Reviewing the effects of food provisioning on wildlife immunity.
While urban expansion increasingly encroaches on natural habitats, many wildlife species capitalize on anthropogenic food resources, which have the potential to both positively and negatively influence their responses to infection. Here we examine how food availability and key nutrients have been reported to shape innate and adaptive immunity in wildlife by drawing from field-based studies, as well as captive and food restriction studies with wildlife species. Examples of food provisioning and key nutrients enhancing immune function were seen across the three study type distinctions, as were cases of trace metals and pharmaceuticals impairing the immunity of wildlife species. More generally, food provisioning in field studies tended to increase innate and adaptive responses to certain immune challenges, whereas patterns were less clear in captive studies. Mild food restriction often enhanced, whereas severe food restriction frequently impaired immunity. However, to enable stronger conclusions we stress a need for further research, especially field studies, and highlight the importance of integrating nutritional manipulation, immune challenge, and functional outcomes. Despite current gaps in research on this topic, modern high throughput molecular approaches are increasingly feasible for wildlife studies and offer great opportunities to better understand human influences on wildlife health.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'.


A randomized controlled trial for the use of thymus honey in decreasing salivary gland damage following radioiodine therapy for thyroid cancer: research protocol.
To test the effectiveness of thymus honey as a complementary intervention for decreasing the salivary gland damage due to Radioiodine ((131) I) therapy. Radioiodine is the treatment of choice in people diagnosed with thyroid cancer following total thyroidectomy. Although its value has been acknowledged in eradicating remnant thyroid tissue and treating residual disease in patients with visible, inoperable, iodine-avid metastases, it has been associated with various salivary gland side effects. This is a randomized controlled trial with a 2 × 3 mixed between-within subjects design. In total, 120 participants of postsurgical differentiated thyroid cancer, who will be referred to this centre for (131) I therapy to ablate the remnant thyroid tissue or to treat metastatic tumour, will be prospectively studied under varying regimens of lemon candy (standard treatment) and thymus honey mouthwashes (experimental intervention). Patients will be randomized in four equally numbered groups based on the assumptions and hypothesis of the study. The recruiting process will be informed by predefined inclusion and exclusion criteria. Mixed statistical modelling will be adopted taking into consideration between and within subjects' effects and repeated measures. The recommended intervention protocol is expected to improve the comprehensive management of salivary gland-related side effects induced by the radioiodine treatment in people diagnosed with thyroid cancer. Through the methodological approach chosen, the ideal intervention protocol in terms of the time to initiate the intervention and the frequency of the intervention to acquire optimal results in minimizing salivary glands damage will be tested.


[Use of millimeter wave therapy in treatment of acute pancreatitis].
The observations were performed in 226 patients with acute destructive pancreatitis. In 152 patients the medical complex was supplemented with a program of photo-millimeter-wave therapy in which the electromagnetic radiation of the millimeter diapason combined with red and green light was used with due regard for the disease stage. The inclusion of photo-millimeter-wave therapy in the complex of treatment starting from the 2-3 days of disease promoted a decrease of the systemic inflammatory reaction, rapidly improved the general condition of the patients, reduced the occurrence of infectious forms of pancreanecrosis, lethality and time of hospital staying of the patients. The inclusion of photo-millimeter-wave therapy since the 10-15th day did not influence the duration of hospitalization but resulted in more favorable course of the disease and less lethality.


Murine xenograft model for human uterine fibroids: an in vivo imaging approach.
Uterine fibroids are the most prevalent benign tumors in women of reproductive age. The current knowledge on the fibroid disease mechanism has derived from studies of the Eker rat model where a unique germ line defect in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene leads to the development of leiomyosarcoma, leiomyoma, and renal cancer. To study fibroids of human origin, we sought to establish fibroid xenografts in immune-compromised mice. We determined that lentiviral-mediated transduction of a green fluorescence protein (GFP)-luciferase (LUC) fusion gene and bioluminescence-based whole animal imaging allowed for the monitoring of transplanted fibroid cells in mice. We used this in vivo imaging approach to test a series of transplantation protocols and found that only freshly dissociated fibroid cells, but not the fibroid-derived smooth muscle cells grown in ex vivo cultures, can generate stable xenografts in subcutaneous Matrigel implants. Formation of the fibroid-xenografts requires the implantation of 17betaestradiol-releasing pellets in the recipient mice. Furthermore, freshly dissociated myometrial cells do not form xenografts under the experimental conditions. The xenograft protocol developed from this study provides an avenue for investigating the pathogenesis and drug responses of human fibroids.


EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines.
Allelic loss in chromosome 3p is one of the most frequent and earliest genetic events in lung carcinogenesis. We investigated if the loss of microRNA-128b, a microRNA located on chromosome 3p and a putative regulator of epidermal growth factor receptor (EGFR), correlated with response to targeted EGFR inhibition. Loss of microRNA-128b would be equivalent to losing a tumor suppressor gene because it would allow increased expression of EGFR. We initially showed that microRNA-128b is a regulator of EGFR in non-small-cell lung cancer (NSCLC) cell lines. We tested microRNA-128b expression levels by quantitative RT-PCR, genomic copy number by quantitative PCR, and mutations in the mature microRNA-128b by sequencing. We determined whether microRNA-128b loss of heterozygosity (LOH) in 58 NSCLC patient samples correlated with response to gefitinib and evaluated EGFR expression and mutation status. We determined that microRNA-128b directly regulates EGFR. MicroRNA-128b LOH was frequent in tumor samples and correlated significantly with clinical response and survival following gefitinib. EGFR expression and mutation status did not correlate with survival outcome. Identifying microRNA regulators of oncogenes could have far-reaching implications for lung cancer patients including improving patient selection for targeted agents, development of novel therapeutics, or development as early biomarkers of disease.


Immunosuppressive treatments in acute myocardial infarction and stroke.
Atherosclerosis is an inflammatory disease that involves formation of atherosclerotic lesions characterized by deposition of lipids and cell debris in the arterial wall, fibrosis and recruitment of various cell types including smooth muscle, endothelial, immune and foam cells. Progressive enlargement of the atherosclerotic plaques together with development of necrosis, intraplaque hemorrhage and ulceration results into rupture of the plaques, with subsequent exposure to thrombotic material and occlusion of the artery. These phenomena culminate in myocardial infarction when they occur in the coronary arteries or stroke when cerebral arteries are affected. Several lines of evidence indicated that innate and adaptive immunity tightly regulate atherogenesis. In particular, activated T cells influence the stability of the atherosclerotic plaque and promote disease progression. Experiments performed on suitable animal models allowed to identify CD4+ lymphocytes as the major T cell subpopulation involved in atherogenesis. Furthermore, immunophenotypic and functional analyses demonstrated that human and murine plaques contain predominantly CD4+ T Helper (TH)1 cells producing proinflammatory cytokines. Taken together, these observations have fostered the evaluation in preclinical models of whether or not immunosuppressive drugs may represent an efficacious therapeutic strategy for atherosclerosis-associated diseases. This review focuses on the role of innate and adaptive immunity in atherogenesis and atherosclerosis progression, and discusses the potential immunosuppressive approaches for the treatment of patients affected by acute myocardial infarction and stroke, with particular emphasis on the use of tacrolimus and stem cell transplantation.


Fractal measures of spatial pattern as a heuristic for return rate in vegetative systems.
Measurement of population persistence is a long-standing problem in ecology; in particular, whether it is possible to gain insights into persistence without long time-series. Fractal measurements of spatial patterns, such as the Korcak exponent or boundary dimension, have been proposed as indicators of the persistence of underlying dynamics. Here we explore under what conditions a predictive relationship between fractal measures and persistence exists. We combine theoretical arguments with an aerial snapshot and time series from a long-term study of seagrass. For this form of vegetative growth, we find that the expected relationship between the Korcak exponent and persistence is evident at survey sites where the population return rate can be measured. This highlights a limitation of the use of power-law patch-size distributions and other indicators based on spatial snapshots. Moreover, our numeric simulations show that for a single species and a range of environmental conditions that the Korcak-persistence relationship provides a link between temporal dynamics and spatial pattern; however, this relationship is specific to demographic factors, so we cannot use this methodology to compare between species.


Prognostic factors on overall survival in lymph node negative gastric cancer patients who underwent curative resection.
To assess independent prognostic factors for lymph node-negative metastatic gastric cancer patients following curative resection is valuable for more effective follow-up strategies. Among 1,874 gastric cancer patients who received curative resection, 967 patients were lymph node-negative. Independent prognostic factors for overall survival in lymph node-negative gastric cancer patients grouped by tumor invasion depth (early gastric cancer versus advanced gastric cancer) were explored with univariate and multivariate analyses. There was a significant difference in the distribution of recurrence pattern between lymph node-negative and lymph node-positive group. In the lymph node-negative group, the recurrence pattern differed by the depth of tumor invasion. In univariate analysis for overall survival of the early gastric cancer group, age, macroscopic appearance, histologic type, venous invasion, lymphatic invasion, and carcinoembryonic antigen level were significant prognostic factors. Multivariate analysis for these factors showed that venous invasion (hazard ratio, 6.695), age (≥59, hazard ratio, 2.882), and carcinoembryonic antigen level (≥5 ng/dl, hazard ratio, 3.938) were significant prognostic factors. Multivariate analysis of advanced gastric cancer group showed that depth of tumor invasion (T2 versus T3, hazard ratio, 2.809), and age (hazard ratio, 2.319) were prognostic factors on overall survival. Based on our results, independent prognostic factors such as venous permeation, carcinoembryonic antigen level, and age, depth of tumor invasion on overall survival were different between early gastric cancer and advanced gastric cancer group in lymph node-negative gastric cancer patients. Therefore, we are confident that our results will contribute to planning follow-up strategies.


