Occupational Therapy Intervention Improves Glycemic Control and Quality of Life Among Young Adults With Diabetes: the Resilient, Empowered, Active Living with Diabetes (REAL Diabetes) Randomized Controlled Trial.
To assess the efficacy of a manualized occupational therapy (OT) intervention (Resilient, Empowered, Active Living with Diabetes [REAL Diabetes]) to improve glycemic control and psychosocial well-being among ethnically diverse young adults with low socioeconomic status (SES) who have type 1 or type 2 diabetes. Eighty-one young adults (age 22.6 ± 3.5 years; hemoglobin A1c [HbA1c] = 10.8%/95 mmol/mol ± 1.9%/20.8 mmol/mol) were randomly assigned to the REAL Diabetes intervention group (IG) or an attention control group (CG) over 6 months. IG participants received biweekly sessions guided by a manual composed of seven content modules; CG participants received standardized educational materials and biweekly phone calls. Blinded assessors collected data at baseline and 6 months. The primary outcome was HbA1c; secondary outcomes included diabetes self-care, diabetes-related quality of life (QOL), diabetes distress, depressive symptoms, and life satisfaction. Change scores were analyzed using Wilcoxon rank sum tests. Intent-to-treat analyses showed that IG participants showed significant improvement in HbA1c (-0.57%/6.2 mmol/mol vs. +0.36%/3.9 mmol/mol, P = 0.01), diabetes-related QOL (+0.7 vs. +0.15, P = 0.04), and habit strength for checking blood glucose (+3.9 vs. +1.7, P = 0.05) as compared with CG participants. There was no statistically significant effect modification by sex, ethnicity, diabetes type, recruitment site, or SES. No study-related serious adverse events were reported. The REAL Diabetes intervention improved blood glucose control and diabetes-related QOL among a typically hard-to-reach population, thus providing evidence that a structured OT intervention may be beneficial in improving both clinical and psychosocial outcomes among individuals with diabetes.


The Vaginal and Urinary Microbiomes in Premenopausal Women With Interstitial Cystitis/Bladder Pain Syndrome as Compared to Unaffected Controls: A Pilot Cross-Sectional Study.
Interstitial cystitis/bladder pain syndrome (ICBPS) may be related to an altered genitourinary microbiome. Our aim was to compare the vaginal and urinary microbiomes between premenopausal women with ICBPS and unaffected controls. This cross-sectional study screened premenopausal women with an O'Leary-Sant questionnaire (ICBPS if score ≥6 on either index; controls <6 on both). Women completed questionnaires on health characteristics, pelvic floor symptoms (OABq, PFDI-20), body image (mBIS), and sexual function (PISQ-IR). Bacterial genomic DNA was isolated from vaginal and clean-catch urinary specimens; the bacterial 16 rRNA gene was sequenced and analyzed using the QIIME pipeline. We performed UniFrac analysis (β-diversity) and generated Chao1 estimator (richness) and Simpson index (richness and evenness) values. We analyzed 23 ICBPS and 18 non-ICBPS patients. ICBPS patients had increased vaginal deliveries, BMI, and public insurance as well as worsened OAB-q, PFDI-20, mBIS, and PISQ-IR domain scores. Lactobacilli was the most abundant genus in both cohorts, and anaerobic or fastidious predominance was similar between groups (p = 0.99). For both the urine and vagina specimens, Chao1 and Simpson indices were similar between ICBPS and unaffected women. Weighted and unweighted UniFrac analyses showed no differences between groups. A significant correlation existed between the urinary and vaginal Simpson indices in ICBPS women, but not in unaffected women. Premenopausal women with ICBPS, despite worsened socioeconomic indicators and pelvic floor function, were not found to have significantly different urinary and vaginal microbiomes compared to women without ICBPS.


Gauging U.S. Emergency Medical Services workers' willingness to respond to pandemic influenza using a threat- and efficacy-based assessment framework.
Emergency Medical Services workers' willingness to report to duty in an influenza pandemic is essential to healthcare system surge amidst a global threat. Application of Witte's Extended Parallel Process Model (EPPM) has shown utility for revealing influences of perceived threat and efficacy on non-EMS public health providers' willingness to respond in an influenza pandemic. We thus propose using an EPPM-informed assessment of EMS workers' perspectives toward fulfilling their influenza pandemic response roles. We administered an EPPM-informed snapshot survey about attitudes and beliefs toward pandemic influenza response, to a nationally representative, stratified random sample of 1,537 U.S. EMS workers from May-June 2009 (overall response rate: 49%). Of the 586 respondents who met inclusion criteria (currently active EMS providers in primarily EMS response roles), 12% indicated they would not voluntarily report to duty in a pandemic influenza emergency if asked, 7% if required. A majority (52%) indicated their unwillingness to report to work if risk of disease transmission to family existed. Confidence in personal safety at work (OR = 3.3) and a high threat/high efficacy ("concerned and confident") EPPM profile (OR = 4.7) distinguished those who were more likely to voluntarily report to duty. Although 96% of EMS workers indicated that they would probably or definitely report to work if they were guaranteed a pandemic influenza vaccine, only 59% had received an influenza immunization in the preceding 12 months. EMS workers' response willingness gaps pose a substantial challenge to prehospital surge capacity in an influenza pandemic. "Concerned and confident" EMS workers are more than four times as likely to fulfill pandemic influenza response expectations. Confidence in workplace safety is a positively influential modifier of their response willingness. These findings can inform insights into interventions for enhancing EMS workers' willingness to respond in the face of a global infectious disease threat.


Promoting consultation recording practice in oncology: identification of critical implementation factors and determination of patient benefit.
The objectives of this implementation study were to (i) address the evidentiary, contextual, and facilitative mechanisms that serve to retard or promote the transfer and uptake of consultation recording use in oncology practice and (ii) follow patients during the first few days following receipt of the consultation recording to document, from the patient's perspective, the benefits realized from listening to the recording. Nine medical and nine radiation oncologists from cancer centers in three Canadian cities (Calgary, Vancouver, and Winnipeg) recorded their primary consultations for 228 patients newly diagnosed with breast (n = 174) or prostate cancer (n = 54). The Digital Recording Use Semi-Structured Interview was conducted at 2 days and 1 week postconsultation. Each oncologist was provided a feedback letter summarizing the consultation recording benefits reported by their patients. Sixty-nine percent of patients listened to at least a portion of the recording within the first week following the consultation. Consultation recording favorableness ratings were high: 93.6% rated the intervention between 75 and 100 on a 100-point scale. Four main areas of benefit were reported: (i) anxiety reduction; (ii) enhanced retention of information; (iii) better informed decision making; and (iv) improved communication with family members. Eight fundamental components of successful implementation of consultation recording practice were identified. Further randomized trials are recommended, using standardized measures of the patient-reported benefit outcomes reported herein, to strengthen the evidence base for consultation recording use in oncology practice.


Plasmodium ovale infection in Malaysia: first imported case.
Plasmodium ovale infection is rarely reported in Malaysia. This is the first imported case of P. ovale infection in Malaysia which was initially misdiagnosed as Plasmodium vivax. Peripheral blood sample was first examined by Giemsa-stained microscopy examination and further confirmed using a patented in-house multiplex PCR followed by sequencing. Initial results from peripheral blood smear examination diagnosed P. vivax infection. However further analysis using a patented in-house multiplex PCR followed by sequencing confirmed the presence of P. ovale. Given that Anopheles maculatus and Anopheles dirus, vectors of P. ovale are found in Malaysia, this finding has significant implication on Malaysia's public health sector. The current finding should serve as an alert to epidemiologists, clinicians and laboratory technicians in the possibility of finding P. ovale in Malaysia. P. ovale should be considered in the differential diagnosis of imported malaria cases in Malaysia due to the exponential increase in the number of visitors from P. ovale endemic regions and the long latent period of P. ovale. It is also timely that conventional diagnosis of malaria via microscopy should be coupled with more advanced molecular tools for effective diagnosis.


Suspected Marfan Syndrome in a Female Basketball Player.
A group of experts met to discuss a case from the University of California, San Diego, School of Medicine. This case conference is part of a series featuring a variety of sports medicine topics.


A cell cycle hypothesis of cooperative oncogenesis (Review).
The development of cancer is a multistep process. To understand oncogenesis and adapt appropriate treatments it is important to have a better definition of a number of factors, including the number and order of oncogenic steps, the identity of the targeted cells and deregulated cellular components, and the genes and pathways altered at each step. We propose here a hypothesis of oncogenesis based on the targeting of the cell cycle in two major steps. Oncogenic hits may occur in two sequences: in one scenario a first oncogenic hit alters the regulation of the G1 phase of the cell cycle leading to a proliferative, premalignant syndrome; oncogenesis is completed when a second oncogenic hit relieves the checkpoints of the late phases of the cell cycle. Alternatively, a genetic alteration may hit the late phases first; this leads to a premalignant disease with signs of senescence. In this scenario, the second hit targets the G1 phase. In the two sequences, oncogenesis is based on the cooperation of two hits targeting different phases of the cell cycle and relieving major checkpoints. Stem cells and progenitor cells of various tissues may be variably sensitive to these hits.


Preparation of gold nanoparticles by novel bacterial exopolysaccharide for antibiotic delivery.
To develop potent drug delivery agents to treat multidrug resistant (MDR) bacterial infections using gold nanoparticles (AuNPs) prepared by bacterial exopolysaccharide (EPS) being a reducing and stabilizing agent. Gold nanoparticles were prepared by EPS, extracted from Lactobacillus plantarum. AuNPs were characterized by UV-visible spectrophotometer, transmission electron microscope (TEM), zeta potential and Fourier transform infrared spectroscopy. Antibiotics used for functionalization of AuNPs were levofloxacin, cefotaxime, ceftriaxone and ciprofloxacin. The resulted functionalized AuNPs were tested against various MDR bacteria by employing different assays such as well diffusion assay, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time killing assay. The nanostructures exhibited excellent bactericidal activity and reduced MIC and MBC against MDR Gram positive and Gram negative bacteria compared to free drugs. Escherichia coli was the most susceptible MDR bacteria followed by Klebsiella pneumoniae and Staphylococcus aureus. TEM results revealed that the bactericidal activity of nanostructures could be mediated by penetration, loss of cytoplasmic contents and cell lysis. Antibiotic functionalized nanostructures were more potent than free drugs and could be used as potent drug delivery vehicles.


KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.
The Hippo pathway controls tissue growth and tumorigenesis by inhibiting cell proliferation and promoting apoptosis. Recent genetic studies in Drosophila identified Kibra as a novel regulator of Hippo signaling. Human KIBRA has been associated with memory performance and cell migration. However, it is unclear whether or how KIBRA is connected to the Hippo pathway in mammalian cells. Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector. Conversely, depletion of KIBRA by RNA interference reduces YAP phosphorylation. Furthermore, KIBRA stabilizes Lats2 by inhibiting its ubiquitination. We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling.


Detection of time delays and directional interactions based on time series from complex dynamical systems.
Data-based and model-free accurate identification of intrinsic time delays and directional interactions is an extremely challenging problem in complex dynamical systems and their networks reconstruction. A model-free method with new scores is proposed to be generally capable of detecting single, multiple, and distributed time delays. The method is applicable not only to mutually interacting dynamical variables but also to self-interacting variables in a time-delayed feedback loop. Validation of the method is carried out using physical, biological, and ecological models and real data sets. Especially, applying the method to air pollution data and hospital admission records of cardiovascular diseases in Hong Kong reveals the major air pollutants as a cause of the diseases and, more importantly, it uncovers a hidden time delay (about 30-40 days) in the causal influence that previous studies failed to detect. The proposed method is expected to be universally applicable to ascertaining and quantifying subtle interactions (e.g., causation) in complex systems arising from a broad range of disciplines.


The Concept of Vulnerability in Mental Health Research: A Mixed Methods Study on Researcher Perspectives.
The concept of vulnerability plays a central role in research ethics in signaling that certain research participants warrant more careful consideration because their risk of harm is heightened due to their participation in research. Despite scholarly debates, the descriptive and normative meanings ascribed to the concept have remained disengaged from the perspective of users of the concept and those concerned by its use. In this study, we report a survey- and interview-based investigation of mental health researcher perspectives on vulnerability. We found that autonomy-based understandings of vulnerability were predominant but that other understandings coexisted, reflecting considerable pluralism. A wide range of challenges were associated with this concept, and further training was recommended by researchers.


Father-Son Communication About Consistent and Correct Condom Use.
: media-1vid15852345835001PEDS-VA_2018-1609Video Abstract OBJECTIVES: With this study, we explore communication about consistent and correct condom use among African American and Latino male adolescents ages 15 to 19 and their fathers. Twenty-five father-son dyads completed semistructured interviews designed to elicit specific preferences for teaching and learning about consistent and correct condom use and strategies for addressing common condom use errors and problems. For analysis, we used in vivo coding and vertical and horizontal analysis techniques. Fathers and sons agreed that communication about condom use is feasible and acceptable. However, fathers tended to convey vague messages regarding protecting oneself from the negative consequences of sexual activity. Furthermore, both fathers and sons reported barriers hindering conversations. Secondly, the style and frequency of condom use conversations can help overcome barriers and support father-son relationship management. Talking frequently in 1-on-1 settings and using strategies to reduce discomfort made communication easier. Lastly, fathers and sons reported distinct preferences for teaching and learning about condom use. Sons wanted fathers to give specific guidance on the use and management of condoms. Fathers expressed interest in opportunities for improving their own condom knowledge and skills. Fathers identified gaps in their own condom use knowledge as a limitation to effective instruction of their sons. A father-focused communication intervention about condom use is feasible and acceptable. Enhancing the intergenerational benefits of father-son communication by addressing specific father-son preferences and learning needs for condom use instruction, as well as communication barriers, represents a novel mechanism for reducing male sexual reproductive health disparities.


Patterns of autism spectrum symptomatology in individuals with Down syndrome without comorbid autism spectrum disorder.
Prevalence estimates of autism spectrum disorder (ASD) in Down syndrome (DS) are highly varied. This variation is partly due to the difficulty of screening for and diagnosing comorbid ASD in individuals with a syndrome that carries its own set of social communicative and behavioral difficulties that are not well documented. The aim of this study was to identify the typical range of social communicative impairments observed in children, adolescents, and young adults with DS who do not have comorbid ASD. We examined patterns of scores from the five subscales of the Social Responsiveness Scale (SRS) in 46 individuals with DS (ages 10-21 years) without comorbid ASD relative to the published normative sample. We also explored the correlations between SRS symptomatology and age, nonverbal cognition, and receptive language. SRS scores were elevated (i.e., more ASD symptoms endorsed), with mean scores falling into the clinically significant range. Analysis by subscale revealed a specific pattern, with Autistic Mannerisms and Social Cognition scores significantly more elevated than Social Communication scores, which were significantly more elevated than Social Awareness and Social Motivation scores. Correlations between SRS scores and the other measures varied by subscale. General elevated ASD symptomatology on the SRS indicates the need for developing population-based norms specific to DS. The pattern of scores across subscales should inform clinicians of the typical range of behaviors observed in DS so that individuals with atypical patterns of behavior can be more easily identified and considered for a full ASD evaluation.


Prospective trial of intense pulsed light for the treatment of meibomian gland dysfunction.
To evaluate the effect of intense pulsed light (IPL) applied to the periocular area for meibomian gland dysfunction (MGD) in a prospective, double-masked, placebo-controlled, paired-eye study. Twenty-eight participants underwent IPL treatment, with homogeneously sequenced light pulses delivered to one eye and placebo treatment to the partner control eye at 1, 15, and 45 days following baseline (BL) evaluation. Lipid layer grade (LLG), noninvasive tear break-up time (NIBUT), tear evaporation rate (TER), tear meniscus height (TMH), and subjective symptom score using visual analogue scales (VAS) were compared with BL and control values at each visit. Lipid layer grade improved significantly from BL to Day (D) 45 in the treated eye (P < 0.001), but not the control eye (P = 0.714), with 82% of treated eyes improving by at least one LLG. Noninvasive tear break-up time also improved significantly from BL to D45 in the treated (P < 0.001) but not in the control eye (P = 0.056) and was significantly longer than in the treated eye at D45 (14.1 ± 9.8 seconds versus 8.6 ± 8.2 seconds, P < 0.001). The tear evaporation rate was not different in the treated eye compared with the control eye at any visit. Tear meniscus height did not change from BL in either eye (P > 0.05). Visual analog scale symptom scores improved from BL in the treated (P = 0.015), but not the control eye (P = 0.245), with 86% of participants noting reduced symptoms in the treated eye by D45. Intense pulsed light with multiple sculpted pulses shows therapeutic potential for MGD, improving tear film quality and reducing symptoms of dry eye. ( https://www.anzctr.org.au number, ACTRN12614000162617.).


A decade of norovirus disease risk among older adults in upper-middle and high income countries: a systematic review.
Noroviruses (NoVs) are the most common cause of acute gastroenteritis (AGE) causing both sporadic and outbreak-associated illness. Norovirus (NoV) infections occur across all ages but certain sub-groups are considered at increased risk due to heightened transmission and/or symptom severity. Older adults are potentially at high risk of NoV-associated illness due to frequent outbreaks in long-term care facilities (LTCFs) and severe health outcomes following infection. Elucidation of NoV risk among older adults will support prevention, treatment and control efforts. We conducted a systematic literature review to summarize the published risk estimates of NoV-associated illness, hospitalization and death among individuals aged 65 years and older. A structured search using defined NoV and gastroenteritis (GE) terms was performed in the PubMed and EMBASE databases of human studies published between January 1, 2003 and May 16, 2013. We identified 39 studies from high income (HI) and upper-middle income (UMI) countries. Thirty-six percent of publications provided risk estimates based on laboratory-confirmed or epidemiologically-linked population-based surveillance data using molecular diagnostic methods. Over the study period, estimated annual NoV rates and extrapolated number of cases among older adults in HI and UMI countries were: 29-120/10,000 or 1.2-4.8 million NoV-associated illnesses; 18-54/10,000 or 723,000-2.2 million NoV-associated outpatient visits; 1-19/10,000 or 40,00-763,000 NoV-associated inpatient visits; 0.04-0.32/10,000 or 2000-13,000 NoV-associated deaths. NoV was responsible for approximately 10-20 % of GE hospitalizations and 10-15 % of all-cause GE deaths among older adults. Older adults experienced a heightened risk of nosocomial infections. Those in LTCFs experience frequent NoV outbreaks and the range in attack rates was 3-45 %, case hospitalization rates 0.5-6 % and case fatality rates 0.3-1.6 %. Older adults are at increased risk of severe NoV-associated health outcomes. NoV-associated hospitalization rates were higher, more severe, resulted in longer stays and incurred greater costs than for younger patients. NoV-associated mortality rates were approximately 200 % higher among individuals 65 years and older compared to <5 years. The burden of NoV among older adults is expected to rise along with societal aging and increased need for institutionalized care. NoV prevention in older adults, including potential vaccination, may significantly impact risk of severe illness.


Clinical prognostic value of RNA viral load and CD4 cell counts during untreated HIV-1 infection--a quantitative review.
The prognostic value of CD4 counts and RNA viral load for identifying treatment need in HIV-infected individuals depends on (a) variation within and among individuals, and (b) relative risks of clinical progression per unit CD4 or RNA difference. We reviewed these measurements across (a) 30 studies, and (b) 16 cohorts of untreated seropositive adults. Median within-population interquartile ranges were 74,000 copies/mL for RNA with no significant change during the course of infection; and 330 cells/microL for CD4, with a slight proportional increase over infection. Applying measurement and physiological fluctuations observed on chronically infected patients, we estimate that 45% of population-level variation in RNA, and 25% of variation in CD4, were due to within-patient fluctuations. Comparing a patient with RNA at upper 75(th) centile with a patient at median RNA, 5-year relative risks were 1.4 (95% CI 1.2-1.7) for AIDS and 1.5 (1.3-1.9) for death, without change over the course of infection. In contrast, for a patient with CD4 count at the lower 75(th) centile, relative risks increased from 1.0 at seroconversion to maxima of 6.3 (4.4-8.9) for AIDS and 5.5 (2.7-10.1) for death by year 6, when the population median had fallen to 300 cells/microL. Below 300 cells/microL, prognostic power did not increase, due to a narrower CD4 range. Findings support the current WHO recommendation (used with clinical criteria) to start antiretroviral treatment in low-income settings at CD4 thresholds of 200-350 cells/microL, without pre-treatment RNA monitoring--while not precluding earlier treatment based on clinical, socio-demographic or public health criteria.


