The effect of metformin on biomarkers associated with breast cancer outcomes: a systematic review, meta-analysis, and dose-response of randomized clinical trials.

PURPOSE: Breast cancer is a leading cause of cancer mortality in developed countries. We performed a meta-analysis of randomized clinical trials to investigate the effect of metformin on biomarkers associated with breast cancer outcomes and to explore the dose-response relationship. METHODS: A systematic search was performed from onset of the database to January 2019 in MEDLINE/PubMed, SCOPUS, and Cochrane library to identify randomized clinical trials investigating the impact of metformin on insulin, glucose, CRP, leptin, body mass indices (BMI), cholesterol, Ki-67, and Homeostatic Model Assessment for Insulin-Resistance (HOMA-IR). Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI) using a random-effects models. RESULTS: Nine studies providing 1,363 participants were included in the meta-analysis. Pooled results showed a significant reduction in insulin (WMD: - 0.99 U/ml, 95% CI - 1.66, - 0.33), glucose (WMD: - 1.78 ml/dl, 95% CI - 2.96, - 0.60), CRP (WMD: - 0.60 mg/l, 95% CI - 0.88, - 0.33), HOMA-IR (WMD: - 0.45, 95% CI - 0.77, - 0.11), leptin (WMD: - 2.44 ng/ml, 95% CI - 3.28, - 1.61), BMI (WMD: - 0.55 kg/m2, 95% CI - 1.00, - 0.11), and Ki-67 (WMD: - 4.06, 95% CI - 7.59, - 0.54). Results of the subgroup analyses showed that insulin, glucose, and BMI decreased more significantly when the duration of administering metformin intervention was above 4 weeks. We did not observe non-linear changes in the dose-response relationship between metformin and biomarkers as outcomes. CONCLUSIONS: Breast cancer patients receiving metformin as treatment for diabetes showed significant reduction in levels of insulin, fasting glucose, CRP, HOMA, leptin, BMI, and Ki-67.

Scrub typhus in patients with acute febrile illness: a 5-year study from India.

BACKGROUND: Scrub typhus was once thought to be a disease of rural origin and was confined to specific pockets in South Asia. Early diagnosis and treatment is extremely important as it is associated with high mortality if left untreated. AIM: To delineate the clinical and molecular epidemiology of scrub typhus in patients presenting with acute febrile illness from various parts of India. METHODS: During the study period of 5 years (October 2013 to October 2018), a total of 1742 patients with acute febrile illness <15 days were enrolled after taking informed consent. Patients were diagnosed using IgM Enzyme-linked immunosorbent assay (ELISA) based on the pre-determined region specific cut offs. Patients with positive IgM ELISA were also subjected to IgM Immunofluorescence assay and nested polymerase chain reaction (PCR) assay. The demographic and relevant clinical details of the patients were documented and analyzed. RESULTS: A total of 210 (12.1%) patients were diagnosed with scrub typhus. Of these, nested PCR was positive in only 85 patients. Sequencing and phylogenetic analysis showed that the predominant circulating genotypes were Gilliam and Karp. On multivariate analysis, acute respiratory distress syndrome, myocarditis, encephalitis/encephalopathy, jaundice and splenomegaly were significantly more common in those patients who were diagnosed with scrub typhus. A total of 14 patients diagnosed with scrub typhus succumbed to the illness. CONCLUSION: Patients with fever, headache, pulmonary manifestations, CNS manifestations, myocarditis, transaminitis or thrombocytopenia presenting in the monsoon and post-monsoon season should be evaluated for scrub typhus irrespective of the geographical location in India.

Hemoadsorption by extracorporeal cytokine adsorption therapy (CytoSorb®) in the management of septic shock: A retrospective observational study.

