Comparative analysis of gO isoforms reveals that strains of human cytomegalovirus differ in the ratio of gH/gL/gO and gH/gL/UL128-131 in the virion envelope.
Herpesvirus glycoprotein complex gH/gL provides a core entry function through interactions with the fusion protein gB and can also influence tropism through receptor interactions. The Epstein-Barr virus gH/gL and gH/gL/gp42 serve both functions for entry into epithelial and B cells, respectively. Human cytomegalovirus (HCMV) gH/gL can be bound by the UL128-131 proteins or gO. The phenotypes of gO and UL128-131 mutants suggest that gO-gH/gL interactions are necessary for the core entry function on all cell types, whereas the binding of UL128-131 to gH/gL likely relates to a distinct receptor-binding function for entry into some specific cell types (e.g., epithelial) but not others (e.g., fibroblasts and neurons). There are at least eight isoforms of gO that differ by 10 to 30% of amino acids, and previous analysis of two HCMV strains suggested that some isoforms of gO function like chaperones, disassociating during assembly to leave unbound gH/gL in the virion envelope, while others remain bound to gH/gL. For the current report, we analyzed the gH/gL complexes present in the virion envelope of several HCMV strains, each of which encodes a distinct gO isoform. Results indicate that all strains of HCMV contain stable gH/gL/gO trimers and gH/gL/UL128-131 pentamers and little, if any, unbound gH/gL. TR, TB40/e, AD169, and PH virions contained vastly more gH/gL/gO than gH/gL/UL128-131, whereas Merlin virions contained mostly gH/gL/UL128-131, despite abundant unbound gO remaining in the infected cells. Suppression of UL128-131 expression during Merlin replication dramatically shifted the ratio toward gH/gL/gO. These data suggest that Merlin gO is less efficient than other gO isoforms at competing with UL128-131 for binding to gH/gL. Thus, gO diversity may influence the pathogenesis of HCMV through effects on the assembly of the core versus tropism gH/gL complexes.


Bcr-abl silencing by specific small-interference RNA expression vector as a potential treatment for chronic myeloid leukemia.
RNA interference (RNAi) is the mechanism of gene silencing-mediated messenger RNA degradation by small interference RNA (siRNA), which becomes a powerful tool for in vivo research, especially in the areas of cancer. In this research, the potential use of an expression vector as a specific siRNA producing tool for silencing of Bcr-abl in K562 cell line has been investigated. siRNA specific for Bcr-abl as short hairpin RNA (shRNA) was designed and cloned in expression vector (pRNAH1.1/Neo). K562 cells were cultured in RPMI media and transfected with shRNA expressing vector using lipofectamin 2000. Successful transfection was confirmed by significant increase of enhanced green fluorescent protein (EGFP) levels in K562-treated cells with expression vector (pEGFP-C1). In vitro studies in human K562 cell line entailed modulation of endogenous Bcr-abl mRNA levels which induced apoptosis. Effects of siRNA treatment on K562 cells were measured by ELISA. Successful expression of siRNA was confirmed by significant reduction of Bcr-abl mRNA levels in K562 cells treated with expression vector (pRNAH1.1/Neo). siRNA directed against Bcr-abl effectively induced apoptosis and reduced viability in human K562 cell lines. Expression vector of siRNA can be used in vitro to target specific RNA and to reduce the levels of the specific gene product in the targeted cells. Results of this work suggest that RNAi has potential application for the treatment of a variety of diseases, including those involving abnormal gene expression and viral contamination.


A family-based, developmental-ecological preventive intervention for high-risk adolescents.
Family-based preventive intervention has emerged as a promising modality for preventing antisocial behavior problems in youth. This article introduces an intensive, family-based preventive intervention for high-risk adolescents: Multidimensional Family Prevention. Multidimensional Family Prevention combines the advantages of standard prevention models (curriculum based and protection focused) with those of psychosocial treatment models (assessment based and problem focused). The model's main features are described: theoretical foundations (risk and protection theory, developmental psychopathology, ecological theory), guidelines for constructing a multidomain prevention program (family and peer relationships, school and prosocial activities, drug use and health issues, cultural themes), and strategies for tailoring and implementing five flexible intervention modules (adolescent, parent, interactional, extended family, extrafamilial). Implemented in the family's home, the intervention works to create a resilient family environment that supports the basic adolescent developmental goals of renegotiated attachment bonds within the family and durable connections with prosocial institutions.


Human Immunodeficiency Virus/Hepatitis C Virus (HCV) Co-infected Patients With Cirrhosis Are No Longer at Higher Risk for Hepatocellular Carcinoma or End-Stage Liver Disease as Compared to HCV Mono-infected Patients.
It is widely accepted that human immunodeficiency virus (HIV) infection is a risk factor for increased severity of hepatitis C virus (HCV) liver disease. However, owing to better efficacy and safety of combination antiretroviral therapy (cART), and increased access to HCV therapy, whether this condition remains true is still unknown. Overall, 1,253 HCV mono-infected patients and 175 HIV/HCV co-infected patients with cirrhosis, included in two prospective French national cohorts (ANRS CO12 CirVir and CO13 HEPAVIH), were studied. Cirrhosis was compensated (Child-Pugh A), without past history of complication, and assessed on liver biopsy. Incidences of liver decompensation (LD), hepatocellular carcinoma (HCC), and death according to HIV status were calculated by a Fine-Gray model adjusted for age. Propensity score matching was also performed to minimize confounding by baseline characteristics. At baseline, HIV/HCV patients were younger (47.5 vs. 56.0 years; P < 0.001), more frequently males (77.1% vs. 62.3%; P < 0.001), and had at baseline and at end of follow-up similar rates of HCV eradication than HCV mono-infected patients. A total of 80.4% of HIV/HCV patients had an undetectable HIV viral load. After adjustment for age, 5-year cumulative incidences of HCC and decompensation were similar in HIV/HCV and HCV patients (8.5% vs. 13.2%, P = 0.12 and 12.8% vs. 15.6%, P = 0.40, respectively). Overall mortality adjusted for age was higher in HIV/HCV co-infected patients (subhazard ratio [SHR] = 1.88; 95% confidence interval [CI], 1.15-3.06; P = 0.011). Factors associated with LD and HCC were age, absence of sustained virological response, and severity of cirrhosis, but not HIV status. Using a propensity score matching 95 patients of each group according to baseline features, similar results were observed. Conclusion: In HCV-infected patients with cirrhosis, HIV co-infection was no longer associated with higher risks of HCC and hepatic decompensation. Increased mortality, however, persisted, attributed to extrahepatic conditions.


Breeding farm, level of feeding and presence of antibiotics in the feed influence rabbit cecal microbiota.
The effect of the production environment and different management practices in rabbit cecal microbiota remains poorly understood. While previous studies have proved the impact of the age or the feed composition, research in the breeding farm and other animal management aspects, such as the presence of antibiotics in the feed or the level of feeding, is still needed. Characterization of microbial diversity and composition of growing rabbits raised under different conditions could help better understand the role these practices play in cecal microbial communities and how it may result in different animal performance. Four hundred twenty-five meat rabbits raised in two different facilities, fed under two feeding regimes (ad libitum or restricted) with feed supplemented or free of antibiotics, were selected for this study. A 16S rRNA gene-based assessment through the MiSeq Illumina sequencing platform was performed on cecal samples collected from these individuals at slaughter. Different univariate and multivariate approaches were conducted to unravel the influence of the different factors on microbial alpha diversity and composition at phylum, genus and OTU taxonomic levels. The animals raised in the facility harboring the most stable environmental conditions had greater, and less variable, microbial richness and diversity. Bootstrap univariate analyses of variance and sparse partial least squares-discriminant analyses endorsed that farm conditions exerted an important influence on rabbit microbiota since the relative abundances of many taxa were found differentially represented between both facilities at all taxonomic levels characterized. Furthermore, only five OTUs were needed to achieve a perfect classification of samples according to the facility where animals were raised. The level of feeding and the presence of antibiotics did not modify the global alpha diversity but had an impact on some bacteria relative abundances, albeit in a small number of taxa compared with farm, which is consistent with the lower sample classification power according to these factors achieved using microbial information. This study reveals that factors associated with the farm effect and other management factors, such as the presence of antibiotics in the diet or the feeding level, modify cecal microbial communities. It highlights the importance of offering a controlled breeding environment that reduces differences in microbial cecal composition that could be responsible for different animal performance.


Predictors of mortality in HIV-1 infected children on antiretroviral therapy in Kenya: a prospective cohort.
Among children, early mortality following highly active antiretroviral therapy (HAART) remains high. It is important to define correlates of mortality in order to improve outcome. HIV-1-infected children aged 18 months-12 years were followed up at Kenyatta National Hospital, Nairobi after initiating NNRTI-based HAART. Cofactors for mortality were determined using multivariate Cox regression models. Between August 2004 and November 2008, 149 children were initiated on HAART of whom 135 were followed for a total of 238 child-years (median 21 months) after HAART initiation. Baseline median CD4% was 6.8% and median HIV-1-RNA was 5.98-log10 copies/ml. Twenty children (13.4%) died at a median of 35 days post-HAART initiation. Mortality during the entire follow-up period was 8.4 deaths per 100 child-years (46 deaths/100 child-years in first 4 months and 1.0 deaths/100 child-years after 4 months post-HAART initiation). On univariate Cox regression, baseline hemoglobin (Hb) <9 g/dl, weight-for-height z-score (WHZ) < -2, and WHO clinical stage 4 were associated with increased risk of death (Hb <9 g/dl HR 3.00 [95% C.I. 1.21-7.39], p = 0.02, WHZ < -2 HR 3.41 [95% C.I. 1.28-9.08], p = 0.01, and WHO clinical stage 4, HR 3.08 [1.17-8.12], p = 0.02). On multivariate analysis Hb < 9 g/dl remained predictive of mortality after controlling for age, baseline CD4%, WHO clinical stage and weight-for-height z-score (HR 2.95 (95% C.I. 1.04-8.35) p = 0.04). High early mortality was observed in this cohort of Kenyan children receiving HAART, and low baseline hemoglobin was an independent risk factor for death.


