Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy.
CIMAvax EGF is a therapeutic anticancer vaccine developed entirely in Cuba and licensed in Cuba for use in adult patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). The vaccine is based on active immunotherapy by which an individual's immune response is manipulated to release its own effector antibodies (Abs) against the epidermal growth factor (EGF). Review pre-clinical and clinical research conducted during development of CIMAvax EGF, primarily studies published by Cuban investigators in international peer-reviewed scientific journals. Methods An automated search for "vaccine" and "EGF" was conducted in PubMed, resulting in 17 articles published by Cuban authors between January 1, 1994 and September 30, 2009. Main findings were described and discussed, along with unpublished preliminary findings of an initial ongoing phase III clinical trial. Articles reviewed describe five phase I/II and one phase II clinical trials conducted in Cuba in 1995-2005. A non-controlled 1995-1996 study resulted in the earliest published scientific evidence of the feasibility of inducing an immune response against autologous EGF in patients with different advanced stage tumors. Subsequent controlled, randomized trials included patients with advanced stage (IIIB/IV) NSCLC. The 2 and 3rd phase I/II trials differentiated immunized patients as poor antibody responders (PAR) and good antibody responders (GAR), according to their anti-EGF antibody response, and confirmed greater immunogenicity with Montanide ISA 51 adjuvant in the vaccine formulation, as well as the benefits of low-dose cyclophosphamide treatment 72 hours before the first immunization. The 4th phase I/II trial found increased immunogenicity with an increased dose divided in 2 anatomical sites and also established correlation between Ab titers, serum EGF concentration and length of survival. In the first 4 phase I/II trials and the phase II trial, vaccine was administered after chemotherapy (ChTVV schedule). In the 5th phase I/III trial, longer survival and increased immunogenicity were achieved using a VChTV schedule and dividing the vaccine dose in 4 anatomical sites. The phase II clinical trial confirmed results of earlier studies as well as the mild-to-moderate adverse event profile associated with CIMAvax EGF Longer survival was observed in all vaccinated patients compared to controls, and the difference was significant (p < 0.05) in the group aged <60 years. CIMAvax EGF's benefits in earlier NSCLC stages and in other tumor locations, as well as in patients unfit for chemotherapy, need to be evaluated. Evidence of the vaccine's safety for chronic use also needs to be systemized.


Six-year follow-up of children with intrauterine growth retardation: long-term, prospective study.
This prospective study was designed to characterize the neurodevelopmental and cognitive difficulties specific to children with intrauterine growth retardation and to detect early clinical predictors of these difficulties. Eighty-one children with intrauterine growth retardation were monitored up to 6 to 7 years of age using biometric parameters, perinatal risk questionnaires, and detailed neurodevelopmental and cognitive assessments. Forty-one children served as age-matched, appropriate for gestational age controls. A significant difference in growth parameters (P < .001), neurodevelopmental score (P < .05), and IQ (P < .05) was found between the children with intrauterine growth retardation and controls. A specific profile of difficulties in coordination, lateralization, spatial and graphomotor skills, and abundance of associated movements is typical of the children with intrauterine growth retardation and hints at possible later learning disabilities. The clinical parameters best predicting neurodevelopmental outcome were the neonatal risk score (P < .05) and the weight and height at 6 years of age (P < .05). The children with intrauterine growth retardation with neonatal complications had lower neurodevelopmental scores than the controls but no difference in IQ. Intrauterine growth retardation children diagnosed prenatally had the same neurodevelopmental and IQ scores as those diagnosed at birth, probably due to the careful perinatal and obstetric care provided. Children with intrauterine growth retardation demonstrate a specific profile of neurodevelopmental disabilities at preschool age. Early diagnosis and intervention could probably reduce these difficulties to a minimum.


Impact of a Local Vision Care Center on Glasses Ownership and Wearing Behavior in Northwestern Rural China: A Cluster-Randomized Controlled Trial.
Visual impairment is common among rural Chinese children, but fewer than a quarter of children who need glasses actually own and use them. To study the effect of rural county hospital vision centers (VC) on self-reported glasses ownership and wearing behavior (primary outcome) among rural children in China, we conducted a cluster-randomized controlled trial at a VC in the government hospital of Qinan County, a nationally-designated poor county. All rural primary schools (n = 164) in the county were invited to participate. Schools were randomly assigned to either the treatment group to receive free vision care and eyeglasses, if needed, or control group, who received glasses only at the end of the study. Among 2806 eligible children with visiual impairment (visual acuity ≤ 6/12 in either eye), 93 (3.31%) were lost to follow-up, leaving 2713 students (45.0% boys). Among these, glasses ownership at the end of the school year was 68.6% among 1252 treatment group students (82 schools), and 26.4% (p < 0.01) among 1461 controls (82 schools). The rate of wearing glasses was 55.2% in the treatment group and 23.4% (p < 0.01) among the control group. In logistic regression models, treatment group membership was significantly associated with spectacle ownership (Odds Ratio [OR] = 11.9, p < 0.001) and wearing behavior (OR = 7.2, p < 0.001). County hospital-based vision centers appear effective in delivering childrens' glasses in rural China.


RESTORE-Cognitive functional therapy with or without movement sensor biofeedback versus usual care for chronic, disabling low back pain: study protocol for a randomised controlled trial.
Low back pain (LBP) is the leading cause of disability globally and its costs exceed those of cancer and diabetes combined. Recent evidence suggests that individualised cognitive and movement rehabilitation combined with lifestyle advice (cognitive functional therapy (CFT)) may produce larger and more sustained effects than traditional approaches, and movement sensor biofeedback may enhance outcomes. Therefore, this three-arm randomised controlled trial (RCT) aims to compare the clinical effectiveness and economic efficiency of individualised CFT delivered with or without movement sensor biofeedback, with usual care for patients with chronic, disabling LBP. Pragmatic, three-arm, randomised, parallel group, superiority RCT comparing usual care (n=164) with CFT (n=164) and CFT-plus-movement-sensor-biofeedback (n=164). Inclusion criteria include: adults with a current episode of LBP >3 months; sought primary care ≥6 weeks ago for this episode of LBP; average LBP intensity of ≥4 (0-10 scale); at least moderate pain-related interference with work or daily activities. The CFT-only and CFT-plus-movement-sensor-biofeedback participants will receive seven treatment sessions over 12 weeks plus a 'booster' session at 26 weeks. All participants will be assessed at baseline, 3, 6, 13, 26, 40 and 52 weeks. The primary outcome is pain-related physical activity limitation (Roland Morris Disability Questionnaire). Linear mixed models will be used to assess the effect of treatment on physical activity limitation across all time points, with the primary comparison being a formal test of adjusted mean differences between groups at 13 weeks. For the economic (cost-utility) analysis, the primary outcome of clinical effect will be quality-adjusted life years measured across the 12-month follow-up using the EuroQol EQ-5D-5L . Approved by Curtin University Human Research Ethics Committee (HRE2018-0062, 6 Feb 2018). Study findings will be disseminated through publication in peer-reviewed journals and conference presentations. Australian New Zealand Clinical Trials Registry (ACTRN12618001396213).


The changing distribution of malaria in the Brazilian Amazon, 2003-2004 and 2008-2009.
More than half of the malaria cases reported in the Americas are from the Brazilian Amazon region. While malaria is considered endemic in this region, its geographical distribution is extremely heterogeneous. Therefore, it is important to investigate the distribution of malaria and to determine regions whereby action might be necessary. Changes in malaria indicators in all municipalities of the Brazilian Amazon between 2003-2004 and 2008-2009 were studied. The malaria indicators included the absolute number of malaria cases and deaths, the bi-annual parasite incidence (BPI), BPI ratios and differences, a Lorenz curve and Gini coefficients. During the study period, mortality from malaria remained low (0.02% deaths/case), the percent of municipalities that became malaria-free increased from 15.6% to 31.7%, and the Gini coefficient increased from 82% to 87%. In 2003, 10% of the municipalities with the highest BPI accumulated 67% of all malaria cases, compared with 2009, when 10% of the municipalities (with the highest BPI) had 80% of the malaria cases. This study described an overall decrease in malaria transmission in the Brazilian Amazon region. As expected, an increased heterogeneity of malaria indicators was found, which reinforces the notion that a single strategy may not bring about uniformly good outcomes. The geographic clustering of municipalities identified as problem areas might help to define better intervention methods.


