Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation.
Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3-dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate L-arginine. Lack of L-arginine results in reduced NO production and eNOS uncoupling, which lead to endothelial dysfunction. Therefore, we hypothesized that L-arginine or L-citrulline supplementation would ameliorate diabetic nephropathy. DBA mice injected with multiple low doses of vehicle or streptozotocin (50 mg/kg ip for 5 days) were provided drinking water with or without L-arginine (1.5%, 6.05 g·kg(-1)·day(-1)) or L-citrulline (1.66%, 5.73 g·kg(-1)·day(-1)) for 9 wk. Nonsupplemented diabetic mice showed significant increases in albuminuria, blood urea nitrogen, glomerular histopathological changes, kidney macrophage recruitment, kidney TNF-α and fibronectin mRNA expression, kidney arginase activity, kidney arginase-2 protein expression, and urinary oxidative stress along with a significant reduction of nephrin and eNOS protein expression and kidney nitrite + nitrate compared with normal mice after 9 wk of diabetes. Surprisingly, L-arginine or L-citrulline supplementation in diabetic mice did not affect any of these parameters despite greatly increasing kidney and plasma arginine levels. These findings demonstrate that chronic L-arginine or L-citrulline supplementation does not prevent or reduce renal injury in a model of type 1 diabetes.


4D Ultrasound Tracking of Liver and its Verification for TIPS Guidance.
In this work we describe a 4D registration method for on the fly stabilization of ultrasound volumes for improving image guidance for transjugular intrahepatic portosystemic shunt (TIPS) interventions. The purpose of the method is to enable a continuous visualization of the relevant anatomical planes (determined in a planning stage) in a free breathing patient during the intervention. This requires registration of the planning information to the interventional images, which is achieved in two steps. In the first step tracking is performed across the streaming input. An approximate transformation between the reference image and the incoming image is estimated by composing the intermediate transformations obtained from the tracking. In the second step a subsequent registration is performed between the reference image and the approximately transformed incoming image to account for the accumulation of error. The two step approach helps in reducing the search range and is robust under rotation. We additionally present an approach to initialize and verify the registration. Verification is required when the reference image (containing planning information) is acquired in the past and is not part of the (interventional) 4D ultrasound sequence. The verification score will help in invalidating the registration outcome, for instance, in the case of insufficient overlap or information between the registering images due to probe motion or loss of contact, respectively. We evaluate the method over thirteen 4D US sequences acquired from eight subjects. A graphics processing unit implementation runs the 4D tracking at 9 Hz with a mean registration error of 1.7 mm.


An infectious way to teach students about outbreaks.
The study of infectious disease outbreaks is required to train today's epidemiologists. A typical way to introduce and explain key epidemiological concepts is through the analysis of a historical outbreak. There are, however, few training options that explicitly utilise real-time simulated stochastic outbreaks where the participants themselves comprise the dataset they subsequently analyse. In this paper, we present a teaching exercise in which an infectious disease outbreak is simulated over a five-day period and subsequently analysed. We iteratively developed the teaching exercise to offer additional insight into analysing an outbreak. An R package for visualisation, analysis and simulation of the outbreak data was developed to accompany the practical to reinforce learning outcomes. Computer simulations of the outbreak revealed deviations from observed dynamics, highlighting how simplifying assumptions conventionally made in mathematical models often differ from reality. Here we provide a pedagogical tool for others to use and adapt in their own settings.


Dermal melanocortin receptor rebound in diffuse systemic sclerosis after anti-TGFβ1 antibody therapy.
Disturbed transforming growth factor beta (TGFβ) signalling leads to enhanced synthesis of extracellular matrix (ECM), which is manifested as systemic sclerosis (SSc), but this may be attenuated by the melanocortin system. Here, we report of rebound reaction in the gene expression of melanocortin receptor (MCR) subtypes and of the precursor of these receptors' ligands, the pro-opio-melanocortin protein (POMC), in the acute skin lesion of diffuse systemic sclerosis (dSSc) after treatment with a recombinant human anti-TGFβ1 antibody. Biopsies, taken from the leading edge of the skin lesion, before and after treatment of a patient with recent onset dSSc, were examined. Before treatment, increased levels of TGFβ mRNA and suppressed levels of POMC mRNA and MCR subtypes MC(1-3, 5) R mRNAs were seen in the lesion, compared with healthy controls. After treatment, there was a rebound expression of POMC, MC(2, 3, 5) R mRNAs. As the melanocortin system regulates collagen and melanin production, our findings add a new understanding to the pathogenetic mechanisms involved in the acute skin lesion of dSSc, which is characterized by enhanced ECM formation and changes in skin pigmentation.


Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium.
Vitamin D is a known modulator of inflammation. Native dietary vitamin D3 is thought to be bio-inactive, and beneficial vitamin D3 effects are thought to be largely mediated by the metabolite 1,25(OH)2D3. Reduced serum levels of the most commonly measured precursor metabolite, 25(OH)D3, is linked to an increased risk of multiple inflammatory diseases, including: cardiovascular disease, arthritis, multiple sclerosis, and sepsis. Common to all of these diseases is the disruption of endothelial stability and an enhancement of vascular leak. We previously performed an unbiased chemical suppressor screen on a genetic model of vascular instability, and identified cholecalciferol (D3, dietary Vitamin D3) as a factor that had profound and immediate stabilizing and therapeutic effects in that model. In this manuscript we show that the presumed inactive sterol, D3, is actually a potent and general mediator of endothelial stability at physiologically relevant concentrations. We further demonstrate that this phenomenon is apparent in vitamin D3 metabolites 25(OH)D3 and 1,25(OH)2D3, and that the effects are independent of the canonical transcription-mediated vitamin D pathway. Our data suggests the presence of an alternative signaling modality by which D3 acts directly on endothelial cells to prevent vascular leak. The finding that D3 and its metabolites modulate endothelial stability may help explain the clinical correlations between low serum vitamin D levels and the many human diseases with well-described vascular dysfunction phenotypes.


SU-E-T-572: A Plan Quality Metric for Evaluating Knowledge-Based Treatment Plans.
In prostate IMRT treatment planning, the variation in patient anatomy makes it difficult to estimate a priori the potentially achievable extent of dose reduction possible to the rectum and bladder. We developed a mutual information-based framework to estimate the achievable plan quality for a new patient, prior to any treatment planning or optimization. The knowledge-base consists of 250 retrospective prostate IMRT plans. Using these prior plans, twenty query cases were each matched with five cases from the database. We propose a simple DVH plan quality metric (PQ) based on the weighted-sum of the areas under the curve (AUC) of the PTV, rectum and bladder. We evaluate the plan quality of knowledge-based generated plans, and established a correlation between the plan quality and case similarity. The introduced plan quality metric correlates well (r2 = 0.8) with the mutual similarity between cases. A matched case with high anatomical similarity can be used to produce a new high quality plan. Not surprisingly, a poorly matched case with low degree of anatomical similarity tends to produce a low quality plan, since the adapted fluences from a dissimilar case cannot be modified sufficiently to yield acceptable PTV coverage. The plan quality metric is well-correlated to the degree of anatomical similarity between a new query case and matched cases. Further work will investigate how to apply this metric to further stratify and select cases for knowledge-based planning.


Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sprouting.
Central poststroke pain (CPSP) is one of the neuropathic pain syndromes that can occur following stroke involving the somatosensory system. However, the underlying mechanism of CPSP remains largely unknown. Here, we established a CPSP mouse model by inducing a focal hemorrhage in the thalamic ventrobasal complex and confirmed the development of mechanical allodynia. In this model, microglial activation was observed in the somatosensory cortex, as well as in the injured thalamus. By using a CSF1 receptor inhibitor, we showed that microglial depletion effectively prevented allodynia development in our CPSP model. In the critical phase of allodynia development, c-fos-positive neurons increased in the somatosensory cortex, accompanied by ectopic axonal sprouting of the thalamocortical projection. Furthermore, microglial ablation attenuated both neuronal hyperactivity in the somatosensory cortex and circuit reorganization. These findings suggest that microglia play a crucial role in the development of CPSP pathophysiology by promoting sensory circuit reorganization.


MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis.
MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14(+) cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68(+) cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14(+) cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14(+) cells reduced TNF-α production. Finally, miR-155-deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.


STRUCTURAL RACISM AND HEALTH INEQUITIES: Old Issues, New Directions.
Racial minorities bear a disproportionate burden of morbidity and mortality. These inequities might be explained by racism, given the fact that racism has restricted the lives of racial minorities and immigrants throughout history. Recent studies have documented that individuals who report experiencing racism have greater rates of illnesses. While this body of research has been invaluable in advancing knowledge on health inequities, it still locates the experiences of racism at the individual level. Yet, the health of social groups is likely most strongly affected by structural, rather than individual, phenomena. The structural forms of racism and their relationship to health inequities remain under-studied. This article reviews several ways of conceptualizing structural racism, with a focus on social segregation, immigration policy, and intergenerational effects. Studies of disparities should more seriously consider the multiple dimensions of structural racism as fundamental causes of health disparities.


Reproducibility of blood pressure dipping: relation to day-to-day variability in sleep quality.
Previous studies of the reproducibility of blood pressure (BP) dipping have yielded inconsistent results. Few have examined factors that may influence day-to-day differences in dipping. Ambulatory BP monitoring was performed on three occasions, approximately 1 week apart, in 115 untreated adult subjects with elevated clinic BPs. The mean ± standard deviation BP dip was 18 ± 7/15 ± 5 mm Hg (sleep/awake BP ratio = 0.87 ± 0.05/0.82 ± 0.06), with a median (interquartile range) day-to-day variation of 5.2 (3.1-8.1)/4.3 (2.8-5.6) mm Hg. There was no decrease in variability with successive measurements. The reproducibility coefficient (5.6 [95% confidence interval, 5.1-6.1] mm Hg) was greater and the intraclass correlation coefficient (0.53 [95% confidence interval, 0.42-0.63]) was smaller for the systolic dip than for 24-hour or awake systolic BPs, suggesting greater day-to-day variability in dipping. Variability in systolic dipping was greater in subjects with higher awake BP, but was not related to age, gender, race, or body mass index. Within individuals, day-to-day variations in dipping were related to variations in the fragmentation index (P < .001), a measure of sleep quality. Although mean 24-hour and awake BPs were relatively stable over repeated monitoring days, our study confirms substantial variability in BP dipping. Day-to-day differences in dipping are related to sleep quality.