Carotid baroreceptor stimulation: a promising approach for the management of resistant hypertension and heart failure.
Many difficult-to-treat clinical entities in the cardiovascular field are characterized by pronounced sympathetic overactivity, including resistant hypertension and heart failure, underlining the need to explore therapeutic options beyond pharmacotherapy. Autonomic modulation via carotid baroreceptor activation has already been evaluated in clinical trials for resistant hypertension, and relevant outcomes with regard to safety and efficacy of the technique are critically presented. The pathophysiological background of heart failure renders carotid baroreceptor stimulation a potential treatment candidate for the disease. Available data from animal models with heart failure point towards significant cardioprotective benefits of this innovative technique. Accordingly, the effects of baroreceptor activation treatment (BAT) on cardiac parameters of hypertensive patients are well-promising, setting the basis for upcoming clinical trials with baroreflex activation on patients with heart failure. However, as the potential therapeutic of BAT unfolds and new perspectives are highlighted, several concerns are raised that should be meticulously addressed before the wide application of this invasive procedure is set in the limelight.


[A confirmatory diagnosis of antibodies anti-Trypanosoma cruzi in donors referred by blood banks in Venezuela].
To establish the confirmatory diagnosis of Trypanosoma cruzi infection, at least two immunoserological tests (ELISA, Indirect hamaglutination, IH, Complement Fixation Test, CFT) were carried out in 254 donors, from public and private blood banks of Venezuela, during 48 months between 1997-1998 and 2003-2004, referred to the Immunology Section of the Tropical Medicine Institute in Caracas. Antibodies anti-T. cruzi were detected in 129/254 (50,79%) by ELISA-IgG or IH and CFT. The "artificial xenodiagnosis" was positive in 10/118 persons with positive confirmed serology. Of 129 donors found positive by the serological tests, 68 were living in the capital region and 61 in the interior of the country. Likewise 113 were born in the interior of the country, 8 in Caracas and 8 in Colombia. Of them, 12 individuals serologically confirmed declared to have donated blood in a minimum of 4 occasions before diagnosis. The present study emphasizes the importance of detection of antibodies against T. cruzi in the integral evaluation of blood donors, since many of them with antibodies anti-T. cruzi, have donated blood several times previous to diagnosis.


A novel framework for differentiating vessel-like objects in coronarography images.
Coronary Artery Disease is the leading cause of death worldwide. Its prevalence will grow while access to specialized medical care will be further limited due to staff shortages. Therefore, any facilitation of diagnosis or treatment is of paramount importance. The diagnosis based on Coronary Angiography can be automated to perform a quantitative evaluation of lesions. This requires precise segmentation of coronary arteries. At the moment, the state-of-the-art algorithms fail to eliminate vessel-like artifacts that are wrongly included in segmentation results (e.g. catheters, stitches). This is a bottleneck for the automatization of the diagnosis workflow that precedes clinical action. In this paper, we propose a 2-step post-segmentation refinement algorithm. A binary segmentation of the coronary arteries is used to extract image features - inputs for an XGBoost Classifier. Its predictions are improved by a neighborhood filter that leverages contextual information to assign correct labels. The algorithm is primarily concerned with differentiating vessels from other vessel-like objects and does so with a 99% accuracy rate. It takes advantage of an original local description of Tamura features, which proved to be one of the most influential factors in decision-making. As a result, the segmentation of coronary arteries is cleaned from artifacts, enabling AI-supported diagnosis workflows to be automated. After re-training, the proposed method can be used to eliminate post-segmentation artifacts in other medical domains.Clinical relevance- The algorithm proposed in this paper allows for the development of software that could automatically calculate the Syntax Score in real time. This would shorten diagnostics time and allow for immediate action in critical cases.


A Qualitative Study Exploring the Barriers and Facilitators for Maintaining Oral Health and Using Dental Service in People with Severe Mental Illness: Perspectives from Service Users and Service Providers.
People with severe mental illness suffer from a high burden of oral diseases, which can negatively impact their physical and mental well-being. Despite the high burden, they are less likely to engage in oral health care including accessing dental services. We aimed to identify both the service users' and service providers' perspective on the barriers and facilitators for maintaining oral health and dental service use in people with severe mental illness. Qualitative exploration was undertaken using dyadic or one-to-one in-depth interviews with service users in the UK with a diagnosis of schizophrenia, schizoaffective disorder or bipolar disorder. Service providers, including mental health and dental health professionals, and informal carers (people identified as family or friend who are not paid carers) were also interviewed. Thematic analysis of the data revealed three main cross-cutting themes at the personal, inter-personal and systems level: amelioration of the problem, using a tailored approach and provision of comprehensive support. The main barriers identified were impact of mental ill-health, lack of patient involvement and tailored approach, and accessibility and availability of dental services including lack of integration of services. The main facilitators identified were service providers' effective communication skills and further support through the involvement of carers. The findings suggest that the integration of dental and mental health services to provide tailored support for overall health and well-being, including the oral health of the patient, can better support people with severe mental illness regarding their oral health needs.


Clinical indicators in accreditation: an effective stimulus to improve patient care.
The Australian Council on Healthcare Standards (ACHS) established the Care Evaluation Program (CEP) of clinical performance measures in its accreditation program to increase the clinical component of that program and to increase medical practitioner involvement in formal quality activities in their health care organizations. From the introduction of a set of generic indicators in 1993 the program expanded through all of the various medical disciplines and from January 2000 there will be 18 sets (well over 200 indicators) in the program. More than half of Australia's acute hospitals (covering the majority of patient separations) are monitoring the indicators and reporting clinical data twice yearly to the ACHS. In turn they receive a 6-monthly feedback of aggregate and peer comparative results. The ACHS policy had no specific requirement for a set number of indicators to be monitored and it was not mandatory to achieve any specific data threshold to be accredited. However, where an organization's results differed unfavorably from those of its peers some action was expected. Qualitative information is also sent to the CEP and this has enabled a determination of the effectiveness of the indicators. There is documented evidence of improved management and numerous examples of improved patient outcomes. The program remains unique in the scope of the medical disciplines covered and in the formal provider involvement with indicator development. Both the clinical component of accreditation and clinician involvement in quality activities have been increased in an educational process. However, not all of the indicators are of equal value and a reduction in the number of indicators to a 'core' group of the most reliable and responsive ones is in process.


The Tempo and Mode of Adaptation in a Complex Natural Population: the Microbiome.
Adaptation is a fundamental process by which populations evolve to grow more fit in their environments. Recent studies are starting to show us that commensal microbes can evolve on short timescales of days and months, suggesting that ecological changes are not the only means by which microbes in complex natural populations respond to selection pressures. However, we still lack a complete understanding of the tempo and mode of adaptation in microbiomes given the many complex forces that natural populations experience, which include ecological pressures, changes in population size, spatial structure, and fluctuations in selection pressures. Advances in modeling complex populations and scenarios will allow us to understand adaptation not only in microbiomes but also more generically in other natural populations that experience similar complexities.


Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer.
Metastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis. Blood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival. We found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006). CYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.


The effect of microvesicular fatty change on liver regeneration after partial hepatectomy.
Hepatic resection for primary and secondary liver tumors and transplantation of segments of liver into patients with severe liver disease has become a common practice. However, the information on the regenerative potential of liver with various underlying diseases, particularly, the common disorder fatty change, is sparse. In the present study we have evaluated the regenerative potential of liver in mice lacking fatty acyl-CoA oxidase (AOX-/-) after partial hepatectomy. Liver regeneration was assessed by measuring mitotic activity and 5-bromo-2'-deoxyuridine (BrdU) labeling using immunohistochemistry. BrdU labeling index in AOX-/- mice was 99 +/- 32, 156 +/- 28, 54 +/- 13, and 120 +/- 33 per 1000 cells at 48, 60, 72 and 84 hours, respectively after partial hepatectomy. Comparable BrdU labeling index was observed in AOX+/+ mice. Similarly, mitotic index in both groups was comparable. These results suggest that DNA synthesis after partial hepatectomy in genetically altered mice with microvesicular fatty change is unaffected.


Predictors and Moderators of Post-traumatic Stress Disorder: An Investigation of Anxiety Sensitivity and Resilience in Individuals with Chronic Pain.
Anxiety sensitivity has been proposed as a psychological vulnerability factor for post-traumatic stress disorder (PTSD). Studies have also supported the protective role of resilience for overcoming the negative effects of trauma exposure. Given the linkages between anxiety sensitivity, resilience, trauma exposure and post-traumatic stress, this study explored the potential moderating roles of anxiety sensitivity and resilience on the association between trauma history and PTSD symptoms in a sample of individuals with chronic pain. A total of 100 patients with chronic pain were recruited from a large public hospital. Patients who had pain lasting for more than 3 months and a pain intensity rating of at least 4/10 were included. The study participants were administered measures of PTSD symptoms (PTSD Checklist - Civilian Version), resilience (Brief Resilient Coping Scale) and anxiety sensitivity (Anxiety Sensitivity Index). An analysis of outcome measures indicated that anxiety sensitivity and resilience were independently associated with PTSD symptoms, where βs were 0.57 and -0.23, respectively. The relationship between trauma and PTSD symptom severity was also moderated by anxiety sensitivity. Trauma history was associated with higher PTSD symptom severity only in those with high anxiety sensitivity. However, contrary to the hypotheses, resilience did not serve as a moderator. There are potential benefits of PTSD interventions that increase resilience and decrease anxiety sensitivity in individuals with chronic pain, especially for those who have experienced a traumatic event. Given that the presence of PTSD symptomatology in chronic pain populations negatively impact patient well-being, it would be important for clinicians to assess, monitor and treat PTSD in individuals with chronic pain.


The effect of lactate on the radiation response of CHO-K1 cells in culture.
The radiobiological effect of lactate is described. Prolonged incubation of CHO-K1 cells over a wide range of lactate concentrations sensitized them to subsequent irradiation. Survival curves indicated that the size of the shoulder was reduced. Short treatment times resulted in a radioprotective effect and an increase in the survival curve slope. Lactate levels used were within physiological limits and are therefore discussed in relation to their possible implications in radiobiology and radiotherapy.