INTRODUCTION: Sepsis results in immunologic disturbances with the release of various inflammatory mediators such as cytokines. Cytokines can damage the cells, and the continuous release of inflammatory mediators leads to severely impaired immunity. Therefore, the reduction in cytokine levels by hemoadsorption represents a new concept for blood purification. CytoSorb® as a hemoadsorption device is a detoxification system, which aims to decrease the cytokines levels. This study was conducted to understand any beneficial effects of CytoSorb® therapy in septic patients. METHODOLOGY: This was a retrospective and observational study, approved by the scientific and ethics committee of Max Super Specialty Hospital, Patparganj, Delhi, India and conducted in compliance with current International Council for Harmonization, Good Clinical Practice, Schedule Y, and Indian Council of Medical Research guidelines. Subjects of either gender (age > 18 year) were included in the study. The data were presented as mean ± standard deviation and categorical as frequency and percentage (%). A p value less than 0.05 (p < 0.05) was considered to be statistically significant. RESULTS: A total number of 36 patients were included in the study. Majority of the patients were male with mean age (56.36 ± 14.83). After therapy, procalcitonin and total leucocyte count levels decreased within 24 h. Post therapy, sepsis-related organ failure assessment (SOFA) score of Day (D)1, D2, and D3 reduced to 10.4 ± 3.63, 8.7 ± 4.02, and 7.8 ± 3.67, respectively. The Acute Physiology and Chronic Health Evaluation (APACHE) II score and predicted mortality were lower in the survivor group as compared to the non-survivor group. CONCLUSION: Hemoadsorption using the extracorporeal adsorption device (CytoSorb®) might be an effective rescue therapy in stabilizing septic shock patients.

Molecular epidemiology of Crimean-Congo haemorrhagic fever virus in India.

Crimean-Congo haemorrhagic fever (CCHF) is an emerging zoonotic disease in India which is prevalent in neighbouring countries. CCHF virus (CCHFV) is a widespread tick-borne virus which is endemic in Africa, Asia, Eastern Europe and the Middle East. In the present study, samples of clinically suspected human cases from different areas of northern-western India were tested for the presence of CCHFV by RT-PCR through amplification of nucleocapsid (N) gene of CCHFV. Positive samples were sequenced to reveal the prevailing CCHFV genotype(s) and phylogenetic relatedness. A phylogenetic tree revealed the emergence of diverse strains in the study region showing maximum identity with the Pakistan, Afghanistan and Iran strains, which was different from earlier reported Indian strains. Our findings reveal for the first time the emergence of the Asia 1 group in India; while earlier reported CCHFV strains belong to the Asia 2 group.

Superiority of targeted neonatal echocardiography for umbilical venous catheter tip localization: accuracy of a clinician performance model.

OBJECTIVES: To compare targeted neonatal echocardiography (TnECHO) and antero-posterior (AP) chest radiographs in the localization of the umbilical venous catheter (UVC) tip and to determine the accuracy of UVC tip localization by TnECHO when performed by a trained cohort of pediatric housestaff physicians. STUDY DESIGN: Prospective, observational study of consecutive neonates requiring UVC insertion, in a tertiary care center, in an 18-month period. Chest radiographs reporting optimal position of the UVC tip were compared with the TnECHO results of the pediatric cardiologist. The latter was also compared with the results of TnECHO performed by the pediatric housestaff physicians. RESULT: Thirty neonates with birth weight ranging between 270 and 4490 g and gestational age ranging between 24 and 44 weeks were enrolled. Nine patients (27%) required UVC tip repositioning as the cardiologist performed TnECHO revealed sub-optimal tip position despite optimal position on chest radiography. Among them, four had the UVC tip in the right atrium and five in the left atrium. Compared with the cardiologist, the housestaff physicians had reported TnECHO with a high-accuracy rate (area under the receiver operating characteristic curve=0.81). CONCLUSION: TnECHO is superior to chest radiography for identifying malpositioned catheters. TnECHO performed by pediatric housestaff physicians with basic training, demonstrated high-accuracy rates.

Sarcocystis and sarcocystosis in India: status and emerging perspectives.

