Glutathone and glutathione ethyl ester supplementation of mice alter glutathione homeostasis during exercise.
The present study examined the effect of glutathione (GSH) and glutathione ethyl ester (GSH-E) supplementation on GSH homeostasis and exercise-induced oxidative stress. Male Swiss-Webster mice were randomly divided into 4 groups: starved for 24 h and injected with GSH or GSH-E (6 mmol/kg body wt, i.p.) 1 h before exercise, starved for 24 h and injected with saline (S); and having free access to food and injected with saline (C). Half of each group of mice was killed either after an acute bout of exhaustive swimming (E) or after rest (R). Plasma GSH concentration was 100-160% (P < 0.05) higher in GSH mice vs. C or S mice at rest, whereas GSH-E injection had no effect. Plasma GSH was not affected by exercise in C or S mice, but was 44 and 34% lower (P < 0.05) in E vs. R mice with GSH or GSH-E injection, respectively. S, GSH- and GSH-E-treated mice had significantly lower liver GSH concentration and the GSH:glutathione disulfide (GSSG) ratio than C mice. Hepatic and renal GSH and the GSH:GSSG ratio were significantly lower in E vs. R mice in all groups. GSH-E-treated mice had a significantly smaller exercise-induced decrease in GSH vs. C, S, and GSH-treated mice and no difference in the GSH:GSSG ratio in the kidney. Activities of gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase in the liver and kidney were not affected by either GSH treatment or exercise. GSH concentration and the GSH:GSSG ratio in quadriceps muscle were not different among C, S and GSH-treated mice, but significantly lower in GSH-E-treated mice (P < 0.05). Hepatic malondialdehyde (MDA) content was greater in exercised mice in all but GSH-E-treated groups. GSH and GSH-E increased MDA levels in the kidney of E vs. R mice, but attenuated exercise-induced lipid peroxidation in muscle. Swim endurance time was approximately 2 h longer in GSH (351 +/- 22 min) and GSH-E (348 +/- 27) than S mice (237 +/- 17). We conclude that 1) acute GSH and GSH-E supplementation at the given doses does not increase tissue GSH content or redox status; 2) both GSH and GSH-E improve endurance performance and prevent muscle lipid peroxidation during prolonged exercise; and 3) while both compounds may impose a metabolic and oxidative stress to the kidney, this side effect is smaller with GSH-E supplementation.


Depressed adolescents demonstrate greater subgenual anterior cingulate activity.
Neuroimaging studies implicate the subgenual anterior cingulate cortex (sgACC) as a critical brain region in adult depression. However, unlike adult depression, little is known about the underlying neural substrates of adolescent depression, and there are no published data examining differences in sgACC activation between depressed and healthy adolescents. This study used functional magnetic resonance imaging to examine sgACC activity in 26 depressed and normal 13-17-year olds during the performance of a stop-signal task. Significantly greater sgACC activation was found in the depressed adolescents relative to controls. These results establish for the first time abnormal functioning of the sgACC in depressed adolescents and have important implications for understanding the underlying neural correlates and potential treatments of adolescent depression.


Early postoperative feeding--results of a North American survey.
Early postoperative feeding (EPOF) practices among North American institutions were investigated using a survey questionnaire to obtain descriptive information regarding the overall utilization and criteria used to identify candidates for EPOF. EPOF was defined as the initiation of enteral nutrition support two to 48 hours postoperatively in major abdominal and thoracic surgical patients. Two hundred and ninety-seven questionnaires were mailed; 170 were completed. Sixty-nine (41%) institutions reported using EPOF. Feeding was initiated less than 12 hours postoperatively in 16% of centres; 84% reported EPOF 13-48 hours postoperatively. The majority (88%) of institutions did not have a specific nutritional guideline for determining which patients should receive EPOF. Objective and subjective nutritional indices, degree of preoperative malnutrition and type of surgery were considered by 23% of respondents when determining the need for EPOF. Percent weight loss, albumin and the anticipated postoperative NPO were considered the most reliable objective indices while decreased dietary intake, cachexic appearance and anorexia were considered the most reliable subjective indices. The results reveal that less than 50% of institutions surveyed use EPOF in major abdominal and thoracic surgical patients and the criteria used to identify candidates for EPOF were found to be variable.


Corticosteroid actions on amino acid-mediated transmission in rat CA1 hippocampal cells.
We here describe actions mediated by mineralo- and glucocorticoid receptors (MRs and GRs, respectively) on intracellularly recorded synaptic responses, evoked in rat CA1 pyramidal cells in vitro by stimulation of the Schaffer collaterals. Neurons in slices from adrenalectomized (ADX) rats, that is, where MRs and GRs are unoccupied, showed a synaptic response consisting of an EPSP, followed by a fast and a slow IPSP; the responses were apparently similar to those in slices from sham-operated rats. However, in the ADX rats, repeated electrical stimulation over a period of 80 min resulted in a gradual decline of the firing probability for synaptically driven action potentials and of the slow IPSP amplitude. Nonsynaptic responses (e.g., membrane potential, accommodation, and afterhyperpolarization) were stable during the 80 min period. Application of 3 nM aldosterone between 20 and 40 min after impalement of cells in slices from ADX rats, thus activating predominantly MRs, yielded stable synaptic and nonsynaptic responses for at least 1 hr after the onset of the steroid application. By contrast, corticosterone (30 nM), which occupies GRs in addition to MRs, reduced the amplitude of both the EPSP and slow IPSP, and the firing probability of synaptically driven action potentials, within 20 min; nonsynaptic properties remained stable. Similar results were obtained with the selective glucocorticoid RU 28362. The EPSP and fast and slow IPSPs of neurons in slices from ADX rats impaled with a time lag of 1-4 hr after the steroid application did not differ significantly from the responses of neurons impaled before steroid application.(ABSTRACT TRUNCATED AT 250 WORDS)


Approaches for Achieving Superlubricity in Two-Dimensional Materials.
Controlling friction and reducing wear of moving mechanical systems is important in many applications, from nanoscale electromechanical systems to large-scale car engines and wind turbines. Accordingly, multiple efforts are dedicated to design materials and surfaces for efficient friction and wear manipulation. Recent advances in two-dimensional (2D) materials, such as graphene, hexagonal boron nitride, molybdenum disulfide, and other 2D materials opened an era for conformal, atomically thin solid lubricants. However, the process of effectively incorporating 2D films requires a fundamental understanding of the atomistic origins of friction. In this review, we outline basic mechanisms for frictional energy dissipation during sliding of two surfaces against each other, and the procedures for manipulating friction and wear by introducing 2D materials at the tribological interface. Finally, we highlight recent progress in implementing 2D materials for friction reduction to near-zero values-superlubricity-across scales from nano- up to macroscale contacts.


Tailored Crumpling and Unfolding of Spray-Dried Pristine Graphene and Graphene Oxide Sheets.
For the first time, pristine graphene can be controllably crumpled and unfolded. The mechanism for graphene is radically different than that observed for graphene oxide; a multifaced crumpled, dimpled particle morphology is seen for pristine graphene in contrast to the wrinkled, compressed surface of graphene oxide particles, showing that surface chemistry dictates nanosheet interactions during the crumpling process. The process demonstrated here utilizes a spray-drying technique to produce droplets of aqueous graphene dispersions and induce crumpling through rapid droplet evaporation. For the first time, the gradual dimensional transition of 2D graphene nanosheets to a 3D crumpled morphology in droplets is directly observed; this is imaged by a novel sample collection device inside the spray dryer itself. The degree of folding can be tailored by altering the capillary forces on the dispersed sheets during evaporation. It is also shown that the morphology of redispersed crumpled graphene powder can be controlled by solvent selection. This process is scalable, with the ability to rapidly process graphene dispersions into powders suitable for a variety of engineering applications.


Linear solutions to metamaterial volume hologram design using a variational approach.
Multiplex volume holograms are conventionally constructed by the repeated exposure of a photosensitive medium to a sequence of external fields, each field typically being the superposition of a reference wave that reconstructs the hologram and the other being a desired signal wave. Because there are no sources of radiation internal to the hologram, the pattern of material modulation is limited to the solutions to Helmholtz's equation in the medium. If the three-dimensional structure of the medium could be engineered at each point rather than limited to the patterns produced by standing waves, more versatile structures may result that can overcome the typical limitations to hologram dynamic range imposed by sequentially superimposing holograms. Metamaterial structures and other synthetic electromagnetic materials offer the possibility of achieving high medium contrast engineered at the subwavelength scale. By posing the multiplex volume holography problem as a linear medium design problem, we explore the potential improvements that such engineered synthetic media may provide over conventional multiplex volume holograms.


Powder and mechanical properties of microcrystalline cellulose with different degrees of polymerization.
This study investigated the influence of the degree of polymerization (DP) of cellulose materials (microcrystalline cellulose [MCC]) on some powder properties and the compression behavior of these materials. The DP was determined by measurements of viscosity (H). The weight average of molecular weight and the weight average of the different DPs were investigated after MCC was modified to cellulose tricarbanilate by light scattering measurements. The DP showed a remarkable influence on the physicochemical properties of the cellulose materials and, consequently, on the behavior of these materials during compression. MCC types with a high DP value showed greater water absorption than the types with a low DP value. No relevant relationship between the crystallinity index and the DP could be observed. DP 190 showed lower compactibility and compressibility parameters than DP 244 and 299. No significant differences could be observed between DP 244 and 299 when the same particle size fraction was compressed. Furthermore, the compressibility was increased by increasing the DP.


