The effect of ponalrestat on sorbitol levels in the lens of obese and diabetic mice

Sorbitol levels were determined in lens of genetically obese (ob/ob) and diabetic (db/db) mice, as well as in lean mice (+/db, +/ob) made diabetic by administration of streptozotocin (STZ). Treatment of lean mice with STZ resulted in hypoinsulinemia, whereas the ob/ob and db/db mice were hyperinsulinemic. Hyperglycemia was present in STZ-treated +/db and +/ob mice and in db/db mice, whereas relative euglycemia was observed in ob/ob mice and untreated +/db and +/ob mice. Sorbitol levels were elevated in lens tissue of db/db mice and STZ-treated +/db. In contrast, no changes in sorbitol content were observed in ob/ob mice and +/ob mice treated with STZ, suggesting that aldose reductase activity in lens of this animal model is considerably less than that present in db/db mice. Oral treatment of db/db mice and STZ-treated +/db mice with Ponalrestat reduced hyperglycemia-induced sorbitol accumulation significantly in lens, indicating that aldose reductase inhibitors may ameliorate long-term complications associated with sorbitol accumulation in diabetes.     

Streptococcus pneumoniae serotype-2 childhood meningitis in Bangladesh: a newly recognized pneumococcal infection threat

Background

Streptococcus pneumoniae is a leading cause of meningitis in countries where pneumococcal conjugate vaccines (PCV) targeting commonly occurring serotypes are not routinely used. However, effectiveness of PCV would be jeopardized by emergence of invasive pneumococcal diseases (IPD) caused by serotypes which are not included in PCV. Systematic hospital based surveillance in Bangladesh was established and progressively improved to determine the pathogens causing childhood sepsis and meningitis. This also provided the foundation for determining the spectrum of serotypes causing IPD. This article reports an unprecedented upsurge of serotype 2, an uncommon pneumococcal serotype, without any known intervention.

Methods and Findings

Cases with suspected IPD had blood or cerebrospinal fluid (CSF) collected from the beginning of 2001 till 2009. Pneumococcal serotypes were determined by capsular swelling of isolates or PCR of culture-negative CSF specimens. Multicenter national surveillance, expanded from 2004, identified 45,437 patients with suspected bacteremia who were blood cultured and 10,618 suspected meningitis cases who had a lumber puncture. Pneumococcus accounted for 230 culture positive cases of meningitis in children <5 years. Serotype-2 was the leading cause of pneumococcal meningitis, accounting for 20.4% (45/221; 95% CI 15%–26%) of cases. Ninety eight percent (45/46) of these serotype-2 strains were isolated from meningitis cases, yielding the highest serotype-specific odds ratio for meningitis (29.6; 95% CI 3.4–256.3). The serotype-2 strains had three closely related pulsed field gel electrophoresis types.

Conclusions

S. pneumoniae serotype-2 was found to possess an unusually high potential for causing meningitis and was the leading serotype-specific cause of childhood meningitis in Bangladesh over the past decade. Persisting disease occurrence or progressive spread would represent a major potential infection threat since serotype-2 is not included in PCVs currently licensed or under development.     

Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core

A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.     

Association between ultrasound-detected synovitis and knee pain: a population-based case–control study with both cross-sectional and follow-up data

Background

An important role for synovial pathology in the initiation and progression of knee osteoarthritis has been emphasised recently. This study aimed to examine whether ultrasonography-detected synovial changes associate with knee pain (KP) in a community population.

Methods

A case–control study was conducted to compare people with early KP (n?=?298), established KP (n?=?100) or no KP (n?=?94) at baseline. Multinomial logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) between groups adjusted for radiographic osteoarthritis (ROA) severity and other confounding factors. After 1 year, 255 participants with early and established KP completed the follow-up questionnaire for changes in KP. Logistic regression with adjustment was used to determine predictors of KP worsening.

Results

At baseline, effusion was associated with early KP (OR 2.64, 95% CI 1.57–4.45) and established KP (OR 5.07, 95% CI 2.74–9.38). Synovial hypertrophy was also associated with early KP (OR 5.43, 95% CI 2.12–13.92) and established KP (OR 13.27, 95% CI 4.97–35.43). The association with effusion diminished when adjusted for ROA. Power Doppler signal was uncommon (early KP 3%, established KP 2%, controls 0%). Baseline effusion predicted worsening of KP at 1 year (OR 1.95, 95% CI 1.05–3.64). However, after adjusting for ROA, the prediction was insignificant (adjusted OR 0.95, 95% CI 0.44–2.02).

Conclusions

Ultrasound effusion and synovial hypertrophy are associated with KP, but only effusion predicts KP worsening. However, the association/prediction is not independent from ROA. Power Doppler signal is uncommon in people with KP. Further study is needed to understand whether synovitis is directly involved in different types of KP.

