Machine learning-based protein signatures for differentiating hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy (HDP) result in major maternal and fetal complications. Our study aimed to find a panel of protein markers to identify HDP by applying machine-learning models. The study was conducted on a total of 133 samples, divided into four groups, healthy pregnancy (HP, n = 42), gestational hypertension (GH, n = 67), preeclampsia (PE, n = 9), and ante-partum eclampsia (APE, n = 15). Thirty circulatory protein markers were measured using Luminex multiplex immunoassay and ELISA. Significant markers were screened for potential predictive markers by both statistical and machine-learning approaches. Statistical analysis found seven markers such as sFlt-1, PlGF, endothelin-1(ET-1), basic-FGF, IL-4, eotaxin and RANTES to be altered significantly in disease groups compared to healthy pregnant. Support vector machine (SVM) learning model classified GH and HP with 11 markers (eotaxin, GM-CSF, IL-4, IL-6, IL-13, MCP-1, MIP-1α, MIP-1ß, RANTES, ET-1, sFlt-1) and HDP with 13 markers (eotaxin, G-CSF, GM-CSF, IFN-gamma, IL-4, IL-5, IL-6, IL-13, MCP-1, MIP-1ß, RANTES, ET-1, sFlt-1). While logistic regression (LR) model classified PE with 13 markers (basic FGF, IL-1ß, IL-1ra, IL-7, IL-9, MIP-1ß, RANTES, TNF-alpha, nitric oxide, superoxide dismutase, ET-1, PlGF, sFlt-1) and APE by 12 markers (eotaxin, basic-FGF, G-CSF, GM-CSF, IL-1ß, IL-5, IL-8, IL-13, IL-17, PDGF-BB, RANTES, PlGF). These markers may be used to diagnose the progression of healthy pregnant to a hypertensive state. Future longitudinal studies with large number of samples are needed to validate these findings.

Integrated metabolomics and machine learning approach to predict hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy account for 3% to 10% of maternal-fetal morbidity and mortality worldwide. This condition has been considered one of the leading causes of maternal deaths in developing countries, such as India. OBJECTIVE: This study aimed to discover hypertensive disorders of pregnancy-specific candidate urine metabolites as markers for hypertensive disorders of pregnancy by applying integrated metabolomics and machine learning approaches. STUDY DESIGN: The targeted urinary metabolomics study was conducted in 70 healthy pregnant controls and 133 pregnant patients having hypertension as cases. Hypertensive disorders of pregnancy-specific metabolites for disease prediction were further extracted using univariate and multivariate statistical analyses. For machine learning analysis, 80% of the data were used for training (79 for hypertensive disorders of pregnancy and 42 for healthy pregnancy) and validation (27 for hypertensive disorders of pregnancy and 14 for healthy pregnancy), and 20% of the data were used for test sets (27 for hypertensive disorders of pregnancy and 14 for healthy pregnancy). RESULTS: The statistical analysis using an unpaired t test revealed 44 differential metabolites. Pathway analysis showed mainly that purine and thiamine metabolism were altered in the group with hypertensive disorders of pregnancy compared with the healthy pregnancy group. The area under the receiver operating characteristic curves of the 5 most predominant metabolites were 0.98 (adenosine), 0.92 (adenosine monophosphate), 0.89 (deoxyadenosine), 0.81 (thiamine), and 0.81 (thiamine monophosphate). The best prediction accuracies were obtained using 2 machine learning models (95% for the gradient boost model and 98% for the decision tree) among the 5 used models. The machine learning models showed higher predictive performance for 3 metabolites (ie, thiamine monophosphate, adenosine monophosphate, and thiamine) among 5 metabolites. The combined accuracies of adenosine from all models were 98.6 in the training set and 95.6 in the test set. Moreover, the predictive performance of adenosine was higher than other metabolites. The relative feature importance of adenosine was also observed in the decision tree and the gradient boost model. CONCLUSION: Among other metabolites, adenosine and thiamine metabolites were found to differentiate participants with hypertensive disorders of pregnancy from participants with healthy pregnancies; hence, these metabolites can serve as a promising noninvasive marker for the detection of hypertensive disorders of pregnancy.

Distal pancreatectomy with autologous islet transplantation in chronic pancreatitis patients: First case series from India.