Adaptive variation regulates the expression of the human SGK1 gene in response to stress.
The Serum and Glucocorticoid-regulated Kinase1 (SGK1) gene is a target of the glucocorticoid receptor (GR) and is central to the stress response in many human tissues. Because environmental stress varies across habitats, we hypothesized that natural selection shaped the geographic distribution of genetic variants regulating the level of SGK1 expression following GR activation. By combining population genetics and molecular biology methods, we identified a variant (rs9493857) with marked allele frequency differences between populations of African and European ancestry and with a strong correlation between allele frequency and latitude in worldwide population samples. This SNP is located in a GR-binding region upstream of SGK1 that was identified using a GR ChIP-chip. SNP rs9493857 also lies within a predicted binding site for Oct1, a transcription factor known to cooperate with the GR in the transactivation of target genes. Using ChIP assays, we show that both GR and Oct1 bind to this region and that the ancestral allele at rs9493857 binds the GR-Oct1 complex more efficiently than the derived allele. Finally, using a reporter gene assay, we demonstrate that the ancestral allele is associated with increased glucocorticoid-dependent gene expression when compared to the derived allele. Our results suggest a novel paradigm in which hormonal responsiveness is modulated by sequence variation in the regulatory regions of nuclear receptor target genes. Identifying such functional variants may shed light on the mechanisms underlying inter-individual variation in response to environmental stressors and to hormonal therapy, as well as in the susceptibility to hormone-dependent diseases.


Lipopolysaccharide and hypoxia significantly alters interleukin-8 and macrophage chemoattractant protein-1 production by human fibroblasts but not fibrosis related factors.
Besides extracellular matrix production, fibroblasts are able to produce various cytokines. Their ubiquitous position makes fibroblasts appropriate cells for sensing various noxious stimuli and for attracting immune cells in the affected area. In the present study the effect of lipopolysaccharide (LPS) and cobalt chloride (CoCl(2)) on the above fibroblasts functions were evaluated in primary human skin fibroblasts cultures. Collagen, matrix metalloproteinase-1, tissue inhibitor of metalloproteinases-1, transforming growth factor-β1, interleukin-8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) were measured in fibroblasts culture supernatants. Fibroblasts proliferation and viability were assessed as well. Hypoxia inducible factor-1α and the phosphorylated p65 portion of NF-κB were assessed in fibroblasts protein extracts. LPS and CoCl(2) had a minor effect on fibrosis related factors in human primary fibroblasts, possibly due to the absence of interplay with other cell types in the used experimental system. On the contrary both LPS and CoCl(2) increased significantly IL-8. LPS also increased considerably MCP-1, but CoCl(2) decreased it. Thus LPS and CoCl(2) induce a sentinel, nevertheless not identical, phenotype in primary human fibroblasts. The last disparity could result in different body response to infectious or hypoxic noxious stimuli.


The Diesel Exhaust in Miners Study: III. Interrelations between respirable elemental carbon and gaseous and particulate components of diesel exhaust derived from area sampling in underground non-metal mining facilities.
Diesel exhaust (DE) has been implicated as a potential lung carcinogen. However, the exact components of DE that might be involved have not been clearly identified. In the past, nitrogen oxides (NO(x)) and carbon oxides (CO(x)) were measured most frequently to estimate DE, but since the 1990s, the most commonly accepted surrogate for DE has been elemental carbon (EC). We developed quantitative estimates of historical exposure levels of respirable elemental carbon (REC) for an epidemiologic study of mortality, particularly lung cancer, among diesel-exposed miners by back-extrapolating 1998-2001 REC exposure levels using historical measurements of carbon monoxide (CO). The choice of CO was based on the availability of historical measurement data. Here, we evaluated the relationship of REC with CO and other current and historical components of DE from side-by-side area measurements taken in underground operations of seven non-metal mining facilities. The Pearson correlation coefficient of the natural log-transformed (Ln)REC measurements with the Ln(CO) measurements was 0.4. The correlation of REC with the other gaseous, organic carbon (OC), and particulate measurements ranged from 0.3 to 0.8. Factor analyses indicated that the gaseous components, including CO, together with REC, loaded most strongly on a presumed 'Diesel exhaust' factor, while the OC and particulate agents loaded predominantly on other factors. In addition, the relationship between Ln(REC) and Ln(CO) was approximately linear over a wide range of REC concentrations. The fact that CO correlated with REC, loaded on the same factor, and increased linearly in log-log space supported the use of CO in estimating historical exposure levels to DE.


Role of pharmacogenomics in the drug development.
Individuals respond differently to drugs and sometimes the effects are unpredictable. Differences in DNA that alter the expression or function of proteins targeted by drugs can contribute significantly to the variation in the individuals responses. The use of pharmacogenomics is to identify genetic polymorphisms that predispose patients to adverse drug effects that, although they may occur in only a small subset of the people treated with a new medication, are sufficiently toxic to jeopardise further development of the drug for all patients. Given the potential value of knowing all the possible factors that influence the effects of new agents, it is likely that pharmacogenomics will have an increasingly important role in drug discovery and development. This article briefly reviews concepts that underlie the emerging fields of pharmacogenetics and pharmacogenomics, with an emphasis on the pharmacogenetics of drug metabolism. Although only a few examples will be provided to illustrate concepts and to demonstrate the potential contribution of pharmacogenetics to medical practice, it is now clear that virtually every pathway of drug metabolism will eventually be found to have genetic variation.


A systemic approach to assess the potential and risks of wildlife culling for infectious disease control.
The maintenance of infectious diseases requires a sufficient number of susceptible hosts. Host culling is a potential control strategy for animal diseases. However, the reduction in biodiversity and increasing public concerns regarding the involved ethical issues have progressively challenged the use of wildlife culling. Here, we assess the potential of wildlife culling as an epidemiologically sound management tool, by examining the host ecology, pathogen characteristics, eco-sociological contexts, and field work constraints. We also discuss alternative solutions and make recommendations for the appropriate implementation of culling for disease control.


Generality and specificity in the effects of musical expertise on perception and cognition.
Performing musicians invest thousands of hours becoming experts in a range of perceptual, attentional, and cognitive skills. The duration and intensity of musicians' training - far greater than that of most educational or rehabilitation programs - provides a useful model to test the extent to which skills acquired in one particular context (music) generalize to different domains. Here, we asked whether the instrument-specific and more instrument-general skills acquired during professional violinists' and pianists' training would generalize to superior performance on a wide range of analogous (largely non-musical) skills, when compared to closely matched non-musicians. Violinists and pianists outperformed non-musicians on fine-grained auditory psychophysical measures, but surprisingly did not differ from each other, despite the different demands of their instruments. Musician groups did differ on a tuning system perception task: violinists showed clearest biases towards the tuning system specific to their instrument, suggesting that long-term experience leads to selective perceptual benefits given a training-relevant context. However, we found only weak evidence of group differences in non-musical skills, with musicians differing marginally in one measure of sustained auditory attention, but not significantly on auditory scene analysis or multi-modal sequencing measures. Further, regression analyses showed that this sustained auditory attention metric predicted more variance in one auditory psychophysical measure than did musical expertise. Our findings suggest that specific musical expertise may yield distinct perceptual outcomes within contexts close to the area of training. Generalization of expertise to relevant cognitive domains may be less clear, particularly where the task context is non-musical.


Attenuated total reflectance Fourier-transform infrared spectroscopic investigation of silicon heterojunction solar cells.
Silicon heterojunction solar cells critically depend on the detailed properties of their amorphous/crystalline silicon interfaces. We report here on the use of attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy to gain precise insight into the vibrational properties of the surfaces and ultrathin layers present in such solar cells. We fabricate ATR prisms from standard silicon wafers similar to those used for device fabrication. In this fashion, we acquire very-high sensitivity FTIR information on device-relevant structures. Our method has no requirement for minimum layer thickness, enabling the study of the impact of the different fabrication process steps on the film microstructure. We discuss the necessary requirements for the method implementation and give a comprehensive overview of all observed vibration modes. In particular, we study vibrational signatures of Si-H(X), Si-H(X)(Si(Y)O(Z)), B-H, hydroxyl groups, and hydrocarbons on the Si(111) surface. We observe subtle effects in the evolution of the chemical state of the surface during sample storage and process-related wafer handling and discuss their effect on the electronic properties of the involved interfaces.


Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial.
Well-tolerated and effective treatments are needed for chronic leg ulcers in sickle cell anaemia. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects. We aimed to assess the safety, tolerability, and pharmacokinetics of topical sodium nitrite in patients with sickle cell disease and chronic leg ulcers. We enrolled adult patients from an ambulatory clinic at the National Institutes of Health (Bethesda, MD, USA) with sickle cell anaemia with leg ulcers (with a surface area of 2.5-100 cm2) persisting for at least 4 weeks into a safety and tolerability phase 1 dose-escalation trial of topical sodium nitrite. Increasing concentrations of sodium nitrite cream were applied twice weekly for 4 weeks to one ulcer per patient at five dose levels (0.5%, 1%, 1.5%, 1.8%, and 2%). The primary endpoints were safety and tolerability, with secondary endpoints of pharmacokinetics, blood flow, and wound healing. Pain relief was analysed post hoc. Endpoints were analysed over time for the whole study population and according to dose level. This study is registered with ClinicalTrials.gov, number NCT01316796. Between April 4, 2011, and March 19, 2013, we enrolled 18 adult patients with sickle cell anaemia and leg ulcers into our trial. We assigned three patients into each cohort, and each cohort was treated with a different concentration of sodium nitrite cream (cohort 1: 0.5%, cohort 2: 1.0%, cohort 3: 1.5%, and cohort 4: 2.0%). Patients were not enrolled into the next cohort dose until we were able to establish that no dose-limiting toxicities were observed. An additional six patients were enrolled to cohort 3a: 1.8%, after two patients in cohort 4 had asymptomatic drops in diastolic blood pressure. No grade 3-4 adverse events were observed, and there were no serious adverse events or dose-limiting side-effects. Pharmacokinetic analysis showed that systemic absorption of sodium nitrite was very low. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging (p=0.0002), corroborated by increased peri-wound skin temperature by infrared thermography (p=0.0119). We recorded a dose-dependent decrease in leg ulcer size (p=0.0012) and pain (p<0.0001). Ulcers healed completely in three patients who received the highest concentrations of topical sodium nitrite (the 1.8% and 2% cream). In our post-hoc analysis of pain, brief pain inventory scores improved in pain severity (p=0.0048) and pain interference (p=0.0013). Our results indicate that topical sodium nitrite 2% cream is suitable for additional clinical trials in adults with sickle cell anaemia to promote healing of leg ulcers. National Heart, Lung and Blood Institute Division of Intramural Research (National Institutes of Health).


Pattern expression nonnegative matrix factorization: algorithm and applications to blind source separation.
Independent component analysis (ICA) is a widely applicable and effective approach in blind source separation (BSS), with limitations that sources are statistically independent. However, more common situation is blind source separation for nonnegative linear model (NNLM) where the observations are nonnegative linear combinations of nonnegative sources, and the sources may be statistically dependent. We propose a pattern expression nonnegative matrix factorization (PE-NMF) approach from the view point of using basis vectors most effectively to express patterns. Two regularization or penalty terms are introduced to be added to the original loss function of a standard nonnegative matrix factorization (NMF) for effective expression of patterns with basis vectors in the PE-NMF. Learning algorithm is presented, and the convergence of the algorithm is proved theoretically. Three illustrative examples on blind source separation including heterogeneity correction for gene microarray data indicate that the sources can be successfully recovered with the proposed PE-NMF when the two parameters can be suitably chosen from prior knowledge of the problem.


An analysis of the use of animal models in predicting human toxicology and drug safety.
Animal use continues to be central to preclinical drug development, in spite of a lack of its demonstrable validity. The current nadir of new drug approvals and the drying-up of pipelines may be a direct consequence of this. To estimate the evidential weight given by animal data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive data set of 2,366 drugs, for which both animal and human data are available, including tissue-level effects and MedDRA Level 1-4 biomedical observations. This was done for three preclinical species (rat, mouse and rabbit), to augment our previously-published analysis of canine data. In common with our dog analysis, the resulting LRs show: a) that the absence of toxicity in the animal provides little or virtually no evidential weight that adverse drug reactions (ADRs) will also be absent in humans; and b) that, while the presence of toxicity in these species can add considerable evidential weight for human risk, the LRs are extremely inconsistent, varying by over two orders of magnitude for different classes of compounds and their effects. Therefore, our results for these additional preclinical species have important implications for their use in predicting human toxicity, and suggest that alternative methods are urgently required.


Temporal binding of auditory and rotational stimuli.
Integration of cues from multiple sensory channels improves our ability to sense and respond to stimuli. Cues arising from a single event may arrive at the brain asynchronously, requiring them to be "bound" in time. The perceptual asynchrony between vestibular and auditory stimuli has been reported to be several times greater than other stimulus pairs. However, these data were collected using electrically evoked vestibular stimuli, which may not provide similar results to those obtained using actual head rotations. Here, we tested whether auditory stimuli and vestibular stimuli consisting of physiologically relevant mechanical rotations are perceived with asynchronies consistent with other sensory systems. We rotated 14 normal subjects about the earth-vertical axis over a raised-cosine trajectory (0.5 Hz, peak velocity 10 deg/s) while isolated from external noise and light. This trajectory minimized any input from extravestibular sources such as proprioception. An 800-Hz, 10-ms auditory tone was presented at stimulus onset asynchronies ranging from 200 ms before to 700 ms after the onset of motion. After each trial, subjects reported whether the stimuli were "simultaneous" or "not simultaneous." The experiment was repeated, with subjects reporting whether the tone or rotation came first. After correction for the time the rotational stimulus took to reach vestibular perceptual threshold, asynchronies spanned from -41 ms (auditory stimulus leading vestibular) to 91 ms (vestibular stimulus leading auditory). These values are significantly lower than those previously reported for stimulus pairs involving electrically evoked vestibular stimuli and are more consistent with timing relationships between pairs of non-vestibular stimuli.


Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K.
We have shown previously that the AKT2 pathway is essential for cell survival and important in malignant transformation. In this study, we demonstrate elevated kinase levels of AKT2 and phosphatidylinositol-3-OH kinase (PI3K) in 32 of 80 primary breast carcinomas. The majority of the cases with the activation are estrogen receptor alpha (ERalpha) positive, which prompted us to examine whether AKT2 regulates ERalpha activity. We found that constitutively activated AKT2 or AKT2 activated by epidermal growth factor or insulin-like growth factor-1 promotes the transcriptional activity of ERalpha. This effect occurred in the absence or presence of estrogen. Activated AKT2 phosphorylates ERalpha in vitro and in vivo, but it does not phosphorylate a mutant ERalpha in which ser-167 was replaced by Ala. The PI3K inhibitor, wortmannin, abolishes both the phosphorylation and transcriptional activity of ERalpha induced by AKT2. However, AKT2-induced ERalpha activity was not inhibited by tamoxifen but was completely abolished by ICI 164,384, implicating that AKT2-activated ERalpha contributes to tamoxifen resistance. Moreover, we found that ERalpha binds to the p85alpha regulatory subunit of PI3K in the absence or presence of estradiol in epithelial cells and subsequently activates PI3K/AKT2, suggesting ERalpha regulation of PI3K/AKT2 through a nontranscriptional and ligand-independent mechanism. These data indicate that regulation between the ERalpha and PI3K/AKT2 pathway (ERalpha-PI3K/AKT2-ERalpha) may play an important role in pathogenesis of human breast cancer and could contribute to ligand-independent breast cancer cell growth.


Identifying Vancomycin as an Effective Antibiotic for Killing Borrelia burgdorferi.
Borrelia burgdorferi is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10 to 20% go on to develop posttreatment Lyme disease syndrome (PTLDS). The nature of PTLDS remains unknown, but currently approved antibiotics for the treatment of Lyme disease do not appear to impact these symptoms after they have developed. We reason that minimizing the time the pathogen interacts with the host will diminish the probability of developing PTLDS, irrespective of its nature. This calls for an efficient eradication of the pathogen during acute infection. In search of a superior killing antibiotic, we examined approved antibiotics for their ability to kill B. burgdorferi Vancomycin proved more effective in killing the pathogen in vitro than ceftriaxone, the standard of care for disseminated B. burgdorferi infection. Both compounds were also the most effective in killing stationary-phase cells. This is surprising, given that inhibitors of cell wall biosynthesis are known to only kill growing bacteria. We found that peptidoglycan synthesis continues in stationary-phase cells of B. burgdorferi, explaining this paradox. A combination of vancomycin and gemifloxacin sterilized a stationary-phase culture of B. burgdorferi Examination of the action of antibiotics in severe combined immunodeficient (SCID) mice showed that doxycycline, a standard of care for uncomplicated acute infection, did not clear the pathogen. In contrast, both ceftriaxone and vancomycin cleared the infection. A trial examining the early use of more potent antibiotics on the development of PTLDS may be warranted.


Immobilization induces changes in presynaptic control of group Ia afferents in healthy humans.
Neural plasticity occurs throughout adult life in response to maturation, use and disuse. Recent studies have documented that H-reflex amplitudes increase following a period of immobilization. To elucidate the mechanisms contributing to the increase in H-reflex size following immobilization we immobilized the left foot and ankle joint for 2 weeks in 12 able-bodied subjects. Disynaptic reciprocal inhibition of soleus (SOL) motoneurons and presynaptic control of SOL group Ia afferents was measured before and after the immobilization as well as following 2 weeks of recovery. Following immobilization, maximal voluntary plantar- and dorsiflexion torque (MVC) was significantly reduced and the maximal SOL H-reflex amplitude increased with no changes in the maximal compound motor response (M(max)). Decreased presynaptic inhibition of the Ia afferents probably contributed to the increase of the H-reflex size, since we observed a significant decrease in the long-latency depression of the SOL H-reflex evoked by peroneal nerve stimulation (D2 inhibition) and an increase in the size of the monosynaptic Ia facilitation of the SOL H-reflex evoked by femoral nerve stimulation. These two measures provide independent evidence of changes in presynaptic inhibition of SOL Ia afferents and taken together suggest that GABAergic presynaptic inhibition of the SOL Ia afferents is decreased following 2 weeks of immobilization. The depression of the SOL H-reflex when evoked at intervals shorter than 10 s (homosynaptic post-activation depression) also decreased following immobilization, suggesting that the activity-dependent regulation of transmitter release from the afferents was also affected by immobilization. We observed no significant changes in disynaptic reciprocal Ia inhibition. Two weeks after cast removal measurements returned to pre-immobilization levels. Together, these observations suggest that disuse causes plastic changes in spinal interneuronal circuitries responsible for presynaptic control of sensory input to the spinal cord. This may be of significance for the motor disabilities seen following immobilization as well as the development of spasticity following central motor lesions.


