P300-based brain-computer interface (BCI) event-related potentials (ERPs): People with amyotrophic lateral sclerosis (ALS) vs. age-matched controls.
Brain-computer interfaces (BCIs) aimed at restoring communication to people with severe neuromuscular disabilities often use event-related potentials (ERPs) in scalp-recorded EEG activity. Up to the present, most research and development in this area has been done in the laboratory with young healthy control subjects. In order to facilitate the development of BCI most useful to people with disabilities, the present study set out to: (1) determine whether people with amyotrophic lateral sclerosis (ALS) and healthy, age-matched volunteers (HVs) differ in the speed and accuracy of their ERP-based BCI use; (2) compare the ERP characteristics of these two groups; and (3) identify ERP-related factors that might enable improvement in BCI performance for people with disabilities. Sixteen EEG channels were recorded while people with ALS or healthy age-matched volunteers (HVs) used a P300-based BCI. The subjects with ALS had little or no remaining useful motor control (mean ALS Functional Rating Scale-Revised 9.4 (±9.5SD) (range 0-25)). Each subject attended to a target item as the items in a 6×6 visual matrix flashed. The BCI used a stepwise linear discriminant function (SWLDA) to determine the item the user wished to select (i.e., the target item). Offline analyses assessed the latencies, amplitudes, and locations of ERPs to the target and non-target items for people with ALS and age-matched control subjects. BCI accuracy and communication rate did not differ significantly between ALS users and HVs. Although ERP morphology was similar for the two groups, their target ERPs differed significantly in the location and amplitude of the late positivity (P300), the amplitude of the early negativity (N200), and the latency of the late negativity (LN). The differences in target ERP components between people with ALS and age-matched HVs are consistent with the growing recognition that ALS may affect cortical function. The development of BCIs for use by this population may begin with studies in HVs but also needs to include studies in people with ALS. Their differences in ERP components may affect the selection of electrode montages, and might also affect the selection of presentation parameters (e.g., matrix design, stimulation rate). P300-based BCI performance in people severely disabled by ALS is similar to that of age-matched control subjects. At the same time, their ERP components differ to some degree from those of controls. Attention to these differences could contribute to the development of BCIs useful to those with ALS and possibly to others with severe neuromuscular disabilities.


Ipriflavone: pharmacological properties and usefulness in postmenopausal osteoporosis.
Ipriflavone (IP) is an isoflavone derivative available in several countries for investigational and/or therapeutic use. Inhibition of bone resorption was demonstrated in several models, both in vitro and in vivo for IP and its metabolites. Their mechanisms of action on bone are not yet fully elucidated but some of them are widely accepted. IP does not possess, per se, any estrogenic activity. It appears that IP-related inhibition of bone resorption might be mediated by an indirect effect on osteoclast and related to an inhibition of recruitment and/or differentiation of pre-osteoclast, maybe through a modulation of osteoblast response to PTH. Clinical studies in Paget's disease of bone or primary hyperparathyroidism have confirmed preferential inhibition of bone resorption suggesting a clinical interest in postmenopausal osteoporosis. Preliminary (1 year) results of double blind placebo controlled studies designed in postmenopausal and senile osteoporosis confirm a reduction in bone turnover rate in patients treated with 600 mg/day of IP, resulting in a significant bone-sparing effect both at lumbar and radial levels. All clinical and pharmacological trials confirm a very good tolerance of IP with a frequency of adverse reactions equal to that observed during administration of a placebo. Providing ongoing studies will confirm the actual promising preliminary results, IP seems a very interesting new non hormonal approach for prevention and treatment of postmenopausal and senile osteoporosis.


Factors affecting secondary sex ratio in Iranian Holsteins.
The objective of this study was to evaluate the factors affecting secondary sex ratio (SSR) in Iranian Holsteins. Data of 942,941 Holstein calving events from the Animal Breeding Center of Iran, recorded between January 1996 and December 2007, were used in the analysis. A multivariable logistic regression model was used to model the logit of the probability of a male calf being born. Male births accounted for 49.6% of the total observations. The ratio of males to females varied from 52.5:47.5 in calving year 1996-1999 (odds ratio (OR)=1.18; P<0.0001), to 48.5:51.5 in calving year 2004-2007. The greatest occurrence of male births was observed in spring (OR=1.02; P<0.0001), and the lowest incidence of male births was for summer or fall calvings. Also, the frequency of male births decreased from parity 1 to parity 4 and beyond (P<0.0001; OR=1.11). The greatest number of sires had the SSR equal to 0.5 with a minimum SSR of 32% while the maximum was 97%. Among cows that had a male birth, the chance of delivering a male calf again was 25.5% when cows had delivered a male once (OR=1.14; P<0.0001), and 12.7% if a male calf was delivered twice by a cow. This indicated that characteristics peculiar to the dam influence the sex of her offspring and suggests some degree of repeatability of calf sex within cows.


Neural substrates of visual masking by object substitution in schizophrenia.
Despite a well-known behavioral finding of visual backward masking impairment in schizophrenia, its underlying neural mechanism remains obscure. This study examined neural correlates of a distinct type of visual backward masking, object substitution masking (OSM), in schizophrenia. Twenty schizophrenia patients and 26 healthy controls completed a 4-Dot OSM task and three functional localizer tasks for the lateral occipital (LO), human motion-sensitive (hMT+), and retinotopic areas in the scanner. In 4-dot masking, subjects detected a target that was followed by a mask consisting of 4 dots that surrounded a target. Stimulus-onset asynchrony (SOA) between target and mask was varied to examine the modulation of masking: (1) within three visual processing areas regions of interest (ROI) (i.e., ROI analysis) and (2) in brain regions outside the three visual processing areas (i.e., whole brain analysis). In the ROI analyses, LO and retinotopic areas showed increased peak amplitude when SOA become longer in both patients and controls. There was also an effect of ROI in that both groups showed higher activation in LO and hMT+ compared with the retinotopic areas. The whole brain analyses revealed a significantly activated area for longer SOAs vs. a short SOA in the occipital cortex in controls only, but the group contrast was not significant. Overall, this study did not find strong evidence for neural abnormalities of OSM in schizophrenia, suggesting that neural substrates of OSM in schizophrenia are not as compromised as those involved in the more common masking methods that rely on disruption of object formation.


The Regulation of Task Performance: A Trans-Disciplinary Review.
Definitions of meta-cognition typically have two components: (1) knowledge about one's own cognitive functioning; and, (2) control over one's own cognitive activities. Since Flavell and his colleagues provided the empirical foundation on which to build studies of meta-cognition and the autonoetic (self) knowledge required for effective learning, the intervening years have seen the extensive dissemination of theoretical and empirical research on meta-cognition, which now encompasses a variety of issues and domains including educational psychology and neuroscience. Nevertheless, the psychological and neural underpinnings of meta-cognitive predictions and reflections that determine subsequent regulation of task performance remain ill understood. This article provides an outline of meta-cognition in the science of education with evidence drawn from neuroimaging, psycho-physiological, and psychological literature. We will rigorously explore research that addresses the pivotal role of the prefrontal cortex (PFC) in controlling the meta-cognitive processes that underpin the self-regulated learning (SRL) strategies learners employ to regulate task performance. The article delineates what those strategies are, and how the learning environment can facilitate or frustrate strategy use by influencing learners' self-efficacy.


Advances in exercise therapy in predialysis chronic kidney disease, hemodialysis, peritoneal dialysis, and kidney transplantation.
Chronic kidney disease (CKD) is characterized by poor levels of physical activity which contribute to increased morbidity across the disease trajectory. The short nature, small samples, and poor methodology across most studies have failed to translate the role of exercise in CKD into its adoption as a frontline adjunct therapeutic option. This review focuses on recent advances surrounding the benefits of exercise interventions across the CKD spectrum. Key recent advances in exercise studies have focused on the efficacy of novel intervention strategies across the CKD spectrum. These include high-intensity interval training, virtual reality gaming, intradialytic yoga, electrical stimulation of muscles, blood flow restriction training, and protocols combining exercise with nutritional supplementation. Research is also beginning to explore the role of prehabilitation for patients prior to dialysis and kidney transplantation. Studies continue to demonstrate wide-ranging benefits of exercise across CKD; however, implementation of exercise remains scarce. Future research needs include evaluating the efficacy of larger and/or more comprehensive interventions on clinically important outcomes. It is hoped with increasing global evidence, high-quality clinical studies, and sustained clinician and patient engagement, exercise programs will become better prioritized in the nephrology field.


Desulfotomaculum genus- and subgenus-specific 16S rRNA hybridization probes for environmental studies.
Based on comparative analysis of 16S rRNA sequences and the recently established phylogeny of the genus Desulfotomaculum, a set of phylogenetically nested hybridization probes was developed and characterized. A genus-specific probe targets all known Desulfotomaculum species (with the exception of Desulfotomaculum acetoxidans), and five specific probes target subclusters within the Desulfotomaculum genus. The dissociation temperature of each probe was determined experimentally. Probe specificities were verified through hybridizations with pure culture rRNA isolated from a wide variety of target and non-target organisms and through an evaluation of probe 'nesting' using samples obtained from four different environments. Fixation and hybridization conditions for fluorescence in situ hybridizations were also optimized. The probes were used in quantitative membrane hybridizations to determine the abundance of Desulfotomaculum species in thermophilic anaerobic digesters, in soil, in human faeces and in pig colon samples. Desulfotomaculum rRNA accounted for 0.3-2.1% of the total rRNA in the digesters, 2.6-6.6% in soil, 1.5-3.3% in human faeces and 2.5-6.2% in pig colon samples.