Molybdenum, phosphorus, and pH do not constrain nitrogen fixation in a tropical forest in the southeastern Amazon.
High rates of biological nitrogen fixation (BNF) are commonly reported for tropical forests, but most studies have been conducted in regions that receive substantial inputs of molybdenum (Mo) from atmospheric dust and sea-salt aerosols. Even in these regions, the low availability of Mo can constrain free-living BNF catalyzed by heterotrophic bacteria and archaea. We hypothesized that in regions where atmospheric inputs of Mo are low and soils are highly weathered, such as the southeastern Amazon, Mo would constrain BNF. We also hypothesized that the high soil acidity, characteristic of the Amazon Basin, would further constrain Mo availability and therefore soil BNF. We conducted two field experiments across the wet and dry seasons, adding Mo, phosphorus (P), and lime alone and in combination to the forest floor in the southeastern Amazon. We sampled soils and litter immediately, and then weeks and months after the applications, and measured Mo and P availability through resin extractions and BNF with the acetylene reduction assay. The experimental additions of Mo and P increased their availability and the lime increased soil pH. While the combination of Mo and P increased BNF at some time points, BNF rates did not increase strongly or consistently across the study as a whole, suggesting that Mo, P, and soil pH are not the dominant controls over BNF. In a separate short-term laboratory experiment, BNF did not respond strongly to Mo and P even when labile carbon was added. We postulate that high nitrogen (N) availability in this area of the Amazon, as indicated by the stoichiometry of soils and vegetation and the high nitrate soil stocks, likely suppresses BNF at this site. These patterns may also extend across highly weathered soils with high N availability in other topographically stable regions of the tropics.


Fourier fluorescence spectrometer for excitation emission matrix measurement.
We demonstrate a fluorescence spectrometer that utilizes principles of Fourier transform spectroscopy to measure excitation emission matrices (EEM) rapidly and with high spectral resolution. For this EEM fluorometer, incoherent excitation light is first input into a differential-delay scanning Michelson interferometer. Light from the output port excites sample fluorescence. The fluorescence remitted from the sample is directed to a second Michelson interferometer, whose differential-delay scanning is synchronized with the first interferometer. The EEM is obtained by two-dimensional Fourier analysis of the detected signal from the output port of the second interferometer. EEM results from the system are verified by comparing with results from a standard spectrometer. The system provides a wide spectral range, adjustable spectral resolution, and fast EEM acquisition speed, which allows EEM's to be acquired in 40 seconds at a spectral resolution of 81-cm-1.


Integrating microarray and proteomics data to predict the response on cetuximab in patients with rectal cancer.
To investigate the combination of cetuximab, capecitabine and radiotherapy in the preoperative treatment of patients with rectal cancer, fourty tumour samples were gathered before treatment (T0), after one dose of cetuximab but before radiotherapy with capecitabine (T1) and at moment of surgery (T2). The tumour and plasma samples were subjected at all timepoints to Affymetrix microarray and Luminex proteomics analysis, respectively. At surgery, the Rectal Cancer Regression Grade (RCRG) was registered. We used a kernel-based method with Least Squares Support Vector Machines to predict RCRG based on the integration of microarray and proteomics data on To and T1. We demonstrated that combining multiple data sources improves the predictive power. The best model was based on 5 genes and 10 proteins at T0 and T1 and could predict the RCRG with an accuracy of 91.7%, sensitivity of 96.2% and specificity of 80%.


Optimizing therapy for acute myeloid leukemia.
The 10-year overall survival for younger patients with newly diagnosed acute myeloid leukemia has improved threefold in the past 2 decades. This improvement has occurred in large part because of advances in supportive care and efforts to optimize standard induction and consolidation therapies applied in a stratified approach based on predictors of individual patient risk. Innovations in diagnostic technologies have broadened the understanding of key prognostic factors, including cytogenetic and molecular status, which define the extensive interpatient heterogeneity of this clonal disease. Despite this progress, only approximately 25% of patients who experience a complete remission with cytotoxic chemotherapy (50%-70% of patients with newly diagnosed disease) remain disease-free. Efforts to develop novel agents are actively ongoing, particularly for older patients (age > or = 60), and targeted therapies, for specific subsets of patients are being based on a better understanding of the biology of the disease.


A strategy for reducing maternal and newborn deaths by 2015 and beyond.
Achievement of Millennium Development Goal (MDG) 4 for child survival requires acceleration of gains in newborn survival, and current trends in improving maternal health will also fall short of reaching MDG 5 without more strategic actions. We present a Maternal Newborn and Child Health (MNCH) strategy for accelerating progress on MDGs 4 and 5, sustaining the gains beyond 2015, and further bringing down maternal and child mortality by two thirds by 2030. The strategy takes into account current trends in coverage and cause-specific mortality, builds on lessons learned about what works in large-scale implementation programs, and charts a course to reach those who do not yet access services. A central hypothesis of this strategy is that enhancing interactions between frontline workers and mothers and families is critical for increasing the effective coverage of life-saving interventions. We describe a framework for measuring and evaluating progress which enables continuous course correction and improvement in program performance and impact. Evidence for the hypothesis and impact of this strategy is being gathered and will be synthesized and disseminated in order to advance global learning and to maximise the potential to improve maternal and neonatal survival.


Preventability of drug-related harms - part I: a systematic review.
'Preventability' is a crucial concept in the literature on adverse drug reactions (ADRs). We have carried out a systematic review in order to identify and analyse the approaches used to define 'preventability' in relation to ADRs. We have restricted this investigation to definitions of preventability and have not dealt with other aspects. We searched MEDLINE (1963-April 2009) and EMBASE (1980-April 2009), without language restriction, for papers in which preventability of ADRs was likely to be defined. We found 234 papers, of which we retrieved 231. Of these, 172 either contained original definitions of preventability or referred to other papers in which preventability was defined. Forty contained no definition, and 19 were not relevant. In the 172 papers selected, we identified eight different general approaches to defining the preventability of ADRs: (1) analysis without explicit criteria; (2) assessment by consensus; (3) preventability linked to error; (4) preventability linked to standards of care; (5) preventability linked to medication-related factors; (6) preventability linked to information technology; (7) categorization of harmful treatments in explicit lists; and (8) a combination of more than one approach. These approaches rely on two general methods: the judgement of one or more investigators or the use of pre-defined explicit criteria; neither is satisfactory. Specific problems include the weakness of consensus as a method (since experts can agree and yet be wrong), inadequacy of definition of standards of care, and circularity in several definitions of preventability. Furthermore, attempts to list all preventable effects are bound to be incomplete and will not always apply to an individual case. We conclude that an approach based on analysis of the mechanisms of adverse reactions and their clinical features could be preferable; such an approach is described in a companion paper (Part II) in this issue of Drug Safety.


Differential uptake of fumarate by Candida utilis and Schizosaccharomyces pombe.
The dicarboxylic acid fumarate is an important intermediate in cellular processes and also serves as a precursor for the commercial production of fine chemicals such as L-malate. Yeast species differ remarkably in their ability to degrade extracellular dicarboxylic acids and to utilise them as their only source of carbon. In this study we have shown that the yeast Candida utilis effectively degraded extracellular fumarate and L-malate, but glucose or other assimilable carbon sources repressed the transport and degradation of these dicarboxylic acids. The transport of both dicarboxylic acids was shown to be strongly inducible by either fumarate or L-malate while kinetic studies suggest that the two dicarboxylic acids are transported by the same transporter protein. In contrast, Schizosaccharomyces pombe effectively degraded extracellular L-malate, but not fumarate, in the presence of glucose or other assimilable carbon sources. The Sch. pombe malate transporter was unable to transport fumarate, although fumarate inhibited the uptake of L-malate.


Amino acid starvation has opposite effects on mitochondrial and cytosolic protein synthesis.
Amino acids are essential for cell growth and proliferation for they can serve as precursors of protein synthesis, be remodelled for nucleotide and fat biosynthesis, or be burnt as fuel. Mitochondria are energy producing organelles that additionally play a central role in amino acid homeostasis. One might expect mitochondrial metabolism to be geared towards the production and preservation of amino acids when cells are deprived of an exogenous supply. On the contrary, we find that human cells respond to amino acid starvation by upregulating the amino acid-consuming processes of respiration, protein synthesis, and amino acid catabolism in the mitochondria. The increased utilization of these nutrients in the organelle is not driven primarily by energy demand, as it occurs when glucose is plentiful. Instead it is proposed that the changes in the mitochondrial metabolism complement the repression of cytosolic protein synthesis to restrict cell growth and proliferation when amino acids are limiting. Therefore, stimulating mitochondrial function might offer a means of inhibiting nutrient-demanding anabolism that drives cellular proliferation.


Pharmacological evidence for feedback regulation of dopamine metabolism in solid fetal substantia nigra transplants.
Solid grafts of fetal ventral mesencephalic tissue transplanted into a cavity overlying a dopamine (DA)-deafferented striatum are known to survive, send terminals into the host striatum and release DA. Using this preparation, we have examined receptor-mediated feedback modulation of DA metabolism in the graft and, separately, in its terminals in the host striatum. For this purpose we administered the DA receptor antagonist, haloperidol, and the DA receptor agonist, apomorphine (APO), systemically, and calculated the dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios as an index of DA turnover in the graft itself as well as in the adjacent host striatum. A marked increase in dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios was seen after haloperidol treatment. This increase was found 1) within the solid transplant tissue itself as well as 2) within the transplant reinnervated regions of the host striatum. The net elevation in DA metabolites associated with the transplant terminals was less than that obtained in the intact striatum. APO significantly decreased the dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios in the transplant-innervated regions of the host striatum; this effect of APO was of a greater magnitude than that seen in intact controls. Within the solid transplant itself, APO caused slight but not significant decreases in DA metabolism. Our findings demonstrate that the transplanted DA neurons are subject to negative feedback regulation mediated via DA receptors and that transplant DA utilization is subject to both increases and decreases in response to drug-induced manipulations of DA receptors.


