Cancer immunotherapy: present status, future perspective, and a new paradigm of peptide immunotherapeutics.
A promising new era of cancer therapeutics with agents that inhibit specific growth stimulatory pathways is finding a new niche in our armamentarium in the war against cancer. Targeted cancer therapeutics, including humanized monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are amongst the major treatment options for cancer today together with cytotoxic chemotherapies. Targeted therapies are more selective for cancer cells and improve the quality of life for cancer patients undergoing treatment. Many of these drugs have been approved by the FDA, and several more are being studied in clinical trials. Although development of targeted therapeutics has improved cancer treatment significantly, the harsh reality is that the "War on Cancer" still exists. Major challenges still exist with the currently marketed inhibitors, including limitations associated with mAbs and TKIs drug types, acquired mechanisms of drug resistance that cause patient relapse, and tumor heterogeneity. Today, there is an urgent need for the development of novel anti-tumor agents that are cheaper, stable, can selectively target cancer dependent pathways without affecting normal cells, and most importantly, avoid development of resistance mechanisms. Peptide mimics have the potential benefits of being highly selective, stable, cheap, and non-toxic. The focus of this review is to discuss the disadvantages associated with the use of monoclonal antibodies and tyrosine kinase inhibitors. A special emphasis will be placed on efforts taken in our laboratory to 1) design peptide vaccines and therapeutics that target cancer dependent pathways and 2) use a combination approach that will shut down alternative mechanisms that lead to resistance.


Maturation of alveolar bone following implantation of an rhGDF-5/PLGA composite into 1-wall intra-bony defects in dogs: 24-week histometric observations.
The aim of this study was to evaluate long-term (24 weeks) alveolar bone maturation following surgical application of recombinant human growth/differentiation factor-5 (rhGDF-5) in an injectable poly-lactide-co-glycolide-acid (PLGA) composite carrier using an established periodontal defect model. Routine, bilateral, 4 × 5 mm (width × depth), 1-wall, critical-size, intra-bony periodontal defects were surgically created at the 2nd and 4th mandibular premolar teeth in 10 Beagle dogs. The animals were randomized to receive (split-mouth design; defect sites in the same jaw quadrant getting the same treatment) rhGDF-5/PLGA high dose (188 μg/defect) versus sham-surgery control (5 animals), and rhGDF-5/PLGA low dose (37 μg/defect) versus carrier control (5 animals). The animals were euthanized for histometric analysis following a 24-week healing interval. Clinical healing was uneventful. The rhGDF-5 high dose significantly increased bone formation compared with controls in terms of bone area (p < 0.05), and a high degree of bone maturation was observed in the rhGDF-5/PLGA high dose group. Root resorption/ankylosis or other aberrant healing events were not observed. The rhGDF-5/PLGA appears to support alveolar bone healing/regeneration and the rhGDF-5/PLGA high dose uniquely increased maturation of the regenerated bone.


Complex retrieval of embedded IVC filters: alternative techniques and histologic tissue analysis.
We evaluated the safety and effectiveness of alternative endovascular methods to retrieve embedded optional and permanent filters in order to manage or reduce risk of long-term complications from implantation. Histologic tissue analysis was performed to elucidate the pathologic effects of chronic filter implantation. We studied the safety and effectiveness of alternative endovascular methods for removing embedded inferior vena cava (IVC) filters in 10 consecutive patients over 12 months. Indications for retrieval were symptomatic chronic IVC occlusion, caval and aortic perforation, and/or acute PE (pulmonary embolism) from filter-related thrombus. Retrieval was also performed to reduce risk of complications from long-term filter implantation and to eliminate the need for lifelong anticoagulation. All retrieved specimens were sent for histologic analysis. Retrieval was successful in all 10 patients. Filter types and implantation times were as follows: one Venatech (1,495 days), one Simon-Nitinol (1,485 days), one Optease (300 days), one G2 (416 days), five Günther-Tulip (GTF; mean 606 days, range 154-1,010 days), and one Celect (124 days). There were no procedural complications or adverse events at a mean follow-up of 304 days after removal (range 196-529 days). Histology revealed scant native intima surrounded by a predominance of neointimal hyperplasia and dense fibrosis in all specimens. Histologic evidence of photothermal tissue ablation was confirmed in three laser-treated specimens. Complex retrieval methods can now be used in select patients to safely remove embedded optional and permanent IVC filters previously considered irretrievable. Neointimal hyperplasia and dense fibrosis are the major components that must be separated to achieve successful retrieval of chronic filter implants.


Population differentiation in the swordtail characin (Corynopoma riisei ): a role for sensory drive?
Sensory drive, where the efficacy of a sexual signal depends on the environment in which it is employed, is a potential mechanism behind divergent evolution of secondary sexual traits. Male swordtail characins are equipped with a narrow and transparent extension of the gill cover with a flag-like structure at its tip. This opercular flag mimics a prey item and is employed by males as a 'lure' to attract the attention of females during mating attempts. We conducted a study of genetic and morphological differentiation across swordtail characin populations throughout their native range in Trinidad. The morphology of the opercular flag varied across populations and several aspects of this variation match the predicted hallmarks of sensory drive. First, morphological differentiation of the flag across populations was unrelated to genetic similarity at neutral genetic markers. Second, the shape of the flag covaried with those aspects of body shape that should reflect adaptation to different feeding regimes. Third, and most importantly, the shape of the flag covaried across populations with those environmental characteristics that should most closely reflect differences in local prey abundance. Overall, our results are consistent with a scenario where the evolution of this male sexual signal tracks food-related shifts in female sensory biases across populations, thus providing at least provisional support for a role for sensory drive in population differentiation.


Biochemical and functional analysis of two Plasmodium falciparum blood-stage 6-cys proteins: P12 and P41.
The genomes of Plasmodium parasites that cause malaria in humans, other primates, birds, and rodents all encode multiple 6-cys proteins. Distinct 6-cys protein family members reside on the surface at each extracellular life cycle stage and those on the surface of liver infective and sexual stages have been shown to play important roles in hepatocyte growth and fertilization respectively. However, 6-cys proteins associated with the blood-stage forms of the parasite have no known function. Here we investigate the biochemical nature and function of two blood-stage 6-cys proteins in Plasmodium falciparum, the most pathogenic species to afflict humans. We show that native P12 and P41 form a stable heterodimer on the infective merozoite surface and are secreted following invasion, but could find no evidence that this complex mediates erythrocyte-receptor binding. That P12 and P41 do not appear to have a major role as adhesins to erythrocyte receptors was supported by the observation that antisera to these proteins did not substantially inhibit erythrocyte invasion. To investigate other functional roles for these proteins their genes were successfully disrupted in P. falciparum, however P12 and P41 knockout parasites grew at normal rates in vitro and displayed no other obvious phenotypic changes. It now appears likely that these blood-stage 6-cys proteins operate as a pair and play redundant roles either in erythrocyte invasion or in host-immune interactions.


Study of in vitro antimicrobial and antiproliferative activities of selected Saharan plants.
The aim of the present study was the evaluation of the antimicrobial and antiproliferative activities of selected Saharan species, which are applied in the traditional medicine but not studied thoroughly from chemical and pharmacological point of view. The studied plants, namely Anthyllis henoniana, Centropodia forskalii, Cornulaca monacantha, Ephedra alata var. alenda, Euphorbia guyoniana, Helianthemum confertum, Henophyton deserti, Moltkiopsis ciliata and Spartidium saharae were collected from remote areas of North Africa, especially from the Tunisian region of Sahara. After drying and applying the appropriate extraction methods, the plant extracts were tested in antimicrobial screening assay, performed on 19 Gram-positive and -negative strains of microbes. The inhibition zones produced by plant extracts were determined by disc-diffusion method. Remarkable antibacterial activities were exhibited by extracts of Ephedra alata var. alenda and Helianthemum confertum against B. subtilis, M. catarrhalis and methicillin-resistant and non-resistant S. aureus. Minimum inhibitory concentrations of these two species were also determined. Antiproliferative effects of the extracts were evaluated against 4 human adherent cell lines (HeLa, A431, A2780 and MCF7). Notable cell growth inhibition was found for extract of Helianthemum confertum and Euphorbia guyoniana. Our results provided data for selection of some plant species for further detailed pharmacological and phytochemical examinations.


Determination of polycyclic aromatic hydrocarbons in industrial harbor sediments by GC-MS.
Analysis of the 16 polycyclic aromatic hydrocarbons (PAHs) of the US Environmental Protection Agency priority pollutant list was carried out in sediment samples of an industrial port in the southern Kaohsiung Harbor of Taiwan which is supposed to be extensively polluted by industrial wastewater discharges. The determination and quantification of PAHs in sediment samples were performed using gas chromatography coupled to mass spectrometry (GC-MS) with the aid of deuterated PAH internal standards and surrogate standards. The total concentrations of the 16 PAHs varied from 4,425 to 51,261 ng/g dw, with a mean concentration of 13,196 ng/g dw. The PAHs concentration is relatively high in the river mouth region, and gradually diminishes toward the harbor region. Diagnostic ratios showed that the possible source of PAHs in the industrial port area could be coal combustion. As compared with the US Sediment Quality Guidelines (SQGs), the various observed levels of PAHs exceeded the effects range median (ERM), and could thus cause acute biological damages. The results can be used for regular monitoring, and future pollution prevention and management should target the various industries in this region for reducing pollution.


Parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring.
We examined parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring. Cases were 538 children diagnosed with neuroblastoma between 1992 and 1994 in the United States or Canada. Age-matched controls were selected by random-digit dialing. Occupational exposures to electrical equipment and radiation sources were classified by an industrial hygienist, and average exposures to extremely low frequency magnetic fields were estimated using a job exposure matrix. Maternal exposure to a broad grouping of sources that produce radiofrequency radiation was associated with an increased incidence of neuroblastoma (odds ratio = 2.8; 95% confidence interval = 0.9-8.7). Paternal exposure to battery-powered forklifts was positively associated with neuroblastoma (odds ratio = 1.6; 95% confidence interval = 0.8-3.2), as were some types of equipment that emit radiofrequency radiation (odds ratios congruent with 2.0); however, the broad groupings of sources that produce ELF fields, radiofrequency radiation, or ionizing radiation were not associated with neuroblastoma. Paternal average extremely low frequency magnetic field exposure >0.4 microTesla was weakly associated with neuroblastoma (odds ratio = 1.6; 95% confidence interval = 0.9-2.8), whereas maternal exposure was not. Overall, there was scant supportive evidence of strong associations between parental exposures in electromagnetic spectrum and neuroblastoma in offspring.