Work stress in the etiology of coronary heart disease--a meta-analysis.
This study focused on estimating the relative risk of coronary heart disease (CHD) in association with work stress, as indicated by the job-strain model, the effort-reward imbalance model, and the organizational injustice model. A systematic review and meta-analysis of prospective cohort studies were carried out. Studies were eligible if they had published a quantitative estimate of the association between work stress and incident CHD or cardiovascular mortality by January 2006. Fourteen prospective cohort studies were identified. For a total of 83 014 employees, the age- and gender-adjusted relative ratio of CHD for high versus low job strain was 1.43 [95% confidence interval (95% CI) 1.15-1.84], but the ratio decreased to 1.16 (95% CI 0.94-1.43) after adjustment for risk factors and potential mediators. The age- and gender-adjusted risk ratio for a combination of high efforts and low rewards was 1.58 (95% CI 0.84-2.97) for 11 528 employees, and no reduction in the risk ratio was seen after further adjustments. For organizational injustice, the age- and gender-adjusted, and multiple-adjusted relative risks were 1.62 (95% CI 1.24-2.13) and 1.47 (95% CI 1.12-1.95), respectively, for a population of 7246 men and women. There was little standardization in the assessment of work stress within all three stress models, and significant heterogeneity in the effects of stress was observed between studies. Few studies were available for female samples. Observational data suggest an average 50% excess risk for CHD among employees with work stress. Further research is needed to confirm that a reduction in work stress will lead to a reduction in CHD risk.


Aging of Liver in Its Different Diseases.
The proportion of elderly people in the world population is constantly increasing. With age, the risk of numerous chronic diseases and their complications also rises. Research on the subject of cellular senescence date back to the middle of the last century, and today we know that senescent cells have different morphology, metabolism, phenotypes and many other characteristics. Their main feature is the development of senescence-associated secretory phenotype (SASP), whose pro-inflammatory components affect tissues and organs, and increases the possibility of age-related diseases. The liver is the main metabolic organ of our body, and the results of previous research indicate that its regenerative capacity is greater and that it ages more slowly compared to other organs. With age, liver cells change under the influence of various stressors and the risk of developing chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) and hepatocellular carcinoma (HCC) increases. It has been proven that these diseases progress faster in the elderly population and in some cases lead to end-stage liver disease that requires transplantation. The treatment of elderly people with chronic liver diseases is a challenge and requires an individual approach as well as new research that will reveal other safe and effective therapeutic modalities.


Staying Engaged: Knowledge and Research Needs in Student Engagement.
In this article, we review knowledge about student engagement and look ahead to the future of study in this area. We begin by describing how researchers in the field define and study student engagement. In particular, we describe the levels, contexts, and dimensions that constitute the measurement of engagement, summarize the contexts that shape engagement and the outcomes that result from it, and articulate person-centered approaches for analyzing engagement. We conclude by addressing limitations to the research and providing recommendations for study. Specifically, we point to the importance of incorporating more work on how learning-related emotions, personality characteristics, prior learning experiences, shared values across contexts, and engagement in nonacademic activities influence individual differences in student engagement. We also stress the need to improve our understanding of the nuances involved in developing engagement over time by incorporating more extensive longitudinal analyses, intervention trials, research on affective neuroscience, and interactions among levels and dimensions of engagement.


Anthropometric indices: predictors of dyslipidemia in children and adolescents from north of Brazil.
Atherosclerosis represents a disease that begins in childhood, and alterations in lipid concentration play a fundamental role in the development of this condition. To evaluate which of the currently applied obesity parameters (the body index mass, the percentage of body fat, the waist circumference and the upper arm fat area) can predict the risk for dyslipidemia in Brazilian children and adolescents. Cross-sectional study, standardized anthropometric data and lipid profile were collected from 874 subjects between the ages of 6 and 19 years. Logistic regression models were used to evaluate the degree of association between the anthropometric measurements and the lipid profile, controlling for potentially confounding variables, such as age and gender. Individuals with excess body weight, elevated percentage of body fat, waist circumference and upper arm fat above the 90th percentile showed a positive correlation with alterations in the lipid profile. After adjusting for age and income, a body mass index above the 85th percentile and an elevated percentage of body fat were the variables most strongly associated with dyslipidemia in the youngest subjects (odds ratio (OR) = 2.00, p < 0.001 and OR = 1.47, p = 0.014, respectively). Children (64.5%) and adolescents aged 10-12 years (51.0%) had the highest rates of dyslipidemia. Compared with other variables, such as the percentage of body fat, the body mass index was the best predictor of dyslipidemia in children and adolescents.


FACT prevents the accumulation of free histones evicted from transcribed chromatin and a subsequent cell cycle delay in G1.
The FACT complex participates in chromatin assembly and disassembly during transcription elongation. The yeast mutants affected in the SPT16 gene, which encodes one of the FACT subunits, alter the expression of G1 cyclins and exhibit defects in the G1/S transition. Here we show that the dysfunction of chromatin reassembly factors, like FACT or Spt6, down-regulates the expression of the gene encoding the cyclin that modulates the G1 length (CLN3) in START by specifically triggering the repression of its promoter. The G1 delay undergone by spt16 mutants is not mediated by the DNA-damage checkpoint, although the mutation of RAD53, which is otherwise involved in histone degradation, enhances the cell-cycle defects of spt16-197. We reveal how FACT dysfunction triggers an accumulation of free histones evicted from transcribed chromatin. This accumulation is enhanced in a rad53 background and leads to a delay in G1. Consistently, we show that the overexpression of histones in wild-type cells down-regulates CLN3 in START and causes a delay in G1. Our work shows that chromatin reassembly factors are essential players in controlling the free histones potentially released from transcribed chromatin and describes a new cell cycle phenomenon that allows cells to respond to excess histones before starting DNA replication.


A newly emerging alphasatellite affects banana bunchy top virus replication, transcription, siRNA production and transmission by aphids.
Banana bunchy top virus (BBTV) is a six-component ssDNA virus (genus Babuvirus, family Nanoviridae) transmitted by aphids, infecting monocots (mainly species in the family Musaceae) and likely originating from South-East Asia where it is frequently associated with self-replicating alphasatellites. Illumina sequencing analysis of banana aphids and leaf samples from Africa revealed an alphasatellite that should be classified in a new genus, phylogenetically related to alphasatellites of nanoviruses infecting dicots. Alphasatellite DNA was encapsidated by BBTV coat protein and accumulated at high levels in plants and aphids, thereby reducing helper virus loads, altering relative abundance (formula) of viral genome components and interfering with virus transmission by aphids. BBTV and alphasatellite clones infected dicot Nicotiana benthamiana, followed by recovery and symptomless persistence of alphasatellite, and BBTV replication protein (Rep), but not alphasatellite Rep, induced leaf chlorosis. Transcriptome sequencing revealed 21, 22 and 24 nucleotide small interfering (si)RNAs covering both strands of the entire viral genome, monodirectional Pol II transcription units of viral mRNAs and pervasive transcription of each component and alphasatellite in both directions, likely generating double-stranded precursors of viral siRNAs. Consistent with the latter hypothesis, viral DNA formulas with and without alphasatellite resembled viral siRNA formulas but not mRNA formulas. Alphasatellite decreased transcription efficiency of DNA-N encoding a putative aphid transmission factor and increased relative siRNA production rates from Rep- and movement protein-encoding components. Alphasatellite itself spawned the most abundant siRNAs and had the lowest mRNA transcription rate. Collectively, following African invasion, BBTV got associated with an alphasatellite likely originating from a dicot plant and interfering with BBTV replication and transmission. Molecular analysis of virus-infected banana plants revealed new features of viral DNA transcription and siRNA biogenesis, both affected by alphasatellite. Costs and benefits of alphasatellite association with helper viruses are discussed.


Inferring population continuity versus replacement with aDNA: a cautionary tale from the Aleutian Islands.
In The Aleutian and Commander Islands and Their Inhabitants (Philadelphia: Wistar Institute of Anatomy and Biology, 1945), Hrdlicka proposed a population replacement event in the Aleutian Islands approximately 1,000 years ago based on a perceived temporal shift in cranial morphology. However, the archaeological record indicates cultural, and presumed population, continuity for more than 4,000 years. We use mtDNA haplogroup data in the series of prehistoric eastern Aleutian samples (n = 86) studied craniometrically by Hrdlicka to test alternative hypotheses regarding population continuity or replacement in the region. This molecular characterization, in conjunction with direct dating of individual specimens, provided increased resolution for hypothesis testing. Results indicate an apparent shift in mtDNA haplogroup frequencies in the eastern Aleutians approximately 1,000 years ago, in concert with changes in mortuary practices and isotopic signatures reflecting resource acquisition strategies. The earliest Aleut populations were characterized by a high frequency of haplogroup A, as are most modern populations of the North American arctic. Later prehistoric peoples in the Aleutians were characterized by a high frequency of haplogroup D and a correspondingly lower frequency of haplogroup A, a pattern typified by modern Aleut populations.


Carbohydrates for training and competition.
An athlete's carbohydrate intake can be judged by whether total daily intake and the timing of consumption in relation to exercise maintain adequate carbohydrate substrate for the muscle and central nervous system ("high carbohydrate availability") or whether carbohydrate fuel sources are limiting for the daily exercise programme ("low carbohydrate availability"). Carbohydrate availability is increased by consuming carbohydrate in the hours or days prior to the session, intake during exercise, and refuelling during recovery between sessions. This is important for the competition setting or for high-intensity training where optimal performance is desired. Carbohydrate intake during exercise should be scaled according to the characteristics of the event. During sustained high-intensity sports lasting ~1 h, small amounts of carbohydrate, including even mouth-rinsing, enhance performance via central nervous system effects. While 30-60 g · h(-1) is an appropriate target for sports of longer duration, events >2.5 h may benefit from higher intakes of up to 90 g · h(-1). Products containing special blends of different carbohydrates may maximize absorption of carbohydrate at such high rates. In real life, athletes undertake training sessions with varying carbohydrate availability. Whether implementing additional "train-low" strategies to increase the training adaptation leads to enhanced performance in well-trained individuals is unclear.


Characterization of peptide attachment on silicon nanowires by X-ray photoelectron spectroscopy and mass spectrometry.
In this paper, we report an original method to immobilize a model peptide on silicon nanowires (SiNWs) via a photolinker attached to the SiNWs' surface. The silicon nanowires were fabricated by a metal assisted chemical etching (MACE) method. Then, direct characterization of the peptide immobilization on SiNWs was performed either by X-ray photoelectron spectroscopy (XPS) or by laser-desorption/ionization mass spectrometry (LDI-MS). XPS allowed us to follow the peptide immobilization and its photorelease by recording the variation of the signal intensities of the different elements present on the SiNW surface. Mass spectrometry was performed without the use of an organic matrix and peptide ions were produced via a photocleavage mechanism. Indeed, thanks to direct photorelease achieved upon laser irradiation, a recorded predictable peak related to the molecular peptide ion has been detected, allowing the identification of the model peptide. Additional MS/MS experiments confirmed the photodissociation site and confirmed the N-terminal immobilization of the peptide on SiNWs.