How well do discharge diagnoses identify hospitalised patients with community-acquired infections?--a validation study.
Credible measures of disease incidence, trends and mortality can be obtained through surveillance using manual chart review, but this is both time-consuming and expensive. ICD-10 discharge diagnoses are used as surrogate markers of infection, but knowledge on the validity of infections in general is sparse. The aim of the study was to determine how well ICD-10 discharge diagnoses identify patients with community-acquired infections in a medical emergency department (ED), overall and related to sites of infection and patient characteristics. We manually reviewed 5977 patients admitted to a medical ED in a one-year period (September 2010-August 2011), to establish if they were hospitalised with community-acquired infection. Using the manual review as gold standard, we calculated the sensitivity, specificity, predictive values, and likelihood ratios of discharge diagnoses indicating infection. Two thousand five hundred eleven patients were identified with community-acquired infection according to chart review (42.0%, 95% confidence interval [95%CI]: 40.8-43.3%) compared to 2550 patients identified by ICD-10 diagnoses (42.8%, 95%CI: 41.6-44.1%). Sensitivity of the ICD-10 diagnoses was 79.9% (95%CI: 78.1-81.3%), specificity 83.9% (95%CI: 82.6-85.1%), positive likelihood ratio 4.95 (95%CI: 4.58-5.36) and negative likelihood ratio 0.24 (95%CI: 0.22-0.26). The two most common sites of infection, the lower respiratory tract and urinary tract, had positive likelihood ratios of 8.3 (95%CI: 7.5-9.2) and 11.3 (95%CI: 10.2-12.9) respectively. We identified significant variation in diagnostic validity related to age, comorbidity and disease severity. ICD-10 discharge diagnoses identify specific sites of infection with a high degree of validity, but only a moderate degree when identifying infections in general.


Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide.
Lipopolysaccharide (LPS) is the main inducer of shock and death in Gram-negative sepsis. Recent evidence suggests that LPS-induced signal transduction begins with CD14-mediated activation of 1 or more Toll-like receptors (TLRs). The lipid A analogues lipid IVa and Rhodobacter sphaeroides lipid A (RSLA) exhibit an uncommon species-specific pharmacology. Both compounds inhibit the effects of LPS in human cells but display LPS-mimetic activity in hamster cells. We transfected human TLR4 or human TLR2 into hamster fibroblasts to determine if either of these LPS signal transducers is responsible for the species-specific pharmacology. RSLA and lipid IVa strongly induced NF-kappaB activity and IL-6 release in Chinese hamster ovary fibroblasts expressing CD14 (CHO/CD14), but these compounds antagonized LPS antagonists in CHO/CD14 fibroblasts that overexpressed human TLR4. No such antagonism occurred in cells overexpressing human TLR2. We cloned TLR4 from hamster macrophages and found that human THP-1 cells expressing the hamster TLR4 responded to lipid IVa as an LPS mimetic, as if they were hamster in origin. Hence, cells heterologously overexpressing TLR4 from different species acquired a pharmacological phenotype with respect to recognition of lipid A substructures that corresponded to the species from which the TLR4 transgene originated. These data suggest that TLR4 is the central lipid A-recognition protein in the LPS receptor complex.


Oesophageal foreign bodies.
Impaction of foreign bodies in the oesophagus was analysed in 54 patients, 45 of whom were children. Of the 45 children 28 were aged 2-4 years. Coins were the most common foreign body in children (27 cases) while in adults a bolus of meat was most common (nine cases). In 41 children there was no predisposing factor, but an underlying mechanism was detected in 88% of the adults. The mechanisms were of three types: oesophageal (stricture), neuromuscular (myasthenia gravis), and extrinsic and mechanical (ankylosing spondylitis). In children most of the foreign bodies were impacted in the upper oesophagus at the cricopharyngeal junction, which is the narrowest part of the oesophagus, while in adults the foreign body was usually impacted at the site of the predisposing lesion or in the lower oesophagus. In all patients oesophagoscopy was performed under general anaesthesia to remove the impacted foreign body. Complications were more frequent in adults, mainly owing to the underlying condition.


Are semen parameters worsening? Comparing semen parameters 10 years apart.
Semen parameters, especially sperm count and motility have been said to be diminishing over time with implications for fertility and infertility treatment. The objective of this study was to study semen parameters 10 years apart and describe any observed change. A retrospective study carried out at Nordica Fertility Centre, Lagos, Nigeria. Semen parameters of 100 consecutive men who sought fertility treatment on account of infertility in 2003 and semen parameters of 100 consecutive men who also sought fertility treatment at the center in 2013 on account of infertility were analyzed and compared. A paired t-test was performed to ascertain whether sperm counts have diminished over the last decade. The World Health Organization semen values were used as standard. They are sperm count, motility, and mean progressive motility. The mean sperm count in the 2003 group was 34.6 × 106/ml (range: 0.1-105.0 106/ml) compared with 21.8 × 106/ml (range: 0.1-80.0 × 106/ml) in the 2013 group. The mean motility was 47.9% in the 2003 group and 45.3% in the 2013 group. The mean progressive motility in the 2003 group was predominantly graded as good (50% good, 44% fair, 2% poor, 4% no motility) while in the 2013 group, the predominant grade of mean progressive motility was fair (15% good, 81% fair, 4% poor). Normal morphology was more commonly seen in the 2013 group compared to the 2003 group. Mean semen volume was 2.7 and 2.6 ml in 2003 and 2013 groups, respectively. The mean difference in sperm count (mean = 12.8, standard deviation = 31.6, n = 100) was significantly >0 providing evidence that sperm counts have diminished in the last decade. There was a statistically significant 37% drop in mean sperm count and mean progressive motility worsened in the last decade. These may have far-reaching effects on infertility and its treatment.


How to integrate physical activity and exercise approaches into inpatient treatment for eating disorders: fifteen years of clinical experience and research.
The importance of physical activity and exercise among patients with eating disorders (EDs) is acknowledged among clinicians and researchers. The lack of clinical guidelines, the differing attitudes towards exercise approaches in treatment, and the lack of specialized competence all influence the management of ED symptoms in specialist ED treatment units. The purpose of the study was to examine 15 years of clinical experience with exercise approaches as an integrated part our inpatients treatment program. From January 2003 to December 2017, 244 patients were admitted to a specialist ED unit in Norway. The treatment program at the ED unit is multidisciplinary. It is based on psychodynamic theory, and designed to enhance patients' recovery and to enable them to adopt a lifestyle that is as healthy as possible. The authors describe the clinical management of patients with reference to practical examples and a case example. The treatment for exercise is not manualized, but adjusted to the specific symptoms and needs of individual ED patients. The treatment approaches to exercise are part of the body-oriented treatment at the Specialist eating disorder unit (Regionalt kompetansesenter for spiseforstyrrelser (RKSF)), and the therapy addresses the entire body and the relation between the body, emotions, and the patient's social situation. It covers a chain of approaches from admission to discharge, from rest and relaxation to regular exercise groups. Our experience and recommendations support earlier proposals for treatment approaches to exercise and exercise-related issues as a beneficial supplement to the treatment of ED inpatients. We have not experienced any adverse influences on patients' recovery processes, such as their rate of weight gain. Our intention is that this paper will be a contribution to the field of ED, the integration of exercise approaches in the inpatient treatment of ED and development of clinical guidelines.


NMDA and glutamate evoke excitotoxicity at distinct cellular locations in rat cortical neurons in vitro.
The development of cortical neurons in vivo and in vitro is accompanied by alterations in NMDA receptor subunit expression and concomitant modifications in the pharmacological profile of NMDA-activated ionic currents. For example, we observed that with decreasing NR2B/NR2A subunit expression ratio, the block of NMDA receptor-mediated whole-cell responses by the NR2B-selective antagonist haloperidol was also decreased. In mature cultures (>22 d in vitro), however, NMDA responses obtained from excised nucleated macropatches, which comprised a large portion of the soma, remained strongly antagonized by haloperidol. These results suggest that in more mature neurons NR1/NR2B receptors appear to be preferentially expressed in the cell body. As predicted from the whole-cell recording pharmacological profile, NMDA-induced toxicity was largely unaffected by haloperidol in mature cultures. However, haloperidol effectively blocked glutamate toxicity in the same cultures, suggesting that the neurotoxic actions of this amino acid were mostly due to the activation of somatic NMDA receptors. In experiments in which the potency of glutamate toxicity was increased by the transport inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid, the neuroprotective effects of haloperidol were significantly diminished. This was likely because of the fact that glutamate, now toxic at much lower concentrations, was able to reach and activate dendritic receptors under these conditions. These results strongly argue that exogenous glutamate and NMDA normally induce excitotoxicity at distinct cellular locations in mature mixed neuronal cultures and that NR1/NR2B receptors remain an important component in the expression of glutamate, but not NMDA-induced excitotoxicity.


A scoping review on the measurement of transnationalism in migrant health research in high-income countries.
Migrants commonly maintain transnational ties as they relocate and settle in a new country. There is a growing body of research examining transnationalism and health. We sought to identify how transnationalism has been defined and operationalized in migrant health research in high income countries and to document which populations and health and well-being outcomes have been studied in relation to this concept. We conducted a scoping review using the methodology recommended by the Joanna Briggs Institute (JBI). We searched nine electronic databases; no time restrictions were applied. Studies published in English or French in peer-reviewed journals were considered. Studies were eligible if they included a measure of transnationalism (or one of its dimensions; social, cultural, economic, political and identity ties and/or healthcare use) and examined health or well-being. Forty-seven studies, mainly cross-sectional designs (81%), were included; almost half were conducted in the United States. The majority studied immigrants, broadly defined; 23% included refugees and/or asylum-seekers while 36% included undocumented migrants. Definitions of transnationalism varied according to the focus of the study and just over half provided explicit definitions. Most often, transnationalism was defined in terms of social connections to the home country. Studies and measures mainly focused on contacts and visits with family and remittance sending, and only about one third of studies examined and measured more than two dimensions of transnationalism. The operationalization of transnationalism was not consistent and reliability and validity data, and details on language translation, were limited. Almost half of the studies examined mental health outcomes, such as emotional well-being, or symptoms of depression. Other commonly studied outcomes included self-rated health, life satisfaction and perceived discrimination. To enhance comparability in this field, researchers should provide a clear, explicit definition of transnationalism based on the scope of their study, and for its measurement, they should draw from validated items/questions and be consistent in its operationalization across studies. To enhance the quality of findings, more complex approaches for operationalizing transnationalism (e.g., latent variable modelling) and longitudinal designs should be used. Further research examining a range of transnationalism dimensions and health and well-being outcomes, and with a diversity of migrant populations, is also warranted.