Maternal sensitivity buffers the adrenocortical implications of intimate partner violence exposure during early childhood.
This study prospectively examined the effect of intimate partner violence (IPV) on adrenocortical reactivity and recovery during early childhood. The sample (n = 1102 mother-infant dyads; 49.2% male) was racially diverse and from predominantly low-income, rural communities. To measure IPV exposure mothers completed the Conflicts Tactics Scale, and her caretaking behaviors were observed when her child was approximately 7, 15, and 24 months of age. Children's saliva samples, later assayed for cortisol, were collected around challenge tasks designed to elicit emotional reactivity. IPV was related to a trajectory of increased cortisol reactivity from infancy to toddlerhood. By contrast, the trajectory for non-IPV-exposed children decreased in cortisol reactivity across 7 to 24 months of age. At the 24-month assessment, on average, toddlers did not exhibit a cortisol reaction; however, those exposed to high levels of violence continued to have reactivity. Accumulative levels of IPV across the first 2 years of life predicted cortisol reactivity at 24 months of age. Early (7-month) sensitive maternal behavior moderated this relationship, so that only children exposed to both early insensitivity and high accumulated IPV exhibited increased reactivity at the 24-month assessment. Findings are discussed in relation to the risky family framework.


epiflows: an R package for risk assessment of travel-related spread of disease.
As international travel increases worldwide, new surveillance tools are needed to help identify locations where diseases are most likely to be spread and prevention measures need to be implemented. In this paper we present epiflows, an R package for risk assessment of travel-related spread of disease. epiflows produces estimates of the expected number of symptomatic and/or asymptomatic infections that could be introduced to other locations from the source of infection. Estimates (average and confidence intervals) of the number of infections introduced elsewhere are obtained by integrating data on the cumulative number of cases reported, population movement, length of stay and information on the distributions of the incubation and infectious periods of the disease. The package also provides tools for geocoding and visualization. We illustrate the use of epiflows by assessing the risk of travel-related spread of yellow fever cases in Southeast Brazil in December 2016 to May 2017.


Vibrational coherence probes the mechanism of ultrafast electron transfer in polymer-fullerene blends.
The conversion of photoexcitations into charge carriers in organic solar cells is facilitated by the dissociation of excitons at the donor/acceptor interface. The ultrafast timescale of charge separation demands sophisticated theoretical models and raises questions about the role of coherence in the charge-transfer mechanism. Here, we apply two-dimensional electronic spectroscopy to study the electron transfer process in poly(3-hexylthiophene)/PCBM (P3HT/PCBM) blends. We report dynamics maps showing the pathways of charge transfer that clearly expose the significance of hot electron transfer. During this ultrafast electron transfer, vibrational coherence is directly transferred from the P3HT exciton to the P3HT hole polaron in the crystalline domain. This result reveals that the exciton converts to a hole with a similar spatial extent on a timescale far exceeding other photophysical dynamics including vibrational relaxation.


Efficacy and safety of bevacizumab plus capecitabine and irinotecan regimen for metastatic colorectal cancer.
Recent phase III trials have proven the fact that adding bevacizumab to irinotecan plus infusional 5-fluorouracil (5-FU)/leucovorin (LV) should be preferred as a first-line treatment for metastatic colorectal cancer (mCRC). But, since the data regarding bevacizumab administered together with capecitabin, an oral fluoropyrimidine, and irinotecan in patients with mCRC is limited, we aimed to analyse the efficacy and safety of bevacizumab with capecitabine plus irinotecan (BEV-CAPIRI) regimen in mCRC patients. Records of patients treated with BEV-CAPIRI regimen between January 2005 and March 2008 were reviewed. Efficacy data regarding response rates (RR) as well as safety data were collected. Progression free survival (PFS) and overall survival (OS) analyses were done by using the Kaplan-Meier method. A total number of 53 metastatic colorectal cancer patients were treated with BEV-CAPIRI regimen. The median age of this population was 57.3 +/- 11.5 (range 29-78). The treatment was well tolerated. The RR was 43.3%, while 30.1% of the patients achieved stable disease (SD). Median PFS and OS were 12.6 +/- 1.4 and 20.6 +/- 1.7 months, respectively. However, median OS was 21.3 months for male and 14.6 months for female patients. In addition, median OS and PFS was 25.3 months and 16.2 months for the patients who received BEV-CAPIRI as first-line treatment, respectively, and for the other patients it was 15.2 months and 10.2 months, respectively. In conclusion, BEV-CAPIRI is an effective and well-tolerated alternative regimen for mCRC, leading to disease control in a vast majority of patients with mCRC.


How few whales were there after whaling? Inference from contemporary mtDNA diversity.
Reconstructing the history of exploited populations of whales requires fitting a trajectory through at least three points in time: (i) prior to exploitation, when abundance is assumed to be at the maximum allowed by environmental carrying capacity; (ii) the point of minimum abundance or 'bottleneck', usually near the time of protection or the abandonment of the hunt; and (iii) near the present, when protected populations are assumed to have undergone some recovery. As historical abundance is usually unknown, this trajectory must be extrapolated according to a population dynamic model using catch records, an assumed rate of increase and an estimate of current abundance, all of which have received considerable attention by the International Whaling Commission (IWC). Relatively little attention has been given to estimating minimum abundance (N(min)), although it is clear that genetic and demographic forces at this point are critical to the potential for recovery or extinction of a local population. We present a general analytical framework to improve estimates of N(min) using the number of mtDNA haplotypes (maternal lineages) surviving in a contemporary population of whales or other exploited species. We demonstrate the informative potential of this parameter as an a posteriori constraint on Bayesian logistic population dynamic models based on the IWC Comprehensive Assessment of the intensively exploited southern right whales (Eubalaena australis) and published surveys of mtDNA diversity for this species. Estimated historical trajectories from all demographic scenarios suggested a substantial loss of mtDNA haplotype richness as a result of 19th century commercial whaling and 20th century illegal whaling by the Soviet Union. However, the relatively high rates of population increase used by the IWC assessment predicted a bottleneck that was implausibly narrow (median, 67 mature females), given our corrected estimates of N(min). Further, high levels of remnant sequence diversity (theta) suggested that pre-exploitation abundance was larger than predicted by the logistic model given the catch record, which is known to be incomplete. Our results point to a need to better integrate evolutionary processes into population dynamic models to account for uncertainty in catch records, the influence of maternal fidelity on metapopulation dynamics, and the potential for inverse density dependence (an 'Allee effect') in severely depleted populations.


The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter.
Three-dimensional organization of chromatin is fundamental for transcriptional regulation. Tissue-specific transcriptional programs are orchestrated by transcription factors and epigenetic regulators. The RUNX2 transcription factor is required for differentiation of precursor cells into mature osteoblasts. Although organization and control of the bone-specific Runx2-P1 promoter have been studied extensively, long-range regulation has not been explored. In this study, we investigated higher-order organization of the Runx2-P1 promoter during osteoblast differentiation. Mining the ENCODE database revealed interactions between Runx2-P1 and Supt3h promoters in several non-mesenchymal human cell lines. Supt3h is a ubiquitously expressed gene located within the first intron of Runx2. These two genes show shared synteny across species from humans to sponges. Chromosome conformation capture analysis in the murine pre-osteoblastic MC3T3-E1 cell line revealed increased contact frequency between Runx2-P1 and Supt3h promoters during differentiation. This increase was accompanied by enhanced DNaseI hypersensitivity along with RUNX2 and CTCF binding at the Supt3h promoter. Furthermore, interplasmid-3C and luciferase reporter assays showed that the Supt3h promoter can modulate Runx2-P1 activity via direct association. Taken together, our data demonstrate physical proximity between Runx2-P1 and Supt3h promoters, consistent with their syntenic nature. Importantly, we identify the Supt3h promoter as a potential regulator of the bone-specific Runx2-P1 promoter.


Surgery and high-dose-rate intraoperative radiation therapy for recurrent squamous-cell carcinoma of the anal canal.
Locoregionally recurrent squamous-cell carcinoma of the anal canal is managed with salvage surgery. High-dose-rate intraoperative radiation therapy has been used in selected patients with this disease to reduce the risk of local recurrence. The aim of this article is to present our institutional experience with this technique. Medical records of 14 patients with locoregionally recurrent squamous-cell carcinoma of the anal canal who underwent this technique between 1992 and 2007 were reviewed. The study was conducted at an academic cancer center. The median age was 45 years (range, 36-77), and 13 of the patients were women. All had prior radiation with or without chemotherapy. The surgical procedures included abdominoperineal resection with or without sacrectomy (n = 8), low anterior resection (n = 2), and pelvic exenteration (n = 4). The median radiation dose was 1500 cGy (range, 1500-1750). All cases of radiographic invasion of adjacent structures correctly predicted pathologic invasion. There was pathologic invasion into adjacent structures in 11 cases (79%), and adherence to the sacrum without invasion in 2 cases (14%). Surgical margins were positive (n = 6), close (<1 mm) (n = 3), and negative (n = 5). The median follow-up from our technique was 17 months (range, 5-145). Subsequent recurrence occurred in 11 cases, at a median of 8 months from treatment. Two-year actuarial control was 7.1%, and the overall survival was 21.4%. Acute toxicities included wound-healing complications (n = 6); gastrointestinal obstruction (n = 5); neurogenic bladder (n = 1); ureteral stricture (n = 3); and peripheral neuropathy (n = 2). This is a small retrospective series in which the meaningful analysis of associations between clinical variables and outcomes was not possible. Salvage surgery with high-dose-rate intraoperative radiation therapy did not appear to be associated with a locoregional control or survival benefit in this series. The addition of high-dose-rate intraoperative radiation therapy to salvage surgery is insufficient to compensate for positive surgical margins. Preoperative imaging should be used to aid in patient selection to identify those patients in whom negative margins can be obtained and to aid in the determination of appropriate salvage surgery.


