in 50 centres in India, 2053 individuals without cardiovascular disease, aged 45-80 years, and with one risk factor were randomly assigned, by a central secure website, to the Polycap (n=412) consisting of low doses of thiazide (12.5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin. The primary outcomes were LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinary 11-dehydrothromboxane B2 for the antiplatelet effects of aspirin, and rates of discontinuation of drugs for safety. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00443794. FINDINGS: Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood pressure by 7.4 mm Hg (95% CI 6.1-8.1) and diastolic blood pressure by 5.6 mm Hg (4.7-6.4), which was similar when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure increased with the number of drugs used (2.2/1.3 mm Hg with one drug, 4.7/3.6 mm Hg with two drugs, and 6.3/4.5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0.70 mmol/L (95% CI 0.62-0.78), which was less than that with simvastatin alone (0.83 mmol/L, 0.72-0.93; p=0.04); both reductions were greater than for groups without simvastatin (p<0.0001). The reductions in heart rate with Polycap and other groups using atenolol were similar (7.0 beats per min), and both were significantly greater than that in groups without atenolol (p<0.0001). The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283.1 ng/mmol creatinine, 95% CI 229.1-337.0) compared with the three blood-pressure-lowering drugs plus aspirin (350.0 ng/mmol creatinine, 294.6-404.0), and aspirin alone (348.8 ng/mmol creatinine, 277.6-419.9) compared with groups without aspirin. Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill. INTERPRETATION: This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk.

Patient and caregiver reported facilitators of self-care among patients with chronic heart failure: report from a formative qualitative study.

Background: Adherence to a complex, yet effective medication regimen improves clinical outcomes in patients with chronic heart failure (CHF). However, patient adherence to an agreed upon plan for medication-taking is sub-optimal and continues to hover at 50% in developed countries. Studies to improve medication-taking have focused on interventions to improve adherence to guideline-directed medication therapy, yet few of these studies have integrated patients' perceptions of what constitutes effective strategies for improved medication-taking and self-care in everyday life. The purpose of this formative study was to explore patient perceived facilitators of selfcare and medication-taking. Methods: We conducted in-depth interviews of patients with long standing heart failure admitted to the cardiology and internal medicine wards of a South Indian tertiary care hospital. We purposively sampled using the following criteria: sex, socio-economic status, health literacy and patient reported medication adherence in the month prior to hospitalization. We employed inductive coding to identify facilitators. At the end of 15 interviews (eight patients and seven caregivers; seven patient-caregiver dyads), we arrived at theoretical saturation for facilitators. Results: Facilitators could be classified into intrinsic (patient traits - situational awareness, self-efficacy, gratitude, resilience, spiritual invocation and support seeking behavior) and extrinsic (shaped by the environment - financial security and caregiver support, company of children, ease of healthcare access, trust in provider/hospital, supportive environment and recognizing the importance of knowledge). Conclusions: We identified and classified a set of key patient and caregiver reported self-care facilitators among Indian CHF patients. The learnings from this study will be incorporated into an intervention package to improve patient engagement, overall self-care and patient-caregiver-provider dynamics.

Using an amplitude analysis to measure the photon polarisation in B → K π π γ decays.

A method is proposed to measure the photon polarisation parameter λ γ in b → s γ transitions using an amplitude analysis of B → K π π γ decays. Simplified models of the K π π system are used to simulate B + → K + π - π + γ and B 0 → K + π - π 0 γ decays, validate the amplitude analysis method, and demonstrate the feasibility of a measurement of the λ γ parameter irrespective of the model parameters. Similar sensitivities to λ γ are obtained with both the charged and neutral hadronic systems. In the absence of any background and distortion due to experimental effects, the statistical uncertainty expected from an analysis of B + → K + π - π + γ decays in an LHCb data set corresponding to an integrated luminosity of 9  fb - 1 is estimated to be 0.009. A similar measurement using B 0 → K + π - π 0 γ decays in a Belle II data sample corresponding to an integrated luminosity of 5  ab - 1 would lead to a statistical uncertainty of 0.018.

Melioidosis.

Melioidosis is an emerging infectious disease in India acquired through percutaneous inoculation or contaminated water. Known risk factors include diabetes mellitus, renal failure, cirrhosis, and malignancy. Melioidosis presents with a febrile illness, with protean manifestations ranging from septicemia to localized abscess formation. We present the case of a 42-year-old male from a non-endemic region who presented with fever of 2 months duration, sepsis, persistent pneumonia, right hip joint pain and hepatic and splenic abscesses. Aspiration of the joint and soft tissue fluid collection and subsequent culture yielded gram negative bacilli identified as Burkholderia pseudomallei. The epidemiology, clinical features, and laboratory diagnosis of this rare infection and its treatment is reviewed.