Two sites in the Delta gene region contribute to naturally occurring variation in bristle number in Drosophila melanogaster.
A restriction enzyme survey of a 57-kb region including the gene Delta uncovered 53 polymorphic molecular markers in a sample of 55 naturally occurring chromosomes. A permutation test, which assesses the significance of the molecular marker with the largest effect on bristle variation in four genetic backgrounds relative to permuted data-sets, found two sites that were independently associated with variation in bristle number. A common site in the second intron of Delta affected only sternopleural bristle number, and another common site in the fifth intron affected only abdominal bristle number in females. Under an additive genetic model, the polymorphism in the second intron may account for 12% of the total genetic variation in sternopleural bristle number due to third chromosomes, and the site in the fifth intron may account for 6% of the total variation in female abdominal bristle number due to the third chromosomes. These results suggest the following: (1) models that incorporate balancing selection are more consistent with observations than deleterious mutation-selection equilibrium models, (2) mapped quantitative trait loci of large effect may not represent a single variable site at a genetic locus, and (3) linkage disequilibrium can be used as a tool for understanding the molecular basis of quantitative variation.


Y and Mitochondrial Chromosomes in the Heterogeneous Stock Rat Population.
Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial Chromosomes. We genotyped the Y and mitochondrial chromosomes in heterogeneous stock rats ( Rattus norvegicus ), which were created in 1984 by intercrossing eight inbred strains and have subsequently been maintained as an outbred population for 100 generations. As the Y and mitochondrial Chromosomes do not recombine, we determined which founder had contributed these chromosomes for each rat, and then performed association analysis for all complex traits (n=12,055; intersection of 12,116 phenotyped and 15,042 haplotyped rats). We found the eight founders had 8 distinct Y and 4 distinct mitochondrial Chromosomes, however only two of each were observed in our modern heterogeneous stock rat population (Generations 81-97). Despite the unusually large sample size, the p-value distribution did not deviate from expectations; there were no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and mitochondrial Chromosomes were strongly associated with expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern heterogeneous stock rats there are no Y and mitochondrial Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and mitochondrial Chromosomes that do not appear in modern heterogeneous stock rats, nor do they address effects that may exist in other rat populations, or in other species. Heterogeneous stock rats were created in 1984 by intercrossing eight inbred strains. This genetically and phenotypically diverse population has been used for numerous genetic studies. We developed a method (leveraging existing data) to identify the founder strain origin of Y and mitochondrial Chromosomes in modern heterogeneous stock rats. We examined effects of these chromosomes' genotype on behavioral, physiological, and gene expression traits among 12,055 rats. We found no significant associations, except for expression of genes located on these chromosomes.


Redox Coenzyme F420 Biosynthesis in Thermomicrobia Involves Reduction by Stand-Alone Nitroreductase Superfamily Enzymes.
Coenzyme F420 is a redox cofactor involved in hydride transfer reactions in archaea and bacteria. Since F420-dependent enzymes are attracting increasing interest as tools in biocatalysis, F420 biosynthesis is being revisited. While it was commonly accepted for a long time that the 2-phospho-l-lactate (2-PL) moiety of F420 is formed from free 2-PL, it was recently shown that phosphoenolpyruvate is incorporated in Actinobacteria and that the C-terminal domain of the FbiB protein, a member of the nitroreductase (NTR) superfamily, converts dehydro-F420 into saturated F420 Outside the Actinobacteria, however, the situation is still unclear because FbiB is missing in these organisms and enzymes of the NTR family are highly diversified. Here, we show by heterologous expression and in vitro assays that stand-alone NTR enzymes from Thermomicrobia exhibit dehydro-F420 reductase activity. Metabolome analysis and proteomics studies confirmed the proposed biosynthetic pathway in Thermomicrobium roseum These results clarify the biosynthetic route of coenzyme F420 in a class of Gram-negative bacteria, redefine functional subgroups of the NTR superfamily, and offer an alternative for large-scale production of F420 in Escherichia coli in the future.IMPORTANCE Coenzyme F420 is a redox cofactor of Archaea and Actinobacteria, as well as some Gram-negative bacteria. Its involvement in processes such as the biosynthesis of antibiotics, the degradation of xenobiotics, and asymmetric enzymatic reductions renders F420 of great relevance for biotechnology. Recently, a new biosynthetic step during the formation of F420 in Actinobacteria was discovered, involving an enzyme domain belonging to the versatile nitroreductase (NTR) superfamily, while this process remained blurred in Gram-negative bacteria. Here, we show that a similar biosynthetic route exists in Thermomicrobia, although key biosynthetic enzymes show different domain architectures and are only distantly related. Our results shed light on the biosynthesis of F420 in Gram-negative bacteria and refine the knowledge about sequence-function relationships within the NTR superfamily of enzymes. Appreciably, these results offer an alternative route to produce F420 in Gram-negative model organisms and unveil yet another biochemical facet of this pathway to be explored by synthetic microbiologists.


Structure, function and evolution of the hemagglutinin-esterase proteins of corona- and toroviruses.
Virus attachment to host cells is mediated by dedicated virion proteins, which specifically recognize one or, at most, a limited number of cell surface molecules. Receptor binding often involves protein-protein interactions, but carbohydrates may serve as receptor determinants as well. In fact, many different viruses use members of the sialic acid family either as their main receptor or as an initial attachment factor. Sialic acids (Sias) are 9-carbon negatively-charged monosaccharides commonly occurring as terminal residues of glycoconjugates. They come in a large variety and are differentially expressed in cells and tissues. By targeting specific Sia subtypes, viruses achieve host cell selectivity, but only to a certain extent. The Sia of choice might still be abundantly present on non-cell associated molecules, on non-target cells (including cells already infected) and even on virus particles themselves. This poses a hazard, as high-affinity virion binding to any of such "false'' receptors would result in loss of infectivity. Some enveloped RNA viruses deal with this problem by encoding virion-associated receptor-destroying enzymes (RDEs). These enzymes make the attachment to Sia reversible, thus providing the virus with an escape ticket. RDEs occur in two types: neuraminidases and sialate-O-acetylesterases. The latter, originally discovered in influenza C virus, are also found in certain nidoviruses, namely in group 2 coronaviruses and in toroviruses, as well as in infectious salmon anemia virus, an orthomyxovirus of teleosts. Here, the structure, function and evolution of viral sialate-O-acetylesterases is reviewed with main focus on the hemagglutinin-esterases of nidoviruses.


Cutaneous melanoma: a model to study cancer metastasis.
Nodal status in melanoma is a critically important prognostic factor for patient outcome. The survival rate drops to <10% when melanoma has spread beyond the regional lymph nodes and includes visceral involvement. In general, the process of melanoma metastasis is progressive in that dissemination of melanoma from the primary site to the regional lymph nodes occurs prior to systemic disease. The goal of this review article is to describe melanoma as a clinical model to study cancer metastasis. A future challenge is to develop a molecular taxonomy to subgroup melanoma patients at various stages of tumor progression for more accurate targeted treatment.


Pharmacodynamic interaction of gallopamil and propranolol in the conscious dog.
The interaction of gallopamil (Procorum) and propranolol was studied in conscious trained dogs by injecting gallopamil intravenously (consecutive injection of 0.0464, 0.1 and 0.215 mg/kg at 30-min intervals) with and without propranolol pre-medication (0.464 mg/kg i.v., 10 min before the first injection of gallopamil). An intraindividual comparison of the cardiovascular effects was made. The interaction was mostly minor and occurred only with the highest dose of gallopamil. It was noticeable most in the influence on myocardial contractility which was more pronounced than the influence on electrophysiological parameters. A shift in threshold doses was not observed. Much more pronounced effects of the gallopamil-propranolol interaction become apparent when the animals were at the same time subjected to vagal blockade (methylatropine). In this situation, combined administration of gallopamil and propranolol led to a greater reduction of contractility, increase of AV block and occurrence of asystole. As regards the latter, a shift in the threshold dose occurred. The differences in the intensity of the interaction between gallopamil and propranolol in animals with or without vagal blockade are therefore a consequence of the presence or absence of reflex regulation. The findings explain, and relativize, the clear-cut interaction in the anaesthetized dog demonstrated by other authors, i.e. experimental conditions matching an autonomic blockade.