Harnessing the cloud of patient experience: using social media to detect poor quality healthcare.
Recent years have seen increasing interest in patient-centred care and calls to focus on improving the patient experience. At the same time, a growing number of patients are using the internet to describe their experiences of healthcare. We believe the increasing availability of patients' accounts of their care on blogs, social networks, Twitter and hospital review sites presents an intriguing opportunity to advance the patient-centred care agenda and provide novel quality of care data. We describe this concept as a 'cloud of patient experience'. In this commentary, we outline the ways in which the collection and aggregation of patients' descriptions of their experiences on the internet could be used to detect poor clinical care. Over time, such an approach could also identify excellence and allow it to be built on. We suggest using the techniques of natural language processing and sentiment analysis to transform unstructured descriptions of patient experience on the internet into usable measures of healthcare performance. We consider the various sources of information that could be used, the limitations of the approach and discuss whether these new techniques could detect poor performance before conventional measures of healthcare quality.


Lipid emulsion for local anesthetic systemic toxicity.
The accidental overdose of local anesthetics may prove fatal. The commonly used amide local anesthetics have varying adverse effects on the myocardium, and beyond a certain dose all are capable of causing death. Local anesthetics are the most frequently used drugs amongst anesthetists and although uncommon, local anaesthetic systemic toxicity accounts for a high proportion of mortality, with local anaesthetic-induced cardiac arrest particularly resistant to standard resuscitation methods. Over the last decade, there has been convincing evidence of intravenous lipid emulsions as a rescue in local anesthetic-cardiotoxicity, and anesthetic organisations, over the globe have developed guidelines on the use of this drug. Despite this, awareness amongst practitioners appears to be lacking. All who use local anesthetics in their practice should have an appreciation of patients at high risk of toxicity, early symptoms and signs of toxicity, preventative measures when using local anesthetics, and the initial management of systemic toxicity with intravenous lipid emulsion. In this paper we intend to discuss the pharmacology and pathophysiology of local anesthetics and toxicity, and the rationale for lipid emulsion therapy.


Characterization and determination of six flavonoids in the ethnomedicine "Dragon's Blood" by UPLC-PAD-MS.
"Dragon's Blood" (DB) has long been used as an ethnomedicine in China to invigorate blood circulation for the treatment of traumatic injuries, blood stasis and pain. To comprehensively assess the quality of DB medicine, a precise and accurate method that can rapidly separate, characterize and quantify multiple active components of DB is crucial. An ultra performance liquid chromatography (UPLC) coupled with photodiode array detection (PAD) and electrospray ionization mass spectrometry (ESI-MS) method was developed for characterization and determination of six flavonoids in DB. A comprehensive validation of the developed method was conducted, and confirmed that the method presented good sensitivity, precision and accuracy. All linear regressions were acquired with R2 > 0.99, and the limits of detection ranged from 0.06 to 0.83 ng. The relative standard deviation (RSD) values were found to be within the range 1.4-3.8% for the method repeatability test. Recovery studies for the quantified compounds were found to be within the range 94.2-102.8% with RSD less than 4.9%. DB samples collected from different geographical regions were analyzed by the present method, and the results demonstrated that the contents of the six flavonoids in DB samples varied significantly. Three major active components among the six flavonoids, namely dracorhodin, (2S)-5-methoxyflavan-7-ol and (2S)-5-methoxy-6-methylflavan-7-ol, are suggested as the index for DB quality evaluation. Overall, the present hyphenation method is highly efficient and reliable, and hence suitable for the characterization and determination of the flavonoids of DB ethnomedicine.


B-cell activity markers are associated with different disease activity domains in primary Sjögren's syndrome.
B-cell activating factor (BAFF), β-2 microglobulin (β2M) and serum free light chains (FLCs) are elevated in primary SS (pSS) and associated with disease activity. We aimed to investigate their association with the individual disease activity domains of the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) in a large well-characterized pSS cohort. Sera from pSS patients enrolled in the UK Primary Sjögren's Syndrome Registry (UKPSSR) (n = 553) and healthy controls (n = 286) were analysed for FLC (κ and λ), BAFF and β2 M. Pearson correlation coefficients were calculated for patient clinical characteristics, including salivary flow, Schirmer's test, EULAR Sjögren's Syndrome Patient Reported Index and serum IgG levels. Poisson regression was performed to identify independent predictors of total ESSDAI and ClinESSDAI (validated ESSDAI minus the biological domain) scores and their domains. Levels of BAFF, β2M and FLCs were higher in pSS patients compared to controls. All three biomarkers associated significantly with the ESSDAI and the ClinESSDAI. BAFF associated with the peripheral nervous system domain of the ESSDAI, whereas β2M and FLCs associated with the cutaneous, biological and renal domains. Multivariate analysis showed BAFF, β2M and their interaction to be independent predictors of ESSDAI/ClinESSDAI. FLCs were also shown to associate with the ESSDAI/ClinESSDAI but not independent of serum IgG. All biomarkers were associated with total ESSDAI scores but with differing domain associations. These findings should encourage further investigation of these biomarkers in longitudinal studies and against other disease activity measures.


Feeding rats diets enriched in lowbush blueberries for six weeks decreases ischemia-induced brain damage.
Oxidative stress is an important element in the etiology of ischemic stroke. Lowbush blueberries (Vaccinium angustifolium Aiton) have a high antioxidant capacity and thus we determined whether consumption of lowbush blueberries would protect neurons from stroke-induced damage. Rats were fed AIN-93G diets containing 0 or 14.3% blueberries (g fresh weight/100 g feed) for 6 weeks. Stroke was then simulated by ligation of the left common carotid artery (ischemia), followed by hypoxia. One week later, plasma and urine were collected, and neuronal damage in the hippocampus was determined histologically. In control rats, hypoxia-ischemia resulted in 40 +/- 2% loss of neurons in the hippocampus of the left cerebral hemisphere, as compared to the right hemisphere. Rats on blueberry-supplemented diets lost only 17 +/- 2% of neurons in the ischemic hippocampus. Neuroprotection was observed in the CA1 and CA2 regions, but not CA3 region, of the hippocampus. The blueberry diet had no detectable effects on the plasma or urine oxygen radical absorbance capacity (ORAC) or plasma lipids. We conclude that consumption of lowbush blueberries by rats confers protection to the brain against damage from ischemia, suggesting that inclusion of blueberries in the diet may improve ischemic stroke outcomes.


Ingestive mastication in horses resembles rumination but not ingestive mastication in cattle and camels.
Horses achieve a higher degree of particle size reduction through ingestive mastication than functional ruminants. We characterized mastication using chew-monitoring halters (RumiWatch) in six domestic horses, cattle, and Bactrian camels each. All animals were offered grass hay of the same batch for 15 min. In cattle and camels, measurements were continued after eating until rumination was observed. Except for one horse, 96% of the horses' ingestive mastication data were identified as "rumination" by the proprietary RumiWatch algorithm, whereas ingestion and rumination by cattle and camels were mostly classified correctly. There were no systematic differences between cattle and camels. In cattle and camels, ingestive mastication was less regular than rumination, indicated by significantly higher standard deviations of chewing peak intervals, peak heights, and peak breadths in intraindividual comparisons. The average standard deviations of these measures were lower in horses than in cattle and camel ingestive mastication, indicating a more consistent chewing pattern in horses. Horse values were similar to those of rumination mastication, suggesting equally regular chewing motions. Regular, rhythmic chewing represents a common feature of horses and functional ruminants, but the less uniform ingestive mastication in functional ruminants represents a deviating pattern, the adaptive value of which remains unclear. In particular, it does not appear to promote a higher ingestion rate. A potential cause may be the avoidance of high tooth wear rates by delaying a more regular, systematic mastication until ingesta has been softened and the grit has been washed off in the forestomach.


Walking dynamics are symmetric (enough).
Many biological phenomena such as locomotion, circadian cycles and breathing are rhythmic in nature and can be modelled as rhythmic dynamical systems. Dynamical systems modelling often involves neglecting certain characteristics of a physical system as a modelling convenience. For example, human locomotion is frequently treated as symmetric about the sagittal plane. In this work, we test this assumption by examining human walking dynamics around the steady state (limit-cycle). Here, we adapt statistical cross-validation in order to examine whether there are statistically significant asymmetries and, even if so, test the consequences of assuming bilateral symmetry anyway. Indeed, we identify significant asymmetries in the dynamics of human walking, but nevertheless show that ignoring these asymmetries results in a more consistent and predictive model. In general, neglecting evident characteristics of a system can be more than a modelling convenience--it can produce a better model.


Acupuncture stimulation improves scopolamine-induced cognitive impairment via activation of cholinergic system and regulation of BDNF and CREB expressions in rats.
Acupuncture is an alternative therapy that is widely used to treat various neurodegenerative diseases and effectively improve cognitive and memory impairment. The aim of this study was to examine whether acupuncture stimulation at the Baihui (GV20) acupoint improves memory defects caused by scopolamine (SCO) administration in rats. We also investigated the effects of acupuncture stimulation at GV20 on the cholinergic system as well as the expression of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) in the hippocampus. SCO (2 mg/kg, i.p.) was administered to male rats once daily for 14 days. Acupuncture stimulation at GV20 was performed for 5 min before SCO injection. After inducing cognitive impairment via SCO administration, we conducted a passive avoidance test (PAT) and the Morris water maze (MWM) test to assess behavior. Acupuncture stimulation at GV20 improved memory impairment as measured by the PAT and reduced the escape latency for finding the platform in the MWM test. Acupuncture stimulation at GV20 significantly alleviated memory-associated decreases in the levels of choline acetyltransferase (ChAT), BDNF and CREB proteins in the hippocampus. Additionally, acupuncture stimulation at GV20 significantly restored the expression of choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT), BDNF and CREB mRNA in the hippocampus. These results demonstrate that acupuncture stimulation at GV20 exerts significant neuroprotective effects against SCO-induced neuronal impairment and memory dysfunction in rats. These findings suggest that acupuncture stimulation at GV20 might be useful in various neurodegenerative diseases to improve cognitive functioning via stimulating cholinergic enzyme activities and regulating BDNF and CREB expression in the brain.


