Esthesioneuroblastoma presenting with proptosis and bilateral neck metastasis: An unusual presentation.
Esthesioneuroblastoma (ENB) presenting simultaneously with proptosis and bilateral neck metastasis is a very rare presentation. ENB is a rare tumor arising from the olfactory epithelium of the nasal vault which frequently invades the cranial base, cranial vault and orbit. ENB has a bimodal age distribution between 11 and 20 years and between 51 and 60 years. ENB accounts for approximately 1 to 5% of intranasal cancers and no consensus has been reached yet regarding the treatment of this tumor. We are reporting a 17-year-old male patient who presented with right eye proptosis with loss of vision and bilateral neck metastasis. Contrast enhanced computed tomography (CECT) and magnetic resonance imaging (MRI) was done which showed Kadish stage C tumor. Nasal biopsy was done to make the diagnosis and the patient was subjected to radiotherapy. Tumor responded to radiotherapy and both the primary lesion and the cervical lymph node metastasis disappeared. The purpose of this study is to report the rare presentation of proptosis along with bilateral cervical lymph node metastasis in this rare sinonasal tumor.


Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice.
Damage to the lateral hypothalamus (LH) causes profound physical inactivity in mammals. Several molecularly distinct types of LH neurons have been identified, including orexin cells and glutamic acid decarboxylase 65 (GAD65) cells, but their interplay in orchestrating physical activity is not fully understood. Here, using optogenetic circuit analysis and cell type-specific deep-brain recordings in behaving mice, we show that orexin cell activation rapidly recruits GAD65LH neurons. We demonstrate that internally initiated GAD65LH cell bursts precede and accompany spontaneous running bouts, that selective chemogenetic silencing of natural GAD65LH cell activity depresses voluntary locomotion, and that GAD65LH cell overactivation leads to hyperlocomotion. These results thus identify a molecularly distinct, orexin-activated LH submodule that governs physical activity in mice.


Prevalence and consequences of the dual diagnosis of substance abuse and severe mental illness.
The co-occurrence of a severe mental illness and a substance use or abuse disorder is common in the United States as well as internationally and could be considered as more the expectation than the exception when assessing patients with serious mental illness. Substance use disorders can occur at any phase of the mental illness, perhaps even inducing psychosis. Causes of this comorbidity may include self-medication, genetic vulnerability, environment or lifestyle, underlying shared origins, and/or a common neural substrate. The consequences of dual diagnosis include poor medication compliance, physical comorbidities and poor health, poor self-care, increased suicide risk or aggression, increased sexual behavior, and possible incarceration. All of these factors contribute to a greater health burden, which reduces the health care system's capacity to adequately treat patients. Therefore, screening, assessment, and integrated treatment plans for dual diagnosis that can address both the addiction disorder and the mental illness are recommended in order to provide accurate treatment, after-care, and other health care to accommodate patients' social and vocational needs.


NF-κB inducing kinase, NIK mediates cigarette smoke/TNFα-induced histone acetylation and inflammation through differential activation of IKKs.
Nuclear factor (NF)-κB inducing kinase (NIK) is a central player in the non-canonical NF κB pathway, which phosphorylates IκB kinase α (IKKα) resulting in enhancement of target gene expression. We have recently shown that IKKα responds to a variety of stimuli including oxidants and cigarette smoke (CS) regulating the histone modification in addition to its role in NF-κB activation. However, the primary signaling mechanism linking CS-mediated oxidative stress and TNFα with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNFα increase NIK levels causing phosphorylation of IKKα, which leads to histone acetylation. To test this hypothesis, we investigated whether NIK mediates effects of CS and TNFα on histone acetylation in human lung epithelial cells in vitro and in lungs of mouse exposed to CS in vivo. CS increased the phosphorylation levels of IKKα/NIK in lung epithelial cells and mouse lungs. NIK is accumulated in the nuclear compartment, and is recruited to the promoters of pro-inflammatory genes, to induce posttranslational acetylation of histones in response to CS and TNFα. Cells in which NIK is knocked down using siRNA showed partial attenuation of CSE- and TNFα-induced acetylation of histone H3 on pro-inflammatory gene promoters. Additional study to determine the role of IKKβ/NF-κB pathway in CS-induced histone acetylation suggests that the canonical pathway does not play a role in histone acetylation particularly in response to CS in mouse lungs. Overall, our findings provide a novel role for NIK in CS- and TNFα-induced histone acetylation, especially on histone H3K9.


Genomic signatures of a global fitness index in a multi-ethnic cohort of women.
The rates of obesity and sedentary lifestyle are on a dramatic incline, with associated detrimental health effects among women in particular. Although exercise prescriptions are useful for overcoming these problems, success can be hampered by differential responsiveness among individuals in cardiovascular fitness indices (i.e. improvements in strength, lipids, VO(2) max). Genomic factors appear to play an important role in determining this inter-individual variation. We performed microarray analyses on mRNA in whole blood from 60 sedentary women from a multi-ethnic cohort who underwent 12 weeks of exercise, to identify gene subsets that were differentially expressed between individuals who experienced the greatest and least improvements in fitness. We identified 43 transcripts in 39 unique genes (FDR<10%; FC>1.5) whose expression increased the most in "high" versus "low" pre-menopausal female responders. These 39 genes were enriched in six biological pathways, including oxidative phosphorylation (p = 8.08 × 10(-3)). Several of the 39 genes (i.e. TIGD7, UQCRH, PSMA6, WDR12, TFB2M, USP15) have previously reported associations with fitness-related phenotypes. In summary, we identified gene signatures based on mRNA analysis that define responsiveness to exercise in a largely minority-based female cohort. Importantly, this study validates several genes/pathways previously associated with exercise responsiveness and extends these findings with additional novel genes.


Nanopore sensing of single-biomolecules: a new procedure to identify protein sequence motifs from molecular dynamics.
Solid-state nanopores have emerged as one of the most versatile tools for single-biomolecule detection and characterization. Nanopore sensing is based on the measurement of variations in ionic current as charged biomolecules immersed in an electrolyte translocate through nanometer-sized channels, in response to an external voltage applied across the membrane. The passage of a biomolecule through a pore yields information about its structure and chemical properties, as demonstrated experimentally with sub-microsecond temporal resolution. However, extracting the sequence of a biomolecule without the information about its position remains challenging due to the fact there is a large variability of sensing events recorded. In this paper, we performed microsecond time scale all-atom non-equilibrium Molecular Dynamics (MD) simulations of peptide translocation (motifs of alpha-synuclein, associated with Parkinson's disease) through single-layer MoS2 nanopores. First, we present an analysis based on the current threshold to extract and characterize meaningful sensing events from ionic current time series computed from MD. Second, a mechanism of translocation is established, for which side chains of each amino acid are oriented parallel to the electric field when they are translocating through the pore and perpendicular otherwise. Third, a new procedure based on the permutation entropy (PE) algorithm is detailed to identify protein sequence motifs related to ionic current drop speed. PE is a technique used to quantify the complexity of a given time series and it allows the detection of regular patterns. Here, PE patterns were associated with protein sequence motifs composed of 1, 2 or 3 amino acids. Finally, we demonstrate that this very promising procedure allows the detection of biological mutations and could be tested experimentally, despite the fact that reconstructing the sequence information remains unachievable at this time.


Effectiveness of the Common Elements Treatment Approach (CETA) in reducing intimate partner violence and hazardous alcohol use in Zambia (VATU): A randomized controlled trial.
Both intimate partner violence (IPV) and alcohol misuse are highly prevalent, and partner alcohol misuse is a significant contributor to women's risk for IPV. There are few evidence-based interventions to address these problems in low- and middle-income countries (LMICs). We evaluated the effectiveness of an evidence-based, multi-problem, flexible, transdiagnostic intervention, the Common Elements Treatment Approach (CETA) in reducing (a) women's experience of IPV and (b) their male partner's alcohol misuse among couples in urban Zambia. This was a single-blind, parallel-assignment randomized controlled trial in Lusaka, Zambia. Women who reported moderate or higher levels of IPV and their male partners with hazardous alcohol use were enrolled as a couple and randomized to CETA or treatment as usual plus safety checks (TAU-Plus). The primary outcome, IPV, was assessed by the Severity of Violence Against Women Scale (SVAWS) physical/sexual violence subscale, and the secondary outcome, male alcohol misuse, by the Alcohol Use Disorders Identification Test (AUDIT). Assessors were blinded. Analyses were intent-to-treat. Primary outcome assessments were planned at post-treatment, 12 months post-baseline, and 24 months post-baseline. Enrollment was conducted between May 23, 2016, and December 17, 2016. In total, 123 couples were randomized to CETA, 125 to TAU-Plus. The majority of female (66%) and a plurality of male (48%) participants were between 18 and 35 years of age. Mean reduction in IPV (via SVAWS subscale score) at 12 months post-baseline was statistically significantly greater among women who received CETA compared to women who received TAU-Plus (-8.2, 95% CI -14.9 to -1.5, p = 0.02, Cohen's d effect size = 0.49). Similarly, mean reduction in AUDIT score at 12 months post-baseline was statistically significantly greater among men who received CETA compared to men who received TAU (-4.5, 95% CI -6.9 to -2.2, p < 0.001, Cohen's d effect size = 0.43). The Data and Safety Monitoring Board recommended the trial be stopped early due to treatment effectiveness following the 12-month post-baseline assessment, and CETA was offered to control participants. Limitations of the trial included the lack of a true control condition (i.e., that received no intervention), self-reported outcomes that may be subject to social desirability bias, and low statistical power for secondary IPV outcomes. Results showed that CETA was more effective than TAU-Plus in reducing IPV and hazardous alcohol use among high-risk couples in Zambia. Future research and programming should include tertiary prevention approaches to IPV, such as CETA, rather than offering only community mobilization and primary prevention. The trial was registered on ClinicalTrials.gov (NCT02790827).