Pancreatectomy and autologous islet transplantation (AIT) are performed in highly specialized centers to alleviate abdominal pain and preserve endocrine function in patients with chronic pancreatitis. We aimed at initiating AIT studies in India for the first time in patients undergoing distal pancreatectomy (DP) to prevent development of diabetes. Four out of 14 chronic pancreatitis patients screened underwent DP with AIT. Pancreatectomy specimen preserved in Wisconsin solution was subjected to islet isolation employing standard protocol using collagenase V. Isolated islets were infused into the liver through portal vein after quality assessment and the four patients were followed for 1 year. During the study period, blood glucose, fasting insulin, and C-peptide were analyzed and glucose tolerance was assessed. Three patients could be infused with islets (4363 Islet equivalents, IEQ/kg, 3860 IEQ/kg, 3600 IEQ/kg) into liver without any infusion-related complications. Two of these patients maintained glucose tolerance and glycemic control (HbA1c: 6.0%) and one became diabetic at the end of 1 year (HbA1c: 7.5%). Circulating fasting insulin increased (2.7-24.4 µU/mL and 4.0-21.2 µU/mL) and C-peptide levels increased (2.2 to 3.6, 3.4-5.6 ng/mL) in these two patients. Circulating insulin was 2.7 µU/mL and C-peptide was 2.4 ng/mL in the patient who became diabetic at the end of 1 year, while insulin was 2.3 µU/mL and C-peptide was 1.2 ng/mL in the patient who could not be infused with islets after DP. Safety and feasibility of autologous islet transplantation is established in India for the first time.

Bach2 repression mediates Th17 cell induced inflammation and associates with clinical features of advanced disease in chronic pancreatitis.

OBJECTIVES: Altered immune homeostasis and involvement of T cells has been reported in chronic pancreatitis (CP). We evaluated the role of Bach2 (BTB and CNC homology basic leucine zipper transcription factor 2), a key regulator of immune homeostasis in the chronicity of CP. METHODS: Expression of Bach2 and T-cell transcription factors, enumeration of BACH2+/CD4+ T-lymphocytes were performed by qRT-PCR and flow cytometry respectively. Bach2silenced human CD4+ T-lymphocytes were exposed to CP tissue extract to assess T-cell lineage commitment. Aryl hydrocarbon receptor (Ahr) and Deubiquitinase enzyme A (DUBA/OTUD5gene) were evaluated as markers of persistent Th17 cell differentiation. Bach2 gene (exons) was sequenced to identify risk variants and functionally validated. RESULTS: Decrease in Bach2 (p < 0.0001) and increase (p < 0.001) in TBX21, RORC, Ahr, PRDM1, IL23R mRNA were noted in pancreatic tissues, while BACH2+/CD4+ T-lymphocytes were decreased (p < 0.01) in circulation and tissues. Exposure of Bach2 silenced CD4+ T-lymphocytes to CP tissue extract showed increased Ahr, decreased OTUD5, and enhanced Th17 cell differentiation. Sequencing of Bach2 gene revealed association of novel variant (rs9111 in 5'-UTR) with advanced disease and luciferase assay confirmed its role in Bach2 repression. CONCLUSION: Bach2 repression mediates Th17 cell induced inflammation and rs9111-TT in individuals with primary genetic susceptibility to CP is associated with clinical features of advanced disease.

Noncatheter-related bacteraemia due to Chryseobacterium indologenes in an immunocompetent patient.

Chryseobacterium indologenes belongs to a group of nonfermentative Gram-negative bacilli and is an uncommon human pathogen. It causes severe infections such as septicaemia and ventilator-associated pneumonia in immunocompromised patients or after prolonged hospitalisation. We report a case of a noncatheter-related bacteraemia in a 22-year-old immunocompetent female whose blood culture showed the growth of C. indologenes, identified by Vitek GNI system (bioMerieux, France). The patient responded to treatment with ciprofloxacin. The pathogenicity and virulence factors of C. indologenes remain unclear. This case indicates that C. indologenes might cause symptomatic disease in immunocompetent persons with otherwise no associated underlying risk factors.

Interferon γ and glycemic status in diabetes associated with chronic pancreatitis.