Mass spectrometry imaging of phosphatidylcholine metabolism in lungs administered with therapeutic surfactants and isotopic tracers.
Mass spectrometry imaging (MSI) visualizes molecular distributions throughout tissues but is blind to dynamic metabolic processes. Here, MSI with high mass resolution together with multiple stable isotope labeling provided spatial analyses of phosphatidylcholine (PC) metabolism in mouse lungs. Dysregulated surfactant metabolism is central to many respiratory diseases. Metabolism and turnover of therapeutic pulmonary surfactants were imaged from distributions of intact and metabolic products of an added tracer, universally 13C-labeled dipalmitoyl PC (U13C-DPPC). The parenchymal distributions of newly synthesized PC species were also imaged from incorporations of methyl-D9-choline. This dual labeling strategy demonstrated both lack of inhibition of endogenous PC synthesis by exogenous surfactant and location of acyl chain remodeling processes acting on the U13C-DPPC-labeled surfactant, leading to formation of polyunsaturated PC lipids. This ability to visualize discrete metabolic events will greatly enhance our understanding of lipid metabolism in diverse tissues and has potential application to both clinical and experimental studies.


Chromosome-Level Genome Assembly of a Human Fungal Pathogen Reveals Synteny among Geographically Distinct Species.
Histoplasma capsulatum, a dimorphic fungal pathogen, is the most common cause of fungal respiratory infections in immunocompetent hosts. Histoplasma is endemic in the Ohio and Mississippi River Valleys in the United States and is also distributed worldwide. Previous studies have revealed at least eight clades, each specific to a geographic location: North American classes 1 and 2 (NAm 1 and NAm 2), Latin American groups A and B (LAm A and LAm B), Eurasian, Netherlands, Australian and African, and an additional distinct lineage (H81) comprised of Panamanian isolates. Previously assembled Histoplasma genomes are highly fragmented, with the highly repetitive G217B (NAm 2) strain, which has been used for most whole-genome-scale transcriptome studies, assembled into over 250 contigs. In this study, we set out to fully assemble the repeat regions and characterize the large-scale genome architecture of Histoplasma species. We resequenced five Histoplasma strains (WU24 [NAm 1], G217B [NAm 2], H88 [African], G186AR [Panama], and G184AR [Panama]) using Oxford Nanopore Technologies long-read sequencing technology. Here, we report chromosomal-level assemblies for all five strains, which exhibit extensive synteny among the geographically distant Histoplasma isolates. The new assemblies revealed that RYP2, a major regulator of morphology and virulence, is duplicated in G186AR. In addition, we mapped previously generated transcriptome data sets onto the newly assembled chromosomes. Our analyses revealed that the expression of transposons and transposon-embedded genes are upregulated in yeast phase compared to mycelial phase in the G217B and H88 strains. This study provides an important resource for fungal researchers and further highlights the importance of chromosomal-level assemblies in analyzing high-throughput data sets. IMPORTANCE Histoplasma species are dimorphic fungi causing significant morbidity and mortality worldwide. These fungi grow as mold in the soil and as budding yeast within the human host. Histoplasma can be isolated from soil in diverse regions, including North America, South America, Africa, and Europe. Phylogenetically distinct species of Histoplasma have been isolated and sequenced. However, for the commonly used strains, genome assemblies have been fragmented, leading to underutilization of genome-scale data. This study provides chromosome-level assemblies of the commonly used Histoplasma strains using long-read sequencing technology. Comparative analysis of these genomes shows largely conserved gene order within the chromosomes. Mapping existing transcriptome data on these new assemblies reveals clustering of transcriptionally coregulated genes. The results of this study highlight the importance of obtaining chromosome-level assemblies in understanding the biology of human fungal pathogens.


Emergence of scarlet fever Streptococcus pyogenes emm12 clones in Hong Kong is associated with toxin acquisition and multidrug resistance.
A scarlet fever outbreak began in mainland China and Hong Kong in 2011 (refs. 1-6). Macrolide- and tetracycline-resistant Streptococcus pyogenes emm12 isolates represent the majority of clinical cases. Recently, we identified two mobile genetic elements that were closely associated with emm12 outbreak isolates: the integrative and conjugative element ICE-emm12, encoding genes for tetracycline and macrolide resistance, and prophage ΦHKU.vir, encoding the superantigens SSA and SpeC, as well as the DNase Spd1 (ref. 4). Here we sequenced the genomes of 141 emm12 isolates, including 132 isolated in Hong Kong between 2005 and 2011. We found that the introduction of several ICE-emm12 variants, ΦHKU.vir and a new prophage, ΦHKU.ssa, occurred in three distinct emm12 lineages late in the twentieth century. Acquisition of ssa and transposable elements encoding multidrug resistance genes triggered the expansion of scarlet fever-associated emm12 lineages in Hong Kong. The occurrence of multidrug-resistant ssa-harboring scarlet fever strains should prompt heightened surveillance within China and abroad for the dissemination of these mobile genetic elements.


Virological investigations of acute encephalopathy in India.
A total of 740 consecutive children aged between 6 months and 12 years who presented with acute encephalopathic illnesses during a three year period were assessed both clinically and by laboratory investigations. Cerebrospinal fluid was examined for the presence of cells or other abnormal substances, and any organisms were cultured. Blood examination included white cell count and estimations of haemoglobin, urea, glucose, and electrolyte concentrations and serum alanine aminotransferase and aspartate aminotransferase. A firm diagnosis was established in 278 patients (38%). Pyogenic meningitis (n = 134), measles encephalopathy (n = 38), and electrolyte imbalance (n = 23) were important causes in this group, cerebral malaria (n = 4) was uncommon and there were no cases of Reye's syndrome. The diagnoses of the remaining 462 were combined under the heading 'acute unexplained encephalopathy'. Altogether 394 of the 462 patients underwent virological investigations for arboviruses and 92 (23%) had one or more indicators of Japanese encephalitis. No other arboviruses could be isolated. Throat swabs from 187 patients with acute unexplained encephalopathy were studied on monkey kidney tissue cell lines of which 14 were positive (8%). These were identified as adenovirus, parainfluenza, influenza, poliomyelitis, Coxsackie, and echovirus; in two cases the virus was untypable. Japanese encephalitis is an important cause of acute childhood encephalopathy in this region. Clinical features of the illness may be mimicked by several disorders which require specific treatment. Thirty four of the 92 died (37%).


Predictors of inpatient admission in the setting of anterior lumbar interbody fusion: a Minimally Invasive Spine Study Group (MISSG) investigation.
While the anterior lumbar interbody fusion (ALIF) procedure may be amenable to ambulatory surgery, it has been hypothesized that limitations such as the risk of postoperative ileus and vascular complications have hindered transition of this procedure to the outpatient setting. Identification of independent risk factors predisposing patients to inpatient stays of ≥ 24 hours after ALIF may facilitate better postsurgical outcomes, target modifiable risk factors, and assist in the development of screening tools to transition appropriate patients to the ambulatory surgery center (ASC) setting for this procedure. The purpose of this study was to identify the most relevant risk factors that predispose patients to ≥ 24-hour admission following ALIF. A prospectively maintained surgical registry was reviewed for patients undergoing single ALIF between May 2006 and December 2019. Demographics, preoperative diagnosis, perioperative variables, and postoperative complications were evaluated according to their relative risk (RR) elevation for an inpatient stay of ≥ 24 hours. A Poisson regression model was used to evaluate predictors of inpatient stays of ≥ 24 hours. Risk factors for inpatient admission of ≥ 24 hours were identified with a stepwise backward regression model. A total of 111 patients underwent single-level ALIF (50.9% female and 52.6% male, ≤ 50 years old). Eleven (9.5%) patients were discharged in < 24 hours and 116 remained admitted for ≥ 24 hours. The average inpatient stay was > 2 days (53.7 hours). The most common postoperative complications were fever (body temperature ≥ 100.4°F; n = 4, 3.5%) and blood transfusions (n = 4, 3.5%). Bivariate analysis revealed a preoperative diagnosis of retrolisthesis or lateral listhesis to elevate the RR for an inpatient stay of ≥ 24 hours (RR 1.11, p = 0.001, both diagnoses). Stepwise multivariate analysis demonstrated significant predictors for inpatient stays of ≥ 24 hours to be an operation on L4-5, coexisting degenerative disc disease (DDD) with foraminal stenosis, and herniated nucleus pulposus (RR 1.11, 95% CI 1.03-1.20, p = 0.009, all covariates). This study provides data regarding the incidence of demographic and perioperative characteristics and postoperative complications as they pertain to patients undergoing single-level ALIF. This preliminary investigation identified the most relevant risk factors to be considered before appropriately transitioning ALIF procedures to the ASC. Further studies of preoperative characteristics are needed to elucidate ideal ASC ALIF patients.