     

Health risk assessment of ‘tiger prawn seed’ collectors exposed to heavy metal pollution in the conserved mangrove forest of Indian Sundarbans: A socio-environmental perspective

Heavy metals contamination from anthropogenic sources in waterways of conserved mangrove ecosystem (Indian Sundarbans) poses serious health hazard to the economically marginalized ‘tiger prawn seed’ (TPS) collectors. Principal component analysis identifies Pb, Ni and Cd as anthropogenic pollutant in Indian Sundarbans. It is observed that Cu, Fe and Zn concentration increases in monsoon, whereas concentration of Cd and Pb decreases in comparison to pre-monsoon levels at all seven fishing villages. Economic status has been assessed using Wealth Rank Tool, which indicates 16–71% of population is in acute economic stress conditions and 5–70% of populations engaged in unsustainable TPS collection for their livelihood. Focus group discussion shows that collectors are exposed (exposure time (ET)) to contaminated water for 3–7 h/d, and lifetime exposure (exposure duration (ED)) varies from 5 to 20 yr. Using site-specific ET and ED results, cumulative hazard quotient (HQ) dermal is estimated to be higher in female than in male. HQ varies from medium (≥1 to <4) to high (>4) due to Cd pollution (0.1–0.26 mg L^-1). The study suggests that promoting alternative sustainable livelihood through group-based organizations (poultry, organic farming, entrepreneurship and transport) could be an effective solution to this problem.     

The Cost and Cost-Effectiveness of Scaling up Screening and Treatment of Syphilis in Pregnancy: A Model

Background

Syphilis in pregnancy imposes a significant global health and economic burden. More than half of cases result in serious adverse events, including infant mortality and infection. The annual global burden from mother-to-child transmission (MTCT) of syphilis is estimated at 3.6 million disability-adjusted life years (DALYs) and $309 million in medical costs. Syphilis screening and treatment is simple, effective, and affordable, yet, worldwide, most pregnant women do not receive these services. We assessed cost-effectiveness of scaling-up syphilis screening and treatment in existing antenatal care (ANC) programs in various programmatic, epidemiologic, and economic contexts.

Methods and Findings

We modeled the cost, health impact, and cost-effectiveness of expanded syphilis screening and treatment in ANC, compared to current services, for 1,000,000 pregnancies per year over four years. We defined eight generic country scenarios by systematically varying three factors: current maternal syphilis testing and treatment coverage, syphilis prevalence in pregnant women, and the cost of healthcare. We calculated program and net costs, DALYs averted, and net costs per DALY averted over four years in each scenario. Program costs are estimated at $4,142,287 – $8,235,796 per million pregnant women (2010 USD). Net costs, adjusted for averted medical care and current services, range from net savings of $12,261,250 to net costs of $1,736,807. The program averts an estimated 5,754 – 93,484 DALYs, yielding net savings in four scenarios, and a cost per DALY averted of $24 – $111 in the four scenarios with net costs. Results were robust in sensitivity analyses.

Conclusions

Eliminating MTCT of syphilis through expanded screening and treatment in ANC is likely to be highly cost-effective by WHO-defined thresholds in a wide range of settings. Countries with high prevalence, low current service coverage, and high healthcare cost would benefit most. Future analyses can be tailored to countries using local epidemiologic and programmatic data.     

Identification of serotype in culture negative pneumococcal meningitis using sequential multiplex PCR: implication for surveillance and vaccine design

Background

PCR-based serotyping of Streptococcus pneumoniae has been proposed as a simpler approach than conventional methods, but has not been applied to strains in Asia where serotypes are diverse and different from other part of the world. Furthermore, PCR has not been used to determine serotype distribution in culture-negative meningitis cases.

Methodology

Thirty six serotype-specific primers, 7 newly designed and 29 previously published, were arranged in 7 multiplex PCR sets, each in new hierarchies designed for overall serotype distribution in Bangladesh, and specifically for meningitis and non-meningitis isolates. Culture-negative CSF specimens were then tested directly for serotype-specific sequences using the meningitis-specific set of primers. PCR-based serotyping of 367 strains of 56 known serotypes showed 100% concordance with quellung reaction test. The first 7 multiplex reactions revealed the serotype of 40% of all, and 31% and 48% non-meningitis and meningitis isolates, respectively. By redesigning the multiplex scheme specifically for non-meningitis or meningitis, the quellung reaction of 43% and 48% of respective isolates could be identified. Direct examination of 127 culture-negative CSF specimens, using the meningitis-specific set of primers, yielded serotype for 51 additional cases.

Conclusions

This PCR approach, could improve ascertainment of pneumococcal serotype distributions, especially for meningitis in settings with high prior use of antibiotics.     

Mildew of oleaster (Elaeagnus oxycarpa Schlecht.) registered in large industrial cities (Pavlodar,Aksu, Ekibastuz) of the Pavlodar region

Purpose: Vegetation plays a very important role in industrial regions in terms of not only air purification, but also oxygen enrichment, air humidity, and city aesthetics. The paper presents the authors’ study of oleaster mildew during 2012–2013 in the cities of Pavlodar, Ekibastuz, and Aksu. Method: The species composition of mildew, patterns of its growth and reproduction, seasonal dynamics, and the level of trees infection according to a six-score scale were determined. Result: Three cultivars of mildew from three genera were registered. The species composition of mildew of oleaster is studied for the first time in large industrial cities of the Pavlodar region. The comparative analysis of the systematic structure of phytopathogenic fungi was followed by the study of the micro flora of green planting in megalopolises. The seasonal dynamics of growth, development, and reproduction was determined. The impact of pests on host-plants was studied. Conclusion: Timely diagnosis and localization of disease outbreak increases the likelihood of successful treatment and saving of plants.