Brain-derived neurotrophic factor ameliorates brain stem cardiovascular dysregulation during experimental temporal lobe status epilepticus

Background

Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20–30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action.

Methodology/Principal Findings

In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47^phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47^phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses.

Conclusions/Significance

We conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II-derived NO leads to a reduction in baroreflex-mediated sympathetic vasomotor tone during experimental TLSE; to be ameliorated by the upregulated BDNF/TrkB signaling via inhibition of p47^phox phosphorylation. This information offers a new vista in devising therapeutic strategy towards minimizing mortality associated with TLSE.     

Carcinogen treatment in mouse selectively expressing activated N-Ras Q61K in melanocytes recapitulates metastatic cutaneous melanoma development

The incidence of melanoma has significantly increased, and a better understanding of its pathogenesis and development of new therapeutic strategies are urgently needed. Here, we describe a murine model of metastatic cutaneous melanoma using C57BL/6 mice expressing a mutated human N-Ras gene under the control of a tyrosinase promoter (TyrRas). These mice were topically exposed to 7,12- dimethylbenzanthracene (DMBA) for brief exposure periods. Cutaneous melanoma developed at the site of exposure on average by 19 weeks of age and in 80% of mice. Importantly, as in humans, melanoma development was associated with subsequent metastasis to tumor-draining lymph nodes. Critically, such metastatic behavior is transplantable, as intradermal inoculation of melanoma cells from TyrRas-DMBA mice into non-transgenic mice led to the growth of melanoma and, again, metastasis to skin-draining lymph nodes. This metastatic melanoma model closely mimics human pathology and should be a useful tool for studying melanoma pathogenesis and developing new therapies.     

Fatal hepatitis E viral infection in pregnant women in Ghana: a case series

ABSTRACT: BACKGROUND: Viral infections during pregnancy can pose serious threats to mother and fetus from the time of conception to the time of delivery. These lead to congenital defects, spontaneous abortion and even death. The definitive diagnosis and management of pregnancy-related viral infections may be challenging especially in less resourced countries. CASE PRESENTATION: We present clinical and laboratory responses to the diagnosis and management of three cases of fulminant hepatitis secondary to Hepatitis E viral infection in pregnancy.Case 1 was a 31-year-old Ghanaian woman who presented with a week's history of passing dark urine as well as yellowish discoloration of the eyes. She subsequently developed fulminant hepatitis secondary to Hepatitis E viral infection, spontaneously aborted at 24 weeks of gestation and later died.Case 2 was also a 31-year-old Ghanaian woman who was admitted with a four-day history of jaundice. She had low grade fever, but no history of abdominal pain, haematuria, pale stool or pruritus. She next developed fulminant hepatitis secondary to Hepatitis E viral infection. However, she did not miscarry but died at 28 weeks of gestation.Case 3 was a 17-year-old Ghanaian woman who was referred to the tertiary health facility on account of jaundice and anaemia. She had delivered a live male infant at maturity of 32 weeks but noticed she was jaundiced and had a presentation of active disease 3 days prior to delivery. The baby was icteric at birth and on evaluation, had elevated bilirubin (mixed type) with normal liver enzymes. Hepatitis E virus infection was confirmed in both mother and baby. However, the jaundice and the hepatomegaly resolved in mother and baby after 5 and 12 days respectively. CONCLUSION: To the best of our knowledge, these are the first documented cases of fatal fulminant hepatic failures resulting from HEV infection in Ghana.     

Robust reference intervals for Liver function test (LFT) analytes in newborns and infants