Contrast sensitivity isocontours of the central visual field.
Standard automated perimetry (SAP), the most common form of perimetry used in clinical practice, is associated with high test variability, impacting clinical decision making and efficiency. Contrast sensitivity isocontours (CSIs) may reduce test variability in SAP by identifying regions of the visual field with statistically similar patterns of change that can be analysed collectively and allow a point (disease)-to-CSI (normal) comparison in disease assessment as opposed to a point (disease)-to-point (normal) comparison. CSIs in the central visual field however have limited applicability as they have only been described using visual field test patterns with low, 6° spatial sampling. In this study, CSIs were determined within the central 20° visual field using the 10-2 test grid paradigm of the Humphrey Field Analyzer which has a high 2° sampling frequency. The number of CSIs detected in the central 20° visual field was greater than previously reported with low spatial sampling and stimulus size dependent: 6 CSIs for GI, 4 CSIs for GII and GIII, and 3 CSIs for GIV and GV. CSI number and distribution were preserved with age. Use of CSIs to assess visual function in age-related macular degeneration (AMD) found CSI guided analysis detected a significantly greater deviation in sensitivity of AMD eyes from normal compared to a standard clinical pointwise comparison (-1.40 ± 0.15 dB vs -0.96 ± 0.15 dB; p < 0.05). This work suggests detection of CSIs within the central 20° is dependent on sampling strategy and stimulus size and normative distribution limits of CSIs can indicate significant functional deficits in diseases affecting the central visual field such as AMD.


Combined effect of natural essential oils, modified atmosphere packaging, and gamma radiation on the microbial growth on ground beef.
Selected Chinese cinnamon, Spanish oregano, and mustard essential oils (EOs) were used in combination with irradiation to evaluate their ability to eliminate pathogenic bacteria and extend the shelf life of medium-fat-content ground beef (23% fat). Shelf life was defined as the time when the total bacterial count reached 10(7) CFU/g. The shelf life of ground beef was determined for 28 days at 4 degrees C after treatment with EOs. The concentrations of EOs were predetermined such that sensory properties of cooked meat were maintained: 0.025% Spanish oregano, 0.025% Chinese cinnamon, and 0.075% mustard. Ground beef samples containing EOs were then packaged under air or a modified atmosphere and irradiated at 1.5 kGy. Ground beef samples (10 g) were taken during the storage period for enumeration of total mesophilic aerobic bacteria, Escherichia coli, Salmonella, total coliforms, lactic acid bacteria, and Pseudomonas. Mustard EO was the most efficient for reducing the total mesophilic aerobic bacteria and eliminating pathogenic bacteria. Irradiation alone completely inhibited the growth of total mesophilic aerobic and pathogenic bacteria. The combination of irradiation and EOs was better for reducing lactic acid bacteria (mustard and cinnamon EOs) and Pseudomonas (oregano and mustard EOs). The best combined treatment for extending the shelf life of ground beef for up to 28 days was EO plus irradiation (1.5 kGy) and modified atmosphere packaging.


Is there evidence for a relationship between cognitive impairment and fatigue after acquired brain injury: a systematic review and meta-analysis.
Fatigue is a major symptom of ABI. Greater fatigue is associated with cognitive impairment. Our aim was to systematically review, describe and analyse the literature on the extent of this relationship. Five databases were searched from inception. Studies were included where: participants had a defined clinical diagnosis of ABI which included TBI, stroke or subarachnoid haemorrhage; a fatigue measure was included; at least one objective cognitive measure was used. Three reviewers individually identified studies and determined quality using the Quality Assessment Tool for Observational Cohort and Cross-sectional Studies. Sixteen of the 412 identified studies, investigating the relationship between cognitive dysfunction and fatigue, comprising a total of 1,745 participants, were included. Quality ranged from fair to good. Meta-analysis found fatigue was significantly associated with an overall pattern of cognitive slowing on tasks of sustained attention. A narrative synthesis found weak associations with fatigue and information processing, attention, memory and executive function. Analysis found sustained attentional performance had stronger associations with fatigue after ABI. Whereas, weak associations were found between fatigue and information processing, attention and to some extent memory and executive function. More focused research on specific cognitive domains is needed to understand the mechanisms of fatigue.


Context-dependent correlation between resting metabolic rate and daily energy expenditure in wild chipmunks.
Several empirical studies have shown that variation in daily energy expenditure (DEE) and resting metabolic rate (RMR) is influenced by environmental and individual factors, but whether these shared influences are responsible for, or independent of, relationships between DEE and RMR remains unknown. The objectives of this study were to (i) simultaneously evaluate the effects of environmental and individual variables on DEE and RMR in free-ranging eastern chipmunks (Tamias striatus) and (ii) quantify the correlation between DEE and RMR before and after controlling for common sources of variation. We found that the influence of individual factors on DEE and RMR is most often shared, whereas the influence of environmental factors tends to be distinct. Both raw and mass-adjusted DEE and RMR were significantly correlated, but this correlation vanished after accounting for the shared effect of reproduction on both traits. However, within reproductive individuals, DEE and RMR remained positively correlated after accounting for all other significant covariates. The ratio of DEE to RMR was significantly higher during reproduction than at other times of the year and was negatively correlated with ambient temperature. DEE and RMR appear to be inherently correlated during reproduction, but this correlation does not persist during other, less energy-demanding periods of the annual cycle.


Turnover of Village Chickens Undermines Vaccine Coverage to Control HPAI H5N1.
Highly pathogenic avian influenza (HPAI) subtype H5N1 remains an enzootic disease of village chickens in Indonesia, posing ongoing risk at the animal-human interface. Previous modelling showed that the fast natural turnover of chicken populations might undermine herd immunity after vaccination, although actual details of how this effect applies to Indonesia's village chicken population have not been determined. We explored the turnover effect in Indonesia's scavenging and mixed populations of village chickens using an extended Leslie matrix model parameterized with data collected from village chicken flocks in Java region, Indonesia. Population dynamics were simulated for 208 weeks; the turnover effect was simulated for 16 weeks after vaccination in two 'best case' scenarios, where the whole population (scenario 1), or birds aged over 14 days (scenario 2), were vaccinated. We found that the scavenging and mixed populations have different productive traits. When steady-state dynamics are reached, both populations are dominated by females (54.5%), and 'growers' and 'chicks' represent the most abundant age stages with 39% and 38% in the scavenging, and 60% and 25% in the mixed population, respectively. Simulations showed that the population turnover might reduce the herd immunity below the critical threshold that prevents the re-emergence of HPAI H5N1 4-8 weeks (scavenging) and 6-9 weeks (mixed population) after vaccination in scenario 1, and 2-6 weeks (scavenging) and 4-7 weeks (mixed population) after vaccination in scenario 2. In conclusion, we found that Indonesia's village chicken population does not have a unique underlying population dynamic and therefore, different turnover effects on herd immunity may be expected after vaccination; nonetheless, our simulations carried out in best case scenarios highlight the limitations of current vaccine technologies to control HPAI H5N1. This suggests that the improvements and complementary strategies are necessary and must be explored.


Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS).
This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients enrolled in the International Randomized Study of Interferon and STI571 (IRIS). Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time. Analyses of event-free survival (EFS) and time to progression to accelerated phase/blast crisis (AP/BC) at 7 years were based on molecular responses using the international scale (IS) at 6-, 12-, and 18-month landmarks. Patients with BCR-ABL transcripts > 10% at 6 months and > 1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response [MMR: BCR-ABL (IS) ≤ 0.1%] by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years. The probability of loss of complete cytogenetic response by 7 years was only 3% for patients in MMR at 18 months versus 26% for patients with complete cytogenetic response but not MMR (P < .001). This study shows a strong association between the degree to which BCR-ABL transcript numbers are reduced by therapy and long-term clinical outcome, supporting the use of time-dependent molecular measures to determine optimal response to therapy. This study is registered at www.clinicaltrials.gov as NCT00006343.


Adhesive micropatterns to study intermediate filament function in nuclear positioning.
The nucleus is generally found near the cell center; however its position can vary in response to extracellular or intracellular signals, leading to a polarized intracellular organization. Nuclear movement is mediated by the cytoskeleton and its associated motors. While the role of actin and microtubule cytoskeletons in nuclear positioning has been assessed in various systems, the contribution of intermediate filaments is less established due in part to the lack of tools to study intermediate filament functions. The methods described here use micropatterned substrates to impose reproducible cell shape and nucleus position. Intermediate filament organization can be perturbed using gene downregulation or upregulation; intermediate filaments can also be visualized using fluorescent intermediate filament proteins. This protocol is valuable for characterizing the role of intermediate filaments in a variety of live or fixed adherent cells.


Psychometric evaluation of the Scandinavian version of the caregiver priorities and child health index of life with disabilities.
To examine test-retest reliability and construct validity of the Scandinavian version of the caregiver priorities and child health index of life with disabilities (CPCHILD) questionnaire for children with cerebral palsy (CP). Families were recruited in Sweden and Norway and stratified according to the gross motor function classification system levels I-V for children born 2000-2011, mean age 7.9 (SD 3.2). Construct validity based on the first questionnaire (n = 106) was evaluated for known groups, using linear regression analysis. Intraclass correlation coefficient was used to estimate test-retest reliability (n = 64), and Cronbach's alpha was calculated as an indicator of internal consistency. The questionnaire showed construct validity and the ability to discriminate between levels of gross motor function for the total score and all domain scores (p < 0.05). Test-retest reliability was high with intraclass correlation coefficient of 0.92 for the total score and of 0.72-0.92 for the domain scores. Cronbach's alpha was 0.96 for the total score and 0.83-0.96 for the domain scores. The Scandinavian version of the CPCHILD for children with CP seems to be a valid and reliable proxy measure for health related quality of life. Implications for rehabilitation Valid and reliable outcome measures are needed to evaluate whether follow-up programs enhance health related quality of life in different countries. The Scandinavian version of the caregiver priorities and child health index of life with disabilities (CPCHILD) was evaluated for known-groups validity and test-retest reliability. The Scandinavian version of the CPCHILD is a sound and valid measurement for evaluation and comparison of health related quality of life of children with cerebral palsy in different countries.