Characteristics of particulate and non-particulate corticosteroids. Indications for their use in chronic pain treatments. / Características de los corticoides particulados y no particulados. Condicionantes para su uso en el tratamiento del dolor crónico.

Corticosteroids been used frequently in pain treatments since the middle of last century (1952). Due to a review of the complications as a result of their application in epidural injections, the United States of America Food and Drug Administration (FDA) issued an «alert controversy¼ requesting that a warning label should be added to injectable corticosteroids, where risks must be described (loss of sight, brain damage, paralysis and death) when administering by this route. It must be mentioned that there are different types of corticosteroids with diverse characteristics, which as a result, may produce different side-effects. Due to the aforementioned developments, the controversies that have arisen, and the lack of well-conducted studies on the use of steroids in epidural injections, we must begin by reviewing their indications in different pain conditions.

Relationship of glucose and insulin levels to the risk of myocardial infarction: a case-control study.

OBJECTIVE: To assess the relationship between dysglycemia and myocardial infarction in nondiabetic individuals. BACKGROUND: Nondiabetic hyperglycemia may be an important cardiac risk factor. The relationship between myocardial infarction and glucose, insulin, abdominal obesity, lipids and hypertension was therefore studied in South Asians-a group at high risk for coronary heart disease and diabetes. METHODS: Demographics, waist/hip ratio, fasting blood glucose (FBG), insulin, lipids and glucose tolerance were measured in 300 consecutive patients with a first myocardial infarction and 300 matched controls. RESULTS: Cases were more likely to have diabetes (OR 5.49; 95% CI 3.34, 9.01), impaired glucose tolerance (OR 4.08; 95% CI 2.31, 7.20) or impaired fasting glucose (OR 3.22; 95% CI 1.51, 6.85) than controls. Cases were 3.4 (95% CI 1.9, 5.8) and 6.0 (95% CI 3.3, 10.9) times more likely to have an FBG in the third and fourth quartile (5.2-6.3 and >6.3 mmol/1); after removing subjects with diabetes, impaired glucose tolerance and impaired fasting glucose, cases were 2.7 times (95% CI 1.5-4.8) more likely to have an FBG >5.2 mmol/l. A fasting glucose of 4.9 mmol/l best distinguished cases from controls (OR 3.42; 95% CI 2.42, 4.83). Glucose, abdominal obesity, lipids, hypertension and smoking were independent multivariate risk factors for myocardial infarction. In subjects without glucose intolerance, a 1.2 mmol/l (21 mg/dl) increase in postprandial glucose was independently associated with an increase in the odds of a myocardial infarction of 1.58 (95% CI 1.18, 2.12). CONCLUSIONS: A moderately elevated glucose level is a continuous risk factor for MI in nondiabetic South Asians with either normal or impaired glucose tolerance.

Isolation by solid-phase extraction and liquid chromatographic determination of mutagenic amines in beef extracts.

A solid-phase extraction method was successfully optimized for the isolation and preconcentration of five mutagenic amines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 3-amino-1-methyl-5H-pyrido[4,3-b]indole, 2-amino-9H-pyrido[2,3-b]indole, 2-amino-3-methyl-9H-pyrido[2,3-b]indole and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine, and two co-mutagens, 1-methyl-9H-pyrido[4,3-b]indole and 9H-pyrido[4,3-b]indole. Coupling of diatomaceous earth, propylsulphonyl silica gel, and octadecylsilane cartridges was used to separate selectively the imidazopyridine and indolpyridine derivatives from those of quinoxaline and quinoline. A method based on this sample preparation was applied to the determination of twelve heterocyclic amines and related substances in a commercial beef extract using HPLC with electrochemical and fluorescence detection. Good recovery values were obtained, ranging between 55 and 99%. The co-mutagens 1-methyl-9H-pyrido[4,3-b]indole (harman) and 9H-pyrido[4,3-b]indole (norharman) were found in the beef extract at levels of 110 and 53 ng g-1, respectively, and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and 2-amino-9H-pyrido[2,3-b]indole (A alpha C) were tentatively identified.

Liquid chromatography-electrospray mass spectrometry with in-source fragmentation for the identification and quantification of fourteen mutagenic amines in beef extracts.

Conditions for the liquid chromatography-electrospray mass spectrometric (LC-ES-MS) determination of the fourteen most abundant heterocyclic amines and related compounds that can be produced in thermally processed foods were established. The simultaneous separation of all HAs on an octadecylsilane microbore column using a gradient elution with 5 mM ammonium acetate, pH 4.0, and acetonitrile was optimized. The mass spectra obtained at different extraction voltages were studied. The highest extraction voltages provided structural information for the characterization of these amines. Good detection limits comparable with those of LC and electrochemical detection were obtained. The method was applied to the analysis of these mutagens in beef extracts after a solid-phase extraction clean-up and in-source fragmentation had been applied for confirmation purposes. The levels of several heterocyclic amines measured were estimated to be in the range of 7.8-135.2 ng g-1.