Mutations in the alpha 2 helix of HLA-A2 affect presentation but do not inhibit binding of influenza virus matrix peptide.
Previous studies have suggested that MHC class I molecules bind and present peptides to CTL in a manner that is analogous to the presentation of peptides by class II molecules to Th. Crystallographic studies of HLA-A2 have led to the assignment of a putative peptide binding site that is bordered by two alpha helices consisting of residues 50-84 and 138-180. In this study, we have investigated whether residues in the alpha 2 helix are involved in the binding and/or presentation of a peptide to CTL. We have generated CTL to type A influenza virus by stimulation of human PBL with a synthetic peptide from the influenza A virus matrix protein (M1 residues 57-68) in the presence of rIL-2. Such HLA-A2.1-restricted influenza virus-immune CTL do not recognize infected HLA-A2.3+ targets. A2.1 and A2.3 differ by three amino acids in the alpha 2 domain: Ala vs. Thr at position 149, Val vs. Glu at position 152, and Leu vs. Trp at position 156. Site-directed mutants of the A2.1 gene that encode A2 molecules that resemble A2.3 at positions 149, 152, and 156 have been constructed, transfected into human cells, and assayed for their ability to present the M1 peptide. The results demonstrate that most, but not all, A2.1-restricted M1-peptide-specific CTL fail to recognize M1 peptide-exposed transfectants with certain single amino acid substitutions at positions 152 and 156. In contrast, M1 peptide-exposed transfectants that express A2 molecules with an Ala----Thr substitution at position 149 were recognized by all CTL tested, but they exhibited an apparent difference in the kinetics of peptide binding. These results indicate that amino acid substitutions at positions 152 and 156 of the putative peptide binding site of the A2 molecule can affect presentation without eliminating binding, and indicate that the failure to recognize complexes between the peptide and the mutant A2 molecules is due to different TCR specificities and not to the failure to bind the peptide.


Treatment Outcome and Relevance of Palliative Chemotherapy in Urachal Cancer.
Urachal cancer is a rare malignancy that accounts for <1% of bladder cancers. There is currently no consensus on the diagnosis and management of urachal cancer and there are very few reports on palliative chemotherapy for unresectable disease. We delineate the clinical features and treatment outcome of urachal cancer, in particular the relevance of palliative chemotherapy in recurrent, metastatic disease. The clinicopathologic variables and treatment outcome of patients who were treated for urachal cancer were retrospectively reviewed. Among 28 eligible patients, 25 had localized disease and 3 had metastatic disease at initial diagnosis. All patients with localized disease underwent curative resection and there was disease recurrence in 10. Out of 13 patients with metastatic disease either at initial diagnosis or during follow-up, the lung was the most common metastatic site (n = 5), followed by the liver, bone and peritoneum. Ten patients received palliative chemotherapy. A total of 24 chemotherapeutic regimens were administered; regimens with a base of fluoropyrimidine (5-FU), taxane and gemcitabine were the most common. The overall response rate of all chemotherapeutic regimens was 16.7%. The 5-FU-based regimens showed a good response, with 2 of 4 patients who received these showing a partial response. One tumor with a partial small-cell component showed a partial response to both an etoposide-based regimen and a taxane-based regimen. In urachal cancer, curative surgery is still the recommended treatment with respect to overall survival. A 5-FU-based chemotherapy regimen could be considered for metastatic recurrent disease.


Socioeconomic status and the risk of colorectal cancer: an analysis of more than a half million adults in the National Institutes of Health-AARP Diet and Health Study.
No previous prospective US study has examined whether the incidence of colorectal cancer (CRC) is disproportionately high in low socioeconomic status (SES) populations of both men and women. This study examined the relationship between both individual and area-level SES and CRC incidence, overall and by tumor location. Data were obtained from the ongoing prospective National Institutes of Health-AARP Diet and Health Study of persons (50-71 years old) who resided in 6 US states and 2 metropolitan areas at baseline in 1995-1996. Incident CRCs were ascertained from tumor registries through December 2006. SES was measured by self-reported education and census-tract socioeconomic deprivation. Baseline and follow-up questionnaires collected detailed information on individual-level CRC risk factors including family history and health behaviors. Among 506,488 participants analyzed, 7676 were diagnosed with primary invasive colorectal adenocarcinomas: 44.6% [corrected] in the right colon, 26.7% in the left colon, and 25.9% in the rectum. The overall incidence of CRC was significantly higher among people who had low educational level or lived in low-SES neighborhoods, relative to respective highest-SES groups, even after accounting for other risk factors. These associations were stronger in the rectum than in left or right colon. In the right colon, there were no significant SES differences by either SES measure after accounting for covariates. SES, assessed by either individual-level education or neighborhood measures, was associated with risk of CRC even after accounting for other risk factors. The relationship between SES and CRC was strongest in the rectum and weakest in the right colon.


FLT3 ligand and not TSLP is the key regulator of IL-7-independent B-1 and B-2 B lymphopoiesis.
Phenotypically and functionally distinct progenitors and developmental pathways have been proposed to exist for fetally derived B-1 and conventional B-2 cells. Although IL-7 appears to be the primary cytokine regulator of fetal and adult B lymphopoiesis in mice, considerable fetal B lymphopoiesis and postnatal B cells are sustained in the absence of IL-7; in humans, B-cell generation is suggested to be largely IL-7-independent, as severe combined immune-deficient patients with IL-7 deficiency appear to have normal B-cell numbers. However, the role of other cytokines in IL-7-independent B lymphopoiesis remains to be established. Although thymic stromal lymphopoietin (TSLP) has been proposed to be the main factor driving IL-7-independent B lymphopoiesis and to distinguish fetal from adult B-cell progenitor development in mice, recent studies failed to support a primary role of TSLP in IL-7-independent fetal B-cell development. However, the role of TSLP in IL-7-independent adult B lymphopoiesis and in particular in regulation of B-1 cells remains to be established. Here we demonstrate that, rather than TSLP, IL-7 and FLT3 ligand are combined responsible for all B-cell generation in mice, including recently identified B-1-specified cell progenitors. Thus, the same IL-7- and FLT3 ligand-mediated signal-ing regulates alternative pathways of fetal and adult B-1 and B-2 lymphopoiesis.


Behavioral task-induced bronchodilation in asthma during active and passive tasks: a possible cholinergic link to psychologically induced airway changes.
This study investigated pulmonary and autonomic reactions to active and passive behavioral laboratory tasks among asthmatic subjects. It also examined the relationship between airway irritability, as measured by the methacholine challenge test (MCT), and autonomic activity and reactivity to these tasks. Fifty-one asthmatic and 37 nonasthmatic subjects were exposed to psychological laboratory tasks involving either active (mental arithmetic and reaction time) or passive (films depicting shop accidents and thoracic surgery) response. The MCT was given to asthmatics in a separate session. Active tasks reduced respiratory impedance, as measured by forced oscillation pneumography. They also increased heart rate and appeared to block vagal activity, as measured by respiratory sinus arrhythmia (RSA). Airway irritability as assessed by the MCT was positively related to amplitude of RSA and to skin conductance levels. Our data suggest that active and passive behavioral tasks may produce different pulmonary effects among both asthmatic and nonasthmatic individuals. Engaging in tasks requiring active responses may produce temporary improvements in pulmonary function. No autonomic differences were obtained between asthmatics and nonasthmatics in physiological response to stress, but greater cholinergic receptor sensitivity was suggested among high responders to methacholine.


Hypertension in employees of a University General Hospital.
To find out the prevalence of hypertension in employees of the Hospital and relate it to social demographic variables. Blood pressure measurement was performed with a mercury sphygmomanometer, using an appropriate cuff size for arm circumference, weight, and height in a population sample of 864 individuals out of the 9,905 employees of a University General Hospital stratified by gender, age, and job position. Hypertension prevalence was 26% (62% of these reported being aware of their hypertension and 38% were unaware but had systolic/diastolic blood pressures of >140 and/or >90 mm Hg at the moment of the measurement). Of those who were aware of having hypertension, 51% were found to be hypertensive at the moment of the measurement. The prevalence was found to be 17%, 23%, and 29% (P <.05) in physicians, nursing staff, and "others", respectively. The univariate analysis showed a significant odds ratio for the male gender, age >50 years, work unit being the Institute of Radiology and the Administration Building, educational level <elementary school, length of work >10 years, and body mass index >30 kg/m2. The multivariate logistic regression model revealed a statistically significant association of hypertension with the following variables: gender, age, skin color, family income, and body mass index. Hypertension prevalence was high, mainly in those who were not physicians or members of the nursing staff. High-risk groups (obese, non-white, men, low family income) should be better advised of prevention and early diagnosis of hypertension by means of special programs.


Phylogenetic approaches to nomenclature: a comparison based on a nemertean case study.
Phylogenetic approaches to biological nomenclature are becoming increasingly common. Here I compare the behaviour of two such approaches, the phylogenetic system of definition and the phylogenetic system of reference, when there is a shift in the preference of phylogenetic hypotheses. The comparison is based on a case study from nemertean systematics and is the first to compare two different phylogenetic approaches throughout three stages of change, including two stages of phylogenetic nomenclature. It is concluded that a phylogenetic system of reference in combination with uninomials is superior in conveying phylogenetic information.


