Inhibition of 5alpha-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice.
Allopregnanolone (ALLO) is a physiologically relevant neurosteroid modulator of GABA(A) receptors, and it exhibits a psychopharmacological profile that closely resembles the post-ingestive effects of ethanol. The 5alpha-reductase inhibitor finasteride (FIN), which inhibits biosynthesis of ALLO and structurally related neurosteroids, was previously demonstrated to reduce the maintenance of limited-access ethanol consumption. The primary aim of the current work was to determine whether FIN would reduce the acquisition of drinking in ethanol-naïve mice. Male C57BL/6J (B6) mice were acclimated to a reverse light/dark schedule, and were provided ad libitum access to chow and water. Following habituation to vehicle injections (VEH; 20% w/v beta-cyclodextrin; i.p.) administered 22-hour prior to drinking sessions with water only, mice were divided into 3 treatment groups: vehicle control (VEH), 50 mg/kg FIN (FIN-50), and 100 mg/kg FIN (FIN-100). Twenty-two hours after the first treatment, mice were permitted the inaugural 2-hour limited access to a 10% v/v ethanol solution (10E) and water. The acquisition of 10E consumption and underlying drinking patterns were assessed during FIN treatment (7 days) and subsequent FIN withdrawal (13 days) phases. FIN dose-dependently blocked the acquisition of 10E drinking and prevented the development of ethanol preference, thereby suggesting that the GABAergic neurosteroids may be important in the establishment of stable drinking patterns. FIN-elicited reductions in 10E intake were primarily attributable to selective and marked reductions in bout frequency, as no changes were observed in bout size, duration, or lick rates following FIN treatment. FIN-treated mice continued to exhibit attenuated ethanol consumption after 2 weeks post-treatment, despite a full recovery in brain ALLO levels. A second study confirmed the rightward and downward shift in the acquisition of ethanol intake following 7 daily FIN injections. While there were no significant group differences in brain ALLO levels following the seventh day of ethanol drinking, ALLO levels were decreased by 28% in the FIN-50 group. Although the exact mechanism is unclear, FIN and other pharmacological interventions that modulate the GABAergic system may prove useful in curbing ethanol intake acquisition in at-risk individuals.


Regulatory T cells differentially modulate the maturation and apoptosis of human CD8+ T-cell subsets.
The balanced manifestation of effector functions and the generation of long-living memory cells is a hallmark of efficient CD8(+) T-cell response. Accumulating data pinpoint CD4(+) CD25(high) regulatory T (Treg) cells as a key factor for the inefficiency of CD8(+) T-cell responses in viral persistence. Little is known about the effects of Treg cells on the homeostasis of healthy donor CD8(+) T cells. The present study demonstrates that Treg cells exert differential effects on CD8(+) T-cell subsets. Treg cells inhibited mostly the polyclonal proliferation of CD27(-) effector cells compared with CD27(+) memory CD8(+) T cells. Moreover, they inhibited the polyclonal and antigen-driven differentiation of memory cells into functional effectors as defined by IFN-gamma secretion and induction of CD160 expression. Finally, Treg cells reduced the apoptosis of memory but not of effector and terminal effector cell populations. These effects were at least in part mediated by a decreased expression of PD-L1, but not of programmed death 1 (PD-1), on CD8(+) T cells after activation. Thus, in the setting of a healthy immune system, Treg cells fine-tune the memory/effector cell balance and promote the accumulation of long-living memory cells in case of strong stimulation.


Lidar inversion with variable backscatter/extinction ratios.
The conventional approach to solving the single-scattering lidar equation makes use of the assumption of a power law relation between backscatter and extinction with a fixed exponent and constant of proportionality. An alternative formulation is given herein which assumes the proportionality factor in the power law relationship is itself a function of range or extinction. The resulting lidar equation is solvable as before, and examples are given to show how even an approximate description of deviations from the power law form can yield an improved inversion solution for the extinction. A further generalization is given which includes the effects of a background of Rayleigh scatterers.


The design of transcription-factor binding sites is affected by combinatorial regulation.
Transcription factors regulate gene expression by binding to specific cis-regulatory elements in gene promoters. Although DNA sequences that serve as transcription-factor binding sites have been characterized and associated with the regulation of numerous genes, the principles that govern the design and evolution of such sites are poorly understood. Using the comprehensive mapping of binding-site locations available in Saccharomyces cerevisiae, we examined possible factors that may have an impact on binding-site design. We found that binding sites tend to be shorter and fuzzier when they appear in promoter regions that bind multiple transcription factors. We further found that essential genes bind relatively fewer transcription factors, as do divergent promoters. We provide evidence that novel binding sites tend to appear in specific promoters that are already associated with multiple sites. Two principal models may account for the observed correlations. First, it may be that the interaction between multiple factors compensates for the decreased specificity of each specific binding sequence. In such a scenario, binding-site fuzziness is a consequence of the presence of multiple binding sites. Second, binding sites may tend to appear in promoter regions that are subject to low selective pressure, which also allows for fuzzier motifs. The latter possibility may account for the relatively low number of binding sites found in promoters of essential genes and in divergent promoters.


Dislocation driven spiral and non-spiral growth in layered chalcogenides.
Two-dimensional materials have shown great promise for implementation in next-generation devices. However, controlling the film thickness during epitaxial growth remains elusive and must be fully understood before wide scale industrial application. Currently, uncontrolled multilayer growth is frequently observed, and not only does this growth mode contradict theoretical expectations, but it also breaks the inversion symmetry of the bulk crystal. In this work, a multiscale theoretical investigation aided by experimental evidence is carried out to identify the mechanism of such an unconventional, yet widely observed multilayer growth in the epitaxy of layered materials. This work reveals the subtle mechanistic similarities between multilayer concentric growth and spiral growth. Using the combination of experimental demonstration and simulations, this work presents an extended analysis of the driving forces behind this non-ideal growth mode, and the conditions that promote the formation of these defects. Our study shows that multilayer growth can be a result of both chalcogen deficiency and chalcogen excess: the former causes metal clustering as nucleation defects, and the latter generates in-domain step edges facilitating multilayer growth. Based on this fundamental understanding, our findings provide guidelines for the narrow window of growth conditions which enables large-area, layer-by-layer growth.


Red algae (Gelidium amansii) reduces adiposity via activation of lipolysis in rats with diabetes induced by streptozotocin-nicotinamide.
Gelidium amansii (GA) is an edible red algae that is distributed mainly in northeastern Taiwan. This study was designed to investigate the effects of GA on plasma glucose, lipids, and adipocytokines in rats with streptozotocin-nicotinamide-induced diabetes. Rats were divided into four groups: (1) rats without diabetes fed a high-fat diet (control group); (2) rats with diabetes fed a high-fat diet; (3) rats with diabetes fed a high-fat diet with thiazolidinedione in the diet; and (4) rats with diabetes fed a high-fat diet and GA. The experimental diet and drinking water were available ad libitum for 11 weeks. After the 11-week feeding study, plasma glucose, triglyceride, and cholesterol concentrations were lower in rats with diabetes fed the GA diet than in animals with diabetes fed the control diet. In addition, cholesterol and triglyceride excretion were significantly higher in rats with diabetes fed the GA diet. Moreover, GA feeding induced lipolysis in both paraepididymal and perirenal adipose tissues. Adipose tissue (paraepididymal and perirenal) weight and triglyceride contents were lower after GA treatment. Plasma adipocytokines including tumor necrosis factor-alpha, interleukin-6, and plasminogen activator inhibitor-1 were reduced by GA feeding in rats with diabetes. The results of the current study suggest that GA feeding may regulate plasma glucose and lipid levels and prevent adipose tissue accumulation in rats with diabetes.


Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated.
Stereotactic body radiation therapy (SBRT) provides high rates of local control (LC) and margin-negative (R0) resections for locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC), respectively, with minimal toxicity. A single-institution retrospective review was performed for patients with nonmetastatic pancreatic cancer treated with induction chemotherapy followed by SBRT. SBRT was delivered over 5 consecutive fractions using a dose painting technique including 7-10 Gy/fraction to the region of vessel abutment or encasement and 5-6 Gy/fraction to the remainder of the tumor. Restaging scans were performed at 4 weeks, and resectable patients were considered for resection. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Seventy-three patients were evaluated, with a median follow-up time of 10.5 months. Median doses of 35 Gy and 25 Gy were delivered to the region of vessel involvement and the remainder of the tumor, respectively. Thirty-two BRPC patients (56.1%) underwent surgery, with 31 undergoing an R0 resection (96.9%). The median OS, 1-year OS, median PFS, and 1-year PFS for BRPC versus LAPC patients was 16.4 months versus 15 months, 72.2% versus 68.1%, 9.7 versus 9.8 months, and 42.8% versus 41%, respectively (all P>.10). BRPC patients who underwent R0 resection had improved median OS (19.3 vs 12.3 months; P=.03), 1-year OS (84.2% vs 58.3%; P=.03), and 1-year PFS (56.5% vs 25.0%; P<.0001), respectively, compared with all nonsurgical patients. The 1-year LC in nonsurgical patients was 81%. We did not observe acute grade ≥3 toxicity, and late grade ≥3 toxicity was minimal (5.3%). SBRT safely facilitates margin-negative resection in patients with BRPC pancreatic cancer while maintaining a high rate of LC in unresectable patients. These data support the expanded implementation of SBRT for pancreatic cancer.