Liquid chromatography-atmospheric-pressure chemical ionization mass spectrometry as a routine method for the analysis of mutagenic amines in beef extracts.

A liquid chromatography-mass spectrometry (LC-MS) method using atmospheric-pressure chemical ionisation as interface was developed for the simultaneous determination of 14 heterocyclic aromatic amines and related compounds in beef extracts. The separation was performed on a conventional C18 column using a binary mobile phase composed of acetonitrile and 50 mM ammonium acetate at pH 5.7, and elution was carried out in gradient mode. Several parameters influencing the mass spectra were optimized, and the effect of the variation of cone voltage on the mass spectra was studied. The [M+H]+ ions and some fragments produced in the source were observed in the mass spectra when several extraction voltages were applied. Quality parameters (run-to-run and day-to-day reproducibility, intervals of linearity, and limits of detection) were studied in the optimum working conditions. The method was used to analyze the heterocyclic amines present in a commercial beef extract. Therefore, a solid-phase extraction clean-up procedure was performed prior the LC-MS analysis due to the complexity of the sample and the compounds Glu-P-1, Harman, Norharman and A alpha C were identified in the samples at ppb levels and successfully confirmed using in-source fragmentation.

Determination of heterocyclic amines by pneumatically assisted electrospray liquid chromatography-mass spectrometry.

Electrospray ionization mass spectrometry was applied to the study of the amines IQ, Trp-P-1, Trp-P-2, PhIP and A alpha C and the co-mutagens harman and norharman. The results obtained on a triple quadrupole mass spectrometer equipped with a pneumatically assisted electrospray source are reported. The chromatographic conditions were optimized with a reversed-phase column (1 mm I.D.) using acetonitrile-5 mM ammonium acetate (pH 6.7) (50:50) as the mobile phase at a flow-rate of 50 microliters min-1. Different parameters influencing the mass spectra were investigated. For these compounds [M + H]+ in the positive-ion mode and also some fragments produced through collisionally activated decomposition in the interface were observed. Detection limits of 5.4-44 pg were obtained for standard solutions of these amines. Analysis of a meat extract was performed by HPLC-MS using single-ion monitoring after a solid-phase extraction clean-up.

Solid-phase extraction for the selective isolation of polycyclic aromatic hydrocarbons, azaarenes and heterocyclic aromatic amines in charcoal-grilled meat.

A method for the simultaneous analysis of 12 mutagenic and/or carcinogenic compounds is described; these substances belong to three different chemical groups: polycyclic aromatic hydrocarbons (PAHs), azaarenes, i.e., nitrogen-containing polycyclic aromatic hydrocarbons (PANHs), and heterocyclic aromatic amines (HAAs). The selective enrichment procedure includes coupling of solid-phase extraction (SPE) steps using diatomaceous earth, propylsulfonic acid, silica gel and octadecylsilane columns. The eluted fractions were analysed by high-performance liquid chromatography with UV and electrochemical detection. Levels measured were estimated to be 4-19 ng g-1. Peak confirmation was carried out by GC-MS for both PAHs and PANHs, and by LC with a photodiode array detector for HAAs. The method was applied to the analysis of charcoal-grilled meat and was judged to be generally applicable for detection of these mutagens at the ppb level in processed foods.

Formation of the mutagen IFP in model systems and detection in restaurant meats.

Mixtures of the free amino acids, creatine and glucose, were dry-heated to model the potential formation of heterocyclic amines in meats. The formation of the mutagenic amine IFP (determined to be 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine) was investigated by varying heating time, heating temperature, and precursors. With an optimized mixture of glutamine, creatine, and glucose, heated at 200 degrees C for 60 min, 2 mg of IFP was purified for studies to define its structure. Trideuteriomethyl-IFP was made from trideuteriomethylcreatinine in the model system for use in LC-MS detection of IFP in foods. Analysis of well-done meats purchased from restaurants showed about half to contain IFP at levels from 1.4 to 46 ng/g of cooked meat, demonstrating human exposure to this mutagen.

Formation of mutagenic/carcinogenic heterocyclic amines in dry-heated model systems, meats, and meat drippings.