Caries-preventive potential of an adhesive patch after thermomechanical loading--a microbial-based in vitro study.
To assess the enamel-protective potential of a newly devised adhesive patch for smooth enamel sealing. Approximal surfaces of 30 extracted molars were divided into three areas: the buccal thirds were treated with a flowable composite (Tetric Flow, Ivoclar Vivadent) and served as negative control sites, the lingual thirds were left untreated and served as positive control sites, and the middle thirds served as the test areas. This was sealed with either 1. a twofold application of an unfilled resin (Heliobond, Ivoclar Vivadent), 2. an adhesive prototype patch (Ivoclar Vivadent), or 3. an adhesive patch in combination with a flowable composite. After thermomechanical loading and demineralization in a microbial-based artificial caries chamber, demineralization depth was assessed using a confocal laser scanning microscope. Negative control sites treated with the flowable composite showed no signs of demineralization. Areas treated with the patch showed no signs of demineralization, irrespective of whether it was used in combination with a flowable composite or directly bonded to the enamel. Caries-like lesions in untreated sites showed a mean depth of 134.3 +/- 35.9 microm. Demineralization depth at sites treated with the unfilled resin was 76.2 +/- 26.5 microm (p = 0.023). Under the conditions of the present study, the adhesive patch under investigation completely protected the underlying enamel from demineralization. This merits further study to assess its potential as an interproximal sealant.


The Epley (canalith repositioning) manoeuvre for benign paroxysmal positional vertigo.
This is an update of a Cochrane Review first published in The Cochrane Library in Issue 1, 2002 and previously updated in 2004 and 2007.Benign paroxysmal positional vertigo (BPPV) is a syndrome characterised by short-lived episodes of vertigo in association with rapid changes in head position. It is a common cause of vertigo presenting to primary care and specialist otolaryngology clinics. Current treatment approaches include rehabilitative exercises and physical manoeuvres, including the Epley manoeuvre. To assess the effectiveness of the Epley manoeuvre for posterior canal BPPV. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; CENTRAL; PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 23 January 2014. Randomised controlled trials of the Epley manoeuvre versus placebo, no treatment or other active treatment for adults diagnosed with posterior canal BPPV (including a positive Dix-Hallpike test). The primary outcome of interest was complete resolution of vertigo symptoms. Secondary outcomes were conversion of a 'positive' Dix-Hallpike test to a 'negative' Dix-Hallpike test and adverse effects of treatment. We used the standard methodological procedures expected by The Cochrane Collaboration. We included 11 trials in the review with a total of 745 patients.Five studies compared the efficacy of the Epley manoeuvre against a sham manoeuvre, three against other particle repositioning manoeuvres (Semont, Brandt-Daroff and Gans) and three against a control (no treatment, medication only, postural restriction). Patients were treated in hospital otolaryngology departments in eight studies and family practices in two studies. All patients were adults aged 18 to 90 years old, with a sex ratio of 1:1.5 male to female.There was a low risk of overall bias in the studies included. All studies were randomised with six applying sealed envelope or external allocation techniques. Eight of the trials blinded the assessors to the participants' treatment group and data on all outcomes for all participants were reported in eight of the 11 studies. Complete resolution of vertigo Complete resolution of vertigo occurred significantly more often in the Epley treatment group when compared to a sham manoeuvre or control (odds ratio (OR) 4.42, 95% confidence interval (CI) 2.62 to 7.44; five studies, 273 participants); the proportion of patients resolving increased from 21% to 56%. None of the trials comparing Epley versus other particle repositioning manoeuvres reported vertigo resolution as an outcome. Conversion of Dix-Hallpike positional test result from positive to negative Conversion from a positive to a negative Dix-Hallpike test significantly favoured the Epley treatment group when compared to a sham manoeuvre or control (OR 9.62, 95% CI 6.0 to 15.42; eight studies, 507 participants). There was no difference when comparing the Epley with the Semont manoeuvre (two studies, 117 participants) or the Epley with the Gans manoeuvre (one study, 58 participants). In one study a single Epley treatment was more effective than a week of three times daily Brandt-Daroff exercises (OR 12.38, 95% CI 4.32 to 35.47; 81 participants). Adverse effects Adverse effects were infrequently reported. There were no serious adverse effects of treatment. Rates of nausea during the repositioning manoeuvre varied from 16.7% to 32%. Some patients were unable to tolerate the manoeuvres because of cervical spine problems. There is evidence that the Epley manoeuvre is a safe, effective treatment for posterior canal BPPV, based on the results of 11, mostly small, randomised controlled trials with relatively short follow-up. There is a high recurrence rate of BPPV after treatment (36%). Outcomes for Epley manoeuvre treatment are comparable to treatment with Semont and Gans manoeuvres, but superior to Brandt-Daroff exercises.


Cortical and subcortical interactions during action reprogramming and their related white matter pathways.
The right inferior frontal gyrus (rIFG) and the presupplementary motor area (pre-SMA) have been identified with cognitive control-the top-down influence on other brain areas when nonroutine behavior is required. It has been argued that they "inhibit" habitual motor responses when environmental changes mean a different response should be made. However, whether such "inhibition" can be equated with inhibitory physiological interactions has been unclear, as has the areas' relationship with each other and the anatomical routes by which they influence movement execution. Paired-pulse transcranial magnetic stimulation (ppTMS) was applied over rIFG and primary motor cortex (M1) or over pre-SMA and M1 to measure their interactions, at a subsecond scale, during either inhibition and reprogramming of actions or during routine action selection. Distinct patterns of functional interaction between pre-SMA and M1 and between rIFG and M1 were found that were specific to action reprogramming trials; at a physiological level, direct influences of pre-SMA and rIFG on M1 were predominantly facilitatory and inhibitory, respectively. In a subsequent experiment, it was shown that the rIFG's inhibitory influence was dependent on pre-SMA. A third experiment showed that pre-SMA and rIFG influenced M1 at two time scales. By regressing white matter fractional anisotropy from diffusion-weighted magnetic resonance images against TMS-measured functional connectivity, it was shown that short-latency (6 ms) and longer latency (12 ms) influences were mediated by cortico-cortical and subcortical pathways, respectively, with the latter passing close to the subthalamic nucleus.


Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes.
During pregnancy, fetal growth causes an increase in the total number of rapidly dividing cells, which leads to increased requirements for folate. Inadequate folate intake leads to a decrease in serum folate concentration, resulting in a decrease in erythrocyte folate concentration, a rise in homocysteine concentration, and megaloblastic changes in the bone marrow and other tissues with rapidly dividing cells To assess the effectiveness of oral folic acid supplementation alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2012) and we contacted major organisations working in micronutrient supplementation, including UNICEF Nutrition Section, World Health Organization (WHO) Maternal and Reproductive Health, WHO Nutrition Division, and National Center on Birth defects and Developmnetal Disabilities, US Centers for Disease Control and Prevention (CDC). All randomised, cluster-randomised and cross-over controlled trials evaluating supplementation of folic acid alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) in pregnancy. Two review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy. Thirty-one trials involving 17,771 women are included in this review. This review found that folic acid supplementation has no impact on pregnancy outcomes such as preterm birth (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.38; three studies, 2959 participants), and stillbirths/neonatal deaths (RR 1.33, 95% CI 0.96 to 1.85; three studies, 3110 participants). However, improvements were seen in the mean birthweight (mean difference (MD) 135.75, 95% CI 47.85 to 223.68). On the other hand, the review found no impact on improving pre-delivery anaemia (average RR 0.62, 95% CI 0.35 to 1.10; eight studies, 4149 participants; random-effects), mean pre-delivery haemoglobin level (MD -0.03, 95% CI -0.25 to 0.19; 12 studies, 1806 participants), mean pre-delivery serum folate levels (standardised mean difference (SMD) 2.03, 95% CI 0.80 to 3.27; eight studies, 1250 participants; random-effects), and mean pre-delivery red cell folate levels (SMD 1.59, 95% CI -0.07 to 3.26; four studies, 427 participants; random-effects). However, a significant reduction was seen in the incidence of megaloblastic anaemia (RR 0.21, 95% CI 0.11 to 0.38, four studies, 3839 participants). We found no conclusive evidence of benefit of folic acid supplementation during pregnancy on pregnancy outcomes.


Hirudin (desirudin) and Hirulog (bivalirudin) in acute ischaemic syndromes and the rationale for the Hirulog/Early Reperfusion Occlusion (HERO-2) Study.
Unlike unfractionated heparin, direct thrombin inhibitors such as hirudin and Hirulog inhibit clot-bound as well as fluid-phase thrombin, escape neutralisation by platelet secretion products, do not require monitoring, and are unassociated with immune thrombocytopenia. They have been shown to have modest advantages over heparin when given after thrombolytic therapy, reducing reinfarction by 14%. In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO 2b) trial, patients treated with streptokinase and adjunctive hirudin had a reduction in death or myocardial infarction of 40% at 30 days (8.6% with hirudin versus 14.4% with heparin, p = 0.004). In the Hirulog Early Reperfusion/Occlusion (HERO 1) trial, 48% of patients who received Hirulog as adjunctive therapy with streptokinase had Thrombolysis in Myocardial Infarction (TIMI) trial grade 3 flow in the infarct-related artery, compared with 35% of patients who received heparin with streptokinase (p < 0.05). The HERO 2 study, involving 17,000 patients, will test the hypothesis that Hirulog and aspirin given before streptokinase will reduce mortality compared with aspirin plus heparin. Early administration of direct thrombin inhibitors may potentially improve the outcome of patients treated with thrombolytic therapy.