Clinical and bacteriological outcomes in patients with urinary tract infections presenting to primary care in Harare, Zimbabwe: a cohort study.
Background: Treatment for urinary tract infections (UTIs) is usually empiric and is based on local antimicrobial resistance data. These data, however, are scarce in low-resource settings. The aim of this study is to determine the impact of antibiotic treatment on clinical and bacteriological outcomes in patients presenting with UTI symptoms to primary care in Harare. Methods: This cohort study enrolled participants presenting with UTI symptoms to 10 primary healthcare clinics in Harare between July 2019 and July 2020. A questionnaire was administered and a urine sample was collected for culture. If the urine culture showed growth of ≥10 5 colony forming units/mL of a uropathogen, a follow up visit at 7-21 days was conducted. Results: The analysis included 168 participants with a median age of 33.6 years (IQR 25.1-51.4) and of whom 131/168 (78.0%) were female. Effective treatment was taken by 54/168 (32.1%) participants. The urine culture was negative at follow up in 41/54 (75.9%) of participants who took appropriate treatment and in 33/114 (28.9%, p<0.001) of those who did not. Symptoms had improved or resolved in 52/54 (96.3%) of those on appropriate treatment and in 71/114 (62.3%, p<0.001) of those without. Conclusion: The findings of this study show that effective treatment leads to symptom resolution and bacterial clearance in people presenting with UTIs to primary care. Although UTIs are not life-threatening and can resolve without treatment, they do impact on quality of life, highlighting the need for optimised treatment recommendations.


Cardiac-specific overexpression of caveolin-3 preserves t-tubular ICa during heart failure in mice.
What is the central question of this study? What is the cellular basis of the protection conferred on the heart by overexpression of caveolin-3 (Cav-3 OE) against many of the features of heart failure normally observed in vivo? What is the main finding and its importance? Cav-3 overexpression has little effect in normal ventricular myocytes but reduces cellular hypertrophy and preserves t-tubular ICa , but not local t-tubular Ca2+ release, in heart failure induced by pressure overload in mice. Thus Cav-3 overexpression provides specific but limited protection following induction of heart failure, although other factors disrupt Ca2+ release. Caveolin-3 (Cav-3) is an 18 kDa protein that has been implicated in t-tubule formation and function in cardiac ventricular myocytes. During cardiac hypertrophy and failure, Cav-3 expression decreases, t-tubule structure is disrupted and excitation-contraction coupling (ECC) is impaired. Previous work has suggested that Cav-3 overexpression (OE) is cardio-protective, but the effect of Cav-3 OE on these cellular changes is unknown. We therefore investigated whether Cav-3 OE in mice is protective against the cellular effects of pressure overload induced by 8 weeks' transverse aortic constriction (TAC). Cav-3 OE mice developed cardiac dilatation, decreased stroke volume and ejection fraction, and hypertrophy and pulmonary congestion in response to TAC. These changes were accompanied by cellular hypertrophy, a decrease in t-tubule regularity and density, and impaired local Ca2+ release at the t-tubules. However, the extent of cardiac and cellular hypertrophy was reduced in Cav-3 OE compared to WT mice, and t-tubular Ca2+ current (ICa ) density was maintained. These data suggest that Cav-3 OE helps prevent hypertrophy and loss of t-tubular ICa following TAC, but that other factors disrupt local Ca2+ release.


The failure to reconstitute the second extracellular matrix-integrin-cytoskeleton system in human endothelial cells on type V collagen.
We examined the formation of F-actin filaments and the expression of beta 1 integrin in human vascular endothelial cells cultured on type V collagen. The cells attached to the exogenous substrate, formed complete F-actin filaments, and expressed vinculin and beta 1 integrin 0.5-1 h after inoculation. These phenomena are referred to as the first ECM-integrin-cytoskeleton system. After 3-6 h, disassembly of the F-actin filaments was observed to occur from the leading edges, and the cells developed focal adhesions only in their central regions. After 12-24 h, the cells on the type V collagen failed to form the second ECM-integrin-cytoskeleton system, and gradually detached from the substrate. In contrast, the cells on type I collagen developed both the first and second system, and acclimatized themselves to the environment. Thrombospondin (TSP), an anti-adhesive protein, was capable of inhibiting the spreading of the cells both after 1 h and 24 h. However, type V collagen treated with TSP inhibited the cell spreading after 1 h, but not after 24 h. The attachment and spreading of the cells on type V collagen were little affected by an anti-TSP antibody and the synthetic peptide GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro), which significantly inhibited the attachment and spreading of the cells on TSP. Taken together, these results suggest that the cell detachment from type V collagen is not attributed to endogenously produced TSP (or member of TSP family) with anti-adhesive properties, but resulted from the failure to reconstitute the second ECM-integrin-cytoskeleton system in focal adhesion.


Cathodic stripping synthesis and cytotoxity studies of glutathione-capped CdTe quantum dots.
A cathodic stripping of Te precursor in the presence of Cd2+ and biocompatible glutathione (GSH) was reported for facile synthesis of lowly cytotoxic and highly luminescent CdTe quantum dots (QDs) in aqueous solution. The photoluminescence, electrogenerated chemiluminescence (ECL), toxicity, and cyto-osmosis of the QDs were evaluated to reveal their potential bio-applications. The morphology and composition of as-prepared QDs were investigated by HRTEM and powder XRD spectroscopy, which indicated that the QDs consisted of a CdTe core coated with a CdS shell. The obtained CdTe/CdS core/shell QDs possessed good crystallinity, narrow monodispersity and long-term stability. These QDs showed high fluorescence quantum yields of 49% to 63% over a broad spectral range of 540-650 nm. Efficient and stable ECL of QDs was observed on the anodic potential region upon the electrode potential cycled between 1.5 and -2.0 V versus Ag/AgCl. Furthermore, human liver cancer HepG2 cells were chosen as model cells for toxicity assay of QDs. Effects of the concentration, size, and incubation time of CdTe QDs capped with GSH or mercaptoacetic acid (MAA) on the cell metabolic viability and cyto-osmosis were evaluated. GSH-capped CdTe QDs could infiltrate cytomembrane and karyothecas, and were less cytotoxic than MAA-capped ones under the same experimental conditions. The reported CdTe QDs could be good candidates of fluorescent and ECL probes for biosensing and cell imaging.


Dynamic Production System Identification for Smart Manufacturing Systems.
This paper presents a methodology, called production system identification, to produce a model of a manufacturing system from logs of the system's operation. The model produced is intended to aid in making production scheduling decisions. Production system identification is similar to machine-learning methods of process mining in that they both use logs of operations. However, process mining falls short of addressing important requirements; process mining does not (1) account for infrequent exceptional events that may provide insight into system capabilities and reliability, (2) offer means to validate the model relative to an understanding of causes, and (3) updated the model as the situation on the production floor changes. The paper describes a genetic programming (GP) methodology that uses Petri nets, probabilistic neural nets, and a causal model of production system dynamics to address these shortcomings. A coloured Petri net formalism appropriate to GP is developed and used to interpret the log. Interpreted logs provide a relation between Petri net states and exceptional system states that can be learned by means of novel formulation of probabilistic neural nets (PNNs). A generalized stochastic Petri net and the PNNs are used to validate the GP-generated solutions. The methodology is evaluated with an example based on an automotive assembly system.


In silico rationalisation of selectivity and reactivity in Pd-catalysed C-H activation reactions.
A computational approach has been developed to automatically generate and analyse the structures of the intermediates of palladium-catalysed carbon-hydrogen (C-H) activation reactions as well as to predict the final products. Implemented as a high-performance computing cluster tool, it has been shown to correctly choose the mechanism and rationalise regioselectivity of chosen examples from open literature reports. The developed methodology is capable of predicting reactivity of various substrates by differentiation between two major mechanisms - proton abstraction and electrophilic aromatic substitution. An attempt has been made to predict new C-H activation reactions. This methodology can also be used for the automated reaction planning, as well as a starting point for microkinetic modelling.


Eosinophilic fasciitis associated with tryptophan ingestion. A manifestation of eosinophilia-myalgia syndrome.
Recently, the ingestion of tryptophan has been associated with eosinophilia-myalgia syndrome, which is characterized by eosinophilia, myalgias, and several less consistently reported findings. We treated 13 patients who exhibited clinical features of eosinophilic fasciitis who were taking high-dose tryptophan before the onset of clinical symptoms. Twelve patients exhibited eosinophilia, with eosinophil counts ranging from 0.13 to 0.88. The remaining patient was taking oral corticosteroids when her eosinophil count was determined. Eight patients complained of myalgias. Other symptoms included arthralgias, pruritus, cutaneous burning, weakness, fever, rashes, malaise, edema, muscle spasms, and alopecia. 5-Hydroxyindoleacetic acid levels were elevated in four of the eight urine specimens that were tested. Our findings suggest that previously diagnosed cases of eosinophilic fasciitis may represent variants of tryptophan-associated eosinophilia-myalgia syndrome. Derangements in the metabolism of tryptophan may play a role in sclerotic diseases.


Physical Activity, Sedentary Behavior, Anxiety, and Pain Among Musicians in the United Kingdom.
Although some exercise-based interventions have been associated with lower levels of pain and performance-related musculoskeletal disorders (PRMDs) among musicians, the evidence is still mixed. Furthermore, little is known about musicians' general engagement in physical activity (PA), their knowledge of PA guidelines, or the relevant training they receive on pain prevention and the sources of such training. Similarly, little is known about the relationship between PA and PRMDs and other risk factors for PRMDs. Following a cross-sectional correlational study design, both standardized and ad hoc measurements were used to investigate self-reported PA [International Physical Activity Questionnaire - Short Form (IPAQ-SF)], knowledge of PA guidelines, and barriers to engaging in PA [Centers for Disease Control (CDC); Determinants of Physical Activity Questionnaire (DPAQ)]; sedentary behavior [Sedentary Behavior Questionnaire (SBQ)]; pain [36-Item Short Form Survey Instrument (SF-36)] and PRMDs (frequency and severity); reported physical exertion (RPE); anxiety [Hospital Anxiety and Depression Scale (HADS)]; practice behaviors (e.g., practice time; taking breaks frequency; warming up); and relevant training among conservatoire students in the United Kingdom. The entire set of questionnaires was administered both online and via hard copies between June 2017 and April 2018. Demographic information was obtained from 111 respondents, mostly undergraduate students (UGs) from seven conservatoires. They reported high levels of engagement in PA, despite poor knowledge of PA guidelines. Teachers were the most frequently mentioned source of pain prevention information (by 43% of respondents), and 62% agreed that they had received advice on why they should engage in cardio PA. Sedentary behavior was comparable to normative data. Levels of bodily pain and PRMDs were low, but 43% showed "abnormal" clinical anxiety and found playing their instruments "somewhat hard" (RPE) on average. Bodily pain interfering with practice and performance was positively correlated with frequency and severity of PRMDs, anxiety, and RPE. Frequency and severity of PRMDs were also associated with sedentary behavior at the weekend. Anxiety was associated with RPE. No association was found between PA and PRMDs. The relationship between PA and PRMDs and pain remains unclear and needs further investigation. While health education needs to be improved, other pathways may need to be taken. Given the high levels of anxiety, the ideology of Western classical music itself may need to be challenged.