Changes in functional brain networks and neurocognitive function in Chinese gynecological cancer patients after chemotherapy: a prospective longitudinal study.
Previous neurocognitive assessments in non-central nervous system cancers highlight the high incidence of neurocognitive dysfunction in this study population. However, there have been few studies exploring neurocognitive dysfunction induced by chemotherapy in gynecological cancer patients. This prospective longitudinal study was conducted to assess neurocognitive functioning and functional brain networks in Chinese gynecological cancer patients pre- and post-chemotherapy, while additionally including age-matched healthy subjects as the control group. All research participants were evaluated using a resting-state functional magnetic resonance imaging and neurocognition assessment. Behavioral data were conducted using SPSS for descriptive statistics, correlation and comparison analyses. Preprocessing of MRI (Magnetic Resonance Imaging) data and network analyses were performed using GRETNA (Graph Theoretical Network Analysis). A total of 40 subjects joined this study, with 20 subjects in each group. With the exception of the mean of psychomotor speed, there was no significant difference pre-chemotherapy between patients and healthy controls in neurocognitive test mean scores (Ps > 0.05). During the post-chemotherapy assessment, there were significant differences in the mean scores of neurocognitive tests (including Digit Span tests, verbal memory, immediate recall, delayed recall, and information processing speed tests) (all Ps < 0 .05). Longitudinal graph analysis revealed statistically significant differences in the patient group, with significant decreases in both local efficiency (P < 0.01) and global efficiency (P = 0.04). Lower raw TMT-A scores were significantly associated with lower local efficiency (r = 0.37, P = 0.03). Lower verbal memory scores were statistically significant and associated with lower global efficiency (r = 0.54, P = 0.02) in the patient group, but not in the healthy control group. This study found that the risk of brain function and neurocognitive changes following chemotherapy could potentially guide patients in making appropriate treatment decisions, and this study may identify a cohort that could be suited for study of an intervention.


Psychometric Performance of Generic Childhood Multi-Attribute Utility Instruments in Preterm and Low Birthweight Populations: A Systematic Review.
Individuals born preterm (gestational age < 37 weeks) and/or at low birthweight (<2500 g) are at increased risk of health impairments from birth to adulthood. This review aimed to evaluate the psychometric performance of generic childhood-specific or childhood-compatible multi-attribute utility instruments (MAUIs) in preterm and/or low birthweight (PLB) populations. Searches covered seven databases, including studies that targeted childhood (aged < 18 years) and/or adult (≥18 years) PLB populations; provided psychometric evidence for generic childhood-specific or compatible MAUI(s) (any language version); and published in English. Eighteen psychometric properties were evaluated using a four-part criteria rating system. Data syntheses identified psychometric evidence gaps and summarised the psychometric assessment methods/results. A total of 42 studies were included, generating 178 criteria rating outputs across four MAUIs: 17D, CHSCS-PS, HUI2, and HUI3. Moreover, 64.0% of outputs concerned the HUI3 MAUI, and 38.2% related to known-group validity. There was no evidence for five psychometric properties. Only 6.7% of outputs concerned reliability and proxy-child agreement. No MAUI outperformed others across all properties. The frequently applied HUI2 and HUI3 lacked content validity evidence. This psychometric evidence catalogue should inform the selection of MAUI(s) suited to the specific aims of applications targeting PLB populations. Further psychometric research is warranted to address the gaps in psychometric evidence.


The use of opioid adjuvants in perioperative multimodal analgesia.
Postoperative analgesia plays a crucial role in day-case surgery. Patients expect effective pain relief after surgery, without side effects, and this may not always be possible when more complicated procedures are performed in ambulatory settings. Moreover, both surgeons and patients expect anaesthesiologists to provide an effective pain treatment service especially after ambulatory surgery, even in private practice settings. The protocols based on intravenous opioids or central neuraxial blockade are no longer appropriate, when a short, uncomplicated postoperative course is anticipated. Multimodal analgesia, combining different groups of analgesics, both opioid and non-opioid, with different mechanisms of action, and targets in central and peripheral nervous systems with minimal side effects may be an answer. In this review, we present and discuss the current status of knowledge, with special reference to the role of adjuvants to opioids in acute postoperative pain.


No effect of low-level chronic neonicotinoid exposure on bumblebee learning and fecundity.
In recent years, many pollinators have declined in abundance and diversity worldwide, presenting a potential threat to agricultural productivity, biodiversity and the functioning of natural ecosystems. One of the most debated factors proposed to be contributing to pollinator declines is exposure to pesticides, particularly neonicotinoids, a widely used class of systemic insecticide. Also, newly emerging parasites and diseases, thought to be spread via contact with managed honeybees, may pose threats to other pollinators such as bumblebees. Compared to honeybees, bumblebees could be particularly vulnerable to the effects of stressors due to their smaller and more short-lived colonies. Here, we studied the effect of field-realistic, chronic clothianidin exposure and inoculation with the parasite Nosema ceranae on survival, fecundity, sugar water collection and learning using queenless Bombus terrestris audax microcolonies in the laboratory. Chronic exposure to 1 ppb clothianidin had no significant effects on the traits studied. Interestingly, pesticide exposure in combination with additional stress caused by harnessing bees for Proboscis Extension Response (PER) learning assays, led to an increase in mortality. In contrast to previous findings, the bees did not become infected by N. ceranae after experimental inoculation with the parasite spores, suggesting variability in host resistance or parasite virulence. However, this treatment induced a slight, short-term reduction in sugar water collection, potentially through stimulation of the immune system of the bees. Our results suggest that chronic exposure to 1 ppb clothianidin does not have adverse effects on bumblebee fecundity or learning ability.


The impact of insider managerial ownership on corporate performance of Taiwanese tourist hotels.
This study examines the impact of insider managerial ownership on financial performance of publicly traded tourist hotels in Taiwan. Insider managerial shareholding (IMS) includes two different classes of owners: managers and directors (i.e., managers' shareholding [MAS] plus directors' shareholding [DIRS]). The indicators of financial performance under consideration are return on assets (ROA), return on equity (ROE), stock return (SR), and Tobin's Q. In addition to analyzing total insider managerial ownership (IMS), the study splits IMS into two components (MAS and DIRS) and examines each of them, separately. Subsequently, panel regression tests examine the effects of IMS, MAS, and DIRS on financial performance of Taiwanese tourist hotels. Test results suggest that IMS explains ROA, ROE and Tobin's Q, but not SR. Further, compared to MAS, DIRS has a more significant impact on hotel performance. Specifically, an inverted U-shape represents the effects of IMS and DIRS on hotel performance (ROA, ROE and Tobin's Q), indicating that both IMS and DIRS have a significantly positive impact on hotel performance up to an optimal point (supporting the convergence-of-interests hypothesis). Further, when IMS and DIRS are greater than their corresponding optimal points, these two factors can significantly deteriorate hotel performance (supporting the entrenchment hypothesis).


Fluctuation of cilia-generated flow on the surface of the tracheal lumen.
Although we inhale air that contains many harmful substances, including, for example, dust and viruses, these small particles are trapped on the surface of the tracheal lumen and transported towards the larynx by cilia-generated flow. The transport phenomena are affected not only by the time- and space-average flow field but also by the fluctuation of the flow. Because flow fluctuation has received little attention, we investigated it experimentally in mice. To understand the origin of flow fluctuation, we first measured the distribution of ciliated cells in the trachea and individual ciliary motions. We then measured the detailed flow field using a confocal micro-PTV system. Strong flow fluctuations were observed, caused by the unsteadiness of the ciliary beat and the spatial inhomogeneity of ciliated cells. The spreading of particles relative to the bulk motion became diffusive if the time scale was sufficiently larger than the beat period. Finally, we quantified the effects of flow fluctuation on bulk flow by evaluating the Peclet number of the system, which indicated that the directional transport was an order of magnitude larger than the isotropic diffusion. These results are important in understanding transport phenomena in the airways on a cellular scale.


Robust Characterization of Two Distinct Glutarate Sensing Transcription Factors of Pseudomonas putida l-Lysine Metabolism.
A significant bottleneck in synthetic biology involves screening large genetically encoded libraries for desirable phenotypes such as chemical production. However, transcription factor-based biosensors can be leveraged to screen thousands of genetic designs for optimal chemical production in engineered microbes. In this study we characterize two glutarate sensing transcription factors (CsiR and GcdR) from Pseudomonas putida. The genomic contexts of csiR homologues were analyzed, and their DNA binding sites were bioinformatically predicted. Both CsiR and GcdR were purified and shown to bind upstream of their coding sequencing in vitro. CsiR was shown to dissociate from DNA in vitro when exogenous glutarate was added, confirming that it acts as a genetic repressor. Both transcription factors and cognate promoters were then cloned into broad host range vectors to create two glutarate biosensors. Their respective sensing performance features were characterized, and more sensitive derivatives of the GcdR biosensor were created by manipulating the expression of the transcription factor. Sensor vectors were then reintroduced into P. putida and evaluated for their ability to respond to glutarate and various lysine metabolites. Additionally, we developed a novel mathematical approach to describe the usable range of detection for genetically encoded biosensors, which may be broadly useful in future efforts to better characterize biosensor performance.