Workload review. Birmingham Research Unit, Royal College of General Practitioners.
Consultation rates, visiting rates and a selection of miscellaneous services were recorded over two weeks in February 1981 by 82 doctors in Bedfordshire and Hertfordshire. The findings are reported here with an emphasis on the variation between individual doctors. Consultations (including visits) were at the rate of 3.27 per patient per year. Undertaking a selection of miscellaneous services for patients is estimated to be equivalent to one third of the doctor's consultation workload. In addition, participating doctors spent an average of 9(1/2) hours in the two weeks undertaking tasks connected with education and health service administration. Time spent in the administration and management of the practice was not included in this study.The home visiting rate reported in this study was 14 per cent of all consultations and, although a little lower than that reported in the General Household Survey, it is similar to the results from the National Morbidity Survey for 1970 and 71 and also similar to other PAA results.The material is presented in such a way that it provides an analysis of workload in a large number of practices, and describes a method which doctors can use to measure their own performance and compare it with the overall results.


TLmutation: Predicting the Effects of Mutations Using Transfer Learning.
A reccurring challenge in bioinformatics is predicting the phenotypic consequence of amino acid variation in proteins. With the recent advancements in sequencing techniques, sufficient genomic data has become available to train models that predict the evolutionary statistical energies, but there is still inadequate experimental data to directly predict functional effects. One approach to overcome this data scarcity is to apply transfer learning and train more models with available data sets. In this study, we propose a set of transfer learning algorithms we call TLmutation, which implements a supervised transfer learning algorithm that transfers knowledge from survival data of a protein to a particular function of that protein. This is followed by an unsupervised transfer learning algorithm that extends the knowledge to a homologous protein. We explore the application of our algorithms in three cases. First, we test the supervised transfer on 17 previously published deep mutagenesis data sets to complete and refine missing data points. We further investigate these data sets to identify which mutations build better predictors of variant functions. In the second case, we apply the algorithm to predict higher-order mutations solely from single point mutagenesis data. Finally, we perform the unsupervised transfer learning algorithm to predict mutational effects of homologous proteins from experimental data sets. These algorithms are generalized to transfer knowledge between Markov random field models. We show the benefit of our transfer learning algorithms to utilize informative deep mutational data and provide new insights into protein variant functions. As these algorithms are generalized to transfer knowledge between Markov random field models, we expect these algorithms to be applicable to other disciplines.


Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials.
Methotrexate has shown efficacy for the treatment of several diseases, especially rheumatoid arthritis (RA). Methotrexate has also been implicated as a causative agent in interstitial lung disease. Patients with RA may develop pulmonary manifestations of their disease and are at increased risk of respiratory infection. The aim of this study was to evaluate the relative risk (RR) of pulmonary disease among patients with RA treated with methotrexate. We searched the PubMed and Cochrane databases (publication dates January 1, 1990 to February 1, 2013) for double-blind, randomized, controlled trials of methotrexate versus placebo or active comparator agents in adults with RA. Studies with <100 subjects or with a duration of <24 weeks were excluded. Two investigators independently searched both databases, and all of the investigators reviewed the selected studies. We compared differences in the RR using the Mantel-Haenszel random-effects method. A total of 22 studies with 8,584 participants met the inclusion criteria. Heterogeneity across studies was not significant (I(2) = 3%), allowing combination of the trial results. Methotrexate was associated with an increased risk of all adverse respiratory events (RR 1.10, 95% confidence interval [95% CI] 1.02-1.19) and respiratory infection (RR 1.11, 95% CI 1.02-1.21). Patients treated with methotrexate were not at increased risk of death due to lung disease (RR 1.53, 95% CI 0.46-5.01) or noninfectious respiratory events (RR 1.02, 95% CI 0.65-1.60). A subgroup analysis of studies in which pneumonitis was described revealed an increased risk associated with methotrexate (RR 7.81, 95% CI 1.76-34.72). Our study demonstrated a small but significant increase in the risk of lung disease in patients with RA treated with methotrexate compared with other disease-modifying antirheumatic drugs and biologic agents.


Catheter for diagnosis and therapy with infrared evanescent waves.
We have developed an optical delivery device (catheter) capable of transmitting broadband infrared light (IR wavelengths from 2 to 10 microm) for both diagnostic and therapeutic applications. The catheter is 1.68 mm in outer diameter and 1 m in length. It consists of two hollow glass waveguides coupled to a high-refractive-index optic tip. The IR light interacts with the tissue at the optic-tissue interface to measure the spectral signatures and perform therapy on the tissue at this interface. Fourier-transform IR spectrophotometer light is used to obtain the spectral signatures, and an IR free-electron laser (FEL) is used to study the therapeutic interaction of evanescent waves with the tissue. We present our catheter design; preliminary IR spectroscopy of aorta, blood, fatty tissue, and muscle; and IR FEL therapy on atheroslerotic aorta.


Development of the aboral domain in Nematostella requires β-catenin and the opposing activities of Six3/6 and Frizzled5/8.
The development of the oral pole in cnidarians and the posterior pole in bilaterians is regulated by canonical Wnt signaling, whereas a set of transcription factors, including Six3/6 and FoxQ2, controls aboral development in cnidarians and anterior identity in bilaterians. However, it is poorly understood how these two patterning systems are initially set up in order to generate correct patterning along the primary body axis. Investigating the early steps of aboral pole formation in the sea anemone Nematostella vectensis, we found that, at blastula stage, oral genes are expressed before aboral genes and that Nvβ-catenin regulates both oral and aboral development. In the oral hemisphere, Nvβ-catenin specifies all subdomains except the oral-most, NvSnailA-expressing domain, which is expanded upon Nvβ-catenin knockdown. In addition, Nvβ-catenin establishes the aboral patterning system by promoting the expression of NvSix3/6 at the aboral pole and suppressing the Wnt receptor NvFrizzled5/8 at the oral pole. NvFrizzled5/8 expression thereby gets restricted to the aboral domain. At gastrula stage, NvSix3/6 and NvFrizzled5/8 are both expressed in the aboral domain, but they have opposing activities, with NvSix3/6 maintaining and NvFrizzled5/8 restricting the size of the aboral domain. At planula stage, NvFrizzled5/8 is required for patterning within the aboral domain and for regulating the size of the apical organ by modulation of a previously characterized FGF feedback loop. Our findings suggest conserved roles for Six3/6 and Frizzled5/8 in aboral/anterior development and reveal key functions for Nvβ-catenin in the patterning of the entire oral-aboral axis of Nematostella.


Improved imaging of the cervico-thoracic junction in computed tomography.
To reduce beam hardening artifacts caused by the shoulder joint, we explored new and unique methods to improve the quality of images, such as varying the injection site and changing the position of patients (swimmers position). Fifth-four patients underwent neck CT examinations performed in routine and swimmers position and with a 64-slice MDCT scanner in spiral scanning. To examine the difference due to the injection sites of contrast material, subjects were divided into right- and left-side groups. For the evaluation of images, we carried out a subjective and objective assessment based on radiologists' ratings and noise measurement. Images of the lower neck in the swimmers position exhibited less hardening and streak artifacts. The subjective and objective evaluations showed that the swimmers position received higher rating by radiologists and had lower noise level than that of routine position. The swimmers position was the most effective for the diagnosis of the cervico-thoracic junction area. As for the injection site, we obtained better images by an injection of contrast material in the right arm than in the left. CT examination of the lower neck in the swimmers position may improve the quality of image and the effectiveness of diagnosis. The injection of a contrast material to the right side rather than the left side reduced foreign body artifacts.


Association Between Cardiovascular Risk Factors and Cognitive Impairment in People With Schizophrenia: A Systematic Review and Meta-analysis.
Schizophrenia is associated with cognitive dysfunction and cardiovascular risk factors, including metabolic syndrome (MetS) and its constituent criteria. Cognitive dysfunction and cardiovascular risk factors can worsen cognition in the general population and may contribute to cognitive impairment in schizophrenia. To study the association between cognitive dysfunction and cardiovascular risk factors and cognitive impairment in individuals with schizophrenia. A search was conducted of Embase, Scopus, MEDLINE, PubMed, and Cochrane databases from inception to February 25, 2020, using terms that included synonyms of schizophrenia AND metabolic adversities AND cognitive function. Conference proceedings, clinical trial registries, and reference lists of relevant publications were also searched. Studies were included that (1) examined cognitive functioning in patients with schizophrenia or schizoaffective disorder; (2) investigated the association of cardiovascular disease risk factors, including MetS, diabetes, obesity, overweight, obesity or overweight, hypertension, dyslipidemia, and insulin resistance with outcomes; and (3) compared cognitive performance of patients with schizophrenia/schizoaffective disorder between those with vs without cardiovascular disease risk factors. Extraction of data was conducted by 2 to 3 independent reviewers per article. Data were meta-analyzed using a random-effects model. The primary outcome was global cognition, defined as a test score using clinically validated measures of overall cognitive functioning. Twenty-seven studies involving 10 174 individuals with schizophrenia were included. Significantly greater global cognitive deficits were present in patients with schizophrenia who had MetS (13 studies; n = 2800; effect size [ES] = 0.31; 95% CI, 0.13-0.50; P = .001), diabetes (8 studies; n = 2976; ES = 0.32; 95% CI, 0.23-0.42; P < .001), or hypertension (5 studies; n = 1899; ES = 0.21; 95% CI, 0.11-0.31; P < .001); nonsignificantly greater deficits were present in patients with obesity (8 studies; n = 2779; P = .20), overweight (8 studies; n = 2825; P = .41), and insulin resistance (1 study; n = 193; P = .18). Worse performance in specific cognitive domains was associated with cognitive dysfunction and cardiovascular risk factors regarding 5 domains in patients with diabetes (ES range, 0.23 [95% CI, 0.12-0.33] to 0.40 [95% CI, 0.20-0.61]) and 4 domains with MetS (ES range, 0.15 [95% CI, 0.03-0.28] to 0.40 [95% CI, 0.20-0.61]) and hypertension (ES range, 0.15 [95% CI, 0.04-0.26] to 0.27 [95% CI, 0.15-0.39]). In this systematic review and meta-analysis, MetS, diabetes, and hypertension were significantly associated with global cognitive impairment in people with schizophrenia.