Action at a distance: dependency sensitivity in a New World primate.
Sensitivity to dependencies (correspondences between distant items) in sensory stimuli plays a crucial role in human music and language. Here, we show that squirrel monkeys (Saimiri sciureus) can detect abstract, non-adjacent dependencies in auditory stimuli. Monkeys discriminated between tone sequences containing a dependency and those lacking it, and generalized to previously unheard pitch classes and novel dependency distances. This constitutes the first pattern learning study where artificial stimuli were designed with the species' communication system in mind. These results suggest that the ability to recognize dependencies represents a capability that had already evolved in humans' last common ancestor with squirrel monkeys, and perhaps before.


Triggering autophagic cell death with a di-manganese(II) developmental therapeutic.
There is an unmet need for novel metal-based chemotherapeutics with alternative modes of action compared to clinical agents such as cisplatin and metallo-bleomycin. Recent attention in this field has focused on designing intracellular ROS-mediators as powerful cytotoxins of human cancers and identifying potentially unique toxic mechanisms underpinning their utility. Herein, we report the developmental di-manganese(II) therapeutic [Mn2(μ-oda)(phen)4(H2O)2][Mn2(μ-oda)(phen)4(oda)2]·4H2O (Mn-Oda) induces autophagy-promoted apoptosis in human ovarian cancer cells (SKOV3). The complex was initially identified to intercalate DNA by topoisomerase I unwinding and circular dichroism spectroscopy. Intracellular DNA damage, detected by γH2AX and the COMET assay, however, is not linked to direct Mn-Oda free radical generation, but is instead mediated through the promotion of intracellular reactive oxygen species (ROS) leading to autophagic vacuole formation and downstream nuclear degradation. To elucidate the cytotoxic profile of Mn-Oda, a wide range of biomarkers specific to apoptosis and autophagy including caspase release, mitochondrial membrane integrity, fluorogenic probe localisation, and cell cycle analysis were employed. Through these techniques, the activity of Mn-Oda was compared directly to i.) the pro-apoptotic clinical anticancer drug doxorubicin, ii.) the multimodal histone deacetylase inhibitor suberoyanilide hydroxamic acid, and iii.) the autophagy inducer rapamycin. In conjunction with ROS-specific trapping agents and established inhibitors of autophagy, we have identified autophagy-induction linked to mitochondrial superoxide production, with confocal image analysis of SKOV3 cells further supporting autophagosome formation.


Endothelin has biological actions at pathophysiological concentrations.
Endothelin is an endothelium-derived peptide that produces sustained contraction of arterial and venous smooth muscle in vitro. Several studies have established endothelin as a systemic, renal, and coronary vasoconstrictor in vivo at pharmacological concentrations. Such concentrations of endothelin were antinatriuretic in association with activation of the renin-angiotensin-aldosterone system. Recent studies have demonstrated that endothelin is present in the plasma and that its plasma concentrations are increased in various pathological states associated with systemic and renal vasoconstriction. To date, it remains unclear if such increases in circulating endothelin are associated with biological activity. Thus, the objective of this study was to determine the biological action of endothelin on cardiorenal and endocrine function through administration of exogenous endothelin, which achieves plasma concentrations that have been reported in various pathophysiological conditions. Experiments were conducted in two groups of anesthetized dogs. In group 1, endothelin-1 was infused intravenously at 2.5 ng/kg/ml (n = 6), which produced a doubling of circulating concentrations. Group 2 (n = 8) received saline vehicle to serve as a time control. The current studies demonstrate that a twofold increase in plasma endothelin concentrations did not affect mean blood pressure or coronary blood flow. Heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis. The present studies demonstrate that endothelin at pathophysiological plasma concentrations produced by exogenous endothelin has biological action. These studies support a functional role for endogenous endothelin as a potentially pathophysiological vasoconstrictor peptide hormone in the regulation of cardiovascular, renal, and endocrine function.


Morphometric analysis of posterior fossa after in utero myelomeningocele repair.
Myelomeningocele (MMC) is characterized by a defect in caudal neurulation and appears at birth with a constellation of neuroanatomical abnormalities, including Chiari malformation Type II. The authors investigated the effects of antenatal versus postnatal repair of MMC through a quantitative analysis of morphometric changes in the posterior fossa (PF). The authors retrospectively reviewed the records of 29 patients who underwent in utero MMC repair, 24 patients who underwent postnatal repair, and 114 fetal and pediatric controls. Tonsillar displacement, cerebellum length, pons length, clivus-supraocciput (CSO) angle, and PF area were compared in antenatal and postnatal MMC repair groups as well as in controls without neural tube defects by using t-tests and correlation coefficients. Initially, the in utero CSO angle was significantly more acute in all patients with MMC--prenatally and postnatally repaired--as compared with controls (57.8° vs 75.4°, p < 0.001); however, the angle rapidly changed and became similar to that in controls between 30 and 31 weeks' gestation to approximately 80°, with antenatal repair having little effect. Postnatally, the CSO angle decreased in controls (R = -0.58) and in the antenatal repair group (R = -0.17). The cerebellum and pons length demonstrated no significant differences in any group. Overall, tonsil descent was corrected in the antenatal repair group as compared with postnatal repair (p < 0.001), and the PF area increased in all 3 groups in utero. Growth was less rapid in patients with MMC compared with controls, but this was corrected by antenatal repair (p = 0.015). Myelomeningocele was associated with tonsillar herniation and a smaller PF than in control fetuses. Antenatal surgical repair corrected both abnormalities. The CSO angle began significantly more acutely in patients with MMC, but normalized with development regardless of when surgery was performed. Determining the clinical effects of antenatal repair requires further follow-up.


Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor.
Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% O2) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% O2). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub-micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.


Size dependence of steric shielding and multivalency effects for globular binding inhibitors.
Competitive binding inhibitors based on multivalent nanoparticles have shown great potential for preventing virus infections. However, general design principles of highly efficient inhibitors are lacking as the quantitative impact of factors such as virus concentration, inhibitor size, steric shielding, or multivalency effects in the inhibition process is not known. Based on two complementary experimental inhibition assays we determined size-dependent steric shielding and multivalency effects. This allowed us to adapt the Cheng-Prusoff equation for its application to multivalent systems. Our results show that the particle and volume normalized IC50 value of an inhibitor at very low virus concentration predominantly depends on its multivalent association constant, which itself exponentially increases with the inhibitor/virus contact area and ligand density. Compared to multivalency effects, the contribution of steric shielding to the IC50 values is only minor, and its impact is only noticeable if the multivalent dissociation constant is far below the virus concentration, which means if all inhibitors are bound to the virus. The dependence of the predominant effect, either steric shielding or multivalency, on the virus concentration has significant implications on the in vitro testing of competitive binding inhibitors and determines optimal inhibitor diameters for the efficient inhibition of viruses.


Introgression and rapid species turnover in sympatric damselflies.
Studying contemporary hybridization increases our understanding of introgression, adaptation and, ultimately, speciation. The sister species Ischnura elegans and I. graellsii (Odonata: Coenagrionidae) are ecologically, morphologically and genetically similar and hybridize. Recently, I. elegans has colonized northern Spain, creating a broad sympatric region with I. graellsii. Here, we review the distribution of both species in Iberia and evaluate the degree of introgression of I. graellsii into I. elegans using six microsatellite markers (442 individuals from 26 populations) and five mitochondrial genes in sympatric and allopatric localities. Furthermore, we quantify the effect of hybridization on the frequencies of the genetically controlled colour polymorphism in females of both species. In a principal component analysis of the microsatellite data, the first two principal components summarised almost half (41%) of the total genetic variation. The first axis revealed a clear separation of I. graellsii and I. elegans populations, while the second axis separated I. elegans populations. Admixture analyses showed extensive hybridization and introgression in I. elegans populations, consistent with I. elegans backcrosses and occasional F1-hybrids, suggesting hybridization is on-going. More specifically, approximately 58% of the 166 Spanish I. elegans individuals were assigned to the I. elegans backcross category, whereas not a single of those individuals was assigned to the backcross with I. graellsii. The mitochondrial genes held little genetic variation, and the most common haplotype was shared by the two species. The results suggest rapid species turnover in sympatric regions in favour of I. elegans, corroborating previous findings that I. graellsii suffers a mating disadvantage in sympatry with I. elegans. Examination of morph frequency dynamics indicates that hybridization is likely to have important implications for the maintenance of multiple female morphs, in particular during the initial period of hybridization.