Ultrafast structural dynamics of the orthorhombic distortion in the Fe-pnictide parent compound BaFe2As2.
Using femtosecond time-resolved hard x-ray diffraction, we investigate the structural dynamics of the orthorhombic distortion in the Fe-pnictide parent compound BaFe2As2. The orthorhombic distortion analyzed by the transient splitting of the (1 0 3) Bragg reflection is suppressed on an initial timescale of 35 ps, which is much slower than the suppression of magnetic and nematic order. This observation demonstrates a transient state with persistent structural distortion and suppressed magnetic/nematic order which are strongly linked in thermal equilibrium. We suggest a way of quantifying the coupling between structural and nematic degrees of freedom based on the dynamics of the respective order parameters.


Structural and Functional Characterization of the Interaction of Snapin with the Dopamine Transporter: Differential Modulation of Psychostimulant Actions.
The importance of dopamine (DA) neurotransmission is emphasized by its direct implication in several neurological and psychiatric disorders. The DA transporter (DAT), target of psychostimulant drugs, is the key protein that regulates spatial and temporal activity of DA in the synaptic cleft via the rapid reuptake of DA into the presynaptic terminal. There is strong evidence suggesting that DAT-interacting proteins may have a role in its function and regulation. Performing a two-hybrid screening, we identified snapin, a SNARE-associated protein implicated in synaptic transmission, as a new binding partner of the carboxyl terminal of DAT. Our data show that snapin is a direct partner and regulator of DAT. First, we determined the domains required for this interaction in both proteins and characterized the DAT-snapin interface by generating a 3D model. Using different approaches, we demonstrated that (i) snapin is expressed in vivo in dopaminergic neurons along with DAT; (ii) both proteins colocalize in cultured cells and brain and, (iii) DAT and snapin are present in the same protein complex. Moreover, by functional studies we showed that snapin produces a significant decrease in DAT uptake activity. Finally, snapin downregulation in mice produces an increase in DAT levels and transport activity, hence increasing DA concentration and locomotor response to amphetamine. In conclusion, snapin/DAT interaction represents a direct link between exocytotic and reuptake mechanisms and is a potential target for DA transmission modulation.


Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior.
Pain is the most common symptom of osteoarthritis (OA), yet where it originates in the joint and how it is driven are unknown. The aim of this study was to identify pain-sensitizing molecules that are regulated in the joint when mice subjected to surgical joint destabilization develop OA-related pain behavior, the tissues in which these molecules are being regulated, and the factors that control their regulation. Ten-week-old mice underwent sham surgery, partial meniscectomy, or surgical destabilization of the medial meniscus (DMM). Pain-related behavior as determined by a variety of methods (testing of responses to von Frey filaments, cold plate testing for cold sensitivity, analgesiometry, incapacitance testing, and forced flexion testing) was assessed weekly. Once pain-related behavior was established, RNA was extracted from either whole joints or microdissected tissue samples (articular cartilage, meniscus, and bone). Reverse transcription-polymerase chain reaction analysis was performed to analyze the expression of 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature hips from wild-type or genetically modified mice or by explanting articular cartilage from porcine joints preinjected with pharmacologic inhibitors. Levels of nerve growth factor (NGF) protein were measured by enzyme-linked immunosorbent assay. Mice developed pain-related behavior 8 weeks after undergoing partial meniscectomy or 12 weeks after undergoing DMM. NGF, bradykinin receptors B1 and B2, tachykinin, and tachykinin receptor 1 were significantly regulated in the joints of mice displaying pain-related behavior. Little regulation of inflammatory cytokines, leukocyte activation markers, or chemokines was observed. When tissue samples from articular cartilage, meniscus, and bone were analyzed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage, although there were some differences between the 2 models. NGF and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a transforming growth factor β-activated kinase 1-, fibroblast growth factor 2-, and Src kinase-dependent manner. Damaged joint tissues produce proalgesic molecules, including NGF, in murine OA.


The onset of collective behavior in social amoebae.
In the social amoebae Dictyostelium discoideum, periodic synthesis and release of extracellular cyclic adenosine 3',5'-monophosphate (cAMP) guide cell aggregation and commitment to form fruiting bodies. It is unclear whether these oscillations are an intrinsic property of individual cells or if they exist only as a population-level phenomenon. Here, we showed by live-cell imaging of intact cell populations that pulses originate from a discrete location despite constant exchange of cells to and from the region. In a perfusion chamber, both isolated single cells and cell populations switched from quiescence to rhythmic activity depending on the concentration of extracellular cAMP. A quantitative analysis showed that stochastic pulsing of individual cells below the threshold concentration of extracellular cAMP plays a critical role in the onset of collective behavior.


Meiotic spindle organization in fertilized Drosophila oocyte: presence of centrosomal components in the meiotic apparatus.
We examined spindle reorganization during the completion of meiosis in fertilized and unfertilized oocytes of Drosophila using indirect immunofluorescence and laser scanning confocal microscopy. The results defined a complex pathway of spindle assembly during resumption of meiosis, and revealed a transient array of microtubules radiating from the equatorial region of the spindle towards discrete foci in the egg cortex. A monastral array of microtubules was observed between twin metaphase II spindles in fertilized and unfertilized eggs. The microtubules originated from disk-shaped material stained with Rb188 antibody specific for an antigen associated with the centrosome of Drosophila embryos. The Drosophila egg, therefore, contains a maternal pool of centrosomal components undetectable in mature inactivated oocytes. These components nucleate microtubules in a monastral array after activation, but are unable to organize bipolar spindles.


Raman spectroscopy of stored red blood cell concentrate within sealed transfusion blood bags.
The standard practice in blood banks worldwide involves storage of red blood cells (RBCs) in plastic bags until they are needed for transfusion. During storage, the cells gradually degrade in functionality, a condition described as RBC storage lesion. Standard analytical techniques cannot assess the blood quality without breaching the sterility of the transfusion bag. In this study, we employed a commercially available spatially offset Raman spectroscopy (SORS) system using a custom designed protocol to non-invasively explore the biochemical changes in RBC concentrate of healthy donors over a storage period of approximately 42 days in standard transfusion bags, under standard storage conditions. The results reveal an increase in the oxygenation state of haemoglobin over the storage period for all donors, but different profiles for each donor. This study demonstrates the feasibility of acquiring consistent biochemical information relevant to the quality of stored blood, in situ through sealed blood transfusion bags using a commercially available instrument.


Non-canonical active site architecture of the radical SAM thiamin pyrimidine synthase.
Radical S-adenosylmethionine (SAM) enzymes use a [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical. Canonical radical SAM enzymes are characterized by a β-barrel-like fold and SAM anchors to the differentiated iron of the cluster, which is located near the amino terminus and within the β-barrel, through its amino and carboxylate groups. Here we show that ThiC, the thiamin pyrimidine synthase in plants and bacteria, contains a tethered cluster-binding domain at its carboxy terminus that moves in and out of the active site during catalysis. In contrast to canonical radical SAM enzymes, we predict that SAM anchors to an additional active site metal through its amino and carboxylate groups. Superimposition of the catalytic domains of ThiC and glutamate mutase shows that these two enzymes share similar active site architectures, thus providing strong evidence for an evolutionary link between the radical SAM and adenosylcobalamin-dependent enzyme superfamilies.


Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia-Related Genes.
Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.


Medication errors: what they are, how they happen, and how to avoid them.
A medication error is a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient. Medication errors can occur in deciding which medicine and dosage regimen to use (prescribing faults--irrational, inappropriate, and ineffective prescribing, underprescribing, overprescribing); writing the prescription (prescription errors); manufacturing the formulation (wrong strength, contaminants or adulterants, wrong or misleading packaging); dispensing the formulation (wrong drug, wrong formulation, wrong label); administering or taking the medicine (wrong dose, wrong route, wrong frequency, wrong duration); monitoring therapy (failing to alter therapy when required, erroneous alteration). They can be classified, using a psychological classification of errors, as knowledge-, rule-, action- and memory-based errors. Although medication errors can occasionally be serious, they are not commonly so and are often trivial. However, it is important to detect them, since system failures that result in minor errors can later lead to serious errors. Reporting of errors should be encouraged by creating a blame-free, non-punitive environment. Errors in prescribing include irrational, inappropriate, and ineffective prescribing, underprescribing and overprescribing (collectively called prescribing faults) and errors in writing the prescription (including illegibility). Avoiding medication errors is important in balanced prescribing, which is the use of a medicine that is appropriate to the patient's condition and, within the limits created by the uncertainty that attends therapeutic decisions, in a dosage regimen that optimizes the balance of benefit to harm. In balanced prescribing the mechanism of action of the drug should be married to the pathophysiology of the disease.


Surface plasmon resonance reveals a different pattern of proinsulin autoantibodies concentration and affinity in diabetic patients.
Type 1 diabetes mellitus (DM) is characterized by autoimmune aggression against pancreatic beta cells resulting in absolute deficiency of insulin secretion. The first detectable sign of emerging autoimmunity during the preclinical asymptomatic period is the appearance of diabetes-related autoantibodies. In children at risk for type 1 DM, high-affinity Insulin autoantibodies reactive to proinsulin, are associated with diabetes risk. Autoantibodies are usually measured by radioligand binding assay (RBA) that provides quasi-quantitative values reflecting potency (product between concentration and affinity) of specific autoantibodies. Aiming to improve the characterization of the specific humoral immune response, we selected surface plasmon resonance (SPR) as an alternative method to measure proinsulin autoantibodies (PAA). This novel technology has allowed real time detection of antibodies interaction and kinetic analysis. Herein, we have employed SPR to characterize the PAA present in sera from 28 childhood-onset (mean age 8.31±4.20) and 23 adult-onset diabetic patients (≥65 years old, BMI<30) in terms of concentration and affinity. When evaluating comparatively samples from both groups, childhood-onset diabetic patients presented lower PAA concentrations and higher affinities (median 67.12×10(-9) M and 3.50×10(7) M(-1), respectively) than the adults (median 167.4×10(-9) M and 0.84×10(7) M(-1), respectively). These results are consistent with those from the reference method RBA (Standard Deviation score median 9.49 for childhood-onset group and 5.04 for adult-onset group) where the binding can be directly related to the intrinsic affinity of the antibody, suggesting that there is a different etiopathogenic pathway between both types of clinical presentation of the disease. This technology has shown to be a useful tool for the characterization of PAAs parameters as an alternative to radioimmunoassay, with high versatility and reproducibility associated to low occupational and environmental risk. However, this technology is not eligible for routine marker screening, but this is a powerful technique for a fine description of the thermodynamic parameters of antigen-antibody interaction.