Towards low-loss telecom-wavelength photonic devices by designing GaBixAs1-x/GaAs core-shell nanowires.
Nanowires are versatile nanostructures, which allow an exquisite control over bandgap energies and charge carrier dynamics making them highly attractive as building blocks for a broad range of photonic devices. For optimal solutions concerning device performance and cost, a crucial element is the selection of a suitable material system which could enable a large wavelength tunability, strong light interaction and simple integration with the mainstream silicon technologies. The emerging GaBixAs1-x alloys offer such promising features and may lead to a new era of technologies. Here, we apply million-atom atomistic simulations to design GaBixAs1-x/GaAs core-shell nanowires suitable for low-loss telecom-wavelength photonic devices. The effects of internal strain, Bi Composition (x), random alloy configuration, and core-to-shell diameter ratio (ρD) are analysed and delineated by systematically varying these attributes and studying their impact on the absorption wavelength and charge carrier confinement. The complex interplay between x and ρD results in two distinct pathways to accomplish 1.55 μm optical transitions: either fabricate nanowires with ρD≥ 0.8 and x∼ 15%, or increase x to ∼30% with ρD≤ 0.4. Upon further analysis of the electron hole wave functions, inhomogeneous broadening and optical transition strengths, the nanowires with ρD≤ 0.4 are unveiled to render favourable properties for the design of photonic devices. Another important outcome of our study is to demonstrate the possibility of modulating the strain character from a compressive to a tensile regime by simply engineering the thickness of the core region. The availability of such a straightforward knob for strain manipulation without requiring any external stressor component or Bi composition engineering would be desirable for devices involving polarisation-sensitive light interactions. The presented results document novel characteristics of the GaBixAs1-x/GaAs nanowires with the possibility of myriad applications in nanoelectronic and nanophotonic technologies.


Contributions of COMT Val¹⁵⁸ Met to cognitive stability and flexibility in infancy.
Adaptive behavior requires focusing on relevant tasks while remaining sensitive to novel information. In adult studies of cognitive control, cognitive stability involves maintaining robust cognitive representations while cognitive flexibility involves updating of representations in response to novel information. Previous adult research has shown that the Met allele of the COMT Val(158) Met gene is associated with enhanced cognitive stability whereas the Val allele is associated with enhanced cognitive flexibility. Here we propose that the stability/flexibility framework can also be applied to infant research, with stability mapping onto early indices of behavioral regulation and flexibility mapping onto indices of behavioral reactivity. From this perspective, the present study examined whether COMT genotype was related to 7-month-old infants' reactivity to novel stimuli and behavioral regulation. Cognitive stability and flexibility were assessed using (1) a motor approach task, (2) a habituation task, and (3) a parental-report measure of temperament. Val carriers were faster to reach for novel toys during the motor approach task and received higher scores on the temperament measure of approach to novelty. Met carriers showed enhanced dishabituation to the novel stimulus during the habituation task and received higher scores on the temperament measures of sustained attention and behavioral regulation. Overall, these results are consistent with adult research suggesting that the Met and Val alleles are associated with increased cognitive stability and flexibility, respectively, and thus suggest that COMT genotype may similarly affect cognitive function in infancy.


Systematic review and meta-analysis of islet autotransplantation after total pancreatectomy in chronic pancreatitis patients.
Islet autotransplantation (IAT) is a viable treatment for patients with severe chronic pancreatitis, this modality may prevent brittle diabetes mellitus after pancreatectomy. This systematic review and meta-analysis was performed to evaluated the outcomes of IAT after TP and discuss the factors that may affect the efficacy of this procedure. MEDLINE, Embase, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1977 to 30 April 2014. Cohort Studies reported patients with IAT after TP were included. The studies and data were identified and extracted by two reviewers independently. Data were analyzed using STATA 12.0 and Comprehensive Meta AnalysisV2 software. Random effects model, meta-regression analysis, sensitivity analysis and publication bias were conducted to improve the comprehensive analysis. Twelve studies reporting the outcomes of 677 patients were included in this review. The insulin independent rate for IAT after TP at last follow-up was 3.72 per 100 person-years (95% CI: 1.00-6.44). The 30-day mortality was 2.1% (95% CI: 1.2-3.8%). The mortality at last follow-up was 1.09 per 100 person-years (95% CI: 0.21-1.97). Factors associated with incidence density of insulin independence in univariate meta-regression analyses included islet equivalents per kg body weight (IEQ/kgBW) (P=0.026). Our systematic review suggests that IAT is a safe modality for patients with CP need to undergo TP. A significant number of patients will achieve insulin independence for a long time after receiving enough IEQ/kgBW.


Regulators of G Protein Signaling in Analgesia and Addiction.
Regulator of G protein signaling (RGS) proteins are multifunctional proteins expressed in peripheral and neuronal cells, playing critical roles in development, physiologic processes, and pharmacological responses. RGS proteins primarily act as GTPase accelerators for activated Gα subunits of G-protein coupled receptors, but they may also modulate signal transduction by several other mechanisms. Over the last two decades, preclinical work identified members of the RGS family with unique and critical roles in intracellular responses to drugs of abuse. New information has emerged on the mechanisms by which RGS proteins modulate the efficacy of opioid analgesics in a brain region- and agonist-selective fashion. There has also been progress in the understanding of the protein complexes and signal transduction pathways regulated by RGS proteins in addiction and analgesia circuits. In this review, we summarize findings on the mechanisms by which RGS proteins modulate functional responses to opioids in models of analgesia and addiction. We also discuss reports on the regulation and function of RGS proteins in models of psychostimulant addiction. Using information from preclinical studies performed over the last 20 years, we highlight the diverse mechanisms by which RGS protein complexes control plasticity in response to opioid and psychostimulant drug exposure; we further discuss how the understanding of these pathways may lead to new opportunities for therapeutic interventions in G protein pathways. SIGNIFICANCE STATEMENT: Regulator of G protein signaling (RGS) proteins are signal transduction modulators, expressed widely in various tissues, including brain regions mediating addiction and analgesia. Evidence from preclinical work suggests that members of the RGS family act by unique mechanisms in specific brain regions to control drug-induced plasticity. This review highlights interesting findings on the regulation and function of RGS proteins in models of analgesia and addiction.


Optimizing quality of life in patients with idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive and ultimately fatal lung disease. The combination of poor prognosis, uncertainty of disease course and severe symptom burden heavily impacts patients' and their families' quality of life. Though new antifibrotic drugs have been shown to decrease disease progression, the effect on health-related quality of life (HRQOL) has not been convincingly demonstrated. In a relentless disease such as IPF, striving to optimize HRQOL should complement the endeavour to prolong life. Unfortunately, there is a paucity of interventions improving symptoms and functionality for patients with IPF, and research focusing on symptom improvement, and assessing and optimizing HRQOL, is limited. This review summarizes the most recent insights into measuring and improving quality of life for patients with IPF, and discusses challenges in the management of this devastating disease. Moreover, we postulate a new model for continuous care in IPF - 'the ABCDE of IPF care': Assessing patients' needs; Backing patients by giving information and support; delivering Comfort care by focusing on treating symptoms and taking into account Comorbidities; striving to prolong life by Disease modification; helping and preparing patients and their caregivers for the eventual End-of-life events that are likely to occur.


Coformer-Dependent Physical Stability in a Series of Naringenin-Based Coamorphous Materials with Caffeine, Theophylline, and Theobromine.
To investigate the production and physical stability of coamorphous materials (CAM) of naringenin (NAR) and coformers-caffeine, theophylline or theobromine (CAF/THY/THE, respectively). We independently assessed the impact of moisture and temperature on the physical stability of CAMs, and transformation products after destabilization were examined. Neat grinding, liquid assisted grinding and water slurry were selected to prepare multi-component materials with NAR and CAF, THY or THE. The physical stability of CAMs was investigated at 65°C/<10%RH, 21°C/85% RH and 21°C/<10% RH. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were employed to monitor for recrystallization during the stability studies. Glass forming ability of amorphous NAR was assessed to understand CAM formation and physical stability. NAR:THY and NAR:THE CAMs showed physical stability for approximately nine months, under 21°C/<10% RH while NAR:CAF CAMs destabilized in 2.5 weeks. All CAMs recrystallized within a week at 65°C/<10%RH, and the physical stability at 21°C/85% RH was in the order of - NAR:THY > NAR:THE > NAR:CAF. NAR:THY produced 1:1 cocrystal under all storage conditions, while NAR:CAF destabilized to a 1:1 cocrystal at high RH but a physical mixture at high temperature. NAR:THE was found to recrystallize as a physical mixture in all conditions. NAR was found to be strong glass, with moderate kinetic fragility and good glass forming ability. Five naringenin-based multi-component solids were generated in this study: 3 new CAMs, 1 new cocrystal, and 1 previously reported cocrystal. Destabilization of CAMs was found to be exposure specific and coformer dependent.


Type of admission is associated with outcome of spontaneous subarachnoid hemorrhage.
Admitting facility may significantly affect outcome for spontaneous subarachnoid hemorrhage patients. We assessed outcomes of patients admitted directly to a comprehensive stroke center with those initially admitted to a general hospital and subsequently transferred. The comprehensive stroke center included a neurocritical care ICU, cerebrovascular neurosurgeons and endovascular specialists. We identified 107 consecutive spontaneous subarachnoid hemorrhage cases. Of these cases, 31 (29%) patients were admitted directly and 76 (71%) were transferred from general hospitals. Univariate and multivariate analyses evaluated differences in mortality, complications, discharge disposition, and in-hospital length of stay. Differences in baseline parameters (age, gender, admission Glasgow Coma Scale, Fisher grade, admission Hunt and Hess grade) were not statistically significant between direct-admit and transfer patients at our institution. Transferred patients developed vasospasm more frequently (58% vs. 32%; P < 0.05) and had a longer delay time to surgery (3.9-days vs. 2.4-days: P < 0.05). Multivariate analysis showed that the likelihood of vasospasm was significantly higher for transfer patients (OR 3.46, CI: 1.2-10.3, P = 0.03). In addition, longer in-hospital stays and higher odds of non-routine discharge were observed in transferred patients (P < 0.01). No differences in outcome could be identified for surgical vs. endovascular treatment rates between direct-admit and transfer patients. An association, but no causative link, can be made between the effect of transfer and the outcomes of SAH patients due to the retrospective nature of our study. Spontaneous subarachnoid hemorrhage patients admitted directly to our comprehensive stroke center showed less complications compared to those transferred from general hospitals. This improvement was independent of time to treatment. Additional research in multiple centers using prospective analysis should be conducted to confirm that preferential direct transport to a comprehensive stroke center would likely yield considerable improvements in public health.