Long-term efficacy of sodium oxybate in 4 patients with chronic cluster headache.
Cluster headache (CH) manifests with periodic attacks of severe unilateral pain and autonomic symptoms. Nocturnal attacks may cause severe sleep disruption. In about 10%of cases, patients present with a chronic form (CCH), which is often medically intractable. Few attempts have been made to improve headache via pharmacologic modulation of sleep. In an open-label study, 4 patients with CCH and disturbed sleep received increasing dosages of sodium oxybate (SO), a compound known to consolidate sleep and to increase slow-wave sleep. Response to SO was monitored by serial polysomnography, and actimetry, along with pain and sleep diaries. SO was effective in all 4 patients as shown by an immediate reduction in frequency (up to 90%) and intensity (>50%) of nocturnal pain attacks and improved sleep quality. These effects were long-lasting in 3 patients (mean 19 months, range 12-29 months) and transient (for 8 months) in one patient. Long-lasting improvement of daytime headaches was achieved with a latency of weeks in 2 patients. SO was safe, with mild to moderate adverse effects (dizziness, vomiting, amnesia, weight loss). SO may represent a new treatment option to reduce nocturnal and diurnal pain attacks and improve sleep quality in CCH. These data also suggest the interest of treating primary headache syndromes by sleep-manipulating substances. This study provides Class IV evidence that oral SO at night improves sleep and reduces the intensity and frequency of headaches in patients with CCH.


Cone beam and micro-computed tomography validation of manual array insertion for minimally invasive cochlear implantation.
Delivering cochlear implants through a minimally invasive tunnel (1.8 mm in diameter) from the mastoid surface to the inner ear is referred to as direct cochlear access (DCA). Based on cone beam as well as micro-computed tomography imaging, this in vitro study evaluates the feasibility and efficacy of manual cochlear electrode array insertions via DCA. Free-fitting electrode arrays were inserted in 8 temporal bone specimens with previously drilled DCA tunnels. The insertion depth angle, procedural time, tunnel alignment as well as the inserted scala and intracochlear trauma were assessed. Seven of the 8 insertions were full insertions, with insertion depth angles higher than 520°. Three cases of atraumatic scala tympani insertion, 3 cases of probable basilar membrane rupture and 1 case of dislocation into the scala vestibuli were observed (1 specimen was damaged during extraction). Manual electrode array insertion following a DCA procedure seems to be feasible and safe and is a further step toward clinical application of image-guided otological microsurgery.


Protein-enriched, milk-based supplement to counteract sarcopenia in acutely ill geriatric patients offered resistance exercise training during and after hospitalisation: study protocol for a randomised, double-blind, multicentre trial.
Age-related loss of muscle mass and strength, sarcopaenia, burdens many older adults. The process is accelerated with bed rest, protein intakes below requirements and the catabolic effect of certain illnesses. Thus, acutely ill, hospitalised older adults are particularly vulnerable. Protein supplementation can preserve muscle mass and/or strength and, combining this with resistance exercise training (RT), may have additional benefits. Therefore, this study investigates the effect of protein supplementation as an addition to offering RT among older adults while admitted to the geriatric ward and after discharge. This has not previously been investigated. In a block-randomised, double-blind, multicentre intervention study, 165 older adults above 70 years, fulfilling the eligibility criteria, will be included consecutively from three medical departments (blocks of n=20, stratified by recruitment site). After inclusion, participants will be randomly allocated (1:1) to receive either ready-to-drink, protein-enriched, milk-based supplements (a total of 27.5 g whey protein/day) or isoenergetic placebo products (<1.5 g protein/day), twice daily as a supplement to their habitual diet. Both groups will be offered a standardised RT programme for lower extremity muscle strength (daily while hospitalised and 4×/week after discharge). The study period starts during their hospital stay and continues 12 weeks after discharge. The primary endpoint is lower extremity muscle strength and function (30 s chair-stand-test). Secondary endpoints include muscle mass, measures of physical function and measures related to cost-effectiveness. Approval is given by the Research Ethic Committee of the Capital Region of Denmark (reference no. H-16018240) and the Danish Data Protection Agency (reference no. HGH-2016-050). There are no expected risks associated with participation, and each participant is expected to benefit from the RT. Results will be published in peer-reviewed international journals and presented at national and international congresses and symposiums. NCT02717819 (9 March 2016).


Can biochemical markers predict bone loss at the hip and spine?: a 4-year prospective study of 141 early postmenopausal women.
A number of recent studies have suggested that non-invasive measures of bone turnover are associated with bone loss at the forearm in postmenopausal women. Whether bone turnover markers are predictive of bone loss from the clinically important sites of lumbar spine and femoral neck remain unclear, and was the aim of this 4-year prospective study. One hundred and forty-one normal, postmenopausal women (mean age 52.0 +/- 3.3 years, mean menopause duration 20.4 +/- 5.7 months) were recruited for the study in 1988. Fasting early morning samples of blood and urine were collected at the baseline visit and stored at -20 degrees C prior to analysis. Serum was assayed for osteocalcin, oestradiol, oestrone, oestrone sulphate, testosterone, sex hormone binding globulin, dehydroepiandrosterone sulphate and total alkaline phosphatase. Urine was assayed for calcium, hydroxyproline, oestrone glucuronide and the collagen cross-links pyridinoline and deoxypyridinoline using high-performance liquid chromatography. Bone density was measured at the lumbar spine and femoral neck using dual photon absorptiometry at time 0, 12, 24 and 48 months. The mean annual percentage change in bone density (SE) was -1.41% (0.18) at the lumbar spine and -0.86% (0.22) at the femoral neck. There was no evidence of bimodality or a fast loser subgroup as the rates of change were normally distributed. Both simple and multiple stepwise regression analyses revealed no significant correlation between the rates of change in bone density with any biochemical marker, either individually or in combination, despite the study having sufficient power (80%) to detect a correlation of 0.5 between any biochemical marker levels and bone loss. We conclude that single measurements of these markers of bone turnover and endogenous sex hormones appear unlikely to be clinically useful in predicting early postmenopausal bone loss from either the spine or the hip.


Endoscopically guided surface repair of inguinal hernia.
A novel tension-free prosthetic mesh repair for an inguinal hernia is described. This is performed through a 2-cm groin incision and the inguinal canal is traversed with the aid of a 5-mm videoendoscope. Spermatic cord mobilization, identification and excision of the indirect sac, and posterior wall repair are carried out under endoscopic guidance. Between October 1993 and January 1994, 22 primary unilateral hernia, and two bilateral repairs were undertaken. The mean (range) age was 47 (35-64) years in 23 men and one woman. The mean (range) operative time was 42 (35-58) min. All patients left hospital on the day after surgery. One patient developed a scrotal swelling that required a scrotal support.


Influence of resource levels, organic compounds and laboratory colonization on interspecific competition between the Asian tiger mosquito Aedes albopictus (Stegomyia albopicta) and the southern house mosquito Culex quinquefasciatus.
The mosquitoes Aedes albopictus (Stegomyia albopicta) (Skuse) and Culex quinquefasciatus (Say) (Diptera: Culicidae) are common inhabitants of tyres and other artificial containers, which constitute important peridomestic mosquito breeding habitats. We tested the hypotheses that interspecific resource competition between the larvae of these species is asymmetrical, that the concentration of chemicals associated with decomposing detritus affects the competitive outcomes of these species, and that wild and colonized strains of Cx. quinquefasciatus are affected differently by competition with Ae. albopictus. We conducted two laboratory competition experiments wherein we measured survivorship and estimated population growth (λ') in both species under multiple mixed-species densities. Under varying resource levels, competition was asymmetrical: Ae. albopictus caused competitive reductions or exclusions of Cx. quinquefasciatus under conditions of limited resources. In a second experiment, which used both wild and colonized strains of Cx. quinquefasciatus, organic chemical compounds associated with decomposing detritus did not affect the competitive outcome. The colonized strain of Cx. quinquefasciatus had greater survivorship and adult mass, and faster development times than the wild strain, but both strains were similarly affected by competition with Ae. albopictus. Competition between these species may have important consequences for vector population dynamics, especially in areas in which tyres and artificial containers constitute the majority of mosquito breeding habitats.


Rapid and dynamic subcellular reorganization following mechanical stimulation of Arabidopsis epidermal cells mimics responses to fungal and oomycete attack.
Plant cells respond to the presence of potential fungal or oomycete pathogens by mounting a basal defence response that involves aggregation of cytoplasm, reorganization of cytoskeletal, endomembrane and other cell components and development of cell wall appositions beneath the infection site. This response is induced by non-adapted, avirulent and virulent pathogens alike, and in the majority of cases achieves penetration resistance against the microorganism on the plant surface. To explore the nature of signals that trigger this subcellular response and to determine the timing of its induction, we have monitored the reorganization of GFP-tagged actin, microtubules, endoplasmic reticulum (ER) and peroxisomes in Arabidopsis plants - after touching the epidermal surface with a microneedle. Within 3 to 5 minutes of touching the surface of Arabidopsis cotyledon epidermal cells with fine glass or tungsten needles, actin microfilaments, ER and peroxisomes began to accumulate beneath the point of contact with the needle. Formation of a dense patch of actin was followed by focusing of actin cables on the site of contact. Touching the cell surface induced localized depolymerization of microtubules to form a microtubule-depleted zone surrounding a dense patch of GFP-tubulin beneath the needle tip. The concentration of actin, GFP-tubulin, ER and peroxisomes remained focused on the contact site as the needle moved across the cell surface and quickly dispersed when the needle was removed. Our results show that plant cells can detect the gentle pressure of a microneedle on the epidermal cell surface and respond by reorganizing subcellular components in a manner similar to that induced during attack by potential fungal or oomycete pathogens. The results of our study indicate that during plant-pathogen interactions, the basal defence response may be induced by the plant's perception of the physical force exerted by the pathogen as it attempts to invade the epidermal cell surface.