Cefepime and Ceftazidime Safety in Hospitalized Infants.
Cefepime and ceftazidime are cephalosporins used for the treatment of serious Gram-negative infections. These cephalosporins are used off-label in the setting of minimal safety data for young infants. We identified all infants discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012 who were exposed to either cefepime or ceftazidime in the first 120 days of life. We reported clinical and laboratory adverse events occurring in infants exposed to cefepime or ceftazidime and used multivariable logistic regression to compare the odds of seizures and death between the 2 groups. A total of 1761 infants received 13,293 days of ceftazidime, and 594 infants received 4628 days of cefepime. Laboratory adverse events occurred more frequently on days of therapy with ceftazidime than with cefepime (373 vs. 341 per 1000 infant days, P < 0.001). Seizure was the most commonly observed clinical adverse event, occurring in 3% of ceftazidime-treated infants and 4% of cefepime-treated infants (P = 0.52). Mortality was similar between the ceftazidime and cefepime groups (5% vs. 3%, P = 0.07). There was no difference in the adjusted odds of seizure [odds ratio (OR) = 0.96 (95% confidence interval: 0.89-1.03)] or the combined outcome of mortality or seizures [OR = 1.00 (0.96-1.04)] in infants exposed to ceftazidime versus those exposed to cefepime. In this cohort of infants, cefepime was associated with fewer laboratory adverse events than ceftazidime, although this may have been due to a significant difference in clinical exposures and severity of illness between the 2 groups. There was no difference in seizure risk or mortality between the 2 drugs.


Alzheimer's disease: specific increases in a G protein subunit (Gs alpha) mRNA in hippocampal and cortical neurons.
The GTP binding protein, Gs, activates adenyl cyclase in direct response to stimulation of several neurotransmitter receptors. In situ hybridization histochemistry (ISHH) with a 35S-labelled oligonucleotide has been used to detect the mRNA encoding the alpha subunit of Gs (Gs alpha) in human hippocampus, temporal and visual cortices and cerebellum, and its level has been compared between Alzheimer's disease (AD) and control brains. A marked regional increase was found in the hippocampus of AD cases. Analysis of levels of Gs alpha mRNA in individual constituent pyramidal cells confirmed this increase (3 to 4-fold in densitometric units) in hippocampal fields CA1, CA3 and CA4, as well as in temporal cortex. Levels of Gs alpha mRNA were also determined relative to total poly(A)+ mRNA in the same cell populations in each case. Gene-specific elevation of Gs alpha mRNA was thereby confirmed in hippocampal fields, and also in temporal cortex. No changes were seen in visual cortex. The increase in Gs alpha mRNA may represent a response by AD neurons in affected areas to receptor alterations, or to an abnormality in receptor-G protein coupling. Alternatively, altered G protein gene expression might be a pathogenic event underlying changes in linked receptor populations.


Attitudes on and usage of balloon catheter technology in rhinology: A survey of the American Rhinologic Society.
Use of balloon catheter dilation in the management of paranasal sinus diseases, including chronic rhinosinusitis (CRS) and recurrent acute rhinosinusitis, remains controversial. In an effort to gain some clarity about its evolving role, we surveyed members of the American Rhinologic Society (ARS). Online survey. ARS Members were sent an invitation by e-mail to participate in an online, anonymous 23-item survey. A total of 231 participants completed the survey, for an overall response rate of 25%. Balloon catheter technology (BCT) played no role in the practices of one-third of all the respondents. Of those who did use BCT, more than 50% performed only 1-4 cases per month on average. This did not differ significantly with practice type (p = 0.2988). The overall use of BCT differed between types of practices with those in private practice reporting greater use of the technology for maxillary and sphenoid sinuses (p = 0.0003 and p = 0.0073, respectively). Participants in private practice appeared significantly more impressed with the results of BCT when compared with those in academia (p = 0.0005) and also thought that patients were more satisfied (p = 0.0002). Opinions toward the strength of available evidence also differed significantly between the two groups (p = 0.0007). Thirty-two respondents had experienced a complication with BCT, although the majority of these did not require any intervention. ARS members surveyed used BCT infrequently in their practices. Attitudes on the role of this technology in CRS management differed between academic and private practitioners, but, despite this, the volume of reported BCT use was the same. Surgeons are more accepting of the technology now compared with 5 years ago, and many of them believe that their use of BCT will increase in the future.


Behavior of cholesteric liquid crystals in a Fabry-Perot cavity.
We investigate the behavior of cholesteric liquid crystals (CLC's) inside a Fabry-Perot (FP) cavity. Although FP cavities filled with various liquid crystals have been extensively studied, to our knowledge the behavior of CLC-based FP cavities has not been reported. In CLC the twisted structure can be changed because the pitch is a function of temperature. In a parallel-rubbed CLC FP cavity the balance between strong surface anchoring and elastic energy yield a steplike resonance spectrum. This corresponds to the quantized effective pitch that the system assumes when both surface alignments are fixed. Experiment results for parallel-rubbed samples are presented and explained theoretically by use of Jones matrix calculations.


Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes.
Folic acid, a micronutrient supporting the natural defense system, may elevate antidepressant responses, although the lymphocyte serotonergic system has not been explored in folate-supplemented depressed patients. Twenty-seven patients were randomly assigned to groups receiving fluoxetine (20 mg) and folic acid (10 mg/day) or fluoxetine and placebo for 6 weeks. Clinical outcome was assessed according to the Hamilton Depression Rating Scale (HDRS) at the beginning, during and at the end of treatment. Blood samples were taken, plasma was separated, and lymphocytes were obtained by density gradient centrifugation with Ficoll/Hypaque and differential adhesion to plastic dishes. Fifteen healthy subjects served as controls. Plasma folate, homocysteine and vitamin B12, and serotonin concentration in lymphocytes were determined by HPLC. The HDRS score was significantly lower in patients receiving fluoxetine and folic acid compared with those receiving fluoxetine and placebo after 6 weeks of treatment (7.43 +/- 1.65 vs. 11.43 +/- 1.31, respectively; p = 0.04). Plasma homocysteine statistically significant decreased after folic acid (p = 0.02), but no significant changes were observed in vitamin B12. Serotonin was significantly reduced after fluoxetine either with folate (p = 0.03) or placebo (p = 0.01) probably by the effect of transporter blockade. 5-Hydroxyindoleacetic acid was lower in lymphocytes of patients receiving folate (p = 0.04), indicating a reduced turnover rate, thus accumulating serotonin in the cells. A significant negative correlation was noted between homocysteine and folate. No significant correlations were present among biochemical parameters and depression severity. Modifications due to treatment with fluoxetine and folic acid may alter lymphocyte function in depression probably indirectly by reducing homocysteine levels and directly on lymphocytes by modifying the serotonergic system.


Outcome of surgical resection for brain metastases and radical treatment of the primary tumor in Chinese non-small-cell lung cancer patients.
Brain metastasis is the most common complication of brain cancer; nevertheless, primary lung cancer accounts for approximately 20%-40% of brain metastases cases. Surgical resection is the preferred treatment for brain metastases. However, no studies have reported the outcome of surgical resection of brain metastases from non-small-cell lung cancer (NSCLC) in the People's Republic of China. Moreover, the optimal treatment for primary NSCLC in patients with synchronous brain metastases is hitherto controversial. We retrospectively analyzed the cases of NSCLC patients with brain metastases who underwent neurosurgical resection at the Sun Yat-sen University Cancer Center, and assessed the efficacy of surgical resection and the necessity of aggressive treatment for primary NSCLC in synchronous brain metastases patients. A total of 62 patients, including 47 men and 15 women, with brain metastases from NSCLC were enrolled in the study. The median age at the time of craniotomy was 54 years (range 29-76 years). At the final follow-up evaluation, 50 patients had died. The median OS time was 15.1 months, and the survival rates were 70% and 37% at 1 and 2 years, respectively. The median OS time of synchronous brain metastases patients was 12.5 months. Univariate analysis revealed that radical treatment of primary NSCLC was positively correlated with survival, and it was an independent prognostic factor in the multivariate analysis. Surgical resection is an effective treatment for brain metastases. Besides craniotomy, radical therapy is necessary for the management of primary NSCLC in patients with synchronous brain metastases.


Multi-modal pain measurements in infants.
A non-invasive integrated method was developed to measure neural and behavioural responses to peripheral sensory and noxious stimulation in human infants. The introduction of a novel event-detection interface allows synchronous recording of: (i) muscle and central nervous system activity with surface electromyography (EMG), scalp electroencephalography (EEG) and near-infrared spectroscopy (NIRS); (ii) behavioural responses with video-recording and (iii) autonomic responses (heart rate, oxygen saturation, respiratory rate and cardiovascular activity) with electrocardiography (ECG) and pulse oximetry. The system can detect noxious heel lance and touch stimuli with precision (33 μs and 624 μs respectively) and accuracy (523 μs and 256 μs) and has 100% sensitivity and specificity for both types of stimulation. Its ability to detect response latencies accurately was demonstrated by a shift in latency of the vertex potential of 20.7 ± 15.7 ms (n=6 infants), following touch of the heel and of the shoulder, reflecting the distance between the two sites. This integrated system has provided reliable and reproducible measurements of responses to sensory and noxious stimulation in human infants on more than 100 test occasions.


