Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: a proof of concept study.
The current drug treatment for Alzheimer's disease (AD) is only partially and temporary effective. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current inducing modulation in cortical excitability. In addition, cognitive training (COG) may improve cognitive functions in AD. Our aim was to treat AD patients combining high-frequency repetitive TMS interlaced with COG (rTMS-COG). Eight patients with probable AD, treated for more than 2 months with cholinesterase inhibitors, were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by maintenance sessions (2/week) for an additional 3 months. Six brain regions, located individually by MRI, were stimulated. COG tasks were developed to fit these regions. Primary objectives were average improvement of Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) and Clinical Global Impression of Change (CGIC) (after 6 weeks and 4.5 months, compared to baseline). Secondary objectives were average improvement of MMSE, ADAS-ADL, Hamilton Depression Scale (HAMILTON) and Neuropsychiatric Inventory (NPI). One patient abandoned the study after 2 months (severe urinary sepsis). ADAS-cog (average) improved by approximately 4 points after both 6 weeks and 4.5 months of treatment (P < 0.01 and P < 0.05) and CGIC by 1.0 and 1.6 points, respectively. MMSE, ADAS-ADL and HAMILTON improved, but without statistical significance. NPI did not change. No side effects were recorded. In this study, rTMS-COG (provided by Neuronix Ltd., Yokneam, Israel) seems a promising effective and safe modality for AD treatment, possibly as good as cholinesterase inhibitors. A European double blind study is underway.


Low rates of Pseudomonas aeruginosa misidentification in isolates from cystic fibrosis patients.
Pseudomonas aeruginosa is an important cause of pulmonary infection in cystic fibrosis (CF). Its correct identification ensures effective patient management and infection control strategies. However, little is known about how often CF sputum isolates are falsely identified as P. aeruginosa. We used P. aeruginosa-specific duplex real-time PCR assays to determine if 2,267 P. aeruginosa sputum isolates from 561 CF patients were correctly identified by 17 Australian clinical microbiology laboratories. Misidentified isolates underwent further phenotypic tests, amplified rRNA gene restriction analysis, and partial 16S rRNA gene sequence analysis. Participating laboratories were surveyed on how they identified P. aeruginosa from CF sputum. Overall, 2,214 (97.7%) isolates from 531 (94.7%) CF patients were correctly identified as P. aeruginosa. Further testing with the API 20NE kit correctly identified only 34 (59%) of the misidentified isolates. Twelve (40%) patients had previously grown the misidentified species in their sputum. Achromobacter xylosoxidans (n = 21), Stenotrophomonas maltophilia (n = 15), and Inquilinus limosus (n = 4) were the species most commonly misidentified as P. aeruginosa. Overall, there were very low rates of P. aeruginosa misidentification among isolates from a broad cross section of Australian CF patients. Additional improvements are possible by undertaking a culture history review, noting colonial morphology, and performing stringent oxidase, DNase, and colistin susceptibility testing for all presumptive P. aeruginosa isolates. Isolates exhibiting atypical phenotypic features should be evaluated further by additional phenotypic or genotypic identification techniques.


Self-Reported Sleep Duration and Quality and Cardiovascular Disease and Mortality: A Dose-Response Meta-Analysis.
Background There is growing evidence that sleep duration and quality may be associated with cardiovascular harm and mortality. Methods and Results We conducted a systematic review, meta-analysis, and spline analysis of prospective cohort studies that evaluate the association between sleep duration and quality and cardiovascular outcomes. We searched MEDLINE and EMBASE for these studies and extracted data from identified studies. We utilized linear and nonlinear dose-response meta-analysis models and used DerSimonian-Laird random-effects meta-analysis models of risk ratios, with inverse variance weighting, and the I2 statistic to quantify heterogeneity. Seventy-four studies including 3 340 684 participants with 242 240 deaths among 2 564 029 participants who reported death events were reviewed. Findings were broadly similar across both linear and nonlinear dose-response models in 30 studies with >1 000 000 participants, and we report results from the linear model. Self-reported duration of sleep >8 hours was associated with a moderate increased risk of all-cause mortality, with risk ratio , 1.14 (1.05-1.25) for 9 hours, risk ratio, 1.30 (1.19-1.42) for 10 hours, and risk ratio, 1.47 (1.33-1.64) for 11 hours. No significant difference was identified for periods of self-reported sleep <7 hours, whereas similar patterns were observed for stroke and cardiovascular disease mortality. Subjective poor sleep quality was associated with coronary heart disease (risk ratio , 1.44; 95% confidence interval, 1.09-1.90), but no difference in mortality and other outcomes. Conclusions Divergence from the recommended 7 to 8 hours of sleep is associated with a higher risk of mortality and cardiovascular events. Longer duration of sleep may be more associated with adverse outcomes compared with shorter sleep durations.


Seeing the body modulates audiotactile integration.
Audiotactile integration has been studied using various experimental setups but so far crossmodal congruency effects (CCEs) have not been found for tactile targets paired with auditory distractors. In the present study we investigated whether audiotactile CCEs exist and, if so, whether these CCEs have similar characteristics to those found by previous authors with visual distractors. We measured audiotactile CCEs by attaching four vibrators to the backs of participants and presented auditory stimuli from four loudspeakers placed, in separate blocks, at different distances in front of or behind the participant's body. Participants discriminated the elevation of tactile stimuli while ignoring the auditory distractors. CCEs were found only when participants were provided with noninformative vision of their own body, as seen from behind via a camera and head-mounted display; they were absent when participants did not view their body. Furthermore, in contrast to visuotactile CCEs, audiotactile CCEs did not depend on whether the distractors were presented on the same or different side as the tactile targets. The present study provides the first demonstration of an audiotactile CCE: incongruent auditory distractors impaired performance on a tactile elevation discrimination task relative to performance with congruent distractors. We show that audiotactile CCEs differ from visuotactile CCEs as they do not appear to be as sensitive to the spatial relations between the distractors and the tactile stimuli. We also show that these CCEs are modulated by vision of the body.


A genome-wide search strategy for identifying quantitative trait loci involved in reading and spelling disability (developmental dyslexia).
Family and twin studies of developmental dyslexia have consistently shown that there is a significant heritable component for this disorder. However, any genetic basis for the trait is likely to be complex, involving reduced penetrance, phenocopy, heterogeneity and oligogenic inheritance. This complexity results in reduced power for traditional parametric linkage analysis, where specification of the correct genetic model is important. One strategy is to focus on large multigenerational pedigrees with severe phenotypes and/or apparent simple Mendelian inheritance, as has been successfully demonstrated for speech and language impairment. This approach is limited by the scarcity of such families. An alternative which has recently become feasible due to the development of high-throughput genotyping techniques is the analysis of large numbers of sib-pairs using allele-sharing methodology. This paper outlines our strategy for conducting a systematic genome-wide search for genes involved in dyslexia in a large number of affected sib-pair familites from the UK. We use a series of psychometric tests to obtain different quantitative measures of reading deficit, which should correlate with different components of the dyslexia phenotype, such as phonological awareness and orthographic coding ability. This enable us to use QTL (quantitative trait locus) mapping as a powerful tool for localising genes which may contribute to reading and spelling disability.


High seroprevalence of antibodies to avian influenza viruses among wild waterfowl in Alaska: implications for surveillance.
We examined seroprevalence (presence of detectable antibodies in serum) for avian influenza viruses (AIV) among 4,485 birds, from 11 species of wild waterfowl in Alaska (1998-2010), sampled during breeding/molting periods. Seroprevalence varied among species (highest in eiders (Somateria and Polysticta species), and emperor geese (Chen canagica)), ages (adults higher than juveniles), across geographic locations (highest in the Arctic and Alaska Peninsula) and among years in tundra swans (Cygnus columbianus). All seroprevalence rates in excess of 60% were found in marine-dependent species. Seroprevalence was much higher than AIV infection based on rRT-PCR or virus isolation alone. Because pre-existing AIV antibodies can infer some protection against highly pathogenic AIV (HPAI H5N1), our results imply that some wild waterfowl in Alaska could be protected from lethal HPAIV infections. Seroprevalence should be considered in deciphering patterns of exposure, differential infection, and rates of AIV transmission. Our results suggest surveillance programs include species and populations with high AIV seroprevalences, in addition to those with high infection rates. Serologic testing, including examination of serotype-specific antibodies throughout the annual cycle, would help to better assess spatial and temporal patterns of AIV transmission and overall disease dynamics.


