Microbial strain improvement for enhanced polygalacturonase production by Aspergillus sojae.
Strain improvement is a powerful tool in commercial development of microbial fermentation processes. Strains of Aspergillus sojae which were previously identified as polygalacturonase producers were subjected to the cost-effective mutagenesis and selection method, the so-called random screening. Physical (ultraviolet irradiation at 254 nm) and chemical mutagens (N-methyl-N'-nitro-N-nitrosoguanidine) were used in the development and implementation of a classical mutation and selection strategy for the improved production of pectic acid-degrading enzymes. Three mutation cycles of both mutagenic treatments and also the combination of them were performed to generate mutants descending from A. sojae ATCC 20235 and mutants of A. sojae CBS 100928. Pectinolytic enzyme production of the mutants was compared to their wild types in submerged and solid-state fermentation. Comparing both strains, higher pectinase activity was obtained by A. sojae ATCC 20235 and mutants thereof. The highest polygalacturonase activity (1,087.2 ± 151.9 U/g) in solid-state culture was obtained by mutant M3, which was 1.7 times increased in comparison to the wild strain, A. sojae ATCC 20235. Additional, further mutation of mutant M3 for two more cycles of treatment by UV irradiation generated mutant DH56 with the highest polygalacturonase activity (98.8 ± 8.7 U/mL) in submerged culture. This corresponded to 2.4-fold enhanced polygalacturonase production in comparison to the wild strain. The results of this study indicated the development of a classical mutation and selection strategy as a promising tool to improve pectinolytic enzyme production by both fungal strains.


Energy Adaptations Persist 2 Years After Sleeve Gastrectomy and Gastric Bypass.
Non-surgical weight loss induces a greater than expected decrease in energy expenditure, a phenomenon known as 'metabolic adaptation'. The effects of different bariatric surgery procedures on metabolic adaptation are not yet known and may partially contribute to weight loss success. We compared resting energy expenditure (REE) in 35 subjects (nine males; age = 46 ± 11 years; BMI = 42.1 ± 6.5 kg/m(2)) undergoing gastric band, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) up to 2 years after surgery. We found a greater than expected reduction of 130-300 kcal/day at 6 weeks after sleeve and bypass surgery which was not explained by changes in body composition; this change was not seen in the band group. The suppression in REE after sleeve and RYGB remained up to 2 years, even after weight loss had plateaued. Our findings suggest that energy adaptation is not a contributing mechanism to medium-term weight maintenance after sleeve and RYGB bariatric surgeries.


Using mechanistic information to support evidence integration and synthesis: a case study with inhaled formaldehyde and leukemia.
Formaldehyde is one of the most comprehensively studied chemicals, with over 30 years of research focused on understanding the development of cancer following inhalation. The causal conclusions regarding the potential for leukemia are largely based on the epidemiological literature, with little consideration of cancer bioassays, dosimetry studies, and mechanistic research, which challenge the biological plausibility of the disease. Recent reanalyzes of the epidemiological literature have also raised significant questions related to the purported associations between formaldehyde and leukemia. Because of this, considerable scientific debate and uncertainty remain on whether there is a causal association between formaldehyde inhalation exposure and leukemia. Further complexity in evaluating this association is related to the endogenous production of formaldehyde. Multiple modes of action (MOA) have been postulated for the development of leukemia following formaldehyde inhalation that includes unsupported hypotheses of direct or indirect toxicity to the target cell population. Herein, the available evidence relevant to evaluating the postulated MOAs for leukemia following formaldehyde inhalation exposure is organized in the IPCS MOA Framework. The integration of all the available evidence clearly highlights the limited amount of data that support any of the postulated MOAs and demonstrates a significant amount of research supporting the null hypothesis that there is no causal association between formaldehyde inhalation exposure and leukemia. These analyses result in a lack of confidence in any of the postulated MOAs, increasing confidence in the conclusion that there is a lack of biological plausibility for a causal association between formaldehyde inhalation exposure and leukemia.


Factors influencing the prevalence of Salmonella spp. in swine farms: a meta-analysis approach.
A systematic review and meta-analysis was conducted to identify study-level variables that could explain the variation in apparent Salmonella spp. prevalence estimates. Electronic and non-electronic literature searches from 1990 until 2005 were carried out to identify all studies related to the prevalence of subclinical Salmonella infection in swine. The searches were restricted to studies published in English, Spanish, and French. Clinical trials or any other study where an intervention was evaluated were excluded from this analysis. A template was designed to retrieve the most relevant variables and data abstraction was performed in duplicate. A total of 98 papers containing 82 animal-level and 156 farm-level studies were used in the analyses. The median farm-level and animal-level prevalences were 59% and 17%, respectively. Meta-regression analyses were carried out on both farm and animal-level data. Diagnostic procedure, sample size, and country where study was conducted were the three most important predictors in explaining the differences in Salmonella prevalences between studies. When compared to a farm with a apparent prevalence of 50% determined by the blood ELISA, prevalences based on culture of fecal samples were 39% lower and prevalences based on cecum and tissue cultures were 16% and 19% lower, respectively. Similar to farm-level models, animal-level models did not show any difference among serological tests and prevalence values based culture procedures were, on average, 9% lower than those from serological tests. Sample size was negatively associated with prevalence estimates. In conclusion, the methodology was useful for identifying and quantifying sources of variation in Salmonella apparent prevalence among studies and for establishing prevalence distributions that could be used as input parameters in risk assessment and decision models. The analysis provides some guidelines when interpreting and comparing apparent Salmonella prevalence results from studies using different study designs.


First study in Qatar to reveal high Legionella counts in cooling towers.
Legionella spp. is transmitted from water to humans by aerosol-generating devices, including cooling towers (CTs). There have not been published reports about Legionella in these systems in Qatar. Ten CTs in Qatar University were sampled on a monthly basis. Bacteria were recovered from 90 water samples by filtration and concentration. Legionella DNA copy number (CN) was assessed by quantitative RT-PCR. Legionella DNA was detected in 100% of the samples. The bacterial counts ranged from 0.006 to 199.56 CFU/mL, and critical counts were found in 51 (56.7 %) samples. Moreover, 7 (7.8%) samples showed a count of more than 100 CFU/mL. The highest counts were found in the months of May and June. These results suggest that this organism is found in high number in tested CTs, presenting a potential health risk to the local population.


Evidence for potential of managing some African fruit fly species (Diptera: Tephritidae) using the mango fruit fly host-marking pheromone.
We investigated conspecific and heterospecific oviposition host discrimination among four economically important fruit fly pests of mango in Africa (Ceratitis capitata, Wiedemann; C. fasciventris, Bezzi; C. rosa, Karsch, and C. cosyra, Walker) with regard to host-marking behavior and fecal matter aqueous solutions. The objective of the study was to get insight into the potential of managing these pests using the host-marking technique. Observations were done on mango slices marked by the flies and treated with aqueous solutions of fecal matter of the flies, respectively. In both host-marking and fecal matter experiments, C. cosyra, which is the most destructive species of the four on mango, was exceptional. It only discriminated against hosts treated with its fecal matter but with lower sensitivity while C. capitata and C.fasciventris discriminated against hosts marked by it or treated with its fecal matter and with higher sensitivity. Our results provide evidence for potential of managing some of the major fruit fly species infesting mango in Africa using the host-marking pheromone of the mango fruit fly, C. cosyra.


A Dual CuH- and Pd-Catalyzed Stereoselective Synthesis of Highly Substituted 1,3-Dienes.
Conjugated dienes are versatile building blocks and prevalent substructures in synthetic chemistry. Herein, we report a method for the stereoselective hydroalkenylation of alkynes, utilizing readily available enol triflates. We leveraged an in situ-generated and geometrically pure vinyl-Cu(I) species to form the Z,Z- or Z,E-1,3-dienes in excellent stereoselectivity and yield. This approach allowed for the synthesis of highly substituted Z-dienes, including pentasubstituted 1,3-dienes, which are difficult to prepare by existing approaches.


Type of symptomatology as a form of volunteer bias.
We sought to explore the relationship between type of psychopathology and consent bias. Using the Brief Psychiatric Rating Scale we assessed a group of 48 forensic psychiatric inpatients. These patients were later independently approached by a researcher who attempted to get their consent for a study on the validity of self-reported criminal behavior. Thirty agreed to participate and 18 did not. The consenting patients were significantly younger and had significantly more negative symptoms than the nonconsenters. The difference in negative symptoms remained significant after age and medication dose, in chlorpromazine equivalents, were covaried out. The authors discuss the implications of these findings for forensic research.


AlphaIIbbeta3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function.
Glanzmann thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation due to defects in integrin alphaIIbbeta3 (ITGA2B, ITGB3), a fibrinogen receptor. Mutations from 24 GT patients and two carriers of various origins, Caucasian, North-African and Asian were characterized. Promoter and exon sequences of alphaIIb and beta3 genes were amplified and directly sequenced. Among 29 identified mutations, 17 new allelic variants resulting from nonsense, missense and deletion/insertion mutations were described. RNA alterations were evaluated by using Web servers. The alphaIIb p.S926L, p.V903F, and beta3 p.C38Y, p.M118R, p.G221D substitutions prevented complex expression at the surface of COS-7 cells by altering the alphaIIb or the beta3 subunit structure. As shown by free energy analyses applied on the resolved structure of alphaIIbbeta3 and structural modeling of the mutant, the p.K253M substitution of beta3 helped to define a key role of the K253 in the interaction of the alphaIIb beta-propeller and the beta3 beta-I domains. finally, the alphaIIb p.Q595H substitution allowed cell surface expression of the complex but its corresponding c.2800G>T mutation is predicted to alter normal RNA splicing. In conclusion, our study yielded the discovery of 17 new GT allelic variants, revealed the key role of K253 of alphaIIb for the alphaIIbbeta3 complex formation and provides an additional example of an apparently missense mutation causing a splicing defect.