Fas ligation induces apoptosis of CD40-activated human B lymphocytes.
Since CD40/CD40 ligand (CD40Lig) interactions are essential in vivo for the generation of germinal center B cells that express Fas (Apo-1/CD95), we explored whether CD40 engagement may modulate Fas expression and function on human B lymphocytes. Resting tonsil B cells, isolated by density gradient centrifugation, express either absent or low levels of Fas. They could be induced to promptly express Fas after ligation of their CD40, however, using either a recombinant human CD40Lig or a cross-linked anti-CD40 mAb. In contrast, engagement of the B cell antigen receptor by immobilized anti-kappa and -lambda antibodies did not turn on Fas expression. Addition of anti-Fas mAb CH11 inhibited the later phases of CD40-induced B cell growth as a result of apoptotic cell death. Furthermore, Fas ligation inhibited proliferation and Ig secretion of CD40-activated B cells in response to recombinant cytokines such as interleukin (IL)-2, IL-4, and IL-10, as well as a cytokine-rich supernatant of phytohemagglutinin-activated T cells, indicating that none of those B cell tropic factors were able to prevent the Fas-induced death. Taken together, the present results show that engagement of CD40 antigen on B cells induces Fas expression and sensitizes them to Fas-mediated apoptosis. The delayed functional response to Fas ligation after CD40 activation may represent a way to limit the size of a specific B cell clone that is generated during T-B cell interactions.


Cell cycle regulation of neuronal apoptosis in development and disease.
Apoptosis of neurons is indispensable to the normal development of the nervous system and contributes to neuronal loss in neurologic injury and disease. Life and death decisions are imposed upon neurons by extracellular and intracellular stimuli including the lack of trophic support, exposure to neurotoxins, oxidative stress, and DNA damage. These stimuli induce signaling pathways that are integrated at the mitochondrial apoptotic machinery culminating in cell survival or death. Growing evidence suggests that cell cycle proteins are expressed in dying neurons in the developing and adult brain. However, the role and mechanisms by which re-activation of cell cycle pathways in postmitotic neurons propagates an apoptotic signal to the cell death machinery are just beginning to be characterized. Here, we will review the molecular mechanisms of neuronal cell death and survival with a focus on recent findings on cell cycle regulation of neuronal apoptosis in primary cultures of neurons, mouse models of neuronal diseases, and human neurodegenerative diseases.


Complementary therapies for acne vulgaris.
Acne is a chronic skin disease characterised by inflamed spots and blackheads on the face, neck, back, and chest. Cysts and scarring can also occur, especially in more severe disease. People with acne often turn to complementary and alternative medicine (CAM), such as herbal medicine, acupuncture, and dietary modifications, because of their concerns about the adverse effects of conventional medicines. However, evidence for CAM therapies has not been systematically assessed. To assess the effects and safety of any complementary therapies in people with acne vulgaris. We searched the following databases from inception up to 22 January 2014: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2014,Issue 1), MEDLINE (from 1946), Embase (from 1974), PsycINFO (from 1806), AMED (from 1985), CINAHL (from 1981), Scopus (from 1966), and a number of other databases listed in the Methods section of the review. The Cochrane CAM Field Specialised Register was searched up to May 2014. We also searched five trials registers and checked the reference lists of articles for further references to relevant trials. We included parallel-group randomised controlled trials (or the first phase data of randomised cross-over trials) of any kind of CAM, compared with no treatment, placebo, or other active therapies, in people with a diagnosis of acne vulgaris. Three authors collected data from each included trial and evaluated the methodological quality independently. They resolved disagreements by discussion and, as needed, arbitration by another author. We included 35 studies, with a total of 3227 participants. We evaluated the majority as having unclear risk of selection, attrition, reporting, detection, and other biases. Because of the clinical heterogeneity between trials and the incomplete data reporting, we could only include four trials in two meta-analyses, with two trials in each meta-analysis. The categories of CAM included herbal medicine, acupuncture, cupping therapy, diet, purified bee venom (PBV), and tea tree oil. A pharmaceutical company funded one trial; the other trials did not report their funding sources.Our main primary outcome was 'Improvement of clinical signs assessed through skin lesion counts', which we have reported as 'Change in inflammatory and non-inflammatory lesion counts', 'Change of total skin lesion counts', 'Skin lesion scores', and 'Change of acne severity score'. For 'Change in inflammatory and non-inflammatory lesion counts', we combined 2 studies that compared a low- with a high-glycaemic-load diet (LGLD, HGLD) at 12 weeks and found no clear evidence of a difference between the groups in change in non-inflammatory lesion counts (mean difference (MD) -3.89, 95% confidence interval (CI) -10.07 to 2.29, P = 0.10, 75 participants, 2 trials, low quality of evidence). However, although data from 1 of these 2 trials showed benefit of LGLD for reducing inflammatory lesions (MD -7.60, 95% CI -13.52 to -1.68, 43 participants, 1 trial) and total skin lesion counts (MD -8.10, 95% CI -14.89 to -1.31, 43 participants, 1 trial) for people with acne vulgaris, data regarding inflammatory and total lesion counts from the other study were incomplete and unusable in synthesis.Data from a single trial showed potential benefit of tea tree oil compared with placebo in improving total skin lesion counts (MD -7.53, 95% CI -10.40 to -4.66, 60 participants, 1 trial, low quality of evidence) and acne severity scores (MD -5.75, 95% CI -9.51 to -1.99, 60 participants, 1 trial). Another trial showed pollen bee venom to be better than control in reducing numbers of skin lesions (MD -1.17, 95% CI -2.06 to -0.28, 12 participants, 1 trial).Results from the other 31 trials showed inconsistent effects in terms of whether acupuncture, herbal medicine, or wet-cupping therapy were superior to controls in increasing remission or reducing skin lesions.Twenty-six of the 35 included studies reported adverse effects; they did not report any severe adverse events, but specific included trials reported mild adverse effects from herbal medicines, wet-cupping therapy, and tea tree oil gel.Thirty trials measured two of our secondary outcomes, which we combined and expressed as 'Number of participants with remission'. We were able to combine 2 studies (low quality of evidence), which compared Ziyin Qinggan Xiaocuo Granule and the antibiotic, minocycline (100 mg daily) (worst case = risk ratio (RR) 0.49, 95% CI 0.09 to 2.53, 2 trials, 206 participants at 4 weeks; best case = RR 2.82, 95% CI 0.82 to 9.06, 2 trials, 206 participants at 4 weeks), but there was no clear evidence of a difference between the groups.None of the included studies assessed 'Psychosocial function'.Two studies assessed 'Quality of life', and significant differences in favour of the complementary therapy were found in both of them on 'feelings of self-worth' (MD 1.51, 95% CI 0.88 to 2.14, P < 0.00001, 1 trial, 70 participants; MD 1.26, 95% CI 0.20 to 2.32, 1 trial, 46 participants) and emotional functionality (MD 2.20, 95% CI 1.75 to 2.65, P < 0.00001, 1 trial, 70 participants; MD 0.93, 95% CI 0.17 to 1.69, 1 trial, 46 participants).Because of limitations and concerns about the quality of the included studies, we could not draw a robust conclusion for consistency, size, and direction of outcome effects in this review. There is some low-quality evidence from single trials that LGLD, tea tree oil, and bee venom may reduce total skin lesions in acne vulgaris, but there is a lack of evidence from the current review to support the use of other CAMs, such as herbal medicine, acupuncture, or wet-cupping therapy, for the treatment of this condition. There is a potential for adverse effects from herbal medicines; however, future studies need to assess the safety of all of these CAM therapies. Methodological and reporting quality limitations in the included studies weakened any evidence. Future studies should be designed to ensure low risk of bias and meet current reporting standards for clinical trials.


The acute effect of stretching on the passive stiffness of the human gastrocnemius muscle tendon unit.
Passive stretching is commonly used to increase limb range of movement prior to athletic performance but it is unclear which component of the muscle-tendon unit (MTU) is affected by this procedure. Movement of the myotendinous junction (MTJ) of the gastrocnemius medialis muscle was measured by ultrasonography in eight male participants (20.5 +/- 0.9 years) during a standard stretch in which the ankle was passively dorsiflexed at 1 deg s(-1) from 0 deg (the foot at right angles to the tibia) to the participants' volitional end range of motion (ROM). Passive torque, muscle fascicle length and pennation angle were also measured. Standard stretch measurements were made before (pre-) and after (post-) five passive conditioning stretches. During each conditioning stretch the MTU was taken to the end ROM and held for 1 min. Pre-conditioning the extension of the MTU during stretch was taken up almost equally by muscle and tendon. Following conditioning, ROM increased by 4.6 +/- 1.5 deg (17%) and the passive stiffness of the MTU was reduced (between 20 and 25 deg) by 47% from 16.0 +/- 3.6 to 10.2 +/- 2.0 Nm deg(-1). Distal MTJ displacement (between 0 and 25 deg) increased from 0.92 +/- 0.06 to 1.16 +/- 0.05 cm, accounting for all the additional MTU elongation and indicating that there was no change in tendon properties. Muscle extension pre-conditioning was explicable by change in length and pennation angle of the fascicles but post-conditioning this was not the case suggesting that at least part of the change in muscle with conditioning stretches was due to altered properties of connective tissue.


Elective cesarean section in mares: eight cases (1980-1989).
From 1980 to 1989, 8 cesarean sections were performed on an elective basis in 5 mares. Four mares had partially obstructed pelvic canals; 2 of these mares had previously lost foals because of dystocia. Cervical adhesions that might obstruct passage of the fetus through the pelvic canal was suspected in the fifth mare. Cesarean section was performed prior to mares entering the first stage of labor. Readiness for birth was estimated by development of the mare's mammary gland and the presence of colostrum in the udder. A ventral midline celiotomy provided excellent exposure and healed without complications in all instances. Eight viable foals were produced. One foal developed bacterial pneumonia and septicemia after surgery and died. Follow-up evaluation of the 7 foals discharged from the hospital failed to reveal complications associated with elective cesarean section. All mares survived the procedure. Fetal membranes were retained for up to 72 hours following surgery; however, systemic complications secondary to retained placenta did not develop. Three mares were bred subsequent to elective cesarean sections, with each mare conceiving the year following surgery. Three foals were produced by 1 mare and 2 foals have been produced by another mare by elective cesarean sections.