Purification, properties and influence of dietary copper on accumulation and functional activity of lysyl oxidase in rat skin.
Lysyl oxidase (protein-lysine 6-oxidase; EC 126.96.36.199) is a copper-containing enzyme that functions extracellularly and catalyses the oxidative deamination of peptidyl lysine. Lysyl oxidase was purified 150-175-fold from urea extracts of rat skin and uteri. Features of the enzyme were similar to those reported previously for lysyl oxidase obtained from rat aorta and bovine ligamenture. However, both approximately 40 and approximately 32 kDa polypeptide chains could be isolated from rat skin with apparent lysyl oxidase activity. Antibodies raised in chickens against the approximately 40 kDa form of lysyl oxidase detected the approximately 32 kDa form in immunoblots. Consequently it is inferred that the approximately 32 kDa form of lysyl oxidase is processed from the approximately 40 kDa form of the enzyme. The antibodies were also used to prepare anti(rat lysyl oxidase) affinity columns to facilitate the separation of lysyl oxidase from other proteins in studies to assess the extent to which lysyl oxidase serves as a reservoir for skin copper. At 16 h after an oral dose of copper, as 67Cu, about 6-8% of the total 67Cu incorporated into rat skin was found in association with lysyl oxidase. The lysyl oxidase concentration in rat skin was 2.5-7.5 nmol/g (determined by e.l.i.s.a.). Changing the copper status of rats by feeding a diet deficient in copper did not appear to influence lysyl oxidase accumulation in skin nor the percentage of incorporation of 67Cu in skin as lysyl oxidase. However, when rats were deprived of copper, the functional activity of lysyl oxidase in skin was one-third to one-half the normal values.


Active video-gaming effects on balance and mobility in individuals with chronic stroke: a randomized controlled trial.
Treatments that provide feedback, increase practice with multiple repetitions, and motivate patients are essential to rehabilitation post stroke. To determine whether playing active video games results in improved balance and mobility post stroke. Thirty participants with chronic (time since stroke = 3.0 [2.9] years) hemiparesis post stroke were randomly assigned to a gaming group or normal activity control group. Gaming systems provided participants with an interactive interface of real-time movement of either themselves or an avatar on the screen. Participants played games 50-60 minutes/day, 4 days/week, for 5 weeks. The intervention was strictly game-play, in standing position, without physical therapy. The control group received no special intervention and continued with normal activity. Both groups were tested prior to, following the 5 weeks (post test), and 3 months following the completion of the study. Outcome measures included the Fugl-Meyer Assessment, Berg Balance Scale, Dynamic Gait Index, Timed Up & Go, 6-minute walk test, 3-meter walk (self-selected and fast), and perception of recovery. No statistically significant differences between or within groups were found through analysis of covariance (covaried for side of hemiparesis) at post test or follow-up. Although the within-group effect sizes were primarily indexed as "small" (< .36), the gaming group exhibited higher within-group effect sizes before and after testing than did the control group on all 7 dependent variables analyzed. Even though the only intervention was game-play, there were small positive effects. Therapist assistance in making more optimum movement choices may be needed before significant improvements are seen with commercially available, general purpose games.


CDK11(p58) is required for centriole duplication and Plk4 recruitment to mitotic centrosomes.
CDK11(p58) is a mitotic protein kinase, which has been shown to be required for different mitotic events such as centrosome maturation, chromatid cohesion and cytokinesis. In addition to these previously described roles, our study shows that CDK11(p58) inhibition induces a failure in the centriole duplication process in different human cell lines. We propose that this effect is mediated by the defective centrosomal recruitment of proteins at the onset of mitosis. Indeed, Plk4 protein kinase and the centrosomal protein Cep192, which are key components of the centriole duplication machinery, showed reduced levels at centrosomes of mitotic CDK11-depleted cells. CDK11(p58), which accumulates only in the vicinity of mitotic centrosomes, directly interacts with the centriole-associated protein kinase Plk4 that regulates centriole number in cells. In addition, we show that centriole from CDK11 defective cells are not able to be over duplicated following Plk4 overexpression. We thus propose that CDK11 is required for centriole duplication by two non-mutually-exclusive mechanisms. On one hand, the observed duplication defect could be caused indirectly by a failure of the centrosome to fully maturate during mitosis. On the other hand, CDK11(p58) could also directly regulate key centriole components such as Plk4 during mitosis to trigger essential mitotic centriole modifications, required for centriole duplication during subsequent interphase.


SiGNet: A signaling network data simulator to enable signaling network inference.
Network models are widely used to describe complex signaling systems. Cellular wiring varies in different cellular contexts and numerous inference techniques have been developed to infer the structure of a network from experimental data of the network's behavior. To objectively identify which inference strategy is best suited to a specific network, a gold standard network and dataset are required. However, suitable datasets for benchmarking are difficult to find. Numerous tools exist that can simulate data for transcriptional networks, but these are of limited use for the study of signaling networks. Here, we describe SiGNet (Signal Generator for Networks): a Cytoscape app that simulates experimental data for a signaling network of known structure. SiGNet has been developed and tested against published experimental data, incorporating information on network architecture, and the directionality and strength of interactions to create biological data in silico. SiGNet is the first tool to simulate biological signaling data, enabling an accurate and systematic assessment of inference strategies. SiGNet can also be used to produce preliminary models of key biological pathways following perturbation.


Tet2 facilitates the derepression of myeloid target genes during CEBPα-induced transdifferentiation of pre-B cells.
The methylcytosine hydroxylase Tet2 has been implicated in hematopoietic differentiation and the formation of myeloid malignancies when mutated. An ideal system to study the role of Tet2 in myelopoeisis is CEBPα-induced transdifferentiation of pre-B cells into macrophages. Here we found that CEBPα binds to upstream regions of Tet2 and that the gene becomes activated. Tet2 knockdowns impaired the upregulation of macrophage markers as well as phagocytic capacity, suggesting that the enzyme is required for both early and late stage myeloid differentiation. A slightly weaker effect was seen in primary cells with a Tet2 ablation. Expression arrays of transdifferentiating cells with Tet2 knockdowns permitted the identification of a small subset of myeloid genes whose upregulation was blunted. Activation of these target genes was accompanied by rapid increases of promoter hydroxy-methylation. Our observations indicate that Tet2 helps CEBPα rapidly derepress myeloid genes during the conversion of pre-B cells into macrophages.


Family support--a burden to patient and caregiver.
The aim of this paper was to describe family support in terms of the sources as well as the consequences of burden for caregivers, patients and family interaction. Caregivers' sources of burden were related to difficulties in coping with patients' emotional responses, physical complaints and altered life style behaviour as well as future oriented factors. Consequences in terms of caregivers' perceptions of emotional distress and personal losses are elucidated. In terms of family support, when focusing on sources of burden for patients' concerning family support, emotional support is emphasised and related to overprotection. Two different definitions of the overprotection concept are used in order to elucidate different consequences of the phenomenon. Sources and consequences of burden are also related to family interaction. The family is regarded as a system in which a cardiac disease may cause an imbalance. Poor marital quality or poor family functioning is described as a hindrance to a new balance. To summarise, the reviewed literature unanimously shows that the interactive support between family members when dealing with cardiac disease constitutes a considerable emotional burden. Therefore the support for emotional communication within the family should take priority. The knowledge described can provide a foundation for the development of family support in the cardiac area.


Towards natural non-invasive hand neuroprostheses for daily living.
In this paper we show how healthy subjects can operate a non-invasive asynchronous BCI for controlling a FES neuroprosthesis and manipulate objects to carry out daily tasks in ecological conditions. Both, experienced and novel subjects proved to be able to deliver mental commands with high accuracy and speed. Our neuroprosthetic approach relies on a natural interaction paradigm, where subjects delivers congruent MI commands (i.e., they imagining a movement of the same hand they control through FES). Furthermore, we have tested our approach in a common daily task such as handwriting, which requires the user to split his/her attention to multitask between BCI control, reaching, and the primary handwriting task itself. Interestingly, the very low number of erroneous trials illustrates how during the experiments subjects were able to deliver commands just when they intended to do so. Similarly, the subjects could perform actions while delivering, or preparing to deliver, mental commands.


Rare Genetic Variants Associated With Sudden Cardiac Death in Adults.
Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.


The evolving integrated vascular surgery residency curriculum.
Since their introduction several years ago, integrated (0 + 5) vascular surgery residency programs are being increasingly developed across the country. To date, however, there is no defined "universal" curriculum for these programs and each program is responsible for creating its own curriculum. The aim of this study was to review the experiences of current 0 + 5 program directors (PDs) to determine what factors contributed to the curricular development within their institution. Semistructured interviews were conducted with 0 + 5 PDs to explore their experiences with program development, factors influencing the latter, and rationale for current curricula. The interview script was loosely structured to explore several factors including time of incoming residents' first exposure to the vascular surgical service, timing and rationale behind the timing of core surgical rotations throughout the 5 year program, educational value of nonsurgical rotations, opportunities for leadership and scholarly activity, and influence the general surgery program and institutional climate had on curricular structure. All interviews were conducted by a single interviewer. All interviews were qualitatively analyzed using emergent theme analysis. Twenty-six 0 + 5 PDs participated in the study. A total of 69% believed establishing professional identity early reduces resident attrition and recommend starting incoming trainees on vascular surgical services. Sixty-two percent spread core surgical rotations over the first 3 years to optimize general surgical exposure and most of the programs have eliminated specific rotations, as they were not considered valuable to the goals of training. Factors considered most important by PDs in curricular development include building on existing institutional opportunities (96%), avoiding rotations considered unsuccessful by "experienced" programs (92%), and maintaining a good working relationship with general surgery (77%). Fifty-eight percent of PDs voiced concern over the lack of standardization among the differing programs and most of the PDs agree that some degree of programmatic standardization is critical for the continued success of the 0 + 5 training paradigm. Qualitative evaluation of PD experiences with the development of 0 + 5 vascular surgery residency programs reveals the key factors that commonly influence program design. Programs continue to evolve in both structure and content as PDs respond to these influences. Learning from the collective experience of PDs and some standardization of the curricula may help current and future programs avoid common pitfalls in curricular development.


Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities.
Nuclear receptors (NRs) activate gene transcription by binding to specific enhancer elements and recruiting coactivators of the p160 family to promoters of target genes. The p160 coactivators in turn enhance transcription by recruiting secondary coactivators, including histone acetyltransferases such as CREB-binding protein (CBP) and p300/CBP-associated factor (p/CAF), as well as the recently identified protein methyltransferase, coactivator-associated arginine methyltransferase 1 (CARM1). In the current study, protein arginine methyltransferase 1 (PRMT1), another arginine-specific protein methyltransferase that shares a region of high homology with CARM1, was also found to act as a coactivator for NRs. PRMT1, like CARM1, bound to the C-terminal AD2 activation domain of p160 coactivators and thereby enhanced the activity of NRs in transient transfection assays. The shape of the graphs of reporter gene activity versus the amounts of CARM1 or PRMT1 expression vector indicated a cooperative relationship between coactivator concentration and activity. Moreover, CARM1 and PRMT1 acted in a synergistic manner to enhance reporter gene activation by both hormone-dependent and orphan NRs. The synergy was most evident at low levels of transfected NR expression vectors, where activation of reporter genes was almost completely dependent on the presence of NR and all three exogenously supplied coactivators, i.e. GRIP1, CARM1, and PRMT1. In contrast, with the higher levels of NR expression vectors typically used in transient transfection assays, NR activity was much less dependent on the combination of coactivators, suggesting that target gene activation occurs by different mechanisms at high versus low cellular concentrations of NR. Because multiple coactivators are presumably required to mediate transcriptional activation of native genes in vivo, the low-NR conditions may provide a more physiologically relevant assay for coactivator function.


Protective effects of hydrogen-rich saline on necrotizing enterocolitis in neonatal rats.
The aim of this study was to test the hypothesis that hydrogen-rich saline (HRS) might have protective effects on the development of necrotizing enterocolitis (NEC) in a neonatal rat model. NEC was induced in male newborn Sprague-Dawley rats by formula feeding, exposure to asphyxia and cold stress. Sixty-four rat pups were divided randomly into four groups: C+NS (n=11), C+H2 (n=11), NEC+NS (n=20), and NEC+H2 (n=22). Rats in the former two groups were mother-fed. Pups received intra-peritoneal injection of HRS (10 ml/kg, 10 min before asphyxia stress twice a day) or the same dose of normal saline. Rats were monitored until 96 h after birth. Body weight, histological NEC score, survival time, malondialdehyde, antioxidant capacity, inflammatory mediators, and mucosal integrity were assessed. HRS treatment maintained the body weight, reduced the incidence of NEC from 85% (17/20) to 54.5% (12/22), increased the survival rate from 25% (5/20) to 68.2% (15/22), and attenuated the severity of NEC. In addition, HRS inhibited the mRNA expression of pro-inflammatory mediators (inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-6), down-regulated lipid peroxidation, enhanced total antioxidant capacity, and prevented the increase of diamine oxidase in serum. However, no significant influence of HRS on the interleukin-10 mRNA expression was observed. HRS showed beneficial effects on neonatal rats with NEC via decreasing oxidative stress, increasing antioxidant capacity, suppressing inflammation, and preserving mucosal integrity.


Triply resonant coherent four-wave mixing in silicon nitride microresonators.
Generation of multiple tones using four-wave mixing (FWM) has been exploited for many applications, ranging from wavelength conversion to frequency comb generation. FWM is a coherent process, meaning that its dynamics strongly depend on the relative phase among the waves involved. The coherent nature of FWM has been exploited for phase-sensitive processing in different waveguide structures, but it has never been studied in integrated microresonators. Waveguides arranged in a resonant way allow for an effective increase in the wavelength conversion efficiency (at the expense of a reduction in the operational bandwidth). In this Letter, we show that phase shaping of a three-wave pump provides an extra degree of freedom for controlling the FWM dynamics in microresonators. We present experimental results in single-mode, normal-dispersion high-Q silicon nitride resonators, and numerical calculations of systems operating in the anomalous dispersion regime. Our results indicate that the wavelength conversion efficiency and modulation instability gain in microcavities pumped by multiple waves can be significantly modified with the aid of simple lossless coherent control techniques.


Oxygen-driven competition between low-dimensional structures of Sr3CoMO6 and Sr3CoMO7-δ with M = Ru, Ir.
We have realized a reversible structure transformation of one-dimensional 1D K4CdCl6-type Sr3CoMO6 with the Co(2+)/M(4+) cation ordering into the two-dimensional 2D double layered Ruddlesden-Popper structure Sr3CoMO7-δ with a random distribution of Co and M (with M = Ru, Ir) upon increasing the partial oxygen pressure. The combined soft and hard X-ray absorption spectroscopy studies show that under transformation, Co and M cations were oxidized to Co(3+) and M(5+). During oxidation, high-spin Co(2+) in Sr3CoMO6 first transforms into high-spin Co(3+) in oxygen-deficient Sr3CoMO7-δ, and then further transforms into low-spin Co(3+) in fully oxidized Sr3CoMO7 upon further increasing the partial pressure of oxygen. The 1D Sr3CoMO6 compound is magnetically ordered at low temperatures with the magnetic moments lying along the c-axis. Their alignment is parallel for Sr3CoRuO6 and antiparallel for Sr3CoIrO6. The 2D compounds reveal a spin-glass-like behavior related to the random distribution of magnetic cations in the structure.


The Caenorhabditis elegans unc-17 gene: a putative vesicular acetylcholine transporter.
Mutations in the unc-17 gene of the nematode Caenorhabditis elegans produce deficits in neuromuscular function. This gene was cloned and complementary DNAs were sequenced. On the basis of sequence similarity to mammalian vesicular transporters of biogenic amines and of localization to synaptic vesicles of cholinergic neurons in C. elegans, unc-17 likely encodes the vesicular transporter of acetylcholine. Mutations that eliminated all unc-17 gene function were lethal, suggesting that the acetylcholine transporter is essential. Molecular analysis of unc-17 mutations will allow the correlation of specific parts of the gene (and the protein) with observed functional defects. The mutants will also be useful for the isolation of extragenic suppressors, which could identify genes encoding proteins that interact with UNC-17.


Minian, an open-source miniscope analysis pipeline.
Miniature microscopes have gained considerable traction for in vivo calcium imaging in freely behaving animals. However, extracting calcium signals from raw videos is a computationally complex problem and remains a bottleneck for many researchers utilizing single-photon in vivo calcium imaging. Despite the existence of many powerful analysis packages designed to detect and extract calcium dynamics, most have either key parameters that are hard-coded or insufficient step-by-step guidance and validations to help the users choose the best parameters. This makes it difficult to know whether the output is reliable and meets the assumptions necessary for proper analysis. Moreover, large memory demand is often a constraint for setting up these pipelines since it limits the choice of hardware to specialized computers. Given these difficulties, there is a need for a low memory demand, user-friendly tool offering interactive visualizations of how altering parameters at each step of the analysis affects data output. Our open-source analysis pipeline, Minian (miniscope analysis), facilitates the transparency and accessibility of single-photon calcium imaging analysis, permitting users with little computational experience to extract the location of cells and their corresponding calcium traces and deconvolved neural activities. Minian contains interactive visualization tools for every step of the analysis, as well as detailed documentation and tips on parameter exploration. Furthermore, Minian has relatively small memory demands and can be run on a laptop, making it available to labs that do not have access to specialized computational hardware. Minian has been validated to reliably and robustly extract calcium events across different brain regions and from different cell types. In practice, Minian provides an open-source calcium imaging analysis pipeline with user-friendly interactive visualizations to explore parameters and validate results.


Peroxiredoxin 6, a novel player in the pathogenesis of diabetes.
Enhanced oxidative stress contributes to the pathogenesis of diabetes and its complications. Peroxiredoxin 6 (PRDX6) is a key regulator of cellular redox balance, with the peculiar ability to neutralize peroxides, peroxynitrite, and phospholipid hydroperoxides. In the current study, we aimed to define the role of PRDX6 in the pathophysiology of type 2 diabetes (T2D) using PRDX6 knockout (-/-) mice. Glucose and insulin responses were evaluated respectively by intraperitoneal glucose and insulin tolerance tests. Peripheral insulin sensitivity was analyzed by euglycemic-hyperinsulinemic clamp, and molecular tools were used to investigate insulin signaling. Moreover, inflammatory and lipid parameters were evaluated. We demonstrated that PRDX6(-/-) mice developed a phenotype similar to early-stage T2D caused by both reduced glucose-dependent insulin secretion and increased insulin resistance. Impaired insulin signaling was present in PRDX6(-/-) mice, leading to reduction of muscle glucose uptake. Morphological and ultrastructural changes were observed in islets of Langerhans and livers of mutant animals, as well as altered plasma lipid profiles and inflammatory parameters. In conclusion, we demonstrated that PRDX6 is a key mediator of overt hyperglycemia in T2D glucose metabolism, opening new perspectives for targeted therapeutic strategies in diabetes care.