Dorsal transosseous reduction and locking plate fixation for articular depressed middle phalangeal base fracture.
An articular depressed fragment at the base of the middle phalanx can be an obstacle to congruent reduction and stable fixation. This study assessed the outcomes of a transosseous reduction technique combined with locking plate fixation for the treatment of articular depressed middle phalangeal base fracture. Between 2015 and 2017, seven patients (eight fingers) with intraarticular comminuted middle phalangeal base fracture were included in this study. Mean follow-up was 19 months (range 12-30 months). All patients showed depression of the articular fragment on sagittal computed tomography (CT) scan and were treated with a transosseous reduction technique and dorsal locking plate fixation. Radiographic evaluation was performed to ensure restoration of a concentric articular surface postoperatively. Total active range of motion (TAM) of the finger, grip strength, and the quick Disabilities of the Arm, Shoulder and Hand (quick DASH) score were evaluated at the last follow-up. Complications were also assessed. All fractures obtained bony union with a concentric joint. There was no significant loss of reduction during the follow-up period. The mean active proximal interphalangeal (PIP) joint and distal interphalangeal joint motion arcs at follow-up were 89° and 61°, respectively. Mean TAM of the affected finger and mean grip strength were 94% (range 80-100%) and 94% (range 86-100%) of the contralateral side, respectively. Mean quick DASH score was 2.3 (range 0-9.1). All patients returned to work. No surgery-related complications occurred. This technique provides satisfactory restoration of articular congruence and enables the early joint mobilization of articular depression-type fractures of the base of the middle phalanx. Therapeutic, level IV.


Hunger in humans induced by 2-deoxy-D-glucose: glucoprivic control of taste preference and food intake.
Intracellular glucopenia induced by 2-deoxy-D-glucose (2DG) administration in man produces increased hunger ratings and magnitude estimates of pleasantness for sucrose solutions. Augmented food intake substantiates these changes in affective behavior and relieves experimentally induced hunger. Intracellular glucopenia activates counterregulatory mechanisms to raise plasma glucose concentrations. Inducing hunger experimentally with 2DG provides a useful method for studying appetitive behavior in humans. The neurohumoral control of pituitary hormone release and other hypothalamic functions may be examined after 2DG infusion.


Prevalence and treatment coverage for depression: a population-based survey in Vidarbha, India.
VISHRAM is a community-based mental health program to address psycho-social distress and risk factors for suicide in a predominantly rural population in Central India, through targeted interventions for the prevention and management of Depression and Alcohol Use Disorders (AUD). The evaluation was designed to assess the impact of program on the contact coverage of evidence-based treatments for depression and AUD through a repeated survey design. This paper describes the baseline prevalence of depression among adults in rural community, association of various demographic and socio-economic factors with depression and estimates contact coverage and costs of care for depression. Population-based cross-sectional survey of adults in 30 villages of Amravati district in Vidarbha region of Central India. The outcome of interest was a probable diagnosis of depression which was measured using the Patient Health Questionnaire (PHQ-9). Data were analyzed using simple and multiple logistic regression. The outcome of current depression (PHQ-9 ≥ 10) was observed in 14.6 % of the sample (95 % CI 12.8-16.4 %). The contact coverage for current depression was only 4.3 % (95 % CI 1.5-7.1 %). Prevalence of depression varied greatly between the two sites of the study; higher age, female gender, lower education, economic status below poverty line and indebtedness were associated with depression; and while a contact coverage with formal health care was very low, a large proportion of affected persons had consulted family members. Our findings clearly indicate that psycho-social distress in rural communities in Maharashtra is strongly associated with social determinants such as gender, poverty and indebtedness and affects the entire population and not just farmers.


Biogeography of the southeastern United States: a comparison of salamander phylogeographic studies.
Most phylogeographic studies of species from the southeastern United States have shown a simple east-west division of mtDNA variation. However, a study of the salamander Ambystoma maculatum resulted in a more complex pattern that includes a close affinity between populations from the Central Highlands of Missouri and Arkansas and the Coastal Plain separated by a genetically distinct central group of populations. We test the generality of this observation by surveying mitochondrial DNA (mtDNA) variation in the closely related species A. talpoideum. An Ambystoma-specific intergenic spacer was amplified and sequenced. The 26 resulting haplotypes varied from 380 to 800 base pairs, and alignments, including the outgroup, required 101 insertions/deletions. Sequence divergence among haplotypes ranged from 0.001 to 0.758. Population subdivision was extensive (theta = 0.64). Phylogenetic analysis of A. talpoideum mtDNA sequence reveals a close relationship between the populations from the Central Highlands and the Coastal Plain. This result is similar to that obtained for A. maculatum, although the A. talpoideum clade is not as well differentiated from its sister clades. We discuss the differences and similarities between the two Ambystoma species and previous studies and call for increased focus on multiple species with similar ecologies as a way to detect subtle biogeographic events.


Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion.
Peripheral artery disease (PAD) is a common circulatory disorder of the lower limb arteries that reduces functional capacity and quality of life of patients. Despite relatively effective available treatments, PAD is a serious public health issue associated with significant morbidity and mortality. Ischemia-reperfusion (I/R) cycles during PAD are responsible for insufficient oxygen supply, mitochondriopathy, free radical production, and inflammation and lead to events that contribute to myocyte death and remote organ failure. However, the chronology of mitochondrial and cellular events during the ischemic period and at the moment of reperfusion in skeletal muscle fibers has been poorly reviewed. Thus, after a review of the basal myocyte state and normal mitochondrial biology, we discuss the physiopathology of ischemia and reperfusion at the mitochondrial and cellular levels. First we describe the chronology of the deleterious biochemical and mitochondrial mechanisms activated by I/R. Then we discuss skeletal muscle I/R injury in the muscle environment, mitochondrial dynamics, and inflammation. A better understanding of the chronology of the events underlying I/R will allow us to identify key factors in the development of this pathology and point to suitable new therapies. Emerging data on mitochondrial dynamics should help identify new molecular and therapeutic targets and develop protective strategies against PAD.


Medical student perceptions of family practice opportunities.
This study was conducted to obtain information concerning family practice opportunities in Chicago and to compare the actual availability with students' perceptions of such opportunities. Questionnaires received from 85 hospital administrators (98% response rate) indicated that 93% of the Chicago-area hospitals had open staff positions for family physicians. Comparison data were obtained from another questionnaire completed by 201 medical students (39%). The students' average estimate of the percentage of hospitals having positions available for family physicians was 45%. This suggested that the students greatly underestimated the availability of staff positions for family physicians.


Photocatalytic activity of TiO2 particulate films prepared by depositing TiO2 particles with various sizes.
TiO2 particles of various sizes were prepared by grinding in cyclohexanone, and TiO2 particulate films were obtained by depositing these TiO2 particles with various sizes onto a glass or quartz substrate. The effect of the particle size and thickness on the photocatalytic properties of the films was evaluated via oxidative degradation of gaseous 2-propanol. The initial rate of 2-propanol degradation under UV light irradiation for the films deposited with 30 nm TiO2 particles increased with increasing film thickness up to 600 nm, and reached a saturated value above this film thickness. Photocatalytic activity for the films with thickness below 600nm was larger when smaller TiO2 particles were deposited onto the substrate, due to the increase in the surface area of the particulate films. Furthermore, saturated values of the photocatalytic activity for thick films were smaller for the films deposited with smaller particles, which is mainly attributed to the change in crystal form of the particles during the grinding treatment.