Neurochemical actions of anesthetic drugs on the gamma-aminobutyric acid receptor-chloride channel complex.
Interaction of intoxicant-anesthetic drugs with the gamma-aminobutyric acid (GABA) receptor-chloride channel complex of mouse brain was studied using the binding of [35S]t-butylbicyclophosphorothionate (TBPS) to isolated membranes and the GABA-stimulated uptake of 36Cl- by membrane vesicles. Anesthetic drugs, including barbiturates, chloroform, diethylether and ethanol, inhibited the binding of TBPS and enhanced the GABA-dependent influx of chloride. In the presence of bicuculline, barbiturates increased the binding of TBPS, but this action was not shared by other anesthetic agents. Inhibition of TBPS binding was found with drug concentrations that produce anesthesia in vivo, whereas augmentation of GABA action occurred at subanesthetic concentrations. Effects of a series of n-alcohols (methanol to decanol) were studied on TBPS binding and membrane fluidity (using 1,6-diphenyl-1,3,5-hexatriene as a fluorescent probe). The potencies of the alcohols for inhibiting TBPS binding and fluidizing synaptic membranes were similar to their anesthetic potencies, but there were differences in the relative potencies of the drugs for inhibition of TBPS binding and membrane fluidization. These results, together with effects of assay temperature, suggest that effects of anesthetics on the GABA receptor-chloride channel complex were not due to changes in bulk membrane fluidity. Correlation of anesthetic potencies of chemically diverse agents with both inhibition of TBPS binding and augmentation of GABA-dependent chloride flux suggests a role for the GABA complex in anesthesia.


The learning styles and the preferred teaching-learning strategies of first year medical students.
The purpose of teaching is to facilitate learning and to encourage the learners to learn more effectively. The learning style is an individual's consistent way of perceiving, processing and retaining new information. Educational researchers have shown an increasing interest in the learning styles, the related instructional methods and the andrgogical teaching techniques. This interest is spurred by a desire to help the students to become capable and successful learners. The aim of this study was to determine the preferred learning styles of medical students as well as their preferences of specific teaching-learning methods. A cross sectional study was conducted on 100 first semester medical students who were enrolled at SMS & R, Sharda University, India. The VARK questionnaire, version 7.1 was used to categorize the learning preferences/modes as visual (V), auditory (A), read and write (R) and kinaesthetic (K). The students were also asked to rank the various teaching methodologies viz. lectures, tutorials, demonstrations and practicals/dissections from the most preferred choice to the least preferred one. The majority (61%) of the students had multimodal VARK preferences. Among them, 41%, 14% and 6% preferred the bimodal, trimodal and the quadrimodal ways of information presentation. 39% of the respondents had one strong (unimodal) learning preference. The most common unimodal preference was kinaesthetic, followed by visual, auditory and read and write. The most preferred teaching methodology was practical/dissection (39%) and tutorial was the least preferred one (12%). One single approach to teaching does not work for every student or even for most of the students. The educators' awareness of the various learning styles of the students and their efforts towards matching the teaching and learning styles may help in creating an effective learning environment for all the students.


Altering plant-microbe interaction through artificially manipulating bacterial quorum sensing.
Many bacteria regulate diverse physiological processes in concert with their population size. Bacterial cell-to-cell communication utilizes small diffusible signal molecules, which the bacteria both produce and perceive. The bacteria couple gene expression to cell density by eliciting a response only when the signalling molecules reach a critical threshold (a point at which the population is said to be 'quorate'). The population as a whole is thus able to modify its behaviour as a single unit. Amongst Gram-negative bacteria, the quorum sensing signals most commonly used are N-acylhomoserine lactones (AHLs). It is now apparent that AHLs are used for regulating diverse behaviours in epiphytic, rhizosphere-inhabiting and plant pathogenic bacteria and that plants may produce their own metabolites that interfere with this signalling. Transgenic plants that produce high levels of AHLs or which can degrade bacterial-produced AHLs have been made. These plants have dramatically altered susceptibilities to infection by pathogenic Erwinia species. In addition, such plants will prove useful tools in determining the roles of AHL-regulated density-dependent behaviour in growth promoting, biological control and pathogenic plant-associated bacterial species.


Malaria in pregnancy.
Pregnant women have a higher risk of malaria compared to non-pregnant women. This review provides an update on knowledge acquired since 2000 on P. falciparum and P.vivax infections in pregnancy. Maternal risk factors for malaria in pregnancy (MiP) include low maternal age, low parity, and low gestational age. The main effects of MIP include maternal anaemia, low birth weight (LBW), preterm delivery and increased infant and maternal mortality.P. falciparum infected erythrocytes sequester in the placenta by expressing surface antigens, mainly variant surface antigen (VAR2CSA), that bind to specific receptors, mainly chondroitin sulphate A. In stable transmission settings, the higher malaria risk in primigravidae can be explained by the non-recognition of these surface antigens by the immune system. Recently, placental sequestration has been described also for P.vivax infections. The mechanism of preterm delivery and intrauterine growth retardation is not completely understood, but fever (preterm delivery), anaemia, and high cytokines levels have been implicated.Clinical suspicion of MiP should be confirmed by parasitological diagnosis. The sensitivity of microscopy, with placenta histology as the gold standard, is 60% and 45% for peripheral and placental falciparum infections in African women, respectively. Compared to microscopy, RDTs have a lower sensitivity though when the quality of microscopy is low RDTs may be more reliable. Insecticide treated nets (ITN) and intermittent preventive treatment in pregnancy (IPTp) are recommended for the prevention of MiP in stable transmission settings. ITNs have been shown to reduce malaria infection and adverse pregnancy outcomes by 28-47%. Although resistance is a concern, SP has been shown to be equivalent to MQ and AQ for IPTp. For the treatment of uncomplicated malaria during the first trimester, quinine plus clindamycin for 7 days is the first line treatment and artesunate plus clindamycin for 7 days is indicated if this treatment fails; in the 2(nd) and 3(rd) trimester first line treatment is an artemisinin-based combination therapy (ACT) known to be effective in the region or artesunate and clindamycin for 7 days or quinine and clindamycin. For severe malaria, in the second and third trimester parenteral artesunate is preferred over quinine. In the first trimester, both artesunate and quinine (parenteral) may be considered as options. Nevertheless, treatment should not be delayed and should be started immediately with the most readily available drug.


Expression of GADS enhances FLT3-induced mitogenic signaling.
GADS is a member of a family of SH2 and SH3 domain-containing adaptors that functions in tyrosine kinase-mediated signaling cascades. Its expression is largely restricted to hematopoietic tissues and cell lines. Therefore, GADS is mainly involved in leukocyte-specific protein tyrosine kinase signaling. GADS is known to interact with tyrosine-phosphorylated SHC, BCR-ABL and KIT. The SH2 domain of GADS has a similar binding specificity to that of GRB2 but its SH3 domain displays a different binding specificity, and thus it is involved in other downstream signaling pathways than GRB2. In the present study, we examined the role of GADS in FLT3 signaling. FLT3 is a type III receptor tyrosine kinase, which is mutated in more than 30% of acute myeloid leukemia (AML) and the most common mutations is the internal tandem duplication (ITD) mutations. We observed that expression of GADS enhanced oncogenic FLT3-ITD-induced cell proliferation and colony formation in vitro. In a mouse xenograft model, GADS accelerated FLT3-ITD-dependent tumor formation. Furthermore, expression of GADS induced a transcriptional program leading to upregulation of MYC and mTORC1 target genes. GADS localizes to the cell membrane and strongly binds to ligand-stimulated wild-type FLT3 or is constitutively associated with the oncogenic mutant FLT3-ITD. We mapped the binding sites in FLT3 to pY955 and pY969 which overlaps with the GRB2 binding sites. Expression of GADS enhanced FLT3-mediated phosphorylation of AKT, ERK1/2, p38 and STAT5. Taken together, our data suggests that GADS is an important downstream component of FLT3 signaling and expression of GADS potentiates FLT3-mediated mitogenic signaling.


Parental smoking and adolescent problem behavior: an adoption study of general and specific effects.
It is essential to understand the effect of parental smoking on offspring tobacco use. In biologically related families, parents who smoke may transmit a nonspecific genetic risk for offspring disinhibited behavior, including tobacco use. Studying adoptive families allows one to control for genetic confounding when examining the environmental effect of exposure to parental smoking. The purpose of this study was to examine the genetic and environmental contributions to the risk represented by exposure to parental smoking and to assess the specificity of that risk. Adolescents adopted in infancy were systematically ascertained from records of three private Minnesota adoption agencies; nonadopted adolescents were ascertained from Minnesota birth records. Adolescents and their rearing parents participated in all assessments in person. The main outcome measures were self-reports of behavioral deviance, substance use, and personality, as well as DSM-IV clinical assessments of childhood disruptive disorders. The data from adoptive families suggest that exposure to parental smoking represents an environmental risk for substance use in adolescent offspring. In biologically related families, the effect of exposure to parental smoking is larger and more diverse, including substance use, disruptive behavior disorders, delinquency, deviant peer affiliations, aggressive attitudes, and preference for risk taking. This study provides evidence for an environmentally mediated pathway by which parental smoking increases risk specifically for substance use in adolescent offspring. The data are also consistent with a genetically mediated pathway by which nonadoptive parents who smoke may also transmit a nonspecific genetic risk to their offspring for disinhibited behavior.


Alternative parametric boundary reconstruction method for biomedical imaging.
Determining the outline or boundary contour of a two-dimensional object, or the surface of a three-dimensional object poses difficulties particularly when there is substantial measurement noise or uncertainty. By adapting the mathematical approach of stochastic function recovery to this task, it is possible to obtain usable estimates for these boundaries, even in the presence of large amounts of noise. The technique is applied to parametric boundary data and has potential applications in biomedical imaging. It should be considered as one of several techniques to improve the visualization of images.


Polygenic risk score predicts prevalence of cardiovascular disease in patients with familial hypercholesterolemia.
Although familial hypercholesterolemia (FH) is a severe monogenic disease, it has been shown that clinical risk factors and common genetic variants can modify cardiovascular disease (CVD) risk. The aim of the study was to evaluate the polygenic contribution to lipid traits and CVD in FH using genetic risk scores (GRSs). Among the 20,434 subjects attending the lipid clinic, we identified and included 725 individuals who carried an FH causing mutation in this retrospective cohort study. We evaluated the association of GRSs for several traits including coronary artery disease (CAD; GRSCAD) as well as plasma concentrations of low-density lipoprotein cholesterol (LDL-C; GRSLDL-C), high-density lipoprotein cholesterol (GRSHDL-C) and triglycerides (GRSTG). A total of 32% (n = 231) of FH subjects presented a CVD event before their first visit. Patients in the highest GRSLDL-C tertile presented an LDL-C 0.4 mmol/L (15.5 mg/dL) higher than the subjects in the lowest tertile (P = .01). The GRSCAD was strongly associated with CVD events (odds ratio 1.80; 95% confidence interval 1.14-2.85; P = .01) even after adjustment for cardiovascular risk factors. Compared with subjects in the first tertile, those in the third GRSCAD tertile had a significantly higher prevalence of events (40.9% vs 24.7%, P < .0001) and a significantly higher number of events (average 0.97 vs 0.57 [P = .0001] events per individual). These results indicate that even in the context of a severe monogenic disease such as FH, common genetic variants can significantly modify the disease phenotype. The use of the 192-SNPs GRSCAD may refine CVD risk prediction in FH patients and this could lead to a more personalized approach to therapy.