Effects of Ethanol Exposure and Withdrawal on Neuronal Morphology in the Agranular Insular and Prelimbic Cortices: Relationship with Withdrawal-Related Structural Plasticity in the Nucleus Accumbens.
The present study investigated the effects of chronic intermittent ethanol exposure and withdrawal on dendritic morphology and spine density in the agranular insular and prelimbic cortices. Adult male Sprague-Dawley rats were passively exposed to vaporized ethanol (~37 mg/L; 12 h/day) or air (control) for ten consecutive days. Dendritic length, branching, and spine density were quantified in layer II/III pyramidal neurons 24 hours or seven days following the final ethanol exposure. Compared to unexposed control animals there were structural alterations on neurons in the prelimbic cortex, and to a lesser extent the agranular insular cortex. The most prominent ethanol-related differences were the transient increases in dendritic length and branching in prelimbic neurons at 24 h post-cessation, and increased mushroom-shaped spines at seven days post-cessation. The results obtained in the prelimbic cortex are the opposite of those previously reported in the nucleus accumbens core (Peterson, et al. 2015), suggesting that these regions undergo distinct functional adaptations following ethanol exposure and withdrawal.


Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke - the Sydney Stroke Study.
The frequency and clinical, neuropsychological and neuroimaging correlates of apathy in patients who have had a stroke are inadequately defined. A total of 167 consecutive patients admitted to the stroke units of two university hospitals after an ischaemic stroke and 109 controls received extensive medical, psychiatric and neuropsychological assessments; a subset received a magnetic resonance imaging (MRI) scan. The groups were matched for sex and age. Patients were assessed 3-6 months after their stroke. The sample for this study comprised 135 patients and 92 controls who completed the Apathy Evaluation Scale (AES). Apathy was present in 26.7% of stroke patients compared to 5.4% of controls. Apathetic stroke patients were older, more functionally dependent and had lower Mini-Mental State Examination (MMSE) scores than those without apathy. Apathy was not associated with risk factors for cerebrovascular disease or stroke severity. There was a weak but significant correlation between apathy and self-reported depression but not with clinician-rated depression. Neuropsychologically, after correction for age, premorbid intelligence (IQ) and depression, apathy was associated with reduced attention and speed of information processing. On neuroimaging there were trends for associations of apathy with the extent of hyperintensities in the right hemisphere and right fronto-subcortical circuit, but not with total stroke volume or number of strokes. Apathy is common following a cerebrovascular event. Presence of apathy may be related to older age and right fronto-subcortical pathway pathology, rather than stroke severity. It is associated with functional impairment and cognitive deficits.


Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients.
Levofloxacin is an antituberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate the area under the concentration curve for the 24-h dosing interval (AUC0-24) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach. The popPK model and Bayesian LSS were developed using data from 30 patients and externally validated with 20 patients. The LSS based on multiple linear regression was internally validated using jackknife analysis. Only clinically suitable LSSs (maximum time span, 8 h; minimum interval, 1 h; 1 to 3 samples) were tested. Performance criteria were root-mean-square error (RMSE) of <15%, mean prediction error (MPE) of <5%, and r2 value of >0.95. A one-compartment model with lag time best described the data while only slightly underestimating the AUC0-24 (mean, -7.9%; standard error [SE], 1.7%). The Bayesian LSS using 0- and 5-h postdose samples (RMSE, 8.8%; MPE, 0.42%; r2 = 0.957) adequately estimated the AUC0-24, with a mean underestimation of -4.4% (SE, 2.7%). The multiple linear regression LSS using 0- and 4-h postdose samples (RMSE, 7.0%; MPE, 5.5%; r2 = 0.977) was internally validated, with a mean underestimation of -0.46% (SE, 2.0%). In this study, we successfully developed a popPK model and two LSSs that could be implemented in clinical practice to assist TDM of levofloxacin. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).


Trends and variation in antidepressant prescribing in English primary care: a retrospective longitudinal study.
Antidepressants are commonly prescribed. There are clear national guidelines in relation to treatment sequencing. This study examines trends and variation in antidepressant prescribing across English primary care. To examine trends and variation in antidepressant prescribing in England, with a focus on: monoamine oxidase inhibitors (MAOIs); paroxetine; and dosulepin and trimipramine. DESIGN & SETTIN: gRetrospective longitudinal study using national and practice-level data on antidepressant items prescribed per year (1998-2018) and per month (2010-2019). Class- and drug-specific proportions were calculated at national and practice levels. Descriptive statistics were generated, percentile charts and maps were plotted, and logistic regression analysis was conducted. Antidepressant prescriptions more than tripled between 1998 and 2018, from 377 items per 1000 population to 1266 per 1000. MAOI prescribing fell substantially, from 0.7% of all antidepressant items in 1998 to 0.1% in 2018. There was marked variation between practices in past year prescribing of paroxetine (median practice proportion [MPP] = 1.7%, interdecile range [IDR] = 2.6%) and dosulepin (MPP = 0.7%, IDR = 1.8%), but less for trimipramine (MPP = 0%, IDR = 0.2%). Rapid growth and substantial variation in antidepressant prescribing behaviour was found between practices. The causes could be explored using mixed-methods research. Interventions to reduce prescribing of specific antidepressants, such as dosulepin, could include review prompts, alerts at the time of prescribing, and clinician feedback through tools like OpenPrescribing.net.


Counterfeit drugs: analytical techniques for their identification.
In recent years, the number of counterfeit drugs has increased dramatically, including not only "lifestyle" products but also vital medicines. Besides the threat to public health, the financial and reputational damage to pharmaceutical companies is substantial. The lack of robust information on the prevalence of fake drugs is an obstacle in the fight against drug counterfeiting. It is generally accepted that approximately 10% of drugs worldwide could be counterfeit, but it is also well known that this number covers very different situations depending on the country, the places where the drugs are purchased, and the definition of what constitutes a counterfeit drug. The chemical analysis of drugs suspected to be fake is a crucial step as counterfeiters are becoming increasingly sophisticated, rendering visual inspection insufficient to distinguish the genuine products from the counterfeit ones. This article critically reviews the recent analytical methods employed to control the quality of drug formulations, using as an example artemisinin derivatives, medicines particularly targeted by counterfeiters. Indeed, a broad panel of techniques have been reported for their analysis, ranging from simple and cheap in-field ones (colorimetry and thin-layer chromatography) to more advanced laboratory methods (mass spectrometry, nuclear magnetic resonance, and vibrational spectroscopies) through chromatographic methods, which remain the most widely used. The conclusion section of the article highlights the questions to be posed before selecting the most appropriate analytical approach.


Atypical relaxation of structural constraints in Hox gene clusters of the green anole lizard.
Hox genes control many aspects of embryonic development in metazoans. Previous analyses of this gene family revealed a surprising diversity in terms of gene number and organization between various animal species. In vertebrates, Hox genes are grouped into tightly organized clusters, claimed to be devoid of repetitive sequences. Here, we report the genomic organization of the four Hox loci present in the green anole lizard and show that they have massively accumulated retrotransposons, leading to gene clusters larger in size when compared to other vertebrates. In addition, similar repeats are present in many other development-related gene-containing regions, also thought to be refractory to such repetitive elements. Transposable elements are major sources of genetic variations, including alterations of gene expression, and hence this situation, so far unique among vertebrates, may have been associated with the evolution of the spectacular realm of morphological variations in the body plans of Squamata. Finally, sequence alignments highlight some divergent evolution in highly conserved DNA regions between vertebrate Hox clusters, which may coincide with the emergence of mammalian-specific features.


Kounis Syndrome—not a Single-organ Arterial Disorder but a Multisystem and Multidisciplinary Disease
Coronary symptoms associated with conditions related to mast cell activation and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, further inducing allergic, hypersensitivity, anaphylactic, or anaphylactic insults, are currently referred to as the Kounis syndrome. Kounis syndrome is caused by inflammatory mediators released during allergic insults, post-inflammatory cell activation, and interactions via multidirectional stimuli. A platelet subset of 20% with high- and low-affinity IgE surface receptors is also involved in this process. Kounis syndrome is not just a single-organ but also a complex multisystem and multi-organ arterial clinical condition; it affects the coronary, mesenteric, and cerebral arteries and is accompanied by allergy–hypersensitivity–anaphylaxis involving the skin, respiratory, and vascular systems in the context of anesthesia, surgery, radiology, oncology, or even dental and psychiatric medicine; further, it has significantly influences both morbidity and mortality. Kounis syndrome might be caused by numerous and continuously increasing causes, with broad clinical symptoms and signs, via multi-organ arterial system involvement, in patients of any age, thereby demonstrating predominant anaphylactic features in terms of a wide spectrum of mast cell-association disorders. Cardiac symptoms, such as chest pain, coronary vasospasm, angina pectoris, myocardial infarction, stent thrombosis, acute cardiac failure, and sudden cardiac death associated with subclinical, clinical, acute, or chronic allergic reactions, constitute the clinical manifestations of this syndrome. Since its first description, a common pathway between allergic and non-allergic coronary events has been demonstrated. The hypothesis is based on the existence of a much higher degree of mast cell degranulation at plaque erosion or rupture sites compared with at the adjacent areas or even more distant segments in post-acute myocardial infarction of non-allergic etiology. Although mast cell activation, differentiation, and mediator release takes days or weeks, the mast cell degranulation may occur just before any acute coronary event, further resulting in coronary artery vasoconstriction and atheromatous plaque rupture. It seems that medications and natural molecules stabilizing the mast cell membrane as well as monoclonal antibodies protecting the mast cell surface can emerge as novel therapeutic modalities for acute coronary and cerebrovascular event prevention.