AREB1, AREB2, and ABF3 are master transcription factors that cooperatively regulate ABRE-dependent ABA signaling involved in drought stress tolerance and require ABA for full activation.
A myriad of drought stress-inducible genes have been reported, and many of these are activated by abscisic acid (ABA). In the promoter regions of such ABA-regulated genes, conserved cis-elements, designated ABA-responsive elements (ABREs), control gene expression via bZIP-type AREB/ABF transcription factors. Although all three members of the AREB/ABF subfamily, AREB1, AREB2, and ABF3, are upregulated by ABA and water stress, it remains unclear whether these are functional homologs. Here, we report that all three AREB/ABF transcription factors require ABA for full activation, can form hetero- or homodimers to function in nuclei, and can interact with SRK2D/SnRK2.2, an SnRK2 protein kinase that was identified as a regulator of AREB1. Along with the tissue-specific expression patterns of these genes and the subcellular localization of their encoded proteins, these findings clearly indicate that AREB1, AREB2, and ABF3 have largely overlapping functions. To elucidate the role of these AREB/ABF transcription factors, we generated an areb1 areb2 abf3 triple mutant. Large-scale transcriptome analysis, which showed that stress-responsive gene expression is remarkably impaired in the triple mutant, revealed novel AREB/ABF downstream genes in response to water stress, including many LEA class and group-Ab PP2C genes and transcription factors. The areb1 areb2 abf3 triple mutant is more resistant to ABA than are the other single and double mutants with respect to primary root growth, and it displays reduced drought tolerance. Thus, these results indicate that AREB1, AREB2, and ABF3 are master transcription factors that cooperatively regulate ABRE-dependent gene expression for ABA signaling under conditions of water stress.


Gait and postural control patterns and rehabilitation in Down syndrome: a systematic review.
[Purpose] To describe (1) the current knowledge on gait and postural control in individuals with Down syndrome in terms of spatiotemporal, kinematics and kinetics, and (2) relevant rehabilitation strategies. [Methods] Randomized and non-randomized clinical trials published between January 1997 and October 2019 were selected by searching four scientific databases. We included studies on patients with Down syndrome involving gait analysis or postural control. A custom data-extraction and appraisal form was developed to collect the key features of each article. The PEDro Scale was used to evaluate the methodological quality of the studies. [Results] A total of 37 out of 146 cross-sectional and longitudinal studies were included in the review. The main abnormalities included: reduction of gait velocity and step length, poor static balance with increased anteroposterior and mediolateral oscillations and a larger step width. [Conclusion] A number of compensatory patterns during movement was observed, with a direct influence on improvements in stability and postural control throughout daily life. Intensive gait training at an early age appears to produce long-term improvements in this population. Future research should focus on the interaction between the motor and cognitive function, and on the functional effects due to the exposure to an enriched environment.


[Recording of the chemiluminescence of the component parts of the blood serum in the presence of divalent iron].
Measurements of chemiluminescence of apo-B-containing lipoproteins of blood serum enables one to evaluate their capability of peroxidation in the presence of ferrous ions. The recording of chemiluminescence changes in the standard chemiluminescent system in the presence of ferrous ions after adding the supernatant remained after the precipitation of apo-B-containing lipoproteins may serve a simple test for the assessment of blood serum antioxidant activity.


Quantifying Bone Strength Deficits in Young Adults Born Extremely Preterm or Extremely Low Birth Weight.
The long-term bone health of young adults born extremely preterm (EP; <28 weeks' gestation) or extremely low birth weight (ELBW; <1000 g birth weight) in the post-surfactant era (since the early 1990s) is unclear. This study investigated their bone structure and estimated bone strength using peripheral quantitative computed tomography (pQCT)-based finite element modeling (pQCT-FEM). Results using this technique have been associated with bone fragility in several clinical settings. Participants comprised 161 EP/ELBW survivors (46.0% male) and 122 contemporaneous term-born (44.3% male), normal birth weight controls born in Victoria, Australia, during 1991-1992. At age 25 years, participants underwent pQCT at 4% and 66% of tibia and radius length, which was analyzed using pQCT-FEM. Groups were compared using linear regression and adjusted for height and weight. An interaction term between group and sex was added to assess group differences between sexes. Parameters measured included compressive stiffness (kcomp ), torsional stiffness (ktorsion ), and bending stiffness (kbend ). EP/ELBW survivors were shorter than the controls, but their weights were similar. Several unadjusted tibial pQCT-FEM parameters were lower in the EP/ELBW group. Height- and weight-adjusted ktorsion at 66% tibia remained lower in EP/ELBW (mean difference [95% confidence interval] -180 [-352, -8] Nm/deg). The evidence for group differences in ktorsion and kbend at 66% tibia was stronger among males than females (pinteractions <0.05). There was little evidence for group differences in adjusted radial models. Lower height- and weight-adjusted pQCT-FEM measures in EP/ELBW compared with controls suggest a clinically relevant increase in predicted long-term fracture risk in EP/ELBW survivors, particularly males. Future pQCT-FEM studies should utilize the tibial pQCT images because of the greater variability in the radius possibly related to lower measurement precision. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


The fate of low grade dysplasia in ulcerative colitis.
The optimal strategy for the management of definite low grade dysplasia (LGD) detected in surveillance in ulcerative colitis (UC) is unknown, because the natural history of LGD has not been well described. We reviewed the Mayo Clinic records of patients with UC found to have flat LGD between 1990 and 1993 in whom a nonoperative strategy was pursued for 2 months or more. Eighteen patients with UC and LGD were observed for a median of 32 months. Nine of 18 patients identified with UC and LGD developed advanced neoplastic lesions during follow-up, which were defined as adenocarcinoma, raised dysplasia, or high grade dysplasia. The cumulative incidence of progression to an advanced lesion was 33% at 5 yr (95% CI = 9-56%). Only one patient developed adenocarcinoma, diagnosed 74 months after his initial finding of LGD and 20 months after his last surveillance exam. Besides this patient, adenocarcinoma was not detected in the colectomy specimens of 13 other patients who underwent surgery. Colectomies were performed for dysplasia or cancer in seven patients, active colitis in five patients, and unknown reasons in two patients. Four patients did not have colectomies. Neoplastic progression in patients with UC and LGD is common. Total proctocolectomy should be offered to all patients with flat LGD. Our study illustrates numerous pitfalls in the practice of surveillance.


Active and inactive renin in human forearm of hypertensive patients.
Although many in vitro and animal studies indicate the existence of a local renin--angiotensin system, data regarding its physiological role are quite controversial, and moreover, evidence suggesting inactive and active renin release from vascular tissue in vivo is lacking both in animal and humans. The aim of our study was to evaluate whether beta-adrenoceptor stimulation, a well-known stimulus to renin production, through isoproterenol might cause local renin production from vessels of the forearm of hypertensive patients. Drugs were infused into the brachial artery at systemically ineffective rates, while forearm blood flow (FBF, venous plethysmography), mean intra-arterial pressure, and heart rate were monitored throughout. Active and inactive vessel renin production was measured by calculating venous-arterial (V-A) differences by simultaneous sampling from brachial artery and an ipsilateral deep vein. Active renin (PRA) and total renin (Sepharose bound trypsin activation) were measured by radioimmunoassay while inactive renin was calculated as the difference between total and active renin. V-A differences were corrected for FBF to calculate renin extraction or production. In a group of 10 patients, isoproterenol, which was infused at increasing cumulative rates (0.03, 0.1, 0.3 micrograms.100 mL-1 forearm tissue.min-1 for 5 min each), caused a dose-dependent increment in FBF that was blunted by intra-arterial propranolol (n = 5) pretreatment (10 micrograms.100 mL-1 forearm tissue.min-1 for 10 min). beta-Adrenoceptor stimulation caused a dose-dependent outflow of both active and inactive renin, an effect antagonized by propranolol. In conclusion, our data represent the first evidence in humans of tissue active and inactive renin production in the forearm vascular bed.


Photolysis intermediates of human rhodopsin.
Photochemical studies were conducted on human rhodopsin at 20 degrees C to characterize the intermediates which precede the formation of metarhodopsin II, the trigger for the enzyme cascade mechanism of visual transduction. Human rhodopsin was prepared from eyes which had previously been used for corneal donations. Time resolved absorption spectra collected from 10(-8) to 10(-6) s after photolysis of human rhodopsin in detergent suspensions displayed biexponential decay kinetics. The apparent lifetimes obtained from the data are 65 +/- 20 and 292 +/- 25 ns, almost a factor of 2 slower than the corresponding rates in bovine rhodopsin. The spectra can be fit well using a model in which human bathorhodopsin decays toward equilibrium with a blue-shifted intermediate (BSI) which then decays to lumirhodopsin. Spectra and kinetic rate constants were determined for all these intermediates using a global analysis which showed that the spectra of the human intermediates are remarkably similar to bovine intermediates. Microscopic rate constants derived from this model are 7.4 x 10(6) s-1 for bathorhodopsin decay and 7.5 x 10(6) s-1 and 4.6 x 10(6) s-1 for the forward and reverse reactions of BSI, respectively. Decay of lumirhodopsin to later intermediates was studied from 10(-6) to 10(-1) s after photolysis of rhodopsin in human disk membrane suspensions. The human metarhodopsin I in equilibrium metarhodopsin II equilibrium appears to be more forward shifted than in comparable bovine studies.


Single-step fabrication of quantum funnels via centrifugal colloidal casting of nanoparticle films.
Centrifugal casting of composites and ceramics has been widely employed to improve the mechanical and thermal properties of functional materials. This powerful method has yet to be deployed in the context of nanoparticles--yet size-effect tuning of quantum dots is among their most distinctive and application-relevant features. Here we report the first gradient nanoparticle films to be constructed in a single step. By creating a stable colloid of nanoparticles that are capped with electronic-conduction-compatible ligands we were able to leverage centrifugal casting for thin-films devices. This new method, termed centrifugal colloidal casting, is demonstrated to form films in a bandgap-ordered manner with efficient carrier funnelling towards the lowest energy layer. We constructed the first quantum-gradient photodiode to be formed in a single deposition step and, as a result of the gradient-enhanced electric field, experimentally measured the highest normalized detectivity of any colloidal quantum dot photodetector.