BACKGROUND/AIMS: Although the role of cytokines in the etiopathology of chronic pancreatitis (CP) is well recognized, information on pancreatic tissue cytokines in CP with/without associated diabetes is unavailable. The aim of the present study was to identify the differences in pancreatic cytokines and observe their correlations with the glycemic status in CP. METHODS: Pancreata were obtained from CP patients (n = 44), with/without associated diabetes and non-diabetic control subjects (n= 20). Patients with CP were classified into two groups after ascertaining their diabetic status. Pancreatic cytokines (IL 1ß, IL 6, IL 8, IL 10, IL 12P70, TNF α, IFN γ) were analyzed by flow cytometer. The influence of individual and cocktail of cytokines on glucose stimulated insulin release (GSIR) was examined by challenging the islets from control subjects. RESULTS: The pancreatic IFN γ levels in diabetic and non diabetic CP patients were significantly higher in comparison to controls. The glucose stimulated insulin release (GSIR) in response to high glucose concentration in control islets, islets from non-diabetic and diabetic CP patients was 8.2, 5.67 and 3.15 µU × 10(-3)/min/islet equivalent respectively. IFN γ resulted in 82.35% decrease in GSIR from the control islet cells at a concentration of >20 pg/ml which was reversed by epigallocatechin-3-gallate (EGCG). CONCLUSION: These results suggest that IFN γ among other cytokines, play a major role in ß-cell dysfunction associated with CP.

ß-Cell dysfunction in chronic pancreatitis.

Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by irreversible destruction of pancreatic secretory parenchyma, fibrosis, exocrine atrophy, and endocrine insufficiency leading to diabetes. Secondary diabetes occurring in CP subsequent to destruction of pancreatic ß-cells is distinct, since it involves ß-cell dysfunction amidst an inflammatory milieu. Even though considerable knowledge is available on the pathophysiology and clinical management of CP, relatively much less is known about the molecular events leading to ß-cell dysfunction. Investigators have demonstrated that altered morphology, reduced ß-cell mass, and ß-cell numbers result in endocrine insufficiency. However, recent reports and our observations suggest that ß-cell dysfunction develops in the early stages of CP while clinical diabetes manifests later, when there is profound fibrosis. In the early stages, altered internal milieu and physiology arising due to inflammation and release of cytokines might lead to deranged signaling pathways and islet dysfunction. Subsequently, development of fibrosis causes islet destruction. This suggests that endocrine deficiency in CP is multifactorial. Although the role of transcription factors (Pdx-1, MafA, NeuroD) on ß-cell functions is understood, alterations in internal milieu of pancreatic tissue that affects ß-cell functions in CP has not been elucidated. In this review, we summarize the factors that have an effect on islet functions. Understanding molecular events of ß-cell dysfunction in CP can lead to the development of targeted preventive and therapeutic modalities.

Making endoscopy mobile: a novel initiative for public healthcare.

Public healthcare has progressed immensely in the past few decades. However, the rural masses in the developing and underdeveloped countries very often have limited access to the advanced healthcare technology. At the Asian Institute of Gastroenterology, Hyderabad, India, the Rural Health Care Project has been initiated in an attempt to provide cost-effective gastrointestinal care to the rural population. The Project was implemented by traveling to remote rural areas in a bus that had been converted into a mobile hospital and equipped with basic diagnostic facilities including a custom-made endoscopy unit. The mobile hospital and endoscopy unit is accompanied by a telemedicine vehicle that transmits all procedures and data to the main telemedicine center at the parent institute in Hyderabad. Our efforts have resulted in cost-effective management and robust data collection of several common gastrointestinal illnesses in remote rural areas of the Indian state of Andhra Pradesh. To date, 32756 endoscopic procedures have been carried out in a population of over 10 million people spanning 4837 villages. Overall, 72% of the population has had a positive finding on upper gastrointestinal endoscopy (primarily related to acid peptic diseases). Interestingly, <1% of the population have had colonic polyps on screening colonoscopy, whereas the prevalence of infective colitis has been high. This whole exercise has produced a high level of satisfaction among both beneficiaries and care-givers; it has also offered doctors in training the opportunity to encounter and manage common public health-related problems. This program is funded by philanthropic donations.

Rate coefficients for the OH + HC(O)C(O)H (glyoxal) reaction between 210 and 390 K.