An evaluation of breastfeeding promotion literature: does it really promote breastfeeding?
Breastfeeding pamphlets are being produced for new mothers by both commercial and nonprofit sources in increasing quantities. A regional lactation committee decided to evaluate these materials on the basis of accuracy, degree of positive approach to breastfeeding, readability and compliance with the WHO/UNICEF Code on the Marketing of Breast Milk Substitutes. Results indicate that materials produced by non-profit sources scored higher in positive approach accuracy and WHO Code compliance compared with commercial sources. Only 2 of 22 pamphlets in the sample were written within the recommended reading level of Grade 5-8. None of the materials met all of the criteria for good promotional breastfeeding literature.


Peripheral lymphatic cannulation for physiological analysis of interstitial fluid compartment in humans.
Analysis of peripheral interstitial concentrations of hormones or substrates in humans has undoubtedly been hampered by the difficulty in performing retrograde peripheral lymphatic cannulation and obtaining adequate flow rates of lymph. We now describe a technique for direct continuous sampling of peripheral lymph. A lymphatic vessel was cannulated in the lower legs of 14 males, and lymph was collected for 24-48 h. Adequate quantities of lymph were obtained basally and during physiological manipulations to make collections at 15-min intervals. Flow rates averaged 1.84 ml/h and ranged from 0.34 to 4.96 ml/h. We conclude that peripheral lymphatic vessels can be cannulated and flow rates are sufficient to measure interstitial concentration of hormones or substrates both at steady state and dynamically in adult humans.


Adaptation of the System for Observing Physical Activity and Recreation in Communities (SOPARC) to assess age groupings of children.
To better measure physical activity (PA) in outdoor environments, McKenzie and colleagues developed the System for Observing Play and Recreation in Communities (SOPARC). However, previous SOPARC research has focused on adults, seniors, teens and children. One avenue for extending this work is to expand the child age group code to capture important nuances that can influence children's PA and their environments. This study reports on the reliability of a measure designed to account for PA in parks among children in different childhood age groups. Three groups were developed: 0 to 5-years-old (Young Children); 6 to 12 (Middle Childhood) and 13 to 18 (Older Children) based on Erikson's stages of child development. Data were obtained by direct observation in 3 neighborhood parks in Raleigh, NC and 20 neighborhood parks in Durham, NC. Kappa coefficients showed high agreement for all age group, gender, and PA codes. For the 3 assessments, the results show that the 3 age group category exhibit acceptable reliability for measuring PA in parks among children. The reliability of measuring PA among children by segmenting children by 3 age groups was established. This approach is recommended for future studies of PA among children in parks and other outdoor environments.


The Clinical and Socio-Economic Relevance of Increased IPMN Detection Rates and Management Choices.
Increased usage of computed tomography and magnetic resonance imaging has led to a large increase in identified pancreatic cysts of up to 25% in population-based studies. The clinical and economic relevance of identifying so many cystic lesions has not been established. Compared to other organs such as liver or kidney, dysontogenetic pancreatic cysts are rare. Pancreatic cysts comprise a variety of benign, premalignant or malignant lesions; however, precise diagnosis before resection has an accuracy of only 80%. The focus of recent research was the malignant potential of intraductal papillary mucinous neoplasms (IPMN) with the aim of establishing clinical pathways addressing risk of malignancy, age and comorbidity, treatment-related morbidity and mortality as well as cost-effectiveness of treatment and surveillance. The focus of this review is to analyze the clinical and socio-economic relevance as well as the cost-benefit relation for IPMNs. For analysis, the following MESH terms were used to identify original articles, reviews, and guidelines in PubMed: ('intraductal papillary mucinous neoplasm' OR 'pancreatic cysts') and (incidence OR relevance OR socio-economic OR economic OR cost-effectiveness OR cost-benefit). The retrieved publications were reviewed with a focus on clinical and socio-economic relevance in relation to the increasing incidence of IPMN. Addressing the increasing prevalence of pancreatic cystic lesions, recent consensus guidelines suggested criteria for risk stratification according to 'worrisome features' and 'high-risk stigmata'. Recent prospective cohort studies evaluated whether these can be applied in clinical practice. Evaluation of three different clinical scenarios with regard to costs and quality-adjusted life years suggested a better effectiveness of surveillance after initial risk stratification by endoscopic ultrasound-guided fine-needle aspiration with cyst fluid analysis compared with immediate resection or follow-up without further intervention. Of interest, the 'immediate surgery' strategy was lowest for cost-effectiveness. The increasing incidence of identified pancreatic cysts requires an improved strategy for non-invasive risk stratification based on advanced imaging strategies. In light of a malignancy risk of 2% for branch-duct IPMN, the socio-economic necessity of a balance between surveillance and resection has to be agreed on.


Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area.
Pulmonary toxicology studies in rats demonstrate that nanoparticles administered to the lung are more toxic than larger, fine-sized particles of similar chemistry at identical mass concentrations. The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled pigment-grade TiO2 particles (rutile-type particle size = approximately 300 nm) versus nanoscale TiO2 rods (anatase = 200 nm x 35 nm) or nanoscale TiO2 dots (anatase = approximately 10 nm) compared with a positive control particle type, quartz. Groups of rats were instilled with doses of 1 or 5 mg/kg of the various particle types in phosphate-buffered saline (PBS). Subsequently, the lungs of PBS- and particle-exposed rats were assessed using bronchoalveolar lavage fluid biomarkers, cell proliferation methods, and by the histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation exposure. Exposures to nanoscale TiO2 rods or nanoscale TiO2 dots produced transient inflammatory and cell injury effects at 24 h postexposure (pe) and were not different from the pulmonary effects of larger sized TiO2 particle exposures. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy lipid-containing alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. The results described herein provide the first example of nanoscale particle types which are not more cytotoxic or inflammogenic to the lung compared to larger sized particles of similar composition. Furthermore, these findings run counter to the postulation that surface area is a major factor associated with the pulmonary toxicity of nanoscale particle types.


Evaluation of surface preparation and maintenance of canal curvature following instrumentation with hand 'K' file and three different Ni-Ti rotary systems: A radiographic and SEM study.
To determine the shaping ability and cleaning efficiency of hand K-flexofiles, ProTaper, LightSpeed and Mtwo instruments during the preparation of curved root canals in extracted human teeth. A total of 120 root canals of mandibular and maxillary molars with curvature more than 20° were divided into four groups of 30 each. In group A, canals were prepared using hand K-flexofiles following the crown down technique. In group B LightSpeed, in group C ProTaper, and in group D Mtwo rotary instruments were used to prepare the root canals. Using pre- and post-instrumentation radiographs, straightening of the canal curvature was determined with Corel Draw 9.0 software tools. The amount of debris and smear layer were quantified at three different areas (coronal, middle, and apical thirds) of root canal using SEM. The collected data were analyzed statistically using Student's paired 't' test. The mean change in curvature for hand K-files was 7.71°, for ProTaper files 6.03°, for Mtwo 5.43°, and for LightSpeed instruments were found to be 4.57°. The percentage change in the curvature for all the four groups was statistically highly significant (P< 0.01). LightSpeed instruments maintained the original canal curvature significantly (P< 0.01) better than the other instruments. For leftover debris, the minimum percentage was found to be associated with ProTaper (65.48%) followed by Mtwo (66.22%), LightSpeed (71.67%) and the maximum with hand K-files (74.16%). However, the difference in mean leftover debris between ProTaper and Mtwo was not significant. ProTaper and Mtwo resulted in good cleaning, and LightSpeed maintained the original canal curvature better than the ProTaper, Mtwo, or Hand K-files.


Targeted mutagenesis in mammalian cells mediated by intracellular triple helix formation.
As an alternative to standard gene transfer techniques for genetic manipulation, we have investigated the use of triple helix-forming oligonucleotides to target mutations to selected genes within mammalian cells. By treating monkey COS cells with oligonucleotides linked to psoralen, we have generated targeted mutations in a simian virus 40 (SV40) vector contained within the cells via intracellular triple helix formation. Oligonucleotide entry into the cells and sequence-specific triplex formation within the SV40 DNA deliver the psoralen to the targeted site. Photoactivation of the psoralen by long-wavelength UV light yields adducts and thereby mutations at that site. We engineered into the SV40 vector novel supF mutation reporter genes containing modified polypurine sites amenable to triplex formation. By comparing the abilities of a series of oligonucleotides to target these new sites, we show that targeted mutagenesis in vivo depends on the strength and specificity of the third-strand binding. Oligonucleotides with weak target site binding affinity or with only partial target site homology were ineffective at inducing mutations in the SV40 vectors within the COS cells. We also show that the targeted mutagenesis is dependent on the oligonucleotide concentration and is influenced by the timing of the oligonucleotide treatment and of the UV irradiation of the cells. Frequencies of intracellular targeted mutagenesis in the range of 1 to 2% were observed, depending upon the conditions of the experiment. DNA sequence analysis revealed that most of the mutations were T.A-to-A.T transversions precisely at the targeted psoralen intercalation site. Several deletions encompassing that site were also seen. The ability to target mutations to selected sites within mammalian cells by using modified triplex-forming oligonucleotides may provide a new research tool and may eventually lead to therapeutic applications.


Basal forebrain projections to the lateral habenula modulate aggression reward.
Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.


Arthropathic group A streptococcal cell walls require specific antibody for activation of human complement by both the classical and alternative pathways.
The induction of acute arthritis in rats by a single intraperitoneal injection of group A streptococcal cell wall is associated with the activation of complement. We have therefore investigated the interaction of arthropathic peptidoglycan-polysaccharide complex of streptococcal cell walls and human complement. The incubation of cell wall in normal human serum results in the formation of complexes of cell wall and the C3 and C4 components of complement. Using agammaglobulinemic serum, we have further shown that the activation of complement and formation of complement-cell wall complexes absolutely requires the presence of a small quantity of specific antibody. This antibody is present in normal human immunoglobulin G and is effective as the Fab fragment (alternative pathway). Although antibodies specific for three cell wall epitopes were capable of inducing complement-cell wall complex formation by the classical complement pathway, only anti-A polysaccharide antibody (N-acetyl-D-glucosamine epitope) was effective by the alternative complement pathway. A complement consumption assay showed that anti-cell wall antibody was required not only for complement-cell wall complex formation, but also for activation of complement by streptococcal cell wall in human serum. These studies suggest that a minimal level of anti-cell wall antibody may be required for the induction of arthritis in rats by streptococcal cell wall.