A comparative study of carotid atherosclerotic plaque microvessel density and angiogenic growth factor expression in symptomatic versus asymptomatic patients.
A challenge facing clinicians is identifying patients with asymptomatic carotid disease at risk of plaque instability. We hypothesise that locally released angiogenic growth factors contribute to plaque instability. Carotid endarterectomy specimens from eight symptomatic and eight asymptomatic patients were interrogated for microvessel density and angiogenic growth factor expression histologically using immunofluorescence, and biochemically using quantitative real-time polymerase chain reaction (q-RT-PCR). Bio-Plex suspension array was used to assess circulating biomarkers in venous blood from the same patients and six healthy age-matched controls. Immunofluorescence demonstrated significantly greater neovessel density in symptomatic plaques (P=0.010) with elevated expression of hepatocyte growth factor (HGF) (P=0.001) and its receptor MET (P=0.011) than in asymptomatic plaques. The q-RT-PCR demonstrated up-regulation of Endoglin (CD105), HGF (P=0.001) and MET (P=0.011) in the plaques of symptomatic versus asymptomatic patients. Bio-Plex suspension array demonstrated elevated HGF (P=0.002) serum levels in symptomatic versus asymptomatic patients and healthy controls, and decreased platelet-derived growth factor (PDGF) (P=0.036) serum levels in symptomatic versus asymptomatic patients. Plaque instability may be mediated by HGF-induced formation of new microvessels, and decreased vessel stability resulting from decreased PDGF. Suspension array technology has the potential to identify circulating biomarkers that correlate with plaque rupture risk.


Enhancing the heterologous expression of latex clearing protein from Streptomyces sp. strain K30 in Escherichia coli through fermentation condition optimization and molecular modification.
Latex clearing protein from Streptomyces sp. strain K30 (LcpK30) is a natural oxidoreductase that can catalyse the cleavage of rubber through dioxygenation. It has significant potential applications in polymer degradation. However, its limited expression in engineered strains restricts its utility. This study aimed to enhance the soluble expression and enzyme activity of LcpK30 in E. coli BL21 (DE3) by optimizing fermentation conditions and making molecular modifications. The enzyme activity reached 5.05 U·mL-1 by optimizing the induction conditions, adding cofactors, and using chemical chaperones, which was 237.1 % of the initial case. Further enhancements in soluble expression were achieved through site mutations guided by the PROSS server, resulting in 8 out of 13 mutants with increased protein expression, a high positive mutation rate of 61.5 %. Subsequently, combined mutants were created by merging single mutants with enhanced protein expression and enzyme activity. The top three double mutants, G91D/S149A, G91D/A210H, and G91D/H296P, displayed expression levels at 173.3 %, 173.3 %, and 153.3 % of the wild-type LcpK30, respectively. These mutants also exhibited enhanced fermentation enzyme activity, reaching 149.5 %, 250.0 %, and 420.2 % compared to the wild-type, along with improved specific activities. This study provides insights for the efficient production of LcpK30 and a practical foundation for its application.


[Toxoplasmosis. Diagnostic considerations. Results of various studies].
Toxoplasmosis as a human disease is briefly described. Concerned investigations developed in Cuba and some aspects of immunological tests performed in our country are pointed out. Results of studies conducted at the National Institute of Hygiene and Epidemiology between 1974 and 1978 are disclosed, and an increase of the number of tests is evidenced. In the thesis work of Dr. G. Delgado it was proved the high sensitivity of the complement fixation test regarding toxoplasmin. For these reasons, it is desirable the decentralization of the laboratory diagnosis of this disease.


The Role of Microbiota in Depression - a brief review.
The microbiota-gut-brain axis is a bidirectional homeostatic route of communication between both of the organs direct via receptors of the CNS or via epigenetic mechanisms of divers metabolites e.g. SCFA, GABA, β-hydroxybutyrate. Thus, a modulation of gut microbiota via nutrition, lifestyle etc. might be effective for emotional status and depressive disorders. The dietary composition has an influence on gut microbiota composition, microbial metabolite profile and the according consequences on emotional status and depression within a system biologic approach. There are changes in gut microbiota composition and gut microbial profile (butyrate, GABA, β-hydroxybutyrate) effecting epigenetic regulation (histone acetylation, DNA methylation) and gene expression of receptors and mediators (SLC6A4, BDNF, GABA, GPRs) involved in depressive disorders.


ASHP national survey of pharmacy practice in hospital settings: Dispensing and administration--2014.
The results of the 2014 ASHP national survey of pharmacy practice in hospital settings that pertain to dispensing and administration are described. A stratified random sample of pharmacy directors at 1435 general and children's medical-surgical hospitals in the United States were surveyed by mail. In this national probability sample survey, the response rate was 29.7%. Ninety-seven percent of hospitals used automated dispensing cabinets in their medication distribution systems, 65.7% of which used individually secured lidded pockets as the predominant configuration. Overall, 44.8% of hospitals used some form of machine-readable coding to verify doses before dispensing in the pharmacy. Overall, 65% of hospital pharmacy departments reported having a cleanroom compliant with United States Pharmacopeia chapter 797. Pharmacists reviewed and approved all medication orders before the first dose was administered, either onsite or by remote order view, except in procedure areas and emergency situations, in 81.2% of hospitals. Adoption rates of electronic health information have rapidly increased, with the widespread use of electronic health records, computer prescriber order entry, barcodes, and smart pumps. Overall, 31.4% of hospitals had pharmacists practicing in ambulatory or primary care clinics. Transitions-of-care services offered by the pharmacy department have generally increased since 2012. Discharge prescription services increased from 11.8% of hospitals in 2012 to 21.5% in 2014. Approximately 15% of hospitals outsourced pharmacy management operations to a contract pharmacy services provider, an increase from 8% in 2011. Health-system pharmacists continue to have a positive impact on improving healthcare through programs that improve the efficiency, safety, and clinical outcomes of medication use in health systems.


Clinical Performance of Two-Piece Zirconia Dental Implants After 5 and Up to 12 Years.
To assess the clinical performance of a two-piece zirconia implant system, with a focus on biologic complications. A total of 39 patients received 91 two-piece zirconia implants. The patients were recruited from two private clinics and were monitored for 5 to 12 years (median: 5.6 years). The primary outcomes were biologic complications, such as peri-implant infections (peri-implant mucositis and peri-implantitis), and the secondary outcome was radiographically evident marginal bone loss (MBL). Three patients (7.7%) with 9 total implants (9.9%) presented with peri-implant mucositis. MBL that did not exceed the first thread was evident at 32 mesial sites (35%) and 25 distal sites (27.4%). MBL exceeding the first thread but not the third thread was evident at 6 mesial and 5 distal sites (thread pitch: 0.7 mm). Only one peri-implant pocket deepened (4 mm) and showed bleeding; however, the estimated MBL did not exceed 1.65 mm. No peri-implantitis occurred, and no implant was lost. This prospective study shows high survival rates and a seemingly low prevalence of biologic and prosthetic complications for this two-piece zirconia implant system over an observation period of up to 12 years.


Social wasp (Hymenoptera: Vespidae) foraging behavior.
Social wasps (Hymenoptera: Vespidae) forage for water, pulp, carbohydrates, and animal protein. When hunting, social wasps are opportunistic generalists and use a variety of mechanisms to locate and choose prey. Individual foragers are influenced by past foraging experience and by the presence of other foragers on resources. A forager's ability to learn odors and landmarks, which direct its return to foraging sites, and to associate cues such as odor or leaf damage with resource availability provide the behavioral foundation for facultative specialization by individual foragers. Social wasps, by virtue of their behavior and numbers, have a large impact on other organisms by consuming them directly. Indirect effects such as disruption of prey and resource depletion may also be important. Community-level impacts are particularly apparent when wasps feed upon clumped prey vulnerable to depredation by returning foragers, or when species with large, long-lived colonies are introduced into island communities. A clearer understanding of these relationships may provide insight into impacts of generalist predators on the evolution of their prey.


Extrapulmonary effects of inhaled nitric oxide: role of reversible S-nitrosylation of erythrocytic hemoglobin.
Early applications of inhaled nitric oxide (iNO), typically in the treatment of diseases marked by acute pulmonary hypertension, were met by great enthusiasm regarding the purported specificity of iNO: vasodilation by iNO was specific to the lung (without a change in systemic vascular resistance), and within the lung, NO activity was said to be confined spatially and temporally by Hb within the vascular lumen. Underlying these claims were classical views of NO as a short-lived paracrine hormone that acts largely through the heme groups of soluble guanylate cyclase, and whose potential activity is terminated on encountering the hemes of red blood cell (RBC) Hb. These classical views are yielding to a broader paradigm, in which NO-related signaling is achieved through redox-related NO adducts that endow NO synthase products with the ability to act at a distance in space and time from NO synthase itself. Evidence supporting the biological importance of such stable NO adducts is probably strongest for S-nitrosothiols (SNOs), in which NO binds to critical cysteine residues in proteins or peptides. The circulating RBC is a major SNO reservoir, and RBC Hb releases SNO-related bioactivity peripherally on O2 desaturation. These new paradigms describing NO transport also provide a plausible mechanistic understanding of the increasingly recognized peripheral effects of inhaled NO. An explanation for the peripheral actions of inhaled NO is discussed here, and the rationale and results of attempts to exploit the "NO delivery" function of the RBC are reviewed.