Rate coefficients, k1(T), over the temperature range of 210-390 K are reported for the gas-phase reaction OH + HC(O)C(O)H (glyoxal) --> products at pressures between 45 and 300 Torr (He, N2). Rate coefficients were determined under pseudo-first-order conditions in OH using pulsed laser photolysis production of OH radicals coupled with OH detection by laser-induced fluorescence. The rate coefficients obtained were independent of pressure and bath gas. The room-temperature rate coefficient, k1(296 K), was determined to be (9.15 +/- 0.8) x 10-12 cm3 molecule-1 s-1. k1(T) shows a negative temperature dependence with a slight deviation from Arrhenius behavior that is reproduced over the temperature range included in this study by k1(T) = [(6.6 +/- 0.6) x 10-18]T2[exp([820 +/- 30]/T)] cm3 molecule-1 s-1. For atmospheric modeling purposes, a fit to an Arrhenius expression over the temperature range included in this study that is most relevant to the atmosphere, 210-296 K, yields k1(T) = (2.8 +/- 0.7) x 10-12 exp[(340 +/- 50)/T] cm3 molecule-1 s-1 and reproduces the rate coefficient data very well. The quoted uncertainties in k1(T) are at the 95% confidence level (2sigma) and include estimated systematic errors. Comparison of the present results with the single previous determination of k1(296 K) and a discussion of the reaction mechanism and non-Arrhenius temperature dependence are presented.

Hepatic calcification following dengue virus-induced fulminant hepatic failure.

Hepatic calcification can be seen with various infectious and neoplastic conditions. We report a 32-year- old man who developed massive calcification in the right lobe of liver following recovery from dengue virus-associated fulminant liver failure.

A longitudinal household study of Streptococcus pneumoniae nasopharyngeal carriage in a UK setting.

A 10-month longitudinal household study of pre-school children and their families was undertaken with monthly visits collecting epidemiological data and nasopharyngeal swabs in Hertfordshire, England from 2001 to 2002. Pneumococcal culture was with standard methods. In total, 121 families (489 individuals) took part. Mean prevalence of carriage ranged from 52% for age groups 0-2 years, 45% for 3-4 years, 21% for 5-17 years and 8% for >or=18 years. Carriage occurred more than once in 86% of children aged 0-2 years compared to 36% of those aged >or=18 years. The most prevalent serotypes in the 0-2 years age group were 6B followed by 19F, 23F, 6A and 14. Young children were responsible for the majority of introductions of new serotypes into a household. Erythromycin resistance (alone or in combination) occurred in 10% of samples and penicillin non-susceptibility in 3.7%. Overall the recently licensed 7-valent conjugate vaccine (PCV) would protect against 64% of serotypes with no intra-serogroup cross protection and 82% with such protection. Nasopharyngeal carriage of S. pneumoniae is common in a UK setting in the pre-conjugate vaccine era. PCV would protect against a large proportion of carriage isolates. However, the impact of vaccination on non-vaccine serotypes will need to be monitored.

Cases of perforated duodenal ulcer treated in College of Medical Sciences, Bharatpur over a period of one year.

BACKGROUND: Eighteen patients were studied in our institution between January and December 2002. Simple closure followed by eradication of Helicobacter Pylori was used to manage the cases of perforated duodenal ulcer. METHOD: After resuscitation, laparoscopy followed by simple closure of perforation reinforced with pedicled omental patch was performed for all the patients. H- Pylori eradication using "triple regime" was done in all. Follow-up between 6 to 12 months was done, for which endoscopy and Visick's grade was used. RESULTS: All the patients were male, maximum incidence (39%) noted in 51 to 60 age group. Mean time interval between start of symptoms and surgery was 60 hours. As a result the patients were moribund with gross purulent peritonitis and poor general condition. Chest infection was the commonest complication (44%) and two patients (11%) with very poor prognosis died during post operative period. Good to excellent results using Visick's grades were obtained in 81% surviving patients. Endoscopy did not show active ulcer in any of the patients. CONCLUSION: Patients with perforated duodenal ulcer were late in presenting to the hospital, precluding the option of definitive surgery for peptic ulcer disease. Simple closure of perforated duodenal ulcer if combined with eradication of H-Pylori is an effective method of treatment of duodenal perforation and is not associated with high recurrence of symptoms of peptic ulcer disease.

Interaction of pathogenic Neisseria with host defenses. What happens in vivo?