Design of a novel automated methanol feed system for pilot-scale fermentation of Pichia pastoris.
Large-scale fermentation of Pichia pastoris requires a large volume of methanol feed during the induction phase. However, a large volume of methanol feed is difficult to use in the processing suite because of the inconvenience of constant monitoring, manual manipulation steps, and fire and explosion hazards. To optimize and improve safety of the methanol feed process, a novel automated methanol feed system has been designed and implemented for industrial fermentation of P. pastoris. Details of the design of the methanol feed system are described. The main goals of the design were to automate the methanol feed process and to minimize the hazardous risks associated with storing and handling large quantities of methanol in the processing area. The methanol feed system is composed of two main components: a bulk feed (BF) system and up to three portable process feed (PF) systems. The BF system automatically delivers methanol from a central location to the portable PF system. The PF system provides precise flow control of linear, step, or exponential feed of methanol to the fermenter. Pilot-scale fermentations with linear and exponential methanol feeds were conducted using two Mut(+) (methanol utilization plus) strains, one expressing a recombinant therapeutic protein and the other a monoclonal antibody. Results show that the methanol feed system is accurate, safe, and efficient. The feed rates for both linear and exponential feed methods were within ± 5% of the set points, and the total amount of methanol fed was within 1% of the targeted volume.


The ASM Curriculum Guidelines for Undergraduate Microbiology: A Case Study of the Advocacy Role of Societies in Reform Efforts.
A number of national reports, including Vision and Change in Undergraduate Biology Education: A Call to Action, have called for drastic changes in how undergraduate biology is taught. To that end, the American Society for Microbiology (ASM) has developed new Curriculum Guidelines for undergraduate microbiology that outline a comprehensive curriculum for any undergraduate introductory microbiology course or program of study. Designed to foster enduring understanding of core microbiology concepts, the Guidelines work synergistically with backwards course design to focus teaching on student-centered goals and priorities. In order to qualitatively assess how the ASM Curriculum Guidelines are used by educators and learn more about the needs of microbiology educators, the ASM Education Board distributed two surveys to the ASM education community. In this report, we discuss the results of these surveys (353 responses). We found that the ASM Curriculum Guidelines are being implemented in many different types of courses at all undergraduate levels. Educators indicated that the ASM Curriculum Guidelines were very helpful when planning courses and assessments. We discuss some specific ways in which the ASM Curriculum Guidelines have been used in undergraduate classrooms. The survey identified some barriers that microbiology educators faced when trying to adopt the ASM Curriculum Guidelines, including lack of time, lack of financial resources, and lack of supporting resources. Given the self-reported challenges to implementing the ASM Curriculum Guidelines in undergraduate classrooms, we identify here some activities related to the ASM Curriculum Guidelines that the ASM Education Board has initiated to assist educators in the implementation process.


Established and novel biomarkers of sepsis.
The increased incidence of sepsis, a systemic response to infection that occurs in some patients, has stimulated interest in identifying infected patients who are at risk and intervening early. When this condition progresses to severe sepsis (characterized by organ dysfunction), mortality is high. Hospitals that have implemented recommendations of the Surviving Sepsis Campaign have seen a reduction in mortality rate for hospital-acquired severe sepsis. They may reduce this further by focusing on new approaches to diagnosing sepsis, especially at an early stage. Sepsis is a complicated syndrome with many physiological derangements and many emerging laboratory markers of sepsis have been proposed as adjuncts to clinical evaluation. The list includes cytokines, acute phase proteins, neutrophil activation markers, markers of abnormal coagulation and, recently, markers of suppression of both the innate and adaptive immune response. The perfect biomarker would accurately identify patients at risk of developing severe sepsis and then guide targeted therapy.


Three-dimensional graphene-based polymer nanocomposites: preparation, properties and applications.
Motivated by the unique structure and outstanding properties of graphene, three-dimensional (3D) graphene-based polymer nanocomposites (3D-GPNCs) are considered as new generation materials for various multi-functional applications. This review presents an overview of the preparation, properties and applications of 3D-GPNCs. Three main approaches for fabricating 3D-GPNCs, namely 3D graphene based template, polymer particle/foam template, and organic molecule cross-linked graphene, are introduced. A thorough investigation and comparison of the mechanical, electrical and thermal properties of 3D-GPNCs are performed and discussed to understand their structure-property relationship. Various potential applications of 3D-GPNCs, including energy storage and conversion, electromagnetic interference shielding, oil/water separation, and sensors, are reviewed. Finally, the current challenges and outlook of these emerging 3D-GPNC materials are also discussed.


Rational design of a biomimetic cell penetrating peptide library.
Cell penetrating peptides have demonstrated potential to facilitate the cellular delivery of therapeutic molecules. Here we develop a set of 50 cell penetrating peptide based formulations with potential to deliver small interfering RNAs intercellularly. The transfection efficacy of siRNA containing lipid-like nanoparticles decorated with different peptides was evaluated both in vitro and in vivo and correlated with the peptide physical and chemical properties. In vitro, these particles were internalized primarily through macropinocytosis. When the peptides were presented to bone marrow-derived dendritic cells, they induce low immunoactivation relative to control cell penetrating peptides including the antennapedia homeodomain and TAT, as quantified by the expression of activation specific surface proteins like CD80, CD86, and major histocompatibility complex class II. In vivo, peptide decorated nanoparticles primarily accumulated in the lungs and the liver. Three human peptides derived from surfactant protein B (a lung surfactant protein), orexin (a neuropeptide hormone, and lactoferricin (a globular glycoprotein) that exist in many physiological fluids facilitated the in vivo delivery of siRNA and induce significant knock down (90%) of a hepatocyte expressed protein, coagulation Factor VII.


Consumption of fruit and vegetables among elderly people: a cross sectional study from Iran.
There is substantial evidence that low consumption of fruit and vegetables (FV) is a major risk factor for many chronic diseases. The aim of this study was to assess FV consumption and the variables that influence it among elderly individuals in Iran aged 60 and over. This was a cross-sectional study to investigate FV intake by a randomly-selected sample of members of elderly centers in Tehran, Iran. A multidimensional questionnaire was used to collect data on demographic characteristics, daily consumption of FV, knowledge, self-efficacy, social support, perceived benefits, and barriers against FV. Data were analyzed using t-tests, one way analysis of variance, Pearson correlation, and logistic regression. In total, 400 elderly individuals took part in the study. The mean age of the participants was 64.07 (SD = 4.49) years, and most were female (74.5%). The mean number of FV servings per day was 1.76 (SD = 1.15). Ninety-seven percent of participants (n = 388) did not know the recommended intake was at least five servings of FV per day. Similarly, 88.3% (n = 353) did not know the size of a single serving. The most frequent perceived benefits of and barriers against FV consumption were availability and expense, respectively. Knowledge (OR = 0.59, 95% CI = 0.39-0.88), perceived benefits (OR = 0.92, 95% CI = 0.88-0.96) and barriers (OR = 1.08, 95% CI = 1.04-1.14), self-efficacy (OR = 0.89, 95% CI = 0.83-0.95) and family support (OR = 0.91, 95% CI = 0.83-0.99) were significantly associated with fruit and vegetable consumption. The findings of this study indicate that FV intake among elderly individuals in Iran was lower than the recommended minimum of five daily servings and varied greatly with age, marital status, educational attainment, and income level. The results also indicated that low perceived benefits, low self-efficacy, and perceived barriers could lead to lower consumption of FV. It seems that in order to improve FV consumption among elderly individuals in Iran, raising awareness, improving perception of benefits and enhancing self-efficacy regarding FV consumption should receive more attention. Indeed, it is essential to plan health education programs and nutritional interventions for this group of the population.


Methane to ethylene with 85 percent yield in a gas recycle electrocatalytic reactor-separator.
Methane was oxidatively coupled to ethylene with an ethylene yield up to 85 percent and a total C(2) hydrocarbon yield up to 88 percent in a gas recycle high-temperature (800 degrees C) electrocatalytic or catalytic reactor where the recycled gas passes continuously through a molecular sieve trap in the recycle loop. Oxygen is supplied either electrocatalytically by means of the solid electrolyte support of the silver-based catalyst or in the gas phase. The C(2) products are obtained by subsequent heating of the molecular sieve trap. The selectivity to ethylene is up to 88 percent for methane conversion up to 97 percent.


Genetic evidence for recombination in Candida albicans based on haplotype analysis.
The possibility of sexual reproduction in the human pathogenic fungus Candida albicans is a question of great interest in medical mycology. Not only is it a fundamental biological issue, but it is also a potential mechanism for contributing to the phenotypic plasticity (and hence the virulence) of the organism. Molecular genotyping methods such as multi-locus sequence typing (MLST) are generating data that can shed light on this question. In the present study we have used MLST information to generate haplotypes that identify many different homologues of a chromosome within a collection of strains. Particular combinations of these haplotypes provide evidence for chromosomal segregation and intra-chromosome recombination. All of our observations of haplotype diversity could also be explained by other mechanisms, such as gene conversion or mitotic recombination, and the resolution of these issues will require a denser map of accurately localised markers. A common event observed in strain evolution is loss of heterozygosity at a particular marker. Our results contribute to the emerging picture of C. albicans as an organism whose primary means of reproduction is clonal, but with a small but important contribution from sexual reproduction, occurring in nature but not under commonly used laboratory conditions.


Engaging with Raman Spectroscopy to Investigate Antibody Aggregation.
In the last decade, a number of studies have successfully demonstrated Raman spectroscopy as an emerging analytical technique for monitoring antibody aggregation, especially in the context of drug development and formulation. Raman spectroscopy is a robust method for investigating protein conformational changes, even in highly concentrated antibody solutions. It is non-destructive, reproducible and can probe samples in an aqueous environment. In this review, we focus on the application and challenges associated with using Raman spectroscopy as a tool to study antibody aggregates.