Intracellular and extracellular acid-base status as a function of temperature in the freshwater channel catfish, Ictalurus punctatus.
The relationship between acid-base status and temperature was studied in the channel catfish, Ictalurus punctatus. The change in blood pH with temperature had a slope of -0.0132/degrees C and involved both a decrease in total CO2 at higher temperatures, and a significant rise in arterial PCO2. The acid-base changes in the intracellular compartment were similar to those in the blood, except that for red and white muscle the slope of the change in pH with temperature had a slightly higher value (-0.0185 and -0.0147, respectively), and for heart muscle it had a smaller value (-0.0117). The net whole-body excretion of acid or base in response to temperature change was relatively small: 0.40 m-mole . kg-1 net OH- was excreted in response to an increase from 22 to 31 degrees C, and 0.31 m-mole . kg-1 net H+ was excreted in response to change from 25 to 15 degrees C. In both cases approximately half was excreted renally and half branchially. Using information on the volumes and buffer capacities of the various body fluid compartments as well as the information above, the ratio of imidazole to phosphate intracellular buffers was calculated to be 5.1 to 1. The amount of intercompartmental (active) transfer required to make temperature adjustments is strongly dependent on the buffer ratio, and on the PCO2. Without the observed changes in PCO2 with temperature, the transfer requirement would have been 3 to 4 times larger.


Maternal Caffeine Consumption during Pregnancy and Risk of Low Birth Weight: A Dose-Response Meta-Analysis of Observational Studies.
Epidemiologic studies have shown inconsistent conclusions about the effect of caffeine intake during pregnancy on the risk of low birth weight (LBW). We performed a meta-analysis and linear-dose response analysis examining the association between caffeine consumption during pregnancy and risk of LBW. PubMed and EMBASE were searched for relevant articles published up to March 2014. Eight cohort and four case-control studies met all inclusion criteria. Using a random-effects model of the twelve studies, the pooled odds ratio (OR) for the risk of LBW comparing the highest versus lowest level of caffeine intake during pregnancy was 1.38 (95% CI: 1.10, 1.73). Linear dose-response analysis showed that every additional 100 mg of caffeine intake (1 cup of coffee or 2 cups of tea) per day during pregnancy was associated with a 3.0% increase in OR for LBW. There was a moderate level of overall heterogeneity with an I-squared value of 55% (95% CI: 13, 76%), and no evidence of publication bias based on Egger's test (P = 0.20) and the funnel plot. Thus, high caffeine intake during pregnancy is associated with a significant increase in the risk of LBW, and this risk appears to increase linearly as caffeine intake increases.


Health services utilization and cost utility analysis of a walking program for residential community elderly.
Promoting the health and improving the ability and confidence of the elderly to live independently can reduce health care expenditures and increase the health of society as a whole. However, the evidence to promote physical activity in order to promote health among the aged population is weak, especially in regards to the economic evaluation of a walking program. These researchers confirmed that the cost utility of a 12-week walking training program is acceptable. Therefore, an outpatient clinic-based walking program for older adults is worth promoting. Cost utility analysis is the critical evaluation method in exercise programs. Health professionals are encouraged to apply the integrated indicators such as the Health Utility Index and the Incremental Cost Utility Ratio to clarify the effects of health-promotion interventions.


Association of human fetuin-A rs4917 polymorphism with obesity in 2 cohorts.
Previous studies have shown association of the multifunctional hepatic protein α2HS-glycoprotein/human fetuin A with insulin resistance, type 2 diabetes mellitus, metabolic syndrome, obesity, and atherosclerosis. Reports of contribution of α2HS-glycoprotein/human fetuin A rs4917 single-nucleotide polymorphism to the development of these pathologic processes are inconsistent. We aimed to investigate the association between variants of rs4917 and parameters of obesity, lipid status, the proinflammatory cytokine tumor necrosis factor α (TNF-α), adipokines (adiponectin, resistin), and insulin resistance in 2 cohorts. Eighty-one healthy persons (cohort 1) and 157 patients with previous myocardial infarction (cohort 2) were included in this cross-sectional study. rs4917 Polymorphism was determined by the allele-specific KASP by design genotyping assays. In cohort 1, T-nucleotide carriers had lower low-density lipoprotein cholesterol levels compared with non-T carriers. The serum concentration of TNF-α was found to be higher carrying the non-T allele in cohort 1; however, this difference was not observed in cohort 2. In cohort 2, T carriers had lower body mass index and abdominal and waist circumferences than did non-T carriers. The T nucleotide was more frequent in nonobese than in obese patients (χ = 5.217, P = 0.022). Nonobese, nondiabetic T carriers still had lower body mass index and waist circumference than did non-T carriers. Our data suggest that the T nucleotide in rs4917 is associated with more favorable lipid status among healthy persons (i.e., lower low-density lipoprotein cholesterol) and anthropologic parameters of obesity in cohort 2. The protective role of the T allele may also be associated with lower TNF-α levels found in healthy individuals.


No evidence for local adaptation of dengue viruses to mosquito vector populations in Thailand.
Despite their epidemiological importance, the evolutionary forces that shape the spatial structure of dengue virus genetic diversity are not fully understood. Fine-scale genetic structure of mosquito vector populations and evidence for genotype × genotype interactions between dengue viruses and their mosquito vectors are consistent with the hypothesis that the geographical distribution of dengue virus genetic diversity may reflect viral adaptation to local mosquito populations. To test this hypothesis, we measured vector competence in all sympatric and allopatric combinations of 14 low-passage dengue virus isolates and two wild-type populations of Aedes aegypti mosquitoes sampled in Bangkok and Kamphaeng Phet, two sites located about 300 km apart in Thailand. Despite significant genotype × genotype interactions, we found no evidence for superior vector competence in sympatric versus allopatric vector-virus combinations. Viral phylogenetic analysis revealed no geographical clustering of the 14 isolates, suggesting that high levels of viral migration (gene flow) in Thailand may counteract spatially heterogeneous natural selection. We conclude that it is unlikely that vector-mediated selection is a major driver of dengue virus adaptive evolution at the regional scale that we examined. Dengue virus local adaptation to mosquito vector populations could happen, however, in places or times that we did not test, or at a different geographical scale.


Does Melatonin and Melatonin Agonists Improve the Metabolic Side Effects of Atypical Antipsychotics?: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
Atypical antipsychotics (AAPs) are increasingly used for the treatment of psychotic disorders but are known to be associated with metabolic abnormalities. This study is a systematic review and meta-analysis of randomized controlled trials (RCTs) studying the effectiveness of melatonin for the amelioration of AAP-induced metabolic syndrome. The MEDLINE (accessed via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials, PsycINFO, LILACS, CINAHL, and OpenGrey databases were searched for RCTs without language restrictions. Inclusion criteria were randomized, double-blind clinical trials comparing melatonin or melatonin agonists with placebo for the amelioration of AAP-induced effects at any age with selected components of metabolic syndrome as outcome measures. Two reviewers independently selected articles and assessed quality using Cochrane risk of bias and concealment tools. Of 53 records, five RCTs were eligible for the systematic review and three for the meta-analysis. The meta-analyses showed no statistically significant difference in any anthropometric or metabolic variable considered. Analysis according to psychiatric diagnosis from one RCT showed significant decreases in diastolic blood pressure (5.5 vs. -5.7 mmHg for the placebo and melatonin groups, respectively; p =0.001), fat mass (2.7 vs. 0.2 kg, respectively; p =0.032), and triglycerides (D) (50.1 vs. -20 mg/dl, respectively; p =0.08) in the bipolar group but not the schizophrenia group. Although limited to five RCTs with small sample sizes, evidence from RCT indicates that melatonin improves AAP-induced metabolic syndrome. This beneficial effect seems more significant in patients with bipolar disorder than those with schizophrenia. Further RCTs are needed to definitively establish the potential ameliorative effect of melatonin and to justify its efficacy as an add-on therapy to curtail AAP-induced metabolic syndrome.


Overexpression of MYC and BCL2 Predicts Poor Prognosis in Patients with Extranodal NK/T-cell Lymphoma, Nasal Type.
Background: Recently double-hit lymphoma or double protein expressor lymphoma has been identified as a distinct group of diffuse large B cell lymphoma with poor prognosis. However, the expression status, clinical and prognostic effect of combined overexpression of MYC and BCL2 in extranodal NK/T-cell lymphoma, nasal type (ENKTL) are not known. Materials and methods: Paraffin-embedded lymphoma samples from 53 patients with newly diagnosed ENKTL were studied using immunohistochemistry for MYC and BCL2, and fluorescent in situ hybridization (FISH) for MYC and BCL2 were done on 5 tissue sections with highest percentages of both MYC and BCL2 positive lymphoma cells. Results: The median percentage of MYC-positive lymphoma cells and BCL2-positive lymphoma cells were 20% (range, 5%-45%) and 70% (10%-95%), respectively. Using median scores as cutoffs, we assigned each patient an IHC double-hit score (DHS) that ranged from 0 to 2. Using this DHS, 15 patients (28.3%) had a DHS of 0, 24 patients (45.3%) had a DHS of 1, and the remaining 14 patients (26.4%) had a DHS of 2. FISH analysis was performed on 5 tissue sections with DHS of 2, and none of them had MYC or BCL2 rearrangement. The DHS was not associated with patients' age, gender, disease stage, LDH level, B symptoms, performance status, or local tumor invasiveness. However, patients with tumor localized in extranasal sites seemed to have higher expression of BCL2 and higher DHS than nasal lesions (p=0.014 and 0.042, respectively). In univariate survival analysis, either high expression of MYC or BCL2 was significantly correlated with inferior PFS and OS (p<0.05). According to the DHS, patients with ENKTL could be divided into three significantly different risk groups for PFS and OS (3-year PFS rate for DHS of 0, 1, and 2 was 60%, 41%, and 21%, respectively, p=0.008; 3-year OS rate for DHS of 0, 1, and 2 was 79%, 49%, and 33%, respectively, p=0.015). In multivariate survival analysis, it was found that DHS was an independent prognostic factor for both PFS and OS (p=0.006 and 0.011, respectively). Conclusions: Our study demonstrated that DHS can help identify patients with newly diagnosed ENKTL who are at a high risk for a poor clinical outcome, which needs to be validated in prospective clinical trials with patients treated uniformly.