Age-related changes in tissue macrophages precede cardiac functional impairment.
Cardiac tissue macrophages (cTMs) are abundant in the murine heart but the extent to which the cTM phenotype changes with age is unknown. This study characterizes aging-dependent phenotypic changes in cTM subsets. Using theCx3cr1(GFP/+) mouse reporter line where GFP marks cTMs, and the tissue macrophage marker Mrc1, we show that two major cardiac tissue macrophage subsets, Mrc1-GFP(hi) and Mrc1+GFP(hi) cTMs, are present in the young (<10 week old) mouse heart, and a third subset, Mrc1+GFP(lo), comprises ~50% of total Mrc1+ cTMs from 30 weeks of age. Immunostaining and functional assays show that Mrc1+ cTMs are the principal myeloid sentinels in the mouse heart and that they retain proliferative capacity throughout life. Gene expression profiles of the two Mrc1+ subsets also reveal that Mrc1+GFP(lo) cTMs have a decreased number of immune response genes (Cx3cr1, Lpar6, CD9, Cxcr4, Itga6 and Tgfβr1), and an increased number of fibrogenic genes (Ltc4s, Retnla, Fgfr1, Mmp9 and Ccl24), consistent with a potential role for cTMs in cardiac fibrosis. These findings identify early age-dependent gene expression changes in cTMs, with significant implications for cardiac tissue injury responses and aging-associated cardiac fibrosis.


Sensory deficits of the paretic and non-paretic upper limbs relate with the motor recovery of the poststroke subjects.
Post stroke, motor paresis has usually been considered to be a crucial factor responsible for the disability; other impairments such as somatosensory deficits may also play a role. To determine the relation between the sensory deficits (paretic and non-paretic upper limbs) and the motor recovery of the paretic upper limb and to predict the potential of motor recovery based on the sensory deficits among stroke subjects. The study was a cross-sectional study conducted in a rehabilitation institute. Ninety-five poststroke hemiparetic subjects having sensory impairment in any of the modalities were considered for this study. Sensory deficits were assessed on both the upper limbs (paretic and non-paretic) primarily using Erasmus MC modification of the revised version of Nottingham Sensory Assessment (Em-NSA) and Nottingham Sensory Assessment (Stereognosis) (NSA-S). The motor recovery was assessed using the Fugl-Meyer assessment (FMA). The measures of sensory deficits exhibited weak but significant correlation [the paretic (Em-NSA and NSA; r = .38 to .58; p < .001) and the non-paretic (Em-NSA and NSA; r = .24 to .38; p = .03 to .001)] with the motor recovery of the paretic upper limb as measured by FMA. The potential of favorable recovery of the paretic upper limb may be predicted using the cutoff scores of Em-NSA (30, 21, and 24) and NSA-S (5, 8, and 5) of the paretic side. In stroke, sensory deficits relate weakly with the recovery of the paretic upper limb and can predict recovery potential of the paretic upper limb.


Hard to Reach and Hidden: Improving the Identification of Young Dementia Carers.
Young dementia carers (YDCs) rarely receive appropriate training and support. Their visibility and identification remain dangerously low, and, consequently, support initiatives being developed are failing to reach them. This study explored the success (or failure) of YDC identification pathways as well as the barriers and enablers to their implementation. An explorative qualitative approach was followed, drawing on the experiences of parents of YDCs, dementia researchers, professionals in the field of dementia/young carers, and young adult carers. Data collection involved semi-structured interviews (n = 17) and a participatory 2-h workshop to discuss and critique preliminary themes as well as explore strategies to increase the visibility and identification of YDCs. Five themes were identified: a "whole-family approach" (as a pathway to identification), "not a carer" (self/family identification), a postcode lottery (high variability of support services), tailored support that is "fit for purpose", and the "power" of peer support. Recommendations on potential initiatives and actions that can help raise awareness and increase the identification success of YDCs are proposed. Our findings support the need for a broad and holistic approach to the identification of YDCs that runs alongside the development of support initiatives that are accessible and relatable. The support itself will play a role in improving subsequent identification or hindering it if not "fit for purpose".


Invariant total heart volume in the intact thorax.
Fast multisliced computerized tomography (Dynamic Spatial Reconstructor or DSR) was used to study the change in total heart volume (content of the pericardial sac) between end diastole (ED) and end systole (ES) with lungs held at 0 and 15 cmH2O airway inflation pressure (Paw). Nine dogs were anesthetized and scanned in the DSR. At 0 cmH2O airway pressure, mean total heart volume changed, on the average, only 2.7 +/- 0.6% (SE) of its ED volume comparing ED with ES. With lungs inflated to 15 cmH2O Paw, total heart volume decreased 12 +/- 0.5%. However, at this new heart volume, the change in total heart volume between ED and ES was only 1.7 +/- 0.5%. The data indicate that the epicardial apex of the heart remains relatively stationary while the atrioventricular groove moves toward the apex during systole and away from the apex during diastole. Thus the atria and ventricles empty and fill reciprocally even when the pericardial contents do not fully distend the pericardial sac. The invariant total heart volume observed in these species would minimize the work of the heart by maximizing the percentage of work expended to move blood and minimizing the work expended to move tissue (i.e., lung).


Predictors of diagnostic success with renal artery duplex ultrasonography.
Renal artery duplex ultrasonography (RA-DUS) is commonly used for the evaluation and follow-up of renal artery atherosclerotic disease. In a complete study, renal artery flow is evaluated from the vessel origin to the intraparenchymal branches. The quality of RA-DUS is in part technologist-dependent, but many factors may affect the ability to complete a diagnostic examination. This study evaluated the clinical and technical factors that predict the ability to obtain a complete RA-DUS examination. A prospective evaluation of all patients undergoing RA-DUS between July 2008 and February 2009 was performed. Factors such as patient age, gender, body mass index, technologists' years of experience, patient care setting (inpatient vs. outpatient), bedside examination, smoking before the examination, fasting status, and recent abdominal surgery were all recorded. Multivariate logistic regression analysis was performed. A p value of ≤ 0.05 was considered significant. During the study period, 250 patients underwent RA-DUS (mean age: 59.9 ± 17.8 years, 57% [143] female). A total of 87 (35%) examinations were incomplete. This included nondiagnostic examinations which did not exhibit any segment of the renal artery. Factors that were associated with an incomplete examination included technologists' years of experience (OR = 0.92, p = 0.042), bedside examination (OR = 4.17, p = 0.016), and recent abdominal surgery (OR = 3.45, p = 0.047). Body mass index, fasting status, and smoking before the examination did not affect the ability to obtain a complete study. One-third of the RA-DUS studies were classified as incomplete by the strict criteria used in this prospective study. An experienced ultrasound technologist is more likely to obtain a complete RA-DUS examination. Recent abdominal surgery and bedside examinations were predictive of a limited examination as well. Vascular laboratories should consider these factors when scheduling examinations so as to obtain complete RA-DUS studies, as well as improve the cost-effectiveness of resource utilization.


Suppressor T cell growth and differentiation: production of suppressor T cell differentiation factor by the murine thymoma BW5147.
Previous studies have identified a lymphokine, termed Ts differentiation factor (TsDF), in primary MLR supernatants that induces effector function of alloantigen-primed MLR-Ts. The present report describes constitutive production of TsDF by the murine thymoma BW5147, and its use to analyze alloantigen and TsDF requirements for MLR-Ts activation to TsF production. Serum-free supernatants of BW5147 restored the capacity of MLR-TsF production to alloantigen-primed MLR-Ts cultured with glutaraldehyde-fixed allogeneic stimulator cells, and were not themselves directly suppressive in the MLR assay. BW5147 supernatant induced MLR-TsF production from primed L3T4-Ly2+ MLR-Ts in the absence of concomitant proliferation, suggesting that the function of BW5147 supernatant, like that of MLR-derived TsDF, is a differentiative rather than a proliferative one, and is required for the synthesis or release of TsF. The differentiative activity of BW5147 supernatant was associated with a molecular species of approximately 14,500 m.w. by HPLC fractionation and was expressed independently of detectable IL 2, IL 3, IFN-gamma, and IL 1. The functional activity of BW5147 supernatant has therefore been provisionally designated BW5147-derived Ts differentiative factor, or BW-TsDF. By using BW-TsDF, it was demonstrated that MLR-Ts fail to respond to TsDF in the absence of, or preceding, reexposure to priming alloantigen. Instead, alloantigen binding by primed MLR-Ts appears to create a transient state of TsDF responsiveness. Primed MLR-Ts were fully sensitive to delayed addition of TsDF for approximately 12 hr after reexposure to alloantigen, but became TsDF-unresponsive within 24 to 36 hr. MLR-Ts cultured alone for 36 hr were fully responsive to the combined addition of TsDF and alloantigen. Thus, MLR-Ts activation to TsF release requires the sequential events of specific alloantigen binding, which induces a TsDF-responsive state, followed by interaction with TsDF. The transience of induced TsDF responsiveness suggests a precise mechanism for control of antigen-initiated Ts activation to effector function.


Covalently bound fatty acids in the gastrointestinal epithelial cell membrane.
Myristic, palmitic, stearic, oleic and linoleic acids have been identified as the covalently bound fatty acids in the monkey gastrointestinal mucosal membrane proteins and among them palmitolation was predominant. Distribution studies in various regions of the gastrointestinal mucosa showed no significant difference in the content and composition of covalently bound fatty acids in these membrane and most of the fatty acids were found to be ester linked. Total membranes from isolated crypt and villus enterocytes and colonocytes had similar composition of these fatty acids. Covalently bound fatty acid levels were higher in the small intestinal brush border membrane. As suggested for the mucus glycoproteins, covalently bound fatty acids in the intestinal epithelial cell membrane may protect these membranes from proteolytic damage from the luminal proteases.


Non-invasive, Brain-controlled Functional Electrical Stimulation for Locomotion Rehabilitation in Individuals with Paraplegia.
Spinal cord injury (SCI) impairs the flow of sensory and motor signals between the brain and the areas of the body located below the lesion level. Here, we describe a neurorehabilitation setup combining several approaches that were shown to have a positive effect in patients with SCI: gait training by means of non-invasive, surface functional electrical stimulation (sFES) of the lower-limbs, proprioceptive and tactile feedback, balance control through overground walking and cue-based decoding of cortical motor commands using a brain-machine interface (BMI). The central component of this new approach was the development of a novel muscle stimulation paradigm for step generation using 16 sFES channels taking all sub-phases of physiological gait into account. We also developed a new BMI protocol to identify left and right leg motor imagery that was used to trigger an sFES-generated step movement. Our system was tested and validated with two patients with chronic paraplegia. These patients were able to walk safely with 65-70% body weight support, accumulating a total of 4,580 steps with this setup. We observed cardiovascular improvements and less dependency on walking assistance, but also partial neurological recovery in both patients, with substantial rates of motor improvement for one of them.