Effect of high aluminum concentration in water resources on human health, case study: Biga Peninsula, northwest part of Turkey.
Widespread and intense zones of silicified, propylitic, and argillic alteration exist as outcrop around the Biga Peninsula, NW Turkey. Most of the springs in the study area surface out from these altered volcanic rocks. The concentrations of aluminum (Al) in these springs ranged from 13.17 to 15.70 ppm in this region. These high levels of Al were found to exceed the maximum allowable limits (0.2 ppm) depicted in national and international standards of drinking water quality. Therefore, the effect of high Al in water resources on human health was evaluated in this research. A total of 273 people aged above 18 years and living in the Kirazli region (whose water supply is from springs emerging from these alteration zones) and in the Ciplak-Halileli region (whose water supply is provided from an alluvium aquifer) were selected as the research group. For this group, a questionnaire was completed that contained questions on descriptive characteristics of humans and a Mini-Mental State Examination (MMSE) was administered by the authors using the face-to-face interview technique. A neurological examination was then performed by the neurology specialist as a second-stage investigation. Finally, 10 ml of venous blood samples were obtained from these people as a third-stage analysis to determine the serum Al levels together with vitamin B(12), folic acid, and thyroid-stimulating hormone parameters. The result typically revealed that the MMSE score was less in 31.9% and there was no statistically significant difference between the two regions. However, the result also showed that neuropathy in the history (including a careful past medical history) was significantly higher in the Kirazli region.


Inside ILSI: How Coca-Cola, Working through Its Scientific Nonprofit, Created a Global Science of Exercise for Obesity and Got It Embedded in Chinese Policy (1995-2015).
Industry influence on health science and policy is a critical issue of our day. In 2015 the New York Times revealed that Coca-Cola paid scientists to form a Global Energy Balance Network promoting the notion that exercise, not dietary restraint, is the solution to the obesity epidemic-a claim few accept. This article examines the organizational dynamics and policy process behind Coke's efforts to sway obesity policy-globally and in China, a critical market-during 1995-2015. In-depth, qualitative research during 2013-18 involved 10 weeks of fieldwork in Beijing, interviews with 25 leading experts, analysis of newsletters documenting all major obesity-related activities in China, interviews with 10 Euro-American experts, and extensive internet research on all major actors. This article tells two intertwined stories (institutional dynamics, science making and policy making) at global and local-Chinese levels. Coke succeeded in redirecting China's obesity science and policy to emphasize physical activity. Key to its success was the industry-funded global nonprofit International Life Sciences Institute (ILSI). Beneath ILSI's public narrative of unbiased science and no policy advocacy lay a maze of hidden channels companies used to advance their interests. Working through those channels, Coca-Cola influenced China's science making and policy making during every phase in the policy process, from framing the issues to drafting official policy. Though China is exceptional, ILSI promoted exercise globally, suggesting potentially significant impacts in other ILSI-branch countries.


Symptom cluster research: conceptual, design, measurement, and analysis issues.
Cancer patients may experience multiple concurrent symptoms caused by the cancer, cancer treatment, or their combination. The complex relationships between and among symptoms, as well as the clinical antecedents and consequences, have not been well described. This paper examines the literature on cancer symptom clusters focusing on the conceptualization, design, measurement, and analytic issues. The investigation of symptom clustering is in an early stage of testing empirically whether the characteristics defined in the conceptual definition can be observed in cancer patients. Decisions related to study design include sample selection, the timing of symptom measures, and the characteristics of symptom interventions. For self-report symptom measures, decisions include symptom dimensions to evaluate, methods of scaling symptoms, and the time frame of responses. Analytic decisions may focus on the application of factor analysis, cluster analysis, and path models. Studying the complex symptoms of oncology patients will yield increased understanding of the patterns of association, interaction, and synergy of symptoms that produce specific clinical outcomes. It will also provide a scientific basis and new directions for clinical assessment and intervention.


Sequential targeted delivery of paclitaxel and camptothecin using a cross-linked "nanosponge" network for lung cancer chemotherapy.
The applicability of a HVGGSSV peptide targeted "nanosponge" drug delivery system for sequential administration of a microtubule inhibitor (paclitaxel) and topoisomerase I inhibitor (camptothecin) was investigated in a lung cancer model. Schedule-dependent combination treatment with nanoparticle paclitaxel (NP PTX) and camptothecin (NP CPT) was studied in vitro using flow cytometry and confocal imaging to analyze changes in cell cycle, microtubule morphology, apoptosis, and cell proliferation. Results showed significant G2/M phase cell cycle arrest, changes in microtubule dynamics that produced increased apoptotic cell death and decreased proliferation with initial exposure to NP PTX, followed by NP CPT in lung cancer cells. In vivo molecular imaging and TEM studies validated HVGGSSV-NP tumor binding at 24 h and confirmed the presence of Nanogold labeled HVGGSSV-NPs in tumor microvascular endothelial cells. Therapeutic efficacy studies conducted with sequential HVGGSSV targeted NP PTX and NP CPT showed 2-fold greater tumor growth delay in combination versus monotherapy treated groups, and 4-fold greater delay compared to untargeted and systemic drug controls. Analytical HPLC/MS methods were used to quantify drug content in tumor tissues at various time points, with significant paclitaxel and camptothecin levels in tumors 2 days postinjection and continued presence of both drugs up to 23 days postinjection. The efficacy of the NP delivery system in sequential treatments was corroborated in both in vitro and in vivo lung cancer models showing increased G2/M phase arrest and microtubule disruption, resulting in enhanced apoptotic cell death, decreased cell proliferation and vascular density.


Cancer multidisciplinary team meetings: impact of logistical challenges on communication and decision-making.
Multidisciplinary teams (MDTs) are widely used in cancer care. Recent research points to logistical challenges impeding MDT decision-making and dissatisfaction among members. This study sought to identify different types of logistical issues and how they impacted team processes. This was a secondary analysis of a cross-sectional observational study. Three cancer MDTs (breast, colorectal, and gynaecological) were recruited from UK hospitals. Validated observational instruments were used to measure decision-making (Metrics of Observational Decision-making, MDT-MODe), communication (Bales' Interaction Process Analysis, Bales' IPA), and case complexity (Measure of Case Discussion Complexity, MeDiC), including logistical challenges (Measure of Case Discussion Complexity, MeDiC), across 822 case discussions from 30 videoed meetings. Descriptive analysis and paired samples t tests were used to identify and compare frequency of different types of logistical challenges, along with partial correlations, controlling for clinical complexity of cases, to understand how such issues related to the MDT decision-making and communication. A significantly higher frequency of administrative and process issues (affecting 30 per cent of cases) was seen compared with the frequency of equipment issues (affecting 5 per cent of cases; P < 0.001) and the frequency of the attendance issues (affecting 16 per cent of cases; P < 0.001). The frequency of the attendance issues was significantly higher than the frequency of equipment issues (P < 0.001). Partial correlation analysis revealed that administrative and process issues, including attendance, were negatively correlated with quality of information (r = -0.15, P < 0.001; r = -0.11, P < 0.001), and equipment issues with the quality of contribution to meeting discussion (r = -0.14, P < 0.001). More questioning and answering by MDT members was evident with the administrative and process issues (r = 0.21, P < 0.001; r = 0.19, P < 0.001). Some differences were observed in teams' socioemotional reactions to the administrative and process issues with the gynaecological MDT showing positive correlation with positive socioemotional reactions (r = 0.20, P < 0.001), and the breast cancer MDT with negative socioemotional reactions (r = 0.17, P < 0.001). Administrative and process issues were the most frequent logistical challenges for the studied teams. Where diagnostic results were unavailable, and inadequate patient details provided, the quality of decision-making was reduced.


Molecular development of fibular reduction in birds and its evolution from dinosaurs.
Birds have a distally reduced, splinter-like fibula that is shorter than the tibia. In embryonic development, both skeletal elements start out with similar lengths. We examined molecular markers of cartilage differentiation in chicken embryos. We found that the distal end of the fibula expresses Indian hedgehog (IHH), undergoing terminal cartilage differentiation, and almost no Parathyroid-related protein (PTHrP), which is required to develop a proliferative growth plate (epiphysis). Reduction of the distal fibula may be influenced earlier by its close contact with the nearby fibulare, which strongly expresses PTHrP. The epiphysis-like fibulare however then separates from the fibula, which fails to maintain a distal growth plate, and fibular reduction ensues. Experimental downregulation of IHH signaling at a postmorphogenetic stage led to a tibia and fibula of equal length: The fibula is longer than in controls and fused to the fibulare, whereas the tibia is shorter and bent. We propose that the presence of a distal fibular epiphysis may constrain greater growth in the tibia. Accordingly, many Mesozoic birds show a fibula that has lost its distal epiphysis, but remains almost as long as the tibia, suggesting that loss of the fibulare preceded and allowed subsequent evolution of great fibulo-tibial disparity.


Velocity profile method for time varying resistance in minimal cardiovascular system models.
This paper investigates the fluid dynamics governing arterial flow used in lumped parameter cardiovascular system (CVS) models, particularly near the heart where arteries are large. Assumptions made in applying equations conventionally used in lumped parameter models are investigated, specifically that of constant resistance to flow. The Womersley number is used to show that the effects of time varying resistance must be modelled in the pulsatile flow through the large arteries near the heart. It is shown that the equation commonly used to include inertial effects in fluid flow calculations is inappropriate for including time varying resistance. A method of incorporating time varying resistance into a lumped parameter model is developed that uses the Navier-Stokes equations to track the velocity profile. Tests on a single-chamber model show a 17.5% difference in cardiac output for a single-chamber ventricle model when comparing constant resistance models with the velocity profile tracking method modelling time varying resistance. This increase in precision can be achieved using 20 nodes with only twice the computational time required. The method offers a fluid dynamically and physiologically accurate method of calculating large Womersley number pulsatile fluid flows in large arteries around the heart and valves. The proposed velocity profile tracking method can be easily incorporated into existing lumped parameter CVS models, improving their clinical application by increasing their accuracy.