The chimeric repressor for the GATA4 transcription factor improves tolerance to nitrogen deficiency in Arabidopsis.
Nitrogen limits crop yield, but application of nitrogen fertilizer can cause environmental problems and much fertilizer is lost without being absorbed by plants. Increasing nitrogen use efficiency in plants may help overcome these problems and is, therefore, an important and active subject of agricultural research. Here, we report that the expression of the chimeric repressor for the GATA4 transcription factor (35S:GATA4-SRDX) improved tolerance to nitrogen deficiency in Arabidopsis thaliana. 35S:GATA4-SRDX seedlings were significantly larger than wild type under nitrogen-sufficient and -deficient conditions (10 and 0.5 mM NH4NO3, respectively). 35S:GATA4-SRDX plants exhibited shorter primary roots, fewer lateral roots, and higher root hair density compared with wild type. The expression levels of NITRATE TRANSPORTER 2.1, ASPARAGINE SYNTHETASE and NITRATE REDUCTASE 1 were significantly higher in roots of 35S:GATA4-SRDX plants than in wild type under nitrogen-sufficient conditions. Under nitrogen-deficient conditions, the expression of genes for cytosolic glutamine synthetases was upregulated in shoots of 35S:GATA4-SRDX plants compared with wild type. This upregulation of nitrogen transporter and nitrogen assimilation-related genes might confer tolerance to nitrogen deficiency in 35S:GATA4-SRDX plants.


Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions.
The Anton supercomputing technology recently developed for efficient molecular dynamics simulations permits us to examine micro- to milli-second events at full atomic resolution for proteins in explicit water and lipid bilayer. It also permits us to investigate to what extent the collective motions predicted by network models (that have found broad use in molecular biophysics) agree with those exhibited by full-atomic long simulations. The present study focuses on Anton trajectories generated for two systems: the bovine pancreatic trypsin inhibitor, and an archaeal aspartate transporter, GltPh. The former, a thoroughly studied system, helps benchmark the method of comparative analysis, and the latter provides new insights into the mechanism of function of glutamate transporters. The principal modes of motion derived from both simulations closely overlap with those predicted for each system by the anisotropic network model (ANM). Notably, the ANM modes define the collective mechanisms, or the pathways on conformational energy landscape, that underlie the passage between the crystal structure and substates visited in simulations. In particular, the lowest frequency ANM modes facilitate the conversion between the most probable substates, lending support to the view that easy access to functional substates is a robust determinant of evolutionarily selected native contact topology.


Core genome and plasmidome of the quorum-quenching bacterium Rhodococcus erythropolis.
Rhodococcus erythropolis is a worldwide-distributed actinobacterium that exhibits a remarkable metabolic versatility illustrated by its ability to degrade complex compounds, such as quorum-sensing signals N-acylhomoserine lactones (NAHLs), phenols, sterols and fuel derivatives. Because of its catabolic properties, R. erythropolis strains are proposed as anti-biofouling agents against NAHL-dependent biofilms, biocontrol agents against NAHL-emitting plant pathogens, and bioremediation agents in contaminated waters and soils. Here, we used the PacBio technology to resolve the complete genome sequence of the biocontrol strain R. erythropolis R138. Its genome consisted in a circular chromosome (6,236,862 bp), a linear plasmid pLRE138 (477,915 bp) and a circular plasmid pCRE138 (91,729 bp). In addition, draft genomes of five R. erythropolis strains were determined by Illumina technology and compared with the other five R. erythropolis genomes that are available in public databases: 5,825 common CDSs were present in all of the eleven analyzed genomes and represented up to 87 % of those identified in R. erythropolis R138. This study highlighted the high proportion of core-genome genes in R. erythropolis, but a high variability of the plasmid content. Key-metabolic pathways which are involved in the degradation of complex molecules, such as NAHLs and phenol, catechol and sterol derivatives are coded by the R. erythropolis core-genome.


Dermatitis herpetiformis.
Dermatitis herpetiformis (DH) is an autoimmune bullous disease, which represents the cutaneous manifestation of gluten sensitivity, in the setting of celiac disease. Although classical DH is characterized clinically by grouped, vesicles on an erythematous base, primary lesions often are absent owing to the intense, associated pruritus. Instead, many cases present only with erythematous erosions with numerous overlying excoriations. As in celiac disease, the core pathogenic mechanisms of DH are likely mediated by immunoglobulin A class autoantibodies against one of several transglutaminase enzymes. As the production of these autoantibodies is directly correlated with gastrointestinal exposure to gliadin, which is an alcohol-soluble fraction of gluten, a gluten-free diet represents the cornerstone of a DH management regimen. In cases refractory to dietary management alone, dapsone is the first-line agent for the treatment of DH, although many other agents have been anecdotally reported as effective.


Increments in cytokines and matrix metalloproteinases in skeletal muscle after injection of tissue-damaging toxins from the venom of the snake Bothrops asper.
Envenomations by the snake Bothrops asper are characterized by prominent local tissue damage (i.e. myonecrosis), blistering, hemorrhage and edema. Various phospholipases A2 and metalloproteinases that induce local pathological alterations have been purified from this venom. Since these toxins induce a conspicuous inflammatory response, it has been hypothesized that inflammatory mediators may contribute to the local pathological alterations described. This study evaluated the local production of cytokines and matrix metalloproteinases (MMPs) as a consequence of intramuscular injections of an Asp-49 myotoxic phospholipase A2 (myotoxin III (MT-III)) and a P-I type hemorrhagic metalloproteinase (BaP1) isolated from B. asper venom. Both enzymes induced prominent tissue alterations and conspicuous increments in interleukin (IL)-1beta, IL-6 and a number of MMPs, especially gelatinase MMP-9, rapidly after injection. In contrast, no increments in tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma were detected. In agreement, MT-III and BaP1 did not induce the synthesis of TNF-alpha by resident peritoneal macrophages in vitro. Despite the conspicuous expression of latent forms of MMPs in muscle, evidenced by zymography, there were no increments in activated MMP-2 and only a small increase in activated MMP-9, as detected by a functional enzymatic assay. This suggests that MMP activity was regulated by a highly controlled activation of latent forms and, probably, by a concomitant synthesis of MMP inhibitors. Since no hemorrhage nor dermonecrosis were observed after injection of MT-III, despite a prominent increase in MMP expression, and since inflammatory exudate did not enhance hemorrhage induced by BaP1, it is suggested that endogenous MMPs released in the tissue are not responsible for the dermonecrosis and hemorrhage characteristic of B. asper envenomation. Moreover, pretreatment of mice with the peptidomimetic MMP inhibitor batimastat did not reduce myotoxic nor edema-forming activities of MT-III, suggesting that MMPs do not play a prominent role in the pathogenesis of these effects in this experimental model. It is concluded that MT-III and BaP1 induce a local inflammatory response associated with the synthesis of IL-1beta, IL-6 and MMPs. MMPs do not seem to play a prominent role in the acute local pathological alterations induced by these toxins in this experimental model.


p53 and retinoblastoma pathways in bladder cancer.
A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma genes and pathways. Examination of the alterations in the molecules in these pathways that regulate the cell cycle and their effects on the prognosis of bladder cancer are areas of active research. While defects in the p53-Mdm2-p14 axis have been implicated in urothelial cancer, perturbations in the cyclin-dependent kinases and their inhibitors have also been extensively studied in this context. Genetic alterations of the retinoblastoma gene and aberrant post-translational modifications of its protein have also been incriminated in invasive bladder cancer. This article reviews the individual prognostic roles of alterations in these molecules in the context of bladder cancer. Additionally, we review findings from recent studies that are attempting to analyze these markers in combination in an effort to construct molecular panels that can serve as more robust outcome predictors. More importantly, alterations in these molecules are now becoming enticing targets for novel therapeutics. We also review some of these agents that can restore the tumor cells' altered homeostatic mechanisms, thereby having potential in transitional cell carcinoma therapy. Future management of bladder cancer will employ validated marker panels for outcome prediction, and novel genetic and pharmacologic agents that will be able to target molecular alterations in individual tumors based on their respective profiles.


Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers.
To determine whether schizophrenics and their nonschizophrenic siblings have a similar pattern of neuropsychological deficit when compared with normal controls. Fifteen probands with schizophrenia, 16 of their nonschizophrenic siblings, and 31 unrelated, demographically balanced, normal individuals underwent evaluation with a comprehensive neuropsychological test battery. All subjects were screened for history of head injury, neurologic illness, major medical conditions, substance use, and axis I psychiatric disorders other than schizophrenia. Probands underwent evaluation twice: once at intake when half had never received neuroleptic medication and the other half had received none for a minimum of 2 weeks, and again at the 2- to 4-week follow-up, after stabilization with neuroleptic medications. Both schizophrenics and their nonschizophrenic siblings were impaired neuropsychologically compared with normal controls, with the nonschizophrenic siblings' performance intermediate between that of the schizophrenic siblings and the normal controls on all measures of functioning. The shapes of the deficit profiles of schizophrenic patients and their siblings were similar; in patients, verbal memory, abstraction, attention, and language functions were significantly more affected compared with spatial abilities, spatial memory, and sensory-motor functions, with a nonsignificant trend in the same direction in siblings. Cognitive functioning in patients was found to be stable across changes in medication status and clinical state. Four fifths of patients obtained more deviant scores than their nonschizophrenic siblings. Among the sibling group, those with probable and certain diagnoses of schizotypal personality disorder were more impaired compared with those without schizophrenia-spectrum symptoms. These results support the hypothesis that impaired information processing aggregates in the family members of schizophrenics and may serve as an indicator of genetic vulnerability to the disorder. Further work is needed to establish whether particular areas of functioning are selectively impaired in relatives and to determine whether the performance deficits are mediated by structural and/or metabolic disturbances in specific brain regions.


[Reconstruction and its prognosis in patients undergoing resection of tracheal bifurcation].
Seventeen resections of tracheal bifurcation were performed: 12 for bronchogenic carcinoma, 2 for primary neoplasm of the trachea, one each for pulmonary sarcoma, inflammatory lesion and metastatic thyroid carcinoma. We performed carinal reconstruction in eight patients, sleeve pneumonectomy in eight patients and wedge pneumonectomy in one. In patients undergoing carinal reconstruction, there were 2 operative deaths and six patients survived over five years after the operation. However, in patients undergoing sleeve (wedge) pneumonectomy, there were 3 operative deaths, four patients died from 3 months to 7 months, and only two patients survived 5 years after the operation. Carinal resection with pneumonectomy had poorer prognosis than carinal reconstruction.


Clinical outcome from mechanical intermittent cervical traction for the treatment of cervical radiculopathy: a case series.
Case series. To describe the clinical outcomes of 15 patients with cervical radiculopathy treated with mechanical intermittent cervical traction. Effectiveness of traction for the treatment of cervical spinal syndromes is controversial and the outcome of this treatment has not been established in the literature. Fifteen patients (45.5 +/- 13 years) completed a course of treatment using mechanical intermittent cervical traction. Eleven patients presented at baseline with radicular symptoms of 12 weeks duration or less, and 4 patients had long-standing radicular symptoms lasting more than 12 weeks. Outcome was measured using the Neck Disability Index (NDI) and the Numeric Pain Rating Scale (NPRS). Eight of the 15 cases (53%) in this series demonstrated complete pain resolution; these patients had symptom duration of 12 weeks and less. Seven of these 8 cases displayed a final NDI of 10% or less. Three out of 4 of the patients with symptom duration more [corrected] than 12 weeks showed no reduction in pain or increased pain rating, with minimal change in perceived disability of 12% or less. In this case series, patients with radicular symptoms lasting for 12 weeks and less demonstrated a reduction in pain and perceived disability. The NDI, when used in conjunction with the NPRS, provides a more comprehensive assessment of the patient with cervical radiculopathy, thus allowing the clinician to make a better judgment about the clinical effects of cervical traction.


Evaluation of the nutritional adequacy of recipes for home-prepared maintenance diets for cats.
To evaluate home-prepared maintenance diet (HPMD) recipes for cats and compare the nutritional profiles with National Research Council (NRC) recommended allowances (RAs) for essential nutrients for adult cats. Evaluation study. 114 recipes (obtained from books and online sources) for HPMDs for cats. Computer software was used to determine nutrient concentrations of HPMD recipes for comparison with NRC RAs for essential nutrients for adult cats. Effects of recipe authorship (veterinarian vs nonveterinarian) and supplementation on the number of nutrient concentrations below RAs were evaluated. Of the 114 HPMD recipes, 113 contained vague instructions regarding preparation, and 46 did not provide feeding directions. Only 94 recipes provided adequately detailed information for computerized nutritional analysis, although most (93/94) still required assumptions regarding ingredients, preparation, or supplementation. Nonveterinarian-authored recipes and recipes without supplement-type products had more nutrient concentrations below NRC RAs, but no recipe met all RAs. With assumptions, 5 veterinarian-authored recipes met NRC RAs for all assessed nutrients except choline; however, taurine adequacy in 2 of those recipes could not be confirmed. Crude protein concentration was below the RA in 6 of 94 (6.4%) recipes. Nutrients most frequently below RAs included choline, iron, thiamine, zinc, manganese, vitamin E, and copper (in 89.7%, 76.6%, 62.8%, 61.7%, 57.4%, 57.4%, and 45.7% of recipes, respectively). Problems with nutritional adequacy were identified in all evaluated HPMD recipes. Appropriate formulation of HPMDs requires specialized knowledge of nutrition and use of computer software to avoid potentially harmful nutrient deficiencies.


14-3-3beta binds to big mitogen-activated protein kinase 1 (BMK1/ERK5) and regulates BMK1 function.
Big mitogen-activated kinase 1 (BMK1/ERK5) is a member of the MAPK family activated by growth factors that mediates cell growth and survival. Previous data show that BMK1 can be activated by steady laminar flow and is atheroprotective by preventing endothelial cells from undergoing apoptosis. The primary structure of BMK1 is distinct from other MAPK members by virtue of a unique long C-tail, suggesting specific mechanisms of regulation. To characterize regulatory mechanisms for BMK1 function, we identified binding proteins by yeast two-hybrid analysis. Among these proteins, the scaffolding protein 14-3-3 was identified. BMK1 bound to 14-3-3beta in vitro and in vivo as demonstrated by glutathione S-transferase (GST)-14-3-3beta fusion protein pull-down assays and coimmunoprecipitation. Phosphorylation of BMK1 was most likely required for this interaction. GST-14-3-3beta pull-down assays using truncated constructs of BMK1 and site-directed BMK1 mutants demonstrated that the interaction requires serine 486 within the C terminus of BMK1. BMK1 bound to 14-3-3beta basally, and the interaction was greatly abrogated when BMK1 was activated. The interaction of 14-3-3beta and BMK1 inhibited kinase activities stimulated by constitutively active (CA)-MEK5 and epidermal growth factor. Mutation of serine 486 (BMK1-S486A) prevented the interaction with 14-3-3beta and enhanced BMK1 activity upon epidermal growth factor stimulation. These data demonstrate an inhibitory function for 14-3-3beta binding to BMK1 and show that serine 486 phosphorylation represents a novel regulatory mechanism for BMK1.


Assessing and improving safety climate in a large cohort of intensive care units.
To evaluate the impact of a comprehensive unit-based safety program on safety climate in a large cohort of intensive care units participating in the Keystone intensive care unit project. A prospective cohort collaborative study to improve quality of care and safety culture by implementing and evaluating patient safety interventions in intensive care units predominantly in the state of Michigan. The comprehensive unit-based safety program was the first intervention implemented by every intensive care unit participating in the collaborative. It is specifically designed to improve the various elements of a unit's safety culture, such as teamwork and safety climate. We administered the validated Safety Attitudes Questionnaire at baseline (2004) and after 2 yrs of exposure to the safety program (2006) to assess improvement. The safety climate domain on the survey includes seven items. Post-safety climate scores for intensive care units. To interpret results, a score of <60% was in the "needs improvement" zone and a ≥10-point discrepancy in pre-post scores was needed to describe a difference. Hospital bed size, teaching status, and faith-based status were included in our analyses. Seventy-one intensive care units returned surveys in 2004 and 2006 with 71% and 73% response rates, respectively. Overall mean safety climate scores significantly improved from 42.5% (2004) to 52.2% (2006), t = -6.21, p < .001, with scores higher in faith-based intensive care units and smaller-bed-size hospitals. In 2004, 87% of intensive care units were in the "needs improvement" range and in 2006, 47% were in this range or did not score ≥10 points or higher. Five of seven safety climate items significantly improved from 2004 to 2006. A patient safety program designed to improve teamwork and culture was associated with significant improvements in overall mean safety climate scores in a large cohort of 71 intensive care units. Research linking improved climate scores and clinical outcomes is a critical next step.


Understanding emotionally relevant situations in primary dental practice. 3. Emerging narratives.
Dentists experience considerable occupational stress. Stressful clinical situations can provoke high levels of negative emotions, and situations which are associated with positive emotions tend to be overlooked by practitioners. Reflection regarding difficult situations is encouraged to facilitate learning. Cognitive behavioural therapy (CBT) formulations may be applied to situations appraised both positively and negatively. Analysis and interpretation of the dentist's coping behaviour and the consequent outcomes facilitate learning and reflection upon individual interactions with patients. Twenty primary care dental practitioners in the greater Lincoln area participated in a semi-structured interview which explored their stressful and positive clinical experiences. Some of the episodes were analysed to create CBT formulations. CBT formulations are presented and the learning points highlighted by this structured presentation are discussed. In particular, it is suggested that this structured reconstruction of events, which highlights dentists' emotions, responses and the transactional effects of coping responses, might well facilitate objective reflective learning either individually or as part of peer to peer support. It should facilitate dentists' emotional processing of events and may thus contribute to stress reduction. CBT formulations of positive and negative dental scenarios may be constructed. It is proposed that this is a useful technique to foster reflection and learning in clinical situations and should lead to improved communication skills and shared decision-making, resulting in fewer complaints and thereby reduced stress. It should also improve dentists' emotional processing.


Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study.
No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation. This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300 cells per μL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1-5 mg every 1-4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov, NCT03557307. Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86-66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62-84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2-3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations. Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm. AstraZeneca.


Effects of physical efforts on injury in elite soccer.
In this study, the influence of physical efforts on occurrence of match injury in a professional soccer club was investigated. Computerised motion-analysis was used to measure the physical efforts of players during 10 injury situations. Total distance and those covered at different movement intensities were measured across the 5-min period preceding injury. If the final run preceding injury involved a high-intensity action (HIA), the distance, duration and speed of the effort and the recovery time between this and the penultimate HIA were measured. To determine the influence of these physical efforts, the results were compared to a normative profile for players computed from data across 5 games for the same variables; habitual distances covered over a 5-min period and characteristics of and recovery time between HIA. Compared to the normative profile, no differences were reported in physical characteristics during the period leading up to injury or for HIA although the latter were substantially higher in intensity (duration and distance). A lower than normal recovery time between HIA prior to injury was observed (35.6+/-16.8 s vs. 98.8+/-17.5 s, p=0.003). Within the limitations of the small sample, these findings may aid in further understanding injury and physical performance in elite soccer.


Source monitoring improvement in patients with schizophrenia receiving antipsychotic medications.
The absence of a relationship between cognitive deficit treatment response and positive symptom treatment response is often assumed, and few data have shed light on this issue. Most of these data have been collected using standard neuropsychological measures, which are ill-designed to assess the types of neurocognitive disturbances associated with psychotic symptoms. This study investigates the effect of treatment on source monitoring performance and its relation to the reduction of certain psychotic symptoms associated with the inability to identify self-generated mental events, known as "autonoetic agnosia". To determine whether risperidone, olanzapine, and haloperidol were differentially effective in reducing autonoetic agnosia and whether changes in this aspect of cognition were related to reduction of specific symptoms of psychosis. From a cohort of 49 patients diagnosed with schizophrenia by DSM-IV criteria and randomly assigned to double-blind treatment with risperidone, olanzapine, or haloperidol, 16 patients were identified with symptoms believed to reflect autonoetic agnosia ("target symptoms") as assessed with the Schneiderian Symptom Rating Scale, and then evaluated during a baseline period, and then at 1, 2, and 3 weeks. Autonoetic agnosia was assessed as the ability of a patient to distinguish self-generated words from both experimenter-generated words and pictorially presented words. Analysis of patients from all treatment groups found a significant reduction in the number of "target" Schneiderian symptoms. Discrimination for items from the self-generated and heard sources significantly improved with treatment, as did the number of self-generated items that patients remembered as coming from the heard source ("self-hear errors"). The correlation between improvement in recognition of self-generated items and reduction in target Schneiderian symptoms after 2 weeks of treatment suggested a modest relationship between symptom improvement and changes in autonoetic agnosia. While the differences between medications were not statistically significant, antipsychotic medication in general was associated with improvements in symptoms and cognitive deficits that may underlie autonoetic agnosia. Improvement of autonoetic agnosia was a weak predictor of positive symptom improvement in a limited sample.


ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice.
ProNGF, the precursor of mature Nerve Growth Factor (NGF), is the most abundant NGF form in the brain and increases markedly in the cortex in Alzheimer's Disease (AD), relative to mature NGF. A large body of evidence shows that the actions of ProNGF and mature NGF are often conflicting, depending on the receptors expressed in target cells. TgproNGF#3 mice, expressing furin-cleavage resistant proNGF in CNS neurons, directly reveal consequences of increased proNGF levels on brain homeostasis. Their phenotype clearly indicates that proNGF can be a driver of neurodegeneration, including severe learning and memory behavioral deficits, cholinergic deficits, and diffuse immunoreactivity for A-beta and A-beta-oligomers. In aged TgproNGF#3 mice spontaneous epileptic-like events are detected in entorhinal cortex-hippocampal slices, suggesting occurrence of excitatory/inhibitory (E/I) imbalance. In this paper, we investigate the molecular events linking increased proNGF levels to the epileptiform activity detected in hippocampal slices. The occurrence of spontaneous epileptiform discharges in the hippocampal network in TgproNGF#3 mice suggests an impaired inhibitory interneuron homeostasis. In the present study, we detect the onset of hippocampal epileptiform events at 1-month of age. Later, we observe a regional- and cellular-selective Parvalbumin interneuron and perineuronal net (PNN) depletion in the dentate gyrus (DG), but not in other hippocampal regions of TgproNGF#3 mice. These results demonstrate that, in the hippocampus, the DG is selectively vulnerable to altered proNGF/NGF signaling. Parvalbumin interneuron depletion is also observed in the amygdala, a region strongly connected to the hippocampus and likewise receiving cholinergic afferences. Transcriptome analysis of TgproNGF#3 hippocampus reveals a proNGF signature with broad down-regulation of transcription. The most affected mRNAs modulated at early times belong to synaptic transmission and plasticity and extracellular matrix (ECM) gene families. Moreover, alterations in the expression of selected BDNF splice variants were observed. Our results provide further mechanistic insights into the vicious negative cycle linking proNGF and neurodegeneration, confirming the regulation of E/I homeostasis as a crucial mediating mechanism.


Colon cancer treatment: are there racial disparities in an equal-access healthcare system?
In the general US population, blacks and whites have been shown to undergo colon cancer treatment at disproportionate rates. Accessibility to medical care may be the most important factor influencing differences in colon cancer treatment rates among whites and blacks. We assessed whether racial disparities in colon cancer surgery and chemotherapy existed in an equal-access health care system. In addition, we sought to examine whether racial differences varied according to demographic and tumor characteristics. Database research using the Department of Defense Military Health System. Patients included 2560 non-Hispanic whites (NHW) and non-Hispanic blacks (NHB) with colon cancer diagnosed from 1998 to 2007. Logistic regression was used to assess the associations between race and the receipt of colon cancer surgery or chemotherapy while controlling for available potential confounders, both overall and stratified by age at diagnosis, sex, and tumor stage. After multivariate adjustment, the odds of receiving colon cancer surgery or chemotherapy for NHBs versus NHWs were similar (OR, 0.75 [95% CI, 0.37-1.53]; OR, 0.79 [95% CI, 0.59-1.04]). In addition, no effect modifications by age at diagnosis, sex, and tumor stage were observed. Treatment data might not be complete for beneficiaries who also had non-Department of Defense health insurance. When access to medical care is equal, racial disparities in the provision of colon cancer surgery and chemotherapy were not apparent. Thus, it is possible that the inequalities in access to care play a major role in the racial disparities seen in colon cancer treatment in the general population.


Mitochondrial Post-translational Modifications and Metabolic Control: Sirtuins and Beyond.
In order to maintain metabolic homeostasis, organisms adjust the capacity and efficiency of ATP generation to changes in energetic demand and supply. While the transcriptional control of mitochondrial biogenesis allows to adapt mitochondrial respiratory capacity with long-term requirements for differential energy demand (e.g.: exercise training), bioenergetic adaptation also needs to take place within shorter time frames in order to properly fine-tune nutrient availability, energy production and demand, either in a circadian fashion or after a meal. These quick metabolic responses can be achieved through exquisite modulation of diverse post-translational modifications, which influence a variety of mitochondrial processes, including mitochondrial dynamics, fatty acid oxidation, lipogenesis and bioenergetic efficiency. In this review, we will specially focus on the role of mitochondrial sirtuin enzymes as modulators of mitochondrial ac(et)ylation and the possible interactions with other posttranslational modification events.


Mutational profile of KIT and PDGFRA genes in gastrointestinal stromal tumors in Peruvian samples.
Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms usually caused by somatic mutations in the genes KIT (c-kit) or PDGFRA. Mutation characterization has become an important exam for GIST patients because it is useful in predicting the response to the inhibitors of receptor tyrosine kinase (RTK). The aim of this study was to determine the frequency of KIT and PDGFRA mutations in 25 GIST samples collected over two years at two national reference hospitals in Peru. There were 21 samples collected from the Instituto Nacional de Enfermedades Neoplásicas (INEN, national cancer center) and 4 samples collected from Hospital A. Loayza. In this retrospective study, we performed polymerase chain reaction (PCR) amplification and deoxyribonucleic acid (DNA) sequencing of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes in 20 FFPE (formalin-fixed, paraffin-embedded) and 5 frozen GIST samples. We report 21 mutations, including deletions, duplications, and missense, no mutations in 2 samples, and 2 samples with no useful DNA for further analysis. Eighty-six percent of these mutations were located in exon 11 of KIT, and 14 % were located in exon 18 of PDGFRA. Our study identified mutations in 21 out of 25 GIST samples from 2 referential national hospitals in Peru, and the mutation proportion follows a global tendency observed from previous studies (i.e., the majority of samples presented KIT mutations followed by a minor percentage of PDGFRA mutations). This study presents the first mutation data of the KIT and PDGFRA genes from Peruvian individuals with GIST.