Sarcocystis spp. are a group of tissue cyst-forming coccidia which infect a vast range of animals as well as human beings. Found frequently in animal carcasses at slaughter, undermining their value, they have also been found associated with clinical disease. Dogs and cats are involved in the transmission. Studies in India point to a vast reservoir of infection with high prevalence rates in various livestock species. However, there is a glaring paucity of reports on the horse and Sarcocystis of the camel has remained totally unexplored so far. At least two different Sarcocystis spp. can parasitize each livestock host species. Experimental transmission studies have provided additional parameters for distinguishing the species. The clinical symptoms are generally non-specific and diagnosis in the living animal, by the presently available means, is almost impossible. Immunodiagnosis till now is beset with problem of cross-reactivity. Treatment with anti-coccidials presently tried do not seem satisfactory. Of the two zoonotic species with cattle-man and pig-man cycles, only the latter seems of some significance in India due to backyard pig-rearing and slaughter practices. It is a paradox that despite high prevalence of S. suihominis in pigs, reports of human cases are limited. This and some of the existing grey areas of information in the Indian context, have been highlighted as also possible directions for future research.

Characterization of hepatitis C virus (HCV) quasispecies dynamics upon short-term dual therapy with the HCV NS5B nucleoside polymerase inhibitor mericitabine and the NS3/4 protease inhibitor danoprevir.

In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.

The first dominant co-circulation of both dengue and chikungunya viruses during the post-monsoon period of 2010 in Delhi, India.

Independent outbreaks of dengue virus (DENV) infection and sporadic cases of chikungunya virus (CHIKV) have been recorded in the metropolitan city of Delhi on several occasions in the past. However, during a recent 2010 arboviral outbreak in Delhi many cases turned negative for DENV. This prompted us to use duplex reverse transcriptase-polymerase chain reaction (D-RT-PCR) to establish the aetiology of dengue/chikungunya through sequencing of CprM and E1 genes of dengue and chikungunya viruses. Interestingly, for the first time, both DENV and CHIKV co-circulated simultaneously and in equally dominant proportion during the post-monsoon period of 2010. DENV-1 genotype III and the East Central South African genotype of CHIKV were associated with post-monsoon spread of these viruses.

Chikungunya fever: a re-emerging viral infection.

Chikungunya (CHIK) fever is a re-emerging viral disease characterized by abrupt onset of fever with severe arthralgia followed by constitutional symptoms and rash lasting for 1-7 days. The disease is almost self-limiting and rarely fatal. Chikungunya virus (CHIKV) is a RNA virus belonging to family Togaviridae, genus Alphavirus. Molecular characterization has demonstrated two distinct lineages of strains which cause epidemics in Africa and Asia. These geographical genotypes exhibit differences in the transmission cycles. In contrast to Africa where sylvatic cycle is maintained between monkeys and wild mosquitoes, in Asia the cycle continues between humans and the Aedes aegypti mosquito. CHIKV is known to cause epidemics after a period of quiescence. The first recorded epidemic occurred in Tanzania in 1952-1953. In Asia, CHIK activity was documented since its isolation in Bangkok, Thailand in 1958. Virus transmission continued till 1964. After hiatus, the virus activity re-appeared in the mid-1970s and declined by 1976. In India, well-documented outbreaks occurred in 1963 and 1964 in Kolkata and southern India, respectively. Thereafter, a small outbreak of CHIK was reported from Sholapur district, Maharashtra in 1973. CHIKV emerged in the islands of South West Indian Ocean viz. French island of La Reunion, Mayotee, Mauritius and Seychelles which are reporting the outbreak since February, 2005. After quiescence of about three decades, CHIKV re-emerged in India in the states of Andhra Pradesh, Karnataka, Maharashtra, Madhya Pradesh and Tamil Nadu since December, 2005. Cases have also been reported from Rajasthan, Gujarat and Kerala. The outbreak is still continuing. National Institute of Communicable Diseases has conducted epidemiological, entomological and laboratory investigations for confirmation of the outbreak. These have been discussed in detail along with the major challenges that the country faced during the current outbreak.

Laccase of Cyathus bulleri: structural, catalytic characterization and expression in Escherichia coli.