Accuracy of diagnostic coding of hospital admissions for cryptogenic fibrosing alveolitis.
To determine the accuracy of diagnostic coding of cryptogenic fibrosing alveolitis, the case notes of 166 admissions to four hospitals were reviewed. These consisted of all admissions that had been coded as "idiopathic fibrosing alveolitis" (ICD code 516.3: 97 admissions) or as "postinflammatory pulmonary fibrosis" (ICD code 515.9: 69 admissions). Of 88 available records of admissions coded as idiopathic fibrosing alveolitis, 70 (80%) patients had definite cryptogenic fibrosing alveolitis, and six (7%) possible cryptogenic fibrosing alveolitis according to predetermined conventional clinical criteria. Only seven (8%) admissions were clearly coded wrongly. Sixty four records were available for patients coded as having postinflammatory pulmonary fibrosis; 16 (25%) of these patients had definite cryptogenic fibrosing alveolitis, a further 12 (19%) had possible cryptogenic fibrosing alveolitis or fibrosing alveolitis with a connective tissue disorder, and the remainder had a very wide range of diagnoses. In this study the idiopathic fibrosing alveolitis (ICD 516.3) code was relatively reliable, but a substantial proportion of admissions coded under postinflammatory pulmonary fibrosis (ICD 515.9) also had cryptogenic fibrosing alveolitis and code 515.9 was of little diagnostic value. The data are inadequate for case finding, though in respect of cryptogenic fibrosing alveolitis may be adequate for planning purposes. There continues to be a need for more medical input into the process of diagnostic coding.


Combined coronary and mitral annulus calcium detection in the non-invasive diagnosis of coronary artery disease in patients with systemic hypertension.
Although the presence of coronary calcium (CC) on fast spiral computed tomography (FSCT) is a powerful predictor of coronary artery disease (CAD), both the specificity and positive predictive value (PPV) of CC in CAD diagnosis are modest. Since previous studies have shown an association between mitral annular calcification (MAC) and coronary atherosclerosis, we aimed to investigate whether combined coronary and MAC detection could improve the non-invasive diagnosis of CAD. Our study comprised 522 patients (284 men and 238 women, age ranged from 52-80 years, mean 65 +/- 6 years) who underwent FSCT of the coronaries as well as echo-Doppler examination. Among them, 97 patients had prior diagnosis of prevalent proven CAD (CAD group) while 425 patients were without clinically manifested CAD (the No CAD group). The prevalence of CC in the CAD group was 95 versus 68% in the No CAD group (P = 0.001). The prevalence of MAC in CAD group was 63 versus 51% in No CAD group (P = 0.03). Sensitivity and negative predictive value (NPV) of CC as a predictor of CAD were 95 and 96% respectively, but specificity and PPV were low: 32 and 24% respectively. Sensitivity and NPV of MAC as predictors of CAD were 63 and 85% respectively; specificity and PPV, 49 and 22% respectively. Using of combined CC and MAC evaluation in the prediction led to some specificity improvement at the expense of a similar sensitivity reduction, without a considerable gain in the total accuracy of the method. Coronary calcium detection on FSCT in hypertensive patients yields excellent sensitivity and NPV but relatively low specificity and PPV for clinically manifested CAD. Mitral annular calcification assessment yields a low sensitivity and specificity and its addition to CC evaluation does not improve non-invasive diagnosis of CAD.


Association between renal injury and reduced interleukin-15 and interleukin-15 receptor levels in acute kidney injury.
Interleukin (IL)-15 serves as a survival factor for a broad array of cells. Renal cells express both IL-15 and its receptor (IL-15R); however, the role of IL-15 in the kidney is yet to be determined. We examined IL-15 and IL-15R levels in sepsis-related renal injury, ischemia-reperfusion injury (IRI), and cisplatin-induced nephrotoxicity. To test the anti-apoptotic effect of IL-15, Bcl-2/Bax mRNA levels were assessed in kidneys of IL-15Ralpha(-/-) mice and in IL-15-stimulated renal epithelial cells (RECs). In addition, RECs were exposed to cisplatin and apoptosis was evaluated by TUNEL staining, caspase-3 activity, and cell cycle analysis. Intrarenal IL-15 levels decreased 24 h after initiation of all three examined pathologies by 5.8-fold (sepsis), 11-fold (IRI), and 23-fold (cisplatin-induced nephrotoxicity). Further experiments revealed that while addition of rIL-15 (1 ng/mL) to wild-type (WT) RECs increased Bcl-2/Bax ratio by 2-fold, kidneys of IL-15Ralpha(-/-) mice exhibited 4-fold lower Bcl-2/Bax ratio compared to WT mice. Accordingly, IL-15 lowered the apoptotic rate in cisplatin-treated cultured REC, and IL-15Ralpha(-/-) renal cells exhibited a higher rate of cisplatin-induced apoptosis. Furthermore, IL-15 levels negatively correlated with BUN of cisplatin-treated mice (R = -0.69, P = 0.003), suggesting that a decline in renal-derived IL-15 is detrimental to renal cell survival and kidney function during pathological stress.


Rotavirus A infection in children under five years old with a double health problem: undernutrition and diarrhoea - a cross-sectional study in four provinces of Mozambique.
Mozambique has a high burden of group A rotavirus (RVA) infection and chronic undernutrition. This study aimed to determine the frequency and potential risk factors for RVA infection in undernourished children under 5 years old with diarrhoea in Mozambique. The analysis was conducted using data from March 2015 to December 2017, regarding children under 5 years old with at least one type of undernutrition. Anthropometric measures were used to calculate indices of weight-for-age, weight-for-height and height-for-age through the Z-Scores. RVA results were extracted from the National Diarrhoea Surveillance database. Descriptive statistics, chi-square test was used for qualitative variables and organized in contingency tables and 95% Confidence Intervals (CI) were considered for the calculation of RVA infection proportion and in the multiple logistic regression models to estimate the adjusted odds ratios (AOR). Of the 842 undernourished children included in the analysis, 27.2% (95% CI: 24.3-30.3%) were positive for RVA. The rate of RVA infection was 42.7% (95% CI: 38.0-47.5%) in the pre-vaccine period, with great reduction to 12.2% (95% CI: 9.4-15.6%) in the post-vaccine period. Most of the RVA undernourished children had severe wasting (33.3%) and severe stunting (32.0%). The risk of infection was significantly high in children from 0 to 11 months (p-value < 0.001) when compared to the age group of 24-59 months. A higher proportion of RVA infection was detected in households with five or more members (p-value = 0.029). Similar proportions of RVA were observed in children fed only by breast milk (34.9%) and breast milk with formula (35.6%). A higher proportion of undernourished HIV-positive children co-infected with RVA (7.4%) was observed. The frequency of RVA infection in undernourished children declined following the introduction of the vaccine in Mozambique. Beyond the temporal variation, Maputo province, age and crowded households were also associated to RVA infection. A high proportion of RVA infection was observed in children with severe wasting and a triple burden of disease: undernutrition, RVA and HIV, highlighting the need to conduct follow-up studies to understand the long-term impact of these conditions on children's development.


Alteration of (Frequency-Dependent) Fitness in Time-Shift Experiments Reveals Cryptic Coevolution and Uncoordinated Stasis in a Virtual Jurassic Park.
Among the major unresolved questions in ecosystem evolution are whether coevolving multispecies communities are dominated more by biotic or by abiotic factors, and whether evolutionary stasis affects performance as well as ecological profile; these issues remain difficult to address experimentally. Digital evolution, a computer-based instantiation of Darwinian evolution in which short self-replicating computer programs compete, mutate, and evolve, is an excellent platform for investigating such topics in a rigorous experimental manner. We evolved model communities with ecological interdependence among community members, which were subjected to two principal types of mass extinction: a pulse extinction that killed randomly, and a selective press extinction involving an alteration of the abiotic environment to which the communities had to adapt. These treatments were applied at two different strengths (Strong and Weak), along with unperturbed Control experiments. We performed several kinds of competition experiments using simplified versions of these communities to see whether long-term stability that was implied previously by ecological and phylogenetic metrics was also reflected in performance, namely, whether fitness was static over long periods of time. Results from Control and Weak treatment communities revealed almost completely transitive evolution, while Strong treatment communities showed higher incidences of temporal intransitivity, with pre-treatment ecotypes often able to displace some of their post-recovery successors. However, pre-treatment carryovers more often had lower fitness in mixed communities than in their own fully native conditions. Replacement and invasion experiments pitting single ecotypes against pre-treatment reference communities showed that many of the invading ecotypes could measurably alter the fitnesses of one or more residents, usually with depressive effects, and that the strength of these effects increased over time even in the most stable communities. However, invaders taken from Strong treatment communities often had little or no effect on resident performance. While we detected periods of time when the fitness of a particular evolving ecotype remained static, this stasis was not permanent and never affected an entire community at once. Our results lend support to the fitness-deterioration interpretation of the Red Queen hypothesis, and highlight community context dependence in determining fitness, the shaping of communities by both biotic factors and abiotic forcing, and the illusory nature of evolutionary stasis. Our results also demonstrate the potential of digital evolution studies to illuminate many aspects of evolution in interacting multispecies communities.


Herpesvirus saimiri ORF57: a post-transcriptional regulatory protein.
Herpesvirus saimiri (HVS) is the prototype gamma-2 herpesvirus and is a useful model to study the basic mechanisms of lytic replication in this herpesvirus subfamily. This review focuses upon the role of an essential lytic protein, ORF57, which is functionally conserved in all classes of herpesviruses. ORF57 is a multidomain, multifunctional protein responsible for both activation and repression of viral gene expression at a post-transcriptional level. ORF57-mediated repression of gene expression is determined by mRNA processing signals, in particular the presence of an intron within the target gene. This may also be linked to the ability of ORF57 to redistribute SC-35 and U2 splicing factors into specific nuclear domains. ORF57 also plays a pivotal role in transactivating viral gene expression by specifically mediating the nuclear export of HVS intronless transcripts. ORF57 has the ability to shuttle between the nucleus and the cytoplasm, bind viral RNA and recruit cellular nuclear export proteins, such as hTREX components and TAP, onto the viral mRNA. This enables the efficient nuclear export and cytoplasmic accumulation of virus intronless mRNA.