Removal of ballistocardiogram artifacts from simultaneously recorded EEG and fMRI data using independent component analysis.
Simultaneous recording of electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) has been studied to identify areas related to EEG events. EEG data recorded in the magnetic resonance (MR) scanner with MR imaging is suffered from two specific artifacts, imaging artifact, and ballistocardiogram (BCG). In this paper, we focus on BCG. In preceding studies, average subtraction was often used for this purpose. However, average subtraction requires an assumption that BCG waveforms are precisely periodic, which seems unrealistic because BCG is a biomedical artifact. We propose the application of independent component analysis (ICA) with a postprocessing of high-pass filtering for the removal of BCG. With this approach, it is not necessary to assume that the BCG waveform is periodic. Empirically, we show that our proposed method removes BCG artifacts as well as does the average subtraction method. Power spectral density analysis of the two approaches shows that, with ICA, distortion of recovered EEG data is also as small as that associated with the average subtraction approach. We also propose a hypothesis for how head movement causes BCGs and show why ICA can remove BCG artifacts arising from this source.


Clinical presentation, causes and outcome of febrile episodes in a prospective cohort of HIV-infected patients.
Fever was frequently caused by opportunistic conditions in HIV-patients in the early years of the epidemic. Little is known about diagnostic spectrum and outcome of febrile episodes in patients with good access to antiretroviral therapy. We prospectively studied clinical presentation, diagnosis and outcome of febrile episodes in a contemporary cohort of HIV-patients with good access to antiretroviral therapy. Fever was defined as temperature 38.3 °C or higher, measured by a health care provider. We found 220 febrile episodes in 146 patients. In 25.9% of episodes the patient had a CD4 less than 200/mm³ and in 78.6% the patient was on antiretroviral therapy. There were multiple episodes in 44 patients. A diagnosis was established in 91.8%. Infection accounted for 82.3%, mainly respiratory tract infections, viral syndromes and abdominal infections. Malignancy, drug reactions and inflammatory conditions accounted together for less than 12% of episodes. Fifteen percent were attributed to opportunistic conditions. Episodes in patients with CD4 less than 200 were less likely to be caused by infection, but more likely to be caused by malignancy, drug reactions and opportunistic conditions. In 6.4% the patient died within six months after the onset of fever. Risk factors for death at six months in multivariable analysis were higher age and lower CD4. HIV-patients with access to antiretroviral therapy present with fever mostly due to conditions common in the general population. HIV-patients with low CD4 remain at risk for fever due to opportunistic conditions and death.


Multivariate trajectories across multiple domains of health-related quality of life in children with new-onset epilepsy.
The diagnosis of epilepsy in children is known to impact the trajectory of their health-related quality of life (HRQOL) over time. However, there is limited knowledge about variations in longitudinal trajectories across multiple domains of HRQOL. This study aims to characterize the heterogeneity in HRQOL trajectories across multiple HRQOL domains and to evaluate predictors of differences among the identified trajectory groups in children with new-onset epilepsy. Data were obtained from the Health Related Quality of Life in Children with Epilepsy Study (HERQULES), a prospective multi-center study of 373 children newly diagnosed with new-onset epilepsy who were followed up over 2years. Child HRQOL and family factors were reported by parents, and clinical characteristics were reported by neurologists. Group-based multi-trajectory modeling was adopted to characterize longitudinal trajectories of HRQOL as measured by the individual domains of cognitive, emotional, physical, and social functioning in the 55-item Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Multinomial logistic regression was used to assess potential factors that explain differences among the identified latent trajectory groups. Three distinct HRQOL trajectory subgroups were identified in children with new-onset epilepsy based on HRQOL scores: "High" (44.7%), "Intermediate" (37.0%), and "Low" (18.3%). While most trajectory groups exhibited increasing scores over time on physical and social domains, both flat and declining trajectories were noted on emotional and cognitive domains. Less severe epilepsy, an absence of cognitive and behavioral problems, lower parental depression scores, better family functioning, and fewer family demands were associated with a "Higher" or "Intermediate" HRQOL trajectory. The course of HRQOL over time in children with new-onset epilepsy appears to follow one of three different trajectories. Addressing the clinical and psychosocial determinants identified for each pattern can help clinicians provide more targeted care to these children and their families.


Bibliometric evaluation of Latin American contributions on COVID-19
Introduction: The propagation of COVID-19, an infectious disease caused by the novel SARS-CoV-2 coronavirus, has become a pandemic which, along with its rapid dissemination worldwide, has brought about an exponential increase in the amount of research related to the subject to which Latin American researchers have contributed actively. Objective: To conduct a descriptive bibliometric study of the main trends in research on COVID-19 produced in Latin America. Materials and methods: We searched in the Web of Science, Scopus, and Pubmed databases to retrieve the Latin American scientific production on COVID-19. Bibliometric indicators of production, visibility, impact, and collaboration were analyzed to assess the regional participation in studies on the subject. Results: The analysis of 142 documents evidenced an exponential growth of scientific production in the period analyzed, an important level of international collaboration (51.4%) in scientific production, and the leadership of regional institutions (71%) in the research with publications in high-visibility jounals especially in Colombia, Brazil, and México. Conclusions: The results regarding the regional participation in the research on COVID-19 were relevant not only in relation to its quantity and exponential growth during the period analyzed but also in terms of its quality and excellence with a high rate of international collaboration and publications in important scientific journals, which besides their visibility, represent a considerable contribution to the research compared to the other geographical contexts.


Mobile genetic element SCCmec-encoded psm-mec RNA suppresses translation of agrA and attenuates MRSA virulence.
Community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) is a socially problematic pathogen that infects healthy individuals, causing severe disease. CA-MRSA is more virulent than hospital associated-MRSA (HA-MRSA). The underlying mechanism for the high virulence of CA-MRSA is not known. The transcription product of the psm-mec gene, located in the mobile genetic element SCCmec of HA-MRSA, but not CA-MRSA, suppresses the expression of phenol-soluble modulin α (PSMα), a cytolytic toxin of S. aureus. Here we report that psm-mec RNA inhibits translation of the agrA gene encoding a positive transcription factor for the PSMα gene via specific binding to agrA mRNA. Furthermore, 25% of 325 clinical MRSA isolates had a mutation in the psm-mec promoter that attenuated transcription, and 9% of the strains had no psm-mec. In most of these psm-mec-mutated or psm-mec-deleted HA-MRSAs, PSMα expression was increased compared with strains carrying intact psm-mec, and some mutated strains produced high amounts of PSMα comparable with that of CA-MRSA. Deletion of psm-mec from HA-MRSA strains carrying intact psm-mec increased the expression of AgrA protein and PSMα, and virulence in mice. Thus, psm-mec RNA suppresses MRSA virulence via inhibition of agrA translation and the absence of psm-mec function in CA-MRSA causes its high virulence property.


Optimizing bone health and calcium intakes of infants, children, and adolescents.
Most older children and adolescents in the United States currently do not achieve the recommended intake of calcium. Maintaining adequate calcium intake during childhood and adolescence is necessary for the development of peak bone mass, which may be important in reducing the risk of fractures and osteoporosis later in life. Optimal calcium intake is especially relevant during adolescence, when most bone mineral accretion occurs. Because of the influence of the family's diet on the diet of children and adolescents, adequate calcium intake by all members of the family is important. Assessment of calcium intake can be performed in the physician's office. A well-rounded diet including low-fat dairy products, fruits, and vegetables and appropriate physical activity are important for achieving good bone health. Establishing these practices in childhood is important so that they will be followed throughout the life span.


[What are the most appropriate operation procedures for endometrial cancer?].
In the treatment of endometrial cancer, surgical treatment, radiotherapy, chemotherapy, and hormonal therapy are available. Since endometrial cancers are adenocarcinoma with a relatively low response to irradiation in most a cases, surgical operation is the first choice in these cases. The operative procedure is chosen according to the cancer staging currently used in Japan (FIGO, 1982), because it is a preoperative staging. In principle, total hysterectomy is done for cases of stage 0, modified radical hysterectomy for stage I, radical hysterectomy for stage II, and radical hysterectomy combined with resection of the metastatic lesions for stage III and IV. In addition, adnexa has to be resected bilaterally. In cases of stage II or higher stages, resection of para-aortic lymph nodes is done in addition to pelvic lymphadenectomy according to the depth of myometrial invasion and histologic type. On the other hand, the new international corpus cancer staging employed by FIGO in 1988 is a surgical staging which determines the stage on the basis of the intraoperative and postoperative histopathological findings. This staging takes into account more prognostic factors, reflecting the prognosis more precisely. In the near future, the Japan Society of Obstetrics and Gynecology will introduce a new staging. Since this staging is, however, determined postoperatively, it cannot be a criterion for choosing operative procedures. In addition, it is well known that preoperative diagnosis is not always consistent with intraabdominal findings. Therefore, it is important to determine most appropriate operative procedure by checking preoperatively the prognostic factors such as histopathology, degree of differentiation, cervical involvement, myometrial invasion and presence or absence of extrauterine progression precisely as far as possible. At the same time, by taking into consideration the intraoperative findings, an extended operation not limited to the above mentioned procedures should be undertaken in cases with higher risk factors.