IL-1Β enriched monocytes mount massive IL-6 responses to common inflammatory triggers among chronically HIV-1 infected adults on stable anti-retroviral therapy at risk for cardiovascular disease.
Chronic infection by HIV increases the risk of cardiovascular disease (CVD) despite effective antiretroviral therapy (ART). The mechanisms linking HIV to CVD have yet to be fully elucidated. High plasma levels of the pro-inflammatory cytokine IL-6, which may be triggered by IL-1β, is a biomarker of CVD risk in HIV-negative adults, and of all-cause mortality in HIV disease. Monocytes play a pivotal role in atherosclerosis, and may be major mediators of HIV-associated inflammation. We therefore hypothesized that monocytes from HIV-infected adults would display high inflammatory responses. Employing a 10-color flow cytometry intracellular cytokine staining assay, we directly assessed cytokine and chemokine responses of monocytes from the cryopreserved peripheral blood of 33 chronically HIV-1 infected subjects. Participants were 45 years or older, on virologically suppressive ART and at risk for CVD. This group was compared to 14 HIV-negative subjects matched for age and gender, with similar CVD risk. We simultaneously detected intracellular expression of IL-1β, IL-6, IL-8 and TNF in blood monocytes in the basal state and after stimulation by triggers commonly found in the blood of treated, chronically HIV-infected subjects: lipopolysaccharide (LPS) and oxidized low-density lipoprotein (oxLDL). In the absence of stimulation, monocytes from treated HIV-infected subjects displayed a high frequency of cells producing IL-1β (median 19.5%), compared to low levels in HIV-uninfected persons (0.9% p<0.0001). IL-8, which is induced by IL-1β, was also highly expressed in the HIV-infected group in the absence of stimulation, 43.7% compared to 1.9% in HIV-uninfected subjects, p<0.0001. Strikingly, high basal expression of IL-1β by monocytes predicted high IL-6 levels in the plasma, and high monocyte IL-6 responses in HIV-infected subjects. Hyper-inflammatory IL-1β enriched monocytes may be a major source of IL-6 production and systemic inflammation in HIV-infected adults, and may contribute to the risk for all-cause mortality and cardiovascular disease in treated HIV infection.


Developing a neurobehavioral animal model of poverty: Drawing cross-species connections between environments of scarcity-adversity, parenting quality, and infant outcome.
Children reared in impoverished environments are at risk for enduring psychological and physical health problems. Mechanisms by which poverty affects development, however, remain unclear. To explore one potential mechanism of poverty's impact on social-emotional and cognitive development, an experimental examination of a rodent model of scarcity-adversity was conducted and compared to results from a longitudinal study of human infants and families followed from birth (N = 1,292) who faced high levels of poverty-related scarcity-adversity. Cross-species results supported the hypothesis that altered caregiving is one pathway by which poverty adversely impacts development. Rodent mothers assigned to the scarcity-adversity condition exhibited decreased sensitive parenting and increased negative parenting relative to mothers assigned to the control condition. Furthermore, scarcity-adversity reared pups exhibited decreased developmental competence as indicated by disrupted nipple attachment, distress vocalization when in physical contact with an anesthetized mother, and reduced preference for maternal odor with corresponding changes in brain activation. Human results indicated that scarcity-adversity was inversely correlated with sensitive parenting and positively correlated with negative parenting, and that parenting fully mediated the association of poverty-related risk with infant indicators of developmental competence. Findings are discussed from the perspective of the usefulness of bidirectional-translational research to inform interventions for at-risk families.


Mechanism of strand displacement synthesis by DNA replicative polymerases.
Replicative holoenzymes exhibit rapid and processive primer extension DNA synthesis, but inefficient strand displacement DNA synthesis. We investigated the bacteriophage T4 and T7 holoenzymes primer extension activity and strand displacement activity on a DNA hairpin substrate manipulated by a magnetic trap. Holoenzyme primer extension activity is moderately hindered by the applied force. In contrast, the strand displacement activity is strongly stimulated by the applied force; DNA polymerization is favoured at high force, while a processive exonuclease activity is triggered at low force. We propose that the DNA fork upstream of the holoenzyme generates a regression pressure which inhibits the polymerization-driven forward motion of the holoenzyme. The inhibition is generated by the distortion of the template strand within the polymerization active site thereby shifting the equilibrium to a DNA-protein exonuclease conformation. We conclude that stalling of the holoenzyme induced by the fork regression pressure is the basis for the inefficient strand displacement synthesis characteristic of replicative polymerases. The resulting processive exonuclease activity may be relevant in replisome disassembly to reset a stalled replication fork to a symmetrical situation. Our findings offer interesting applications for single-molecule DNA sequencing.


Preventive Effects on Birth Outcomes: Buffering Impact of Maternal Stress, Depression, and Anxiety.
Although maternal stress, anxiety, and depression have been linked to negative birth outcomes, few studies have investigated preventive interventions targeting maternal mental health as a means of reducing such problems. This randomized controlled study examines whether Family Foundations (FF)-a transition to parenthood program for couples focused on promoting coparenting quality, with previously documented impact on maternal stress, depression, and anxiety-can buffer the negative effects of maternal mental health problems. To assess the effects of FF, we used a randomized block design with a sample of 259 expectant mothers assigned to FF or a control condition and analyzed using propensity score models. We examine two-way interactions of condition (intervention vs. control) with maternal mental health problems (financial stress, depression, and anxiety) on birth outcomes (birth weight, days in hospital for mothers and infants). For birth weight, we assess whether intervention effects depend on length of gestation by including a third interaction term. FF buffered (p < 0.05) the negative impact of maternal mental health problems on birth weight and both mother and infant length of post-partum hospital stay. For birth weight, assignment to FF was associated with higher birth weight for infants born before term. These results demonstrate that a psycho-educational program for couples focused on enhancing mutual coparental support, with preventive effects on maternal mental health, can reduce incidence of birth problems among women at elevated risk. Such improvements in birth outcomes could translate into substantial reductions in public and personal healthcare costs. Future work should assess mediating mechanisms of intervention impact and cost-benefit ratio of the intervention. The Family Foundations follow-up intervention study is currently registered with www.clinicaltrials.gov . The study identifier is NCT01907412.


Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice.
Dopamine D2 receptors are postulated to play an important role in modulating the reinforcing effects of abused drugs including ethanol. This experiment examined operant ethanol self-administration in dopamine D2 receptor knockout (KO) mice and wild-type (WT) mice using a continuous access procedure. Adult male KO and WT mice were trained in 30-min sessions to perform a lever press response for access to 10% v/v ethanol. After training, the mice were placed in test chambers on a continuous (23 h/day) basis with access to food (one lever press, i.e., FR1), 10% v/v ethanol (four lever presses, i.e., FR4), and water from a sipper tube (phase 1). After 30 consecutive sessions, response patterns were determined for 0, 5, 10, 20 and 30% v/v ethanol (phase 2). Saccharin (0.2% w/v) was subsequently added to the ethanol mixture and responding was examined for 0, 5, 10 and 20% ethanol (phase 3). During phase 1, WT mice displayed higher ethanol-lever responding compared to KO mice. Food lever responding and water intake was the same in both genotypes. During phase 2, WT mice displayed concentration-dependent ethanol lever responding, whereas KO mice responded at low rates regardless of ethanol concentration. WT mice also responded more for food compared to KO mice. Each genotype showed similar water intakes except at the 20% ethanol concentration, where WT mice had lower intakes. During phase 3, WT mice continued to show higher responding for all concentrations including saccharin alone. WT mice also continued to respond more for food compared to KO mice, but drank less water. In each phase, WT mice displayed episodic (bout) responding on the ethanol lever. KO mice did not respond for ethanol in bouts. Reduced responding in the KO mice for several reinforcers including ethanol indicates a more general role for dopamine D2 receptors in motivated responding rather than a specific role in ethanol reinforcement.


Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the 'Arimidex and tamoxifen alone or in combination' (ATAC) trial.
The ATAC trial evaluates in a randomized, double-blind design, Arimidextrade mark (anastrozole) alone or in combination with tamoxifen, relative to tamoxifen alone as 5-year adjuvant treatment in postmenopausal women with early breast cancer. Patients included in the pharmacokinetic (PK) sub-protocol had been in ATAC for > or =3 months, taking their medication in the morning and were 100% compliant for the preceding 14 days. Blood samples were collected 24 +/- 4 h after last dose. Trough (C(min)) plasma concentrations of anastrozole, tamoxifen and desmethyltamoxifen (DMT) were measured by validated methods. The PK results were based on a total of 347 patients (131 anastrozole (1 mg o.d.), 111 tamoxifen (20 mg o.d.), 105 anastrozole and tamoxifen (1 and 20 mg o.d. respectively)). The geometric mean steady-state trough plasma concentrations of tamoxifen and DMT were statistically equivalent in patients receiving tamoxifen alone or in combination with anastrozole: geometric mean tamoxifen = 94.8 ng ml(-1)and 95.3 ng ml(-1)in tamoxifen alone and combination groups, respectively; geometric mean DMT = 265.1 and 277.6 ng ml(-1)in the tamoxifen and anastrozole and tamoxifen groups, respectively. The geometric mean anastrozole levels were 27% lower (90% Cl 20-33%;P< 0.001) in the presence of tamoxifen than with anastrozole alone. Baseline plasma oestradiol levels were not obtained in the PK sub-protocol, however, such information was available from a similar ATAC sub-protocol, which evaluated bone mineral density. Mean oestradiol levels were 21.3, 19.3, and 21.6 pmol l(-1)prior to treatment and 3.7, 20.9 and 3.6 pmol l(-1)after 3 months in the anastrozole, tamoxifen, and combination groups, respectively (n = 167). On-treatment values were below the detection limit (3 pmol l(-1)) in 43.6 and 38.5% of the anastrozole alone and anastrozole in combination with tamoxifen groups, respectively. As a result of (a) the lack of effect of anastrozole on tamoxifen and DMT levels and (b) the observed fall in blood anastrozole levels having no significant effect on oestradiol suppression by anastrozole, we conclude that the observed reduction in anastrozole levels by tamoxifen is unlikely to be of clinical significance when anastrozole and tamoxifen are administered together.