Cervical Infection with Cutaneous Beta and Mucosal Alpha Papillomaviruses.
Background: Alpha-human papillomavirus (α-HPV) plays a causal role in cervical cancer, but little is known about the epidemiology of genital Beta-human papillomavirus (β-HPV) infection.Methods: We used Luminex and PCR hybridization to detect β- and α-HPVs prevalence at enrollment and 12-month follow-up in cervical samples from 505 women enrolled in the Ludwig-McGill cohort study. We compared epidemiologic correlates of both β- and α-HPVs and compared genotypes between these genera with respect to co-occurrence and association with cervical cytologic abnormalities.Results: Infection with β-HPV types was more prevalent than that with α-HPV types at both visits (cumulative prevalences: 27.3% vs. 21.6%, respectively, P = 0.034). β-HPVs were mostly transient; however, only 1.98% women retained their original positivity at 12 months, whereas persistence was higher for α-HPVs (5.15%; P = 0.007). Age, parity, and sexual activity variables were predictors of α-HPV but not of β-HPV. α- and β-HPV types occurred independently. Increased risk of cervical abnormalities was restricted to women infected with α-9 or α-6 HPV types. We found no epidemiologic correlates for β-HPV infections.Conclusions: Detection of β-HPV types in the cervix tends to occur as random and transient episodes not explained via the sexual-transmission correlates that characterize infections by α-HPVs.Impact: Although it is plausible that β-HPVs may play a direct or indirect carcinogenic role, the lack of epidemiologic correlates for detection episodes of these viruses and lack of association with cervical lesions speak against their ancillary role as sexually transmitted agents in cervical carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(8); 1312-20. ©2017 AACR.


Inhibition of GATA2 in prostate cancer by a clinically available small molecule.
Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.


Zymography of Hybrid Layers Created Using Extrafibrillar Demineralization.
A chelate-and-rinse extrafibrillar calcium chelation dentin bonding concept has recently been developed and investigated for its effectiveness in improving resin-dentin bonding by bridging the gap between wet and dry dentin bonding. The objective of the present study was to evaluate the gelatinolytic activity of hybrid layers (HLs) created using the chelate-and-rinse bonding technique. Gelatinolytic activity within the HL was examined using in situ zymography and confocal laser-scanning microscopy after 24-h storage or after thermomechanical cycling. Dentin specimens were bonded with Prime&Bond NT (Dentsply Sirona) after conditioning with 15 wt% phosphoric acid for 15 s (control) or 15 wt% polymeric chelators (sodium salt of polyacrylic acid; PAAN) of 2 different molecular weights for 60 s. For each reagent, bonding was performed using dry-bonding and wet-bonding techniques ( n = 10). Slices containing the adhesive-dentin interface were covered with fluorescein-conjugated gelatin and examined with a confocal laser-scanning microscope. Fluorescence intensity emitted by the hydrolyzed fluorescein-conjugated gelatin was quantified. Gelatinolytic activity was expressed as the percentage of green fluorescence emitted within the HL. After storage for 24 h, enzymatic activity was only detected within the completely demineralized phosphoric acid-etched dentin, with values derived from dry bonding higher than those from wet bonding ( P < 0.05). Almost no fluorescence signals were detected within the HL when dentin was conditioned with PAANs compared with the controls ( P < 0.05). After thermomechanical cycling, enzymatic activities significantly increased for the phosphoric acid-conditioned, drying-bonding group compared with 24-h storage ( P < 0.05). The present study showed that the use of the chelate-and-rinse bonding concept for both dry-bonding and wet-bonding approaches results in the near absence of matrix-bound collagenolytic activities in the HL even after aging. This may be attributed to fossilization of endogenous proteases via preservation of intrafibrillar minerals within the dentin collagen matrix.


Laparoscopic hepaticoplasty using gallbladder as a subcutaneous tunnel for hepatolithiasis.
To investigate the feasibility, efficacy and safety of laparoscopic hepaticoplasty using gallbladder as subcutaneous tunnel and sphincter-of-Oddi preservation for hepatolithiasis. From January 2010 to July 2013, six patients with hepatolithiasis were treated at our institution. All the patients underwent laparoscopic surgery. The procedures included common hepatic duct exploration, stone clearance by fiberoptic choledochoscopy, hilar bile duct hepaticoplasty with preservation of the sphincter of Oddi, anastomosis between the hilar bile duct and neck of the gallbladder, and establishment of a subcutaneous tunnel with the gallbladder. Two patients underwent left lateral hepatectomy simultaneously. Clinical data including operation time, intraoperative blood loss, operative morbidity, hospital mortality, stone clearance, and recurrence rate were analyzed. All patients successfully completed laparoscopic surgery. The mean length of hospital stay was 4.5 ± 0.9 d (range: 3-6 d). The mean blood loss of the hepatectomy was 450 mL (range: 200-700 mL), and the blood loss of the other four was 137 ± 151 mL (range: 50-400 mL). The mean operative time was 318 ± 68 min (range: 236-450 min). The operative morbidity and hospital mortality were zero. The immediate stone clearance rate was 100%. All patients were followed up for an average of 17 mo (range: 7-36 mo). One of the six patients had abdominal mass with pain, and subcutaneous tunnel cholangiography showed severe gallbladder-biliary anastomotic stricture at 4 mo postoperatively. There was no stone recurrence and no cholangitis during follow-up. Laparoscopic hepaticoplasty using gallbladder with a subcutaneous tunnel and preserving the sphincter of Oddi is feasible, safe and effective for hepatholithiasis.


Are compound leaves more complex than simple ones? A multi-scale analysis.
The question of which cellular mechanisms determine the variation in leaf size has been addressed mainly in plants with simple leaves. It is addressed here in tomato taking into consideration the expected complexity added by the several lateral appendages making up the compound leaf, the leaflets. Leaf and leaflet areas, epidermal cell number and areas, and endoreduplication (co-) variations were analysed in Solanum lycopersicum considering heteroblastic series in a wild type (Wva106) and an antisense mutant, the Pro35S:Slccs52AAS line, and upon drought treatments. All plants were grown in an automated phenotyping platform, PHENOPSIS, adapted to host plants grown in 7 L pots. Leaf area, leaflet area and cell number increased with leaf rank until reaching a plateau. In contrast, cell area slightly decreased and endoreduplication did not follow any trend. In the transgenic line, leaf area, leaflet areas and cell number of basal leaves were lower than in the wild type, but higher in upper leaves. Reciprocally, cell area was higher in basal leaves and lower in upper leaves. When scaled up at the whole sympodial unit, all these traits did not differ significantly between the transgenic line and the wild type. In response to drought, leaf area was reduced, with a clear dose effect that was also reported for all size-related traits, including endoreduplication. These results provide evidence that all leaflets have the same cellular phenotypes as the leaf they belong to. Consistent with results reported for simple leaves, they show that cell number rather than cell size determines the final leaf areas and that endoreduplication can be uncoupled from leaf and cell sizes. Finally, they re-question a whole-plant control of cell division and expansion in leaves when the Wva106 and the Pro35S:Slccs52AAS lines are compared.


Aqueous Extract of Solanum nigrum Leaves Induces Autophagy and Enhances Cytotoxicity of Cisplatin, Doxorubicin, Docetaxel, and 5-Fluorouracil in Human Colorectal Carcinoma Cells.
Colorectal cancer is a common cancer worldwide, and chemotherapy is a mainstream approach for advanced and recurrent cases. Development of effective complementary drugs could help improve tumor suppression efficiency and control adverse effects from chemotherapy. The aqueous extract of Solanum nigrum leaves (AE-SN) is an essential component in many traditional Chinese medicine formulas for treating cancer, but there is a lack of evidence verifying its tumor suppression efficacy in colorectal cancer. The purpose of this study is to evaluate the tumor suppression efficacy of AE-SN using DLD-1 and HT-29 human colorectal carcinoma cells and examine the combined drug effect when combined with the chemotherapeutic drugs cisplatin, doxorubicin, docetaxel, and 5-fluorouracil. The results indicated that AE-SN induced autophagy via microtubule-associated protein 1 light chain 3 A/B II accumulation but not caspase-3-dependent apoptosis in both cell lines. The IC50s after 48 hours of treatment were 0.541 and 0.948 mg/ml AE-SN in DLD-1 and HT-29, respectively. AE-SN also demonstrated a combined drug effect with all tested drugs by enhancing cytotoxicity in tumor cells. Our results suggest that AE-SN has potential in the development of complementary chemotherapy for colorectal cancer.


The processive endoglucanase EngZ is active in crystalline cellulose degradation as a cellulosomal subunit of Clostridium cellulovorans.
Clostridium cellulovorans produces an efficient enzyme complex for the degradation of lignocellulosic biomass. In our previous study, we detected and identified protein spots that interacted with a fluorescently labeled cohesin biomarker via two-dimensional gel electrophoresis. One novel, putative cellulosomal protein (referred to as endoglucanase Z) contains a catalytic module from the glycosyl hydrolase family (GH9) and demonstrated higher levels of expression than other cellulosomal cellulases in Avicel-containing cultures. Purified EngZ had optimal activity at pH 7.0, 40°C, and the major hydrolysis product from the cellooligosaccharides was cellobiose. EngZ's specific activity toward crystalline cellulose (Avicel and acid-swollen cellulose) was 10-20-fold higher than other cellulosomal cellulase activities. A large percentage of the reducing ends that were produced by this enzyme from acid-swollen cellulose were released as soluble sugar. EngZ has the capability of reducing the viscosity of Avicel at an intermediate-level between exo- and endo-typing cellulases, suggesting that it is a processive endoglucanase. In conclusion, EngZ was highly expressed in cellulolytic systems and demonstrated processive endoglucanase activity, suggesting that it plays a major role in the hydrolysis of crystalline cellulose and acts as a cellulosomal enzyme in C. cellulovorans.