The protective effect of ophthalmic viscoelastic devices on endothelial cell loss during cataract surgery: a meta-analysis using mixed treatment comparisons.
To compare ophthalmic viscoelastic devices (OVDs) in protecting the cornea from endothelial cell loss during cataract surgery. A systematic review yielded 21 randomised controlled trials including 1769 patients. OVDs were classified according to the Arshinoff classification. Traditional pairwise meta-analyses were performed for each direct comparison. Mixed treatments comparisons (MTC) analysis was also performed to combine all direct and indirect comparisons. The outcome measure was loss in endothelial cell density 3 months after surgery. Direct comparison meta-analysis showed that viscoadaptives lead to a lower loss in cell density compared with very low viscosity dispersives, and compared with super viscous cohesives. The soft shell technique, a combination of viscous cohesives and medium viscosity dispersives, showed a lower loss compared with viscous cohesives, but was not compared with the other treatments. The MTC analysis shows that comparing all treatment options together, all mean differences were ≤ 100 cells/mm(2). The probability of being the best treatment option is 80% for viscoadaptives and 18% for the soft shell technique. Viscoadaptives may be superior to the other OVDs, but absolute differences in loss in endothelial cell density are <100 cells/mm(2).


Optical trapping of NaYF4:Er3+,Yb3+ upconverting fluorescent nanoparticles.
We report on the first experimental observation of stable optical trapping of dielectric NaYF4:Er(3+),Yb(3+) upconverting fluorescent nanoparticles (~26 nm in diameter) using a continuous wave 980 nm single-beam laser. The laser serves both to optically trap and to excite visible luminescence from the nanoparticles. Sequential loading of individual nanoparticles into the trap is observed from the analysis of the emitted luminescence. We demonstrate that the trapping strength and the number of individual nanoparticles trapped are dictated by both the laser power and nanoparticle density. The possible contribution of thermal effects has been investigated by performing trapping experiment in both heavy water and into distilled water. For the case of heavy water, thermal gradients are negligible and optical forces dominate the trap loading behaviour. The results provide a promising path towards real three dimensional manipulation of single NaYF4:Er(3+),Yb(3+) nanoparticles for precise fluorescence sensing in biophotonics experiments.


Current trends in the clinical management of an old enemy: congestive heart failure in the elderly.
Much has been learned in the past decade, through quality medical and nursing research, regarding the pathophysiology and management of congestive heart failure. Primary care practitioners are challenged to apply the latest data to the clinical management of these patients when there is clear evidence of improvement in the control of symptoms and quality of life. Because of the complexities of the disease process, older adults with congestive heart failure require a comprehensive approach that is particularly well suited to the knowledge and skills of the advanced practice nurse.


Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36.
Parkinson disease (PD) is a relatively common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. About 5%-10% of PD cases are inherited. Mutations in the Parkin gene, which encodes a protein that can function as an E3 ubiquitin ligase, are a common cause of familial PD. Such mutations act in a loss-of-function manner and impair the ability of the encoded protein to mediate substrate ubiquitination, although the subsequent molecular pathway that precipitates neuronal degeneration is poorly defined. In this issue of the JCI, Kim and colleagues describe painstaking evidence using a number of dissecting approaches in intact animals and cultured cells to functionally link Parkin and the class B scavenger receptor CD36, suggesting a novel and complex connection between PD and fatty acid metabolism.


Control of synaptic strength by glial TNFalpha.
Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFalpha has the opposite effects. Thus, the continual presence of TNFalpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFalpha may play roles in synaptic plasticity and modulating responses to neural injury.


Folding circular permutants of IL-1β: route selection driven by functional frustration.
Interleukin-1β (IL-1β) is the cytokine crucial to inflammatory and immune response. Two dominant routes are populated in the folding to native structure. These distinct routes are a result of the competition between early packing of the functional loops versus closure of the β-barrel to achieve efficient folding and have been observed both experimentally and computationally. Kinetic experiments on the WT protein established that the dominant route is characterized by early packing of geometrically frustrated functional loops. However, deletion of one of the functional loops, the β-bulge, switches the dominant route to an alternative, yet, as accessible, route, where the termini necessary for barrel closure form first. Here, we explore the effect of circular permutation of the WT sequence on the observed folding landscape with a combination of kinetic and thermodynamic experiments. Our experiments show that while the rate of formation of permutant protein is always slower than that observed for the WT sequence, the region of initial nucleation for all permutants is similar to that observed for the WT protein and occurs within a similar timescale. That is, even permutants with significant sequence rearrangement in which the functional-nucleus is placed at opposing ends of the polypeptide chain, fold by the dominant WT "functional loop-packing route", despite the entropic cost of having to fold the N- and C- termini early. Taken together, our results indicate that the early packing of the functional loops dominates the folding landscape in active proteins, and, despite the entropic penalty of coalescing the termini early, these proteins will populate an entropically unfavorable route in order to conserve function. More generally, circular permutation can elucidate the influence of local energetic stabilization of functional regions within a protein, where topological complexity creates a mismatch between energetics and topology in active proteins.


Alveolar nonselective channels are ASIC1a/α-ENaC channels and contribute to AFC.
A thin fluid layer in alveoli is normal and results from a balance of fluid entry and fluid uptake by transepithelial salt and water reabsorption. Conventional wisdom suggests the reabsorption is via epithelial Na+ channels (ENaC), but if all Na+ reabsorption were via ENaC, then amiloride, an ENaC inhibitor, should block alveolar fluid clearance (AFC). However, amiloride blocks only half of AFC. The reason for failure to block is clear from single-channel measurements from alveolar epithelial cells: ENaC channels are observed, but another channel is present at the same frequency that is nonselective for Na+ over K+, has a larger conductance, and has shorter open and closed times. These two channel types are known as highly selective channels (HSC) and nonselective cation channels (NSC). HSC channels are made up of three ENaC subunits since knocking down any of the subunits reduces HSC number. NSC channels contain α-ENaC since knocking down α-ENaC reduces the number of NSC (knocking down β- or γ-ENaC has no effect on NSC, but the molecular composition of NSC channels remains unclear). We show that NSC channels consist of at least one α-ENaC and one or more acid-sensing ion channel 1a (ASIC1a) proteins. Knocking down either α-ENaC or ASIC1a reduces both NSC and HSC number, and no NSC channels are observable in single-channel patches on lung slices from ASIC1a knockout mice. AFC is reduced in knockout mice, and wet wt-to-dry wt ratio is increased, but the percentage increase in wet wt-to-dry wt ratio is larger than expected based on the reduction in AFC.


Alternatives to animal experimentation in basic research.
In contrast to animal testing required by law to guarantee minimum safety standards for the licensing of drugs and chemicals, there are no regulations in basic research forcing scientists to perform animal tests. By (usually) free choice, questions are posed and hypotheses are examined which, in many cases, can only be answered by means of animal tests. Just as easily, different questions could be asked or different hypotheses could be examined which do not require animal tests. The only criterion for the choice of a topic is its relevance which cannot necessarily be judged in the short-term. Thus, it is up to the individual scientist to judge what is worth studying and therefore worth animal consumption. The educated mind will consider ethical aspects of this choice. However, on the other hand, this decision is largely influenced by questions of efficacy or (in a negative sense) by the obstacles posed to an animal consuming approach. Here, peer review and general attitude will strongly influence the methodology chosen. Availability and awareness of adequate in vitro techniques represent the prerequisites for the use of alternative methods. The least one can do in basic research is to avoid tests which cause severe suffering to animals, as is required in Switzerland and other European countries by binding ethical principles and guidelines. The increasing standard of approval and control procedures has improved the situation over the years. There are many examples of successful alternative methods in basic research. But, the application of such methods is in most cases limited to the laboratories in which they were developed, calling for technology transfer. Exceptions are procedures that are used worldwide, like the production of monoclonal antibodies, which instead of using the ascites mouse can also be performed in vitro with some good will. In these cases, commercialisation of the techniques has aided their spread within the scientific community. Sadly, many methods, even if published in the scientific literature, are little standardised and reproducible. The suggestion is put forward that publicly accessible databases should make available more detailed descriptions of methodologies. Due to limitations in space, many scientific journals cannot publish detailed methodological descriptions. However, nowadays a supplementary central deposit of methods could easily be linked to the respective article. In numerous cases though, there is simply a lack of will to change procedures to methods without animal tests or to pose questions differently in order to avoid the use of animals or to reduce their number or, at least, to reduce stress. In other cases, researchers are simply not aware of the limitations of the animal experiment as such. A thorough review of the validity of critical animal experiments should be carried out and made available publicly. For example, many animal experiments are dramatically "under-powered", i.e. carried out with groups that are too small to allow conclusions to be drawn from the outcome. This stands in marked contrast to in vitro experiments where replicate experiments usually represent no major problem. Since in vitro models are generally more prone to artefacts due to the numerous variables, e.g. of cell culture, the key requirement for their application is their validation and quality control. Guided by the experience from validation studies for alternative methods in toxicology, concepts of a Good Cell Culture Practice (GCCP) are currently being developed which aim to define minimum quality standards for in vitro techniques. This initiative aiming to increase quality must be complemented by a concept to systematically assess the relevance of the tests in order to finally achieve an evidence-based biomedical research. A change in this direction is only possible if those public funds, which were previously assigned predominantly to alternatives to the animal tests required by law, are now channelled increasingly into developing those for basic research. A financial incentive is necessary to change procedures in basic research to animal free procedures. Ethical considerations alone will bring little movement or change. It is unacceptable that, while numbers of animal tests decrease in development and notification of drugs and chemicals, they are increasing in basic research. Due to the central role of publishing scientific results, the key options for control are the respective rules of journals for the acceptance of articles. By demanding certain standards in the instructions for authors, e.g. of quality (GCCP), relevance and in case of animal experiments proof that no alternative is available, pressure could be dramatically increased. It is suggested to hold a consensus conference of journals in the life sciences on this topic.