The HBV DNA cutoff value for discriminating patients with HBeAgnegative chronic hepatitis B from inactive carriers.
Patients with HBeAg-negative chronic hepatitis B (CHB) has a significantly different prognosis than inactive carriers; there is however, no reliable strategy for accurately differentiating these two disease conditions. To determine a strategy for discriminating patients with HBeAg-negative CHB from inactive carriers. Consecutive inactive carriers (i.e. HBeAg-negativity, anti-HBe-positivity, normal ALT levels, and HBV DNA < 2000 IU/mL) were enrolled. HBV reactivation was defined as the elevation of the HBV DNA level to ≥ 2000 IU/mL. Patients were classified into true inactive carriers when their HBV DNA levels remained at < 2000 IU/mL or false inactive carriers when their HBV DNA levels increased to ≥ 2000 IU/mL during the first year. The Mean ± SD age of 208 inactive carriers (140 males) was 47.7 ± 12.6 years. The Mean ± SD serum ALT and HBV DNA levels were 22.8 ± 8.6 IU/L and 360 ± 482 IU/mL, respectively. HBV reactivation developed in 41 (19.7%) patients during the first year. Baseline HBV DNA and ALT levels differed significantly between true inactive and false inactive carriers. The AUROCs of the baseline ALT and HBV DNA levels for predicting a false inactive carrier were 0.609 and 0.831, respectively. HBV reactivation developed more often in patients with a baseline HBV DNA level of ≥ 200 IU/mL than in those with a baseline HBV DNA level of < 200 IU/mL during a Mean ± SD follow-up of 622 ± 199 days. The HBV DNA level was useful for discriminating patients with HBeAg-negative CHB from true inactive carriers. The follow-up strategies applied to inactive carriers need to vary with their HBV DNA levels.


Venous thromboembolism in women undergoing pelvic reconstructive surgery with mechanical prophylaxis alone.
The objective of this study was determine the frequency of symptomatic perioperative venous thromboembolism (VTE) and risk factor(s) associated with VTE occurrence in women undergoing elective pelvic reconstructive surgery using only intermittent pneumatic compression (IPC) for VTE prophylaxis. A multi-center case-cohort retrospective review was conducted at six clinical sites over a 66-month period. All sites utilize IPC as standard VTE prophylaxis for urogynecological surgery. VTE cases occurring during the same hospitalization and up to 6 weeks postoperatively were identified by ICD9 code query. Four controls were temporally matched to each case. Information collected included demographics, medical history, route of surgery, operative time, and intraoperative characteristics. Univariate and multivariate backward stepwise logistic regression analyses were performed to identify potential risk factors for VTE. Symptomatic perioperative VTE was diagnosed in 27 subjects from a cohort of 10,627 women who underwent elective urogynecological surgery (0.25 %). Univariate analysis identified surgical route (laparotomy vs others), type of surgery ("major" vs "minor"), history of gynecological cancer, surgery time, and patient age as risk factors for VTE (P < 0.05). Multivariate analysis identified increased frequency of VTE with laparotomy, age ≥ 70, and surgery duration ≥ 5 h. In our study cohort, the frequency of symptomatic perioperative VTE was low. Laparotomy, age ≥ 70 years, and surgery duration ≥ 5 h were associated with VTE occurrence.


Health Care Expenditures Among Adults With Diabetes After Oregon's Medicaid Expansion.
To compare trends in Medicaid expenditures among adults with diabetes who were newly eligible due to the Affordable Care Act (ACA) Medicaid expansion to trends among those previously eligible. Using Oregon Medicaid administrative data from 1 January 2014 to 30 September 2016, a retrospective cohort study was conducted with propensity score-matched Medicaid eligibility groups (newly and previously eligible). Outcome measures included total per-member per-month (PMPM) Medicaid expenditures and PMPM expenditures in the following 12 categories: inpatient visits, emergency department visits, primary care physician visits, specialist visits, prescription drugs, transportation services, tests, imaging and echography, procedures, durable medical equipment, evaluation and management, and other or unknown services. Total PMPM Medicaid expenditures for newly eligible enrollees with diabetes were initially considerably lower compared with PMPM expenditures for matched previously eligible enrollees during the first postexpansion quarter (mean values $561 vs. $793 PMPM, P = 0.018). Within the first three postexpansion quarters, PMPM expenditures of the newly eligible increased to a similar but slightly lower level. Afterward, PMPM expenditures of both groups continued to increase steadily. Most of the overall PMPM expenditure increase among the newly eligible was due to rapidly increasing prescription drug expenditures. Newly eligible Medicaid enrollees with diabetes had slightly lower PMPM expenditures than previously eligible Medicaid enrollees. The increase in PMPM prescription drug expenditures suggests greater access to treatment over time.


A theoretical model for intraperitoneal delivery of cisplatin and the effect of hyperthermia on drug penetration distance.
A theoretical model for the intraperitoneal (i.p.) delivery of cisplatin and heat to tumor metastases in tissues adjacent to the peritoneal cavity is presented. The penetration distance (the depth to which drug diffuses directly from the cavity into tissues) is predicted to be on the order of 0.5 mm. The model shows that exchange with the microvasculature has more effect than cellular uptake in limiting the penetration distance. Possible effects of hyperthermia are simulated, including increased cell uptake of drug, increased cell kill at a given level of intracellular drug, and decreased microvascular density. The model suggests that the experimental finding of elevated intracellular platinum levels up to a depth of 3 to 5 mm when drug is delivered i.p. by a heated infusion solution is due to penetration of heat to this distance, causing increased cell uptake of drug. Beyond a depth of about 0.5 mm, the drug is delivered mainly through the circulation. Use of sodium thiosulfate to deactivate systemic cisplatin may therefore be counterproductive when heat is delivered locally. The model suggests that i.p. delivery of heat, combined with systemic delivery of drug, may be as effective as i.p. delivery of heat and drug.


Educating public health physicians for the future: a current perspective from Aotearoa New Zealand.
Persisting, and in some cases widening, inequalities in health within and between countries present significant challenges to the focus and practice of contemporary public health, and by association, to public health education. As public health physicians and academic educators of medically- and non-medically trained public health practitioners, we call for a radical re-think of current approaches to public health medicine education and training in order to address these challenges. The public health physicians of the future, we argue, require not merely technical knowledge and skills but also a set of values that underpin a commitment to ethical principles, social equity, human rights, compassionate action, advocacy and leadership. Furthermore, while they will need to have their action firmly grounded in local realities they should think, if not speak and act, from an informed awareness of global issues. Drawing from our experience in Aotearoa New Zealand, as well as with marginalised communities overseas, we proffer our suggestions for the process and content of public health physician education and training for the future, with the intention of stimulating debate.


Temporary hearing threshold shifts and restitution after energy-equivalent exposures to industrial noise and classical music.
In order to investigate whether the energy-equivalence principle is at least acceptable for exposures with a duration in the range of hours and in order to disclose the actual physiological responses to exposures which varied with respect to the time structure and the semantic quality of sounds, a series of tests was carried out where physiological costs associated with varying exposures were measured audiometrically. In a cross-over test design, 10 Subjects (Ss) participated in test series with 3 energetically equal sound exposures on different days. The exposures corresponded with a tolerable rating level of 85 dB / 8 h. In a first test series (TS I), the Ss were exposed to a prototype of industrial noise with a sound pressure level of 94 dB(A) / 1 h. In a second test series (TS II), the same type of noise was applied, but the exposure time of a reduced level of 91 dB(A) was increased to 2 hours. In a third test series (TS III), classical music was provided also for 2 h at a mean level of 91 dB(A). The physiological responses to the 3 exposures were recorded audiometrically via the temporary threshold shift TTS2, the restitution time t(0 dB), and the IRTTS-value. IRTTS is the integrated restitution temporary threshold shift which is calculated by the sum of all threshold shifts. It represents the total physiological costs the hearing must "pay" for the sound exposure. Physiological responses of the hearing to the industrial noise exposures in TS I and TS II, all in all, were identical in the 3 parameters. Maximum threshold shifts of approximately 25 dB occurred which did not dissipate completely until 2.5 h after the end of the exposure and IRTTS-values of about 800 dBmin were calculated. Therefore, at least for exposure times in the range of hours, the equilibration of intensity and duration of sound exposures according to the energy-equivalence principle seems to have no influence on the hearing. Classical music was associated with the least severe TTS of less than 10 dB which disappeared much more quickly. IRTTS added up to just about 100 dBmin and, in comparison with 800 dBmin as specific responses to industrial noise, amounted to only about 12%. The substantially lower physiological costs of classical music apparently indicate a decisive influence of the type of sound exposures. Making inferences from the results of the study, the conventional approach of rating sound exposures exclusively by the principle of energy equivalence can lead to gravely misleading assessments of their actual physiological costs.


Emotions and Strategic Behaviour: The Case of the Ultimatum Game.
Human behaviour in economic interactions has attracted an increasing amount of attention over the last decades. The economic assumption that people would behave focusing on their own material self-interest was proved incomplete, once the empirical evidence consistently showed that many other motives may influence such behaviour. Therefore, models that can incorporate rational decision process as well as other intervening factors are a key issue to both understand the observations from economic experiments and to apply the lessons learned from them. In this paper, we incorporate the influence of emotions to the utility function in an explicit manner, using the Ultimatum Game as a case study. Our model is amenable to analytical study, and is connected with the Circumplex model of emotions and with Kahneman's two-system theory. The simplicity of the model allows to obtain predictions for the offers and acceptance thresholds. We study two specific examples, when the model parameters are distributed uniformly or normally, and show that in the latter case the results are already qualitatively correct. Although this work can be considered as a first approach, it includes what we believe are the main stylized facts, is able to qualitatively reproduce experimental results in a very simple manner, and can be straightforwardly extended to other games.