Truck driving and bladder cancer mortality in rural New England.
The relationship between truck driving and bladder cancer mortality was investigated in a case-control study in New Hampshire and Vermont. In-person interviews were conducted with the next-of-kin of 325 bladder cancer cases and 673 controls who died during 1975-79. There were 35 cases and 53 controls who had ever been employed as truck drivers [odds ratio (OR)=1.5, 95% confidence interval (CI)=0.9, 2.6]. There was a statistically significant, but inconsistent, positive association between number of years of truck driving and the OR's, rising to 2.3 (1.2,4.1) for 5 years or more of truck driving. Risk was greatest in men who began driving in the 1930's and 1940's (OR=2.6, 95% CI=1.3,5.1) and among residents of two of the most urbanized counties (OR=3.0, 95% CI=1.2,7.4). The association of bladder cancer with truck driving was unaffected by control for possible confounding factors, such as cigarette smoking and coffee drinking. It was not possible to determine whether the risks associated with truck driving were specifically due to diesel fumes. Truck drivers reporting diesel exposures had an OR=1.8 (95% CI=0.5,7.0), but those without diesel exposure still had an OR=1.5 (95% CI=0.8,2.7). Twenty-six cases and 39 controls reported exposure to diesel emissions in any occupation (OR=1.5, 95% CI=0.8,2.8), and a significant duration-response relationship was seen, rising to threefold for those employed in such jobs for 30-39 years.


Phage-Host Interaction Analysis Using Flow Cytometry.
Phage-host interactions are commonly evaluated by culture-based methods. However, these techniques are very laborious and time-consuming. Therefore, other time-efficient, not labor-intensive, and cost-effective methods have been developed.This chapter describes the methodology used to assess the susceptibility of planktonic cultures of bacteria to phage infection and to study their interactions over time by flow cytometry.


Anergy and not clonal ignorance determines the fate of B cells that recognize a physiological autoantigen.
Autoantibodies to insulin arise spontaneously in the insulin autoimmune syndrome and in type I diabetes. In addition, administration of insulin to individuals without autoimmune disease routinely results in Abs that bind autologous hormone. These observations and findings in transgenic models of tolerance led to an inference that physiological levels of hormones and growth factors, such as insulin, are not sufficient to induce tolerance in B cells, a state termed clonal ignorance. In contrast, we have discovered that virtually all conventional B cells expressing a low affinity anti-insulin transgene interact with endogenous insulin and are effectively silenced for Ig production and for T cell-dependent immune responses. A fraction of transgenic B cells escapes silencing and functions autonomously to produce insulin Abs that may lower fasting blood sugars similar to an insulin autoimmune syndrome. These B cells have characteristics of a B1-like subset and are depleted by hypotonic peritoneal lysis. These findings question the concept of clonal ignorance and show that physiological concentrations of Ag may effectively silence conventional B cells even when the affinity for autoantigen is low. Self-reactivity may arise in the repertoire because of compartmental differences that govern the fate of B cells and not as a result of true clonal ignorance.


Characterization of β-d-N4-Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus.
Chikungunya virus (CHIKV) represents a reemerging global threat to human health. Recent outbreaks across Asia, Europe, Africa, and the Caribbean have prompted renewed scientific interest in this mosquito-borne alphavirus. There are currently no vaccines against CHIKV, and treatment has been limited to nonspecific antiviral agents, with suboptimal outcomes. Herein, we have identified β-d-N4-hydroxycytidine (NHC) as a novel inhibitor of CHIKV. NHC behaves as a pyrimidine ribonucleoside and selectively inhibits CHIKV replication in cell culture.


Effects of copper, cadmium, and zinc on the hatching success of brine shrimp (Artemia franciscana).
Previous studies indicate that the hatching success of brine shrimp (Artemia franciscana) cysts is surprisingly sensitive to ambient metal concentrations. These studies estimated median effective concentrations (EC50s) of 7, 5, and 28 microg l-1 for Cd, Cu, and Zn, suggesting that the hatching end point for A. franciscana is the most sensitive tested to date for Cd and Zn in saline environments and comparable in sensitivity with the most sensitive tested to date for Cu. Furthermore, these data suggest that brine shrimp are at significant risk from Cu and Zn in Great Salt Lake (GSL), UT, where ambient concentrations as high as 10 and 14 microg l-1, respectively, have been measured. Given that brine shrimp appear to be successfully reproducing in GSL, we hypothesized that these toxicity values were either biased low as a result of an artifact of the test method used or that site-specific water-quality conditions in the lake had decreased metal bioavailability such that brine shrimp could successfully reproduce. To test these hypotheses, we initiated a step-wise series of experiments. First we investigated the effects of pretreatment of brine shrimp cysts with antibiotics on brine shrimp sensitivity to metals because previous investigators as part of their test methods have used antibiotics. Next we considered the effect of ionic composition of the artificial test media on sensitivity. Finally, we evaluated the effects of the site-specific water quality of the GSL on metal bioavailability and toxicity. Results indicate that pretreatment of cysts with antibiotics had no effect on sensitivity. However, we were unable to repeat the previous values for Cd and Zn, obtaining EC50s of 11,859 and 289 microg l-1 for Cd and Zn, respectively. For Cu, however, we estimated an EC50 of 12 microg l-1, so we conducted further testing on the artificial media, adjusting the media composition to better reflect the Ca2+ and HCO3- concentration of normal seawater. This increased the EC50 to 28 microg l-1. Finally we evaluated the toxicity of Cu in GSL water and obtained an EC50 of 68 microg l-1, suggesting that the increased dissolved organic carbon in GSL has a significant protective effect. Overall, the results of this study suggest that brine shrimp hatching success is not particularly sensitive to Cd and Zn, but it is sensitive to Cu. However, site-specific water-quality conditions ensure that brine shrimp cyst hatching success is not significantly affected by any of these metals at the normal background concentrations that occur in GSL (<15 microg l-1).


A "FLP-Out" system for controlled gene expression in Caenorhabditis elegans.
We present a two-part system for conditional FLP-out of FRT-flanked sequences in Caenorhabditis elegans to control gene activity in a spatially and/or temporally regulated manner. Using reporters, we assess the system for efficacy and demonstrate its use as a cell lineage marking tool. In addition, we construct and test a dominant-negative form of hlh-12, a gene that encodes a basic helix-loop-helix (bHLH) transcription factor required for proper distal tip cell (DTC) migration. We show that this allele can be conditionally expressed from a heat-inducible FLP recombinase and can interfere with DTC migration. Using the same DTC assay, we conditionally express an hlh-12 RNAi-hairpin and induce the DTC migration defect. Finally, we introduce a set of traditional and Gateway-compatible vectors to facilitate construction of plasmids for this technology using any promoter, reporter, and gene/hairpin of interest.


Genital candidiasis: topical management with clotrimazole.
Clotrimazole was administered in the form of 100 mg tablets to patients with vaginal candidiasis, and in the form of a 1% solution to patients with cutaneous candidiasis of the genital and perigenital areas. The clinical and mycological response observed and the excellent tolerance and lack of side effects indicate that clotrimazole may be proposed as a treatment for candidiasis.


Flexible esophagoscopy as a diagnostic tool for traumatic esophageal injuries.
The management and clinical outcome of patients suffering esophageal trauma depends on a prompt diagnosis. The detection of esophageal injuries by clinical examination, esophagography, or computed tomography is limited. This study aimed to assess the yield and clinical utility of flexible esophagoscopy (FE) in the diagnosis of traumatic esophageal injuries. During 7 years, we conducted a retrospective (1998-2003) and prospective (2003-2005) study of 163 victims admitted to a trauma hospital, and submitted to FE because of suspected esophageal trauma. Esophageal injury was defined as laceration or perforation, hematoma, abrasion, hematin spots, or ecchymosis. The endoscopic diagnosis was compared with surgical findings or clinical follow-up. No traumatic lesion was observed in 139 patients (85.3%), esophageal injuries were detected in 23 (14.1%), and one examination was inconclusive (esophageal stricture, 0.6%). Lacerations were detected in 14 patients and confirmed surgically. Esophageal contusion was observed in nine patients and out of these, five patients underwent surgical exploration and four were managed nonoperatively. The assessment of esophageal injury by FE demonstrated 95.8% sensitivity, 100% specificity, 99.3% accuracy, 100% positive predictive value, and 99.2% negative predictive value. The likelihood ratio for a negative examination was 0.041 and the Youden J Index was 99.2%. FE appears to be an accurate diagnostic tool in the assessment of esophageal injuries. Two main lesions were noted: laceration and contusion. Laceration requires surgical repair. Contusion represents a nonperforative injury of the esophageal wall, requires correlation with computed tomography, and may be managed nonoperatively.


Hypothesis: differentiation of the human lymphoid system based on cell surface markers.
Human lymphocytes can be separated into distinct populations based upon receptors on their cell surface. Thymus-derived (T-cell) lymphocytes can be identified by their ability to form rosetts with sheep erythrocytes (SRBC); bone marrow-derived (B-cell) lymphocytes bear characteristic surface markers for immunoglobulin, complement, and the Fc portion of IgG. Recently, populations of lymphocytes having either multiple markers or no detectable markers (null cells) have been observed. Based on studies of cell surface markers, a scheme is proposed that expands the known differentiation of the lymphod cell to include subpopulations which represent developmental stages. It is suggested that lymphocyte maturation involves alloantigenic changes in a circulating stem cell-drived nill cell, leading to a cell bearing markers for both T- and B-cells. It is from this latter cell that the classic T- and B-cells ultimately arise. Maturational defects which may explain the origin of primary lymphoproliferative diseases are discussed.