Person-years of life lost due to cancer in the United States, 1970 and 1984.
The number of deaths due to cancer in the United States reached an all-time high of 453,450 deaths in 1984 and, due to the dynamics of population growth, will continue to increase if the risk of dying from cancer does not change. Between 1970 and 1984, the total Person-Years of Life Lost (PYLL), the sum of the difference between the actual age at death and the expected remaining lifetime for each person who died of cancer, increased for most cancer sites as well as for all sites combined. In 1984, 6,881,281 person-years of life were lost due to cancer deaths, up from 5,303,668 in 1970. The exceptions are those cancers for which there has been major progress in either prevention or treatment; e.g., stomach and cervix uteri (prevention) and testicular, Hodgkin's disease, leukemia, and childhood cancers (treatment). The Average Years of Life Lost (AYLL) per person dying from cancer in 1984 was generally less than in 1970. Overall, each person who died from cancer in 1984 died 15.2 years earlier than his/her life expectancy. The greatest loss was for those who died of childhood cancers (66.9 years earlier), followed by testicular cancer (35.8 years earlier). The least loss relative to the expectation of life was for those who died of prostate cancer. The 25,400 men who died from prostate cancer in 1984 died an average of nine years earlier than otherwise expected.


In vivo and in vitro analysis of the Rhodobacter sphaeroides chemotaxis signaling complexes.
This chapter describes both the in vivo and in vitro methods that have been successfully used to analyze the chemotaxis pathways of R. sphaeroides, showing that two operons each encode a complete chemosensory pathway with each forming into independent signaling clusters. The methods used range from in vitro analysis of the chemotaxis phosphorylation reactions to protein localization experiments. In vitro analysis using purified proteins shows a complex pattern of phosphotransfer. However, protein localization studies show that the R. sphaeroides chemotaxis proteins are organized into two distinct sensory clusters -- one containing transmembrane receptors located at the cell poles and the other containing soluble chemoreceptors located in the cytoplasm. Signal outputs from both clusters are essential for chemotaxis. Each cluster has a dedicated chemotaxis histidine protein kinase (HPK), CheA. There are a total of eight chemotaxis response regulators in R. sphaeroides, six CheYs and two CheBs, and each CheA shows a different pattern of phosphotransfer to these response regulators. The spatial separation of homologous proteins may mean that reactions that happen in vitro do not occur in vivo, suggesting great care should be taken when extrapolating from purely in vitro data to cell physiology. The methods described in this chapter are not confined to the study of R. sphaeroides chemotaxis but are applicable to the study of complex two-component systems in general.


Deep-Learning-Based Emergency Stop Prediction for Robotic Lower-Limb Rehabilitation Training Systems.
Robotic lower-limb rehabilitation training is a better alternative for the physical training efforts of a therapist due to advantages, such as intensive repetitive motions, economical therapy, and quantitative assessment of the level of motor recovery through the measurement of force and movement patterns. However, in actual robotic rehabilitation training, emergency stops occur frequently to prevent injury to patients. However, frequent stopping is a waste of time and resources of both therapists and patients. Therefore, early detection of emergency stops in real-time is essential to take appropriate actions. In this paper, we propose a novel deep-learning-based technique for detecting emergency stops as early as possible. First, a bidirectional long short-term memory prediction model was trained using only the normal joint data collected from a real robotic training system. Next, a real-time threshold-based algorithm was developed with cumulative error. The experimental results revealed a precision of 0.94, recall of 0.93, and F1 score of 0.93. Additionally, it was observed that the prediction model was robust for variations in measurement noise.


Liver disease in ulcerative colitis: an epidemiological and follow up study in the county of Stockholm.
In an epidemiological study of the incidence of ulcerative colitis (UC) in the county of Stockholm between 1955 and 1979, 1274 patients with UC were discovered. Almost all these patients had regularly been investigated with liver function tests; 142 (11%) of them showed signs of hepatobiliary disease. A follow up study on all 142 patients with abnormal liver function and UC was made between 1989 and 1991 to evaluate the cause of the liver abnormality and to find out if the liver disease had affected the survival rates. At follow up, eight patients were reclassified as having Crohn's disease, 60 had developed normal liver function as judged from test results, while the remaining 74 still had signs of hepatobiliary disease. The most common explanation for a transient abnormality in liver function was active colitis. The temporary signs of liver injury were not associated with changes in survival rates for these patients. Infections, especially those because of hepatitis B and C virus transmitted by blood transfusions accounted for the abnormalities in liver function in 21 patients, nine of which had a chronic, but non-fatal course. Twenty nine (2.3%) of the patients developed primary sclerosing cholangitis (PSC), and 12 of them died during the study period four because of cholangiocarcinoma and eight because of hepatic failure; one patient had a transplant. The estimated median time of survival from the first presentation of evidence of a liver function, compatible with the diagnosis of PSC, to death or liver transplantation was 21 years. A comparison of survival rates in patients with UC and patients with UC and concurrent PSC showed, a significant reduction in survival in the PSC group (p<0.0001). The number of patients with UC who developed PSC remained constant during the study period. Thus, although evidence of abnormal liver function is a common finding in UC, a spontaneous return to normal levels is common. In this study, which did not have a selection bias, the median time of survival among PSC patients was far longer than previously described although development of PSC among patients with UC does significantly reduce the estimated median time of survival.


NF-κB drives epithelial-mesenchymal mechanisms of lung fibrosis in a translational lung cell model.
In the progression phase of idiopathic pulmonary fibrosis (IPF), the normal alveolar structure of the lung is lost and replaced by remodeled fibrotic tissue and by bronchiolized cystic airspaces. Although these are characteristic features of IPF, knowledge of specific interactions between these pathological processes is limited. Here, the interaction of lung epithelial and lung mesenchymal cells was investigated in a coculture model of human primary airway epithelial cells (EC) and lung fibroblasts (FB). Single-cell RNA sequencing revealed that the starting EC population was heterogenous and enriched for cells with a basal cell signature. Furthermore, fractions of the initial EC and FB populations adopted distinct pro-fibrotic cell differentiation states upon cocultivation, resembling specific cell populations that were previously identified in lungs of patients with IPF. Transcriptomic analysis revealed active NF-κB signaling early in the cocultured EC and FB, and the identified NF-κB expression signatures were found in "HAS1 High FB" and "PLIN2+ FB" populations from IPF patient lungs. Pharmacological blockade of NF-κB signaling attenuated specific phenotypic changes of EC and prevented FB-mediated interleukin-6, interleukin-8, and CXC chemokine ligand 6 cytokine secretion, as well as collagen α-1(I) chain and α-smooth muscle actin accumulation. Thus, we identified NF-κB as a potential mediator, linking epithelial pathobiology with fibrogenesis.


In vitro and in vivo immunosuppressive effects of supernatants from human choriocarcinoma cell lines.
Local immunosuppression mediated by placental suppressor factors may contribute to the absence of consistently demonstrable cellular immunity against the fetus. In this context, we have investigated the immunosuppressive capabilities of supernatants from human trophoblastic choriocarcinoma cell lines (HCS) by testing the effects of HCS on immune responses in vitro and in vivo in the human and murine systems. HCS suppresses mitogen-induced proliferation and mixed lymphocyte reactions in humans and in mice, as well as antigen-induced T cell proliferation in mice. HCS also suppresses the in vivo response of mice to allogeneic cells. Furthermore, HCS when injected intraperitoneally causes the induction of suppressor cells in mice which in turn prevent the mounting of an allogeneic response in other strains of mice. These results indicate that human choriocarcinoma cell lines secrete a suppressor factor(s) which induces suppression in vitro as well as in vivo through the generation of suppressor cells.


HIV evolution and diversity in ART-treated patients.
Characterizing HIV genetic diversity and evolution during antiretroviral therapy (ART) provides insights into the mechanisms that maintain the viral reservoir during ART. This review describes common methods used to obtain and analyze intra-patient HIV sequence data, the accumulation of diversity prior to ART and how it is affected by suppressive ART, the debate on viral replication and evolution in the presence of ART, HIV compartmentalization across various tissues, and mechanisms for the emergence of drug resistance. It also describes how CD4+ T cells that were likely infected with latent proviruses prior to initiating treatment can proliferate before and during ART, providing a renewable source of infected cells despite therapy. Some expanded cell clones carry intact and replication-competent proviruses with a small fraction of the clonal siblings being transcriptionally active and a source for residual viremia on ART. Such cells may also be the source for viral rebound after interrupting ART. The identical viral sequences observed for many years in both the plasma and infected cells of patients on long-term ART are likely due to the proliferation of infected cells both prior to and during treatment. Studies on HIV diversity may reveal targets that can be exploited in efforts to eradicate or control the infection without ART.


Felbamate inhibits dihydropyridine-sensitive calcium channels in central neurons.
The effect of the antiepileptic drug felbamate (FBM) on high-voltage-activated Ca++ currents was studied in cortical and neostriatal neurons acutely isolated from adult rats. Patch-clamp recordings in the whole-cell configuration were performed. Ba++ ions as the charge carrier for Ca++ channels were used. In pyramidal cortical cells, FBM dose-dependently reduced high-voltage-activated Ca++ currents in all the tested neurons. At concentrations of 30 to 100 nM, FBM already produced a significant inhibition of high-voltage-activated Ca++ currents (-6/-15%). At saturating concentrations (1-3 microM), FBM-mediated inhibition averaged 44%. The responses were fully reversible. The dose-response curves revealed IC50 of 504 nM. In striatal neurons, FBM decreased the same conductances by about 28%; the threshold dose was 1 to 2 microM, with an IC50 of 18.7 microM. In both structures, the observed inhibitions were unaffected by omega-conotoxin GVIA and omega-agatoxin IVA, suggesting that N-like channels and P-Like channels were not involved in the FBM-mediated responses. In addition, when omega-conotoxin GVIA and omega-agatoxin IVA (100 nM) were coapplied, the FBM-mediated inhibition on the remaining Ca++ currents averaged 87%. The FBM responses were occluded by micromolar concentrations of nifedipine, supporting a direct interference with dihydropyridine-sensitive channels. It is concluded that the described effect of FBM might represent an efficacious mechanism for either controlling spike discharge from epileptic foci or protecting neurons from excessive Ca++ loading. In both cases, FBM would act as a broad spectrum neuroprotective agent.