Vascular Malformations and Health-Related Quality of Life: A Systematic Review and Meta-analysis.
Patients with vascular malformations (VAMs) and vascular overgrowth syndromes have lower health-related quality of life (HRQoL) attributable to social stigmatization, poor mental health, severity, and pain. However, the factors that contribute to this decreased HRQoL are not clear. To perform a systematic review and meta-analysis of studies that used validated HRQoL instruments to compare the HRQoL of persons with VAMs with the US general population. A comprehensive search was performed in MEDLINE, Embase, PsycINFO, CINAHL, and Scopus from 1946 to March 31, 2017, with the consultation of an experienced librarian. All VAM studies with validated HRQoL instruments published in the English language were included. Case reports, review articles, non-English-language publications, and studies about the development of new HRQoL instruments were not included. Two reviewers assessed studies' eligibility and the risk of bias and performed data extraction. The meta-analysis was performed using the random-effects model. Comparisons of means were performed using the unpaired, 2-sample t test. The outcome was HRQoL. Eleven studies met the inclusion criteria for a total of 692 patients with VAMs. Six studies (320 patients) were included in the meta-analysis, whereas 5 studies were included in the qualitative analysis (372 patients). Those with VAMs had lower 36-Item Short-Form Health Survey scores in bodily pain (mean difference, -11.87; 95% CI, -21.45 to -2.29; I2 = 92%; P = .02) and mental health (mean difference, -6.04; 95% CI, -11.55 to -0.52; I2 = 83%; P = .03) compared with the US general population. Patients with VAMs had increased pain and psychosocial distress compared with the US general population. Pain and psychological morbidity are associated with poorer HRQoL and may serve as indicators for quality of life.


A novel NKX3-2 mutation associated with perinatal lethal phenotype of spondylo-megaepiphyseal-metaphyseal dysplasia in a neonate.
Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is an autosomal recessive skeletal dysplasia, characterized by disproportionate short stature with a short and stiff neck and trunk. SMMD is caused by inactivating mutations in NKX3-2, which encodes a homeobox-containing protein. Because of the rarity of the disorder, the diagnostic feature has not been fully established yet. We describe an affected newborn with dysmorphic facial features and severe short trunk. The patient required immediate intubation at the delivery room and duodenal atresia was detected during his course in neonatal intensive care unit. Skeletal survey revealed total absence of the ossification of the vertebral bodies, pubis, and ischia. Mainly the femora was short and broad with mild flaring of the metaphyses. The downward sloping or tented appearance of the ribs was distinctive. A diagnosis of SMMD was made on clinical and radiological grounds. Molecular analysis revealed homozygosity for a novel mutation, c.507-508delCA (p.Gly171Cysfs*55) in exon 2 of NKX3-2. The patient was operated on postnatal day 7 for duodenal atresia. In the post-operative period he developed sepsis and respiratory failure and he died on postnatal day 14. Although no neuroradiologic imaging could be performed, the findings of clubfoot, neuromuscular respiratory insufficiency requiring invasive mechanical ventilation and downward sloping or tented appearance of the ribs were suggestive of very early cervical cord compression leading to perinatal mortality. To our knowledge this patient yet represents one of the most severe postnatal phenotypes of SMMD.


Study of Repetitive Movements Induced Oscillatory Activities in Healthy Subjects and Chronic Stroke Patients.
Repetitive movements at a constant rate require the integration of internal time counting and motor neural networks. Previous studies have proved that humans can follow short durations automatically (automatic timing) but require more cognitive efforts to track or estimate long durations. In this study, we studied sensorimotor oscillatory activities in healthy subjects and chronic stroke patients when subjects were performing repetitive finger movements. We found the movement-modulated changes in alpha and beta oscillatory activities were decreased with the increase of movement rates in finger lifting of healthy subjects and the non-paretic hands in stroke patients, whereas no difference was found in the paretic-hand movements at different movement rates in stroke patients. The significant difference in oscillatory activities between movements of non-paretic hands and paretic hands could imply the requirement of higher cognitive efforts to perform fast repetitive movements in paretic hands. The sensorimotor oscillatory response in fast repetitive movements could be a possible indicator to probe the recovery of motor function in stroke patients.


The Schizosaccharomyces pombe Pfh1p DNA helicase is essential for the maintenance of nuclear and mitochondrial DNA.
Schizosaccharomyces pombe Pfh1p is an essential member of the Pif family of 5'-3' DNA helicases. The two Saccharomyces cerevisiae homologs, Pif1p and Rrm3p, function in nuclear DNA replication, telomere length regulation, and mitochondrial genome integrity. We demonstrate here the existence of multiple Pfh1p isoforms that localized to either nuclei or mitochondria. The catalytic activity of Pfh1p was essential in both cellular compartments. The absence of nuclear Pfh1p resulted in G(2) arrest and accumulation of DNA damage foci, a finding suggestive of an essential role in DNA replication. Exogenous DNA damage resulted in localization of Pfh1p to DNA damage foci, suggesting that nuclear Pfh1p also functions in DNA repair. The absence of mitochondrial Pfh1p caused rapid depletion of mitochondrial DNA. Despite localization to nuclei and mitochondria in S. pombe, neither of the S. cerevisiae homologs, nor human PIF1, suppressed the lethality of pfh1Delta cells. However, the essential nuclear function of Pfh1p could be supplied by Rrm3p. Expression of Rrm3p suppressed the accumulation of DNA damage foci but not the hydroxyurea sensitivity of cells depleted of nuclear Pfh1p. Together, these data demonstrate that Pfh1p has essential roles in the replication of both nuclear and mitochondrial DNA.


Synthetic water soluble di-/tritopic molecular receptors exhibiting Ca2+/Mg2+ exchange.
Structural integration of two synthetic water soluble receptors for Ca2+ and Mg2+, namely 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and o-aminophenol-N,N,O-triacetic acid (APTRA), respectively, gave novel di- and tritopic ionophores (1 and 2). As Mg2+ and Ca2+ cannot be simultaneously complexed by the receptors, allosteric control of complexation results. Potentiometric measurements established stepwise protonation constants and showed high affinity for Ca2+ (log K = 6.08 and 8.70 for 1 and 2, respectively) and an excellent selectivity over Mg2+ (log K = 3.70 and 5.60 for 1 and 2, respectively), which is compatible with magnesium-calcium ion exchange. While ion-exchange of a single Mg2+ for a single Ca2+ is possible in both 1 and 2, the simultaneous binding of two Mg2+ by 2 appears prohibitive for replacement of these two ions by a single Ca2+. Ion-binding and exchange was further rationalized by DFT calculations.


Efficient site-specific transgenesis and enhancer activity tests in medaka using PhiC31 integrase.
Established transgenesis methods for fish model systems allow efficient genomic integration of transgenes. However, thus far a way of controlling copy number and integration sites has not been available, leading to variable transgene expression caused by position effects. The integration of transgenes at predefined genomic positions enables the direct comparison of different transgenes, thereby improving time and cost efficiency. Here, we report an efficient PhiC31-based site-specific transgenesis system for medaka. This system includes features that allow the pre-selection of successfully targeted integrations early on in the injected generation. Pre-selected embryos transmit the correctly integrated transgene through the germline with high efficiency. The landing site design enables a variety of applications, such as reporter and enhancer switch, in addition to the integration of any insert. Importantly, this allows assaying of enhancer activity in a site-specific manner without requiring germline transmission, thus speeding up large-scale analyses of regulatory elements.


Cystic echinococcosis in South America: a call for action.
Cystic echinococcosis (CE) or hydatidosis, a parasitic zoonosis caused by a cestode of the family Taeniidae, species Echinococcus granulosus, is endemic in Argentina, Chile, Peru, Uruguay, and southern Brazil. This report presents CE figures for these five countries in 2009 - 2014 and proposes indicators to measure national control programs. Nearly 5 000 new CE cases were diagnosed annually in the five countries during the study period. The average case fatality rate was 2.9%, which suggests that CE led to approximately 880 deaths in these countries during the 6-year period. CE cases that required secondary or tertiary health care had average hospital stays of 10.6 days, causing a significant burden to health systems. The proportion of new cases (15%) in children less than 15 years of age suggests ongoing transmission. Despite figures showing that CE is not under control in South America, the long-standing implementation of national and local control programs in three of the five countries has achieved reductions in some of the indicators. The Regional Initiative for the Control of CE, which includes the five countries and provides a framework for networking and collaboration, must intensify its efforts.


Targeted disruption of pancreatic-derived factor (PANDER, FAM3B) impairs pancreatic beta-cell function.
Pancreatic-derived factor (PANDER, FAM3B) is a pancreatic islet-specific cytokine-like protein that is secreted from beta-cells upon glucose stimulation. The biological function of PANDER is unknown, and to address this we generated and characterized a PANDER knockout mouse. To generate the PANDER knockout mouse, the PANDER gene was disrupted and its expression was inhibited by homologous recombination via replacement of the first two exons, secretion signal peptide and transcriptional start site, with the neomycin gene. PANDER(-/-) mice were then phenotyped by a number of in vitro and in vivo tests to evaluate potential effects on glucose regulation, insulin sensitivity, and beta-cell morphology and function. Glucose tolerance tests demonstrated significantly higher blood glucose levels in PANDER(-/-) versus wild-type male mice. To identify the mechanism of the glucose intolerance, insulin sensitivity and pancreatic beta-cell function were examined. Hyperinsulinemic-euglycemic clamps and insulin tolerance testing showed similar insulin sensitivity for both the PANDER(-/-) and wild-type mice. The in vivo insulin response following intraperitoneal glucose injection surprisingly produced significantly higher insulin levels in the PANDER(-/-) mice, whereas insulin release was blunted with arginine administration. Islet perifusion and calcium imaging studies showed abnormal responses of the PANDER(-/-) islets to glucose stimulation. In contrast, neither islet architecture nor insulin content was impacted by the loss of PANDER. Interestingly, the elevated insulin levels identified in vivo were attributed to decreased hepatic insulin clearance in the PANDER(-/-) islets. Taken together, these results demonstrated decreased pancreatic beta-cell function in the PANDER(-/-) mouse. These results support a potential role of PANDER in the pancreatic beta-cell for regulation or facilitation of insulin secretion.