Proton-Promoted and Anion-Enhanced Epoxidation of Olefins by Hydrogen Peroxide in the Presence of Nonheme Manganese Catalysts.
We report a remarkable Brønsted acid effect in the epoxidation of olefins by nonheme manganese catalysts and aqueous hydrogen peroxide. More specifically, a mononuclear nonheme manganese complex bearing a tetradentate N4 ligand, Mn(II)(Dbp-MCP)(OTf)2 (Dbp-MCP = (1R,2R)-N,N'-dimethyl-N,N'-bis((R)-(3,5-di-tert-butyl-phenyl)-2-pyridinylmethyl)cyclohexane-1,2-diamine; OTf(-) = CF3SO3(-)), is a highly efficient catalyst in the epoxidation of olefins by aqueous H2O2 in the presence of H2SO4 (1-3 mol %). The yields of epoxide products as well as the chemo- and enantioselectivities increase dramatically in the presence of H2SO4; no formation of epoxides is observed in the absence of H2SO4. In addition, the product yields and enantioselectivities are dependent significantly on the manganese catalysts and Brønsted acids. The catalytic epoxidation of olefins by other oxidants, such as peracids, alkyl hydroperoxides, and iodosylbenzene, is also affected by the presence of H2SO4; product yields and enantioselectivities are high and similar irrespective of the oxidants in the presence of H2SO4, suggesting that a common epoxidizing intermediate is generated in the reactions of [Mn(II)(Dbp-MCP)](2+) and the oxidants. Mechanistic studies, performed with (18)O-labeled water (H2(18)O) and cumyl hydroperoxide, reveal that a high-valent manganese-oxo species is formed as an epoxidizing intermediate via O-O bond heterolysis of Mn-OOH(R) species. The role of H2SO4 is proposed to facilitate the formation of a high-valent Mn-oxo species and to increase the oxidizing power and enantioselectivity of the Mn-oxo oxidant in olefin epoxidation reactions. Density functional theory (DFT) calculations support experimental results such as the formation of a Mn(V)-oxo species as an epoxidizing intermediate.


[Effect of ascorbic acid concentration on the ESR signal intensity of dry tissue].
A high concentration (r greater than 0.9; p less than 0.001) between the intensity of free radical ESR-signal (delta H max = 8-10 oe, g-factor 2.0057) in dry tissues of various organs of quinea pigs and concentration of free ascorbic acid in the same tissues was detected. Additional administration of ascorbic acid did not affect the correlation value of organs. The correlation coefficient was low in blood of control animals (r = 0.27; p greater than 0.05) and increased after administration of ascorbic acid (r = 0.95; p less than 0.001).


Puralpha, a single-stranded deoxyribonucleic acid binding protein, augments placental lactogen gene transcription.
Placental lactogen (PL) is thought to alter maternal metabolism to increase the pool of nutrients available for the fetus and to stimulate fetal nutrient uptake. The ovine (o) PL gene is expressed in chorionic binucleate cells (oBNC) and cis-elements located within the proximal promoter (-124 to +16 bp) are capable of trophoblast-specific expression in human (BeWo) and rat (Rcho-1) choriocarcinoma cells. Protein-DNA interactions were identified with oBNC nuclear extracts, and mutational analysis of these regions revealed a previously undefined cis-element from -102/-123 bp that enhances promoter activity in BeWo cells but not Rcho-1 cells. Characterization of this region identified the nucleotide sequence CCAGCA (-105/-110; o110) as the responsible cis-acting element. Southwestern analysis with this element identified a binding protein with an apparent M(r) of approximately 41,000. Expression screening of an ovine placental cDNA library identified six homologous cDNAs, which shared identity with human (97%) and mouse (95%) Pur alpha, a single-stranded DNA binding protein. The Pur alpha-o110 interaction was confirmed by electrophoretic mobility-supershift assays with oBNC and BeWo extracts but was absent with Rcho-1 extracts. Furthermore, overexpression of ovine Pur alpha enhanced transactivation of the oPL gene proximal promoter in both choriocarcinoma cell lines through this novel cis-element. This study identified a previously undefined cis-element, which interacts with Pur alpha to augment PL gene transcription.


[Quality assurance: concepts, actions and reflexions].
Importance that the topic of quality of medical care has acquired in recent years, a number of concepts have been utilized to mean many strategies to improve the quality of care. This situation has frequently created confusion between terms such as: quality assessment, quality assurance, total quality management, quality guarantee, etc. The purpose of this paper is to propose a conceptual framework that allows not only to clarify the concepts but also the actions towards the improvement of the quality of care. Therefore, a multidimensional matrix is also proposed in order to classify the multiple actions referred about in the literature and to organize them. The conclusions are: 1) The term "Quality guarantee", at least in spanish, is absolutely pertinent when referred to the quality of medical care; 2) This concept becomes a solid starting point to implement concret actions by integrating different concepts and avoiding confusions; 3) The multidimensional matrix allows to systematize multiple actions; 4) Since there was not a similar conceptual framework it is expected that this paper allows to close the gap between thinking and doing on behalf of every body.


Risk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: a retrospective cohort study.
Co-existence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) is referred to as overlap syndrome. Overlap patients have greater degree of hypoxia and pulmonary hypertension than patients with OSA or COPD alone. Studies showed that elderly patients with OSA alone do not have increased risk of atrial fibrillation (AF) but it is not known if overlap patients have higher risk of AF. To determine whether elderly patients with overlap syndrome have an increased risk of AF. In this single center, community-based retrospective cohort analysis, data were collected on 2,873 patients > 65 years of age without AF, presenting in the year 2006. Patients were divided into OSA group (n = 60), COPD group (n = 416), overlap syndrome group (n = 28) and group with no OSA or COPD (n = 2369). The primary endpoint was incidence of new-onset AF over the following two years. Logistic regression was performed to adjust for heart failure (HF), coronary artery disease, hypertension (HTN), cerebrovascular disease, cardiac valve disorders, diabetes mellitus, hyperlipidemia, chronic kidney disease (CKD) and obesity. The incidence of AF was 10% in COPD group, 6% in OSA group and 21% in overlap syndrome group (P < 0.05). After adjusting for age, sex, HF, CKD, and HTN, patients with overlap syndrome demonstrated a significant association with new-onset AF (OR = 3.66, P = 0.007). HF, CKD and HTN were also significantly associated with new-onset AF (P < 0.05). Among elderly patients, the presence of overlap syndrome is associated with a marked increase in risk of new-onset AF as compared to the presence of OSA or COPD alone.


Multi-omics analyses from a single sample: prior metabolite extraction does not alter the 16S rRNA-based characterization of prokaryotic community in a diversity of sample types.
Massive sequencing of the 16S rRNA gene has become a standard first step to describe and compare microbial communities from various samples. Parallel analysis of high numbers of samples makes it relevant to the statistical testing of the influence of natural or experimental factors and variables. However, these descriptions fail to document changes in community or ecosystem functioning. Nontargeted metabolomics are a suitable tool to bridge this gap, yet extraction protocols are different. In this study, prokaryotic community compositions are documented by 16S rRNA gene sequencing after direct DNA extraction or after metabolites extraction followed by DNA extraction. Results obtained using the V3-V4 region on nonaxenic cultures of cyanobacteria, lake water column, biofilm, and gut of wild and lab-reared fish indicate that prior extraction of metabolites does not influence the obtained image of prokaryotic communities. This validates sequential extraction of metabolites followed by DNA as a way to combine 16S rRNA sequencing with metabolome characterization from a single sample. This approach has the potential to complement community structure characterization with a proxy of their functioning, without the uncertainties associated with the use of separate samples.


NOX2 deficiency attenuates markers of adiposopathy and brain injury induced by high-fat diet.
The consumption of high-fat/calorie diets in modern societies is likely a major contributor to the obesity epidemic, which can increase the prevalence of cancer, cardiovascular disease, and neurological impairment. Obesity may precipitate decline via inflammatory and oxidative signaling, and one factor linking inflammation to oxidative stress is the proinflammatory, pro-oxidant enzyme NADPH oxidase. To reveal the role of NADPH oxidase in the metabolic and neurological consequences of obesity, the effects of high-fat diet were compared in wild-type C57Bl/6 (WT) mice and in mice deficient in the NAPDH oxidase subunit NOX2 (NOX2KO). While diet-induced weight gains in WT and NOX2KO mice were similar, NOX2KO mice had smaller visceral adipose deposits, attenuated visceral adipocyte hypertrophy, and diminished visceral adipose macrophage infiltration. Moreover, the detrimental effects of HFD on markers of adipocyte function and injury were attenuated in NOX2KO mice; NOX2KO mice had improved glucose regulation, and evaluation of NOX2 expression identified macrophages as the primary population of NOX2-positive cells in visceral adipose. Finally, brain injury was assessed using markers of cerebrovascular integrity, synaptic density, and reactive gliosis, and data show that high-fat diet disrupted marker expression in WT but not NOX2KO mice. Collectively, these data indicate that NOX2 is a significant contributor to the pathogenic effects of high-fat diet and reinforce a key role for visceral adipose inflammation in metabolic and neurological decline. Development of NOX-based therapies could accordingly preserve metabolic and neurological function in the context of metabolic syndrome.


Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. Discovery of highly selective hMC3R, hMC4R, and hMC5R analogues.
It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in alpha-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in gamma-MSH, two different series of gamma-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native gamma-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr-Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH(2) with Gly(4)) is more important for selectivity. The 2nd series is made of d-2-naphthylalanine (d-Nal(2')) scan of the gamma-MSH sequence at position 6 and 8 and the replacement of His(5) with Pro (analogue 13). Analogue 12, H-Tyr-Val-Nle-Gly-His-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr-Val-Nle-Gly-Pro-d-Nal(2')-Arg-Trp-Asp-Arg-Phe-Gly-NH(2), which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.


Recognition and resistance in TEM beta-lactamase.
Developing antimicrobials that are less likely to engender resistance has become an important design criterion as more and more drugs fall victim to resistance mutations. One hypothesis is that the more closely an inhibitor resembles a substrate, the more difficult it will be to develop resistant mutations that can at once disfavor the inhibitor and still recognize the substrate. To investigate this hypothesis, 10 transition-state analogues, of greater or lesser similarity to substrates, were tested for inhibition of TEM-1 beta-lactamase, the most widespread resistance enzyme to penicillin antibiotics. The inhibitors were also tested against four characteristic mutant enzymes: TEM-30, TEM-32, TEM-52, and TEM-64. The inhibitor most similar to the substrate, compound 10, was the most potent inhibitor of the WT enzyme, with a K(i) value of 64 nM. Conversely, compound 10 was the most susceptible to the TEM-30 (R244S) mutant, for which inhibition dropped by over 100-fold. The other inhibitors were relatively impervious to the TEM-30 mutant enzyme. To understand recognition and resistance to these transition-state analogues, the structures of four of these inhibitors in complex with TEM-1 were determined by X-ray crystallography. These structures suggest a structural basis for distinguishing inhibitors that mimic the acylation transition state and those that mimic the deacylation transition state; they also suggest how TEM-30 reduces the affinity of compound 10. In cell culture, this inhibitor reversed the resistance of bacteria to ampicillin, reducing minimum inhibitory concentrations of this penicillin by between 4- and 64-fold, depending on the strain of bacteria. Notwithstanding this activity, the resistance of TEM-30, which is already extant in the clinic, suggests that there can be resistance liabilities with substrate-based design.


HyperBIRD: a sensitivity-enhanced approach to collecting homonuclear-decoupled proton NMR spectra.
Samples prepared following dissolution dynamic nuclear polarization (DNP) enable the detection of NMR spectra from low-γ nuclei with outstanding sensitivity, yet have limited use for the enhancement of abundant species like (1)H nuclei. Small- and intermediate-sized molecules, however, show strong heteronuclear cross-relaxation effects: spontaneous processes with an inherent isotopic selectivity, whereby only the (13)C-bonded protons receive a polarization enhancement. These effects are here combined with a recently developed method that delivers homonuclear-decoupled (1)H spectra in natural abundance samples based on heteronuclear couplings to these same, (13)C-bonded nuclei. This results in the HyperBIRD methodology; a single-shot combination of these two effects that can simultaneously simplify and resolve complex, congested (1)H NMR spectra with many overlapping spin multiplets, while achieving 50-100 times sensitivity enhancements over conventional thermal counterparts.


Blunt traumatic injuries to the colon and rectum.
Experience in the treatment of patients with blunt colonic injuries is based on isolated case reports, and it is unclear whether the principles that guide the management of penetrating colonic injuries should be applied to these patients. Reviews of patients with these injuries suggest that such injuries present unique problems for diagnosis and treatment and are accompanied by excessive morbidity and mortality. A 42-month retrospective case series was analyzed. Data from 27 patients were analyzed, accounting for 8.5 percent of all colon and rectal injuries and for 0.5 percent of total blunt trauma admissions. Automobile crashes were the cause of injuries in 20 patients (74 percent). The mean Injury Severity Score was 28. All but 2 patients were operated on within 3 hours after admission. No significant difference was found in the morbidity and mortality rates based on the operation performed to manage the colonic injury. Indications for early exploration included a positive diagnostic peritoneal lavage in 23 patients, abnormal radiologic findings in 2, and positive clinical abdominal findings in the remaining 2 patients. Blunt colonic and rectal injuries are uncommon and pose problems for diagnosis and treatment. Associated injuries are common, and steering wheel compression of the upper abdomen as well as lap belts seem to predispose to colonic injuries. Initial diagnosis is made at the time of operation, and a thorough exploration of the abdominal cavity is important to diagnose associated injuries. Treatment must be individualized; however, based on our observations, the creation of ostomies is not mandatory for the treatment of these injuries.


Effects of whole body cryotherapy and cold water immersion on knee skin temperature.
This study sought to (a) compare and contrast the effect of 2 commonly used cryotherapy treatments, 4 min of -110 °C whole body cryotherapy and 8 °C cold water immersion, on knee skin temperature and (b) establish whether either protocol was capable of achieving a skin temperature (<13 °C) believed to be required for analgesic purposes. After ethics committee approval and written informed consent was obtained, 10 healthy males (26.5±4.9 yr, 183.5±6.0 cm, 90.7±19.9 kg, 26.8±5.0 kg/m2, 23.0±9.3% body fat; mean±SD) participated in this randomised controlled crossover study. Skin temperature around the patellar region was assessed in both knees via non-contact, infrared thermal imaging and recorded pre-, immediately post-treatment and every 10 min thereafter for 60 min. Compared to baseline, average, minimum and maximum skin temperatures were significantly reduced (p<0.001) immediately post-treatment and at 10, 20, 30, 40, 50 and 60 min after both cooling modalities. Average and minimum skin temperatures were lower (p<0.05) immediately after whole body cryotherapy (19.0±0.9 °C) compared to cold water immersion (20.5±0.6 °C). However, from 10 to 60 min post, the average, minimum and maximum skin temperatures were lower (p<0.05) following the cold water treatment. Finally, neither protocol achieved a skin temperature believed to be required to elicit an analgesic effect.


Reducing by 50% the incidence of maternal hypotension during elective caesarean delivery under spinal anesthesia: Effect of prophylactic ondansetron and/or continuous infusion of phenylephrine - a double-blind, randomized, placebo controlled trial.
Prophylactic administrations of ondansetron or phenylephrine have been reported to provide a protective effect against hypotension in women undergoing cesarean delivery under spinal anesthesia (SA). The main hypothesis is that ondansetron improves the hemodynamic response, especially combined with phenylephrine infusion. This prospective, double-blind, randomized, placebo-controlled study included 265 healthy pregnant women scheduled for elective cesarean delivery under SA. Women were randomly allocated into four groups to receive either placebo (control), ondansetron (O) 8 mg intravenously before induction of SA, phenylephrine infusion (50 mcg/min) (P) or ondansetron plus phenylephrine (OP). Demographic, obstetric, intraoperative timing, and anesthetic variables were assessed at 16 time points. Anesthetic variables assessed included blood pressure, heart rate, oxygen saturation, nausea, vomiting, electrocardiographic changes, skin flushing, discomfort or pruritus, and vasopressor requirements. There were differences (P = 0.0001) in the number of patients with hypotension (50.8% control, 44.6% O, 20.9% P, 25.0% OP), the percentage of time points (P = 0.0001) with systolic hypotension per patient (17.4% control, 8.7% O, 2.1% P, 6.7% OP) and the number of patients requiring supplementary boluses of ephedrine (P = 0.003), phenylephrine (P = 0.017) or atropine (P = 0.0001). A 50 μg/min phenylephrine infusion reduces by 50%, the incidence of maternal hypotension compared with placebo, but infusions of phenylephrine are still not routine in our environment. Prophylactic ondansetron 8 mg might be considered in this situation, because it does not reduce the incidence of maternal hypotension but diminishes its severity, reducing the number of hypotensive events per patient by 50%.