Penile duplication in newborn with multiple anomalies.
We present a case of male, premature born child with multiple anomalies. The physical status was dominated by penile duplication, with additional, abortion scrotum in the median line, without palpable content and omphalocele with semi septum of the anus. By ultrasound examination of internal organs, we found a complex congenital heart anomaly, multiple anomalies in abdomen and micro calcifications in the central nervous system. General condition of the child required a prolonged mechanical ventilation and intensive care, so with clinical picture of liver failure at the age of 45 days occurred fetal outcome.


Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.


Estimation of Gait Mechanics Based on Simulated and Measured IMU Data Using an Artificial Neural Network.
Enhancement of activity is one major topic related to the aging society. Therefore, it is necessary to understand people's motion and identify possible risk factors during activity. Technology can be used to monitor motion patterns during daily life. Especially the use of artificial intelligence combined with wearable sensors can simplify measurement systems and might at some point replace the standard motion capturing using optical measurement technologies. Therefore, this study aims to analyze the estimation of 3D joint angles and joint moments of the lower limbs based on IMU data using a feedforward neural network. The dataset summarizes optical motion capture data of former studies and additional newly collected IMU data. Based on the optical data, the acceleration and angular rate of inertial sensors was simulated. The data was augmented by simulating different sensor positions and orientations. In this study, gait analysis was undertaken with 30 participants using a conventional motion capture set-up based on an optoelectronic system and force plates in parallel with a custom IMU system consisting of five sensors. A mean correlation coefficient of 0.85 for the joint angles and 0.95 for the joint moments was achieved. The RMSE for the joint angle prediction was smaller than 4.8° and the nRMSE for the joint moment prediction was below 13.0%. Especially in the sagittal motion plane good results could be achieved. As the measured dataset is rather small, data was synthesized to complement the measured data. The enlargement of the dataset improved the prediction of the joint angles. While size did not affect the joint moment prediction, the addition of noise to the dataset resulted in an improved prediction accuracy. This indicates that research on appropriate augmentation techniques for biomechanical data is useful to further improve machine learning applications.


Modulation of olfactory sensitivity and glucose-sensing by the feeding state in obese Zucker rats.
The Zucker fa/fa rat has been widely used as an animal model to study obesity, since it recapitulates most of its behavioral and metabolic dysfunctions, such as hyperphagia, hyperglycemia and insulin resistance. Although it is well established that olfaction is under nutritional and hormonal influences, little is known about the impact of metabolic dysfunctions on olfactory performances and glucose-sensing in the olfactory system of the obese Zucker rat. In the present study, using a behavioral paradigm based on a conditioned olfactory aversion, we have shown that both obese and lean Zucker rats have a better olfactory sensitivity when they are fasted than when they are satiated. Interestingly, the obese Zucker rats displayed a higher olfactory sensitivity than their lean controls. By investigating the molecular mechanisms involved in glucose-sensing in the olfactory system, we demonstrated that sodium-coupled glucose transporters 1 (SGLT1) and insulin dependent glucose transporters 4 (GLUT4) are both expressed in the olfactory bulb (OB). By comparing the expression of GLUT4 and SGLT1 in OB of obese and lean Zucker rats, we found that only SGLT1 is regulated in genotype-dependent manner. Next, we used glucose oxidase biosensors to simultaneously measure in vivo the extracellular fluid glucose concentrations ([Gluc]ECF) in the OB and the cortex. Under metabolic steady state, we have determined that the OB contained twice the amount of glucose found in the cortex. In both regions, the [Gluc]ECF was 2 fold higher in obese rats compared to their lean controls. Under induced dynamic glycemia conditions, insulin injection produced a greater decrease of [Gluc]ECF in the OB than in the cortex. Glucose injection did not affect OB [Gluc]ECF in Zucker fa/fa rats. In conclusion, these results emphasize the importance of glucose for the OB network function and provide strong arguments towards establishing the OB glucose-sensing as a key factor for sensory olfactory processing.


Single nucleotide variants of the TGACTCA motif modulate energetics and orientation of binding of the Jun-Fos heterodimeric transcription factor.
The Jun-Fos heterodimeric transcription factor is the terminal link between the transfer of extracellular information in the form of growth factors and cytokines to the site of DNA transcription within the nucleus in a wide variety of cellular processes central to health and disease. Here, using isothermal titration calorimetry, we report detailed thermodynamics of the binding of bZIP domains of Jun-Fos heterodimer to synthetic dsDNA oligos containing the TGACTCA cis element and all possible single nucleotide variants thereof encountered widely within the promoters of a diverse array of genes. Our data show that Jun-Fos heterodimer tolerates single nucleotide substitutions and binds to TGACTCA variants with affinities in the physiologically relevant micromolar to submicromolar range. The energetics of binding are richly favored by enthalpic forces and opposed by entropic changes across the entire spectrum of TGACTCA variants in agreement with the notion that protein-DNA interactions are largely driven by electrostatic interactions and intermolecular hydrogen bonding. Of particular interest is the observation that the Jun-Fos heterodimer binds to specific TGACTCA variants in a preferred orientation. Our 3D atomic models reveal that such orientational preference results from asymmetric binding and may in part be attributable to chemically distinct but structurally equivalent residues R263 and K148 located within the basic regions of Jun and Fos, respectively. Taken together, our data suggest that the single nucleotide variants of the TGACTCA motif modulate energetics and orientation of binding of the Jun-Fos heterodimer and that such behavior may be a critical determinant of differential regulation of specific genes under the control of this transcription factor. Our study also bears important consequences for the occurrence of single nucleotide polymorphisms within the TGACTCA cis element at specific gene promoters between different individuals.


Comparison of the sedimentation and gel-filtration behaviour of human apotransferrin and its copper and iron complexes.
Equilibrium-dialysis experiments showed that Tris or citrate in the solution prevented copper from occupying completely the specific metal-binding sites on human transferrin. Differential measurements of sedimentation velocity under conditions where two atoms of copper per molecule of protein were bound showed an increase in s(0) (20,w), relative to that of the apoprotein, practically the same as that produced by two atoms of iron. Gel-filtration experiments made under the same conditions to investigate the effect of copper binding on the Stokes radius of the protein showed merely that it lost most of the metal as it passed down the column.


Dysregulated CD46 shedding interferes with Th1-contraction in systemic lupus erythematosus.
IFN-γ-producing T helper 1 (Th1) cell responses mediate protection against infections but uncontrolled Th1 activity also contributes to a broad range of autoimmune diseases. Autocrine complement activation has recently emerged as key in the induction and contraction of human Th1 immunity: activation of the complement regulator CD46 and the C3aR expressed by CD4+ T cells via autocrine generated ligands C3b and C3a, respectively, are critical to IFN-γ production. Further, CD46-mediated signals also induce co-expression of immunosuppressive IL-10 in Th1 cells and transition into a (self)-regulating and contracting phase. In consequence, C3 or CD46-deficient patients suffer from recurrent infections while dysregulation of CD46 signaling contributes to Th1 hyperactivity in rheumatoid arthritis and multiple sclerosis. Here, we report a defect in CD46-regulated Th1 contraction in patients with systemic lupus erythematosus (SLE). We observed that MMP-9-mediated increased shedding of soluble CD46 by Th1 cells was associated with this defect and that inhibition of MMP-9 activity normalized release of soluble CD46 and restored Th1 contraction in patients' T cells. These data may deliver the first mechanistic explanation for the increased serum CD46 levels observed in SLE patients and indicate that targeting CD46-cleaving proteases could be a novel avenue to modulate Th1 responses.


Spirituality and healthcare organizations.
In recent years, the place of spirituality in organizations has become increasingly discussed and advocated. On a personal level, this may involve achieving personal fulfillment or spiritual growth in the workplace. In the broader sense, spirituality is considered by many to be essential in an organization's interactions with employees, customers, and the community. This article describes a possible role for greater spirituality in healthcare organizations, whose cultures in recent decades have largely excluded spirituality or religiousness. This is the consequence of an analytical, scientific perspective on human health; a reductionist paradigm in biomedical research; and the inevitable bureaucratization occurring in large healthcare organizations. However, in recent decades, numerous scientific articles supporting a connection between faith or religiousness and positive health outcomes have been published. Because individuals seek meaning when experiencing severe illnesses, and humans universally respond to compassion and caring, spirituality among healthcare workers and managers appears highly appropriate. The article describes organizational barriers to the greater inclusion of spirituality in healthcare and presents several approaches to developing a more caring organization. These include eliciting extensive input from all staff and clinicians in identifying core or common values, ethics, and a philosophy of caring. Programs should ensure that the views of nonreligious staff and patients are respected and that clear guidelines are established for the extent and nature of affective or spiritual support for patients.


A comprehensive study of whole-brain functional connectivity in children and young adults.
Over the past decade, examination of functional connectivity using functional magnetic resonance imaging has become an important tool to investigate functional changes in patient populations, healthy aging, and recently also child development. Most prior developmental studies focused on functional connectivity between brain regions important for cognitive or emotional control and the so-called "default-mode network." In the present study, we investigated whole-brain functional connectivity in children (11-13 years; N = 19) and young adults (19-25 years; N = 29), without a priori restrictions to specific regions. We found similar patterns of functionally connected regions in children and young adults, but there were differences in the size of functionally connected regions (i.e., the number of voxels), as well as in the strength of functional connectivity (i.e., the correlation value) between brain regions. This indicates that functional connectivity continues to change during adolescence. Developmental differences were found across the whole brain, but the effects differed for functional connectivity patterns associated with higher cognitive or emotional functions and functional connectivity patterns associated with basic visual and sensorimotor functions. Finally, we showed that the majority of functional connectivity differences could not be explained on the basis of gray matter density alone.


[Aspergillosis of the central nervous system in glioblastoma multiforme].
A 45 year-old male with a butterfly glioma received stereotactic biopsy for histologic confirmation of the clinical diagnosis. Microscopically, the results were controversial since some biopsy specimens showed distinct inflammatory changes, while others displayed typical features of a malignant glioma. The patient died four days after the stereotactic approach due to therapy-resistant intracranial pressure rise. In addition to a large butterfly glioblastoma originating from the frontal part of the corpus callosum, neuropathologic examination revealed a mycotic encephalitis with formation of numerous fungi-containing inflammatory foci in all parts of the brain and in the glioma. General autopsy disclosed pulmonary aspergillosis as the source of the inflammatory spread. A previous steroid medication over several weeks for treatment of increased intracranial pressure may be considered as an important factor in the origin of the pulmonary aspergillosis complicating the butterfly glioma.