Relationship between selected micronutrient deficiencies and oxidative stress biomarkers in diabetes mellitus patients with foot ulcers in Ibadan, Nigeria
Background/aim: Micronutrients are indispensable in the prevention of diseases and maintenance of good health. Their deficiencies have been implicated in several diseases associated with oxidative stress (OS). This study aimed at investigating the levels of some vitamins and minerals in association with OS markers in diabetic foot ulcer (DFU) patients in Ibadan, Oyo State, Nigeria. Materials and methods: Seventy DFU patients and 50 apparently healthy volunteers (controls) were recruited for the study. Blood samples of 10 mL were collected after a 10-h overnight fast from each participant after obtaining their consent. Levels of oxidative stress biomarkers such as lipid peroxide (LPO), 8-hydroxyl-2?-deoxyguanosine (8-OHdG), total antioxidant status (TAS), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and micronutrients such as vitamin C, vitamin E, copper, selenium, and zinc were determined. Results: Significant increases in the levels of LPO and 8-OHdG and GPx activity were found in DFU patients compared to controls (P < 0.001). Significant decreases in vitamin C (P = 0.003), selenium, vitamin E, and TAS concentrations were detected between DFU patients and controls (P < 0.001). However, nonsignificant decreases in SOD activity and copper and zinc levels were observed when DFU patients and controls were compared (P > 0.05). Vitamin C was significantly positively correlated with GPx and selenium was significantly negatively correlated with 8-OHdG in the DFU group. However, nonsignificant correlations were observed between other micronutrients and oxidative stress biomarkers of both the DFU and control groups. Conclusion: Diabetes mellitus patients with foot ulcers may require micronutrient supplementation for proper control and maintenance of oxidant/antioxidant homeostasis.


Are Nonfatal Suicide Attempts Instrumental in Achieving Personal and Interpersonal Goals?
This study focused on the well-being of the survivors of suicide attempts and the well-being of their interpersonal relationships after the attempt. The data came from a sample of 392 college students from 10 Muslim majority countries who reported having attempted suicide in the last 4 years. Suicide was conceptualized as a goal-directed behavior embedded in a sociocultural context and motivated by personal or interpersonal goals. We tested a process that linked culturally shaped self-construal to the postsuicidal personal and interpersonal well-being. We posited that this process would operate through the attitudes towards suicide, motives for suicide, the strength of the intention to die. Our model indicated that the acceptability of suicide was positively associated with escape motives, and this association was even stronger for the individuals with interdependent self-construals. Escape motives were negatively associated with postsuicidal personal and interpersonal well-being, but communication motives were not associated with these outcomes. We also found evidence that having an interdependent self-construal might be beneficial for postsuicidal personal and interpersonal well-being. Our results further suggested that the postsuicidal personal and interpersonal well-being of highly interdependent individuals may depend on the interpretation of their act of suicide by their close others.


Chaos analysis of the brain topology in first-episode psychosis and clinical high risk patients.
Structural MRI studies in first-episode psychosis (FEP) and in clinical high risk (CHR) patients have consistently shown volumetric abnormalities in frontal, temporal, and cingulate cortex areas. The aim of the present study was to employ chaos analysis for the identification of brain topology differences in people with psychosis. Structural MRI were acquired from 77 FEP, 73 CHR and 44 healthy controls (HC). Chaos analysis of the gray matter distribution was performed: First, the distances of each voxel from the center of mass in the gray matter image was calculated. Next, the distances multiplied by the voxel intensity were represented as a spatial-series, which then was analyzed by extracting the Largest-Lyapunov-Exponent (lambda). The lambda brain map depicts thus how the gray matter topology changes. Between-group differences were identified by (a) comparing the lambda brain maps, which resulted in statistically significant differences in FEP and CHR compared to HC; and (b) matching the lambda series with the Morlet wavelet, which resulted in statistically significant differences in the scalograms of FEP against CHR and HC. The proposed framework using spatial-series extraction enhances the between-group differences of FEP, CHR and HC subjects, verifies diagnosis-relevant features and may potentially contribute to the identification of structural biomarkers for psychosis.


Predictors of the use of orthotopic bladder reconstruction after radical cystectomy for bladder cancer: data from a pilot study of 1756 cases 2004-2011.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: How often orthotopic reconstruction should be used after radical cystectomy is uncertain. Male sex, younger age, affluence, white ethnicity and treatment in specialist hospitals may be associated with more frequent use. More evidence about the level and likely variation in the use of orthotopic surgery is needed to establish whether there are inequalities and unmet need. In England during the study period orthotopic bladder reconstruction was likely to be used in about one in 15 patients treated by radical cystectomy. This is lower than previously reported in US series or European studies. Men and younger patients were more likely to be treated by orthotopic reconstruction, as were more affluent patients and those with less advanced disease. Whether clinical reasons or patient choice can explain some of this variation is unclear. There was no evidence for variation between different English cancer networks. A specific procedure code to allow routine analysis of population-based nationwide data would be invaluable for ongoing monitoring of potential inequalities and unmet need. To examine variation in the use of orthotopic bladder reconstruction. Variability in the use of orthotopic reconstruction may indicate potential for quality improvement. We analysed data from the British Association of Urological Surgeons Cancer Registry Complex Operations data set and Hospital Episode Statistics, covering the period 2004-2011. Three-level (patient, consultant and cancer network) mixed effect logistic regression models were used to examine sociodemographic and organizational variation in use of orthotopic reconstruction. The primary outcome was the odds ratio for use of orthotopic reconstruction for different patient groups. The final analysis sample included 1756 patients with bladder cancer who were treated by cystectomy by 121 consultants in 17 cancer networks. Of these, 120 (6.8%) were treated by orthotopic bladder reconstruction by 49 consultants in 14 cancer networks. In multivariable analysis, use of orthotopic surgery was higher in younger patients (odds ratio [OR] = 0.37 per increasing 10-year age group from 30-39 to ≥70, P ≤ 0.001) and men (OR = 2.31, P = 0.005). There was also some evidence of less frequent use among more deprived patients (OR per decreasing deprivation quintile 1.17, P = 0.037) and those with advanced disease (OR per increase in stage category 0.8, P = 0.037). After accounting for patient- and consultant-level variation, there was very limited variation in the use of orthotopic reconstruction between different cancer networks. Within the study context, use of orthotopic surgery was relatively rare and variable between patients with different characteristics but not between different cancer networks. The extent by which this variation reflects variation in quality of care or patient choice is uncertain. Examining the dissemination of orthotopic surgery use using nationwide data is advisable.


Sturgeons, sharks, and rays have multifocal crystalline lenses and similar lens suspension apparatuses.
Crystalline lenses with multiple focal lengths in monochromatic light (multifocal lenses) are present in many vertebrate groups. These lenses compensate for chromatic aberration and create well-focused color images. Stabilization of the lens within the eye and the ability to adjust focus are further requirements for vision in high detail. We investigated the occurrence of multifocal lenses by photorefractometry and lens suspension structures by light and electron microscopy in sturgeons (Acipenseriformes, Chondrostei) as well as sharks and rays (Elasmobranchii, Chondrichthyes). Multifocal lenses were found in two more major vertebrate groups, the Chondrostei represented by Acipenseriformes and Chondrichthyes represented by Elasmobranchii. The lens suspension structures of sturgeons, sharks, and rays are more complex than described previously. The lens is suspended by many delicate suspensory fibers in association with a ventral papilla in all groups studied. The arrangements of the suspensory fibers are most similar between sturgeons and sharks. In rays, the lens is suspended by a smaller ventral papilla and the suspensory fibers are arranged more concentrically to the lens.


Multiple Introductions and Recent Spread of the Emerging Human Pathogen Mycobacterium ulcerans across Africa.
Buruli ulcer (BU) is an insidious neglected tropical disease. Cases are reported around the world but the rural regions of West and Central Africa are most affected. How BU is transmitted and spreads has remained a mystery, even though the causative agent, Mycobacterium ulcerans, has been known for more than 70 years. Here, using the tools of population genomics, we reconstruct the evolutionary history of M. ulcerans by comparing 165 isolates spanning 48 years and representing 11 endemic countries across Africa. The genetic diversity of African M. ulcerans was found to be restricted due to the bacterium's slow substitution rate coupled with its relatively recent origin. We identified two specific M. ulcerans lineages within the African continent, and inferred that M. ulcerans lineage Mu_A1 existed in Africa for several hundreds of years, unlike lineage Mu_A2, which was introduced much more recently, approximately during the 19th century. Additionally, we observed that specific M. ulcerans epidemic Mu_A1 clones were introduced during the same time period in the three hydrological basins that were well covered in our panel. The estimated time span of the introduction events coincides with the Neo-imperialism period, during which time the European colonial powers divided the African continent among themselves. Using this temporal association, and in the absence of a known BU reservoir or-vector on the continent, we postulate that the so-called "Scramble for Africa" played a significant role in the spread of the disease across the continent.