Identification of the genes involved in odorant reception and detection in the palm weevil Rhynchophorus ferrugineus, an important quarantine pest, by antennal transcriptome analysis.
The Red Palm Weevil (RPW) Rhynchophorus ferrugineus (Oliver) is one of the most damaging invasive insect species in the world. This weevil is highly specialized to thrive in adverse desert climates, and it causes major economic losses due to its effects on palm trees around the world. RPWs locate palm trees by means of plant volatile cues and use an aggregation pheromone to coordinate a mass-attack. Here we report on the high throughput sequencing of the RPW antennal transcriptome and present a description of the highly expressed chemosensory gene families. Deep sequencing and assembly of the RPW antennal transcriptome yielded 35,667 transcripts with an average length of 857 bp and identified a large number of highly expressed transcripts of odorant binding proteins (OBPs), chemosensory proteins (CSPs), odorant receptors/co-receptors (ORs/Orcos), sensory neuron membrane proteins (SNMPs), gustatory receptors (GRs) and ionotropic receptors (IRs). In total, 38 OBPs, 12 CSPs, 76 ORs, 1 Orco, 6 SNMPs, 15 GRs and 10 IRs were annotated in the R. ferrugineus antennal transcriptome. A comparative transcriptome analysis with the bark beetle showed that 25% of the blast hits were unique to R. ferrugineus, indicating a higher, more complete transcript coverage for R. ferrugineus. We categorized the RPW ORs into seven subfamilies of coleopteran ORs and predicted two new subfamilies of ORs. The OR protein sequences were compared with those of the flour beetle, the cerambycid beetle and the bark beetle, and we identified coleopteran-specific, highly conserved ORs as well as unique ORs that are putatively involved in RPW aggregation pheromone detection. We identified 26 Minus-C OBPs and 8 Plus-C OBPs and grouped R. ferrugineus OBPs into different OBP-subfamilies according to phylogeny, which indicated significant species-specific expansion and divergence in R. ferrugineus. We also identified a diverse family of CSP proteins, as well as a coleopteran-specific CSP lineage that diverged from Diptera and Lepidoptera. We identified several extremely diverged IR orthologues as well as highly conserved insect IR co-receptor orthologous transcripts in R. ferrugineus. Notably, GR orthologous transcripts for CO2-sensing and sweet tastants were identified in R. ferrugineus, and we found a great diversity of GRs within the coleopteran family. With respect to SNMP-1 and SNMP-2 orthologous transcripts, one SNMP-1 orthologue was found to be strikingly highly expressed in the R. ferrugineus antennal transcriptome. Our study presents the first comprehensive catalogue of olfactory gene families involved in pheromone and general odorant detection in R. ferrugineus, which are potential novel targets for pest control strategies.


Real-world experience with echinocandin MICs against Candida species in a multicenter study of hospitals that routinely perform susceptibility testing of bloodstream isolates.
Reference broth microdilution methods of Candida echinocandin susceptibility testing are limited by interlaboratory variability in caspofungin MICs. Recently revised Clinical and Laboratory Standards Institute (CLSI) breakpoint MICs for echinocandin nonsusceptibility may not be valid for commercial tests employed in hospital laboratories. Indeed, there are limited echinocandin susceptibility testing data from hospital laboratories. We conducted a multicenter retrospective study of 9 U.S., Australian, and New Zealand hospitals that routinely tested Candida bloodstream isolates for echinocandin susceptibility from 2005 to 2013. Eight hospitals used Sensititre YeastOne assays. The Candida spp. were C. albicans (n=1,067), C. glabrata (n=911), C. parapsilosis (n=476), C. tropicalis (n=185), C. krusei (n=104), and others (n=154). Resistance and intermediate rates were ≤1.4% and ≤3%, respectively, for each echinocandin against C. albicans, C. parapsilosis, and C. tropicalis. Resistance rates among C. glabrata and C. krusei isolates were ≤7.5% and ≤5.6%, respectively. Caspofungin intermediate rates among C. glabrata and C. krusei isolates were 17.8% and 46.5%, respectively, compared to ≤4.3% and ≤4.4% for other echinocandins. Using CLSI breakpoints, 18% and 19% of C. glabrata isolates were anidulafungin susceptible/caspofungin nonsusceptible and micafungin susceptible/caspofungin nonsusceptible, respectively; similar discrepancies were observed for 38% and 39% of C. krusei isolates. If only YeastOne data were considered, interhospital modal MIC variability was low (within 2 doubling dilutions for each agent). In conclusion, YeastOne assays employed in hospitals may reduce the interlaboratory variability in caspofungin MICs against Candida species that are observed between reference laboratories using CLSI broth microdilution methods. The significance of classifying isolates as caspofungin intermediate and anidulafungin/micafungin susceptible will require clarification in future studies.


Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.
Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.


Bis[bis-(penta-methyl-cyclo-penta-dien-yl)cobalt(III)] tetra-chlorido-cobaltate(II) di-chloro-methane disolvate.
The title compound, [Co(C10H15)2]2[CoCl4]·2CH2Cl2, was isolated as a dichloromethane solvate and was formed in the reaction between lithium penta-methyl-cyclo-penta-dienide and anyhydrous cobalt(II) chloride in tetra-hydro-furan. There are two deca-methyl-cobaltocenium cations, one tetrachloridocobaltate(II) anion and two di-chloro-methane solvent mol-ecules in the formula unit. There is a slight disorder of the di-chloro-methane solvent which was treated with a two-site model [occupancy rates = 0.765 (4) and 0.235 (4)]. The di-chloro-methane mol-ecules display significant C-H⋯Cl inter-actions with the tetrachloridocobaltate(II) dianion. The cobalt atom of the deca-methyl-cobaltocenium cation sits on a twofold rotation axis, with only one penta-methyl-cyclo-penta-diene ligand being unique and the second generated by symmetry. The cobalt atom of the [CoCl4](-2) ion sits on a special site with -4 symmetry, with one unique chloride ligand and the others generated by the fourfold inversion axis.


Optimization of thermoelectric efficiency in SnTe: the case for the light band.
p-Type PbTe is an outstanding high temperature thermoelectric material with zT of 2 at high temperatures due to its complex band structure which leads to high valley degeneracy. Lead-free SnTe has a similar electronic band structure, which suggests that it may also be a good thermoelectric material. However, stoichiometric SnTe is a strongly p-type semiconductor with a carrier concentration of about 1 × 10(20) cm(-3), which corresponds to a minimum Seebeck coefficient and zT. While in the case of p-PbTe (and n-type La3Te4) one would normally achieve higher zT by using high carrier density in order to populate the secondary band with higher valley degeneracy, SnTe behaves differently. It has a very light, upper valence band which is shown in this work to provide higher zT than doping towards the heavier second band. Therefore, decreasing the hole concentration to maximize the performance of the light band results in higher zT than doping into the high degeneracy heavy band. Here we tune the electrical transport properties of SnTe by decreasing the carrier concentration with iodine doping, and increasing the carrier concentration with Gd doping or by making the samples Te deficient. A peak zT value of 0.6 at 700 K was obtained for SnTe0.985I0.015 which optimizes the light, upper valence band, which is about 50% higher than the other peak zT value of 0.4 for GdzSn1-zTe and SnTe1+y which utilize the high valley degeneracy secondary valence band.


Short-range shock formation and coalescence in numerical simulation of broadband noise propagation.
The number of jet and rocket noise studies has increased in recent years as researchers have sought to better understand aeroacoustic source and radiation characteristics. Although jet and rocket noise is finite-amplitude in nature, little is known about the existence of shock formation and coalescence close to the source. A numerical experiment is performed to propagate finite-amplitude noise and determine the extent of the nonlinearity over short distances with spherical spreading. The noise is filtered to have a haystack shape in the frequency domain, as is typical of such sources. The effect of the nonlinearity is compared in both the temporal and frequency domains as a function of distance. Additionally, the number of zero-crossings and overall sound pressure level is compared at several distances. The results indicate that the center frequency plays a particularly important role in the amount of coalescence and spectral redistribution that occurs. The general applicability of these results to actual near-field finite-amplitude jet and rocket noise experiments is also presented.


High-Intensity Focused Ultrasound for the Treatment of Prostate Cancer: A Review.
Over the past 25 years, the average life expectancy for men has increased almost 4 years, and the age of prostate cancer detection has decreased an average of 10 years with diagnosis increasingly made at early-stage disease where curative therapy is possible. These changing trends in the age and extent of malignancy at diagnosis have revealed limitations in conventional curative therapies for prostate cancer, including a significant risk of aggressive cancer recurrence, and the risk of long-term genitourinary morbidity and its detrimental impact on patient's quality of life (QOL). Greater awareness of the shortcomings in radical prostatectomy, external radiotherapy, and brachytherapy has prompted the search for alternative curative therapies that offer comparable rates of cancer control and less treatment-related morbidity to better preserve QOL. High-intensity focused ultrasound (HIFU) possesses characteristics that make it an attractive curative therapy option. HIFU is a noninvasive approach that uses precisely delivered ultrasound energy to achieve tumor cell necrosis without radiation or surgical excision. In current urologic oncology, HIFU is used clinically in the treatment of prostate cancer and is under experimental investigation for therapeutic use in multiple malignancies. Clinical research on HIFU therapy for localized prostate cancer began in the 1990s, and there have now been ∼65,000 prostate cancer patients treated with HIFU, predominantly with the Ablatherm (EDAP TMS, Lyon, France) device. Neoadjuvant transurethral resection of the prostate has been combined with HIFU since 2000 to reduce prostate size, facilitate tissue destruction, and to minimize side effects. Advances in imaging technologies are expected to further improve the already superior efficacy and morbidity outcomes, and ongoing investigation of HIFU as a focal therapy in salvage and palliative indications is serving to expand the role of HIFU as a highly versatile noninvasive therapy for prostate cancer.