Endotoxin-induced activation of the nuclear transcription factor kappa B and expression of E-selectin messenger RNA in hepatocytes, Kupffer cells, and endothelial cells in vivo.
Endotoxin causes neutrophil sequestration in the liver and severe vascular and parenchymal cell injury. Inducible adhesion molecules such as intercellular adhesion molecule-1 and selectins are involved in neutrophil recruitment to an inflammatory site in vivo. The objective of our study was to characterize the translocation of the nuclear factor kappa B (NF-kappa B) from the cytoplasm to the nucleus (NF-kappa B activation) during endotoxemia using the electrophoretic mobility shift assay and to investigate its role in regulation of E-selectin gene transcription in liver cells in vivo. Administration of 0.5 mg/kg Salmonella enteritidis endotoxin to male Fischer rats induced a drastic but transient activation of NF-kappa B at the whole liver level. Major subunits identified were p50 (NF-kappa B1), p65 (RelA), and c-Rel, but not p52 (NF-kappa B2). Isolation of liver cells from control animals induced substantial NF-kappa B activation in Kupffer cells and endothelial cells and minor activation in hepatocytes. One hour after endotoxin treatment in vivo, NF-kappa B was uniformly activated in all isolated cells. At 5 h, NF-kappa B activation was reduced to various degrees in all cell types, with hepatocytes showing only a moderate decrease. Northern blot analysis indicated no E-selectin mRNA in all control cells; however, at 1 h, endotoxin induced E-selectin gene transcription transiently in endothelial cells and in Kupffer cells but not in hepatocytes. These data support the hypothesis that NF-kappa B activation is important for E-selectin gene transcription in hepatic vascular lining cells. However, the fact that hepatic parenchymal cells, despite NF-kappa B activation do not express E- selectin mRNA, suggests that NF-kappa B activation alone is not sufficient for E-selectin gene transcription in vivo.


Maternal Factors Associated With Infant Neurodevelopment in HIV-Exposed Uninfected Infants.
This study evaluated maternal factors associated with infant neurodevelopmental outcomes among HIV-exposed uninfected (HEU) infants in rural South Africa. This study followed pregnant women living with HIV pre- and postpartum and evaluated sociodemographic factors, use of antiretrovirals (ARVs), and mental health factors as predictors of HEU infant developmental outcomes (cognitive, receptive, and expressive communication, fine and gross motor skills). Participants were 80 mother-infant dyads. Mothers were assessed during pregnancy, and HEU infant development was assessed at a mean (SD) of 13.36 (1.89) months of age. Women were an average (SD) of 28.9 (5.2) years of age, and infants were on average 13.4 (1.9) months old. An analysis of covariance indicated that infants whose mothers had ARV detected in dry blood spots at 32 weeks of pregnancy had lower functioning scores in the cognitive domain than those with undetected ARV (n = 14; M, 15.3 vs 17.2; P = .048). Antenatal physical intimate partner violence was also associated with delayed cognitive functioning (F (1, 74), 4.96; P = .029). This study found risks for delayed infant cognitive development to be associated with the use of ARV during pregnancy and intimate partner violence, although findings merit replication due to the low sample size. Given the growing number of HEU infants, the necessity to better understand the potential toxicity of ARV exposure in utero is apparent. Similarly, the need for preventing intimate partner violence and screening for, and managing, developmental delays among these infants is increasing.


Colloidal characterization and thermodynamic stability of binary eye lens protein mixtures.
We present a study of binary mixtures of eye lens crystallin proteins. A coarse-grained model of aqueous alpha- and gamma-crystallin mixtures based on molecular dynamics simulations and SANS experiments is proposed. Thermodynamic perturbation theory is implemented to obtain the stability boundaries, or spinodal surface, of the binary mixture in the full parameter space. The stability of these high-concentration crystallin mixtures was found to depend on the alpha-gamma attraction in a manner that is both extremely sensitive and nonmonotonic; stronger or weaker attraction resulted in a spectacularly enhanced instability. The relevance of these mechanisms as possible sources of the alteration of the spatial distribution of the lens proteins encountered in cataract disease is discussed.


Patient Advocacy Organizations, Industry Funding, and Conflicts of Interest.
Patient advocacy organizations (PAOs) are influential health care stakeholders that provide direct counseling and education for patients, engage in policy advocacy, and shape research agendas. Many PAOs report having financial relationships with for-profit industry, yet little is known about the nature of these relationships. To describe the nature of industry funding and partnerships between PAOs and for-profit companies in the United States. A survey was conducted from September 1, 2013, to June 30, 2014, of a nationally representative random sample of 439 PAO leaders, representing 5.6% of 7865 PAOs identified in the United States. Survey questions addressed the nature of their activities, their financial relationships with industry, and the perceived effectiveness of their conflict of interest policies. Amount and sources of revenue as well as organizational experiences with and policies regarding financial conflict of interest. Of the 439 surveys mailed to PAO leaders, 289 (65.8%) were returned with at least 80% of the questions answered. The PAOs varied widely in terms of size, funding, activities, and disease focus. The median total revenue among responding organizations was $299 140 (interquartile range, $70 000-$1 200 000). A total of 165 of 245 PAOs (67.3%) reported receiving industry funding, with 19 of 160 PAOs (11.9%) receiving more than half of their funding from industry. Among the subset of PAOs that received industry funding, the median amount was $50 000 (interquartile range, $15 000-$200 000); the median proportion of industry support derived from the pharmaceutical, device, and/or biotechnology sectors was 45% (interquartile range, 0%-100%). A total of 220 of 269 respondents (81.8%) indicated that conflicts of interest are very or moderately relevant to PAOs, and 94 of 171 (55.0%) believed that their organizations' conflict of interest policies were very good. A total of 22 of 285 PAO leaders (7.7%) perceived pressure to conform their positions to the interests of corporate donors. Patient advocacy organizations engage in wide-ranging health activities. Although most PAOs receive modest funding from industry, a minority receive substantial industry support, raising added concerns about independence. Many respondents report a need to improve their conflict of interest policies to help maintain public trust.


Ontogeny of circadian and light regulation of melatonin release in Xenopus laevis embryos.
The retinal photoreceptors of Xenopus laevis contain a circadian clock that controls the synthesis and release of melatonin, resulting in high levels during the night and low levels during the day. Light is also an important regulator of melatonin synthesis and acts directly to acutely suppress melatonin synthesis during the day and indirectly to entrain the circadian clock. We examined the development of circadian and light regulation of melatonin release in Xenopus retinas and pineal glands. Pineal glands are capable of making measurable melatonin in culture soon after they evaginate from the diencephalon at stage 26. In cyclic light, the melatonin rhythms are robust, with higher overall levels and greater amplitudes than in constant darkness. However, the rhythm of melatonin release damps strongly and quickly toward baseline in constant darkness. Similar results are observed in older (stage 47) embryos, indicating that cyclic light has a positive effect on melatonin synthesis in this tissue. Optic vesicles dissected at stage 26 do not release melatonin in culture until the second or third day. It is weakly rhythmic in cyclic light, but in constant dark it is released at constitutively high levels throughout the day. By stage 41, the eyes release melatonin rhythmically in both cyclic light and constant darkness with similar amplitude. Our results show that Xenopus embryos develop a functional, photoresponsive circadian clock in the eye within the first few days of life and that rhythmic melatonin release from the pineal gland at comparable stages is highly dependent on a light-dark cycle.


Altered spring phenology of North American freshwater turtles and the importance of representative populations.
Globally, populations of diverse taxa have altered phenology in response to climate change. However, most research has focused on a single population of a given taxon, which may be unrepresentative for comparative analyses, and few long-term studies of phenology in ectothermic amniotes have been published. We test for climate-altered phenology using long-term studies (10-36 years) of nesting behavior in 14 populations representing six genera of freshwater turtles (Chelydra, Chrysemys, Kinosternon, Malaclemys, Sternotherus, and Trachemys). Nesting season initiation occurs earlier in more recent years, with 11 of the populations advancing phenology. The onset of nesting for nearly all populations correlated well with temperatures during the month preceding nesting. Still, certain populations of some species have not advanced phenology as might be expected from global patterns of climate change. This collection of findings suggests a proximate link between local climate and reproduction that is potentially caused by variation in spring emergence from hibernation, ability to process food, and thermoregulatory opportunities prior to nesting. However, even though all species had populations with at least some evidence of phenological advancement, geographic variation in phenology within and among turtle species underscores the critical importance of representative data for accurate comprehensive assessments of the biotic impacts of climate change.


Prenatal cocaine: quantity of exposure and gender moderation.
Animal but few human studies have demonstrated gender-influenced differences in outcome related to prenatal cocaine exposure. Pregnant participants in a prospective pregnancy study were interviewed for drug use. Exposure was considered positive if history or laboratory tests were positive. An ordinal measure of exposure was also constructed. Six years later, the child and primary caretaker were tested to assess drug use in the home since birth and teacher-assessed child behavior. Data were complete for 473 children (204 cocaine exposed). Twenty-four of the exposed children (12%) were considered to have persistent pregnancy exposure based on positive urine screen at delivery. Boys with any prenatal cocaine exposure scored significantly higher (more problem behaviors) than nonexposed boys on the hyperactivity item. In contrast, no similar cocaine effect was observed for girls. When cocaine exposure was expressed as the three-level ordinal variable, boys, but not girls, with persistent exposure had more behavior problems (0.5 to 1.0 SD higher). Even after control for important covariates, boys with persistent exposure had more problems in central processing, motor skills, handling abstract concepts, and passivity to the environment. The magnitude of the relations reported in this research were moderate to large. In summary, both gender and the level of exposure had a significant behavioral effect on school-age behavior. In these analyses, the behavior of boys, but not girls, prenatally exposed to cocaine was significantly and negatively affected, and these findings remained after control for covariates, including prenatal alcohol or other illicit drug exposures and postnatal drug use in the home.


Scalable low-cost SnS(2) nanosheets as counter electrode building blocks for dye-sensitized solar cells.
A new type of semitransparent SnS2 nanosheet (NS) films were synthesized using a simple and environmentally friendly solution-processed approach, which were subsequently used as a counter electrode (CE) alternative to the noble metal Pt for triiodide reduction in dye-sensitized solar cells (DSSCs). The resultant SnS2 -based CE with a thickness of about 300 nm exhibited excellent electrochemical catalytic activity for catalyzing the reduction of triiodide and demonstrated comparable power conversion efficiency of 7.64 % with that of expensive Pt-based CE in DSSCs (7.71 %). When functionalized with a small amount of carbon nanoparticles, the SnS2 NS-based CE showed even better performance of 8.06 % than Pt under the same conditions. Considering the facile fabrication method, optical transparency, low cost, and remarkable catalytic property, this study on SnS2 NSs may shed light on the large-scale production of electrocatalytic electrode materials for low-cost photovoltaic devices.