A Comparative Study Between the Wingate and Force-Velocity Anaerobic Cycling Tests: Effect of Physical Fitness.
To verify the hypothesis that the peak power (PP) of a Wingate test (WT) is an underestimation of maximal power (P(max)) computed from the force-velocity test (FVT), to examine possible fatigue effect on P(max), and to investigate the effect of load on mean power (MP) and fatigue index (FI) during a WT in trained and recreational men. Ten recreational (22.9 ± 1.7 y, 1.81 ± 0.06 m, 73.3 ± 10.4 kg) and 10 highly trained subjects (22.7 ± 1.4 y, 1.85 ± 0.05 m, 78.9 ± 6.6 kg) performed 2 WTs with 2 loads (8.7% and 11% of body mass [BM]) and an FVT on the same cycle ergometer, in randomized order. Optimal load was equal to 10% BM in recreational participants. Given the quadratic relationship between load and power, the underestimation of P(max) was lower than 10% for the average values of trained and recreational participants with both loads. However, PP with a load equal to 8.7% BM was a large underestimation (~30%) of P(max) in the most powerful individuals. In addition, PP was not greater than P(max) of FVT for the same load. FI was independent of the load only if it was expressed relative to PP. The optimal load for MP during WT was close to the optimal load for PP. The optimal load for WT performance should be approximately equal to 10% BM in recreational subjects. In powerful subjects, the FVT appears to be more appropriate in assessing maximal power, and loads higher than 11% BM should be verified for the WT.


TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands.
TLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance. Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054). Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.


Can ginkgo biloba combat diseases?
Herbal remedies have been widely used in many countries for centuries, and the products enjoyed a surge in popularity in the USA during the late '90s. During the past 20 years, an estimated 2 billion daily doses (120 mg) of Ginkgo biloba (GB) have been sold. French and German agencies consider it to be effective for the treatment of several diseases, and the immense amount of clinical studies concerning GB makes it worth revising the existing literature about this notable plant. Also, the National Institutes of Health (NIH) supports research on alternative therapies that include examining the effects of GB. With the rapid expansion of herbal medicine use in the United States, it is clear that our understanding of herb-herb, drug-herb and food-herb interactions should increase.


Dispersive-grating distributed feedback lasers.
This paper proposed a novel distributed feedback (DFB) laser by incorporating a dispersive grating, whose coupling strength is dependent on the operating wavelength. Analysis of the laser threshold conditions shows that the proposed structure guarantees single-mode operation due to the inherent threshold gain discrimination on the two otherwise degenerated lasing modes.


Relationship of extracellular dopamine in striatum of newborn piglets to cortical oxygen pressure.
The present studies describes the relationship between extracellular dopamine in striatum of newborn piglets and cortical oxygen pressure. The extracellular level of dopamine was measured by in vivo microdialysis and the oxygen pressure in the cortex was measured by phosphorescence lifetime of oxygen probe in the blood. Controlled, graded levels of hypoxic insult to the brain of animals were generated by decreasing of the oxygen fraction in the inspired gas (FiO2) from 21% to 14%, 11%, and 9%. This resulted in decrease in the cortical oxygen pressure from 31-35 Torr to about 24 Torr, 15 Torr and 4 Torr, respectively. The changes in extracellular level of dopamine, DOPAC and HVA were dependent on changes in cortical oxygen pressure. Stepwise decrease in the cortical oxygen pressure (see above) caused increases in extracellular dopamine of about 80%, 200% and 550%, respectively. The levels of DOPAC and HVA progressively decreased and when cortical oxygen decreased to 4-6 Torr were about 50% and 70% of control, respectively. After return of FiO2 to control (21%), the cortical oxygen pressure rapidly increased to above normal, then returned to control values. The extracellular levels of dopamine, DOPAC, and HVA recovered more slowly, attaining control values in about 30 minutes. The data show that extracellular levels of dopamine increase with even very small decreases in oxygen pressure. Thus, there is no "oxygen reserve" which protects dopamine release and metabolism from decrease in oxygen pressure.


Sonographically guided posterior subtalar joint injections: anatomic study and validation of 3 approaches.
To describe and validate 3 different approaches to perform sonographically guided posterior subtalar joint (PSTJ) injections. Sonographically guided procedures performed on cadaveric specimens. Procedural skills lab at a tertiary medical facility. Three ultrasound-guided approaches to inject the PSTJ: anterolateral, posteromedial, and posterolateral were derived based on anatomic review, published fluoroscopic and computed tomography (CT) techniques, and clinical experience. Three separate unembalmed cadaveric ankle-foot specimens were injected by a single, experienced operator using a 25-gauge, 38-mm stainless steel needle. A different approach was used on each specimen. The needles were left in place and each specimen was subsequently dissected by co-investigators to confirm accurate needle placement and determine the proximity of each needle to local tendons and neurovascular structures. Direct assessment of needle placement within posterior subtalar joint. All 3 approaches provided accurate needle placement into the posterior subtalar joint while avoiding nearby tendinous and neurovascular structures. Sonographically guided PSTJ injections are technically feasible. All 3 approaches provide accurate needle placement while minimizing the risk of needle entry into adjacent soft tissue structures not visualized by other modalities such as fluoroscopy or CT.


Ultrafast all-optical switching in a silicon-nanocrystal-based silicon slot waveguide at telecom wavelengths.
We demonstrate experimentally all-optical switching on a silicon chip at telecom wavelengths. The switching device comprises a compact ring resonator formed by horizontal silicon slot waveguides filled with highly nonlinear silicon nanocrystals in silica. When pumping at power levels about 100 mW using 10 ps pulses, more than 50% modulation depth is observed at the switch output. The switch performs about 1 order of magnitude faster than previous approaches on silicon and is fully fabricated using complementary metal oxide semiconductor technologies.


Influence of conversation technique seminars on the doctoral therapeutic attitude in doctor-patient communication.
This study investigates medical students' therapeutic attitude before and after communication skills training seminars with simulated patients. The aim was to find out whether the therapeutic attitude of medical students is trainable and whether there is a difference in therapeutic attitude before and after the communication skills training with standardized patients. The participating groups are medical students in their 4th year. The collected parameter is the therapeutic attitude on the basis of the therapeutic attitude questionnaire. The questionnaires are filled out at two different points in time, which are the following: once before and the second time after the communication skills training. The results of this study indicate that therapeutic attitude is trainable. Further studies in the area of communication skills training in medical students are needed to emphasise these results.


Basic mechanisms involved in the anti-cancer effects of melatonin.
It is commonly accepted that melatonin (N-acetyl-5-methoxytryptamine), the most relevant pineal secretory product, has oncostatic properties in a wide variety of tumors and, especially, in those identified as being hormonedependent. The objective of the present article is to offer a global and integrative view of the mechanisms involved in the oncostatic actions of this indoleamine. Due to the wide spectrum of melatonin's actions, the mechanisms that may be involved in its ability to counteract tumor growth are varied. These include: a) antioxidant effects; b) regulation of the estrogen receptor expression and transactivation; c) modulation of the enzymes involved in the local synthesis of estrogens; d) modulation of cell cycle and induction of apoptosis; e) inhibition of telomerase activity; f) inhibition of metastasis; g) prevention of circadian disruption; h) antiangiogenesis; i) epigenetic effects; j) stimulation of cell differentiation; and k) activation of the immune system. The data supporting each of these oncostatic actions of melatonin are summarized in this review. Moreover, the list of actions described may not be exhaustive in terms of how melatonin modulates tumor growth.


Intrapulmonary gas transport and perfusion during high-frequency oscillation.
The effects of high-frequency oscillation (HFO) on 1) regional pulmonary 133Xe clearance after equilibration, 2) regional distribution and subsequent clearance of 133Xe after right atrial bolus injection, and 3) pulmonary gas exchange were examined in anesthetized supine dogs. After equilibration 133Xe cleared similarly from all lung regions with HFO at 16 and 30 Hz and a stroke volume of 2.6 ml/kg. Pulmonary gas exchange was adequate. 133Xe, injected as a bolus into the right atrium, was preferentially distributed to dependent lung regions during both HFO and apnea, indicating vertical gradients in pulmonary perfusion. During the subsequent pulmonary clearance of 133Xe, regional 133Xe concentrations (CrXe) increased initially in nondependent regions. By contrast, CrXe decreased immediately in the dependent lung region; after CrXe's became similar in dependent and nondependent regions, all lung regions started to clear at similar rates. The initial increases of CrXe in nondependent regions were attributed to interregional mixing, which may contribute to the uniformity in regional pulmonary 133Xe clearance after equilibration.


[A patient with acute abdominal pain and vomiting due to the cannabinoid hyperemesis syndrome].
An adolescent patient with acute abdominal pain and vomiting presented in the emergency room. Bathing in hot water relieved his symptoms. Physical examination, basic laboratory testing and imaging showed no abnormalities. The patient was diagnosed with cannabinoid hyperemesis syndrome, which is characterized by chronic cannabis use, recurrent episodes of intractable vomiting and compulsively hot showering or bathing to relieve the symptoms. Unfamiliarity with the syndrome can easily lead to unnecessary diagnostic testing and inappropriate treatment. The consulting psychiatrist could play a role in the diagnostic process and treatment. Furthermore, early recognition of this syndrome in the emergency room may lead to a proper addiction treatment program.