Improving school management in low and middle income countries: A systematic review.
Improving school quality in low and middle income countries (LMICs) is a global priority. One way to improve quality may be to improve the management skills of school leaders. In this systematic review, we analyze the impact of interventions targeting school leaders' management practices on student learning. We begin by describing the characteristics and responsibilities of school leaders using data from large, multi-country surveys. Second, we review the literature and conduct a meta-analysis of the causal effect of school management interventions on student learning, using 39 estimates from 20 evaluations. We estimate a statistically significant improvement in student learning of 0.033 standard deviations. We show that effect sizes are not related to program scale or intensity. We complement the meta-analysis by identifying common limitations to program effectiveness through a qualitative assessment of the studies included in our review. We find three main factors which mitigate program effectiveness: (1) low take-up; (2) lack of incentives or structure for implementation of recommendations; and (3) the lengthy causal chain linking management practices to student learning. Finally, to assess external validity of our review, we survey practitioners to compare characteristics between evaluated and commonly implemented programs. Our findings suggest that future work should focus on generating evidence on the marginal effect of common design elements in these interventions, including factors that promote school leader engagement and accountability.


Antioxidative effects of whey protein on peroxide-induced cytotoxicity.
Myoblastic toxicity is a major adverse effect caused by reactive oxygen species (ROS) when exercising heavily. Although protection or alleviation of ROS toxicity can be achieved by administration of antioxidant vitamins such as vitamin E and vitamin C, their protective effect remains controversial. Thus, alternative natural antioxidants may be potential candidates for foods for athletes. In this research, we investigated the antioxidative effect of whey protein against hydrogen peroxide (H(2)O(2)) toxicity using C(2)C(12) myoblasts. Whey protein pre-incubation prevented the decrease in cell viability after H(2)O(2) treatment. The production of 8-hydroxydeoxyguanosine associated with DNA oxidative damage was also inhibited by the whey protein pre-incubation. Endogenous antioxidant defense, such as glutathione, catalase, and superoxide dismutase activity, was also modulated by the antioxidant. At the same time, enhanced mRNA expression levels of heme oxygenase-1 and NADPH quinone oxidoreductase-1 were observed in cells pre-incubated with whey protein before H(2)O(2) abuse. These findings suggest that whey protein improved the antioxidant capacity against acute oxidative stress through multiple pathways and this protein may serve as an alternative source of antioxidants for prevention of athletic injuries caused by ROS.


Qualitative causal analyses of biosimulation models.
We describe an approach for performing qualitative, systems-level causal analyses on biosimulation models that leverages semantics-based modeling formats, formal ontology, and automated inference. The approach allows users to quickly investigate how a qualitative perturbation to an element within a model's network (an increment or decrement) propagates throughout the modeled system. To support such analyses, we must interpret and annotate the semantics of the models, including both the physical properties modeled and the dependencies that relate them. We build from prior work understanding the semantics of biological properties, but here, we focus on the semantics for dependencies, which provide the critical knowledge necessary for causal analysis of biosimulation models. We describe augmentations to the Ontology of Physics for Biology, via OWL axioms and SWRL rules, and demonstrate that a reasoner can then infer how an annotated model's physical properties influence each other in a qualitative sense. Our goal is to provide researchers with a tool that helps bring the systems-level network dynamics of biosimulation models into perspective, thus facilitating model development, testing, and application.


Factors associated with differential uptake of seasonal influenza immunizations among underserved communities during the 2009-2010 influenza season.
Influenza vaccination coverage remains low and disparities persist. In New York City, a community-based participatory research project (Project VIVA) worked to address this issue in Harlem and the South Bronx by supplementing existing vaccination programs with non-traditional venues (i.e., community-based organizations). We conducted a 10 min survey to assess access to influenza vaccine as well as attitudes and beliefs towards influenza vaccination that could inform intervention development for subsequent seasons. Among 991 participants recruited using street intercept techniques, 63% received seasonal vaccine only, 11% seasonal and H1N1, and 26% neither; 89% reported seeing a health care provider (HCP) during the influenza season. Correlates of immunization among those with provider visits during the influenza season included being US-born, interest in getting the vaccine, concern about self or family getting influenza, an HCP's recommendation and comfort with government. Among those without an HCP visit, factors associated with immunization included being US born, married, interest in getting the vaccine, understanding influenza information, and concern about getting influenza. Factors associated with lack of interest in influenza vaccine included being born outside the US, Black and uncomfortable with government. In medically underserved areas, having access to routine medical care and understanding the medical implications of influenza play an important role in enhancing uptake of seasonal influenza vaccination. Strategies to improve vaccination rates among Blacks and foreign-born residents need to be addressed. The use of non-traditional venues to provide influenza vaccinations in underserved communities has the potential to reduce health disparities.


Chemical synthesis of biologically active tat trans-activating protein of human immunodeficiency virus type 1.
Full-length (86-residue) polypeptide corresponding to the human immunodeficiency virus type 1 tat trans-activating protein was chemically synthesized on a semiautomated apparatus, using an Fmoc amino acid continuous-flow strategy. The bulk material was relatively homogeneous, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and isoelectric focusing, and it showed trans-activating activity when scrape loaded into cells containing a human immunodeficiency virus long terminal repeat-chloramphenicol acetyl-transferase reporter plasmid. Reverse-phase high-pressure liquid chromatography yielded a rather broad elution profile, and assays across the column for biological activity indicated a sharper peak. Thus, high-pressure liquid chromatography provided for enrichment of biological activity. Fast atom bombardment-mass spectrometry of tryptic digests of synthetic tat identified several of the predicted tryptic peptides, consistent with accurate chemical synthesis.


Synthesis, characterization, photophysical properties, and catalytic activity of an SCS bis(N-heterocyclic thione) (SCS-NHT) Pd pincer complex.
Treatment of 1,3-bis(3'-butylimidazolyl-1'-yl)benzene diiodide with elemental sulfur in the presence of a base produced a bis(N-heterocyclic thione) (NHT) pincer ligand precursor. Its reaction with PdCl2(CH3CN)2 produced chloro[1,3-bis(3'-butylimidazole-2'-thione-κ-S)benzene-κ-C]palladium(ii), a 6,6-fused ring SCS-NHT palladium pincer complex. This air stable compound is, to our knowledge, the first SCS pincer complex that utilizes N-heterocyclic thione (NHT) donor groups. The molecular structures of the ligand precursor and the palladium complex were determined by X-ray crystallography and computational studies provided insight into the interconversion between its rac and meso conformations. The photophysical properties of the complex were established, and its catalytic activity in Suzuki, Heck, and Sonogashira cross-coupling reactions was evaluated.


Improving tumour heterogeneity MRI assessment with histograms.
By definition, tumours are heterogeneous. They are defined by marked differences in cells, microenvironmental factors (oxygenation levels, pH, VEGF, VPF and TGF-α) metabolism, vasculature, structure and function that in turn translate into heterogeneous drug delivery and therapeutic outcome. Ways to estimate quantitatively tumour heterogeneity can improve drug discovery, treatment planning and therapeutic responses. It is therefore of paramount importance to have reliable and reproducible biomarkers of cancerous lesions' heterogeneity. During the past decade, the number of studies using histogram approaches increased drastically with various magnetic resonance imaging (MRI) techniques (DCE-MRI, DWI, SWI etc.) although information on tumour heterogeneity remains poorly exploited. This fact can be attributed to a poor knowledge of the available metrics and of their specific meaning as well as to the lack of literature references to standardised histogram methods with which surrogate markers of heterogeneity can be compared. This review highlights the current knowledge and critical advances needed to investigate and quantify tumour heterogeneity. The key role of imaging techniques and in particular the key role of MRI for an accurate investigation of tumour heterogeneity is reviewed with a particular emphasis on histogram approaches and derived methods.


[Experiences of Individuals With Suicidal Ideation and Attempts].
Suicide is a major public health problem. It covers about half of violent deaths and results in approximately one million deaths annually. Although completed suicide rates in Colombia are relatively low when compared with other countries, suicidal behavior, represented not only by completed suicide, is a significant mental health problem. To understand life experiences of a group of subjects related to the phenomenon of ideation and suicide attempt. A qualitative study with a psychodynamic approach. In-depth interviews were conducted in order to explore thought processes, emotions, motivations and experiences that underlie and accompany the suicide attempt. Five women and 3 men were interviewed. The average age was 29 years. The exploration of subjective experiences in the present study showed that loneliness and psychic pain were linked to hopelessness, pessimism and discouragement. Also, the illusion of death represents an invitation to suicide attempt. It is important to consider the subjective assessment that patients with suicidal risk make of their depression and stressful life situations. Additionally, the concepts of loneliness and psychic pain have a leading role in the interaction between discourse and the experiences of the participants interviewed.


Are birds smarter than mathematicians? Pigeons (Columba livia) perform optimally on a version of the Monty Hall Dilemma.
The "Monty Hall Dilemma" (MHD) is a well known probability puzzle in which a player tries to guess which of three doors conceals a desirable prize. After an initial choice is made, one of the remaining doors is opened, revealing no prize. The player is then given the option of staying with their initial guess or switching to the other unopened door. Most people opt to stay with their initial guess, despite the fact that switching doubles the probability of winning. A series of experiments investigated whether pigeons (Columba livia), like most humans, would fail to maximize their expected winnings in a version of the MHD. Birds completed multiple trials of a standard MHD, with the three response keys in an operant chamber serving as the three doors and access to mixed grain as the prize. Across experiments, the probability of gaining reinforcement for switching and staying was manipulated, and birds adjusted their probability of switching and staying to approximate the optimal strategy. Replication of the procedure with human participants showed that humans failed to adopt optimal strategies, even with extensive training.