Reduced exercise capacity and clinical outcomes following acute myocardial infarction.
Reduced exercise capacity is known to be an important predictor of poor prognosis and disability in patients with cardiovascular diseases and chronic heart failure, and even members of the general population. However, data about exercise capacity assessed by cardiopulmonary exercise testing (CPX) in acute myocardial infarction (AMI) patients who underwent primary percutaneous coronary intervention (PCI) is scarce. Among 594 consecutive AMI patients who underwent primary PCI, we examined 136 patients (85.3% men, 64.9 ± 11.9 years) who underwent CPX during hospitalization for AMI. CPX was usually performed 5 days after the onset of AMI. Reduced exercise capacity was defined as peak VO2 ≤ 12. Clinical outcomes including all-cause death, myocardial infarction, and hospitalization due to heart failure were followed. Among 136 patients, reduced exercise capacity (peak VO2 ≤ 12) was seen in 38 patients (28%). Patients with reduced exercise capacity were older, more likely to have hypertension, and had lower renal function. In echocardiography, patients with reduced exercise capacity had higher E/e' and larger left atrial dimension. Multivariate logistic analysis showed that E/e' (OR 1.19, 95% CI 1.09-1.31, p < 0.001) was an independent predictor of reduced exercise capacity (peak VO2 ≤ 12). Median follow-up term was 12 months (IQR 9-22). The occurrence of composite endpoints of all-cause death, myocardial infarction, and hospitalization due to heart failure was significantly higher in patients with peak VO2 ≤ 12 than those with peak VO2 > 12 (p < 0.001). Reduced exercise capacity following primary PCI in AMI patients is associated with diastolic dysfunction and may lead to poorer clinical outcomes.


Intratumoral TIGIT+ CD8+ T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer.
T-cell immunoglobulin and ITIM domain (TIGIT) is identified as a novel checkpoint receptor that can facilitate immune escape via mediating T-cell exhaustion in tumors. However, the clinical significance and immune contexture correlation of intratumoral TIGIT+ CD8+ T-cells remain to be further explored in muscle-invasive bladder cancer (MIBC). 259 patients with MIBC from two clinical centers (Zhongshan Hospital, n=141; Shanghai Cancer Center, n=118) were analyzed to evaluate the prognostic value and immune contexture association of TIGIT+ CD8+ T-cells through immunohistochemistry. Fresh tumor tissue samples from 26 patients with MIBC were examined to discover the phenotype of this CD8 subpopulation by flow cytometry. High infiltration of intratumoral TIGIT+ CD8+ T-cells predicted poor overall survival (OS) and recurrence-free survival (RFS) in MIBC. For patients with stage II MIBC with low infiltration of TIGIT+ CD8+ cells, adjuvant chemotherapy (ACT) could significantly prolong their OS and RFS. Intratumoral TIGIT+ CD8+ T-cell abundance was correlated with impaired CD8+ T-cell cytotoxicity and exhibited production of immunosuppressive cytokine IL-10. Further analysis of tumor-infiltrating immune cell landscape revealed TIGIT+ CD8+ T-cells were associated with suppressive immune contexture, including Th2 cells, regulatory T-cells, mast cells and neutrophils. Intratumoral TIGIT+ CD8+ T-cell abundance could serve as an independent prognosticator for clinical outcome and a predictive biomarker for inferior ACT responsiveness. Intratumoral TIGIT+ CD8+ T-cell abundance correlated with dampened CD8+ T-cell antitumor immunity and immunosuppressive contexture abundance, highlighting a tumor-promoting role of TIGIT+ CD8+ T-cells.


Paeonol Inhibits Pancreatic Cancer Cell Migration and Invasion Through the Inhibition of TGF-β1/Smad Signaling and Epithelial-Mesenchymal-Transition.
Paeonol, a natural product derived from the root of Cynanchum paniculatum (Bunge) K. Schum and the root of Paeonia suffruticosa Andr. (Ranunculaceae) has attracted extensive attention for its anti-cancer proliferation effect in recent years. The present study examined the role of paeonol in suppressing migration and invasion in pancreatic cancer cells by inhibiting TGF-β1/Smad signaling. Cell viability was evaluated by MTT and colonial formation assay. Migration and invasion capabilities were examined by cell scratch-wound healing assay and the Boyden chamber invasion assay. Western Blot and qRT-PCR were used to measure the protein and RNA levels of vimentin, E-cadherin, N-cadherin, and TGF-β1/Smad signaling. At non-cytotoxic dose, 100 μΜ and 150 μΜ of paeonol showed significant anti-migration and anti-invasion effects on Panc-1 and Capan-1 cells (p<0.01). Paeonol inhibited epithelial-mesenchymal-transition by upregulating E-cadherin, and down regulating N-cadherin and vimentin expressions. Paeonol inhibited TGF-β1/Smad signaling pathway by downregulating TGF-β1, p-Smad2/Smad2 and p-Smad3/Smad3 expressions. Further, TGF-β1 attenuated the anti-migration and anti-invasion capacities of paeonol in Panc-1 and Capan-1 cells. These findings revealed that paeonol could suppress proliferation and inhibit migration and invasion in Panc-1 and Capan-1 cells by inhibiting the TGF-β1/Smad pathway and might be a promising novel anti-pancreatic cancer drug.


Arsenic in glacial aquifers: sources and geochemical controls.
A total of 176 wells in sand-and-gravel glacial aquifers in central Illinois were sampled for arsenic (As) and other chemical parameters. The results were combined with archived and published data from several hundred well samples to determine potential sources of As and the potential geochemical controls on its solubility and mobility. There was considerable spatial variability in the As concentrations. High concentrations were confined to areas smaller than 1 km in diameter. Arsenic and well depth were uncorrelated. Arsenic solubility appeared to be controlled by oxidation-reduction (redox) conditions, especially the presence of organic matter. Geochemical conditions in the aquifers are typically reducing, but only in the most reducing water does As accumulate in solution. In wells in which total organic carbon (TOC) was below 2 mg/L and sulfate (SO4(2-)) was present, As concentrations were low or below the detection limit (0.5 microg/L). Arsenic concentrations >10 microg/L were almost always found in wells where TOC was >2 mg/L and SO4(2-) was absent or at low concentrations, indicating post-SO4 (2-)reducing conditions. Iron (Fe) is common in the aquifer sediments, and Fe oxide reduction appears to be occurring throughout the aquifers. Arsenic is likely released from the solid phase as Fe oxide is reduced.


Immune Myopathy With Perimysial Pathology Associated With Interstitial Lung Disease and Anti-EJ Antibodies.
We report a case of immune myopathy with perimysial pathology associated with anti-glycyl-transfer RNA synthetase (anti-EJ) antibody and an excellent treatment response. Chart review. A 36-year-old woman presented with 3 months of fatigue, weight loss, progressive weakness in a scapuloperoneal distribution, and dysphagia. Nerve conduction studies, electromyography, and ultrasound suggested an irritable myopathy. She had marked elevations of creatine kinase and positive anti-glycyl-transfer RNA synthetase (anti-EJ) antibodies. A left biceps muscle biopsy revealed inflammation of the perimysium and surrounding perimysial blood vessels with focal fragmentation of the perimysium. Further evaluation revealed interstitial lung disease. Treatment with prednisone and mycophenolate mofetil led to marked clinical improvement of her symptoms. Our case adds to the growing spectrum of inflammatory myopathies and highlights the importance of performing a comprehensive, multisystem workup.


Splenectomy for hereditary spherocytosis: complete, partial or not at all?
Hereditary spherocytosis (HS) is an hematologic disorder, common in the Northern European population, which is characterized by hemolytic anemia and splenomegaly. The pathophysiological bedrock of HS consists of the retention and damage of abnormal red cells, caused by an intrinsic erythrocyte membrane defect. Hemolysis within the spleen is the main detrminant of erythrocyte destruction in patients with HS. Splenectomy removes the primary ?graveyard? for spherocytes and, thus, eliminates anemia and hyperbilirubinemia and lowers the high reticulocyte number to nearly normal levels. Spleen removal is an effective therapeutic option but it is not without risks. The incidence and public health impact of spleen surgery in children with HS is substantial. Unfortunately, splenectomy is sometimes recommended erroneously for young children who have a mild clinical phenotype or is performed without relying on careful assessment of the risks and benefits. This article aims to present criticism and address controversy about HS management. Unclear and still controversial issues are tackled according to the author?s personal viewpoint, because strong evidence in different aspects of HS management is lacking.


Assessment of dietary adequacy in a remote Inuvialuit population.
Traditional foods are rich sources of essential nutrients, but Inuvialuit in the Northwest Territories (NWT), Canada, have been undergoing a nutrition transition, characterised by an increased consumption of non-nutrient-dense foods. The present study aimed to characterise energy, nutrient and food intakes amongst adult Inuvialuit. The study collected up to three 24-h dietary recalls on nonconsecutive days for each participant in spring/summer of 2008 in one remote community in the NWT. Recall data were analysed for energy and nutrient intake, dietary adequacy, most commonly reported foods, and food contributors to energy and nutrients. Participants included 14 men and 50 women (response rate 79%). Median daily energy intake was 9.4 (interquartile range=5.7) MJ for men and 8.3 (3.6) MJ for women. The majority of adult Inuvialuit did not meet the recommendation for vitamins A [median intake=344.7 (246.3) μg-RAE in men, 248.9 (213.8) μg-RAE in women], B(6) [0.9 (0.8) mg in men, 1.0 (0.5) mg in women] and E [2.4 (2.1) mg in men, 1.8 (1.0) mg in women], dietary fibre [7.7 (5.7) g in men, 8.7 (4.4) g in women], calcium [779.6 (842.0) mg in men, 610.4 (431.5) mg in women] and total folate [222.6 (57.7) μg in men, 264.6 (127.5) μg in women]. Vitamin D intake was below the recommendation for most women [median intake=100.0 (119.2) IU]. Traditional foods contributed substantially to protein and iron intake. Juices were the main contributors to energy, carbohydrate and calcium. The present study revealed an inadequate consumption of essential nutrients in an Inuvialuit population. If these nutrient deficiencies continue, this population will face an increased burden of chronic diseases and malnutrition.


Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection.
Severe acute respiratory syndrome coronavirus (SARS-CoV) caused an acute human respiratory illness with high morbidity and mortality in 2002-2003. Several studies have demonstrated the role of neutralizing antibodies induced by the spike (S) glycoprotein in protecting susceptible hosts from lethal infection. However, the anti-SARS-CoV antibody response is short-lived in patients who have recovered from SARS, making it critical to develop additional vaccine strategies. SARS-CoV-specific memory CD8 T cells persisted for up to 6 years after SARS-CoV infection, a time at which memory B cells and antivirus antibodies were undetectable in individuals who had recovered from SARS. In this study, we assessed the ability of virus-specific memory CD8 T cells to mediate protection against infection in the absence of SARS-CoV-specific memory CD4 T or B cells. We demonstrate that memory CD8 T cells specific for a single immunodominant epitope (S436 or S525) substantially protected 8- to 10-month-old mice from lethal SARS-CoV infection. Intravenous immunization with peptide-loaded dendritic cells (DCs) followed by intranasal boosting with recombinant vaccinia virus (rVV) encoding S436 or S525 resulted in accumulation of virus-specific memory CD8 T cells in bronchoalveolar lavage fluid (BAL), lungs, and spleen. Upon challenge with a lethal dose of SARS-CoV, virus-specific memory CD8 T cells efficiently produced multiple effector cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin 2 [IL-2]) and cytolytic molecules (granzyme B) and reduced lung viral loads. Overall, our results show that SARS-CoV-specific memory CD8 T cells protect susceptible hosts from lethal SARS-CoV infection, but they also suggest that SARS-CoV-specific CD4 T cell and antibody responses are necessary for complete protection. Virus-specific CD8 T cells are required for pathogen clearance following primary SARS-CoV infection. However, the role of SARS-CoV-specific memory CD8 T cells in mediating protection after SARS-CoV challenge has not been previously investigated. In this study, using a prime-boost immunization approach, we showed that virus-specific CD8 T cells protect susceptible 8- to 10-month-old mice from lethal SARS-CoV challenge. Thus, future vaccines against emerging coronaviruses should emphasize the generation of a memory CD8 T cell response for optimal protection.


Isokinetic eccentric exercise of quadriceps femoris does not affect running economy.
The purpose of this study was to investigate whether running economy is affected by isokinetic eccentric exercise designed to cause muscle damage. Twenty-four young healthy men performed 120 maximal voluntary eccentric actions at each thigh's quadriceps muscle at an angular velocity of 60 degrees .s. The participants were then randomly divided into 2 equal groups, 1 of which exercised 24 hours later, while the other group rested. Muscle damage indicators (i.e., serum creatine kinase, delayed onset muscle soreness, and eccentric, concentric, and isometric peak torque) and running economy indicators (i.e., oxygen consumption, pulmonary ventilation, respiratory exchange ratio, respiratory rate, and heart rate during treadmill running at 2.2 and 3.3 m.s) were assessed prior to and 48 hours following the eccentric exercise. All muscle damage indicators changed significantly in both groups (p < 0.05) in a way suggestive of considerable muscle damage. Running economy indicators of the exercise group demonstrated only an elevation of respiratory rate at 48 hours (p < 0.05) and a tendency to lower economy compared to the resting group. It can be concluded that isokinetic eccentric exercise applied to the quadriceps femoris muscles did not affect running economy 48 hours later and that resting during this period tended to result in more economical running compared to exercising at 24 hours.


Thiamine requirement of Eikenella corrodens.
The thiamine requirement for growth of Eikenella corrodens was investigated. Autoclaved thiamine at a concentration of 1.0 microgram/ml supported maximal growth whereas for the same growth, filter-sterilized thiamine was required at 50-100 micrograms/ml. Studies with two thiamine degradation products, 2-methyl-4-amino-5-hydroxymethylpyrimidine and 4-methyl-5-(B-hydroxyethyl) thiazole, indicated that selected strains grew poorly or not at all in the presence of either moiety alone. However, the two moieties at a combined concentration of 0.02 microgram/ml supported growth equivalent to that of 1.0 microgram/ml of autoclaved thiamine. The requirement for a high concentration of filter-sterilized thiamine may reflect a faulty thiamine uptake apparatus and the observed growth response may be due to the presence of the moieties in the commercial thiamine preparation.


Adherence with Medical Therapy for Primary Open-Angle Glaucoma in Kenya - A Pilot Study.
Adherence is a major challenge in topical glaucoma therapy, particularly in an African context. We report a pilot study assessing adherence independently for the first time in an African context. Participants with newly diagnosed open-angle glaucoma received a weighed bottle of Lumigan 0.01% with counselling on therapy. The bottles were returned monthly for renewal and weighed on return to estimate drops taken during the period. Data collection was for one year with a short compliance questionnaire. 11 patients participated. 5 (45%) failed to complete one full year of topical therapy. The overall mean number of drops per eye per day was 1.74 (SD 0.69) for the 6 with one year of monthly returned bottles and controlled IOPs at each visit. Self-perception of compliance in these patients was good. The signs of poor adherence based on both self-report (previous literature), and in this small-scale study of an objective measure suggest medication may not be the first-line treatment of choice in this environment. Our report does, however, raise the possibility that those patients who return for repeat prescriptions and review are indeed adhering to their treatment regimens.


Phospholipase A2 is important for glucose induction of rhythmic Ca2+ signals in pancreatic beta cells.
Pancreatic beta cells respond to glucose stimulation with pulses of insulin release generated by oscillatory rises of the cytoplasmic Ca2+ concentration ([Ca2+]i). The observation that exposure to external ATP and other activators of cytoplasmic phospholipase A2 (cPLA2) rapidly induces rises of [Ca2+]i similar to ordinary oscillations made it important to analyze whether suppression of the cPLA2 activity affects glucose-induced [Ca2+]i rhythmicity in pancreatic beta cells. Ratiometric fura-2 technique was used for measuring [Ca2+]i in single beta cells and small aggregates prepared from ob/ob mouse islets. Testing the effects of different inhibitors of cPLA2 in the presence of 20 mM glucose, it was found that N-(p-amylcinnamoyl)anthranilic acid (ACA) removed the oscillations at a concentration of 25 microM, arachidonyl trifluoromethyl ketone (AACOCF3) at 10 microM, and bromoenol lactone (BEL) at 10 to 15 microM. Withdrawal of ACA and BEL resulted in reappearance of the oscillations. Suppression of the arachidonic acid production by addition of 5 microM of the diacylglycerol lipase inhibitor 1,6-bis-(cyclohexyloximinocarbonylamino)-hexane (RHC 80267) effectively removed the [Ca2+]i oscillations, an effect reversed by removal of the inhibitor or addition of 100 microM tolbutamide. Suppression of the arachidonic acid production had a restrictive influence also on the transients of [Ca2+]i supposed to synchronize the beta-cell rhythmicity. Although less sensitive than the oscillations, most transients disappeared during exposure to 50 microM ACA or 35 microM RHC 80267. The results support the idea that cyclic variations of cPLA2 activity are important for the generation and synchronization of the beta-cell [Ca2+]i oscillations responsible for pulsatile release of insulin.


[Molecular-genetic aspects of neurofibromatosis].
Two forms of neurofibromatosis, type 1 (NF1) and type 2 (NF2) are connected with genes localized on chromosomes 17 and 22, respectively. The genes that are inactivated in neurofibromatosis code for the proteins neurofibromine and merline, respectively. Since inactivation leads to neoplasia, they are called tumour suppressor genes. Neurofibromine shows resemblances to proteins that serve to inactivate oncogenes. Merline has a relationship with proteins that connect the cytoskeleton and the cell membrane. The precise function of the proteins is still unknown. The NF1 gene is characterized by extraordinarily high sensitivity to mutation; half the NF1 patients have not inherited the disease. In the familial form of neurofibromatosis, a mutated gene is inherited and the normal allele in the tumour is inactivated, making tumour growth possible. In the sporadic form of neurofibromatosis, both normal alleles are inactivated locally in the tissue so that a tumour develops in that place.


Mast cell involvement in gastritis with or without Helicobacter pylori infection.
Mast cells are initiators and regulators of inflammation, but their role in the human stomach remains unclear. Therefore, the extent and distribution of mast cell involvement in gastritis with or without Helicobacter pylori infection was investigated. Mapped biopsy specimens from 17 H. pylori-positive and 20 H. pylori-negative subjects were examined. Sections were assessed for infection and inflammation and stained with anti-human mast cell tryptase to count mucosal and epithelial mast cells. Density of mast cells in different gastric compartments, their response to infection treatment, and their relationship with other inflammatory cells were evaluated. Mast cell degranulation was evaluated by electron microscopy. Mast cell density was significantly greater in the mucosa with gastritis, with or without H. pylori infection, than in the mucosa of noninfected normal subjects. In the antrum, density was much greater in H. pylori-infected peptic ulcer subjects than in the other gastritis groups. It also correlated significantly with the intensity of inflammation. Mast cell degranulation was demonstrated by electron microscopy in H. pylori-infected mucosa. Mast cell density in ulcer patients decreased significantly after cure of H. pylori infection. Mast cells may be important effector cells in the pathogenesis of gastritis, especially in H. pylori-associated peptic ulcer.


Enhancing Electronic Nose Performance Based on a Novel QPSO-KELM Model.
A novel multi-class classification method for bacteria detection termed quantum-behaved particle swarm optimization-based kernel extreme learning machine (QPSO-KELM) based on an electronic nose (E-nose) technology is proposed in this paper. Time and frequency domain features are extracted from E-nose signals used for detecting four different classes of wounds (uninfected and infected with Staphylococcu aureus, Escherichia coli and Pseudomonas aeruginosa) in this experiment. In addition, KELM is compared with five existing classification methods: Linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), extreme learning machine (ELM), k-nearest neighbor (KNN) and support vector machine (SVM). Meanwhile, three traditional optimization methods including particle swarm optimization algorithm (PSO), genetic algorithm (GA) and grid search algorithm (GS) and four kernel functions (Gaussian kernel, linear kernel, polynomial kernel and wavelet kernel) for KELM are discussed in this experiment. Finally, the QPSO-KELM model is also used to deal with another two experimental E-nose datasets in the previous experiments. The experimental results demonstrate the superiority of QPSO-KELM in various E-nose applications.