Effect of different light intensities on total phenolics and flavonoids synthesis and anti-oxidant activities in young ginger varieties (Zingiber officinale Roscoe).
Nowadays, phytochemicals and antioxidants in plants are raising interest in consumers for their roles in the maintenance of human health. Phenolics and flavonoids are known for their health-promoting properties due to protective effects against cardiovascular disease, cancers and other disease. Ginger (Zingiber officinale) is one of the traditional folk medicinal plants and it is widely used in cooking in Malaysia. In this study, four levels of glasshouse light intensities (310, 460, 630 and 790 μmol m(-2)s(-1)) were used in order to consider the effect of light intensity on the production, accumulation and partitioning of total phenolics (TP), total flavonoids (TF) and antioxidant activities in two varieties of Malaysian young ginger (Zingiber officinale). TF biosynthesis was highest in the Halia Bara variety under 310 μmol m(-2)s(-1) and TP was high in this variety under a light intensity of 790 μmol m(-2)s(-1). The highest amount of these components accumulated in the leaves and after that in the rhizomes. Also, antioxidant activities determined by the 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) assay in both of varieties, increased significantly (p ≤ 0.01) with increasing TF concentration, and high antioxidant activity was observed in the leaves of Halia Bara grown under 310 μmol m(-2)s(-1). The ferric reducing (FRAP) activity of the rhizomes was higher than that of the leaves in 310 μmol m(-2)s(-1) of sun light. This study indicates the ability of different light intensities to enhance the medicinal components and antioxidant activities of the leaves and young rhizomes of Zingiber officinale varieties. Additionally, this study also validated their medicinal potential based on TF and TP contents.


Differential display: identifying genes involved in cardiomyocyte proliferation.
An estimated 15,000 different mRNA species are expressed in a typical mammalian cell. The differential expression of mRNAs in both a temporal and cell-specific manner determines the fate of the cell and creates the organism. Analysis of this differential gene expression has become a central aim of many laboratories attempting to understand the mechanisms underlying various biological processes. Currently, we are using a technique called differential display to analyze the differential expression of genes in cardiomyocytes. Differential display is a rapid and powerful technique that was introduced by Liang and Pardee in 1992. Since that time, it has been successfully applied by several groups, and it is quickly becoming a standard method for studying differential gene expression. Here, we present a detailed article discussing the differential display methodology and how we have utilized it to identify potential genes involved in cardiomyocyte proliferation. Furthermore, we have provided a list of materials and supplied examples of data obtained, in an effort to allow the reader to perform the technique with success in their own laboratory.


Hypertension in the elderly.
There is no doubt that hypertension is of importance to the health of the elderly, in terms of both mortality and disability. There is mounting evidence that antihypertensive therapy is effective in reducing target organ disease. More data are needed to arrive at optimal treatment regimens and to examine the efficacy of therapy in pure systolic hypertension. A stepped care, cautious approach to therapy should prove to be safe and beneficial.


Rademikibart (CBP-201), a next-generation monoclonal antibody targeting human IL-4Rα: Two phase I randomized trials, in healthy individuals and patients with atopic dermatitis.
IL-4 and IL-13 signaling via IL-4Rα plays key roles in the pathogenesis of atopic dermatitis (AD) and asthma. Rademikibart (formerly CBP-201), a next-generation human IgG4 kappa monoclonal antibody, blocks IL-4Rα-mediated signal transduction. We performed two phase I, randomized, double-blind, placebo-controlled trials. In a single-ascending dose trial, 40 healthy adults were randomized 3:1 to rademikibart (75-600 mg s.c., 300 mg i.v.) or placebo, with 12 weeks of follow-up. In the multiple-ascending dose trial, 31 adults with moderate-to-severe AD were randomized 4:1 to once weekly rademikibart (75-300 mg s.c.) or placebo for 4 weeks, plus 7 weeks of follow-up. Most treatment-emergent adverse events (TEAEs) were mild; none were serious. Two s.c. injection site reactions and one TEAE of conjunctivitis were reported, all were mild. Rapid and sustained improvements were observed in AD severity and in quality of life (QoL), without plateauing. At week 4, efficacy scores improved by a maximum of -74.4% (Eczema Area and Severity Index), -62.7% (body surface area), -52.8% (Pruritus Numerical Rating Scale [PNRS] severity), -54.4% (PNRS frequency), and - 69.9% (Dermatology Life Quality Index). Thymus activation regulated chemokine inflammatory biomarker concentrations decreased in both trials (-55.4% in the pooled rademikibart arms vs. +18.0% with placebo, at week 5, in patients with AD). Exposure to rademikibart increased in a greater than dose-proportional manner, suggesting nonlinear clearance. In summary, rademikibart was well-tolerated and associated with rapid and sustained improvements in eczematous lesions, pruritus, QoL, and inflammatory biomarker concentrations during 4 weeks of treatment. Efficacy responses did not plateau and were generally dose dependent. These promising findings support further development of rademikibart in patients with AD.


Wageningen Evaluating Programmes for Analytical Laboratories (WEPAL).
The paper describes three of the Wageningen Evaluating Programmes for Analytical Laboratories (WEPAL). These include the analyses of numerous compounds and elements and different parameters such as inorganic chemical composition, organic matter, polycyclic hydrocarbons (PAH), polychlorinated biphenyls (PCB), organochlorine pesticides, some herbicides, heavy metals, particle size, and so on in soil, sediment, compost, manure, and sludge. One programme includes the analysis of inorganic chemical composition, nutritional values, and selected vitamins and amino acids in plant samples. Finally, the paper describes how the results are reported and statistically evaluated.


Adding fingers to an engineered zinc finger nuclease can reduce activity.
Zinc finger nucleases (ZFNs) have been used to direct precise modifications of the genetic information in living cells at high efficiency. An important consideration in the design of ZFNs is the number of zinc fingers that are required for efficient and specific cleavage. We examined dimeric ZFNs composed of [1]+[1], [2]+[2], [3]+[3], [4]+[4], [5]+[5], and [6]+[6] zinc fingers, targeting 6, 12, 18, 24, 30, and 36 bp, respectively. We found that [1]+[1] and [2]+[2] fingers supported neither in vitro cleavage nor single-strand annealing in a cell-based recombination assay. An optimal ZFN activity was observed for [3]+[3] and [4]+[4] fingers. Surprisingly, [5]+[5] and [6]+[6] fingers exhibited significantly reduced activity. While the extra fingers were not found to dramatically increase toxicity, directly inhibit recombination, or perturb the ZFN target site, we demonstrate the ability of subsets of three fingers in six-finger arrays to bind independently to regions of the target site, possibly explaining the decrease in activity. These results have important implications for the design of new ZFNs, as they show that in some cases an excess of fingers may actually negatively affect the performance of engineered multifinger proteins. Maximal ZFN activity will require an optimization of both DNA binding affinity and specificity.


Ion-transfer voltammetry of local anesthetics at an organic solvent/water interface and pharmacological activity vs. ion partition coefficient relationship.
The ion-transfer reaction of local anesthetics at an organic solvent/water interface has been studied using cyclic voltammetry (CV) with a stationary nitrobenzene (NB)/water (W) interface. Procaine and seven other local anesthetics gave reversible or quasi-reversible voltammograms at the NB/W interface in the pH range between 0.9 and 9.6. These drugs are present in aqueous solution in either neutral or ionic form, or both forms. The half-wave potential, as determined by the midpoint potential in CV, vs. pH curves, were determined and analyzed to determine the partition coefficients of both neutral and ionic forms of the drugs between NB and W. The partition coefficients of the ionic forms were derived from their formal potential of transfer at an NB/W interface. The dissociation constants of ionic forms of the drugs in NB were also deduced. A high correlation between the pharmacological activity and the partition coefficient of the ionic form of amide-linked local anesthetics has been shown.


Nanostructuring polymeric materials by templating strategies.
This contribution summarizes efforts in designing, assembling/synthesizing, and structurally and functionally characterizing nanostructured materials using anodized aluminum oxide (AAO) as a thin-film template. Optical waveguide spectroscopy, using a nanoporous template as the guiding structure, is a particularly powerful analytical tool. The layer-by-layer approach for the fabrication of multilayer assemblies is shown to allow the fabrication of nanotube arrays. In addition to using dendrimers as building blocks, semiconducting nanomaterial (e.g., quantum dot) hybrid architectures with very interesting photophysical properties can be assembled. These can be employed, for example, in biosensing applications. Other strategies for using the AAO layers as templates include the growth of polymeric nanorod arrays from different functional monomers, which, after the dissolution of the template, are still able to guide light. This opens up novel concepts for integrated optics platforms with nanostructured materials.