Radiation therapy for ductal carcinoma in situ: a decision analysis.
The benefit of adding radiation therapy after excision of ductal carcinoma in situ (DCIS) is widely debated. Randomized clinical trials are underpowered to delineate long-term outcomes after radiation. The authors of this report constructed a Markov decision model to simulate the clinical course of DCIS in a woman aged 60 years who received treatment with either of 2 breast-conserving strategies: excision alone or excision plus radiation therapy. Sensitivity analyses were used to study the influence of risk of local recurrence, likelihood of invasive disease at recurrence, surgical choice at recurrence, and patient age at diagnosis on treatment outcomes. The addition of radiation therapy was associated with slight improvements in invasive disease-free and overall survival. However, radiation therapy decreased the chance of having both breasts intact over a patient's lifetime. Radiation therapy improved survival by 2.1 months for women who were diagnosed with DCIS at age 60 years but decreased the chance of having both breasts by 8.6% relative to excision alone. The differences in outcomes between the treatment strategies became smaller with increasing age at diagnosis. Sensitivity analyses revealed a greater benefit for radiation with an increased likelihood of invasive recurrence. The decrement in breast preservation with radiation therapy was mitigated by an increased likelihood of mastectomy at the time of recurrence or new breast cancer diagnosis. The current analysis quantified the benefits of radiation after excision of DCIS but also revealed that radiation therapy may increase the likelihood of eventual mastectomy. Therefore, the authors concluded that patient age and preferences should be considered when making the decision to add or forgo radiation for DCIS.


The Impact of Peplau's Therapeutic Communication Model on Anxiety and Depression in Patients Candidate for Coronary Artery Bypass.
Anxiety and depression are among the psychological disorders in heart surgeries. Establishing a simple communication is essential to reduce anxiety and depression. Hence, the objective of the present studywas to examine the impact of Peplau therapeutic communication model on anxiety and depression in patients, who were candidate for coronary artery bypass in Al-Zahra Heart Hospital, Shiraz during 2012-2013. This is a clinical trial in which 74 patients were randomly divided into intervention and control groups, each consisted of 37 patients. Anxiety and depression levels were assessed before, and two and four months after intervention using the Hospital Anxiety and Depression Scale (HADS). Seven therapeutic communication sessions were held in four stages. Data were analyzed with the SPSS (version 16) using analysis of covariance. The mean anxiety and depression levels decreased in the intervention group after the therapeutic communication (p<0.01). Anxiety scores in the intervention group before and after intervention were 10.23 and 9.38, respectively. While the corresponding scores in the control group were 10.26 and 11.62, respectively. Depression scores in the intervention group before and after intervention were 11 and 9.13, respectively. The corresponding scores in the control group were 11.30 and 12.08, respectively. The results demonstrated the positive role of therapeutic communication in reducing anxiety and depression of the patients. Therefore, the therapeutic communication is recommended as a simple, cost effective and efficient method in this area.


The effects of cytomegalovirus serology on graft and recipient survival in cadaveric renal transplantation: implications for organ allocation.
The potential benefits from allocating donated cadaveric kidneys based on donor and recipient cytomegalovirus (CMV) serology remain controversial. We estimated graft survival and recipient survival using bivariate Kaplan-Meier models and multivariate Cox proportional hazards models for 24,543 first cadaveric renal transplantations performed in the United States between 1989, coinciding with the introduction of ganciclovir, and 1994. The effects of donor and recipient CMV serology were estimated, and the implications of these estimates for CMV-based allocation of cadaveric kidneys were considered. From Kaplan-Meier estimates, the 3-year impact of CMV-seropositive donor kidneys was a 3.6% reduction in graft survival and a 2.4% reduction in recipient survival for CMV-seronegative recipients, and a 3.9% reduction in graft survival and a 3.0% reduction in recipient survival for CMV-seropositive recipients. Multivariate Cox analysis demonstrated an adverse impact of donor CMV seropositivity regardless of recipient CMV status. D-/R- CMV serologic pairs had the best 3-year outcomes, with 73.4% graft survival and 87.7% recipient survival. D+/R+ CMV serologic pairs were found to have the worst 3-year outcomes, with 68.4% graft survival and 83.1% recipient survival, and were significantly worse than D+/R- pairs in terms of recipient survival. The maximum estimated impact of a program allocating donor kidneys to maximize the number of D-/R- CMV serologic pairs, assuming no impact on HLA mismatches, was a 0.1% reduction in aggregate 3-year graft survival and a 0.2% reduction in aggregate recipient survival. An alternative program allocating donor kidneys to minimize the number of D+/R+ pairs had no estimated effect on either graft or recipient survival. We conclude that during the ganciclovir era, CMV continues to have an important impact on first cadaveric renal transplantation. However, even under ideal conditions, CMV-based kidney allocation to either maximize the number of D-/R- pairs or minimize the number of D+/R+ pairs is likely to provide little benefit to the population of cadaveric renal transplant recipients.


Dental findings in Morquio syndrome (mucopolysaccharidoses type IVa).
Morquio syndrome is a disorder of mucopolysaccharide metabolism with specific skeletal features. The clinical and radiographic appearance of the teeth resembles hypoplastic amelogenesis imperfecta with thin enamel of normal radiodensity. The dental practitioner has a part to play in collaboration with medical colleagues in the recognition and diagnosis of this condition.


The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs.
The Mycobacterium tuberculosis phoP mutant strain SO2 has previously been shown to have reduced multiplication in mouse macrophages and in vivo using the mouse intravenous-infection model. In this study we demonstrate that the M. tuberculosis SO2 is highly attenuated when compared with the parental M. tuberculosis MT103 strain and also more attenuated than BCG in severe combined immunodeficiency disease (SCID) mice. Complementation of the M. tuberculosis SO2 with the wild-type phoP gene restored the virulence of the strain in the SCID mice, confirming that the attenuated phenotype is due to the phoP mutation. In Balb/c mice subcutaneously vaccinated with either M. tuberculosis SO2 or BCG, the proportions of CD4+ and CD8+ populations measured in the spleen were significantly higher in the M. tuberculosis SO2 vaccinated group. In addition, the proportion of antigen-stimulated CD4+/CD8+ cells expressing IFN-gamma was significantly higher in the M. tuberculosis SO2 vaccinated group when compared with the BCG group. Balb/c mice subcutaneously vaccinated with the M. tuberculosis SO2 strain were also protected against intra-venous challenge with M. tuberculosis H37Rv at levels comparable to mice vaccinated with BCG, as measured by reduced bacterial counts in lung and spleens. Guinea pigs subcutaneously vaccinated with the M. tuberculosis SO2 strain were protected against aerosol challenge with M. tuberculosis H37Rv delivered at different doses. A high dose aerosol challenge of M. tuberculosis SO2 vaccinated guinea pigs resulted in superior levels of protection when compared with BCG vaccination, as measured by guinea pig survival and reduction in disease severity in the lung.


Corneal Endothelial Changes in Behçet's Patients with Inactive Ocular Involvement.
The purpose of this article is to evaluate alterations in the corneal endothelial layer in Behçet's disease (BD) with inactive ocular involvement using specular microscopy. Thirty-three eyes of 33 BD patients who had at least one anterior segment involvement and no active inflammation in the last 3 months were included in the study (group 1). Twenty-seven of the 33 BD patients had an anterior uveitis attack and six of them had a panuveitis (both anterior and posterior involvement) attack. Thirty-three eyes of 33 age- and sex-matched healthy subjects were enrolled in the control group (group 2). Corneal endothelial cell density (CD), coefficient of variation (CV), hexagonal cell ratio (HEX), and central corneal thickness (CCT) were measured using specular microscopy (Konan Medical, Nishinomiya, Japan), and the results were compared between groups. The mean CD was 2739 ± 164.18 cells/mm2 in group 1 and 2922 ± 107.60 cells/mm2 in group 2 (p = 0.001). The mean CV was 32.9 ± 4.76 in group 1 and 28.5 ± 3.06 in group 2 (p = 0.001). The mean HEX was 44.7 ± 6.51 in group 1 and 49.7 ± 6.10 in group 2 (p = 0.019). The mean CCT was 545.75 ± 40.89 μ in group 1 and 545.66 ± 30.09 μ in group 2 (p > 0.05). Ocular attacks in our BD patients may have caused permanent changes in the corneal endothelial layer. However, these changes did not lead to corneal decompensation, but further studies are necessary to confirm these results.


Identification of serum proton NMR metabolomic fingerprints associated with hepatocellular carcinoma in patients with alcoholic cirrhosis.
Metabolomics depicts metabolic changes in biologic systems using a multiparametric analysis technique. This study assessed the metabolomic profiles of serum, obtained by proton nuclear magnetic resonance (NMR) spectroscopy, from cirrhotic patients with and without hepatocellular carcinoma (HCC). The study included 154 consecutive patients with compensated biopsy-proven alcoholic cirrhosis. Among these, 93 had cirrhosis without HCC, 28 had biopsy-proven HCC within the Milan criteria and were eligible for curative treatment (small HCC), and 33 had HCC outside the Milan criteria (large HCC). Proton spectra were acquired at 500 MHz. An orthogonal partial latent structure [orthogonal projection to latent structure (OPLS)] analysis model was built to discriminate large HCC spectra from cirrhotic spectra. Small HCC spectra were secondarily projected using previously built OPLS discriminant components. The OPLS model showed discrimination between cirrhotic and large HCC spectra. Metabolites that significantly increased with large HCC were glutamate, acetate, and N-acetyl glycoproteins, whereas metabolites that correlated with cirrhosis were lipids and glutamine. Projection of small HCC samples into the OPLS model showed a heterogeneous distribution between large HCC and cirrhotic samples. Small HCC patients with metabolomic profile similar to those of large HCC group had higher incidences of recurrence or death during follow-up. Serum NMR-based metabolomics identified metabolic fingerprints that could be specific to large HCC in cirrhotic livers. From a metabolomic standpoint, some patients with small HCC, who are eligible for curative treatments, seem to behave as patients with advanced cancerous disease. It would be useful to further prospectively investigate these patients to define a subgroup with a worse prognosis.


American society of echocardiography report. Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology.
Noninvasive measures of atherosclerosis have emerged as adjuncts to standard cardiovascular disease (CVD) risk factors in an attempt to refine risk stratification and the need for more aggressive preventive strategies. Two such approaches, carotid artery imaging and brachial artery reactivity testing (BART), are ultrasound based. Numerous carotid artery imaging protocols have been used, and methodologic aspects are described in detail in this review. The panel recommends that protocols: (1) use end-diastolic (minimum dimension) images for intimal-medial thickness (IMT) measurements; (2) provide separate categorization of plaque presence and IMT; (3) avoid use of a single upper limit of normal for IMT because the measure varies with age, sex, and race; and (4) incorporate lumen measurement, particularly when serial measurements are performed to account for changes in distending pressure. Protocols may vary in the number of segments wherein IMT is measured, whether near wall is measured in addition to far wall, and whether IMT measurements are derived from B-mode or M-mode images, depending on the application. BART is a technique that requires meticulous attention to patient preparation and methodologic detail. Its application is substantially more challenging than is carotid imaging and remains largely a research technique that is not readily translated into routine clinical practice.