Cyathus bulleri, a ligninolytic fungus, produces a single laccase the internal peptides (3) of which bear similarity to laccases of several white rot fungi. Comparison of the total amino acid composition of this laccase with several fungal laccases indicated dissimilarity in the proportion of some basic and hydrophobic amino acids. Analysis of the circular dichroism spectrum of the protein indicated 37% alpha-helical, 26% beta-sheet and 38% random coil content which differed significantly from that in the solved structures of other laccases, which contain higher beta-sheet structures. The critical role of the carboxylic group containing amino acids was demonstrated by determining the kinetic parameters at different pH and this was confirmed by the observation that a critical Asp is strongly conserved in both Ascomycete and Basidiomycete laccases. The enzyme was denatured in the presence of a number of denaturing agents and refolded back to functional state with copper. In the folding experiments under alkaline conditions, zinc could replace copper in restoring 100% of laccase activity indicating the non-essential role of copper in this laccase. The laccase was expressed in Escherichia coli by a modification of the ligation-anchored PCR approach making it the first fungal laccase to be expressed in a bacterial host. The laccase sequence was confirmed by way of analysis of a 435 bp sequence of the insert.

Development and evaluation of an in vitro isolation of street rabies virus in mouse neuroblastoma cells as compared to conventional tests used for diagnosis of rabies.

In vitro isolation of rabies virus using mouse neuroblastoma cells (MNA) was evaluated. The sensitivity and reliability of in vitro procedure was performed in comparison with mouse inoculation test (MIT), the in vivo method of virus isolation, direct fluorescent antibody test (FAT) and Sellers staining. Of the 33 animal brain samples tested, 24 (72.72%) were positive by MIT. Sensitivity of Sellers stain, FAT and rapid tissue culture infection test (RTCIT) was found to be 54.16, 100 and 91.6% respectively. Concordance of Sellers stain, FAT, RTCIT with MIT was found to be 66.6, 100 and 93.93% respectively. Two samples which were positive by FAT and MIT showed gross contamination in cell lines, which is one of the drawbacks of RTCIT. However, rabies virus could be isolated in MNA cells from two of the eight human cerebrospinal fluid (CSF) samples from clinico-epidemiologically suspected cases of rabies. Both MIT and FAT showed negative results in the two CSF samples. RTCIT appears to be a fast and reliable alternative to MIT and holds promise in antemortem diagnosis of rabies, which is otherwise, a challenging task for a reference laboratory.

Community based trials and informed consent in rural north India.

Disease control has increasingly shifted towards large scale, disease specific, public health interventions. The emerging problems of HIV, hepatitis, malaria, typhoid, tuberculosis, childhood pneumonia, and meningitis have made community based trials of interventions a cost effective long term investment for the health of a population. The authors conducted this study to explore the complexities involved in obtaining informed consent to participation in rural north India, and how people there make decisions related to participation in clinical research.

Status of lifestyle modifications in hypertension.

Hypertension is essentially the elevation of arterial blood pressure beyond an arbitrary cut off point, though the dividing line between normal and elevated BP is lacking. Hypertension can be classified into primary, essential or idiopathic hypertension on one hand, and secondary one due to some disease itself. In treating hypertension, antihypertensives have their role, but attention may be directed towards some lifestyle modifications. As regarding dietary interventions, calorie restriction may influence the minimisation of BP. Body weight reduction, less alcohol consumption, salt restriction, potassium and calcium supplementation can enhance the process of lowering BP. The role of magnesium in hypertension is debatable. Serum cholesterol level is commonly elevated in hypertensive patients and its reduction reduces the risk of non-fatal coronary events. Diet rich in plant fibres either alone or with a low fat, low sodium could lower the BP by about 5 mm Hg in hypertensives. The omega-3-polyunsaturated fatty acids found in highest concentrations in cold water fishes have a modest antihypertensive effect. Caffeine contained in two cups of coffee may raise the BP by 5 mm Hg in infrequent users but in habitual users, caffeine has no role. Deficiency of vitamin C might lead to hypertension. As regarding behavioural changes, stopping smoking, regular physical exercise, relaxation therapies like yoga, etc, have definite beneficial effect on hypertensives. The antihypertensive effect of lifestyle modifications may obviate drug therapy. For this one or more of the lifestyle modifications should be tried initially in all hypertensive patients.

Diagnostic value of push-type enteroscopy: a report from India.