Harmine is a potent antimalarial targeting Hsp90 and synergizes with chloroquine and artemisinin.
Previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of Guiera senegalensis from Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited Plasmodium falciparum heat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [K(d)] of 40 μM). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (K(d) of 224 μM) more tightly than PfHsp90 (K(d) of 7,010 μM). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisinin in vitro and in the Plasmodium berghei mouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials.


Plant DNA polymerase lambda, a DNA repair enzyme that functions in plant meristematic and meiotic tissues.
Little is known about the functions of DNA polymerase lambda (Pol lambda) recently identified in mammals. From the genomic sequence information of rice and Arabidopsis, we found that Pol lambda may be the only member of the X-family in higher plants. We have succeeded in isolating the cDNA and recombinant protein of Pol lambda in a higher plant, rice (Oryza sativa L. cv. Nipponbare) (OsPol lambda). OsPol lambda had activities of DNA polymerase, terminal deoxyribonucleotidyl transferase and deoxyribose phosphate lyase, a marker enzyme for base excision repair. It also interacted with rice proliferating cell nuclear antigen (OsPCNA) in a pull-down assay. OsPCNA increased the processivity of OsPol lambda. Northern blot analysis showed that the level of OsPol lambda expression correlated with cell proliferation in meristematic and meiotic tissues, and was induced by DNA-damaging treatments. These properties suggest that plant Pol lambda is a DNA repair enzyme which functions in plant meristematic and meiotic tissues, and that it can substitute for Pol beta and terminal deoxyribonucleotidyl transferase.


Altered cortical activation patterns associated with baroreflex unloading following 24 h of physical deconditioning.
Cardiovascular arousal is associated with patterned cortical activity changes. Head-down-tilt bed rest (HDBR) dimishes the baroreflex-mediated cardiac control. The present study tested the hypothesis that HDBR deconditioning would modify the forebrain organization for heart rate (HR) control during baroreflex unloading. Heart rate variability (HRV), blood pressure and plasma hormones were analysed at rest, whereas HR and cortical autonomic activation patterns (functional magnetic resonance imaging) were measured during graded and randomly assigned lower body negative pressure treatments (LBNP, -15 and -35 mmHg) both before (Pre) and after (Post) a 24 h HDBR protocol (study 1; n = 8). An additional group was tested before and following diuretic-induced hypovolaemia (study 2; n = 9; spironolactone, 100 mg day(-1) for 3 days) that mimicked the plasma volume lost during HDBR (-15% in both studies; P < 0.05). Head-down bed rest with hypovolaemia did not affect baseline HR, mean arterial pressure, HRV or plasma catecholamines. Head-down bed rest augmented the LBNP-induced HR response (P < 0.05), and this was associated with bed-rest-induced development of the following changes: (i) enhanced activation within the genual anterior cingulate cortex and the right anterior insular cortex; and (ii) deactivation patterns within the subgenual regions of the anterior cingulate cortex. Diuretic treatment (without HDBR) did not affect baseline HR and mean arterial pressure, but did reduce resting HRV and elevated circulating noradrenaline and plasma renin activity (P < 0.05). The greater HR response to LBNP following diuretic (P < 0.05) was associated with diminished activation of the right anterior insula. Our findings indicate that 24 h of HDBR minimized the impact of diuretic treatment on baseline autonomic and cardiovascular variables. The findings also indicate that despite the similar augmentation of HR responses to LBNP and despite similar pre-intervention cortical activation patterns, HDBR and diuretic treatment produced different effects on the cortical responses, with HDBR affecting anterior cingulate cortex and right insula regions, whereas diuretic treatment affected primarily the right insula alone, but in a direction that was opposite to HDBR. The data indicate that physical deconditioning can induce rapid functional changes within the cortical circuitry associated with baroreflex unloading, changes that are distinct from diuretic-induced hypovolaemia. The results suggest that physical activity patterns exert a rapid and notable impact on the cortical circuitry associated with cardiovascular control.


[Conjunctival tumors].
Conjunctival tumors are one of the most frequent of the eye and adnexa. They comprise a large variety of conditions, from benign lesions such as nevus or papilloma, to malignant lesions such as epidermoid carcinoma or melanoma which may threaten visual function and the life of the patient. They can arise from any cellular component, but the most frequent are of epithelial and melanocytic origin. Early diagnosis is essential for preventing ocular and systemic spread and to preserve visual function. In this paper we review the clinical characteristics of the most frequent conjunctival tumors, and we discuss tumor management.


Frequent substitution polymorphisms in African green monkey CCR5 cluster at critical sites for infections by simian immunodeficiency virus SIVagm, implying ancient virus-host coevolution.
In contrast to humans, several primate species are believed to have harbored simian immunodeficiency viruses (SIVs) since ancient times. In particular, the geographically dispersed species of African green monkeys (AGMs) are all infected with highly diversified SIVagm viruses at high prevalences (greater than 50% of sexually mature individuals) without evident diseases, implying that the progenitor monkeys were infected prior to their dispersal. If this is correct, AGMs would be expected to have accumulated frequent resistance-conferring polymorphisms in host genes that are important for SIV replication. Accordingly, we analyzed the coding sequences of the CCR5 coreceptors from 26 AGMs (52 alleles) in distinct populations of the four species. These samples contained 29 nonsynonymous coding changes and only 15 synonymous nucleotide substitutions, implying intense functional selection. Moreover, 24 of the resulting amino acid substitutions were tightly clustered in the CCR5 amino terminus (D13N in the vervets and Y14N in the tantalus species) or in the first extracellular loop (Q93R and Q93K in all species). The Y14N substitution was extremely frequent in the 12 wild-born African tantalus, with 7 monkeys being homozygous for this substitution and 4 being heterozygous. Although two of these heterozygotes and the only wild-type homozygote were naturally infected with SIVagm, none of the Y14N homozygotes were naturally infected. A focal infectivity assay for SIVagm indicated that all five tested SIVagms efficiently use CCR5 as a coreceptor and that they also use CXCR6 (STRL33/Bonzo) and GPR15 (BOB) with lower efficiencies but not CXCR4. Interestingly, the D13N, Y14N, Q93R, and Q93K substitutions in AGM CCR5 all strongly inhibited infections by the SIVagm isolates in vitro. The Y14N substitution eliminates a tyrosine sulfation site that is important for infections and results in partial N-linked glycosylation (i.e., 60% efficiency) at this position. Nevertheless, the CCR5(Y14N) component that lacks an N-linked oligosaccharide binds the chemokine MIP-lbeta with a normal affinity and is fully active in signal transduction. Similarly, D13N and Q93R substitutions did not interfere with signal transduction. Thus, the common substitution polymorphisms in AGM CCR5 strongly inhibit SIVagm infections while substantially preserving chemokine signaling. In contrast, polymorphisms of human CCR5 are relatively infrequent, and the amino acid substitutions are randomly situated and generally without effects on coreceptor function. These results support an ancient coevolution of AGMs and SIVagm viruses and establish AGMs as a highly informative model for learning about host proteins that play critical roles in immunodeficiency virus infections.


Self-Reported Long-Term Autonomic Function After Laparoscopic Total Mesometrial Resection for Early-Stage Cervical Cancer: A Multicentric Study.
This multicentric retrospective study investigates the early and long-term self-reported urinary, bowel, and sexual dysfunctions in early-stage cervical cancer patients who submitted to laparoscopic total mesometrial resection (L-TMMR), total laparoscopic radical hysterectomy, vaginal-assisted laparoscopic radical hysterectomy, and laparoscopic-assisted radical vaginal hysterectomy. Cervical cancer patients, FIGO (International Federation of Gynecology and Obstetrics) stage IA2-IB1/IIA1 who submitted to nerve-sparing radical hysterectomy were recruited. Pelvic functions were assessed within 30 days (early outcome) and 12 months after surgery (long-term outcome). Two hundred thirteen subjects receiving nerve-sparing radical hysterectomy were enrolled. Laparoscopic total mesometrial resection was performed in 46 patients (21.6%), total laparoscopic radical hysterectomy in 65 patients (30.5%), vaginal-assisted laparoscopic radical hysterectomy in 54 patients (25.4%), and laparoscopic-assisted radical vaginal hysterectomy in 48 women (22.5%). Operative time was significantly lower in the L-TMMR group (240 minutes; range, 120-670 minutes; P = 0.001). The overall perioperative complication rate was 11.3%, with no statistically significant differences among the 4 groups. Stress incontinence and sensation of bladder incomplete emptying were detected, respectively, in 54 patients (25.6%) and 65 patients (30.7%) with a significantly lower prevalence among those in the L-TMMR group, which resulted, respectively, in 11.1% (P = 0.022) and 13.3% (P = 0.036). The prevalence rates of constipation, sensation of incomplete bowel emptying, and effort during evacuation were significantly higher among those in the L-TMMR group, resulting in, respectively, 37% (P = 0.001), 42.3% (P = 0.012), and 50% (P = 0.039). One hundred forty-nine patients (70%) were sexually active. Fifty-eight women (38.9%) reported low enjoyment, 83 women (55.7%) medium enjoyment, and 8 women (5.4%) reported high enjoyment, without statistically significant differences among the 4 groups. Laparoscopic total mesometrial resection is associated with improved long-term urinary autonomic functions and worse gastrointestinal autonomic outcome. Further larger prospective trials are needed to evaluate both the oncological and functional outcomes in order to establish the most appropriate surgical approach for early-stage cervical cancer patients.