Systematic analysis of bypass suppression of essential genes.
Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole-genome sequencing and detailed genetic analysis, we investigated the genetic interactions and genome alterations underlying bypass suppression. Dispensable essential genes often had paralogs, were enriched for genes encoding membrane-associated proteins, and were depleted for members of protein complexes. Functionally related genes frequently drove the bypass suppression interactions. These gene properties were predictive of essential gene dispensability and of specific suppressors among hundreds of genes on aneuploid chromosomes. Our findings identify yeast's core essential gene set and reveal that the properties of dispensable essential genes are conserved from yeast to human cells, correlating with human genes that display cell line-specific essentiality in the Cancer Dependency Map (DepMap) project.


Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation.
Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized. We present an assessment of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI. Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions.


Unraveling virus relationships by structure-based phylogenetic classification.
Delineation of the intricacies of protein function from macromolecular structure constitutes a continual obstacle in the study of cell and pathogen biology. Structure-based phylogenetic analysis has emerged as a powerful tool for addressing this challenge, allowing the detection and quantification of conserved architectural properties between proteins, including those with low or no detectable sequence homology. With a focus on viral protein structure, we highlight how a number of investigations have utilized this powerful method to infer common functionality and ancestry.


Observations on the passage of apoproteins from plasma lipoproteins into peripheral lymph in two men.
1. The passage of radioactive apolipoproteins into lymph draining the foot was investigated in two men, each given a single intravenous injection of low-density lipoprotein containing 131I-labelled apoprotein B and of very-low-density lipoprotein containing 125I-labelled apoprotein A and apoprotein C. 2. Protein-bound 125I and 131I appeared in the lymph of both subjects. Immunoelectrophoresis of lymph lipoproteins against anti-(high-density lipoprotein) and anti-(low-density lipoprotein) showed the presence of apo-high-density lipoprotein and apo-low-density lipoprotein with faster mobilities than plasma high-density and low-density lipoprotein respectively. Most of the protein-bound 131I in lymph was recovered in the precipitin line formed by the apoprotein B-containing lipoprotein after immunoelectrophoresis. Polyacrylamide gel electrophoresis of the lymph lipoprotein fraction showed the presence of 125I-containing bands with mobilities similar to those of the apoprotein A of high-density lipoprotein and of three of the fast-moving C apoproteins. 3. These results suggest that most, if not all, of the apoproteins of plasma lipoproteins reach the interstitial fluids and that some lipoproteins undergo modification during their passage into peripheral lymph.


Arts-based psychiatric rehabilitation programs in the community: Perceptions of healthcare professionals.
Despite the increase in arts-based programs in community rehabilitation services in many countries, little is known about how these programs are perceived by health professionals who can refer individuals with mental health conditions to community-based psychiatric rehabilitation services. This study examined how senior professionals with key positions in the public health system perceive the integration of the arts in community-based psychiatric rehabilitation services in Israel. Semistructured interviews were conducted with 10 professionals. The thematic analysis revealed 2 main themes. The first reflected "the perceived position of arts-based programs among other rehabilitation services," and had 2 subthemes: arts as a legitimate supplemental service, and arts as a motivating rehabilitation. The second theme reflected "the unique contribution of the arts to recovery processes," and had 3 subthemes: art-making facilitates self-expression and communication and bypasses resistance, art-making facilitates socialization, and art-making shapes and enhances personal identity. Because most of the professionals were exposed to the creative arts in their workplace, they valued their contribution to the rehabilitation process. Thus, direct contact can provide more information, more accurate perceptions, and a better understanding of the benefits of arts-based services, which may in turn encourage service managers and policymakers to include these services. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Thoracic scales of moths as a stealth coating against bat biosonar.
Many moths are endowed with ultrasound-sensitive ears that serve the detection and evasion of echolocating bats. Moths lacking such ears could still gain protection from bat biosonar by using stealth acoustic camouflage, absorbing sound waves rather than reflecting them back as echoes. The thorax of a moth is bulky and hence acoustically highly reflective. This renders it an obvious target for any bat. Much of the thorax of moths is covered in hair-like scales, the layout of which is remarkably similar in structure and arrangement to natural fibrous materials commonly used in sound insulation. Despite this structural similarity, the effect of thorax scales on moth echoes has never been characterized. Here, we test whether and how moth thorax scales function as an acoustic absorber. From tomographic echo images, we find that the thin layer of thoracic scales of diurnal butterflies affects the strength of ultrasound echoes from the thorax very little, while the thorax scales of earless moths absorbs an average of 67 ± 9% of impinging ultrasonic sound energy. We show that the thorax scales of moths provide acoustic camouflage by acting as broadband (20-160 kHz) stealth coating. Modelling results suggest the scales are acting as a porous sound absorber; however, the thorax scales of moths achieve a considerably higher absorption than technical fibrous porous absorbers with the same structural parameters. Such scales, despite being thin and lightweight, constitute a broadband, multidirectional and efficient ultrasound absorber that reduces the moths' detectability to hunting bats and gives them a survival advantage.


Couple serostatus patterns in sub-Saharan Africa illuminate the relative roles of transmission rates and sexual network characteristics in HIV epidemiology.
HIV prevalence has surpassed 30% in some African countries while peaking at less than 1% in others. The extent to which this variation is driven by biological factors influencing the HIV transmission rate or by variation in sexual network characteristics remains widely debated. Here, we leverage couple serostatus patterns to address this question. HIV prevalence is strongly correlated with couple serostatus patterns across the continent; in particular, high prevalence countries tend to have a lower ratio of serodiscordancy to concordant positivity. To investigate the drivers of this continental pattern, we fit an HIV transmission model to Demographic and Health Survey data from 45,041 cohabiting couples in 25 countries. In doing so, we estimated country-specific HIV transmission rates and sexual network characteristics reflective of pre-couple and extra-couple sexual contact patterns. We found that variation in the transmission rate could parsimoniously explain between-country variation in both couple serostatus patterns and prevalence. In contrast, between-country variation in pre-couple or extra-couple sexual contact rates could not explain the observed patterns. Sensitivity analyses suggest that future work should examine the robustness of this result to between-country variation in how heterogeneous infection risk is within a country, or to assortativity, i.e. the extent to which individuals at higher risk are likely to partner with each other.


Influences of aortic motion and curvature on vessel expansion in murine experimental aneurysms.
To quantitatively compare aortic curvature and motion with resulting aneurysm location, direction of expansion, and pathophysiological features in experimental abdominal aortic aneurysms (AAAs). MRI was performed at 4.7 T with the following parameters: (1) 3D acquisition for vessel geometry and (2) 2D cardiac-gated acquisition to quantify luminal motion. Male 24-week-old mice were imaged before and after AAA formation induced by angiotensin II (AngII)-filled osmotic pump implantation or infusion of elastase. AngII-induced AAAs formed near the location of maximum abdominal aortic curvature, and the leftward direction of expansion was correlated with the direction of suprarenal aortic motion. Elastase-induced AAAs formed in a region of low vessel curvature and had no repeatable direction of expansion. AngII significantly increased mean blood pressure (22.7 mm Hg, P<0.05), whereas both models showed a significant 2-fold decrease in aortic cyclic strain (P<0.05). Differences in patterns of elastin degradation and localization of fluorescent signal from protease-activated probes were also observed. The direction of AngII aneurysm expansion correlated with the direction of motion, medial elastin dissection, and adventitial remodeling. Anterior infrarenal aortic motion correlated with medial elastin degradation in elastase-induced aneurysms. Results from both models suggest a relationship between aneurysm pathological features and aortic geometry and motion.


The influence of shc proteins and aging on whole body energy expenditure and substrate utilization in mice.
While it has been proposed that Shc family of adaptor proteins may influence aging by regulating insulin signaling and energy metabolism, the overall impact of Shc proteins on whole body energy metabolism has yet to be elucidated. Thus, the purpose of this study was to determine the influence of Shc proteins and aging on whole body energy metabolism in a mouse model under ambient conditions (22°C) and acute cold exposure (12°C for 24 hours). Using indirect respiration calorimetry, we investigated the impact of Shc proteins and aging on EE and substrate utilization (RQ) in p66 Shc-/- (ShcKO) and wild-type (WT) mice. Calorimetry measurements were completed in 3, 15, and 27 mo mice at 22°C and 12°C. At both temperatures and when analyzed across all age groups, ShcKO mice demonstrated lower 24 h total EE values than that of WT mice when EE data was expressed as either kJ per mouse, or adjusted by body weight or crude organ mass (ORGAN) (P≤0.01 for all). The ShcKO mice also had higher (P<0.05) fed state RQ values than WT animals at 22°C, consistent with an increase in glucose utilization. However, Shc proteins did not influence age-related changes in energy expenditure or RQ. Age had a significant impact on EE at 22°C, regardless of how EE data was expressed (P<0.05), demonstrating a pattern of increase in EE from age 3 to 15 mo, followed by a decrease in EE at 27 mo. These results indicate a decline in whole body EE with advanced age in mice, independent of changes in body weight (BW) or fat free mass (FFM). The results of this study indicate that both Shc proteins and aging should be considered as factors that influence energy expenditure in mice.


Safety and efficacy of Lactobacillus buchneri DSM 29026 as a silage additive for all animal species.
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on Lactobacillus buchneri DSM 29026 when used as a technological additive to improve ensiling of forage. The additive is intended for use with all forages and for all animal species at a proposed minimum concentration of 1 × 108 colony-forming units (CFU)/kg forage if used alone, or 5 × 107 CFU/kg forage if used in combination with other authorised microorganisms. The bacterial species L. buchneri is considered by the EFSA to be suitable for the qualified presumption of safety approach to safety assessment. As the identity of the strain has been clearly established and no acquired antimicrobial resistance determinants of concern were detected, the use of the strain as a silage additive is considered safe for livestock species, for consumers of products from animals fed the treated silage and for the environment. In the absence of data, the FEEDAP Panel cannot conclude on the potential of the additive to be a skin/eye irritant or skin sensitiser. Given the proteinaceous nature of the active agent, the additive should be considered a respiratory sensitiser. The FEEDAP Panel concluded that Lactobacillus buchneri DSM 29026 at a minimum concentration of 5 × 107 CFU/kg may improve the production of silage from easy and moderately difficult to ensile forage material.