Immunodeficiency-related lymphoproliferative disorders: prospective data from the United Kingdom Children's Cancer Study Group Registry.
Clinical data and biological samples were prospectively collected in 42 children with lymphoproliferative disease (LPD) secondary to organ/bone marrow transplant-related immunosuppression (30: 11 liver, 10 heart/lung, 8 kidney and 1 bone marrow), other drug-induced immunosuppression (2), congenital immunodeficiency (8) or human immunodeficiency virus (HIV)-related immune dysfunction (2). Ages ranged from 10 months to 17 years and there were 15 girls. Pathology was centrally reviewed and showed polymorphic features in 5 cases, monomorphic in 23, mixed pattern in 5 patients and 9 other types. Using the Revised European-American Classification of Lymphoid Neoplasms, 5 were B lymphoblastoid, 24 were high-grade B and 14 were other subtypes. Using the Pittsburgh classification, 9 were lymphadenopathic, 10 were systemic, 25 were lymphomatous and, with the Murphy grouping for non-Hodgkin's lymphoma (NHL), 10 were localized and 32 non-localized. Twenty-four out of 38 evaluable cases were Epstein-Barr virus positive. Thirty-five patients were evaluable for clonality; 24 were monoclonal and 11 were polyclonal. Reduced immunosuppression in solid organ transplant patients resulted in resolution of disease in 14/24, which was sustained in 11. Nineteen patients received chemotherapy, 14/18 evaluable responded, which was sustained in 8 cases. Seven out of 29 solid organ transplant and 10/13 other immune-deficient patients died. In the largest group of patients, solid organ transplants, no significant clinical or biological characteristics that predicted outcome were identified. In the transplant group close monitoring of response during reduction in immunosuppression is essential and the early use of B NHL chemotherapy may be effective.


Novel X-ray phase-contrast tomography method for quantitative studies of heat induced structural changes in meat.
The objective of this study was to evaluate the use of X-ray phase-contrast tomography combined with 3D image segmentation to investigate the heat induced structural changes in meat. The measurements were performed at the Swiss synchrotron radiation light source using a grating interferometric setup. The non-destructive method allowed the same sample to be measured before and after cooking. Heat denaturation resulted in a 36% decrease in the volume of the muscle fibers, while solubilization of the connective tissues increased the volume from 8.4%to 24.9%. The cooking loss was quantified and separated into a water phase and a gel phase formed by the sarcoplasmic proteins in the exudate. The results show that X-ray phase contrast tomography offers unique possibilities in studies both the meat structure and the different meat component such as water, fat, connective tissue and myofibrils in a qualitative and quantitative manner without prior sample preparation as isolation of single muscle components, calibration or histology.


Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.
Acute and chronic graft-versus-host disease (GVHD) continues to be the major causes of morbidity and mortality after allogeneic bone marrow transplantation (BMT). In this study, we have evaluated the clinical effects of selective in vitro T-cell depletion of donor allogeneic bone marrow by using a single monoclonal antibody ([MoAb] anti-T12, CD6) and rabbit complement. This antibody recognizes mature T cells, but not other cellular elements such as natural-killer (NK) cells, B cells, and myeloid precursors. From August 1983 to April 1991, 112 consecutive adult patients with hematologic malignancies underwent BMT with bone marrow from HLA-identical sibling donors. Marrow was harvested and depleted of mature T lymphocytes ex vivo by the use of three rounds of incubation with an anti-T12 antibody and rabbit complement. The preparative regimen consisted of cyclophosphamide and fractionated total body irradiation (TBI) in 108 patients. No patients received prophylactic immune suppression post-BMT. Purgation by anti-T12 was used as the only method for the prevention of GVHD. Twenty patients (18%) developed acute GVHD (grade 2 to 4); only eight patients developed chronic GVHD. The incidence of GVHD did not increase significantly with age. Only three of 112 patients (2.7%) exhibited acute graft failure. One patient developed late graft failure that was associated with cytomegalovirus (CMV) infection. Within the subset of 50 patients who had not previously undergone unsuccessful conventional therapy (acute leukemia in first remission or chronic myelogenous leukemia [CML] in stable phase), we estimated by the Kaplan-Meier method that the probability of disease-free survival was 50% at 3 years post-BMT, with a median follow-up of 44 months. The treatment-related mortality rate in this group was only 14% and was independent of patient age. We conclude that selective in vitro T-cell depletion with an anti-T12 monoclonal antibody effectively reduces the incidence of both acute and chronic GVHD after allogeneic BMT without compromising engraftment. Moreover, depletion of CD6-positive cells from donor marrow obviates the need to administer immune suppressive medications to the majority of patients. This approach reduces the morbidity and mortality of allogeneic BMT and permits the BMT of older patients.


Clinical effects and complications of TIPS for portal hypertension due to cirrhosis: a single center.
To determine the clinical effects and complications of transjugular intrahepatic portosystemic shunt (TIPS) for portal hypertension due to cirrhosis. Two hundred and eighty patients with portal hypertension due to cirrhosis who underwent TIPS were retrospectively evaluated. Portal trunk pressure was measured before and after surgery. The changes in hemodynamics and the condition of the stent were assessed by ultrasound and the esophageal and fundic veins observed endoscopically. The success rate of TIPS was 99.3%. The portal trunk pressure was 26.8 ± 3.6 cmH2O after surgery and 46.5 ± 3.4 cmH2O before surgery (P < 0.01). The velocity of blood flow in the portal vein increased. The internal diameters of the portal and splenic veins were reduced. The short-term hemostasis rate was 100%. Esophageal varices disappeared completely in 68% of patients and were obviously reduced in 32%. Varices of the stomach fundus disappeared completely in 80% and were obviously reduced in 20% of patients. Ascites disappeared in 62%, were markedly reduced in 24%, but were still apparent in 14% of patients. The total effective rate of ascites reduction was 86%. Hydrothorax completely disappeared in 100% of patients. The incidence of post-operative stent stenosis was 24% at 12 mo and 34% at 24 mo. The incidence of post-operative hepatic encephalopathy was 12% at 3 mo, 17% at 6 mo and 19% at 12 mo. The incidence of post-operative recurrent hemorrhage was 9% at 12 mo, 19% at 24 mo and 35% at 36 mo. The cumulative survival rate was 86% at 12 mo, 81% at 24 mo, 75% at 36 mo, 57% at 48 mo and 45% at 60 mo. TIPS can effectively lower portal hypertension due to cirrhosis. It is significantly effective for hemorrhage of the digestive tract due to rupture of esophageal and fundic veins and for ascites and hydrothorax caused by portal hypertension.


URG4/URGCP enhances the angiogenic capacity of human hepatocellular carcinoma cells in vitro via activation of the NF-κB signaling pathway.
Angiogenesis is essential for tumor growth. Hepatocellular carcinoma (HCC) is characterized by hypervascularity; high levels of angiogenesis are associated with poor prognosis and a highly invasive phenotype in HCC. Up-regulated gene-4 (URG4), also known as upregulator of cell proliferation (URGCP), is overexpressed in multiple tumor types and has been suggested to act as an oncogene. This study aimed to elucidate the effect of URG4/URGCP on the angiogenic capacity of HCC cells in vitro. Expression of URG4/URGCP in HCC cell lines and normal liver epithelial cell lines was examined by Western blotting and quantitative real-time PCR. URG4/URGCP was stably overexpressed or transiently knocked down using a shRNA in two HCC cell lines. The human umbilical vein endothelial cell (HUVEC) tubule formation and Transwell migration assays and chicken chorioallantoic membrane (CAM) assay were used to examine the angiogenic capacity of conditioned media from URG4/URGCP-overexpressing and knockdown cells. A luciferase reporter assay was used to examine the transcriptional activity of nuclear factor kappa - light - chain - enhancer of activated B cells (NF-κB). NF-κB was inhibited by overexpressing degradation-resistant mutant inhibitor of κB (IκB)-α. Expression of vascular endothelial growth factor C (VEGFC), tumor necrosis factor-α (TNFα), interleukin (IL)-6, IL-8 and v-myc avian myelocytomatosis viral oncogene homolog (MYC) were examined by quantitative real-time PCR; VEGFC protein expression was analyzed using an ELISA. URG4/URGCP protein and mRNA expression were significantly upregulated in HCC cell lines. Overexpressing URG4/URGCP enhanced - while silencing URG4/URGCP decreased - the capacity of HCC cell conditioned media to induce HUVEC tubule formation and migration and neovascularization in the CAM assay. Furthermore, overexpressing URG4/URGCP increased - whereas knockdown of URG4/URGCP decreased - VEGFC expression, NF-κB transcriptional activity, the levels of phosphorylated (but not total) IκB kinase (IKK) and IκB-α, and expression of TNFα, IL-6, IL-8 and MYC in HCC cells. Additionally, inhibition of NF-κB activity in HCC cells abrogated URG4/URGCP-induced NF-κB activation and angiogenic capacity. This study suggests that URG4/URGCP plays an important pro-angiogenic role in HCC via a mechanism linked to activation of the NF-κB pathway; URG4/URGCP may represent a potential target for anti-angiogenic therapy in HCC.