[Shivering during epidural anesthesia with and without fentanyl: comparative study.].
Most studies in the literature correlating epidural opioids to postoperative shivering were carried out with obstetric patients whose thermoregulation center response might be different from non-pregnant patients. Our study aimed at comparing intra and postoperative shivering and other complications of epidural block with and without fentanyl in patients submitted to varicose vein surgery under epidural anesthesia with 0.5% bupivacaine and 1:200,000 epinephrine. Participated in this study 34 patients, physical status ASA I and II, submitted to lower limbs varicose vein surgery, who were randomly distributed in 2 groups (n = 17) and received intravenous midazolam (0.05 mg.kg-1) followed by lumbar epidural anesthesia. Group S received 20 mL of 0.5% bupivacaine (with epinephrine) associated to 2 mL of 0.9% saline solution, and Group F received 20 mL of 0.5% bupivacaine (with epinephrine) associated to fentanyl (100 microg). Shivering, temperature, meperidine need, nausea and vomiting were evaluated in the following moments: M1 - admission to the operating room; M2 - immediately before anesthesia; M3 - 30 minutes after local anesthetic injection; M4 - 60 minutes after local anesthetic injection; M5 - 90 minutes after local anesthetic injection; M6 - end of anesthesia; M7 - immediately before PACU discharge. There have been no statistically significant differences between groups in demographics, physical status, mean anesthesia and surgery duration, patients and operating room temperature, and the incidence of nausea and vomiting. There have been statistically significant differences in shivering occurrence at 60 (M4) and 90 minutes (M5) after epidural block, with higher incidence of shivering in Group S as compared to Group F. A greater demand for meperidine was observed in patients submitted to epidural block without fentanyl. In the conditions of our study, 100 microg fentanyl associated to epidural local anesthetics did not abolish shivering but is able to decrease its incidence without increasing the incidence of nausea and vomiting.


The association between malaria and non-typhoid Salmonella bacteraemia in children in sub-Saharan Africa: a literature review.
Plasmodium falciparum malaria and non-typhoid Salmonella (NTS) bacteraemia are both major causes of morbidity and mortality in children in sub-Saharan Africa. Co-infections are expected to occur because of their overlapping geographical distribution, but accumulating evidence indicates that malaria is a risk factor for NTS bacteraemia. A literature review was undertaken to provide an overview of the evidence available for this association, the epidemiology of malaria-NTS co-infection (including the highest risk groups), the underlying mechanisms, and the clinical consequences of this association, in children in sub-Saharan Africa. The burden of malaria-NTS co-infection is highest in young children (especially those less than three years old). Malaria is one of the risk factors for NTS bacteraemia in children, and the risk is higher with severe malaria, especially severe malarial anaemia. There is insufficient evidence to determine whether asymptomatic parasitaemia is a risk factor for NTS bacteraemia. Many mechanisms have been proposed to explain how malaria causes susceptibility to NTS, ranging from macrophage dysfunction to increased gut permeability, but the most consistent evidence is that malarial haemolysis creates conditions which favour bacterial growth, by increasing iron availability and by impairing neutrophil function. Few discriminatory clinical features have been described for those with malaria and NTS co-infection, except for a higher risk of anaemia compared to those with either infection alone. Children with malaria and NTS bacteraemia co-infection have higher case fatality rates compared to those with malaria alone, and similar to those with bacteraemia alone. Antimicrobial resistance is becoming widespread in invasive NTS serotypes, making empirical treatment problematic, and increasing the need for prevention measures. Observational studies indicate that interventions to reduce malaria transmission might also have a substantial impact on decreasing the incidence of NTS bacteraemia.


Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.
The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD(+)-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.


Do funding applications where peer reviewers disagree have higher citations? A cross-sectional study.
Background: Decisions about which applications to fund are generally based on the mean scores of a panel of peer reviewers. As well as the mean, a large disagreement between peer reviewers may also be worth considering, as it may indicate a high-risk application with a high return. Methods: We examined the peer reviewers' scores for 227 funded applications submitted to the American Institute of Biological Sciences between 1999 and 2006. We examined the mean score and two measures of reviewer disagreement: the standard deviation and range. The outcome variable was the relative citation ratio, which is the number of citations from all publications associated with the application, standardised by field and publication year. Results: There was a clear increase in relative citations for applications with a better mean. There was no association between relative citations and either of the two measures of disagreement. Conclusions: We found no evidence that reviewer disagreement was able to identify applications with a higher than average return. However, this is the first study to empirically examine this association, and it would be useful to examine whether reviewer disagreement is associated with research impact in other funding schemes and in larger sample sizes.


Structural insights into the mechanism for recognizing substrate of the cytochrome P450 enzyme TxtE.
Thaxtomins, a family of phytotoxins produced by Streptomyces spp., can cause dramatic plant cell hypertrophy and seedling stunting. Thaxtomin A is the dominant form from Streptomyces scabies and has demonstrated herbicidal action. TxtE, a cytochrome P450 enzyme from Streptomyces scabies 87.22, catalyzes direct nitration of the indolyl moiety of L-tryptophan to L-4-nitrotryptophan using nitric oxide, dioxygen and NADPH. The crystal structure of TxtE was determined at 2.1 Å resolution and described in this work. A clearly defined substrate access channel is observed and can be classified as channel 2a, which is common in bacteria cytochrome P450 enzymes. A continuous hydrogen bond chain from the active site to the external solvent is observed. Compared with other cytochrome P450 enzymes, TxtE shows a unique proton transfer pathway which crosses the helix I distortion. Polar contacts of Arg59, Tyr89, Asn293, Thr296, and Glu394 with L-tryptophan are seen using molecular docking analysis, which are potentially important for substrate recognition and binding. After mutating Arg59, Asn293, Thr296 or Glu394 to leucine, the substrate binding ability of TxtE was lost or decreased significantly. Based on the docking and mutation results, a possible mechanism for substrate recognition and binding is proposed.


Degradation of 2-hydroxybiphenyl and 2,2'-dihydroxybiphenyl by Pseudomonas sp. strain HBP1.
Pseudomonas sp. strain HBP1 was found to grow on 2-hydroxy- and 2,2'-dihydroxy-biphenyl as the sole carbon and energy sources. The first step in the degradation of these compounds was catalyzed by an NADH-dependent monooxygenase. The enzyme inserted a hydroxyl group adjacent to the already existing hydroxyl group to form 2,3-dihydroxybiphenyl when acting on 2-hydroxybiphenyl and to form 2,2',3-trihydroxybiphenyl when acting on 2,2'-dihydroxybiphenyl. To be substrates of the monooxygenase, compounds required a 2-hydroxyphenyl-R structure, with R being a hydrophobic group (e.g., methyl, ethyl, propyl, sec-butyl, phenyl, or 2-hydroxyphenyl). Several chlorinated hydroxybiphenyls served as pseudosubstrates by effecting consumption of NADH and oxygen without being hydroxylated. Further degradation of 2,3-dihydroxy- and 2,2',3-trihydroxybiphenyl involved meta cleavage, with subsequent formation of benzoate and salicylate, respectively.


Cytosine-functionalized bioinspired hydrogels for ocular delivery of antioxidant transferulic acid.
Contact lenses (CLs) are being pointed out as feasible platforms for controlled delivery of ophthalmic drugs. Bioinspired strategies may endow CLs with affinity for a given drug by mimicking its physiological receptor using adequate functional monomers and tuning their conformation in the space through the molecular imprinting technology. However, there are some active substances, such as efficient antioxidant agents, that cannot be used as templates because they degrade during polymerization or even hinder the polymerization itself. Therefore, the development of CLs able to sustain the release of antioxidants for the prevention and/or treatment of several age-related and light-induced eye diseases has not been explored yet. Searching for an alternative bioinspired strategy, the present work relies on the fact that some drugs owe their therapeutic action to their ability to interact with nucleotides that build up DNA and RNA. Thus, the aim of this work was to design hydrogels functionalized with the nitrogenous base cytosine for the controlled uptake and release of transferulic acid (TA) having a complementary chemical structure in terms of hydrogen bonding and π-π stacking ability. Hydrogels were prepared from mixtures of 2-hydroxyethyl methacrylate (HEMA), glycidyl methacrylate (GMA) and ethyleneglycolphenylether methacrylate (EGPEM). GMA was used as a bridge to immobilize cytosine after hydrogel synthesis, while EGPEM was added to reinforce hydrophobic interactions with TA. The hydrogels were characterized in terms of suitability to be used as CLs (swelling, light transmission, mechanical properties, biocompatibility) and capability to host TA and sustain its release in lachrymal fluid while maintaining the antioxidant activity. Relevantly, the bioinspired CLs favored TA accumulation in cornea and sclera tissues.


Ablation of the kinase NDR1 predisposes mice to the development of T cell lymphoma.
Defective apoptosis contributes to the development of various human malignancies. The kinases nuclear Dbf2-related 1 (NDR1) and NDR2 mediate apoptosis downstream of the tumor suppressor proteins RASSF1A (Ras association domain family member 1A) and MST1 (mammalian Ste20-like kinase 1). To further analyze the role of NDR1 in apoptosis, we generated NDR1-deficient mice. Although NDR1 is activated by both intrinsic and extrinsic proapoptotic stimuli, which indicates a role for NDR1 in regulating apoptosis, NDR1-deficient T cells underwent apoptosis in a manner similar to that of wild-type cells in response to different proapoptotic stimuli. Analysis of the abundances of NDR1 and NDR2 proteins revealed that loss of NDR1 was functionally compensated for by an increase in the abundance of NDR2 protein. Despite this compensation, NDR1(-/-) and NDR1(+/-) mice were more prone to the development of T cell lymphomas than were wild-type mice. Tumor development in mice and humans was accompanied by a decrease in the overall amounts of NDR proteins in T cell lymphoma samples. Thus, reduction in the abundance of NDR1 triggered a decrease in the total amount of both isoforms. Together, our data suggest that a reduction in the abundances of the NDR proteins results in defective responses to proapoptotic stimuli, thereby facilitating the development of tumors.