Transport of rice cyclobutane pyrimidine dimer photolyase into mitochondria relies on a targeting sequence located in its C-terminal internal region.
The cyclobutane pyrimidine dimer (CPD), which represents a major type of DNA damage induced by ultraviolet-B (UVB) radiation, is a principal cause of UVB-induced growth inhibition in plants. CPD photolyase is the primary enzyme for repairing CPDs and is crucial for determining the sensitivity of Oryza sativa (rice) to UVB radiation. CPD photolyase is widely distributed among species ranging from eubacteria to eukaryotes, and is classified into class I or II based on its primary structure. We previously demonstrated that rice CPD photolyase (OsPHR), which belongs to class II and is encoded by a single-copy gene, is a unique nuclear/mitochondrial/chloroplast triple-targeting protein; however, the location and nature of the organellar targeting information contained within OsPHR are unknown. Here, the nuclear and mitochondrial targeting signal sequences of OsPHR were identified by systematic deletion analysis. The nuclear and mitochondrial targeting sequences are harbored within residues 487-489 and 391-401 in the C-terminal region of OsPHR (506 amino acid residues), respectively. The mitochondrial targeting signal represents a distinct topogenic sequence that differs structurally and functionally from classical N-terminal pre-sequences, and this region, in addition to its role in localization to the mitochondria, is essential for the proper functioning of the CPD photolyase. Furthermore, the mitochondrial targeting sequence, which is characteristic of class-II CPD photolyases, was acquired before the divergence of class-II CPD photolyases in eukaryotes. These results indicate that rice plants have evolved a CPD photolyase that functions in mitochondria to protect cells from the harmful effects of UVB radiation.


Cooperative behaviour in monomeric enzymes. Change of negative to positive cooperativity by effect of a ligand.
Three steady-state models were analysed to see if they could reproduce the following kinetic characteristics in a monomeric enzyme with two substrates: a) kinetic cooperativity with respect to the first substrate but not to the second; b) modulation of the kinetic cooperativity for the first substrate by the concentration of the second; c) change in the sign of the kinetic cooperativity at very low concentrations of the second substrate. A slow transition model previously proposed for vertebrate "glucokinase" (hexokinase D), model I, (Olavarría et al., 1982) was able to reproduce characteristics a and b, but never c. The "mnemonical" model (Ricard et al., 1974), model II, also reproduced characteristics a and b, and failed to reproduce c. Thus when observations were performed at concentrations of the first substrate around K0.5 it was possible to observe a decrease in the Hill coefficient (h) relative to the decrease in the concentration of the second substrate, but values lower than 1.0 were never obtained. At extremely high substrate concentrations, the second substrated did not affect the cooperativity of the enzyme for the first substrate. Model III was similar to Model I, but it was considered that only the enzyme conformer with the higher affinity for the first substrate was catalytically active. With this model it was possible to change positive cooperativity into negative if the second substrated altered the frequency of the conformational transition.


The familial aggregation of adolescent suicide attempts.
The objective of this study was to determine whether the familial aggregation of suicidal behaviour is explained by the familial aggregation of personality disorder and aggression. The relatives of 62 clinically referred adolescent suicide attempters were compared with 70 never-suicidal psychiatric controls. The first-degree relatives of the suicide attempters had a higher rate of suicide attempts/completion than those of the psychiatric controls. This rate remained significantly higher after controlling for Axis I and II differences in the probands and the relatives, but familial personality disorder was significantly associated with suicidal risk in probands. Among the adolescent attempters, high scores on a measure of assaultiveness were associated with significantly higher familial rates of suicide attempts/completion. Our results support the hypothesis that suicidal behaviour may be transmitted as a trait independent of Axis I and II psychopathology but that, in addition, personality disorder has a role in the transmission of suicidal behaviour. An interrelationship between proband assaultiveness and the familial aggregation of suicidality was noted.


Impact of prenatal stress on neuroendocrine programming.
Since life emerged on the Earth, the development of efficient strategies to cope with sudden and/or permanent changes of the environment has been virtually the unique goal pursued by every organism in order to ensure its survival and thus perpetuate the species. In this view, evolution has selected tightly regulated processes aimed at maintaining stability among internal parameters despite external changes, a process termed homeostasis. Such an internal equilibrium relies quite heavily on three interrelated physiological systems: the nervous, immune, and endocrine systems, which function as a permanently activated watching network, communicating by the mean of specialized molecules: neurotransmitters, cytokines, and hormones or neurohormones. Potential threats to homeostasis might occur as early as during in utero life, potentially leaving a lasting mark on the developing organism. Indeed, environmental factors exert early-life influences on the structural and functional development of individuals, giving rise to changes that can persist throughout life. This organizational phenomenon, encompassing prenatal environmental events, altered fetal growth, and development of long-term pathophysiology, has been named early-life programming. Over the past decade, increased scientific activities have been devoted to deciphering the obvious link between states of maternal stress and the behavioral, cognitive, emotional, and physiological reactivity of the progeny. This growing interest has been driven by the discovery of a tight relationship between prenatal stress and development of short- and long-term health disorders. Among factors susceptible of contributing to such a deleterious programming, nutrients and hormones, especially steroid hormones, are considered as powerful mediators of the fetal organization since they readily cross the placental barrier. In particular, variations in circulating maternal glucocorticoids are known to impact this programming strongly, notably when hormonal surges occur during sensitive periods of development, so-called developmental windows of vulnerability. Stressful events occurring during the perinatal period may impinge on various aspects of the neuroendocrine programming, subsequently amending the offspring's growth, metabolism, sexual maturation, stress responses, and immune system. Such prenatal stress-induced modifications of the phenotypic plasticity of the progeny might ultimately result in the development of long-term diseases, from metabolic syndromes to psychiatric disorders. Yet, we would like to consider the outcome of this neuroendocrine programming from an evolutionary perspective. Early stressful events during gestation might indeed shape internal parameters of the developing organisms in order to adapt the progeny to its everyday environment and thus contribute to an increased reproductive success, or fitness, of the species. Moreover, parental care, adoption, or enriched environments after birth have been shown to reverse negative long-term consequences of a disturbed gestational environment. In this view, considering the higher potential for neonatal plasticity within the brain in human beings as compared to other species, long-term consequences of prenatal stress might not be as inexorable as suggested in animal-based studies published to date.


Thyrotropin receptor antibodies following treatment with recombinant alpha-interferon in patients with hepatitis.
We measured thyrotropin receptor antibodies in serum obtained from 2 groups of patients participating in clinical trials of recombinant interferon-alpha 2b for viral hepatitis. Group I: Patients with hepatitis B (N = 8), received interferon 5 x 10(6) units thrice weekly for 4 months. Group II: Patients with non-A, non-B hepatitis (N = 16) were randomized to receive interferon in a dose of either 0.25 x 10(6) or 3 x 10(6) U thrice weekly for 6 months and then crossed over to receive the other dosage schedule for a further 6 months. None of the patients developed thyrotoxicosis. Thyrotropin receptor antibody activity was detectable within the "normal range" (less than 10 U/l) in 6 patients prior to treatment. In Group I, thyrotropin receptor antibodies became detectable in 6 patients on treatment, in 4 of whom it was 10 U/l. In Group II, thyrotropin receptor antibody activity was unchanged on low-dose interferon, but on the higher dose became detectable in 9 patients, in 7 of whom it was greater than 10 U/l. We conclude that treatment with interferon is associated with the development of thyrotropin receptor antibodies in a large proportion of patients. It is possible that in some patients treated with higher doses of interferon the increase in thyrotropin receptor antibody activity may be sufficient to induce hyperthyroidism.


Early introduction of oral paricalcitol in renal transplant recipients. An open-label randomized study.
In stable renal transplant recipients with hyperparathyroidism, previous studies have indicated that vitamin D agonist treatment might have anti-proteinuric effects. Animal studies indicate possible anti-fibrotic and anti-inflammatory effects. Early introduction of paricalcitol in de novo renal transplant recipients might reduce proteinuria and prevent progressive allograft fibrosis. We performed a single-center, prospective, randomized, open-label trial investigating effects of paricalcitol 2 μg/day added to standard care. Participants were included 8 weeks after engraftment and followed for 44 weeks. Primary end point was change in spot urine albumin/creatinine ratio. Exploratory microarray analyses of kidney biopsies at study end investigated potential effects on gene expression. Secondary end points included change in glomerular filtration rate (GFR), pulse wave velocity (PWV), and endothelial function measured by peripheral arterial tonometry as reactive hyperemia index (RHI). Seventy-seven de novo transplanted kidney allograft recipients were included, 37 receiving paricalcitol. Paricalcitol treatment lowered PTH levels (P = 0.01) but did not significantly reduce albuminuria (P = 0.76), change vascular parameters (PWV; P = 0.98, RHI; P = 0.33), or influence GFR (P = 0.57). Allograft gene expression was not influenced. To summarize, in newly transplanted renal allograft recipients, paricalcitol reduced PTH and was well tolerated without negatively affecting kidney function. Paricalcitol did not significantly reduce/prevent albuminuria, improve parameters of vascular health, or influence allograft gene expression.


Alcohol consumption and cancer risk.
This review focuses on selected aspects of the relation between alcohol consumption and cancer risk. Heavy alcohol consumption (i.e., ≥4 drinks/day) is significantly associated with an increased risk of about 5-fold for oral and pharyngeal cancer and esophageal squamous cell carcinoma, 2.5-fold for laryngeal cancer, 50% for colorectal and breast cancers, and 30% for pancreatic cancer. These estimates are based on a large number of epidemiological studies and are generally consistent across strata of several covariates. The evidence suggests that at low doses of alcohol consumption (i.e., ≤1 drink/day) the risk is also increased by about 20% for oral and pharyngeal cancer and 30% for esophageal squamous cell carcinoma. Thus, for these sites there is little evidence of a threshold effect. While consumption of fewer than 3 alcoholic drinks/wk is not associated with an increased risk of breast cancer, an intake of 3 to 6 drinks/wk might already yield a (small) increase in risk. On the other hand, intakes up to 1 drink/day are not associated to the risk of laryngeal, colorectal, and pancreatic cancer. The positive association between alcohol consumption and the risk of head and neck cancers is independent from tobacco exposure.