[Urinary lithiasis secondary to medication in HIV+ patients receiving Indinavir].
Therapy with protease inhibitors is commonly used in patients infected by human inmunodeficency virus (HIV). 20% of the administered dose is excreted by the kidney, and when alkaline urine is present, indinavir may crystallize forming stones and patients may experience renal colic due to this fact. Between January 1998 and June 2005, 26 patients receiving antiretroviral treatment with protease inhibitors received care at our hospital because of renal colic or flank pain. All of them underwent physical examination, echography and urography as well as blood and urine analysis. Patients were treated ambulatory excepting those in whom oral analgesics were insufficient to control the pain. All patients had been treated with indinavir for longer than 12 months. They represented 4% of all patients treated with the recommended dose of Crivixan. Most of them presented flank pain, associated in most cases to microhaematuria. Five of them required hospitalization because of persistent pain in spite of endovenous analgesia. Imaging tests (echography and urography) showed functional delay of the kidney (2 cases), ureteral stasis (4 cases) and little lithiasic concretions of mild radiologic density (5 cases). Urinalysis revealed suggestive christaluria and alkaline pH. All patients required hidratation and analgesic treatment. In 3 patients indinavir dose was reduced, it was retired in another one, and 100 mg of rito-navir were added in another one. Unsuccesfuly ureteral cateterization was tried in one patient. All of them presented symptomatic improvement. We ought to know the capability of indinavir to form urolithiasis in HIV patients treated with protease inhibitors, although its use is decreasing along time. Prevalence of urolithiasis in these patients seems to be higher as length of treatment becomes longer. Metabolic alterations in urine have been proved in these patients, contributing to a higher incidence of lithiasis than in general population.


Functional analysis of the integration host factor site of the σ(54) Pu promoter of Pseudomonas putida by in vivo UV imprinting.
The integration host factor (IHF) of Pseudomonas putida connects cell growth to transcriptional activity of distinct promoters. The IHF site of the σ(54) promoter Pu of the TOL (m-xylene biodegradation) plasmid pWW0 of P. putida has been examined to define experimentally a relationship between occupation of the promoter by this factor, the biological activity of the protein and the tolerance of the target site to single-base changes through the bound DNA core sequence. The use of an in vivo high-intensity UV imprinting procedure to examine such an occupation of Pu by IHF allowed inspection of the interplay between the factor and cognate site variants under the physiologically relevant conditions of monocopy gene dosage. The resulting data were merged in a structural model for establishing key features of the IHF-DNA interaction. A functional consensus for first-order IHF binding was instrumental for a genome-wide survey of sequences with potential regulatory value. This search revealed that very few, if any, of the maximum 330 sites within intergenic regions were placed in locations controlling expression of central metabolic genes. It thus seems that the IHF regulon of P. putida has a degree of functional specialization that is not evenly distributed through all gene categories.


Fast voluntary trunk flexion movements in standing: motor patterns.
The electromyographical (EMG) activity was studied during voluntary flexion movements of the trunk in erect standing man. The movements were performed at maximal velocity with successively increasing amplitude to cover the whole range of motion. The EMG activity was recorded from agonist-antagonist pairs of muscles at the ankle, knee, hip and trunk. The angular displacements at the corresponding joints were recorded using a Selspot optoelectronic system. The duration of initiating activity in prime movers (rectus abdominis and rectus femoris) as well as time to onset of activity in muscles braking the primary movement (erector spinae, gluteus maximus and hamstrings) were highly correlated with amplitude, duration, peak velocity and time to peak velocity of the movement (r = 0.59-0.91). The corresponding correlations for peak acceleration and deceleration of the movement were low (r = 0.03-0.38), indicating that acceleration and deceleration of a movement was not coded in the temporal aspects of the EMG. Onset of activity in rectus abdominis and rectus femoris as well as an early appearing burst of activity in vastus lateralis were invariant in relation to start of movement over the whole movement range. In the initial phase of a fast trunk flexion, activity in tibialis anterior appeared successively earlier with increasing movement amplitude. This resulted in a changed order of activation for the muscles from proximal to distal (rectus abdominis first) to distal to proximal (tibialis anterior first). Two different forms of associated postural adjustments are present during a fast trunk flexion, one early fast knee flexion and a later slower angle extension. Prior to knee flexion, no activity was recorded from muscles flexing at the knee implying that some other force must create a flexing torque around the knee. It is suggested that activity in rectus abdominis initiating the primary movement also initiates knee flexion through the upward pulling of pelvis. This would be possible since rectus femoris stabilizes the pelvis in relation to the leg, allowing the force in rectus abdominis to be transmitted below the hip joint and act extending around the ankle joint. However, when tibialis anterior is activated it stabilizes the shank which in turn will cause a knee flexion controlled by a lengthening contraction in vastus lateralis. During the subsequent ankle extension activity appears in lateral gastrocnemius and soleus causing the associated postural adjustment at the ankle. It can be concluded that activation of postural muscles prior to prime mover muscles is not always necessary.(ABSTRACT TRUNCATED AT 400 WORDS)


LncRNA MORT (ZNF667-AS1) in Cancer-Is There a Possible Role in Gynecological Malignancies?
Gynecological cancers (GCs) are currently among the major threats to female health. Moreover, there are different histologic subtypes of these cancers, which are defined as 'rare' due to an annual incidence of <6 per 100,000 women. The majority of these tend to be associated with a poor prognosis. Long non-coding RNAs (lncRNAs) play a critical role in the normal development of organisms as well as in tumorigenesis. LncRNAs can be classified into tumor suppressor genes or oncogenes, depending on their function within the cellular context and the signaling pathways in which they are involved. These regulatory RNAs are potential therapeutic targets for cancer due to their tissue and tumor specificity. However, there still needs to be a deeper understanding of the mechanisms by which lncRNAs are involved in the regulation of numerous biological functions in humans, both in normal health and disease. The lncRNA Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) has been identified as a tumor-related lncRNA. ZNF667-AS1 gene, located in the human chromosome region 19q13.43, has been shown to be silenced by DNA hypermethylation in several cancers. In this review, we report on the biological functions of ZNF667-AS1 from recent studies and describe the regulatory functions of ZNF667-AS1 in human disease, including cancer. Furthermore, we discuss the emerging insights into the potential role of ZNF667-AS1 as a biomarker and novel therapeutic target in cancer, including GCs (ovarian, cervical, and endometrial cancers).


Environmental gradients predict the genetic population structure of a coral reef fish in the Red Sea.
The relatively recent fields of terrestrial landscape and marine seascape genetics seek to identify the influence of biophysical habitat features on the spatial genetic structure of populations or individuals. Over the last few years, there has been accumulating evidence for the effect of environmental heterogeneity on patterns of gene flow and connectivity in marine systems. Here, we investigate the population genetic patterns of an anemonefish, Amphiprion bicinctus, along the Saudi Arabian coast of the Red Sea. We collected nearly one thousand samples from 19 locations, spanning approximately 1500 km, and genotyped them at 38 microsatellite loci. Patterns of gene flow appeared to follow a stepping-stone model along the northern and central Red Sea, which was disrupted by a distinct genetic break at a latitude of approximately 19°N. The Red Sea is characterized by pronounced environmental gradients along its axis, roughly separating the northern and central from the southern basin. Using mean chlorophyll-a concentrations as a proxy for this gradient, we ran tests of isolation by distance (IBD, R(2) = 0.52) and isolation by environment (IBE, R(2) = 0.64), as well as combined models using partial Mantel tests and multiple matrix regression with randomization (MMRR). We found that genetic structure across our sampling sites may be best explained by a combined model of IBD and IBE (Mantel: R(2) = 0.71, MMRR: R(2) = 0.86). Our results highlight the potential key role of environmental patchiness in shaping patterns of gene flow in species with pelagic larval dispersal. We support growing calls for the integration of biophysical habitat characteristics into future studies of population genetic structure.


Recombinant peptides in thrombolysis.
Recombinant thrombolytic peptides are mainly represented by recombinant forms of tissue plasminogen activator (t-PA), a proteolytic enzyme that catalyzes the conversion of plasminogen into active plasmin, which then functions to dissolve clots. The three clinically relevant recombinant thrombolytic peptides are alteplase (t-PA), reteplase (r-PA), and tenecteplase (TNK). r-PA and TNK have been structurally modified from native t-PA to increase their half-life and fibrin specificity. Thrombolytics play an important role in several diseases, including ST-segment elevation myocardial infarction (STEMI), deep vein thrombosis (DVT) and pulmonary embolism (PE), ischemic stroke, and peripheral arterial disease. Thrombolytic therapy has evolved into an alternative treatment for STEMI, reserved predominantly for patients who do not have access to timely percutaneous coronary intervention. In patients with DVT/PE or arterial related critical limb ischemia, the use of thrombolytic therapy is limited to specific patient populations. Thrombolytic therapy is the treatment of choice for ischemic stroke in patients who present <or=3 hours following the onset of symptoms. Moreover, thrombolytic therapy is used to restore function to stenotized central venous access devices as well as occluded hemodialysis access grafts.


Localized bleaching and quick recovery in Hong Kong's coral communities.
During the summer of 2017 we visited 33 sites with substantial coral cover across Hong Kong waters. At six sites where coral bleaching was observed, video-transect surveys were conducted, which revealed 18.7% to 56.1% bleached colonies and 5.9% to 57.6% bleached coral covered area per site. Mainly affected were three plate-like and three massive coral species. Water quality parameters were analyzed, which indicated that hyposalinity might have triggered the bleaching event. Tagging and follow-up field observation revealed a pattern of recovery depending on coral growth form, with high recovery rates (>93%) at five sites dominated by massive and submassive corals, but moderate (70%) at a site dominated by plate-like corals. Our study shows that the corals of Hong Kong exhibit differential susceptibility to bleaching and ability to recover, therefore it is imperative to establish a long-term monitoring programme to detect the changes in community structure over time.