OBJECTIVE: We sought to assess the diagnostic value of push-type enteroscopy in relation to indications. METHODS: Ninety-nine consecutive patients (mean age, 42+/-15 yr; 65 men) with suspected small bowel disorders underwent push enteroscopy. The indications were chronic diarrhea (n = 54), obscure gastrointestinal (GI) bleeding (n = 21), abdominal pain (n = 10), abnormal radiological studies of small bowel (n = 5), iron deficiency anemia (n = 5), and others (n = 4). Push enteroscopy was performed using the Olympus SIF-10 (160-cm) enteroscope. RESULTS: Endoscopic examination of the jejunum was successful in all the patients, except one with a distal duodenal stricture. The length of the jejunum examined ranged from 10 to 70 cm. The time taken to complete the procedure varied from 2 to 30 min. Lesions were found in nine (42.8%) patients with obscure GI bleeding; six (28.5%) had worms (Ascaris lumbricoides [n = 3], Ankylostoma duodenale [n = 3]) in the jejunum, producing multiple erosions and bleeding points. In the chronic diarrhea group, a diagnosis was made in 13 (24%) patients on enteroscopic visualization and jejunal histology: celiac disease (n = 6), tropical sprue (n = 3), Crohn's disease (n = 1), secondary lymphangiectasia (n = 1), strongyloidiasis (n = 1), and nodular lymphoid hyperplasia with giardiasis (n = 1). In patients with abdominal pain, enteroscopy provided a diagnosis in one (10%) patient. No positive diagnosis could be made on enteroscopy in patients with iron deficiency anemia and abnormal radiological studies of small bowel. CONCLUSION: Push-type enteroscopy is a useful test in the evaluation of patients with obscure GI bleeding and chronic diarrhea. In developing countries, in patients with obscure GI bleeding, the presence of worms in the jejunum is an important finding on enteroscopy. Tropical sprue, giardiasis, and strongyloidiasis are distinct findings in patients with chronic diarrhea in the present series.

Anomalous origin of the right coronary artery from the main pulmonary artery: diagnosis and management.

Anomalous origin of the right coronary artery (ARCA) from the main pulmonary artery (MPA) is a rare congenital anomaly, with only 18 reported cases in the pediatric age group. More than half of these had associated cardiac anomalies that masked the presence of ARCA. Conversely, in many patients with ARCA as an isolated anomaly, the diagnosis has been missed during lifetime. The only patient with an isolated ARCA who was diagnosed in infancy presented with congestive heart failure. Asymptomatic infants with ARCA from the MPA have not been previously reported. Three additional cases, two infants and a child with ARCA from the MPA, are reported in this paper. The diagnostic dilemmas and the prognosis are discussed and management is recommended.

Choledochal cysts in infants and children.

OBJECTIVE: To study the clinical spectrum and management of choledochal cyst in children below 12 years of age. DESIGN: Descriptive study. SETTING: Tertiary care hospital. METHODS: Twenty three children with choledochal cysts were managed between January 1991 to September 1997 and their clinical details, investigations and management were recorded. Choledochal cyst was diagnosed by ultrasonography and confirmed by ERCP or peroperative cholangioram (POC) Children were treated with antibiotics and/or percutaneous transhepatic biliary drainage if there was cholangitis and subsequently subjected to surgery (excision of the cyst and jejunal loop interposition hepaticoduodenostomy). RESULTS: The median age of these children was 3 years with an almost equal sex ratio. Predominant presentation was jaundice in 18, pain abdomen in 15, fever in 12, and lump abdomen in 9 cases. The classical triad of jaundice, pain and lump was present in only 4 cases. ERCP conducted in 7 and POC in 14 cases yielded positive findings in all. Clinically there were two distinct forms of presentation: (i) infantile form (< or = 1 year) comprised 9 infants which presented with jaundice in all, acholic stool in 6, lump abdomen in 4 but only one had classical triad; and (ii) childhood form (> 1 year) presented with pain abdomen in 12 and jaundice and cholangitis in 9 subjects each. Type I cyst was seen in 20 and type IVa in 3. Two children refused surgery, and the rest underwent surgery. Three infants died after surgery, the remaining 18 were alive and well on follow-up (median 25 months). Secondary biliary cirrhosis was seen in 6, extra hepatic biliary artresia in 2 and congenital hepatic fibrosis in 1 on histology. CONCLUSIONS: Choledochal cysts present in two clinically distinct forms. Infantile form is an important cause of cholestasis of infancy. Early diagnosis and referral is essential to prevent complications and death, and prognosis after surgery is good.