Individual fate and gut microbiome composition in the European wild rabbit (Oryctolagus cuniculus).
Studies connecting microbiome composition and functional performance in wildlife have received little attention and understanding their connections with wildlife physical condition are sorely needed. We studied the variation in gut microbiota (hard fecal pellets) between allopatric subspecies of the European wild rabbit in wild populations and in captured individuals studied under captivity. We evaluated the influence of environmental and host-specific factors. The microbiome of wild rabbit populations reduced its heterogeneity under controlled conditions. None of the host-specific factors tested correlated with the microbiota composition. We only observed significant intra-group dispersion for the age factor. The most diverse microbiomes were rich in Ruminococcaceae potentially holding an enriched functional profile with dominance of cellulases and xylanases, and suggesting higher efficiency in the digestion of fiber-rich food. Conversely, low diversity gut microbiomes showed dominance of Enterobacteriaceae potentially rich in amylases. We preliminary noticed geographical variations in field populations with higher dominance of Ruminococcaceae in south-western than in north-eastern Spain. Spatial differences appeared not to be subspecies driven, since they were lost in captivity, but environmentally driven, although differences in social structure and behavior may also play a role that deserve further investigations. A marginally significant relationship between the Ruminococcaceae/Enterobacteriaceae ratio and potential life expectancy was observed in captive rabbits. We hypothesize that the gut microbiome may determine the efficiency of feeding resource exploitation, and can also be a potential proxy for life expectancy, with potential applications for the management of declining wild herbivorous populations. Such hypotheses remain to be explored in the future.


Pedal cyclists, crash helmets and risk.
As a rate per million kilometres travelled, the 'risk' of cycling appears to be high in relation to other forms of transport. Yet, in absolute numbers, there are far fewer cyclist deaths than pedestrian or motor vehicle occupant deaths, and most deaths and serious injuries to pedal cyclists are caused by other road users--principally motor vehicles. The large majority of pedal cyclist deaths are due to head injuries after collision with a motor vehicle. It is therefore commonly proposed that cyclists should wear crash helmets for their own 'safety'. Helmets may protect against fall injuries, but current models are not designed to withstand the impact of collisions with motor vehicles. Evidence for the benefit of pedal cyclists wearing helmets is limited: the existing studies cannot exclude the possibility of different risk-taking behaviour, either by cyclists or by motor vehicle drivers, for helmet wearers compared with non-wearers. A public health policy towards reducing pedal cyclist deaths should seek prevention of accidents, rather than protection from their consequences. Cycling in greater safety would reduce the 'risk' per kilometre travelled, but more cycling might not reduce total cyclist deaths or injuries--because of greater exposure. The 'risk' of cycling--the risk of injury or death--is a complex mix of exposure, 'danger' of the environment, and the perceived risk affecting our precautionary preventive behaviour.


Real-space identification of intermolecular bonding with atomic force microscopy.
We report a real-space visualization of the formation of hydrogen bonding in 8-hydroxyquinoline (8-hq) molecular assemblies on a Cu(111) substrate, using noncontact atomic force microscopy (NC-AFM). The atomically resolved molecular structures enable a precise determination of the characteristics of hydrogen bonding networks, including the bonding sites, orientations, and lengths. The observation of bond contrast was interpreted by ab initio density functional calculations, which indicated the electron density contribution from the hybridized electronic state of the hydrogen bond. Intermolecular coordination between the dehydrogenated 8-hq and Cu adatoms was also revealed by the submolecular resolution AFM characterization. The direct identification of local bonding configurations by NC-AFM would facilitate detailed investigations of intermolecular interactions in complex molecules with multiple active sites.


Focused attention meditation changes the boundary and configuration of functional networks in the brain.
Research has shown that focused attention meditation not only improves our cognitive and motivational functioning (e.g., attention, mental health), it influences the way our brain networks [e.g., default mode network (DMN), fronto-parietal network (FPN), and sensory-motor network (SMN)] function and operate. However, surprisingly little attention has been paid to the possibility that meditation alters the architecture (composition) of these functional brain networks. Here, using a single-case experimental design with intensive longitudinal data, we examined the effect of mediation practice on intra-individual changes in the composition of whole-brain networks. The results showed that meditation (1) changed the community size (with a number of regions in the FPN being merged into the DMN after meditation) and (2) led to instability in the community allegiance of the regions in the FPN. These results suggest that, in addition to altering specific functional connectivity, meditation leads to reconfiguration of whole-brain network architecture. The reconfiguration of community architecture in the brain provides fruitful information about the neural mechanisms of meditation.


Production of androgenetic zebrafish (Danio rerio).
To help investigate the evolutionary origin of the imprinting (parent-of-origin mono-allelic expression) of paternal genes observed in mammals, we constructed haploid and diploid androgenetic zebrafish (Danio rerio). Haploid androgenotes were produced by fertilizing eggs that had been X-ray irradiated to eliminate the maternal genome. Subsequent inhibition of the first mitotic division of haploid androgenotes by heat shock produced diploid androgenotes. The lack of inheritance of maternal-specific DNA markers (RAPD and SSR) by putative diploid and haploid androgenotes confirmed the androgenetic origin of their genomes. Marker analysis was performed on 18 putative androgenotes (five diploids and 13 haploids) from six families. None of 157 maternal-specific RAPD markers analyzed, some of which were apparently homozygous, were passed on to any of these putative androgenotes. A mean of 7.7 maternal-specific markers were assessed per family. The survival of androgenetic zebrafish suggests that if paternal imprinting occurs in zebrafish, it does not result in essential genes being inactivated when their expression is required for development. Production of haploid androgenotes can be used to determine the meiotic recombination rate in male zebrafish. Androgenesis may also provide useful information about the mechanism of sex determination in zebrafish.


Cognitive deficits in youth with familial and clinical high risk to psychosis: a systematic review and meta-analysis.
It is likely that cognitive deficits are vulnerability markers for developing schizophrenia, as these deficits are already well-established findings in first-episode psychosis. Studies at-risk adolescents and young adults are likely to provide information about cognitive deficits that predate the onset of the illness. We conducted meta-analyses of studies comparing familial-high risk (FHR) or ultra-high risk (UHR; n = 2113) and healthy controls (n = 1748) in youth studies in which the mean age was between 15 and 29. Compared with controls, high risk subjects were impaired in each domain in both UHR (d = 0.34-0.71) and FHR (d = 0.24-0.81). Heterogeneity of effect sizes across studies was modest, increasing confidence to the findings of the current meta-analysis (I(2) = 0-0.18%). In both risk paradigms, co-occurrence of genetic risk with attenuated symptoms was associated with more severe cognitive dysfunction. In UHR, later transition to psychosis was associated with more severe cognitive deficits in all domains (d = 0.31-0.49) except sustained attention. However, cognitive impairment has a limited capacity to predict the outcome of high-risk patients. Cognitive deficits are already evident in adolescents and young adults who have familial or clinical risk for psychosis. Longitudinal developmental studies are important to reveal timing and trajectory of emergence of such deficits.


Target identification and mechanism of action in chemical biology and drug discovery.
Target-identification and mechanism-of-action studies have important roles in small-molecule probe and drug discovery. Biological and technological advances have resulted in the increasing use of cell-based assays to discover new biologically active small molecules. Such studies allow small-molecule action to be tested in a more disease-relevant setting at the outset, but they require follow-up studies to determine the precise protein target or targets responsible for the observed phenotype. Target identification can be approached by direct biochemical methods, genetic interactions or computational inference. In many cases, however, combinations of approaches may be required to fully characterize on-target and off-target effects and to understand mechanisms of small-molecule action.


An unusual ocular manifestation of discoid lupus erythematosus.
Discoid lupus erythematosus is a chronic skin disease characterized by well-demarcated papules and plaques. Mucous membrane changes are common; however, conjunctival involvement is unusual. We report a case of unilateral, chronic, isolated discoid lupus erythematosus of the conjunctiva. A 32-year-old man presented for evaluation of chronic conjunctivitis of the right eye that had persisted for 9 years. A biopsy of the bulbar conjunctiva revealed a mixed mononuclear cellular infiltrate distributed along the epithelial basement membrane zone and around the stromal blood vessels. Immunohistopathologic examination revealed a diffuse, granular pattern of fluorescence corresponding to immunoglobulins and complement components along the epithelial basement membrane zone and in the walls of the stromal blood vessels. Electron microscopy demonstrated changes in the epithelial basal lamina consistent with discoid lupus erythematosus, including areas that were multilayered. Immunoelectron microscopy identified sub-basal lamina deposits of immunoglobulin G. Discoid lupus erythematosus should be a suspected cause of chronic conjunctival inflammation; the diagnosis is substantiated by immunopathologic and ultrastructural studies.


Subjective complaints of people living near mobile phone base stations in Poland.
The aim of our study was to assess the health conditions and subjective symptoms of the inhabitants living in the base stations vicinity and to analyse the relationship between the complaints and level of exposure to electromagnetic fields (EMF). Our study was performed in housing estates located in five regions of Łódź. The electric field measurements were performed in the buildings located closest to the azimuth of the antennas. Respondents were selected by trained interviewers using an uniform procedure. The number of the households to be examined was set at a minimum of 420. The questionnaire contained: demographic data, occupational and environmental exposure to EMF, health condition, subjective complaints. Results were adjusted for confounders (age, gender, EMF at the workplace and EMF emitted by household equipment) using multiple regression model. 181 men and 319 women from 500 households were examined. Electric field above 0.8 V/m was recorded in 12% of flats. There was no significant correlation between electric field strength and the distance of examined flats from the base stations. To make possible comparison with relevant literature, we analysed also the frequency of the reported symptoms vs. the distance. Headache was declared by 57% people, most frequently (36.4%) living 100-150 m away from the base station compared to people living at longer distances (p = 0.013). 24.4% subjects, mostly living at a distance above 150 m, declared impaired memory. Difference was statistically significant in comparison with people living at other distances (p = 0.004). The explanation why we did not find any correlation between the electric field strength and frequency of subjective symptoms but found a correlation between subjective symptoms and distance from base station needs further studies. Maybe new metrics of exposure assessment should be adopted for this purpose.