Functional characterization of two 5-HT3 receptor splice variants isolated from a mouse hippocampal cell line.
Two splice variants of the ligand-gated 5-hydroxytryptamine or serotonin 5-HT3 receptor that differ in a six-amino-acid deletion were cloned by polymerase chain reaction from the hippocampus x neuroblastoma cell line HN9.10e. When expressed in Xenopus oocytes, both variants individually formed 5-HT3 receptors that revealed no significant differences in current responses to the agonists 5-HT and 1-phenylbiguanide and block by the specific antagonist LY-278, 584-maleate. For both receptors, the monovalent cations Na+, K+, Rb+ and Li+ showed the same relative permeability; NH4(+)permeated approximately 2.7 times better than Na+, and Tris+ was only poorly permeable. In contrast to other reports, the receptors were completely and reversibly blocked by extracellular Cs+ in both oocytes and native HN9.10 cells. Moreover, Ca2+ was not permeant and exhibited a concentration-dependent decrease (0.9-18 mM) of the 5-HT-induced currents without affecting the inward rectification of the current/voltage relation. The two receptors were reversibly inhibited by nanomolar concentrations of the specific inhibitor of protein kinase C (PKC) bisindolylmaleimide, but not by the equipotent and less specific inhibitor staurosporine. A regulatory effect on both 5-HT3 receptor subunits by PKC-mediated protein phosphorylation might be possible, however, a functional role of the two splice variants present in one cell remains to be determined.


Combined nevi of the conjunctiva.
To report the clinical and histologic features of combined nevi of the conjunctiva, a type of nevus that is not uncommon in the skin but has rarely been reported in the conjunctiva. Conjunctival nevi and melanomas from the files of the University of California, San Francisco, eye pathology laboratory were reviewed from 1984 to 1999 for the presence of features of both standard nevocytic nevi and blue nevi. Clinical histories and, when available, clinical photographs were obtained. Thirty-one combined nevi were discovered during the 15-year period between 1984 and 1999. One case before 1984 had been incorrectly diagnosed as a junctional nevus. The dendritic and spindle-shaped blue nevus cells had been overlooked because they were not recognized as distinct from the standard nevocytic nevus cells. The recognition of a blue as well as a brown color, a deep as well as a superficial component in the lesion, or a history of pigmentation since birth may help to establish the correct clinical diagnosis and prevent an unnecessarily deep surgical resection. Although growth of the lesion or "satellites" in some patients may favor a clinical diagnosis of melanoma, none of the lesions in this series were malignant. Despite a paucity of reports of combined nevi of the conjunctiva in the medical literature, this type of nevus--a combination of a nevocytic and a blue nevus--is common and has been overlooked in the past.


CDC-defined diseases and opportunistic infections in Jamaican children with HIV/AIDS.
To document the frequency of Centers for Disease Control and Prevention (CDC)-defined clinical conditions, opportunistic and co-infections among children with HIV/AIDS. This prospective, observational study reports the findings of 110 HIV-infected children followed in multicentre ambulatory clinics during September 1, 2002, to August 31, 2003, from the 239 children enrolled in the Kingston Paediatric and Perinatal HIV/AIDS Programme, Jamaica. We describe the clinico-pathologic characteristics of these children with HIV/AIDS, using the CDC criteria. The client distribution by clinic site was as follows: the University Hospital of the West Indies, 71 (64.6%), Bustamante Hospital for Children, 23 (20.9%), Comprehensive Health Centre 13 (11.8/%) and Spanish Town Hospital, 3 (2.7%). The median age of the 110 children with HIV/AIDS was 6.0 years (range 0.9-17.5). Mode of transmission was primarily mother-to-child (88.0%) and only 4% maternal/infant pairs received antiretroviralprophylaxis. Grouped by CDC category: 17 (15.4%) were asymptomatic (N), 22 (20.0%) mildly symptomatic (A), 30 (27.3%) moderately symptomatic (B) and 41 (37.3%) severely symptomatic (C). The most common CDC-defining symptoms were lymphadenopathy (12, 42.8%) and asymptomatic (6, 21.4%) in category N; lymphadenopathy (30, 29.7%), dermatitis (20, 19.8%) and persistent or recurrent upper respiratory tract infections (20, 19.8%) in category A; bacterial sepsis (18, 34.6%) and recurrent diarrhoea (11, 21.2%) in category B; and wasting (28, 30.0%), encephalopathy (26, 27.9%), and serious bacterial infections (15, 16.1%) in category C; Pulmonary tuberculosis (7, 7.5%) and Pneumocystis (jiroveci) carinii pneumonia; (5, 5.4%) were the most frequent opportunistic infections. Streptococcus pneumoniae (10, 30.3%) was the most common invasive bacterial pathogen causing sepsis and Escherichia coli (14, 34.2%) was the most common bacterial pathogen causing urinary tract infections, among the cohort. Thirty-three per cent commenced antiretroviral drugs (ARVs). There were 57 hospitalizations and five deaths. The study is an important step toward documentation of the natural history of paediatric HIV/AIDS in a primarily ARV-naive population from a developing country. It promotes training in paediatric HIV management as we move toward affordable access to antiretroviral agents in the wider Caribbean and the implementation of clinical trials.


Acute kidney injury is an independent marker of severity in Clostridium difficile infection: a nationwide survey.
To examine clinical outcomes in hospitalized Clostridium difficile infection (CDI) patients with acute kidney injury (AKI) using the National Hospital Discharge Survey for 2005 to 2009. CDI can cause serious complications in hospitalized adults. On the basis of expert opinion, guidelines recommend AKI as a marker of severe CDI, but this has not been extensively validated. CDI and AKI patients were identified using International Classification of Diseases 9th edition codes. Weighted data analyses were performed to provide national estimates and compare outcomes in patients with AKI and CDI to CDI patients without AKI. There were an estimated 1,261,712 patients with CDI identified with a median age of 75 years; 59.2% were female and 17.5% developed AKI. On multiple variable analysis, after adjusting for age, sex, and comorbid conditions, AKI was independently associated with length of hospital stay increase by 1.9 days, risk of colectomy with an odds ratio (OR) of 1.35, all-cause in-hospital mortality (OR, 2.76), and dismissal to a care facility (OR, 1.43), all P<0.0001. These data support prior consensus opinion that AKI is an independent marker associated with adverse outcomes in CDI and provides key prognostic information.


Classical many-particle systems with unique disordered ground states.
Classical ground states (global energy-minimizing configurations) of many-particle systems are typically unique crystalline structures, implying zero enumeration entropy of distinct patterns (aside from trivial symmetry operations). By contrast, the few previously known disordered classical ground states of many-particle systems are all high-entropy (highly degenerate) states. Here we show computationally that our recently proposed "perfect-glass" many-particle model [Sci. Rep. 6, 36963 (2016)10.1038/srep36963] possesses disordered classical ground states with a zero entropy: a highly counterintuitive situation . For all of the system sizes, parameters, and space dimensions that we have numerically investigated, the disordered ground states are unique such that they can always be superposed onto each other or their mirror image. At low energies, the density of states obtained from simulations matches those calculated from the harmonic approximation near a single ground state, further confirming ground-state uniqueness. Our discovery provides singular examples in which entropy and disorder are at odds with one another. The zero-entropy ground states provide a unique perspective on the celebrated Kauzmann-entropy crisis in which the extrapolated entropy of a supercooled liquid drops below that of the crystal. We expect that our disordered unique patterns to be of value in fields beyond glass physics, including applications in cryptography as pseudorandom functions with tunable computational complexity.


Advantages of blue InGaN light-emitting diodes with AlGaN barriers.
The advantages of blue InGaN light-emitting diodes (LEDs) with AlGaN barriers are studied numerically. The performance curves, energy band diagrams, electrostatic fields, and carrier concentrations are investigated. The simulation results show that the InGaNAlGaN LED has better performance than its conventional InGaNGaN counterpart owing to the increase of hole injection and the enhancement of electron confinement. The simulation results also suggest that the efficiency droop is markedly improved when the traditional GaN barriers are replaced by AlGaN barriers.


Self-ordering properties of functionalized acenes for annealing-free organic thin film transistors.
Presented here is a study of the molecular self-ordering properties of four bis(phenylethynyl) anthracene based organic semiconductors related to their electronic structure employing X-ray spectroscopy techniques and density functional theory (DFT) calculations. The local molecular order through polarization dependence of C 1s → π* transitions revealed ordered π-stacking nearly perpendicular to the substrate due to van der Waals interactions between alkyl groups. DFT calculations were used to deconvolute the measured electronic structure and examine effects of small changes in molecular geometry in relation to measured charge carrier mobility in top contact field effect transistors. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are found to be conjugated from the anthracene core across the bridging ethynyl groups to the thiophene and phenyl end groups. The inclusion of ethynyl bridges connecting the thiophenes has a twofold effect of both reducing the rotational freedom of this functional group and increasing HOMO/LUMO conjugation across the molecules. These features help create a more rigid upright structure for HB-ant-THT with better molecular orbital conjugation and subsequent higher mobility. With this understanding of how different functional groups interact with an acene core, future synthesis of new materials may be directed toward annealing-free organic semiconducting materials.


Family physicians' continuing professional development activities: current practices and potential for new options.
As part of needs assessment processes, our Faculty of Medicine (FOM) continuing professional development office investigated the differences between physicians who do and those who do not frequently participate in planned group learning to gain insight into their interest in new forms of continuing professional development (CPD). We sent a 19 item questionnaire to 485 randomly selected physicians of the 1050 family physicians in Eastern Ontario. The questionnaire examined present participation and satisfaction with CPD activities and perceptions regarding the potential impact of those; and appetite for new opportunities to meet their learning needs. Of the 151 (31%) physicians responding, 61% reported attending at least one FOM group learning program in the past 18 months (attenders) and 39% had not (non-attenders). Non-attenders indicated less satisfaction (p = 0.04) with present opportunities and requested development in newer approaches such as support for self-learning, on-line opportunities, and simulation. Although there are high levels of satisfaction with the present CPD system that predominantly offers large group learning options, a substantial number of physicians expressed interest in accessing new options such as personal study and on-line resources.