Beyond the volcano limitations in electrocatalysis--oxygen evolution reaction.
Oxygen evolution catalysis is restricted by the interdependence of adsorption energies of the reaction intermediates and the surface reactivity. The interdependence reduces the number of degrees of freedom available for catalyst optimization. Here it is demonstrated that this limitation can be removed by active site modification. This can be achieved on ruthenia by incorporation of Ni or Co into the surface, which activates a proton donor-acceptor functionality on the conventionally inactive bridge surface sites. This enhances the actual measured oxygen evolution activity of the catalyst significantly compared to conventional ruthenia.


The Status and Distinct Characteristics of Endocrine Diseases in North Korean Articles Published between 2006 and 2015.
Past decades of division have led to substantial differences in medical environments between South and North Korea. However, little is known about North Korea's medical status and research field, especially regarding endocrinology. In this study, we report the characteristics of North Korea's articles regarding endocrine-related diseases. Among the nine medical journals, articles published in Internal Medicine between 2006 and 2015 were reviewed. A total of 2,092 articles were included; among them, 96 articles were associated with endocrinology. We analyzed these articles according to the disease categories they focused on and evaluated their features. Articles related to diabetes mellitus accounted for 55.2% (n=53) and those to thyroid disease accounted for 28.1% (n=27). Other disease categories, including adrenal gland (n=1), pituitary gland (n=1), and osteoporosis (n=3), comprised minor portions. Regarding diabetes mellitus, more than half the articles (n=33) focused on treatment and complications. Experimental studies were conducted with old hypoglycemic drugs or natural substances for the treatment of hyperglycemia. Regarding thyroid disease, articles related to hyperthyroidism were the most common (51.9%, n=14), followed by thyroid nodule/cancer (18.5%, n=5). Unique article features were short length, no figures, and less than five references. North Korea's endocrinology articles mainly focused on diabetes mellitus and thyroid disease. Persistent studies have been carried out in North Korea with dedication despite the poor medical environment. We hope that this study will be the beginning of mutual medical exchange and collaboration between North and South Korea.


Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability.
Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. 'Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.


Dectin-2 deficiency promotes Th2 response and mucin production in the lungs after pulmonary infection with Cryptococcus neoformans.
Dectin-2 is a C-type lectin receptor that recognizes high mannose polysaccharides. Cryptococcus neoformans, a yeast-form fungal pathogen, is rich in polysaccharides in its cell wall and capsule. In the present study, we analyzed the role of Dectin-2 in the host defense against C. neoformans infection. In Dectin-2 gene-disrupted (knockout) (Dectin-2KO) mice, the clearance of this fungus and the inflammatory response, as shown by histological analysis and accumulation of leukocytes in infected lungs, were comparable to those in wild-type (WT) mice. The production of type 2 helper T (Th2) cytokines in lungs was higher in Dectin-2KO mice than in WT mice after infection, whereas there was no difference in the levels of production of Th1, Th17, and proinflammatory cytokines between these mice. Mucin production was significantly increased in Dectin-2KO mice, and this increase was reversed by administration of anti-interleukin 4 (IL-4) monoclonal antibody (MAb). The levels of expression of β1-defensin, cathelicidin, surfactant protein A (Sp-A), and Sp-D in infected lungs were comparable between these mice. In in vitro experiments, IL-12p40 and tumor necrosis factor alpha (TNF-α) production and expression of CD86 and major histocompatibility complex (MHC) class II by bone marrow-derived dendritic cells and alveolar macrophages were completely abrogated in Dectin-2KO mice. Finally, the disrupted lysates of C. neoformans, but not of whole yeast cells, activated Dectin-2-triggered signaling in an assay with nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Dectin-2 may oppose the Th2 response and IL-4-dependent mucin production in the lungs after infection with C. neoformans, and it may not be required for the production of Th1, Th17, and proinflammatory cytokines or for clearance of this fungal pathogen.


Outcomes for Elderly Patients Aged 70 to 80 Years or Older with Locally Advanced Oral Cavity Squamous Cell Carcinoma: A Propensity Score-Matched, Nationwide, Oldest Old Patient-Based Cohort Study.
Purpose: Although clinicians encounter patients aged ≥70 years with locally advanced oral cavity squamous cell carcinoma (LA-OCSCC), no evidence is available to facilitate decision making regarding treatment for this elderly population. Methods: We selected elderly (≥70 years) patients from the Taiwan Cancer Registry database who had received a diagnosis of LA-OCSCC. Propensity score matching was performed. Cox proportional hazards model curves were used to analyze all-cause mortality in patients in different age groups receiving different treatments. Results: The matching process yielded a final cohort of 976 patients in concurrent chemoradiotherapy (CCRT), non-treatment, radiotherapy (RT) alone, and surgery cohorts who were eligible for further analysis. After stratified analysis, the adjusted hazard ratios (aHRs) (95% confidence intervals [CIs]) derived for surgery, RT alone, and non-treatment compared with CCRT were 0.66 (0.52 to 0.83), 1.02 (0.81 to 1.28), and 1.52 (1.21 to 1.91), respectively, in patients aged 70 to 80 years. In the oldest patients (aged >80 years), multivariate analysis indicated that the results of surgery or RT alone were nonsignificant compared with those of CCRT. The aHR (95% CI) derived for the highest mortality was 1.81 (1.11 to 2.40) for non-treatment compared with CCRT. Conclusions: Surgery for elderly patients with LA-OCSCC is associated with a significant survival benefit, but the association is nonsignificant in the oldest elderly patients. No survival differences were observed between RT alone and CCRT in these elderly patients. Non-treatment should not be an option for these patients.


Association between tea and coffee consumption and risk of laryngeal cancer: a meta-analysis.
Epidemiological studies evaluating the association of tea and coffee consumption and the risk of laryngeal cancer have produced inconsistent results. Thus, we conducted a meta-analysis to assess the relationship between tea and coffee consumption and laryngeal cancer risk. Pertinent studies were identified by a search in PubMed, Web of Knowledge and Wan Fang Med Online. The random effect model was used based on heterogeneity test. Publication bias was estimated using Egger's regression asymmetry test. As a result, 11 articles were included in this meta-analysis. For tea consumption and laryngeal cancer, data from 8 studies including 2167 laryngeal cancer cases were used, and the pooled results suggested that highest tea consumption versus lowest level wasn't associated with the risk of laryngeal cancer [summary RR = 0.909, 95% CI = 0.674-1.227]. Eight studies comprising 2596 laryngeal cancer cases for coffee consumption and laryngeal cancer risk were included, and no association was found (summary RR = 1.218, 95% CI = 0.915-1.622). Finding from this meta-analysis suggested that tea and coffee consumption weren't associated with the risk of laryngeal cancer. Since the potential biases and confounders could not be ruled out completely in this meta-analysis, further studies are warranted to confirm this result.


A pathway approach to evaluating the association between the CHIEF pathway and risk of colorectal cancer.
Inflammation, hormones and energy-related factors have been associated with colorectal cancer (CRC) and it has been proposed that convergence and interactions of these factors importantly influence CRC risk. We have previously hypothesized that genetic variation in the CHIEF (convergence of hormones, inflammation and energy-related factors) pathway would influence risk of CRC. In this paper, we utilize an Adaptive Rank Truncation Product (ARTP) statistical method to determine the overall pathway significance and then use that method to identify the key elements within the pathway associated with disease risk. Data from two population-based case-control studies of colon (n = 1555 cases and 1956 controls) and rectal (n = 754 cases and 959 controls) cancer were used. We use ARTP to estimate pathway and gene significance and polygenic scores based on ARTP findings to further estimate the risk associated with the pathway. Associations were further assessed based on tumor molecular phenotype. The CHIEF pathway was statistically significant for colon cancer (P(ARTP)= 0.03) with the most significant interferons (P(ARTP) = 0.0253), JAK/STAT/SOCS (P(ARTP) = 0.0111), telomere (P(ARTP) = 0.0399) and transforming growth factor β (P(ARTP) = 0.0043) being the most significant subpathways for colon cancer. For rectal cancer, interleukins (P(ARTP) = 0.0235) and selenoproteins (P ARTP = 0.0047) were statistically significant although the pathway overall was of borderline significance (P(ARTP) = 0.06). Interleukins (P(ARTP) = 0.0456) and mitogen-activated protein kinase (P(ARTP) = 0.0392) subpathways were uniquely significant for CpG island methylator phenotype-positive colon tumors. Increasing number of at-risk alleles was significantly associated with both colon [odds ratio (OR) = 6.21, 95% confidence interval (CI): 4.72, 8.16] and rectal (OR = 7.82, 95% CI: 5.26, 11.62) cancer. We conclude that elements of the CHIEF pathway are important for CRC risk.


Plausibility of inferred ancestral phenotypes and the evaluation of alternative models of limb evolution in scincid lizards.
Phylogenetic approaches to inferring ancestral character states are becoming increasingly sophisticated; however, the potential remains for available methods to yield strongly supported but inaccurate ancestral state estimates. The consistency of ancestral states inferred for two or more characters affords a useful criterion for evaluating ancestral trait reconstructions. Ancestral state estimates for multiple characters that entail plausible phenotypes when considered together may reasonably be assumed to be reliable. However, the accuracy of inferred ancestral states for one or more characters may be questionable where combined reconstructions imply implausible phenotypes for a proportion of internal nodes. This criterion for assessing reconstructed ancestral states is applied here in evaluating inferences of ancestral limb morphology in the scincid lizard clade Lerista. Ancestral numbers of digits for the manus and pes inferred assuming the models that best fit the data entail ancestral digit configurations for many nodes that differ fundamentally from configurations observed among known species. However, when an alternative model is assumed for the pes, inferred ancestral digit configurations are invariably represented among observed phenotypes. This indicates that a suboptimal model for the pes (and not the model providing the best fit to the data) yields accurate ancestral state estimates.