Recommendations for the design of laboratory studies on non-target arthropods for risk assessment of genetically engineered plants.
This paper provides recommendations on experimental design for early-tier laboratory studies used in risk assessments to evaluate potential adverse impacts of arthropod-resistant genetically engineered (GE) plants on non-target arthropods (NTAs). While we rely heavily on the currently used proteins from Bacillus thuringiensis (Bt) in this discussion, the concepts apply to other arthropod-active proteins. A risk may exist if the newly acquired trait of the GE plant has adverse effects on NTAs when they are exposed to the arthropod-active protein. Typically, the risk assessment follows a tiered approach that starts with laboratory studies under worst-case exposure conditions; such studies have a high ability to detect adverse effects on non-target species. Clear guidance on how such data are produced in laboratory studies assists the product developers and risk assessors. The studies should be reproducible and test clearly defined risk hypotheses. These properties contribute to the robustness of, and confidence in, environmental risk assessments for GE plants. Data from NTA studies, collected during the analysis phase of an environmental risk assessment, are critical to the outcome of the assessment and ultimately the decision taken by regulatory authorities on the release of a GE plant. Confidence in the results of early-tier laboratory studies is a precondition for the acceptance of data across regulatory jurisdictions and should encourage agencies to share useful information and thus avoid redundant testing.


The TRANSPLANTA collection of Arabidopsis lines: a resource for functional analysis of transcription factors based on their conditional overexpression.
Transcription factors (TFs) are key regulators of gene expression in all organisms. In eukaryotes, TFs are often represented by functionally redundant members of large gene families. Overexpression might prove a means to unveil the biological functions of redundant TFs; however, constitutive overexpression of TFs frequently causes severe developmental defects, preventing their functional characterization. Conditional overexpression strategies help to overcome this problem. Here, we report on the TRANSPLANTA collection of Arabidopsis lines, each expressing one of 949 TFs under the control of a β-estradiol-inducible promoter. Thus far, 1636 independent homozygous lines, representing an average of 2.6 lines for every TF, have been produced for the inducible expression of 634 TFs. Along with a GUS-GFP reporter, randomly selected TRANSPLANTA lines were tested and confirmed for conditional transgene expression upon β-estradiol treatment. As a proof of concept for the exploitation of this resource, β-estradiol-induced proliferation of root hairs, dark-induced senescence, anthocyanin accumulation and dwarfism were observed in lines conditionally expressing full-length cDNAs encoding RHD6, WRKY22, MYB123/TT2 and MYB26, respectively, in agreement with previously reported phenotypes conferred by these TFs. Further screening performed with other TRANSPLANTA lines allowed the identification of TFs involved in different plant biological processes, illustrating that the collection is a powerful resource for the functional characterization of TFs. For instance, ANAC058 and a TINY/AP2 TF were identified as modulators of ABA-mediated germination potential, and RAP2.10/DEAR4 was identified as a regulator of cell death in the hypocotyl-root transition zone. Seeds of TRANSPLANTA lines have been deposited at the Nottingham Arabidopsis Stock Centre for further distribution.


Neurological complications of cervical laminoplasty for patients with ossification of the posterior longitudinal ligament-a multi-institutional retrospective study.
Retrospective multi-institutional study. To investigate the incidence of neurological deficits after cervical laminoplasty for ossification of the posterior longitudinal ligament (OPLL). According to analysis of long-term results, laminoplasty for cervical OPLL has been reported as a safe and effective alternative procedure with few complications. However, perioperative neurological complication rates of laminoplasty for cervical OPLL have not been well described. Subjects comprised 581 patients (458 men and 123 women; mean age: 62 ± 10 years; range: 30-86 years) who had undergone laminoplasty for cervical OPLL at 27 institutions between 2005 and 2008. Continuous-type OPLL was seen in 114, segmental-type in 146, mixed-type in 265, local-type in 24, and not judged in 32 patients. Postoperative neurological complications within 2 weeks after laminoplasty were analyzed in detail. Cobb angle between C2 and C7 (C2/C7 angle), maximal thickness, and occupying rate of OPLL were investigated. Pre- and postoperative magnetic resonance imaging was performed on patients with postoperative neurological complications. Open-door laminoplasty was conducted in 237, double-door laminoplasty in 311, and other types of laminoplasty in 33 patients. Deterioration of lower-extremity function occurred after laminoplasty in 18 patients (3.1%). Causes of deterioration were epidural hematoma in 3, spinal cord herniation through injured dura mater in 1, incomplete laminoplasty due to vertebral artery injury while making a trough in 1, and unidentified in 13 patients. Prevalence of unsatisfactory recovery not reaching preoperative level by 6-month follow-up was 7/581 (1.2%). Mean occupying rate of OPLL for patients with deteriorated lower-extremity function was 51.2 ± 13.6% (range, 21.0%-73.3%), significantly higher than the 42.3 ± 13.0% for patients without deterioration. OPLL thickness was also higher in patients with deterioration (mean, 6.6 ± 2.2 mm) than in those without deterioration (mean, 5.7 ± 2.0 mm). No significant difference in C2/C7 lordotic angle was seen between groups. Although most neurological deterioration can be expected to recover to some extent, the frequency of short-term neurological complications was higher than the authors expected.


OAS Gene Family Expression Is Associated with HIV-Related Neurocognitive Disorders.
HIV-associated neurocognitive disorders are common in HIV-infected individuals, even in the combination antiretroviral therapy (c-ART) era. Several mechanisms are involved in neuronal damage, including chronic inflammation immune activation. Mammalian 2'-5'-oligoadenylate synthetase (OAS) genes are produced in response to interferon (IFN), mainly by monocytes, and exert their antiviral functions by activation of RNase L that degrades viral and cellular RNAs. In this study, we aimed at exploring OAS gene family RNA expression in simian immunodeficiency virus encephalitis (SIVE), in HIV-associated neurocognitive disorders (HAND), and in HIV-associate dementia (HAD). We analyzed three microarray datasets obtained from the NCBI in order to assess the expression levels of OAS gene family network in brain biopsies of macaques with SIVE vs uninfected animals, as well as post-mortem brain of individuals with HAND (on or off ART) vs uninfected controls and three brain regions of HIV-infected individuals with both neurocognitive impairment (HAD) and encephalitis (HIVE). All OAS genes were upregulated both in SIVE and in HAND. OAS expression was significantly higher in high-viremic individuals; increased expression levels persisted in cART subjects when compared to healthy controls. OAS gene network analysis showed that several genes belonging to the type I IFN pathway, especially CXCL10 and IFIT3, were similarly upregulated in SIVE/HAND. Furthermore, we identified a significant upregulation of OAS gene family RNA expression in basal ganglia, white matter, and frontal cortex of HIV-1, HAD, and HAD/HIVE patients compared to healthy subjects. OAS gene family expression is increased in brain sections from individuals with HAND, HAD, and HIVE as well as macaques with SIVE. OAS family expression is likely to be induced by IFN as a consequence of viral replication in the CNS. Its long-term upregulation may contribute to the chronic inflammatory status and neurocognitive impairment we still observe in virologically suppressed individuals on c-ART.


Blood pressure, body fat, and dehydroepiandrosterone sulfate variation in adolescence.
Several significant interrelations among variation in blood pressure, body fat, and adrenal androgen levels, as assessed by serum dehydroepiandrosterone sulfate concentrations, were found in black male and female adolescents, aged 12 to 16 years. In girls, high levels of dehydroepiandrosterone sulfate were associated with significantly higher levels of blood pressure (alpha = 0.05), even after adjusting for the significant association between increased levels of dehydroepiandrosterone sulfate and body fat. The increased body fat (i.e., body mass index) found with higher levels of dehydroepiandrosterone sulfate in girls was related to significantly greater (alpha = 0.05) accumulations of fat in the upper trunk, as opposed to the limb. In boys, high levels of serum dehydroepiandrosterone sulfate, low body mass index, and significantly higher blood pressure were interrelated (alpha = 0.05). In addition to the interaction of increased body mass index or body fat and increased levels of dehydroepiandrosterone sulfate in association with higher blood pressure, high levels of the adrenal androgen, even in boys with low body mass index, were associated independently with relatively higher blood pressure. Body proportion analyses for these boys indicated that they were tall and thin, in contrast to the other boys with low body mass index, who were generally short and thin.


Consequences of bed rest.
Bed rest is frequently prescribed for critically ill patients because it is assumed to be beneficial for preventing complications, for conserving scarce metabolic resources, and for providing patient comfort. Furthermore, higher levels of physical activity in critically ill patients have been assumed to be impractical or not feasible. Bed rest has been prescribed in the past for several other clinical conditions including acute flares of rheumatoid arthritis, cavitary tuberculosis, acute myocardial infarction, and acute low back pain. However, randomized, controlled, clinical trials failed to demonstrate beneficial effects of bed rest in most of these conditions. Bed rest can cause several complications that may delay or prevent recovery from critical illnesses including disuse muscle atrophy, joint contractures, thromboembolic disease, and insulin resistance. Recent studies demonstrated the feasibility and safety of physical medicine programs in critically ill patients including those with acute respiratory failure requiring mechanical ventilation. Other physical medicine tools, such as neuromuscular electrical stimulation and passive stretching of muscles, may also reduce some complications of bed rest.


Urgent computed tomography for determining the optimal timing of colonoscopy in patients with acute lower gastrointestinal bleeding.
We evaluated the diagnostic performance of computed tomography (CT) as an initial radiologic test for assessing the optimal timing of colonoscopy in patients with acute lower gastrointestinal bleeding (LGIB) and investigated the effectiveness of contrast-enhanced (CE) CT for detecting colonic diverticular bleeding. This was a retrospective study of 1,604 consecutive patients who visited or were referred to St. Marianna University Hospital due to acute LGIB and underwent colonoscopy within three months after presentation between September 2004 and December 2012. The clinicopathological data of the subjects were obtained from their medical records. Among the 1,604 patients presenting with LGIB, 879 (55%) underwent a CT scan. Elective colonoscopy was considered in cases in which typical colonic wall thickening was observed on CT, suggesting colonic inflammation or malignancy (239 patients; 27%). The diagnoses in the elective cases included ischemic colitis (38%), infectious colitis (8%), inflammatory bowel disease (8%) and malignancy (5%). Urgent colonoscopy was performed after the CT examination in 640 cases (73%). The most common presumptive CT diagnosis was diverticulum (402/640; 63%). Of the 638 patients who underwent CE-CT, diverticula were observed in 346 cases, including 104 cases of extravasation indicating ongoing diverticular bleeding. Among these 104 patients, the site of bleeding was identified in 71 subjects (68%) during colonoscopy. The rate of detection of the bleeding source on colonoscopy was significantly higher in the patients with extravasation on CE-CT than in those without extravasation on CE-CT (68% vs. 20%, respectively; p<0.001). Urgent CT is useful for determining the optimal timing of colonoscopy in cases of acute LGIB. CE-CT may be used to depict the presence and location of active hemorrhage and provides useful information for subsequent colonoscopy, especially in patients with diverticular bleeding.