ABSTRACT: Back groundReference intervals (RIs) are ranges of upper and lower limits of a given analyte which are used for a laboratory test to determine whether a disease is present or absent or to know if the patient is at risk for future disease states. In Ethiopia, a country with highly diversified population groups and geographical sites, there are no established RIs to metabolic analytes including the liver function test (LFT) analytes for the pediatric population though it has been known that liver function assessment in this population is vital as a result of varied vulnerability to both endogenous and xenobiotic substances. METHODS: A cross sectional study was conducted in Tikur Anbessa Specialized Hospital (TASH) and Teklehaymanot Health Center (THC) from November 2010 to April 2011. 117 cord blood (from newborns) and venous blood samples (from infants) were collected and analyzed using HumaStar 300. All pre-analytical, analytical and post-analytical aspects were thoroughly controlled. A robust, CLSI/ IFCC recommended, method was used for the determination of upper and lower end points covering 95% of the reference values of each analyte with respective 90% CIs using MedCalc(R) software. RESULTS: Combined RIs for newborns and infants were established for albumin, AST, ALP, direct bilirubin and total bilirubin to be 3.88-5.82 g/dl, 16.1-55.4U/l, 130-831U/l, <0.41 mg/dl and <1.37 mg/dl respectively. But, separated RIs were indicated for ALT and GGT as 1.2-23.1U/l and 6.94-24.8U/l ALT; and 30.6-160.7U/L and 10--28.2U/l GGT for newborns and infants respectively. Some maternal and infantile factors were identified to affect the values of analytes. CONCLUSION: Almost all analytes were different from previously reported values for other target population of similar age group, kit insert values and adult values. So, interpretation of values of these analytes in newborns and infants of Ethiopian population sounds better to be performed by using such RIs taking the effect of some maternal and infantile factors in to account.     

Relationship between treatment preference and weight loss in the context of a randomized controlled trial

Randomized controlled trials (RCTs) are considered the gold standard used to assess the efficacy of treatment. While a well implemented RCT can produce an unbiased estimate of the relative difference between treatment groups, the generalizability of these findings may be limited. Specific threats to the external validity include treatment preference. The purposes of this study were to: (i) assess whether receiving one's treatment preference was associated with weight loss and retention and (ii) whether receiving one's treatment preference modified the relationship between the treatments and weight loss. Treatment preference was assessed in 250 subjects prior to but independent of randomization into either low-carbohydrate or low-fat diets. Treatment preference was a predictor of weight loss (P = 0.002) but not retention (P = 0.90). Participants who received their preference lost less weight (-7.7 kg, 95% confidence interval (CI): -9.3 to -6.1) than participants who did not receive their preference (-9.7 kg, 95% CI: -11.4 to -8.1) and participants who did not report a strong preference at baseline (-11.2 kg, 95% CI: -12.6 to -9.7) (P = 0.04 and P = 0.0004, respectively). Treatment preference did not modify the effect of the treatment on weight loss. Contrary to conceptual predictions, this study failed to identify an interaction between treatment preference and weight loss in the setting of a randomized trial. Until treatment preference effects are definitively ruled out in this domain, future studies might consider stratifying their randomization procedure by treatment preference rather than excluding participants with strong treatment preferences.     

C-terminal functionalization of nylon-3 polymers: effects of C-terminal groups on antibacterial and hemolytic activities

Nylon-3 polymers contain β-amino-acid-derived subunits and can be viewed as higher homologues of poly(α-amino acids). This structural relationship raises the possibility that nylon-3 polymers offer a platform for development of new materials with a variety of biological activities, a prospect that has recently begun to receive experimental support. Nylon-3 homo- and copolymers can be prepared via anionic ring-opening polymerization of β-lactams, and use of an N-acyl-β-lactam as coinitiator in the polymerization reaction allows placement of a specific functional group, borne by the N-acyl-β-lactam, at the N-terminus of each polymer chain. Controlling the unit at the C-termini of nylon-3 polymer chains, however, has been problematic. Here we describe a strategy for specifying C-terminal functionality that is based on the polymerization mechanism. After the anionic ring-opening polymerization is complete, we introduce a new β-lactam, approximately 1 equiv relative to the expected number of polymer chains. Because the polymer chains bear a reactive imide group at their C-termini, this new β-lactam should become attached at this position. If the terminating β-lactam bears a distinctive functional group, that functionality should be affixed to most or all C-termini in the reaction mixture. We use the new technique to compare the impact of N- and C-terminal placement of a critical hydrophobic fragment on the biological activity profile of nylon-3 copolymers. The synthetic advance described here should prove to be generally useful for tailoring the properties of nylon-3 materials.     

Sweet block copolymer nanoparticles: preparation and self-assembly of fully oligosaccharide-based amphiphile

The preparation of biocompatible nanocarriers that have potential applications in the cosmetic and health industries is highly desired. The self-assembly of amphiphilic block copolymers displaying biosourced polysaccharides at the surface is one of the most promising approaches. In the continuity of our works related to the preparation of "hybrid" amphiphilic oligosaccharide-based block copolymers, we present here the design of a new generation of self-assembled nanoparticles composed entirely of oligosaccharide-based amphiphilic block co-oligomers (BCO). These systems are defined by a covalent linkage of the two saccharidic blocks through their reducing end units, resulting in a sweet "head-to-head" connection. As an example, we have prepared and studied a BCO in which the hydrophilic part is composed of a free maltoheptaosyl derivative clicked to a hydrophobic part composed of a peracetylated maltoheptaosyl derivative. This amphiphilic BCO self-assembles to form spherical micelles in water with an average diameter of 30 nm. The efficient enzymatic hydrolysis of the maltoheptaose that constitutes the shell of the micelles was followed by light scattering and colorimetric methods.     