Directing an appropriate immune response: the role of defense collagens and other soluble pattern recognition molecules.
Defense collagens and other soluble pattern recognition receptors contain the ability to recognize and bind molecular patterns associated with pathogens (PAMPs) or apoptotic cells (ACAMPs) and signal appropriate effector-function responses. PAMP recognition by defense collagens C1q, MBL and ficolins leads to rapid containment of infection via complement activation. However, in the absence of danger, such as during the clearance of apoptotic cells, defense collagens such as C1q, MBL, ficolins, SP-A, SP-D and even adiponectin have all been shown to facilitate enhanced phagocytosis and modulate induction of cytokines towards an anti-inflammatory profile. In this way, cellular debris can be removed without provoking an inflammatory immune response which may be important in the prevention of autoimmunity and/or resolving inflammation. Indeed, deficiencies and/or knock-out mouse studies have highlighted critical roles for soluble pattern recognition receptors in the clearance of apoptotic bodies and protection from autoimmune diseases along with mediating protection from specific infections. Understanding the mechanisms involved in defense collagen and other soluble pattern recognition receptor modulation of the immune response may provide important novel insights into therapeutic targets for infectious and/or autoimmune diseases and additionally may identify avenues for more effective vaccine design.


Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain.
The ionotropic glutamate receptor (GluR) subunits GluR2, GluR5 and GluR6 are subject to RNA editing at their Q/R sites, resulting in significant alterations in the channel properties of the receptors. RNA editing at the Q/R site of GluRs is both developmentally and regionally regulated. Here we provide the first quantitative measurements of both mRNAs of the GluR subunits and mRNAs of the RNA editing enzymes ADAR1-ADAR3 in a comparison of the efficiency of editing at the Q/R site with the expression levels of ADAR mRNA in human brain. We demonstrate that the Q/R site of GluRs in white matter is edited significantly less than in grey matter. In addition, by means of quantitative reverse transcription-polymerase chain reaction methods, we demonstrate that the relative abundance of ADAR2 mRNA to GluR2 mRNA is significantly lower in white matter than in grey matter and that the GluR2 Q/R site editing decreased only when the ratio of ADAR2 mRNA (not that of ADAR1 mRNA) to GluR2 mRNA dropped below a threshold (20 x 10(-3)). These results suggest that Q/R site of GluRs editing is regulated in a regional, and hence presumably cell-specific, manner and that the GluR2 Q/R site editing is critically regulated by ADAR2 in human brain.


Expression and distribution of the type 1 and type 3 inositol 1,4, 5-trisphosphate receptor in developing vascular smooth muscle.
The recent discoveries of inositol 1,4,5-trisphosphate (IP3) receptor subtypes with different affinities for IP3 and their potential involvement in development has important consequences for vascular smooth muscle. This study has examined the expression and distribution of the type 1 and type 3 IP3 receptor subtypes in developing rat vascular smooth muscles. Immunoblotting of portal vein and aorta from neonatal (2 to 4 days) and fully developed (6 weeks) rats revealed significantly higher levels of the type 3 IP3 receptor expression in neonatal, compared with developed, vascular smooth muscles. In contrast, expression of the type 1 IP3 receptor in neonates was lower compared with developed vascular smooth muscles. Immunolocalization of the type 3 IP3 receptors in neonatal tissues revealed that staining corresponded to the distribution of the sarcoplasmic reticulum (visualized by osmium ferricyanide staining of thin tissue sections), which suggested localization of the type 3 IP3 receptor throughout the sarcoplasmic reticulum network. We conclude that type 3 IP3 receptors are the predominant subtype in the development of vascular smooth muscle and are distributed throughout the sarcoplasmic reticulum in these cells. The switch in isoforms of the IP3 receptor during development from the type 3 with low affinity for IP3 to the higher-affinity type 1 receptor may play a role in calcium-mediated regulation of developing vascular smooth muscle.


[Recombinant monoclonal antibodies to the Lassa virus: the formation of reactive paratopes].
Eighteen hybrid lines secreting recombinant monoclonal antibodies to Lassa virus were produced by fusion of mouse splenocytes with antibody-secreting X-63 myeloma cells. Interrelations between the structure and reactivity of the antibodies were studied by different serological and immunochemical methods. Monoclonal antibodies were divided into different groups according to their serological properties and macromolecular structure. A comparative analysis of the structure and reactivity of the recombinant monoclonal antibodies showed that the light and heavy Ig-specific chains could form the reactive antibodies when the chains were present in different paratopes of Ig molecules.


The process of apoptosis in a holocrine gland as shown by the avian uropygial gland.
This study was designed to elucidate the presence of apoptosis and the localization of apoptosis-related Bax and survivin proteins and proliferating cell nuclear antigen (PCNA) within the chicken uropygial gland, a specialized holocrine secretory gland. In day-old chicks, survivin and Bax immunoreactivities were observed in the cell cytoplasm of the germinative and secretory layers of the luminal epithelium and tubules. During this period, the TUNEL reaction, an indication of apoptosis, was only sporadically positive in the tubules. From the 7th day to the 150th day of posthatching, survivin was detected in the cytoplasm of cells in the germinative layer and in the nuclei of some cells in the secretory layers of the gland. The germinative layer cells showed weak homogeneous cytoplasmic staining for Bax, whereas the cells of the secretory and intermediate layers of luminal epithelium and tubules exhibited granular cytoplasmic staining. After day 7, TUNEL-positive cells were observed in the secretory and degenerative layers of the luminal epithelium and central tubules. After day 12, some TUNEL-positive cells were also seen in the peripheral tubules. At all posthatch ages, the cytoplasm and nucleus of the germinative layers of luminal epithelium and tubules reacted with PCNA, whereas only a small number of cell nuclei in the secretory layers were immunopositive. These results support the theory that specific PCNA/Bax/survivin expression patterns could reflect particular cell differentiation states in the uropygial gland and that holocrine secretion in the gland is realized mainly by way of apoptosis.


[Isolation, purification and properties of acid deoxyribonuclease from silkworm Bombyx mori eggs].
The acid deoxyribonuclease was isolated from Bombyx mori eggs and its physico-chemical properties were investigated. The enzyme purified 160-fold did not contain admixtures of phosphomono- and phosphodiesterases or ribonuclease. The molecular weight of the enzyme is 40 000 +/- 1000, isoelectric point lies at 6.5. The maximum activity is revealed at pH 5.2, 50 degrees. The DNAase is insignificantly activated by Mg2+ and is inhibited by Cu2+ and Zn2+. The enzyme preferentially hydrolyzes native DNA and is an endonuclease splitting DNA down to 5'-oligonucleotides.


4-(1H)-Quinolones and 1,2,3,4-Tetrahydroacridin-9(10H)-ones prevent the transmission of Plasmodium falciparum to Anopheles freeborni.
Malaria kills approximately 1 million people a year, mainly in sub-Saharan Africa. Essential steps in the life cycle of the parasite are the development of gametocytes, as well as the formation of oocysts and sporozoites, in the Anopheles mosquito vector. Preventing transmission of malaria through the mosquito is necessary for the control of the disease; nevertheless, the vast majority of drugs in use act primarily against the blood stages. The study described herein focuses on the assessment of the transmission-blocking activities of potent antierythrocytic stage agents derived from the 4(1H)-quinolone scaffold. In particular, three 3-alkyl- or 3-phenyl-4(1H)-quinolones (P4Qs), one 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), and one 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) were assessed for their transmission-blocking activity against the mosquito stages of the human malaria parasite (Plasmodium falciparum) and the rodent parasite (P. berghei). Results showed that all of the experimental compounds reduced or prevented the exflagellation of male gametocytes and, more importantly, prevented parasite transmission to the mosquito vector. Additionally, treatment with ICI 56,780 reduced the number of sporozoites that reached the Anopheles salivary glands. These findings suggest that 4(1H)-quinolones, which have activity against the blood stages, can also prevent the transmission of Plasmodium to the mosquito and, hence, are potentially important drug candidates to eradicate malaria.


Adult and near-adult height in patients with severe insulin-like growth factor-I deficiency after long-term therapy with recombinant human insulin-like growth factor-I.
Treatment with recombinant human insulin-like growth factor-I (IGF-I) stimulates linear growth in children with severe IGF-I deficiency (IGFD). To evaluate the efficacy and safety of treatment with IGF-I in patients with severe IGFD treated until adult or near-adult height. Twenty-one children with severe IGFD were treated until adult or near-adult height under a predominantly open-label design. All patients were naive to IGF-I. Recombinant human IGF-I was administered subcutaneously in doses between 60 and 120 µg/kg twice daily. Nine patients received additional therapy with gonadotropin- releasing hormone (GnRH) analog for a mean period of 2.9 ± 1.8 years. Mean duration of treatment was 10.0 years. Mean height velocity increased from 3.1 cm/year prior to treatment to 7.4 cm/year during the first year of treatment. Height velocities during the subsequent years were lower, but remained above baseline for up to 12 years. Cumulative mean Δ height SD score at (near) adult height was +2. The observed mean gain in height was 13.4 cm more than had been expected without treatment. The adult height achieved by the patients also treated with GnRH analog was not different from those who received IGF-I therapy alone. There were no new safety signals identified in these patients, a subset of those previously reported. Long-term therapy with IGF-I improves adult height of patients with severe IGFD. Most patients did not bring their heights into the normal adult range.


A dynamic approach to fluid and electrolyte management of the newborn.
The most constant feature of neonatal physiology and pathophysiology is change. To meet the needs of each individual baby we must first arm ourselves with knowledge of neonatal physiology and pathophysiology. Next, the effects of the applied fluid program are continually monitored and the program accordingly readjusted. We must "read the book" and then "read the baby." This paper discusses the results of "reading the book" and proposes a tentative dynamic fluid and electrolyte program. The "reading of the baby" is beyond the scope of this paper, but should be simple, utilizing commonly available methods that can safely be done as frequently as every four to eight hours including repeated physical examinations, simple laboratory tests in blood and urine, and the determination of the body weight.