The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle.
The ovary and uterus undergo extensive tissue remodeling throughout each reproductive cycle. This remodeling of the extracellular environment is dependent upon the cyclic hormonal changes associated with each estrous or menstrual cycle. In the ovary, tissue remodeling is requisite for growth and expansion of the follicle, breakdown of the follicular wall during the ovulatory process, transformation of the postovulatory follicle into the corpus luteum, as well as the structural dissolution of the corpus luteum during luteal regression. In the uterus, there is extraordinary turnover of the endometrial connective tissue matrix during each menstrual cycle. This turnover encompasses the complete breakdown and loss of this layer, followed by its subsequent regrowth. With implantation, extensive remodeling of the uterus occurs to support placentation. These dynamic changes in the ovarian and uterine extracellular architecture are regulated, in part, by the matrix metalloproteinase (MMP) system. The MMP system acts to control connective tissue remodeling processes throughout the body and is comprised of both a proteolytic component, the MMPs, and a regulatory component, the associated tissue inhibitors of metalloproteinases. The current review will highlight the key features of the MMPs and tissue inhibitors of metalloproteinases, focus on the changes and regulation of the MMP system that take place throughout the estrous and menstrual cycles, and address the impact of the dynamic tissue remodeling processes on ovarian and uterine physiology.


Seizure control, stress, and access to care during the COVID-19 pandemic in New York City: The patient perspective.
Our epilepsy population recently experienced the acute effects of the COVID-19 pandemic in New York City. Herein, we aimed to determine patient-perceived seizure control during the surge, specific variables associated with worsened seizures, the prevalence of specific barriers to care, and patient-perceived efficacy of epilepsy care delivered via telephone and live video visits during the pandemic. We performed a cross-sectional questionnaire study of adult epilepsy patients who had a scheduled appointment at a single urban Comprehensive Epilepsy Center (Montefiore Medical Center) between March 1, 2020 and May 31, 2020 during the peak of the COVID-19 pandemic in the Bronx. Subjects able to answer the questionnaire themselves in English or Spanish were eligible to complete a one-time survey via telephone or secure online platform (REDCap). Of 1212 subjects screened, 675 were eligible, and 177 adequately completed the questionnaire. During the COVID-19 pandemic, 75.1% of patients reported no change in seizure control, whereas 17.5% reported that their seizure control had worsened, and 7.3% reported improvement. Subjects who reported worsened seizure control had more frequent seizures at baseline, were more likely to identify stress and headaches/migraines as their typical seizure precipitants, and were significantly more likely to report increased stress related to the pandemic. Subjects with confirmed or suspected COVID-19 did not report worsened seizure control. Nearly 17% of subjects reported poorer epilepsy care, and 9.6% had difficulty obtaining their antiseizure medications; these subjects were significantly more likely to report worse seizure control. Of the nearly 20% of subjects who reported worsened seizure control during the COVID-19 pandemic, stress and barriers to care appear to have posed the greatest challenge. This unprecedented pandemic exacerbated existing and created new barriers to epilepsy care, which must be addressed.


Brain stem structures responsible for the electroencephalographic patterns of desynchronized sheep.
Contrary to the results of transecting one half of the rostral pons, unilateral partial lesions of the rostral pons, involving either "specific" or "aspecific" structures, do not prevent the appearance of the desynchronized electroencephalographic patterns of deep sleep in the ipsilateral hemi sphere in cats. This effect, however, is obtained by lesions of the medial as well as lateral tegmental structures of the midbrain. These findings seem to indicate that (i) there is not a single pontine structure or group of structures of crucial importance for the EEG desynchronization of deep sleep; the whole rostral pons appears to contrib ute to the EEG-desynchronizing influ ence; (ii) this influence runs rostrally through the midbrain tegmentum, without following any known fiber pathway.


Drought limitations to leaf-level gas exchange: results from a model linking stomatal optimization and cohesion-tension theory.
We merge concepts from stomatal optimization theory and cohesion-tension theory to examine the dynamics of three mechanisms that are potentially limiting to leaf-level gas exchange in trees during drought: (1) a 'demand limitation' driven by an assumption of optimal stomatal functioning; (2) 'hydraulic limitation' of water movement from the roots to the leaves; and (3) 'non-stomatal' limitations imposed by declining leaf water status within the leaf. Model results suggest that species-specific 'economics' of stomatal behaviour may play an important role in differentiating species along the continuum of isohydric to anisohydric behaviour; specifically, we show that non-stomatal and demand limitations may reduce stomatal conductance and increase leaf water potential, promoting wide safety margins characteristic of isohydric species. We used model results to develop a diagnostic framework to identify the most likely limiting mechanism to stomatal functioning during drought and showed that many of those features were commonly observed in field observations of tree water use dynamics. Direct comparisons of modelled and measured stomatal conductance further indicated that non-stomatal and demand limitations reproduced observed patterns of tree water use well for an isohydric species but that a hydraulic limitation likely applies in the case of an anisohydric species.


Occupational asthma due to zinc.
We describe a subject who developed asthma symptoms 2 yrs after being employed at a plant where metals were galvanized in heated zinc. The subject was not atopic. Baseline spirometry was normal three months after he left work but there was mild bronchial hyperresponsiveness to methacholine. Monitoring of forced expiratory volume in one second (FEV1) during a day at work showed a maximum fall in FEV1 of 24% at the end of the day and an increase in bronchial responsiveness on the following day. Environmental monitoring revealed that zinc and iron were present in the working environment at concentrations that were lower than the "threshold limit value-short term exposure level" (TLV-STEL) standards. Positive immediate skin tests to zinc sulphate at concentrations of 1 and 10 mg.ml-1 were obtained, although no specific immunoglobulin E (IgE) antibodies to zinc could be found. Skin tests with copper, chromium and cobalt were negative. Specific inhalation challenges were performed, having the subject inhale a solution of zinc sulphate at a 10 mg.ml-1 concentration for 6 min. An immediate reaction was elicited (maximum fall in FEV1 of 23%). We conclude that zinc can cause occupational asthma.


Older paternal ages and grandpaternal ages at conception predict longer telomeres in human descendants.
Telomere length (TL) declines with age in most human tissues, and shorter TL appears to accelerate senescence. By contrast, men's sperm TL is positively correlated with age. Correspondingly, in humans, older paternal age at conception (PAC) predicts longer offspring TL. We have hypothesized that this PAC effect could persist across multiple generations, and thereby contribute to a transgenerational genetic plasticity that increases expenditures on somatic maintenance as the average age at reproduction is delayed within a lineage. Here, we examine TL data from 3282 humans together with PAC data across four generations. In this sample, the PAC effect is detectable in children and grandchildren. The PAC effect is transmitted through the matriline and patriline with similar strength and is characterized by a generational decay. PACs of more distant male ancestors were not significant predictors, although statistical power was limited in these analyses. Sensitivity analyses suggest that the PAC effect is linear, not moderated by offspring age, or maternal age, and is robust to controls for income, urbanicity and ancestry. These findings show that TL reflects the age at the reproduction of recent male matrilineal and patrilineal ancestors, with an effect that decays across generations.


Assembly of robust bacterial microcompartment shells using building blocks from an organelle of unknown function.
Bacterial microcompartments (BMCs) sequester enzymes from the cytoplasmic environment by encapsulation inside a selectively permeable protein shell. Bioinformatic analyses indicate that many bacteria encode BMC clusters of unknown function and with diverse combinations of shell proteins. The genome of the halophilic myxobacterium Haliangium ochraceum encodes one of the most atypical sets of shell proteins in terms of composition and primary structure. We found that microcompartment shells could be purified in high yield when all seven H. ochraceum BMC shell genes were expressed from a synthetic operon in Escherichia coli. These shells differ substantially from previously isolated shell systems in that they are considerably smaller and more homogeneous, with measured diameters of 39±2nm. The size and nearly uniform geometry allowed the development of a structural model for the shells composed of 260 hexagonal units and 13 hexagons per icosahedral face. We found that new proteins could be recruited to the shells by fusion to a predicted targeting peptide sequence, setting the stage for the use of these remarkably homogeneous shells for applications such as three-dimensional scaffolding and the construction of synthetic BMCs. Our results demonstrate the value of selecting from the diversity of BMC shell building blocks found in genomic sequence data for the construction of novel compartments.


A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells.
There is increasing evidence that vascular endothelial growth factor (VEGF) has autocrine as well as paracrine functions in tumour biology. Vascular endothelial growth factor-mediated cell survival signalling occurs via the classical tyrosine kinase receptors Flt-1, KDR/Flk-1 and the more novel neuropilin (NP) receptors, NP-1 and NP-2. A 24-mer peptide, which binds to neuropilin-1, induced apoptosis of murine and human breast carcinoma cells, whereas a peptide directed against KDR had no effect. Both anti-NP1 and anti-KDR peptides induced endothelial cell apoptosis. Confocal microscopy using 5-(6)-carboxyfluorescein-labelled peptides showed that anti-NP1 bound to both tumour and endothelial cells, whereas anti-KDR bound endothelial cells only. This study demonstrates that NP-1 plays an essential role in autocrine antiapoptotic signalling by VEGF in tumour cells and that NP1-blockade induces tumour cell and endothelial cell apoptosis. Specific peptides can therefore be used to target both autocrine (tumour cells) and paracrine (endothelial cells) signalling by VEGF.