[Regulation of nasal resistance in children].
By means of active anterior rhinorheomanometry we searched for nasal cycles in children of 3-10 years of age. We measured the nasal air flow every 15 minutes for a period of 2 hours on both sides in relation to a pressure of 1 mbar. In the group of the 7-10 year old children we found nasal cycles in 79 per cent according to Hasegawa's and Kern's definition. In contrast to other authors nasal cycles were also ascertained in 50 per cent of the 3-6 year old children: Computing the correlation coefficient between the difference of one measurement from the right and left mean nasal air flow, we could demonstrate that the nasal cycle was actually subject to a regulatory mechanism. In contrast "solidary movements" showed no regulation in our challenge-controlled measurements.


Remission of idiopathic retroperitoneal fibrosis after sequential therapy with corticosteroids and tamoxifen.
The most favored therapy for idiopathic retroperitoneal fibrosis is the surgical relief of ureteral obstruction and use of corticosteroids to prevent recurrence. Although effective, long-term corticosteroid treatment could be associated with serious side effects. We would like to present a case of idiopathic retroperitoneal fibrosis treated successfully with intraperitonealization of the ureters and sequential therapy with steroids and tamoxifen to minimize the side effects.


Phenotypic and molecular characterization of Colletotrichum species associated with anthracnose of banana (Musa spp) in Malaysia.
Anthracnose caused by Colletotrichum species is a common postharvest disease of banana fruit. We investigated and identified Colletotrichum species associated with anthracnose in several local banana cultivars based on morphological characteristics and sequencing of ITS regions and of the β-tubulin gene. Thirty-eight Colletotrichum isolates were encountered in anthracnose lesions of five local banana cultivars, 'berangan', 'mas', 'awak', 'rastali', and 'nangka'. Based on morphological characteristics, 32 isolates were identified as Colletotrichum gloeosporioides and 6 isolates as C. musae. C. gloeosporioides isolates were divided into two morphotypes, with differences in colony color, shape of the conidia and growth rate. Based on ITS regions and β-tubulin sequences, 35 of the isolates were identified as C. gloeosporioides and only 3 isolates as C. musae; the percentage of similarity from BLAST ranged from 95-100% for ITS regions and 97-100% for β-tubulin. C. gloeosporioides isolates were more prevalent compared to C. musae. This is the first record of C. gloeosporioides associated with banana anthracnose in Malaysia. In a phylogenetic analysis of the combined dataset of ITS regions and β-tubulin using a maximum likelihood method, C. gloeosporioides and C. musae isolates were clearly separated into two groups. We concluded that C. gloeosporioides and C. musae isolates are associated with anthracnose in the local banana cultivars and that C. gloeosporioides is more prevalent than C. musae.


Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria.
The pathogenesis of filarial disease is characterized by acute and chronic inflammation. Inflammatory responses are thought to be generated by either the parasite, the immune response, or opportunistic infection. We show that soluble extracts of the human filarial parasite Brugia malayi can induce potent inflammatory responses, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and nitric oxide (NO) from macrophages. The active component is heat stable, reacts positively in the Limulus amebocyte lysate assay, and can be inhibited by polymyxin B. TNF-alpha, IL-1beta, and NO responses were not induced in macrophages from lipopolysaccharide (LPS)-nonresponsive C3H/HeJ mice. The production of TNF-alpha after chemotherapy of microfilariae was also only detected in LPS-responsive C3H/HeN mice, suggesting that signaling through the Toll-like receptor 4 (TLR4) is necessary for these responses. We also show that CD14 is required for optimal TNF-alpha responses at low concentrations. Together, these results suggest that extracts of B. malayi contain bacterial LPS. Extracts from the rodent filaria, Acanthocheilonema viteae, which is not infected with the endosymbiotic Wolbachia bacteria found in the majority of filarial parasites, failed to induce any inflammatory responses from macrophages, suggesting that the source of bacterial LPS in extracts of B. malayi is the Wolbachia endosymbiont. Wolbachia extracts derived from a mosquito cell line induced similar LPS-dependent TNF-alpha and NO responses from C3H/HeN macrophages, which were eliminated after tetracycline treatment of the bacteria. Thus, Wolbachia LPS may be one of the major mediators of inflammatory pathogenesis in filarial nematode disease.


An aberration in gamma-ray-enhanced reactivation of irradiated adenovirus in ataxia telangiectasia fibroblasts.
Ataxia telangiectasia (AT) is a rare human genetic disorder, whose numerous clinical hallmarks include a predisposition to lymphoreticular cancers and a hypersensitivity to conventional radiotherapy. Furthermore, AT cells in vitro exhibit a hypersensitivity to ionising radiation that appears to be correlated with an increased frequency of chromosomal aberrations, a resistance of de novo DNA synthesis to inhibition by radiation-induced DNA damage, a reduced mitotic delay and possible defects in DNA repair. In this study, a sensitive viral assay has been used to investigate the capacity of gamma-irradiated AT cells to support the replication of undamaged virus, as well as the extent to which the survival of radiation-damaged virus was affected by gamma-irradiation of these host cells prior to infection. The expression of such enhanced reactivation (ER) of both u.v.-irradiated (u.v. dose = 1.2 X 10(3) J/m2) and gamma-irradiated (dose = 2 Mrad) adenovirus type 2 (Ad2) was examined in a variety of normal and AT human fibroblast strains. Unirradiated and gamma-irradiated fibroblasts were infected with unirradiated or irradiated Ad2, either immediately or at different times after cell monolayer irradiation, and at 48 h after infection cultures were examined by indirect immunofluorescence to determine the number of cells in which Ad2 viral structural antigen (Vag) was expressed. For immediate infection of normal human fibroblasts, both a decrease in unirradiated virus expression and an increase in ER were observed with increasing gamma-ray dose to the cells. In contrast, AT fibroblasts were found to be deficient in gamma-ray ER of irradiated Ad2, and this defect appeared to be related to a marked relative radioresistance of unirradiated virus expression in AT compared to normal cells. The potential significance of these results is discussed in the context of mammalian ER, which is believed to be, at least in part, an expression of a mutagen-inducible (and possibly error-prone) DNA repair mechanism.


Selecting the highest of three binomial probabilities.
A sequential elimination procedure for selecting the highest probability in binomial trials, proposed by Levin and Robbins [Levin, B. & Robbins, H. (1981) Proc. Natl. Acad. Sci. USA 78, 4663-4666], is examined further in the special case of trials involving three probabilities. A conjectured inequality relating ratios of selection probabilities to odds ratios is shown to hold only under certain necessary and sufficient conditions. Weaker conjectured inequalities involving the probability of correct selection are shown to hold without restriction.


TRPA5, an Ankyrin Subfamily Insect TRP Channel, is Expressed in Antennae of Cydia pomonella (Lepidoptera: Tortricidae) in Multiple Splice Variants.
Transient receptor potential (TRP) channels are an ancient family of cation channels, working as metabotropic triggers, which respond to physical and chemical environmental cues. Perception of chemical signals mediate reproductive behaviors and is therefore an important target for sustainable management tactics against the codling moth Cydia pomonella L. (Lepidoptera: Tortricidae). However, olfactory behavior strongly depends on diel periodicity and correlation of chemical with physical cues, like temperature, and physical cues thus essentially contribute to the generation of behavioral response. From an antennal transcriptome generated by next generation sequencing, we characterized five candidate TRPs in the codling moth. The coding DNA sequence of one of these was extended to full length, and phylogenetic investigation revealed it to be orthologous of the TRPA5 genes, reported in several insect genomes as members of the insect TRPA group with unknown function but closely related to the thermal sensor pyrexia Reverse transcription PCR revealed the existence of five alternate splice forms of CpTRPA5. Identification of a novel TRPA and its splice forms in codling moth antennae open for investigation of their possible sensory roles and implications in behavioral responses related to olfaction.


Boston Keratoprosthesis Type 1 in Chemical Burns.
To describe and further analyze the long-term results in visual acuity (VA), anatomical retention, and rate of complications from patients who underwent Boston keratoprosthesis (B-Kpro) type 1 after ocular chemical burns in the Dominican Republic. A retrospective review of 42 eyes (22 OD:20 OS) of 36 patients who underwent B-Kpro type 1 implantation after severe ocular burn at Hospital Elías Santana in Santo Domingo, Dominican Republic, between April 2006 and October 2014, were included. Demographics, VA, anatomical retention, and the rates of postoperative complications and concurrent surgeries were evaluated. The excellent anatomical retention rates and visual outcomes presented in this study support the remarkable capability of B-Kpro type 1 to restore functional VA in eyes with severe chemical injuries. However, strict control of the postoperative complications is necessary for long-term success. In conclusion, the use of a B-Kpro type 1 after severe chemical burn is a viable option in patients otherwise condemned to the high risk of failure associated with conventional corneal grafts.


Management options for large plants of glyphosate-resistant feather fingergrass (Chloris virgata) in Australian fallow conditions.
Chloris virgata has become one of the most difficult glyphosate-resistant (GR) grass weeds in summer fallows in the eastern region of Australia. It germinates in several cohorts following rainfall events; therefore, growers are often tempted to wait for most of the weeds to emerge before herbicide application. However, by that time, some seedlings have reached an advanced stage and there is limited information on the efficacy and reliability of alternate herbicides when targeting large plants of GR C. virgata. A series of experiments were conducted to determine the efficacy of alternate herbicides for the control of GR C. virgata. Haloxyfop (80 g a.i. ha-1) on its own, in mixtures, or sequential applications of haloxyfop and paraquat or glufosinate provided 97 to 100% mortality of the 8-10 leaf stage plants. Glufosinate (1500 g a.i. ha-1) also provided complete control of plants at this growth stage. For larger plants at the 24-28 leaf stage, glufosinate, with or without additional tank-mixed adjuvants, generally did not provide full control, however did show very high levels of biomass reduction and panicle suppression at application rates of 750 or 1500 g a.i. ha-1. Haloxyfop (40 to 160 g a.i. ha-1) and clethodim (180 g a.i. ha-1) on their own achieved 96 to 100% mortality at this growth stage. When applied to large plants (40-50 leaf stage), a tank-mix of isoxaflutole plus paraquat demonstrated significantly higher levels of plant mortality and biomass reduction than either herbicide used alone, and this mixture appears to be synergistic when tested via the Colby equation for synergy or antagonism. Plant mortality was greater (83%) when isoxaflutole (75 g a.i. ha-1) plus paraquat (300 g a.i. ha-1) was taken up through the foliage and soil, compared with the foliage alone. This study identified alternative herbicide options for large plants of GR C. virgata.