Multicenter prospective phase II trial of concurrent chemoradiotherapy with weekly low-dose carboplatin for cisplatin-ineligible patients with advanced head and neck squamous cell carcinoma.
The optimal chemotherapy regimen in concurrent chemoradiotherapy (CCRT) for cisplatin-ineligible head and neck squamous cell carcinoma (HNSCC) has not been established. We aimed to evaluate the feasibility, efficacy, and safety of CCRT with weekly low-dose carboplatin for the treatment of advanced HNSCC in patients who are cisplatin-ineligible. This prospective phase II study enrolled adult patients (age ≥ 20 years) with HNSCC receiving whole-neck irradiation including bilateral levels II-IV and who were aged (≥ 75-year-old patients with 40 mL/min estimated glomerular filtration rate [eGFR] or better) or had renal dysfunction (< 75-year-old patients with 30-60 mL/min eGFR). Carboplatin was administered weekly (area under the plasma concentration-time curve = 2.0) for up to seven cycles during concurrent radiotherapy (70 Gy/35 Fr). The primary endpoint was the completion rate of CCRT. Secondary endpoints included overall response rate and incidence of adverse events. Among the 30 patients enrolled, 28 were men. The median age was 73.5 years. Seventeen patients were < 75 years whereas 13 were ≥ 75 years old. The completion rate of CCRT was 90%. The overall response rate was 90%. Grade 3 adverse events that occurred in 10% or more patients were oral/pharyngeal mucositis (47%), leukocytopenia (20%), and neutropenia (10%). Grade 4 adverse events occurred in one patient (elevation of alanine aminotransferase level). No treatment-related deaths occurred. CCRT with weekly low-dose carboplatin is a promising treatment option, with favorable feasibility, efficacy, and acceptable toxicity, for patients who are cisplatin-ineligible with advanced HNSCC. jRCTs031190028.


The Effect of Aquaporin 1-Inhibition on Vasculogenic Mimicry in Malignant Mesothelioma.
Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes, with poor overall survival and quality of life. Limited targeted treatment strategies exist due to restricted knowledge of pathogenic pathways. Vasculogenic mimicry (VM) is a newly described phenomenon associated with increased aggressiveness in other malignancies, and has been characterized in MM. Normal mesothelium expresses aquaporin 1 (AQP1) and retained expression has been associated with improved survival in MM. AQP1 is expressed by normal vascular endothelium and is involved in mediating MM cell motility and proliferation. We investigated the role of AQP1 in VM, and its interaction with the pro-angiogenic factor vascular endothelial growth factor A (VEGFA), which is variably expressed in MM. Matrigel VM assays were performed using NCI-H226 and NCI-H28 MM cell lines and primary cells in hypoxia and normoxia. The synthetic blocker AqB050 and siRNA were used to inhibit AQP1, and bevacizumab was used to inhibit VEGF. Inhibition of AQP1 resulted in increased VEGFA secretion by MM cells and reduced VM in MM cell lines in hypoxia but not normoxia. No change in VM was seen in MM primary cells. Combined inhibition of AQP1 and VEGF had no effect on VM in normoxia. In a heterotopic xenograft mouse model, AqB050 treatment did not alter vessel formation. AQP1 may interact with VEGFA and play a role in VM, especially under hypoxic conditions, but the heterogeneity of MM cells may result in different dominant pathways between patients.


Long term preservation of femoral bone following hemiresurfacing.
Long term femoral fixation, bone remodeling and neck preservation are demonstrated histologically in three hips treated with hemiresurfacing. They were performed in young patients for Ficat stage III or early IV osteonecrosis as a "time buying procedure". The cases were revised after 13, 16 and 22 years because of cartilage wear which was anticipated. One head was resurfaced using titanium and two with custom alumina ceramic components. Fixation was achieved using early bone cleansing and cementing techniques. Retrieval analysis found remarkable preservation of bone stock and viability without neck narrowing.


Does access to improved sanitation reduce childhood diarrhea in rural India?
Almost nine million children under 5 years of age die every year. Diarrhea is considered to be the second leading cause of under-five mortality in developing countries. About one out of five deaths is caused by diarrhea. In this paper, we use the newly available data set District Level Household Survey 3 to quantify the impact of access to improved sanitation on diarrheal morbidity for children less than 5 years of age in India. Using propensity score matching, we find that access to improved sanitation reduces the risk of contracting diarrhea by 2.2 percentage points. There is considerable heterogeneity in the impacts of improved sanitation. We find statistically insignificant treatment effects for children in low or middle socioeconomic status households and for girls; however, boys and children in high socioeconomic status households experienced economically significant treatment effects. The magnitude of the treatment effect differs largely by hygiene behavior.


Phyllodulcin, a Natural Sweetener, Regulates Obesity-Related Metabolic Changes and Fat Browning-Related Genes of Subcutaneous White Adipose Tissue in High-Fat Diet-Induced Obese Mice.
Phyllodulcin is a natural sweetener found in Hydrangea macrophylla var. thunbergii. This study investigated whether phyllodulcin could improve metabolic abnormalities in high-fat diet (HFD)-induced obese mice. Animals were fed a 60% HFD for 6 weeks to induce obesity, followed by 7 weeks of supplementation with phyllodulcin (20 or 40 mg/kg body weight (b.w.)/day). Stevioside (40 mg/kg b.w./day) was used as a positive control. Phyllodulcin supplementation reduced subcutaneous fat mass, levels of plasma lipids, triglycerides, total cholesterol, and low-density lipoprotein cholesterol and improved the levels of leptin, adiponectin, and fasting blood glucose. In subcutaneous fat tissues, supplementation with stevioside or phyllodulcin significantly decreased mRNA expression of lipogenesis-related genes, including CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferator activated receptor γ (PPARγ), and sterol regulatory element-binding protein-1C (SREBP-1c) compared to the high-fat group. Phyllodulcin supplementation significantly increased the expression of fat browning-related genes, including PR domain containing 16 (Prdm16), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), compared to the high-fat group. Hypothalamic brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) signaling was upregulated by phyllodulcin supplementation. In conclusion, phyllodulcin is a potential sweetener that could be used to combat obesity by regulating levels of leptin, fat browning-related genes, and hypothalamic BDNF-TrkB signaling.


Gastric residual in growing preterm infants: effect of body position.
Studies of the effect of body position during and after bolus feeding upon gastric emptying or gastric residual have not had consistent results. We tested the hypotheses that right lateral decubitus leads to less gastric residual than left lateral decubitus and that the prone position leads to less gastric residual than the supine position. A prospective randomized clinical trial with triple crossover of healthy growing, appropriate for gestational age preterm infants. Each infant was successively studied while fed in the four different positions. Gastric residuals were measured at 1 and 3 hours after initiation of feeding and returned. Thirty-one patients were studied. At 1 hour, right lateral decubitus led to less significant residuals than the left lateral decubitus and the prone position led to less residual than the left lateral decubitus. The amount of gastric residuals 1 hour after a meal appears to be in the following decreasing order: left, supine, prone, right.


Assessing ecological effects of radionuclides: data gaps and extrapolation issues.
By inspection of the FASSET database on radiation effects on non-human biota, one of the major difficulties in the implementation of ecological risk assessments for radioactive pollutants is found to be the lack of data for chronic low-level exposure. A critical review is provided of a number of extrapolation issues that arise in undertaking an ecological risk assessment: acute versus chronic exposure regime; radiation quality including relative biological effectiveness and radiation weighting factors; biological effects from an individual to a population level, including radiosensitivity and lifestyle variations throughout the life cycle; single radionuclide versus multi-contaminants. The specificities of the environmental situations of interest (mainly chronic low-level exposure regimes) emphasise the importance of reproductive parameters governing the demography of the population within a given ecosystem and, as a consequence, the structure and functioning of that ecosystem. As an operational conclusion to keep in mind for any site-specific risk assessment, the present state-of-the-art on extrapolation issues allows us to grade the magnitude of the uncertainties as follows: one species to another > acute to chronic = external to internal = mixture of stressors > individual to population > ecosystem structure to function.


Real-time multichannel neural spike recognition with DSPs.
Data acquisition technology that uses relatively inexpensive digital signal processors (DSPs) for the rapid acquisition of neuronal action potential (spike) data was investigated. Three spike sorting techniques were considered. The simplest classification routine tested was peak windowing. Spikes were considered to belong to the same class when their peak amplitude fell within a user-specified interval. Another approach required computing the RMS error between stored templates of each unit's spike waveform and the spike most recently detected. The new spike was classified according to the minimum of the RMS errors computed. In the third algorithm, two optimal coefficient vectors, called principal components, were computed from previously acquired template waveforms and stored. These principal components were used to compute two vector products for each newly detected spike waveform vector. The resulting two values were features that were used to classify the waveform. The test system that was constructed is described, and results obtained with each of the algorithms are compared and evaluated.


Polymer-optical-fiber-based sensor system for simultaneous measurement of angle and temperature.
This paper presents a polymer-optical-fiber (POF)-based sensor system for simultaneous measurement of angle and temperature. The main contribution is obtaining a sensor with higher temperature sensitivity and lower hysteresis on the angle measurements. The annealing was made on the fibers under the conditions of low relative humidity and under water, and a third set of samples without any heat treatment was applied for comparison with the annealed ones. Results of temperature and angle characterization show that the fibers annealed under water presented higher temperature sensitivity and lower errors when compared with the fibers annealed with low humidity or the fibers without annealing. Furthermore, the fibers annealed under water also presented lower hysteresis on the angle characterization. For these reasons, such fibers were employed for the temperature and angle measurements, which results in a sensor system capable of simultaneously measuring the angle and temperature with root-mean-squared error of 0.82°C for temperature and 2.20° for angle, which is further reduced to 1.20° after the application of a dynamic compensation technique for POF curvature sensors.