Mixtures of amino acids, creatine, and glucose simulating the composition of six different kinds of meats (beef, chicken breast, chicken thigh, turkey breast, pork, and fish) were dry-heated to simulate the formation of heterocyclic amines in meats. The presence of 16 heterocyclic amines was investigated in the model systems and in the six meats and their corresponding meat drippings to determine the importance of meat composition to heterocyclic amine formation. Nine mutagenic amines (IQ, MeIQ, 8-MeIQx, 4,8-DiMeIQx, PhIP, IQx, IFP, DMIP, and TMIP) were found to be present at concentrations >0.1 ng/g in some of the model systems and in some of the meats or pan residues. Heterocyclic amine concentrations clearly are affected by precursor composition in this model system, and the same nine heterocyclic amines formed in the meat and in the model system show that this is a well-controlled surrogate for the reaction conditions that occur in meats during cooking.

Food heating and the formation of heterocyclic aromatic amine and polycyclic aromatic hydrocarbon mutagens/carcinogens.

Heterocyclic aromatic amines (HAA) and polycyclic aromatic hydrocarbons (PAH) are mutagens and animal carcinogens sometimes formed when foods are heated or processed. Determining their role in cancer etiology depends on comparing human exposures and determining any significant dose-related effects. Chemical analysis of foods shows that flame-grilling can form both PAH and HAA, and that frying forms predominantly HAA. With detection limits of about 0.1 ng/g, amounts found in commercially processed or restaurant foods range from 0.1 to 14 ng/g for HAA, and levels of PAH up to 1 ng/g in a liquid smoke flavoring. Laboratory fried samples have greater amounts of PAH, up to 38 ng/g in hamburgers, and high levels of HAA, over 300 ng/g, are measured in grilled chicken breast. Understanding the processing conditions that form PAH and HAA can lead to methods to greatly reduce their occurrence in processed foods.

Use of the logistic organ dysfunction system to study mortality in an Indian intensive care unit.

BACKGROUND: Mortality in Indian intensive care units has not been well studied. Scoring systems are used to predict mortality of patients admitted to such units. Some scoring systems predict hospital mortality while others predict mortality in intensive care units. We used the logistic organ dysfunction system to study the hospital and intensive care unit mortalities in our intensive care unit. METHODS: We prospectively studied 527 consecutively admitted patients in 1997 to the medical intensive care unit in St John's Medical College Hospital, Bangalore. The outcomes studied were death in hospital and death in the intensive care unit. Using standardized mortality ratios, we compared our observed hospital and intensive care unit mortalities with the hospital mortality predicted by the logistic organ dysfunction system. RESULTS: The standardized mortality ratios for hospital deaths was 1.3 with a confidence interval of 1.17-1.49 and for intensive care unit deaths it was 1.0 with a confidence interval of 0.89-1.18. The hospital mortality rates in our setting are significantly higher (p < 0.05) than the predicted hospital mortality rates of the published western model for intensive care unit patients. The intensive care unit mortality rates are not significantly different from the predicted hospital mortality rates of the published western model for intensive care unit patients. CONCLUSION: Our intensive care unit mortality rate is comparable to the western hospital mortality rate. However, after transfer of patients out of the unit, the hospital mortality is higher.

Teaching medical ethics in a medical college in India.

To the best of our knowledge, medical ethics is not taught as a separate subject in Indian medical colleges. St John's Medical College has a programme for teaching medical ethics to its undergraduate students. We describe here the structure of our programme, the syllabus and the teaching methodology. We feel that we have an effective way of teaching medical ethics at our medical college and would encourage other medical colleges to introduce the subject in their curriculum.

Changing pattern of antibiotic sensitivity of Salmonella typhi.

BACKGROUND: The emergence of multidrug-resistant Salmonella typhi led to the use of quinolones as the first-line drug in the treatment of adult patients with typhoid fever. However, over the last few years there has been an impression that patients on ciprofloxacin tended to take longer to defervesce. We studied the response and antibiotic sensitivity patterns during 2 time periods to assess the changes that may have occurred. METHODS: A retrospective analysis was done of blood culture-positive patients with Salmonella typhi infection during 1991 and 1996-97. The mode of presentation treatment history, antibiotic sensitivity pattern, antibiotics administered, response to therapy and the complications that ensued were studied. RESULTS: In vitro sensitivity to ciprofloxacin was found to be 100% in both the study groups. It was found that a greater number of patients were sensitive to ampicillin (80%), chloramphenicol (80%) and co-trimoxazole (80%) during 1996-97 as compared to 1991, when sensitivity to ampicillin was 63%, chloramphenicol 65% and co-trimoxazole 65%. The mean (SD) defervescence period in 1991 was 6 (2.3) days and in 1996-97 was 6 (2) days (p > 0.05). CONCLUSION: In vitro sensitivity of Salmonella typhi to ciprofloxacin remains 100%. There was an increase in the sensitivity to ampicillin, chloramphenicol and co-trimoxazole which have been rarely used over the past few years. There was no significant difference in the time taken to defervesce between the two study periods.