Recombinant Newcastle disease viruses with targets for PCR diagnostics for rinderpest and peste des petits ruminants.
Since February 1st 2011, rinderpest (RP) has been officially declared eradicated worldwide. National authorities have been requested to destroy all their RP related materials. Nonetheless, their national reference laboratories performing real time reverse transcription polymerase chain reaction assays (PCR diagnostics) need RP positive control samples, since some countries still prefer to maintain diagnostic capability for RP for several reasons. In the future, a similar situation will arise for peste des petits ruminants (PPR) as the ambition has been expressed to eradicate PPR. Anticipating on this, we intended to perform qualified PCR diagnostics without use of infectious RPV or PPRV. Therefore, Newcastle disease virus (NDV) with small RNA inserts based on RPV or PPRV sequences were generated and used as positive control material. Recombinant NDVs (recNDVs) were differentially detected by previously established PCR diagnostics for RPV or PPRV. Both recNDVs contain a second PCR target showing that additional targets in NDV are feasible and would increase the diagnostic sensitivity by use of two PCR assays. RecNDV with small PCR targets is not classified as RPV or PPRV containing material, and can be used to mimic RPV or PPRV. Using these recNDVs as virus positive material contributes to the ambition of worldwide eradication, while qualified PCR diagnostics for these OIE-listed diseases remains operational.


Bacterial contamination of patients' medical charts in a surgical ward and the intensive care unit: impact on nosocomial infections.
The purpose of this study was to determine the degree of bacterial contamination of patients' files, and to compare the colonized bacteria between files from the surgical intensive care unit (ICU) and the surgical ward at the Wan Fang Hospital, Taipei, Taiwan. 180 medical charts were randomly selected from the surgical ICU (n = 90) and the surgical ward (n = 90). The charts were sampled using sterile swabs moistened with sterile normal saline. The swabs were immediately transferred to trypticase soy broth and incubated aerobically for 48 h, then subcultured to separated sheep blood and eosin-methylene blue agars. Microorganisms were identified by the standard methods used in the microbiological laboratory. Ninety percent of charts in the surgical ICU (n = 81) and 72.2% in the surgical ward (n = 65) were contaminated with pathogenic or potentially pathogenic bacteria (p = 0.0023). Coagulase-negative staphylococci (CoNS) were the most commonly isolated bacteria, both in the surgical ICU (n = 40, 44.44%) and in the surgical ward (n = 48, 53.33%). Several bacteria isolated from the charts, including multidrug-resistant Acinetobacter baumannii, Stenotrophomonas maltophilia, and Klebsiella pneumoniae, had the same antibiogram as the same bacteria isolated from patients. This study showed that the patients' charts in the ICU were usually contaminated with pathogenic and potentially pathogenic bacteria. Contaminated charts can serve as a source for cross-infection. Health care personnel should wash their hands before and after contact with the chart to reduce the nosocomial infection rate.


[Information is more than just the number].
In order to be able to make informed choices, it is important that patients have transparent information about the pros and cons of treatment. When using the number unnecessarily treated (NUT) as information for patients, we should take the following into account. First, patients should understand that non-effective treatment may still do harm. This might be in contradiction with their ideas about the effects of treatment. Second, as many patients have difficulties understanding numbers and probabilities, the usefulness of NUT may be limited. Third, it is very important to use the proper presentation format to make the information intuitively meaningful for patients. A natural frequency tree and not a population diagram appears to be the optimal format for this purpose. When giving patient information the premise is that the form of the message is more important than the numbers.


Validation of ART Calculator for Predicting the Number of Metaphase II Oocytes Required for Obtaining at Least One Euploid Blastocyst for Transfer in Couples Undergoing in vitro Fertilization/Intracytoplasmic Sperm Injection.
This multicenter study evaluated the reliability of the recently published ART calculator for predicting the minimum number of metaphase II (MII) oocytes (MIImin) to obtain at least one euploid blastocyst in patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). We used clinical and embryonic retrospective data of 1,464 consecutive infertile couples who underwent IVF/ICSI with the intention to have preimplantation genetic testing for aneuploidy. The validation procedure followed a stepwise approach. Firstly, we assessed the distribution of euploid blastocysts per patient and found that it followed a negative binomial distribution. Secondly, we used generalized linear models and applied the Lasso procedure-including MII oocytes to adjust the data-to select the factors predicting the response variable "euploid blastocyst." Third, a logistic regression model-fit to the binomial response euploid (yes/no) for each MII oocyte-was built using the relevant factors. The observational unit was the "woman" whereas the response was the pair (m, n), where n is the number of retrieved MII oocytes and m the corresponding number of euploid blastocysts. The model was internally validated by randomly splitting the data into training and validation sets. The R-squares (~0.25) and the area under the ROC curve (~0.70) did not differ between the training and validation datasets. Fourth, mathematical equations and the calculated probabilities generated by the validation model were used to determine the MIImin required for obtaining at least one euploid blastocyst according to different success probabilities. Lastly, we compared the fittings generated by the validation model and the ART calculator and assessed the predictive value of the latter using the validation dataset. The fittings were sufficiently close for both the estimated probabilities of blastocyst euploid per MII oocyte (r = 0.91) and MIImin (r = 0.88). The ART calculator positive predictive values, i.e., the frequency of patients with at least one euploid blastocyst among those who achieved the estimated MIImin, were 84.8%, 87.5%, and 90.0% for 70%, 80%, and 90% predicted probabilities of success, respectively. The ART calculator effectively predicts the MIImin needed to achieve at least one euploid blastocyst in individual patients undergoing IVF/ICSI. The prediction tool might be used for counseling and planning IVF/ICSI treatments.


Sensitivity of Monilinia fructicola from Stone Fruit to Thiophanate-Methyl, Iprodione, and Tebuconazole.
Sensitivity in Monilinia fructicola to three fungicides was determined by measuring mycelial growth in fungicide-amended media. Resistance to thiophanate-methyl was found in 39 of 52 isolates (75%) collected from 1992 to 1998 (historic population) and 22 of 100 isolates (22%) collected in 2002 (current population). Three groups having distinct ranges of values for 50% effective concentration (EC50) to thiophanate-methyl were identified. Benzimidazole-sensitive (benS) isolates had EC50 values less than 2.0, low-resistant (benL) isolates between 2.0 and 30.0, and high-resistant (benH) isolates greater than 30.0 μg/ml. One (2%) isolate from the historic and three (3%) isolates from the current population were benH. Inoculation of untreated nectarine blossoms with four isolates from each of the three groups, individually or combined using equal numbers of conidia from each isolate, showed that the benS, benL, and benH isolates were equally pathogenic and competitive. Use of thiophanate-methyl at 300 μg a.i./ml (half dosage) and 600 μg a.i./ml (full dosage) effectively reduced the percentage of blighted blossoms caused by the benS group but not that caused by the benL and benH groups. The benH isolates caused significantly greater percentage of blighted blossoms than the benL isolates at both dosage levels. None of the tested isolates of M. fructicola were resistant to either iprodione or tebuconazole.


[Gastric mucosal immunity induced by H. pylori infection].
H. pylori infection induces various humoral and cellular immunities in gastric mucosa. Some reports indicate predominant CD4+ cells infiltrate in H. pylori infected gastric mucosa, and these cells express the T helper 1 phenotype. Local humoral immunity is also induced. Gastric plasma cells produce anti-H. pylori antibodies, however, their protective immunity is not enough to eradicate bacteria in human. We found heat shock protein 60 kDa (hsp60) may be closely associated with pathogenesis in MALT lymphoma. IgG1 antibodies to hsp60 were significantly correlated with the antibodies to H. pylori whole cell in patients with MALT lymphoma. CD40-CD40L dependent B cell proliferation was induced by cytokine and/or hsp60 stimulations in those patients. Cytotoxicity of gastric epithelial cells which is associated with host immunity induced by H. pylori infection is still unclear. We found that lymphocytes from patients with peptic ulcer showed cytotoxicity to gastric cell line HGC-27 in vitro. Cytotoxicity was enhanced by cytokine stimulus to T-lymphocytes and by heat stress and/or patients' antibodies treatment of HGC-27 cells. The pathogenicity of H. pylori may involve not only bacterial virulence factor but also host immunity. Studies of mucosal local immunity will help explain the mechanisms of H. pylori induced gastrodoudenal diseases.


Diurnal variations of psychometric indicators in Twitter content.
The psychological state of a person is characterised by cognitive and emotional variables which can be inferred by psychometric methods. Using the word lists from the Linguistic Inquiry and Word Count, designed to infer a range of psychological states from the word usage of a person, we studied temporal changes in the average expression of psychological traits in the general population. We sampled the contents of Twitter in the United Kingdom at hourly intervals for a period of four years, revealing a strong diurnal rhythm in most of the psychometric variables, and finding that two independent factors can explain 85% of the variance across their 24-h profiles. The first has peak expression time starting at 5am/6am, it correlates with measures of analytical thinking, with the language of drive (e.g power, and achievement), and personal concerns. It is anticorrelated with the language of negative affect and social concerns. The second factor has peak expression time starting at 3am/4am, it correlates with the language of existential concerns, and anticorrelates with expression of positive emotions. Overall, we see strong evidence that our language changes dramatically between night and day, reflecting changes in our concerns and underlying cognitive and emotional processes. These shifts occur at times associated with major changes in neural activity and hormonal levels.


Low-dose curcumin stimulates proliferation, migration and phagocytic activity of olfactory ensheathing cells.
One of the promising strategies for neural repair therapies is the transplantation of olfactory ensheathing cells (OECs) which are the glial cells of the olfactory system. We evaluated the effects of curcumin on the behaviour of mouse OECs to determine if it could be of use to further enhance the therapeutic potential of OECs. Curcumin, a natural polyphenol compound found in the spice turmeric, is known for its anti-cancer properties at doses over 10 µM, and often at 50 µM, and it exerts its effects on cancer cells in part by activation of MAP kinases. In contrast, we found that low-dose curcumin (0.5 µM) applied to OECs strikingly modulated the dynamic morphology, increased the rate of migration by up to 4-fold, and promoted significant proliferation of the OECs. Most dramatically, low-dose curcumin stimulated a 10-fold increase in the phagocytic activity of OECs. All of these potently stimulated behavioural characteristics of OECs are favourable for neural repair therapies. Importantly, low-dose curcumin gave a transient activation of p38 kinases, which is in contrast to the high dose curcumin effects on cancer cells in which these MAP kinases tend to undergo prolonged activation. Low-dose curcumin mediated effects on OECs demonstrate cell-type specific stimulation of p38 and ERK kinases. These results constitute the first evidence that low-dose curcumin can modulate the behaviour of olfactory glia into a phenotype potentially more favourable for neural repair and thereby improve the therapeutic use of OECs for neural repair therapies.