DiffTools: electron diffraction software tools for DigitalMicrograph.
A suite of software tools (DiffTools) has been developed for DigitalMicrograph--a software platform widely used in transmission electron microscopy (TEM) laboratories world-wide. These tools include capabilities for calibration, center determination, rotational averaging with automatic peak location, pattern spot spacing and interspot angle determination, rotation and inset of a pattern into an image, pattern intensity inversion and enhancement, and calculation of basic crystallographic data. The implementation and application of these tools to experimental diffraction patterns is illustrated and measurement of d-spacings with an accuracy of 0.63% or better is demonstrated. These tools, which are freely available via the Internet, enable users to rapidly and efficiently process selected area electron diffraction patterns. This can be performed entirely within the DigitalMicrograph environment using familiar menu-based commands and user-friendly dialog-based scripts.


Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis-B surface antigen (HBSAG) seropositive cancer patients undergoing cytotoxic chemotherapy.
Hepatitis B virus (HBV) is one of the major causes of chronic liver disease worldwide. Cancer patients who are chronic carriers of HBV have a higher hepatic complication rate while receiving cytotoxic chemotherapy (CT) and this has mainly been attributed to HBV reactivation. In this study, cancer patients who have solid and hematological malignancies with chronic HBV infection received the antiviral agent lamivudine prior and during CT compared with historical control group who did not receive lamivudine. The objectives were to assess the efficacy of lamivudine in reducing the incidence of HBV reactivation, and diminishing morbidity and mortality during CT. Two groups were compared in this study. The prophylactic lamivudin group consisted of 37 patients who received prophylactic lamivudine treatment. The historical controls consisted of 50 consecutive patients who underwent CT without prophylactic lamivudine. They were followed up during and for 8 weeks after CT. The outcomes were compared for both groups. Of our control group (n= 50), 21 patients (42%) were established hepatitis. Twelve (24%) of them were evaluated as severe hepatitis. In the prophylactic lamivudine group severe hepatitis were observed only in 1 patient (2.7%) of 37 patients (p < 0.006). Comparison of the mean ALT values revealed significantly higher mean alanine aminotransferase (ALT) values in the control group than the prophylactic lamivudine group; 154:64 (p < 0.32). Our study suggests that prophylactic lamivudine significantly decreases the incidence of HBV reactivation and overall morbidity in cancer patients during and after immunosuppressive therapy. Further studies are needed to determine the most appropriate nucleoside or nucleotide analogue for antiviral prophylaxis during CT and the optimal duration of administration after completion of CT.


Impact of T wave amplitude in lead aVR on predicting cardiac events in ischemic and nonischemic cardiomyopathy patients with an implantable cardioverter defibrillator.
T wave amplitudes during ventricular repolarization in the lead aVR (TAaVR) are shown to be associated with adverse cardiac events in patients with several cardiovascular diseases, such as postmyocardial infarction. However, the utility of TAaVR has not been previously evaluated in patients with cardiomyopathy who have received implantable cardioverter defibrillators (ICD). Patients with ischemic or nonischemic cardiomyopathy (ICM or NICM, respectively) and who received an ICD may experience worsening of their condition due to the introduction of electric shock during treatment. This study aimed to investigate the utility of TAaVR in the prediction of cardiac events in ICM or NICM patients with ICD. Ninety-three consecutive ICM or NICM patients with ICD were retrospectively analyzed (median age: 64 years; male: 77.4%; ICD for secondary prevention: 76.3%; NICM: 64.5%). The median follow-up period was 31 months. The primary endpoint was defined as composite cardiac events, including cardiac death, major ventricular arrhythmic events (MVAE), or hospitalization due to heart failure (HHF). Multivariate Cox regression analysis demonstrated that less negative TAaVR (-0.1 mV ≤ TAaVR <0 mV and 0 mV ≤ TAaVR) was independently associated with the primary endpoint (HR: 3.75; 95% confidence interval [CI]: 1.09-23.7; p = .04). Kaplan-Meier curve also revealed that the event free survival rate in the less negative TAaVR group was significantly lower than that in the normal TAaVR group (<-0.1 mV) (p < .01). TAaVR is useful in risk stratification for cardiac events in ICM or NICM patients with ICD.


Analysis of codon usage in beta-tubulin sequences of helminths.
Codon usage bias has been shown to be correlated with gene expression levels in many organisms, including the nematode Caenorhabditis elegans. Here, the codon usage (cu) characteristics for a set of currently available beta-tubulin coding sequences of helminths were assessed by calculating several indices, including the effective codon number (Nc), the intrinsic codon deviation index (ICDI), the P2 value and the mutational response index (MRI). The P2 value gives a measure of translational pressure, which has been shown to be correlated to high gene expression levels in some organisms, but it has not yet been analysed in that respect in helminths. For all but two of the C. elegans beta-tubulin coding sequences investigated, the P2 value was the only index that indicated the presence of codon usage bias. Therefore, we propose that in general the helminth beta-tubulin sequences investigated here are not expressed at high levels. Furthermore, we calculated the correlation coefficients for the cu patterns of the helminth beta-tubulin sequences compared with those of highly expressed genes in organisms such as Escherichia coli and C. elegans. It was found that beta-tubulin cu patterns for all sequences of members of the Strongylida were significantly correlated to those for highly expressed C. elegans genes. This approach provides a new measure for comparing the adaptation of cu of a particular coding sequence with that of highly expressed genes in possible expression systems.Finally, using the cu patterns of the sequences studied, a phylogenetic tree was constructed. The topology of this tree was very much in concordance with that of a phylogeny based on small subunit ribosomal DNA sequence alignments.


Isolation and characterization of fimbriae from a sparsely fimbriated strain of Porphyromonas gingivalis.
Porphyromonas gingivalis W50 (ATCC 53978) possesses the gene for fimbriae; however, the surface-expressed fimbriae are sparse and have not been previously isolated and characterized. We purified fimbriae from strain W50 to homogeneity by ammonium sulfate precipitation and reverse-phase high-performance liquid chromatography [H. T. Sojar, N. Hamada, and R. J. Genco, Protein Expr. Purif. 9(1):49-52, 1997]. Negative staining of purified fimbriae viewed by electron microscopy revealed that the fimbriae were identical in diameter to fimbriae of other P. gingivalis strains, such as 2561, but were shorter in length. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, the apparent molecular weight of isolated fimbrillin from strain W50 was found to be identical to that of the fimbrillin molecule of strain 2561. Unlike 2561 fimbriae, W50 fimbriae, under reducing condition, exhibited a monomeric structure on SDS-PAGE at room temperature. However, under nonreduced conditions, even at 100 degrees C, no monomer was observed. In immunoblot analysis as well as immunogold labeling of isolated fimbriae, polyclonal antibodies against 2561 fimbriae, as well as antibodies against peptide I (V-V-M-A-N-T-G-A-M-E-V-G-K-T-L-A-E-V-K-Cys) and peptide J (A-L-T-T-E-L-T-A-E-N-Q-E-A-A-G-L-I-M-T-A-E-P-Cys), reacted. However, antifimbrial antibodies against strain 2561 reacted very weakly compared to anti-peptide I and anti-peptide J. Negative staining of whole W50 cells, as well as immunogold electron microscopy with anti-peptide I and anti-peptide J, showed fimbriae shorter in length and very few in number compared to those of strain 2561. Purified fimbriae showed no hemagglutinating activity. Amino acid composition was very similar to that of previously reported fimbriae of the 2561 strain.


The need for enzymatic steering in abietic acid biosynthesis: gas-phase chemical dynamics simulations of carbocation rearrangements on a bifurcating potential energy surface.
Abietic acid, a constituent of pine resin, is naturally derived from abietadiene --a process that requires four enzymes: one (abietadiene synthase) for conversion of the acyclic, achiral geranylgeranyl diphosphate to the polycyclic, chiral abietadiene (a complex process involving the copalyl diphosphate intermediate) and then three to oxidize a single methyl group of abietadiene to the corresponding carboxylic acid. In previous work (Nature Chem.2009, 1, 384), electronic structure calculations on carbocation rearrangements leading to abietadienyl cation revealed an interesting potential energy surface with a bifurcating reaction pathway (two transition-state structures connected directly with no intervening minimum), which links two products--one natural and one not yet isolated from Nature. Herein we describe direct dynamics simulations of the key step in the formation of abietadiene (in the gas phase and in the absence of the enzyme). The simulations reveal that abietadiene synthase must intervene in order to produce abietadiene selectively, in essence steering this reaction to avoid the generation of byproducts with different molecular architectures.


CXXC finger protein 1 restricts the Setd1A histone H3K4 methyltransferase complex to euchromatin.
CXXC finger protein 1 (Cfp1), encoded by the CXXC1 gene, is a component of the euchromatic Setd1A histone H3K4 methyltransferase complex, and is a critical regulator of histone methylation, cytosine methylation, cellular differentiation, and vertebrate development. Murine embryonic stem (ES) cells lacking Cfp1 (CXXC1(-/-)) are viable but show increased levels of global histone H3K4 methylation, suggesting that Cfp1 functions to inhibit or restrict the activity of the Setd1A histone H3K4 methyltransferase complex. The studies reported here reveal that ES cells lacking Cfp1 contain decreased levels of Setd1A and show subnuclear mislocalization of both Setd1A and trimethylation of histone H3K4 with regions of heterochromatin. Remarkably, structure-function studies reveal that expression of either the N-terminal fragment of Cfp1 (amino acids 1-367) or the C-terminal fragment of Cfp1 (amino acids 361-656) is sufficient to restore appropriate levels of Setd1A in CXXC1(-/-) ES cells. Furthermore, functional analysis of various Cfp1 point mutations reveals that retention of either Cfp1 DNA-binding activity or association with the Setd1 histone H3K4 methyltransferase complex is required to restore normal Setd1A levels. In contrast, expression of full-length Cfp1 in CXXC1(-/-) ES cells is required to restrict Setd1A and histone H3K4 trimethylation to euchromatin, indicating that both Cfp1 DNA-binding activity and interaction with the Setd1A complex are required for appropriate genomic targeting of the Setd1A complex. These studies illustrate the complexity of Cfp1 function, and identify Cfp1 as a regulator of Setd1A genomic targeting.