Predicting Escherichia coli loads in cascading dams with machine learning: An integration of hydrometeorology, animal density and grazing pattern.
Accurate prediction of Escherichia coli contamination in surface waters is challenging due to considerable uncertainty in the physical, chemical and biological variables that control E. coli occurrence and sources in surface waters. This study proposes a novel approach by integrating hydro-climatic variables as well as animal density and grazing pattern in the feature selection modeling phase to increase E. coli prediction accuracy for two cascading dams at the US Meat Animal Research Center (USMARC), Nebraska. Predictive models were developed using regression techniques and an artificial neural network (ANN). Two adaptive neuro-fuzzy inference system (ANFIS) structures including subtractive clustering and fuzzy c-means (FCM) clustering were also used to develop models for predicting E. coli. The performances of the predictive models were evaluated and compared using root mean squared log error (RMSLE). Cross-validation and model performance results indicated that although the majority of models predicted E. coli accurately, ANFIS models resulted in fewer errors compared to the other models. The ANFIS models have the potential to be used to predict E. coli concentration for intervention plans and monitoring programs for cascading dams, and to implement effective best management practices for grazing and irrigation during the growing season.


WHODAS 2.0 Can Predict Institutionalization among Patients with Traumatic Brain Injury.
Patients with traumatic brain injury (TBI) often present with disabilities associated with a high burden of care for caregivers or family members at home. When family members cannot afford to care for patients with TBI, they are often required to find them residence in long-term care institutions. To date, there are no quantitative assessment tools developed to predict institutionalization. Therefore, this study analyzed the accuracy of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for predicting the institutionalization of patients with TBI. We designed a cross-sectional study using a nationwide disability database. We analyzed the data of 8630 patients with TBI with injury for more than six months from the Taiwan Data Bank of Persons with Disability during July 2012-October 2018. The demographic data and WHODAS 2.0 standardized scores of patients with TBI who resided in community and long-term care institutions were analyzed. Receiver operating characteristic curve (ROC) analysis was performed to investigate the predictive accuracy of WHODAS 2.0 for being institutionalized, and the optimal cut-off point was determined using the Youden index. Binary logistic regression was employed to determine the predictors of the participants being institutionalized. The WHODAS 2.0 scores in each domain were lower in the community group than in the institutionalized group. ROC analysis revealed the highest accuracy for the summary scores of WHODAS 2.0 (area under the curve = 0.769). Binary logistic regression revealed that age, gender, work status, urbanization level, socioeconomic status, severity of impairment, and WHODAS 2.0 domain scores were factors associated with the institutionalization status of patients with TBI. Our results suggest that WHODAS 2.0 may be a feasible assessment tool for predicting the institutionalization of patients with TBI.


Red Blood Cell Membrane Conductance in Hereditary Haemolytic Anaemias.
Congenital haemolytic anaemias are inherited disorders caused by red blood cell membrane and cytoskeletal protein defects, deviant hemoglobin synthesis and metabolic enzyme deficiencies. In many cases, although the causing mutation might be known, the pathophysiology and the connection between the particular mutation and the symptoms of the disease are not completely understood. Thus effective treatment is lagging behind. As in many cases abnormal red blood cell cation content and cation leaks go along with the disease, by direct electrophysiological measurements of the general conductance of red blood cells, we aimed to assess if changes in the membrane conductance could be a possible cause. We recorded whole-cell currents from 29 patients with different types of congenital haemolytic anaemias: 14 with hereditary spherocytosis due to mutations in α-spectrin, β-spectrin, ankyrin and band 3 protein; 6 patients with hereditary xerocytosis due to mutations in Piezo1; 6 patients with enzymatic disorders (3 patients with glucose-6-phosphate dehydrogenase deficiency, 1 patient with pyruvate kinase deficiency, 1 patient with glutamate-cysteine ligase deficiency and 1 patient with glutathione reductase deficiency), 1 patient with β-thalassemia and 2 patients, carriers of several mutations and a complex genotype. While the patients with β-thalassemia and metabolic enzyme deficiencies showed no changes in their membrane conductance, the patients with hereditary spherocytosis and hereditary xerocytosis showed largely variable results depending on the underlying mutation.


RiDs db: Repeats in diseases database.
The non-coding fraction of the human genome, which is approximately 98%, is mainly constituted by repeats. Transpositions, expansions and deletions of these repeat elements contribute to a number of diseases. None of the available databases consolidates information on both tandem and interspersed repeats with the flexibility of FASTA based homology search with reference to disease genes. Repeats in diseases database (RiDs db) is a web accessible relational database, which aids analysis of repeats associated with Mendelian disorders. It is a repository of disease genes, which can be searched by FASTA program or by limitedor free- text keywords. Unlike other databases, RiDs db contains the sequences of these genes with access to corresponding information on both interspersed and tandem repeats contained within them, on a unified platform. Comparative analysis of novel or patient sequences with the reference sequences in RiDs db using FASTA search will indicate change in structure of repeats, if any, with a particular disorder. This database also provides links to orthologs in model organisms such as zebrafish, mouse and Drosophila. The database is available for free at http://22.214.171.124/ridsdb/index.php.


Social Media in the Dental School Environment, Part B: Curricular Considerations.
The goal of this article is to describe the broad curricular constructs surrounding teaching and learning about social media in dental education. This analysis takes into account timing, development, and assessment of the knowledge, skills, attitudes, and behaviors needed to effectively use social media tools as a contemporary dentist. Three developmental stages in a student's path to becoming a competent professional are described: from undergraduate to dental student, from the classroom and preclinical simulation laboratory to the clinical setting, and from dental student to licensed practitioner. Considerations for developing the dental curriculum and suggestions for effective instruction at each stage are offered. In all three stages in the future dentist's evolution, faculty members need to educate students about appropriate professional uses of social media. Faculty members should provide instruction on the beneficial aspects of this communication medium and help students recognize the potential pitfalls associated with its use. The authors provide guidelines for customizing instruction to complement each stage of development, recognizing that careful timing is not only important for optimal learning but can prevent inappropriate use of social media as students are introduced to novel situations.


Association of telomere length and mitochondrial DNA copy number with risperidone treatment response in first-episode antipsychotic-naïve schizophrenia.
Accumulating evidence indicates a putative association of telomere length and mitochondrial function with antipsychotics response in schizophrenia (SCZ). However, pharmacological findings were limited and no previous work has assessed this in a prospective longitudinal study. This study assessed telomere length and mitochondrial DNA copy number in first-episode antipsychotic-naïve SCZ patients with 8-week risperidone treatment to evaluate the association between these biomarkers and clinical treatment response. We recruited 137 first-episode antipsychotic-naive SCZ patients (and 144 controls) at baseline and 89 patients completed the 8-week follow-up. Patients, completed follow-up, were divided into Responders (N = 46) and Non-Responders (N = 43) according to the percentage of symptoms improvement. Linear regression analyses show that SCZ patients had significantly lower mtDNA copy number (β = -0.108, p = 0.002), and no alteration of telomere length when compared with healthy controls. In addition, compared with Non-Responders, Responders had significantly lower mtDNA copy number (β = -0.178, p = 0.001), and longer telomere length (β = 0.111, p = 0.071) before the 8-week treatment. After treatment, Responders persisted lower mtDNA copy number comparing with No-Responders (partial η(2) = 0.125, p = 0.001). These findings suggest that telomere length and mtDNA copy number may hold the potential to serve as predictors of antipsychotic response of SCZ patients.


Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol.
Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.


Label-free characterization of emerging human neuronal networks.
The emergent self-organization of a neuronal network in a developing nervous system is the result of a remarkably orchestrated process involving a multitude of chemical, mechanical and electrical signals. Little is known about the dynamic behavior of a developing network (especially in a human model) primarily due to a lack of practical and non-invasive methods to measure and quantify the process. Here we demonstrate that by using a novel optical interferometric technique, we can non-invasively measure several fundamental properties of neural networks from the sub-cellular to the cell population level. We applied this method to quantify network formation in human stem cell derived neurons and show for the first time, correlations between trends in the growth, transport, and spatial organization of such a system. Quantifying the fundamental behavior of such cell lines without compromising their viability may provide an important new tool in future longitudinal studies.


Prolonged Neoadjuvant Therapy for Locally Advanced Pancreatic Cancer.
The purpose of this study was to investigate if prolonged neoadjuvant therapy, for locally advanced pancreatic cancer could be used to identify those patients who could benefit from resection surgery. Thirty-four patients with locally advanced pancreatic cancer invading the adjacent major arteries underwent chemoradiotherapy, followed by 6 months of systemic chemotherapy, unless their tumor was already resectable. After this combination treatment, surgical resection was performed on those patients with tumors judged to be at least borderline resectable. Reevaluation after chemoradiotherapy revealed that, at that stage, surgery was only possible for one case; resection was successfully performed. Following 6 months of systemic chemotherapy, a further 7 patients were diagnosed with borderline resectable lesions; 4 underwent surgery with no postoperative complications. The median survival time of the patients following surgery was 3.63 years; this was reduced to approximately a third in patients not undergoing surgery (1.01 years; p = 0.0005). For patients with locally advanced pancreatic cancer, prolonged neoadjuvant therapy was successfully used to select candidates that could benefit from surgical resection of their tumor. Resection significantly increased the long-term survival rate.