Pitch shifts of mistuned partials: a time-domain model.
Mistuning one partial of a complex harmonic tone makes that partial easier to hear as a tone separate from the complex. At the same time, two pitch shifts may be observed. First, the low pitch of the complex is shifted in the direction of the mistuning, as if it were "pulled" by the partial. Second, the mistuning of the partial is perceptually exaggerated, as if the pitch of the partial were "pushed" away from the harmonic series defined by the complex. This paper shows how the latter effect can emerge within a hypothetical neural circuit. The circuit involves a gating neuron fed by three pathways, one direct and excitatory and the other two delayed and inhibitory. The neuron responds to any excitatory input spike unless it is accompanied by an inhibitory input spike on either delayed input, thus acting as a kind of "anticoincidence counter." The first delay is fixed and tuned to the period of the background harmonic complex. Its purpose is to weaken correlates of in-tune components and allow the mistuned partial to stand out. The second delay is variable and used to estimate the period of the mistuned partial, by searching for a minimum output as a function of delay. With an appropriate choice of parameters, the estimate is subject to shifts that are of the same sign as the mistuning and that peak at about 4% mistuning and decrease beyond, as observed experimentally.


[Pharmacotherapy for acute respiratory infections caused by influenza viruses: current possibilities].
Routinely the influenza virus significantly contributes to the formation of the annual incidence of acute respiratory infections, with a peak in winter season. The high level of mutagenic potential of influenza viruses is a standard factor determining the complexity of the rational choice of pharmacotherapy. The upcoming epidemiological season 20202021 brings additional challenges for health care practitioners mediated by the widespread prevalence in the human population of a new infection caused by the SARS-CoV-2 virus affecting the respiratory system among many organs and systems. An adequate choice of pharmacotherapy tools should be based on high efficiency and safety of drugs, with a possible reduction in such negative factors as polypharmacy. This review includes comparative pharmacological characteristics of drugs with activity against RNA viruses, along with parameters of their clinical efficacy.


Pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma.
To determine the pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma (UUT-TCC). From 1993 to 2003, 82 patients without a history of bladder cancer underwent nephroureterectomy or segmental distal ureterectomy for UUT-TCC. We reviewed the pathologic features of the subsequent bladder tumors, including stage, grade, and progression to cystectomy in these patients at a median follow-up of 44.1 months. A total of 36 (44%) of 82 patients developed bladder tumors after definitive therapy for UUT-TCC at a mean interval of 13.9 months. The mean number of bladder tumors diagnosed per patient in the follow-up interval was 2.1 (range 1 to 6), for a total of 74 bladder tumors. Of the 74 bladder tumors, 71 (96%) were superficial (Stage Ta, Tis, T1), 49 of these superficial tumors (69%) being low grade (grade 1 and 2) and 22 (31%) high grade (grade 3). Three patients had high-grade, muscle-invasive disease, and all progressed to cystectomy during follow-up. A greater than 75% concordance was found in pathologic grade between the UUT lesion and subsequent bladder tumors. The stage of the UUT malignancy, however, did not correlate with subsequent bladder tumor pathologic findings. Bladder tumors developed in 44% of patients after treatment of UUT-TCC. Of these bladder tumors, over 60% were superficial, low-grade lesions, yielding a similar pathologic distribution to that of bladder cancer de novo. The grade, but not the stage, of the UUT tumors correlated with the pathologic findings of subsequent bladder tumor recurrence. Aggressive surveillance with cystoscopy and urinary cytology after surgical management of UUT-TCC is imperative.


Vitrectomy in endophthalmitis. Results of study using vitrectomy, intraocular antibiotics, or a combination of both.
A rabbit model of endophthalmitis was produced by inoculating Staphylococcus epidermidis and S aureus into the vitreous cavity. Elimination of microorganisms was compared using intravitreal administration of 0.1 mg of gentamicin alone, vitrectomy alone, and a combination of gentamicin and vitrectomy. In the case of S. epidermidis treated 24 hours after inoculation, all untreated eyes were culture-positive at one week, eyes treated with gentamicin alone or intravitreal gentamicin in combination with vitrectomy were all culture-negative, and vitrectomy alone rendered half of the eyes culture-negative. In the case of S aureus, eyes not treated by vitrectomy alone were all culture-positive at one week. Eyes treated with intravitreal gentamicin 25 to 31 hours after infection were culture-negative for S aireus in 33% at one week, while eyes treated with combined vitrectomy plus intraocular gentamicin were culture-negative in 83% of cases. When treatment was delayed 40 to 49 hours after inoculation of S aureus, intravitreal rendered 50% culture-negative at one week, while vitrectomy combined with intravitreal gentamicin eliminated the infection in 100% of eyes.


Platelet-rich plasma in bone repair of irradiated tibiae of Wistar rats.
To evaluate the influence of PRP addition on bone repair of circular defects created in irradiated tibiae of rats by histometric analysis. Sixty male Wistar rats had the right tibiae irradiated with 30 Gy. After 30 days monocortical defects were created and platelet-rich plasma was applied in 30 rats. In the control group defects were created but not filled. The animals were desanguinated after 4, 7, 14, 21, 56 and 84 days and the tibiae removed for histological processing. There was a tendency in the PRP group to increased bone neoformation from 14-days to 84-days; in the control group increased bone neoformation was not seen after 21 days or later. The addition of platelet-rich plasma had a beneficial effect in the initial cellular regeneration period and enhanced bone formation in later periods when compared to control.


Chronic Chlamydophila pneumoniae infection in lung cancer, a risk factor: a case-control study.
The relationship between chronic Chlamydophila (formerly Chlamydia) pneumoniae infection and lung carcinoma was investigated. A total of 123 patients who were smokers and diagnosed with lung carcinoma based on clinical and laboratory (radiological, cytological) findings were examined. Of these patients, 70 had small-cell, 28 squamous-cell and seven large-cell carcinomas, while 18 had adenocarcinoma. A total of 123 healthy persons matching patients in age, sex, duration of smoking and locality were chosen as controls. Blood samples (5 ml) were withdrawn at the time of diagnosis and 1 month later. The values between IgG >/= 512 and IgA >/= 40 were set as the criteria for chronic Chlamydophila pneumoniae infections. In male patients with lung carcinoma, Chlamydophila pneumoniae IgG antibody titres of >/= 512 and IgA antibody titres of >/= 40 were found at a higher rate than in the control group. This ratio was not significant for the female patients. In chronic Chlamydophila pneumoniae infections, Chlamydophila pneumoniae antibody titres with values IgG >/= 512 and IgA >/= 40 were found in a total of 62 (50.4 %) cases. Chronic Chlamydophila pneumoniae infections were seen statistically more often in male patients with carcinoma who were aged 55 years or younger. This study supports the idea that chronic Chlamydophila pneumoniae infection increases the risk of lung carcinoma.


[Bezoars as a cause for acute small intestinal obstruction].
Results of treatment of 12 patients with acute small intestinal obstruction due to bezoars were analyzed. Mean age of the patients was 67,5+/-3,7 years. In 9 of them bezoars were localized in the ileum, in 3 -- in the jejunum. Mechanisms of bezoars formation are analyzed. Clinical symptoms of intestinal obstruction due to bezoars are regarded. Necessity of surgical treatment of these patients is noted. Bezoars were removed with enterotomy in 10 patients, in 2 -- with fragmentation and transposition in the cecum. Recommendations on surgical techniques are presented. All operated patients have recovered. There were no complications.


Analysis, cloning, and high-level expression of 2,4-dichlorophenoxyacetate monooxygenase gene tfdA of Alcaligenes eutrophus JMP134.
Plasmid pJP4 of Alcaligenes eutrophus JMP134 contains all genes for the degradation of 2,4-dichlorophenoxyacetic acid (2,4-D). Five of these genes, tfdB, tfdC, tfdD, tfdE, and tfdF, have recently been localized and cloned (R. H. Don, A. J. Weightman, H.-J. Knackmuss, and K. N. Timmis, J. Bacteriol. 161:85-90, 1985). Gene tfdA, which codes for the 2,4-D monooxygenase, has now been found by mutagenesis with transposon Tn5. A 3-kilobase fragment of pJP4 cloned in a broad-host-range vector could complement the 2,4-D-negative phenotype of two mutants which lacked 2,4-D monooxygenase activity. The cloned tfdA gene was also transferred to A. eutrophus JMP222, which is a cured derivative of JMP134. The recombinant strain could utilize phenoxyacetic acid as a sole source of carbon and energy. Pseudomonas sp. strain B13, containing the cloned tfdA, was able to degrade phenoxyacetic acid and 4-chlorophenoxyacetic acid. Gene tfdA was subcloned and analyzed by deletions. Expression of 2,4-D monooxygenase in Escherichia coli containing a 1.4-kilobase subfragment was demonstrated by radioisotopic enzyme assay, and a protein of 32,000-dalton molecular mass was detected by labeling experiments. A 2-kilobase subfragment containing tfdA has been sequenced. Sequence analysis revealed an open reading frame of 861 bases which was identified as the coding region of tfdA by insertion mutagenesis.


Evaluation of anemia in children.
Anemia is defined as a hemoglobin level of less than the 5th percentile for age. Causes vary by age. Most children with anemia are asymptomatic, and the condition is detected on screening laboratory evaluation. Screening is recommended only for high-risk children. Anemia is classified as microcytic, normocytic, or macrocytic, based on the mean corpuscular volume. Mild microcytic anemia may be treated presumptively with oral iron therapy in children six to 36 months of age who have risk factors for iron deficiency anemia. If the anemia is severe or is unresponsive to iron therapy, the patient should be evaluated for gastrointestinal blood loss. Other tests used in the evaluation of microcytic anemia include serum iron studies, lead levels, and hemoglobin electrophoresis. Normocytic anemia may be caused by chronic disease, hemolysis, or bone marrow disorders. Workup of normocytic anemia is based on bone marrow function as determined by the reticulocyte count. If the reticulocyte count is elevated, the patient should be evaluated for blood loss or hemolysis. A low reticulocyte count suggests aplasia or a bone marrow disorder. Common tests used in the evaluation of macrocytic anemias include vitamin B12 and folate levels, and thyroid function testing. A peripheral smear can provide additional information in patients with anemia of any morphology.