Ultrastructural clues for the protective effect of ascorbic acid and N-acetylcysteine against oxidative damage on caerulein-induced pancreatitis.
Oxygen free radicals (OFR) have been implicated in the induction of acute pancreatitis (AP). The aim of this study was to determine the effect of ascorbic acid and N-acetylcysteine (NAC), potent antioxidants, against oxidative stress in AP. AP was induced by two i.p. injections of caerulein at 2-hour intervals (50 microg/kg BW). One group received additionally an antioxidant mixture composed of L(+)-ascorbic acid (14.3 mg/kg BW) and NAC (181 mg/kg BW) i.p. The rats were sacrificed 12 h after the last injection. Oxidative stress markers were evaluated. Light-microscopic and ultrastructural examination was performed. Formation of vacuoles, mitochondrial damage, and dilatation of rough endoplasmic reticulum, margination and clumping of chromatin were major ultrastructural alterations in AP group. Ascorbic acid + NAC prevented these changes. Small vacuoles were present within the cytoplasm of some of the acinar cells. Pancreas damage was accompanied by an increase in tissue malondialdehyde (MDA) levels (p < 0.05), whereas a decrease was seen in catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities and total glutathione (GSH) levels (p < 0.005). Ascorbic acid + NAC decreased MDA levels but increased CAT, SOD, GPx activities and GSH levels (p < 0.005). These results suggest that ascorbic acid + NAC is potentially capable of limiting pancreatic damage produced during AP via protecting fine structure of acinar cells and tissue antioxidant enzyme activities.


Position-dependent termination and widespread obligatory frameshifting in Euplotes translation.
The ribosome can change its reading frame during translation in a process known as programmed ribosomal frameshifting. These rare events are supported by complex mRNA signals. However, we found that the ciliates Euplotes crassus and Euplotes focardii exhibit widespread frameshifting at stop codons. 47 different codons preceding stop signals resulted in either +1 or +2 frameshifts, and +1 frameshifting at AAA was the most frequent. The frameshifts showed unusual plasticity and rapid evolution, and had little influence on translation rates. The proximity of a stop codon to the 3' mRNA end, rather than its occurrence or sequence context, appeared to designate termination. Thus, a 'stop codon' is not a sufficient signal for translation termination, and the default function of stop codons in Euplotes is frameshifting, whereas termination is specific to certain mRNA positions and probably requires additional factors.


Population Structure and Genetic Diversity among Isolates of Coccidioides posadasii in Venezuela and Surrounding Regions.
Coccidioides posadasii is a pathogenic fungus that causes coccidioidomycosis in many arid regions of the Americas. One of these regions is bordered by the Caribbean Sea, and the surrounding landscape may play an important role in the dispersion of C. posadasii across South America through southeastern Mexico, Honduras, Guatemala, and Venezuela. Comparative phylogenomic analyses of C. posadasii reveal that clinical strains from Venezuela are genetically distinct from the North American populations found in (i) Arizona and (ii) Texas, Mexico, and the rest of South America (TX/MX/SA). We find evidence for admixture between the Venezuela and the North American populations of C. posadasii in Central America. Additionally, the proportion of Venezuelan alleles in the admixed population decreases as latitude (and distance from Venezuela) increases. Our results indicate that the population in Venezuela may have been subjected to a recent bottleneck and shows a strong population structure. This analysis provides insight into potential for Coccidioides spp. to invade new regions.IMPORTANCE Valley Fever is a fungal disease caused by two species of fungi: Coccidioides immitis and C. posadasii These fungi are found throughout the arid regions of North and South America; however, our understanding of genetic diversity and disease in South America is limited. In this report, we analyze 10 new genomes of Coccidioides posadasii from regions bordering the Caribbean Sea. We show that these populations are distinct and that isolates from Venezuela are likely a result of a recent bottleneck. These data point to patterns that might be observed when investigating recently established populations.


MAPK signaling in equations and embryos.
The Extracellularly Regulated Kinase/Mitogen Activated Protein Kinase (ERK/MAPK) signaling pathway is a critical regulator of cellular processes in adult and developing tissues. Depending on the cellular context, MAPK cascade can act as a rheostat, a switch, or an oscillator. The highly conserved structure of the cascade does not imply a rigid function, as was suggested by the early mathematical models of MAPK signaling, and can instead produce a wide range of input-output maps. Given a large number of pathway components and modes of regulation, it is essential to establish experimental systems that will allow both manipulating the MAPK cascade and monitoring its dynamics. The terminal patterning system in the Drosophila embryo appears to be ideally suited for this purpose. Our recent experiments characterized dynamics of the MAPK phosphorylation gradient in the terminal system and proposed that it is regulated by a cascade of diffusion-trapping modules. Here we discuss a biophysical model that can describe the observed dynamics and guide future experiments for exploring the relative importance of multiple layers of MAPK cascade regulation.


Developing Cost-Effective Field Assessments of Carbon Stocks in Human-Modified Tropical Forests.
Across the tropics, there is a growing financial investment in activities that aim to reduce emissions from deforestation and forest degradation, such as REDD+. However, most tropical countries lack on-the-ground capacity to conduct reliable and replicable assessments of forest carbon stocks, undermining their ability to secure long-term carbon finance for forest conservation programs. Clear guidance on how to reduce the monetary and time costs of field assessments of forest carbon can help tropical countries to overcome this capacity gap. Here we provide such guidance for cost-effective one-off field assessments of forest carbon stocks. We sampled a total of eight components from four different carbon pools (i.e. aboveground, dead wood, litter and soil) in 224 study plots distributed across two regions of eastern Amazon. For each component we estimated survey costs, contribution to total forest carbon stocks and sensitivity to disturbance. Sampling costs varied thirty-one-fold between the most expensive component, soil, and the least, leaf litter. Large live stems (≥10 cm DBH), which represented only 15% of the overall sampling costs, was by far the most important component to be assessed, as it stores the largest amount of carbon and is highly sensitive to disturbance. If large stems are not taxonomically identified, costs can be reduced by a further 51%, while incurring an error in aboveground carbon estimates of only 5% in primary forests, but 31% in secondary forests. For rapid assessments, necessary to help prioritize locations for carbon- conservation activities, sampling of stems ≥20cm DBH without taxonomic identification can predict with confidence (R2 = 0.85) whether an area is relatively carbon-rich or carbon-poor-an approach that is 74% cheaper than sampling and identifying all the stems ≥10cm DBH. We use these results to evaluate the reliability of forest carbon stock estimates provided by the IPCC and FAO when applied to human-modified forests, and to highlight areas where cost savings in carbon stock assessments could be most easily made.


Solar geoengineering as part of an overall strategy for meeting the 1.5°C Paris target.
Solar geoengineering refers to deliberately reducing net radiative forcing by reflecting some sunlight back to space, in order to reduce anthropogenic climate changes; a possible such approach would be adding aerosols to the stratosphere. If future mitigation proves insufficient to limit the rise in global mean temperature to less than 1.5°C above preindustrial, it is plausible that some additional and limited deployment of solar geoengineering could reduce climate damages. That is, these approaches could eventually be considered as part of an overall strategy to manage the risks of climate change, combining emissions reduction, net-negative emissions technologies and solar geoengineering to meet climate goals. We first provide a physical-science review of current research, research trends and some of the key gaps in knowledge that would need to be addressed to support informed decisions. Next, since few climate model simulations have considered these limited-deployment scenarios, we synthesize prior results to assess the projected response if solar geoengineering were used to limit global mean temperature to 1.5°C above preindustrial in an overshoot scenario that would otherwise peak near 3°C. While there are some important differences, the resulting climate is closer in many respects to a climate where the 1.5°C target is achieved through mitigation alone than either is to the 3°C climate with no geoengineering. This holds for both regional temperature and precipitation changes; indeed, there are no regions where a majority of models project that this moderate level of geoengineering would produce a statistically significant shift in precipitation further away from preindustrial levels.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.


Robotic endoscopic surgery of the skull base: a novel surgical approach.
To describe a novel robotic surgical approach that allows adequate endoscopic access for resection of tumors involving the anterior and central skull base and allows 2-handed, tremor-free, endoscopic dissection and precise suturing of dural defects. Transnasal endoscopic approaches are being increasingly used for surgical access and resection of tumors of the anterior and central skull base. One major disadvantage of this approach is the inability to provide watertight dural closure and reconstruction, which limits its safety and widespread adoption in surgery of intracranial skull base tumors. Other disadvantages include limited depth perception and several ergonomic constraints. Four human cadaver specimens were used for this study. The surgical approach starts with bilateral sublabial incisions and wide anterior maxillary antrostomies (Caldwell-Luc). Transantral access to the nasal cavity is gained through bilateral wide middle meatal antrostomies. A posterior nasal septectomy facilitates bilateral access by joining both nasal cavities into 1 surgical field. The da Vinci Surgical System is then "docked" by introducing the camera arm port through the nostril and the right and left surgical arm ports through the respective anterior and middle antrostomies, into the nasal cavity. A 5-mm dual-channel endoscope coupled with a dual charge-coupled device camera is inserted in the camera port and allows for 3-dimensional visualization of the surgical field at the surgeon's console. Using the robotic surgical arms, the surgeon may perform endoscopic anterior or posterior ethmoidectomy, sphenoidotomy, or resection of the middle or superior turbinates depending on the extent of needed surgical exposure. In addition, resection of the cribriform plate is performed robotically with sharp dissection of the skull base. The dural defect is then repaired with a 6-0 nylon suture. Adequate access to the anterior and central skull base, including the cribriform plate, fovea ethmoidalis, medial orbits, planum sphenoidale, sella turcica, suprasellar and parasellar regions, nasopharynx, pterygopalatine fossa, and clivus, was obtained in all cadaveric dissections. The 3-dimensional visualization obtained by the dual-channel endoscope at the surgeon's console provided excellent depth perception. The most significant advantage was the ability of the surgeon to perform 2-handed tremor-free endoscopic closure of dural defects. Transantral robotic surgery provides adequate endoscopic access to the anterior and central skull base. To our knowledge, this is the first study to report the feasibility and advantages of robotic-assisted endoscopic surgery of the skull base. This novel approach also allows for 3-dimensional, 2-handed, tremor-free endoscopic dissection and precise closure of dural defects. These advantages may expand the indications of minimally invasive endoscopic approaches to the skull base.