N. gonorrhoeae initiates infection by adhering to and invading columnar epithelial cells. Over time these activities often induce inflammation, with the influx of neutrophils and serum into the urethral lumen, cervical os, conjunctiva, and the like. At least some of these infected niches contain CMP-NANA (cytidine monophospho-N-acetyl neuraminic acid, also called CMP-sialic), contain sialylated gonococci, and are relatively or strictly anaerobic due to neutrophil and gonococcal metabolism and to the site of disease, that is, the peritoneal cavity. Gonococci thus encounter environmental conditions, reagents, and substrates in the human body that are not normally present in vitro. Knapp and Clark were the first to successfully grow gonococci anaerobically in an easily reproducible system, allowing researchers to begin to investigate in vitro the effects of anaerobiosis on gonococcal virulence traits. As a result of a series of elegant and in depth studies, Smith and Parsons and their colleagues showed that growth in CMP-NANA confers on the gonococcus a high degree of phenotypic (readily reversible) serum resistance and that CMP-NANA is available in vivo at sites of gonococcal infection and disease; gonococci become covalently coated with sialic acid and they become serum resistant (reviewed in refs. 8-10). Given that gonococci growing in the absence of oxygen or in the presence of CMP-NANA probably more closely resemble gonococci growing inside the human host, we studied several possible virulence traits of gonococci cultivated under these conditions. We first observed that anaerobic growth (in the absence of CMP-NANA) increases gonococcal resistance to killing by low (but not high) concentrations of normal human serum. We also asked whether anaerobic growth affected gonococcal association with host cells. Contrary to the effects on serum killing, anaerobic growth (in the absence of CMP-NANA) does not appear to affect the ability of gonococci (expressing certain adhesive outer membrane proteins called Opa proteins) to bind to and enter human epithelial cell lines or to bind to or resist killing by human neutrophils. The results from studies investigating the modulatory role of CMP-NANA were more striking. Growth in CMP-NANA dramatically inhibits the adherence of Opa+ gonococci to human neutrophils. It does not, however, appear to significantly decrease their sensitivity to phagocytic killing or to in vitro killing by lysosomal contents (aqueous extracts of human neutrophil granules).(ABSTRACT TRUNCATED AT 400 WORDS)

Kinetics of the OH Reaction with Methyl Chloroform and Its Atmospheric Implications.

The rate coefficients for the reaction of hydroxyl (OH) radicals with methyl chloroform (CH(3)CCI(3)) were measured between 243 and 379 kelvin with the pulsed photolysis-laserinduced fluorescence method. The measured rate coefficients at 298 and 277 kelvin were approximately 20 and approximately 15%, respectively, lower than earlier values. These results will increase the tropospheric OH concentrations derived from the CH(3)CCI(3) budget analysis by approximately 15%. The predicted atmospheric lifetimes of species whose main loss process is the reaction with OH in the troposphere will be lowered by 15% with consequent changes in their budgets, global warming potentials, and ozone depletion potentials.

Atmospheric Lifetime of CHF2Br, a Proposed Substitute for Halons.

The rate coefficients, k(1), for the reaction of OH with CHF(2)Br have been measured using pulsed photolysis and discharge flow techniques at temperatures (T) between 233 and 432 K to be k(1), = (7.4 +/- 1.6) x 10(-13) exp[-(1300 +/- 100)/T] cubic centimeters per molecule per second. The ultraviolet absorption cross sections, sigma, of this molecule between 190 and 280 nanometers were measured at 296 K. The k(1), and sigma values were used in a one-dimensional model to obtain an atmospheric lifetime of approximately 7 years for CHF(2)Br. This lifetime is shorter by approximately factors of 10 and 2 than those for CF(3)Br and CF(2)ClBr, respectively. The ozone depletion potentials of the three compounds will reflect these lifetimes.

Comparing the productivity of family planning operations: an American experience.

This paper reports a comparison of the productivity of 77 public family planning programs in North Carolina. It combines an empirical statistical approach to identify differences with field studies of high and low performers based on our expanding knowledge of service organization performance and productivity. Its applicability in less developed countries is discussed in the context of existing productivity studies. After adjustment of performance for demographic and environmental factors, high performance was found in centers with flexible layouts and patient flows, flexibility in staffing patterns and schedules, creativity in circumventing manpower shortages, greater ingenuity in reaching target groups, especially teenagers, and more responsiveness to client demands. Poor performers were characterized by lack of the above and had more satisfied staffs. The key appears to be the role of the department director and board in setting more demanding standards for performance and in providing creativity, flexibility, and urgency in problem solving.