Assessing the optimal preparation strategy to minimize the variability of cardiac pyruvate dehydrogenase flux measurements with hyperpolarized MRS.
Hyperpolarized [1-13 C] pyruvate MRS can measure cardiac pyruvate dehydrogenase (PDH) flux in vivo through 13 C-label incorporation into bicarbonate. Using this technology, substrate availability as well as pathology have been shown to modulate PDH flux. Clinical protocols attempt to standardize PDH flux with oral glucose loading prior to scanning, while rodents in preclinical studies are usually scanned in the fed state. We aimed to establish which strategy was optimal to maximize PDH flux and minimize its variability in both control and Type II diabetic rats, without affecting the pathological variation being assessed. We found similar variances in the bicarbonate to pyruvate ratio, reflecting PDH flux, in fed and fasted/glucose-loaded animals, which showed no statistically significant differences. Furthermore, fasting/glucose loading did not alter the low PDH flux seen in Type II diabetic rats. Overall this suggests that preclinical cardiac hyperpolarized magnetic resonance studies could be performed either in the fed or in the fasted/glucose-loaded state. Centres planning to start new clinical studies with cardiac hyperpolarized magnetic resonance in man may find it beneficial to run small proof-of-concept trials to determine whether metabolic standardizations by oral or intravenous glucose load are beneficial compared with scanning patients in the fed state.


Human Cytomegalovirus gH/gL Forms a Stable Complex with the Fusion Protein gB in Virions.
Human cytomegalovirus (HCMV) is a ubiquitous virus that is a major pathogen in newborns and immunocompromised or immunosuppressed patients. HCMV infects a wide variety of cell types using distinct entry pathways that involve different forms of the gH/gL glycoprotein: gH/gL/gO and gH/gL/UL128-131 as well as the viral fusion glycoprotein, gB. However, the minimal or core fusion machinery (sufficient for cell-cell fusion) is just gH/gL and gB. Here, we demonstrate that HCMV gB and gH/gL form a stable complex early after their synthesis and in the absence of other viral proteins. gH/gL can interact with gB mutants that are unable to mediate cell-cell fusion. gB-gH/gL complexes included as much as 16-50% of the total gH/gL in HCMV virus particles. In contrast, only small amounts of gH/gL/gO and gH/gL/UL128-131 complexes were found associated with gB. All herpesviruses express gB and gH/gL molecules and most models describing herpesvirus entry suggest that gH/gL interacts with gB to mediate membrane fusion, although there is no direct evidence for this. For herpes simplex virus (HSV-1) it has been suggested that after receptor binding gH/gL binds to gB either just before, or coincident with membrane fusion. Therefore, our results have major implications for these models, demonstrating that HCMV gB and gH/gL forms stable gB-gH/gL complexes that are incorporated virions without receptor binding or membrane fusion. Moreover, our data is the best support to date for the proposal that gH/gL interacts with gB.


cDNA cloning and developmental expression of fibroblast growth factor receptors from Xenopus laevis.
The heparin-binding growth factors constitute a family of homologous polypeptides including basic and acidic fibroblast growth factors (FGFs). These factors participate in a variety of processes, including wound healing, angiogenesis, neuronal survival, and inductive events in the early amphibian embryo. We have isolated three closely related species of cDNA clones for Xenopus FGF receptors. One of these, designated XFGFR-A1, encodes an open reading frame of 814 amino acids. A second class encodes an identical amino acid sequence with the exception of an 88-amino-acid deletion near the 5' end. This species probably arises through alternative splicing. A third class of cDNA corresponding to the shorter form of XFGFR-A1 was isolated and shown to be 95% homologous and is designated XFGFR-A2. Xenopus FGF receptors are similar to FGF receptors from other species in that they contain a transmembrane domain, a tyrosine kinase domain split by a 14-amino-acid insertion, and a unique conserved stretch of eight acidic residues in the extracellular domain. Overexpression of Xenopus FGF receptor protein by transfection of COS1 cells with the corresponding cDNA in a transient expression vector leads to the appearance of new FGF binding sites on transfected cells, consistent with these cDNAs encoding for FGF receptors. RNA gel blot analysis demonstrates that Xenopus FGF receptor mRNA is a maternal message and is expressed throughout early development. When blastula-stage ectoderm is cultured in control amphibian salt solutions, Xenopus FGF receptor mRNA declines to undetectable levels by late neurula stages. However, when cultured in the presence of FGF of XTC mesoderm-inducing factor, Xenopus FGF receptor RNA expression is maintained.


Can the intermittent low-speed function of left ventricular assist device prevent aortic insufficiency?
Aortic insufficiency (AI) is known to associate with a persistently closed aortic valve during continuous-flow ventricular assist device support. Some devices carry an intermittent low-speed (ILS) function, which facilitates aortic valve opening, but whether this function prevents AI is unknown. In this study, the Jarvik 2000 device, which is programmed to reduce the pump speed each minute for 8 s, was chosen to examine this potential effect. Prospectively collected data of 85 heart transplant-eligible Jarvik 2000 recipients who met the study criteria (no pre-existing AI and aortic valve surgery) were retrospectively analyzed for the incidence, correlating factors, and clinical outcomes of de novo AI. All data were provided by the Japanese Registry for Mechanically Assisted Circulatory Support. De novo AI occurred in 58 patients, 23 of whom developed at least moderate AI during a median support duration of 23.5 months. Freedom from moderate or greater AI was 84.4%, 66.1% and 60.2% at 1, 2 and 3 years, respectively. Multivariate analyses revealed that progressive AI was correlated with decreased pulse pressure after implantation (hazard ratio 1.060, 95% confidence interval 1.001-1.127, p = 0.045). No correlation was found for mortality or other adverse events, including stroke, bleeding, infection, pump failure, hemolysis, and readmission. The benefit of the Jarvik 2000's current ILS mode against AI appears to be minimal. However, in this limited cohort where all recipients underwent implantation as a bridge to transplantation, the impact of de novo progressive AI on other clinical adversities was also minimal.


Phosphorus availability for plant uptake in a phosphorus-enriched noncalcareous sandy soil.
Mining soil phosphorus (i.e., harvesting P taken up from the soil by a crop grown without external P addition) has been proposed as a possible management strategy for P-enriched soils to decrease the risk of P leaching. We performed a pot experiment in a greenhouse where grass was cropped on a P-enriched noncalcareous sandy soil at zero P application over a period of 978 d. We determined the long-term availability of soil P and evaluated the effectiveness of mining soil P to decrease P in different pools. There were two treatments: soil layers in the pots of either 5 or 10 cm thickness. Soils were analyzed at various stages of the experiment. Phosphorus in soil solution and the total pool of sorbed P were estimated using 1:10 (w/v) 0.01 M CaCl2 extracts and acid ammonium oxalate (P(ox)), respectively. A desorption isotherm was constructed, which described the relationship between P in soil solution and the total pool of sorbed P for the soils of the 5- and 10-cm treatments. The Langmuir equation gave a very good description of the isotherm. In the long-term, 65% of P(ox) in the initial soil can be removed by plant uptake, as was calculated from the Langmuir equation and a critical P concentration in soil solution at which P uptake can just be maintained. Thus, P(ox) may be largely plant available. From the strong nonlinearity of the desorption isotherm, it can be understood why the relative decrease of the P concentration in the CaCl2 extracts was much larger than the relative decrease of P(ox). Mining soil P decreased the P concentration in soil solution effectively and, therefore, risk of P leaching from our P-enriched soil.


Clients' Experience and Satisfaction of Utilizing Healthcare Services in a Community Based Health Insurance Program in Bangladesh.
Background: Community-based health insurance is recognized as a promising tool for health system improvement for low-income people that improves the health status of enrolees and enhances productivity and labor supply. The experience and opinion of the clients who utilized health services through the insurance scheme are important for improving healthcare services, shaping health policies and providing feedback on the quality, availability, and responsiveness of healthcare services. However, studies focusing on clients' satisfaction provided by the health insurance scheme are still limited globally. Objective: To address this knowledge gap, this current study attempted to measure the degree of clients' satisfaction towards healthcare services and insurance scheme, based on their experience of health care which will serve the future reference point to implement potential quality improvement initiatives of community-based health insurance program. Methods: A cross-sectional household survey was conducted within the catchment area of a community-based health insurance pilot program named Labor Association for Social Protection (LASP) during April⁻June 2014 to compare the evaluation of healthcare services provided by LASP scheme. In the descriptive analyses, the characteristics of the study participants were presented regarding frequency and the percentages with 95% confidence interval. Spearman correlation analysis was conducted between the satisfaction score of each indicator and overall satisfaction score; multivariate linear regression analysis was used to identify the factors associated with overall health scheme satisfaction. Results: The overall satisfaction mean score was 4.17 ± 0.04 (95% CI: 4.08⁻4.26) out of 5.00. The most satisfied domains were related to the diagnostic services (4.46 ± 0.98), explanation about the prescribed medicine (4.23 ± 0.81), the surrounding environment of healthcare facility (4.21 ± 0.70) and the behavior of health personnel toward clients (4.18 ± 0.73). Conclusions: Our study observed that the overall satisfaction level towards health services is quite favorable, but satisfaction scores can still be improved. These findings could contribute towards developing and designing the healthcare services packages of community-based health scheme which is in line with the health care financing strategy of Bangladesh as well as the recommendation of the World Health Organization for developing social health insurance as part of path to Universal Health Coverage.