Administration of Lactobacillus paracasei ameliorates type 2 diabetes in mice.
Probiotics have been proposed as an option for the prevention of type 2 diabetes mellitus (T2DM). The objective of this study was to evaluate the hypoglycemic effects of Lactobacillus paracasei on diabetic mice and explore the possible underlying molecular mechanism. The α-glucosidase inhibitory activities of eight L. paracasei strains were assessed in vitro. L. paracasei TD062 with high α-glucosidase inhibitory activity (31.9%) showed an excellent antidiabetic ability and it could survive in simulated gastrointestinal juices. To investigate the beneficial effects of L. paracasei TD062, diabetic mice were treated with the strain at 109, 108 and 107 CFU ml-1. The results indicated that the administration of L. paracasei TD062 could regulate the levels of fasting blood glucose (FBG), postprandial blood glucose (PBG), glucose tolerance, hepatic glycogen and lipid metabolism. In addition, the antioxidant capacity was also improved by oral administration of L. paracasei TD062. And the hypoglycemic effects exhibited dose dependence to some extent. Furthermore, it was revealed that L. paracasei TD062 had a positive effect on the expression levels of genes related to glucose metabolism and the PI3K/Akt pathway. These results demonstrated that L. paracasei TD062 played an important role in preventing the development of T2DM and might be applied as a new type of hypoglycemic agent in functional foods.


Self-assembly of hierarchical MoSx/CNT nanocomposites (2<x<3): towards high performance anode materials for lithium ion batteries.
Two dimension (2D) layered molybdenum disulfide (MoS2) has emerged as a promising candidate for the anode material in lithium ion batteries (LIBs). Herein, 2D MoSx (2 ≤ x ≤ 3) nanosheet-coated 1D multiwall carbon nanotubes (MWNTs) nanocomposites with hierarchical architecture were synthesized via a high-throughput solvent thermal method under low temperature at 200°C. The unique hierarchical nanostructures with MWNTs backbone and nanosheets of MoSx have significantly promoted the electrode performance in LIBs. Every single MoSx nanosheet interconnect to MWNTs centers with maximized exposed electrochemical active sites, which significantly enhance ion diffusion efficiency and accommodate volume expansion during the electrochemical reaction. A remarkably high specific capacity (i.e., > 1000 mAh/g) was achieved at the current density of 50 mA g(-1), which is much higher than theoretical numbers for either MWNTs or MoS2 along (~372 and ~670 mAh/g, respectively). We anticipate 2D nanosheets/1D MWNTs nanocomposites will be promising materials in new generation practical LIBs.


Mechanism of action and clinical benefits of colloidal oatmeal for dermatologic practice.
Colloidal oatmeal has a long history of beneficial use in dermatology. It is a natural product that has an excellent safety record and has demonstrated efficacy for the treatment of atopic dermatitis, psoriasis, drug-induced rash and other conditions. In recent years, in vitro and in vivo studies have begun to elucidate the multiple mechanisms of action of naturally derived colloidal oatmeal. Evidence now describes its molecular mechanisms of anti-inflammatory and antihistaminic activity. The avenanthramides, a recently described component of whole oat grain, are responsible for many of these effects. Studies have demonstrated that avenanthramides can inhibit the activity of nuclear factor kappaB and the release of proinflammatory cytokines and histamine, well known key mechanisms in the pathophysiology of inflammatory dermatoses. Topical formulations of natural colloidal oatmeal should be considered an important component of therapy for atopic dermatitis and other conditions and may allow for reduced use of corticosteroids and calcineurin inhibitors.


The neglected repercussions of a physician advertising ban.
Although the adverse implications of physician advertising are the subject of a fierce and sustained debate, there is almost no scholarly discussion on the ethical repercussions of physician advertising bans. The present paper draws attention to these repercussions as they exist today in most of the world, with particular focus on three serious implications for the public: (a) uncertainty about the physician's interests, namely, that patients must trust the physician to put patient wellbeing ahead of possible gains when taking medical decisions; (b) uncertainty about alternative treatments, namely, that patients must trust in the physician's treatment decisions; and (c) uncertainty about the exclusive patient-physician relationship, namely, that patients must develop and maintain a good relationship with one physician. Physician advertising bans continue to tell the public in most of the modern world that these are irrelevant or inappropriate issues, meaning that they are effectively left to the public to resolve.


Endothelium-derived relaxing factor participates in the increased blood flow in response to pentagastrin in the rat stomach mucosa.
The stimulation of gastric-acid secretion by pentagastrin, a synthetic analogue of the endogenous peptide gastrin, is associated with an increased blood flow to the stomach mucosa, commonly referred to as functional hyperaemia. There are at least two potent vasodilator substances, the local release of which from endothelial cells could contribute to this hyperaemia, endothelium-derived relaxing factor (EDRF) and prostacyclin. EDRF has been identified as nitric oxide, released enzymatically from the guanidino group of L-arginine. In the present studies, the involvement of prostacyclin in the pentagastrin-induced increase in stomach blood flow was eliminated by using the cyclo-oxygenase inhibitor indomethacin. Thus this work was designed to elucidate the participation of EDRF/NO in the pentagastrin-induced hyperaemia and not its relative importance to prostacyclin. The increase in blood flow to the gastric mucosa in response to pentagastrin was measured by laser Doppler flowmetry in situ. Inhibition of EDRF/NO biosynthesis with the L-arginine analogues NG-monomethyl-L-arginine (MeArg) or N omega-nitro-L-arginine (NO2Arg) significantly attenuated (by more than 80%) the increase in mucosal blood flow in response to pentagastrin. However, infusions of the natural substrate L-arginine reversed the inhibitor effect of MeArg on pentagastrin-induced increase in mucosal blood flow. Local intra-arterial injections of the endothelium-independent vasodilator glyceryl trinitrate produced a dose-related increase in blood flow to the rat stomach mucosa that was unaffected by infusion of MeArg. Thus, in the absence of prostacyclin, EDRF/NO participates in the pentagastrin-induced increase in blood flow to the rat stomach mucosa.


Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility.
A spike protein mutation D614G became dominant in SARS-CoV-2 during the COVID-19 pandemic. However, the mutational impact on viral spread and vaccine efficacy remains to be defined. Here we engineer the D614G mutation in the SARS-CoV-2 USA-WA1/2020 strain and characterize its effect on viral replication, pathogenesis, and antibody neutralization. The D614G mutation significantly enhances SARS-CoV-2 replication on human lung epithelial cells and primary human airway tissues, through an improved infectivity of virions with the spike receptor-binding domain in an "up" conformation for binding to ACE2 receptor. Hamsters infected with D614 or G614 variants developed similar levels of weight loss. However, the G614 virus produced higher infectious titers in the nasal washes and trachea, but not lungs, than the D614 virus. The hamster results confirm clinical evidence that the D614G mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increases transmission. For antibody neutralization, sera from D614 virus-infected hamsters consistently exhibit higher neutralization titers against G614 virus than those against D614 virus, indicating that (i) the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19 and (ii) therapeutic antibodies should be tested against the circulating G614 virus before clinical development.


Viral interference between infectious hypodermal and hematopoietic necrosis virus and white spot syndrome virus in Litopenaeus vannamei.
White spot syndrome virus (WSSV) is highly virulent and has caused significant production losses to the shrimp culture industry over the last decade. Infectious hypodermal and hematopoietic necrosis virus (IHHNV) also infects penaeid shrimp and, while being less important than WSSV, remains a major cause of significant production losses in Litopenaeus vannamei (also called Penaeus vannamei) and L. stylirostris (also called Penaeus stylirostris). These 2 viruses and their interactions were previously investigated in L. stylirostris. We report here laboratory challenge studies carried out to determine if viral interference between IHHNV and WSSV also occurs in L. vannamei, and it was found that experimental infection with IHHNV induced a significant delay in mortality following WSSV challenge. L. vannamei infected per os with IHHNV were challenged with WSSV at 0, 10, 20, 30, 40 and 50 d post-infection. Groups of naïve shrimp infected with WSSV alone died in 3 d whereas shrimp pre-infected with IHHNV for 30, 40 or 50 d died in 5 d. Real-time PCR analysis showed that the delay correlated to the IHHNV load and that WSSV challenge induced a decrease in IHHNV load, indicating some form of competition between the 2 viruses.


Dietary soy isoflavones and bone mineral density: results from the study of women's health across the nation.
Isoflavones are naturally occurring selective estrogen receptor modulators, with potential bone protective effects. To study the relation between soy isoflavone intake and bone mineral density (BMD), the authors analyzed baseline data from the Study of Women's Health Across the Nation, a US community-based cohort study of women aged 42-52 years. Their 1996-1997 analysis included African-American (n = 497), Caucasian (n = 1,003), Chinese (n = 200), and Japanese (n = 227) participants. Genistein and daidzein intakes were highly correlated (r = 0.98); therefore, analyses were conducted by using genistein. Median intakes of genistein (measured in micrograms/day) by African Americans and Caucasians were too low to pursue relational analyses further. For Chinese and Japanese women, median genistein intakes were 3,511 and 7,151 microg/day, respectively. Ethnic-specific, linear models were used to predict BMD as a function of energy-adjusted tertile of intake, controlled for relevant covariates. For Chinese women, no association between genistein and BMD was found. Premenopausal, but not perimenopausal, Japanese women whose intakes were greater had higher spine and femoral neck BMD. Adjusted mean spinal BMD of those in the highest tertile of intake was 7.7% greater than that of women in the lowest tertile (p = 0.02); femoral neck BMD was 12% greater in the highest versus the lowest tertile (p < 0.0001).