Invariance of Initiation Mass and Predictability of Cell Size in Escherichia coli.
It is generally assumed that the allocation and synthesis of total cellular resources in microorganisms are uniquely determined by the growth conditions. Adaptation to a new physiological state leads to a change in cell size via reallocation of cellular resources. However, it has not been understood how cell size is coordinated with biosynthesis and robustly adapts to physiological states. We show that cell size in Escherichia coli can be predicted for any steady-state condition by projecting all biosynthesis into three measurable variables representing replication initiation, replication-division cycle, and the global biosynthesis rate. These variables can be decoupled by selectively controlling their respective core biosynthesis using CRISPR interference and antibiotics, verifying our predictions that different physiological states can result in the same cell size. We performed extensive growth inhibition experiments, and we discovered that cell size at replication initiation per origin, namely the initiation mass or unit cell, is remarkably invariant under perturbations targeting transcription, translation, ribosome content, replication kinetics, fatty acid and cell wall synthesis, cell division, and cell shape. Based on this invariance and balanced resource allocation, we explain why the total cell size is the sum of all unit cells. These results provide an overarching framework with quantitative predictive power over cell size in bacteria.


Biochemical studies on the mechanism of chemical and physical inactivation of reovirus.
We have examined the effects of heat and several chemical inactivating agents on the buoyant density, particle-associated polypeptides and ultrastructure of reovirus particles. Treatment at pH 11 removed polypeptide sigma 1 from the outer capsid of reovirus type 2 but not from type 1; resultant particles were unchanged in their buoyant density and morphology. Treatment of reovirus types 2 and 3 with 2.5 M-guanidine-HCl produced particles with unchanged polypeptide content but an increased buoyant density, and caused aggregation of type 3 but not type 2. Treatment with 1% SDS removed polypeptide sigma 3 from both types 1 and 2 and increased the buoyant density of the virus particles. The outer capsid of SDS-treated virions was greatly altered and often indistinct. Treatment of type 3 with either 1% phenol or 33% ethanol produced particles that had a full complement of polypeptides, were unaltered in buoyant density, but were greatly aggregated. Thus, these inactivating agents affect reovirus particles in specific and distinct ways. The differential effects of such treatments can thus be used to study the structure and function of the reovirus capsid components.


Improved cadmium uptake and accumulation in the hyperaccumulator Sedum alfredii: the impact of citric acid and tartaric acid.
The elucidation of a natural strategy for metal hyperaccumulation enables the rational design of technologies for the clean-up of metal-contaminated soils. Organic acid has been suggested to be involved in toxic metallic element tolerance, translocation, and accumulation in plants. The impact of exogenous organic acids on cadmium (Cd) uptake and translocation in the zinc (Zn)/Cd co-hyperaccumulator Sedum alfredii was investigated in the present study. By the addition of organic acids, short-term (2 h) root uptake of (109)Cd increased significantly, and higher (109)Cd contents in roots and shoots were noted 24 h after uptake, when compared to controls. About 85% of the (109)Cd taken up was distributed to the shoots in plants with citric acid (CA) treatments, as compared with 75% within controls. No such effect was observed for tartaric acid (TA). Reduced growth under Cd stress was significantly alleviated by low CA. Long-term application of the two organic acids both resulted in elevated Cd in plants, but the effects varied with exposure time and levels. The results imply that CA may be involved in the processes of Cd uptake, translocation and tolerance in S. alfredii, whereas the impact of TA is mainly on the root uptake of Cd.


Association of Copy Number Variation at Intron 3 of HMGA2 With Navel Length in Bos indicus.
Navel injuries caused by friction against the pasture can promote infection, reproductive problems and costly treatments in beef cattle raised in extensive systems. A haplotype-based genome-wide association study (GWAS) was performed for visual scores of navel length at yearling in Nellore cattle (Bos indicus) using data from 2,016 animals and 503,088 single nucleotide polymorphism (SNP) markers. The strongest signal (p = 1.01 × 10-9) was found on chromosome 5 spanning positions 47.9-48.2 Mbp. This region contains introns 3 and 4 and exons 4 and 5 of the high mobility group AT-hook 2 gene (HMGA2). Further inspection of the region with whole genome sequence data of 21 Nellore bulls revealed correlations between counts of the significant haplotype and copy number gains of a ∼6.2 kbp segment of intron 3 of HMGA2. Analysis of genome sequences from five African B. indicus and four European Bos taurus breeds revealed that the copy number variant (CNV) is indicine-specific. This intronic CNV was then validated through quantitative polymerase chain reaction (qPCR) using Angus animals as copy neutral controls. Importantly, the CNV was not detectable by means of conventional SNP-based GWAS or SNP probe intensity analyses. Given that HMGA2 affects the expression of the insulin-like growth factor 2 gene (IGF2) together with the pleomorphic adenoma gene 1 (PLAG1), and that the latter has been repeatedly shown to be associated with quantitative traits of economic importance in cattle, these findings highlight the emerging role of variants impacting the insulin-like growth factor pathway to cattle breeding.


Alterations in the recognition of nucleoside analogues as substrates by the deoxythymidine kinase of a 5-methoxymethyldeoxyuridine-resistant mutant of herpes simplex virus type 1.
Inhibition constants (Kis) were used as an estimate of the ability of various nucleoside analogues to be recognized as substrates by the deoxythymidine kinases (dTKs) of a 5-methoxymethyldeoxyuridine-resistant (MMdUr) mutant of herpes simplex virus type 1 (HSV-1) and its parent wild-type (wt). It was found that the Kis for the 5-position analogues MMdU, [E]-5-(2-bromovinyl)deoxyuridine, bromodeoxyuridine and iododeoxyuridine were increased approximately three-to fivefold, suggesting that they were poorer substrates for the MMdUr dTK than for the wt dTK. With the 2' analogues arabinosylthymine and 2' fluoro 5-methylarabinosyluracil, however, the Kis were increased to a much greater extent, 80- and 240-fold, respectively. These findings suggest that the resistance of the mutant MMdUr to these analogues may be due to a mutation(s) in the viral dTK that directly affects binding at the 2' recognition site and indirectly at the 5, while still allowing substantial activity with the natural substrate deoxythymidine.


Design of a lidar receiver with fiber-optic output.
Design considerations for a coaxial lidar receiver are examined, including details of coupling to an optical fiber for transfer of return light to a remote detector box. Attention is concentrated on the influence of fiber position on return-light capture efficiency and dynamic range of the return signal. The effect of a central obstruction on short-range signals is included. The analysis is augmented with simulations of lidar receiver performance.


Perinatal Outcomes after Short versus Prolonged Indomethacin for Tocolysis in Women with Preterm Labor.
Objective Indomethacin tocolysis is generally limited to 48 hours. Indomethacin has been administered for longer durations to prolong gestation in extreme prematurity. Our aim is to compare perinatal outcomes after a prolonged course, > 48 hours versus ≤ 48 hours in preterm labor. Methods A retrospective chart review of women admitted with preterm labor < 32 weeks gestation who received indomethacin for tocolysis. The primary maternal outcome was latency from admission until delivery. The primary neonatal outcome was a composite of severe neonatal morbidities. Results A total of 73 women were included: 32 (43.8%) received indomethacin for > 48 hours (prolonged) and 41 (56.2%) for ≤ 48 hours (standard). Prolonged group started on indomethacin at an earlier gestational age compared with standard group (23.9 [23.1-27.3] vs. 25.7 [23.8-28.5] weeks, p = 0.03). Latency from admission until delivery was longer in the prolonged group versus the standard group (1.8 [1.1-3] vs. 0.4 [0.1-0.8] weeks, p < 0.001). Prolonged use was not associated with increased risk of the composite neonatal outcome; however, there was a trend for more necrotizing enterocolitis. Conclusion A prolonged course of indomethacin may be an option for women with preterm labor at risk of extreme prematurity; it may also be associated with higher risks of some adverse neonatal outcomes.


Differential RNAi screening provides insights into the rewiring of signalling networks during oxidative stress.
Reactive Oxygen Species (ROS) are a natural by-product of cellular growth and proliferation, and are required for fundamental processes such as protein-folding and signal transduction. However, ROS accumulation, and the onset of oxidative stress, can negatively impact cellular and genomic integrity. Signalling networks have evolved to respond to oxidative stress by engaging diverse enzymatic and non-enzymatic antioxidant mechanisms to restore redox homeostasis. The architecture of oxidative stress response networks during periods of normal growth, and how increased ROS levels dynamically reconfigure these networks are largely unknown. In order to gain insight into the structure of signalling networks that promote redox homeostasis we first performed genome-scale RNAi screens to identify novel suppressors of superoxide accumulation. We then infer relationships between redox regulators by hierarchical clustering of phenotypic signatures describing how gene inhibition affects superoxide levels, cellular viability, and morphology across different genetic backgrounds. Genes that cluster together are likely to act in the same signalling pathway/complex and thus make "functional interactions". Moreover we also calculate differential phenotypic signatures describing the difference in cellular phenotypes following RNAi between untreated cells and cells submitted to oxidative stress. Using both phenotypic signatures and differential signatures we construct a network model of functional interactions that occur between components of the redox homeostasis network, and how such interactions become rewired in the presence of oxidative stress. This network model predicts a functional interaction between the transcription factor Jun and the IRE1 kinase, which we validate in an orthogonal assay. We thus demonstrate the ability of systems-biology approaches to identify novel signalling events.