Internet-based interventions for smoking cessation.
Tobacco use is estimated to kill 7 million people a year. Nicotine is highly addictive, but surveys indicate that almost 70% of US and UK smokers would like to stop smoking. Although many smokers attempt to give up on their own, advice from a health professional increases the chances of quitting. As of 2016 there were 3.5 billion Internet users worldwide, making the Internet a potential platform to help people quit smoking. To determine the effectiveness of Internet-based interventions for smoking cessation, whether intervention effectiveness is altered by tailoring or interactive features, and if there is a difference in effectiveness between adolescents, young adults, and adults. We searched the Cochrane Tobacco Addiction Group Specialised Register, which included searches of MEDLINE, Embase and PsycINFO (through OVID). There were no restrictions placed on language, publication status or publication date. The most recent search was conducted in August 2016. We included randomised controlled trials (RCTs). Participants were people who smoked, with no exclusions based on age, gender, ethnicity, language or health status. Any type of Internet intervention was eligible. The comparison condition could be a no-intervention control, a different Internet intervention, or a non-Internet intervention. To be included, studies must have measured smoking cessation at four weeks or longer. Two review authors independently assessed and extracted data. We extracted and, where appropriate, pooled smoking cessation outcomes of six-month follow-up or more, reporting short-term outcomes narratively where longer-term outcomes were not available. We reported study effects as a risk ratio (RR) with a 95% confidence interval (CI).We grouped studies according to whether they (1) compared an Internet intervention with a non-active control arm (e.g. printed self-help guides), (2) compared an Internet intervention with an active control arm (e.g. face-to-face counselling), (3) evaluated the addition of behavioural support to an Internet programme, or (4) compared one Internet intervention with another. Where appropriate we grouped studies by age. We identified 67 RCTs, including data from over 110,000 participants. We pooled data from 35,969 participants.There were only four RCTs conducted in adolescence or young adults that were eligible for meta-analysis.Results for trials in adults: Eight trials compared a tailored and interactive Internet intervention to a non-active control. Pooled results demonstrated an effect in favour of the intervention (RR 1.15, 95% CI 1.01 to 1.30, n = 6786). However, statistical heterogeneity was high (I2 = 58%) and was unexplained, and the overall quality of evidence was low according to GRADE. Five trials compared an Internet intervention to an active control. The pooled effect estimate favoured the control group, but crossed the null (RR 0.92, 95% CI 0.78 to 1.09, n = 3806, I2 = 0%); GRADE quality rating was moderate. Five studies evaluated an Internet programme plus behavioural support compared to a non-active control (n = 2334). Pooled, these studies indicated a positive effect of the intervention (RR 1.69, 95% CI 1.30 to 2.18). Although statistical heterogeneity was substantial (I2 = 60%) and was unexplained, the GRADE rating was moderate. Four studies evaluated the Internet plus behavioural support compared to active control. None of the studies detected a difference between trial arms (RR 1.00, 95% CI 0.84 to 1.18, n = 2769, I2 = 0%); GRADE rating was moderate. Seven studies compared an interactive or tailored Internet intervention, or both, to an Internet intervention that was not tailored/interactive. Pooled results favoured the interactive or tailored programme, but the estimate crossed the null (RR 1.10, 95% CI 0.99 to 1.22, n = 14,623, I2 = 0%); GRADE rating was moderate. Three studies compared tailored with non-tailored Internet-based messages, compared to non-tailored messages. The tailored messages produced higher cessation rates compared to control, but the estimate was not precise (RR 1.17, 95% CI 0.97 to 1.41, n = 4040), and there was evidence of unexplained substantial statistical heterogeneity (I2 = 57%); GRADE rating was low.Results should be interpreted with caution as we judged some of the included studies to be at high risk of bias. The evidence from trials in adults suggests that interactive and tailored Internet-based interventions with or without additional behavioural support are moderately more effective than non-active controls at six months or longer, but there was no evidence that these interventions were better than other active smoking treatments. However some of the studies were at high risk of bias, and there was evidence of substantial statistical heterogeneity. Treatment effectiveness in younger people is unknown.


Nitro-Heterocyclic compounds induce apoptosis-like effects in Leishmania (L). amazonensis promastigotes.
Three drugs - pentavalent antimonials, amphotericin B and pentamidine - are currently used for leishmaniasis treatment. They are administered for long periods, only parenterally, and have high cardiac, renal and hepatic toxicities. Therefore, the investigation of new compounds is required. Nitro-heterocyclic derivatives have been used as possible drug candidates to treat diseases caused by trypanosomatids. Leishmania (L.) amazonensis promastigotes (MHO/BR/73/M2269), maintained in the Laboratório de Soroepidemiologia - Instituto de Medicina Tropical- USP, were exposed to five nitroheterocyclic derivatives, with differences at phenyl-ring position 4: BSF-C4H9, BSF-H, BSF-NO2, BSF-CH3 and BSF-Cl, for 48 hours. After analyzing viability (MTT assay), we evaluated cellular-morphology activity of compounds by transmission electron microscopy (TEM) and measurement of apoptosis (phosphatidylserine expression) by flow cytometry. EC50 of amphotericin B and BSF-CH3 were 0.50 (M and 0.39 (M respective. Other nitro-heterocyclic compounds presented EC50 higher than amphotericin B. All compounds showed greater AV- and PI-positive expression than amphotericin B at 100 (M, except BSF-NO2. TEM showed complete nuclear disfigurement with 100 (M of BSF-NO2, 25 and 6.25 (M of BSF-H, and 6.25 (M BSF-Cl; presence of vesicles within the flagellar pocket with 25 (M BSF-H; alteration of the kinetoplast with 25 (M BSF-C4H9, 25 (M of BSF-H, 6.25 (M BSF-CH3 and 6.25 (M of BSF-Cl. Nitro-heterocyclic compounds have shown activity against promastigotes of L. amazonensis, at lower concentrations. However, improvement of compound scaffolds are needed to assist the elucidation of the mechanism of action and to achieve greater activity.


Repeat Exposure to Leg Swing Perturbations During Treadmill Training Induces Long-Term Retention of Increased Step Length in Human SCI: A Pilot Randomized Controlled Study.
To determine whether repeat exposure to force perturbations during treadmill training can induce long-term retention of improved step length and overall improvements in locomotor function in persons with spinal cord injury. Fourteen patients with spinal cord injury were recruited and randomly assigned to swing resistance or swing assistance training groups. A controlled swing resistance or assistance force, for resistance or assistance training groups, respectively, was applied to both legs through a cable-driven robotic system during treadmill training. Each participant trained 3 times per week for 6 weeks. Step length, walking speed, 6-minute walking distance, and other clinical assessments were evaluated before and after 6 weeks of training and 8 weeks after the end of training. A significant increase in step length was observed after 6 weeks of resistance training (P = 0.04). Step length tended to increase after assistance treadmill training, but the change was not significant (P = 0.18). The changes in step length and functional gains had no significant difference between 2 groups. Repeat exposure to swing resistance during treadmill training may induce a prolonged retention of increased step length, although it remains unclear whether swing resistance versus assistance is more effective in inducing increased step length.


Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer.
While viral antigens in human papillomavirus (HPV)-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from patients with stage III-IV oropharyngeal cancer undergoing concomitant chemoradiotherapy with or without induction chemotherapy. Circulating immunocytes including CD4(+) and CD8(+) T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T-cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T-cell assays in the presence of blocking antibody. While HPV-specific T-cell responses were present in 13 of 18 patients before treatment, 10 of 13 patients lost these responses within 3 months after chemoradiotherapy. Chemoradiotherapy decreased circulating T cells and markedly elevated MDSCs. PD-1 expression on CD4(+) T cells increased by nearly 2.5-fold after chemoradiotherapy, and ex vivo culture with PD-1-blocking antibody enhanced HPV-specific T-cell responses in 8 of 18 samples tested. Chemoradiotherapy suppresses circulating immune responses in patients with HPVOPC by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4(+) T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care chemoradiotherapy for HPVOPC.


Histopathologic findings predicting lymph node metastasis and prognosis of patients with superficial esophageal carcinoma: analysis of 240 surgically resected tumors.
If it were possible to elucidate the histopathologic findings predicting lymph node metastasis and prognosis in superficial squamous cell carcinoma of the esophagus (SSCCE), they could be used as markers to identify patients who do not require additional surgical resection after endoscopic mucosal resection (EMR). Two hundred forty surgically resected SSCCEs were examined histopathologically. Histopathologic factors including vertical tumor invasion depth in the submucosal layer (VTIDsm), degree of nuclear atypia (low, one point; high, two points), growth pattern (expansive, one point; infiltrative, two points), and histologic grade (calculated by adding the latter two scores to obtain Grade 1, two points; Grade 2, three points; and Grade 3, four points) were evaluated to investigate the associations among these factors, lymph node metastasis, and prognosis. No lymph node metastasis was found in 54 patients with carcinoma limited to the lamina propria. Their 5-year survival rate was 100%. Multivariate analysis of 186 carcinomas invading beyond the lamina propria showed that lymphatic permeation correlated with lymph node metastasis (P<0.0001) and the presence of lymph node metastasis and a high histologic grade were independent factors indicating a poor prognosis (P = 0.0061 and 0.023, respectively). In 53 patients whose tumors had invaded the lamina muscularis or slightly invaded the submucosa (VTIDsm <500 microm), no lymph node metastasis was found in the lymphatic permeation negative and blood vessel permeation negative patients with VTIDsm values <200 microm and histologic Grades 1 or 2. Lymphatic permeation is a good predictor of lymph node metastasis in patients with SSCCE. Lymph node metastasis and the histologic grade are independent prognostic factors. Vessel permeation, VTIDsm, and histologic grade were found to be important factors for identifying patients who did not require additional surgical treatment after EMR.