Sliding window analyses for optimal selection of mini-barcodes, and application to 454-pyrosequencing for specimen identification from degraded DNA

DNA barcoding remains a challenge when applied to diet analyses, ancient DNA studies, environmental DNA samples and, more generally, in any cases where DNA samples have not been adequately preserved. Because the size of the commonly used barcoding marker (COI) is over 600 base pairs (bp), amplification fails when the DNA molecule is degraded into smaller fragments. However, relevant information for specimen identification may not be evenly distributed along the barcoding region, and a shorter target can be sufficient for identification purposes. This study proposes a new, widely applicable, method to compare the performance of all potential 'mini-barcodes' for a given molecular marker and to objectively select the shortest and most informative one. Our method is based on a sliding window analysis implemented in the new R package SPIDER (Species IDentity and Evolution in R). This method is applicable to any taxon and any molecular marker. Here, it was tested on earthworm DNA that had been degraded through digestion by carnivorous landsnails. A 100 bp region of 16 S rDNA was selected as the shortest informative fragment (mini-barcode) required for accurate specimen identification. Corresponding primers were designed and used to amplify degraded earthworm (prey) DNA from 46 landsnail (predator) faeces using 454-pyrosequencing. This led to the detection of 18 earthworm species in the diet of the snail. We encourage molecular ecologists to use this method to objectively select the most informative region of the gene they aim to amplify from degraded DNA. The method and tools provided here, can be particularly useful (1) when dealing with degraded DNA for which only small fragments can be amplified, (2) for cases where no consensus has yet been reached on the appropriate barcode gene, or (3) to allow direct analysis of short reads derived from massively parallel sequencing without the need for bioinformatic consolidation.     

Increasing incidence and age at diagnosis among children with type 1 diabetes mellitus over a 20-year period in Auckland (New Zealand)

Background

We aimed to evaluate the incidence of type 1 diabetes mellitus in children <15 years of age (yr) in the Auckland region (New Zealand) over 20 years (1990–2009).

Methods

We performed a retrospective review of all patients <15 yr diagnosed with type 1 diabetes, from an unselected complete regional cohort.

Results

There were 884 new cases of type 1 diabetes, and age at diagnosis rose from 7.6 yr in 1990/1 to 8.9 yr in 2008/9 (r² = 0.31, p = 0.009). There was a progressive increase in type 1 diabetes incidence among children <15 yr (p<0.0001), reaching 22.5 per 100,000 in 2009. However, the rise in incidence did not occur evenly among age groups, being 2.5-fold higher in older children (10–14 yr) than in the youngest group (0–4 yr). The incidence of new cases of type 1 diabetes was highest in New Zealand Europeans throughout the study period in all age groups (p<0.0001), but the rate of increase was similar in New Zealand Europeans and Non-Europeans. Type 1 diabetes incidence and average annual increase were similar in both sexes. There was no change in BMI SDS shortly after diagnosis, and no association between BMI SDS and age at diagnosis.

Conclusions

There has been a steady increase in type 1 diabetes incidence among children <15 yr in Auckland over 20 years. Contrary to other studies, age at diagnosis has increased and the greatest rise in incidence occurred in children 10–14 yr. There was little change in BMI SDS in this population, providing no support for the ‘accelerator hypothesis’.     

Theories of willpower affect sustained learning

Building cognitive abilities often requires sustained engagement with effortful tasks. We demonstrate that beliefs about willpower-whether willpower is viewed as a limited or non-limited resource-impact sustained learning on a strenuous mental task. As predicted, beliefs about willpower did not affect accuracy or improvement during the initial phases of learning; however, participants who were led to view willpower as non-limited showed greater sustained learning over the full duration of the task. These findings highlight the interactive nature of motivational and cognitive processes: motivational factors can substantially affect people's ability to recruit their cognitive resources to sustain learning over time.