Do Fencers Require a Weapon-Specific Approach to Strength and Conditioning Training?
There are 3 types of weapons used in Olympic fencing: the épée, foil, and sabre. The aim of this study was to determine if fencers exhibited different physical characteristics across weapons. Seventy-nine male (n = 46) and female (n = 33) national standard fencers took part in this study. Fencers from each weapon (male and female), i.e., épée (n = 19 and 10), foil (n = 22 and 14), and sabre (n = 13 and 10), were (mean ± SD) 15.9 ± 0.7 years of age, 178.5 ± 7.9 cm tall, 67.4 ± 12.2 kg in mass and had 6.3 ± 2.3 years fencing experience; all were in regular training (∼4 times per week). Results revealed that across all performance tests (lower-body power, reactive strength index, change of direction speed, and repeat lunge ability), there was no significant main effect for weapon in male fencers (p = 0.63) or female fencers (p = 0.232), but a significant main affect for gender (p < 0.001). Pairwise comparisons revealed that male fencers scored better during the countermovement jump, change of direction speed, and repeat lunge ability test (p < 0.001). The former findings may be because of similarities in bout intensity and time, movement types (lunging and changing direction), and the need to execute competition actions as explosively as possible. Based on the findings of the present study, it could be indicated that épée, foil, and sabre fencers do not require a weapon-specific approach to strength and conditioning training. Each fencer should target the area they are weakest at, rather than an area that they feel best represents the unique demands of their weapon.


[A pathohistological study on experimental brucellosis in inbred mice].
A pathohistological study was carried out in BALB/C and C57/BL inbred mice models infected with B. melitensis, B. abortus, and B. suis respectively. The results showed that a chronic pathological lesion was developed due to repeated infectious processes occurred in various organs at different stages of brucella infection. Significant pathological changes was observed in the reticuloendothelial system including the lymphocytes, spleen and liver etc. and less remarkable changes were seen in the lung, heart and kidney in sequence. Comparing the pathological changes induced by the three species of brucella infection, lesions developed in BALB/C was more remarkable and the pathological change induced by B. abortus infection was the most significant in both BALB/C and C57/BL mice.


[Diagnostic potentials of NMR tomography of the kidneys of patients with symptomatic renal hypertension].
Thirty seven patients with arterial hypertension of renal genesis (chronic diffuse glomerulonephritis, chronic pyelonephritis, renal cystic disease and congenital abnormalities) were subjected to NMR-tomography. The comparison group comprised 12 patients with essential hypertension and 18 normal individuals constituted the control group. The examination was effected in the axial, frontal and sagittal planes using the BMT-1100 NMR-tomograph (Brucker, FRG) with the magnetic intensity of 0.235 T, the coil diameter of 60 cm, and the working frequency of 9.95 MHz. The technique made it possible to draw conclusions as to the presence or absence of the kidneys, their form, size, location and the structure of their cortex and medulla. The anatomo-tomographic picture of the kidneys in patients with chronic diffuse glomerulonephritis without renal insufficiency resembled that in cases of essential hypertension. In patients with chronic pyelonephritis the kidney contour was uneven and when renal insufficiency was present the kidneys were small and the borderline the cortex and the medulla was poorly differentiated. The technique proved especially informative in renal cystic disease and congenital abnormalities (renal aplasia and hypoplasia). The results obtained were compared with the data provided by other examination techniques.


Spatial distribution of white-matter hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging.
White-matter hyperintensities (WMHs) detected by magnetic resonance imaging are thought to represent the effects of cerebral small-vessel disease and neurodegenerative changes. We sought to determine whether the spatial distribution of WMHs discriminates between different disease groups and healthy aging individuals and whether these distributions are related to local cerebral perfusion patterns. We examined the pattern of WMHs by T2/fluid-attenuated inversion recovery-weighted magnetic resonance imaging in 3 groups of subjects: cerebral amyloid angiopathy (n=32), Alzheimer disease or mild cognitive impairment (n=41), and healthy aging (n=29). WMH frequency maps were calculated for each group, and spatial distributions were compared by voxel-wise logistic regression. WMHs were also analyzed as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography atlas. Although WMH volume was greater in cerebral amyloid angiopathy and Alzheimer disease/mild cognitive impairment than in healthy aging, there was no consistent difference in the spatial distributions when controlling for total WMH volume. Hyperintensities were most frequent in the deep periventricular WM in all 3 groups. A strong inverse correlation between hyperintensity frequency and normal perfusion was demonstrated in all groups, demonstrating that WMHs were most common in regions of relatively lower normal cerebral perfusion. WMHs show a common distribution pattern and predilection for cerebral WM regions with lower atlas-derived perfusion, regardless of the underlying diagnosis. These data suggest that across diverse disease processes, WM injury may occur in a pattern that reflects underlying tissue properties, such as relative perfusion.


Drug-Induced Liver Injury from Anti-Tuberculosis Treatment: A Retrospective Cohort Study.
BACKGROUND The aim of this study was to investigate the clinical characteristics and the risk factors associated with anti-tuberculosis (anti-TB) drug-induced liver injury (DILI). MATERIAL AND METHODS This retrospective study enrolled 140 hospitalized patients diagnosed with anti-TB DILI during January 2009 to December 2015. We assessed the baseline characteristics and performed regular follow-up up to the 24th week to assess the possible risk factors associated with the condition. RESULTS The study population was 58.6% male and 41.4% female patients; 20.7% were diagnosed with grades 4-5 DILI and 79.3% with grades 1-3 DILI. Female patients were significantly more likely to be diagnosed with grades 4-5 DILI than with grades 1-3 DILI (58.6% vs. 36.9%, p=0.036). Patients treated with a multidrug anti-TB regimen were more commonly affected with grades 4-5 DILI (86.2% vs. 68.5%, p=0.045). A significant number of patients who reinitiated anti-TB therapy suffered severe liver injury in comparison to patients with grades 1-3 DILI (41.4% vs. 10.8%, P<.001). Laboratory examinations revealed significantly higher values for total bilirubin (TBL), International normalized ratio (INR), and Hy's law (P<.001) in the grades 4-5 group compare to the grades 1-3 group. CONCLUSIONS Female gender, combination therapy for antitubercular drugs (isoniazid, rifampicin and pyrazinamide), re-challenge were the risk factors associated with the severity of anti-TB DILI.


A Traditional Chinese Herb Citri Reticulatae Pericarpium Induced Melanonychia.
The common causes for melanonychia include melanoma, repetitive trauma, underlying systemic diseases, onychomycosis, pseudomonas infection and drugs. Drug-induced melanonychia usually affects numerous nails and appears as light brown to black pigmentation on the deck or nail bed with longitudinal, transverse or diffuse distribution. In previous cases, a number of chemotherapeutic agents such as azathioprine, bleomycin sulfate, cyclophosphamide, hydroxyurea and methotrexate were usually linked to melanonychia. Citri reticulatae pericarpium (CRP) is a traditional Chinese herb which is widely used in many foods and health care products in China. Up till now, there were no adverse reactions of CRP reported throughout the literature. Herein, we firstly reported a case of melanonychia in a 67-year-old man caused by CRP for external use.


A practical mortality risk score for emergent colectomy.
Critically ill patients requiring emergent colectomy have significant mortality risk. A national administrative database was used to compose a simple scoring scheme for predicting in-hospital mortality risk. The 2007 to 2009 Nationwide Inpatient Sample was queried to identify patients requiring nonelective colectomy. Multivariable binary logistic regression analysis was used to identify predictors that increased mortality. Each predictor was given a point value, based on the corresponding logit, the sum of which constituted a risk score. The scoring system was tested by using k-partitions cross-validation. This study is based on database analysis. A total of 338,348 cases were identified. Mean age was 64, and 53% of the patients were women. The primary outcomes measured were mortality and risk score development. The overall mortality risk was 9%. Regression analysis identified the following risk factors and assigned points: acute renal failure (6), hemodialysis (6), age >65 (4), peripheral vascular disease (4), myocardial infarction (4), chronic obstructive pulmonary disease (2), cardiac arrhythmia (1), and congestive heart failure (1). The maximum score observed was 26 (of a possible 28), which corresponded to 100% mortality. Receiver operator characteristic analysis showed an area under the curve of 0.81. This study was limited because of its retrospective nature, and because it used database data with variability in coding among participating institutions. With the use of a simple 8-variable scoring system, inpatient mortality estimates can be made for patients requiring emergent colectomy. When used judiciously, it can be used as a tool when counseling patients and family both before and after surgery.


Novel melatonin-based therapies: potential advances in the treatment of major depression.
Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT(2C)) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.


Hemiparetic cerebral palsy: etiological risk factors and neuroimaging.
The purpose of this paper, which was conducted on 175 children with hemiparetic cerebral palsy (H-CP), was to verify the etiological risk period for this disease. Etiological risk factors (ERF) were detected through anamnesis: 23% in the prenatal period, 18% in the perinatal period and 59% of the patients the period was undefined (ERF in the prenatal and perinatal period was 41% and no ERF was 18% of the cases. The computerized tomographic scan (CT) and MRI were performed on all the patients, who were then classified according to their etiopathogenic data: CT1= normal (18%); CT 2= unilateral ventricular enlargement (25%); CT 3= cortical/ subcortical cavities (28%); CT4= hemispheric atrophy and other findings (14%); CT 5= malformations (15%). CT 5 was associated with physical malformations beyond the central nervous system and with prenatal ERF's, while CT 2 was associated with the perinatal ERF's, mainly in premature births. Magnetic resonance imaging was performed on 57 patients and demonstrated a good degree of concordance with the CT. Etiology remained undefined in only 37% of the cases after neuroimaging was related to ERF. A high perinatal RF frequency (59%) was observed and emphasized the need for special care during this period.


The nuclear pore complex and nuclear transport.
Internal membrane bound structures sequester all genetic material in eukaryotic cells. The most prominent of these structures is the nucleus, which is bounded by a double membrane termed the nuclear envelope (NE). Though this NE separates the nucleoplasm and genetic material within the nucleus from the surrounding cytoplasm, it is studded throughout with portals called nuclear pore complexes (NPCs). The NPC is a highly selective, bidirectional transporter for a tremendous range of protein and ribonucleoprotein cargoes. All the while the NPC must prevent the passage of nonspecific macromolecules, yet allow the free diffusion of water, sugars, and ions. These many types of nuclear transport are regulated at multiple stages, and the NPC carries binding sites for many of the proteins that modulate and modify the cargoes as they pass across the NE. Assembly, maintenance, and repair of the NPC must somehow occur while maintaining the integrity of the NE. Finally, the NPC appears to be an anchor for localization of many nuclear processes, including gene activation and cell cycle regulation. All these requirements demonstrate the complex design of the NPC and the integral role it plays in key cellular processes.