[Should the new criteria of positivity in the exercise test be used?].
Until recent years the negative deflection of the ST-segment of an ECG was almost the only means of interpreting exercise tests in the diagnosis of heart disease. Recent publications have suggested new criteria of positivity. Most of these studies have focused on the absence of a decrease in the amplitude of the R wave in V5 or CM5 derivation, but the results tend to disagree and suffer from lack of reproducibility thus rendering interpretation of this criterion uncertain. Claims have also been made for other criteria with a predictive value at least equal to that of the ST-segment, but very few studies have been devoted to these criteria. The absence of the Q wave in V5 (three studies on a total of 278 patients) has a sensitivity of 82 per cent and a specificity of 76 per cent. Inversion of the U wave in CC5 (one study on a total of 248 patients) has a sensitivity of 21 per cent and a specificity of 99 per cent. Traces of the pressure in abnormally increased recovery (a study on a total of 87 patients) has a sensitivity of 95 per cent and a specificity of 90 per cent. These results cannot replace those obtained with the ST-segment which relate to hundreds of studies on tens of thousands of patients. For this reason it is important to specify better the value of these new criteria and to assess their contribution in association with changes in the ST-segment.(ABSTRACT TRUNCATED AT 250 WORDS)


Real-World Implementation of Digital Pathology: Results From an Intercontinental Survey.
The past 70 years have been characterized by rapid advancements in computer technology, and the health care system has not been immune to this trend. However, anatomical pathology has remained largely an analog discipline. In recent years, this has been changing with the growing adoption of digital pathology, partly driven by the potential of computer-aided diagnosis. As part of an international collaboration, we conducted a comprehensive survey to gain a deeper understanding of the status of digital pathology implementation in Europe and Asia. A total of 127 anatomical pathology laboratories participated in the survey, including 75 from Europe and 52 from Asia, with 72 laboratories having established digital pathology workflow and 55 without digital pathology. Laboratories using digital pathology for diagnostic (n = 29) and nondiagnostic (n = 43) purposes were thoroughly questioned about their implementation strategies and institutional experiences, including details on equipment, storage, integration with laboratory information system, computer-aided diagnosis, and the costs of going digital. The impact of the digital pathology workflow was also evaluated, focusing on turnaround time, specimen traceability, quality control, and overall satisfaction. Laboratories without access to digital pathology were asked to provide insights into their perceptions of the technology, expectations, barriers to adoption, and potential facilitators. Our findings indicate that although digital pathology is still the future for many, it is already the present for some. This decade may be a time when anatomical pathology finally embraces digital revolution on a larger scale.


A randomized, comparative pilot trial of family-based interpersonal psychotherapy for reducing psychosocial symptoms, disordered-eating, and excess weight gain in at-risk preadolescents with loss-of-control-eating.
Preadolescent loss-of-control-eating (LOC-eating) is a risk factor for excess weight gain and binge-eating-disorder. We evaluated feasibility and acceptability of a preventive family-based interpersonal psychotherapy (FB-IPT) program. FB-IPT was compared to family-based health education (FB-HE) to evaluate changes in children's psychosocial functioning, LOC-eating, and body mass. A randomized, controlled pilot trial was conducted with 29 children, 8 to 13 years who had overweight/obesity and LOC-eating. Youth-parent dyads were randomized to 12-week FB-IPT (n = 15) or FB-HE (n = 14) and evaluated at post-treatment, six-months, and one-year. Changes in child psychosocial functioning, LOC-eating, BMI, and adiposity by dual-energy-X-ray-absorptiometry were assessed. Missing follow-up data were multiply imputed. FB-IPT feasibility and acceptability were indicated by good attendance (83%) and perceived benefits to social interactions and eating. Follow-up assessments were completed by 73% FB-IPT and 86% FB-HE at post-treatment, 60% and 64% at six-months, and 47% and 57% at one-year. At post-treatment, children in FB-IPT reported greater decreases in depression (95% CI -7.23, -2.01, Cohen's d = 1.23) and anxiety (95% CI -6.08, -0.70, Cohen's d = .79) and less odds of LOC-eating (95% CI -3.93, -0.03, Cohen's d = .38) than FB-HE. At six-months, children in FB-IPT had greater reductions in disordered-eating attitudes (95% CI -0.72, -0.05, Cohen's d = .66) and at one-year, tended to have greater decreases in depressive symptoms (95% CI -8.82, 0.44, Cohen's d = .69) than FB-HE. There was no difference in BMI gain between the groups. Family-based approaches that address interpersonal and emotional underpinnings of LOC-eating in preadolescents with overweight/obesity show preliminary promise, particularly for reducing internalizing symptoms. Whether observed psychological benefits translate into sustained prevention of disordered-eating or excess weight gain requires further study.


Prevalence of Coxsackie B virus antibodies in patients with juvenile dermatomyositis.
A number of viruses have been implicated as being the cause of various forms of myositis, including acute transient myositis, chronic polymyositis, and dermatomyositis. However, the cause of juvenile dermatomyositis (JDM) has remained elusive. Our study of serum samples taken within 4 months of the onset of disease in 12 children with JDM showed that 83% had detectable titers of complement-fixing (CF) antibody to 1 or more coxsackie B viral antigens. Detectable titers were found in only 25% of age-, sex-, and date-matched control sera taken from 24 patients with juvenile rheumatoid arthritis (JRA), and in 25% of serum samples taken from 2,192 "normal" children who had been hospitalized because of viral syndromes. Titers of CF antibody to coxsackie B1, B2, and B4 were positive in 58%, 50%, and 58%, respectively, of the JDM patients. In matched JRA controls, the respective values were 8%, 13%, and 8%. There were no significant antiviral titers and no significant differences in the results of tests for 13 other viral CF antigens, hepatitis B surface antigen, and Mycoplasma pneumoniae CF antigen in the JDM patient sera compared with the JRA patient sera. When titers of neutralizing antibody were determined, 58%, 58%, and 67% of the JDM patients were positive for coxsackie B2, B4, and B5, respectively, whereas 16%, 26%, and 21%, respectively, of the JRA controls were positive for the 3 antigens. These data suggest that the host response to coxsackie B virus might be related to the pathophysiology of JDM.


Fetal alcohol syndrome: the 'American Paradox'.
Nearly all cases of fetal alcohol syndrome (FAS) identified in prospective epidemiological studies have been conducted in the United States of America. The very high incidence rate for FAS in the USA and the relatively low rate in other countries does not correspond to measures of alcohol consumption. By analogy with the 'French paradox', we have termed the high rate of FAS in the USA coupled with its relatively low level of alcohol consumption, the 'American paradox'.


Mothers' responses to care given by male nursing students during and after birth.
To describe the rationale maternity patients use in determining whether to accept care by a male student nurse. Information about the activities that women are comfortable having male nursing students perform is inconsistent and the reasons for women's comfort or discomfort are unclear. Furthermore, little is known about what factors patients consider when assigned a male nursing student. Yet, knowledge of such factors can enhance understanding and guide the selection of students in maternity units. Focused ethnography using a purposive convenience sample of 32 women, aged 20 to 40 years, who spoke English, and who had given birth to normal newborns in one small community hospital in the mid-Atlantic region of the United States. Patients were excluded if they or their infants were in an unstable physical or mental condition. The study was conducted in 1995. The women were interviewed using a semi-structured format. Data from participants pertained to personal and contextual factors. Personal factors were perception of postpartum self and personal feelings. Contextual factors were student characteristics, establishment of relationships, nursing care activities, and partner viewpoint. Women during and after giving birth have definite thoughts about male student nurses caring for them. Nurse educators should consider these when assigning men. Educators should encourage professionalism and competence in their students.


Development and validation of a food frequency questionnaire for Japanese athletes (FFQJA).
Food frequency questionnaires are considered an effective method for assessing habitual dietary intake, but they must be developed or validated with the target population. Portion size, supplement use and food choice are thought to be especially important methodological considerations for assessing athletes' dietary intake. This study aimed to develop and validate a food frequency questionnaire for Japanese athletes using data from this population. We used dietary records from 440 Japanese athletes involved in our previous projects. Food items were analyzed using cumulative percentage contributions and multiple regression analysis, to give a selection of 62 basic food items and four supplemental items. The validity of the questionnaire was evaluated among another 77 Japanese athletes by comparing nutrient intakes assessed using the questionnaire with dietary records. Reproducibility was evaluated by comparing a second questionnaire completed 2-3 weeks later by 36 of the athletes in the validation study. Validity was assessed using crude Spearman's correlation coefficients (CCs), energy-adjusted CCs, intraclass CCs (ICCs), and Kappa index values. Reproducibility was assessed by CCs, energy-adjusted CCs, and ICCs. In the validation analysis, the median crude CC for all of the nutrients was 0.407, ranging from 0.222 for dietary fiber to 0.550 for carbohydrate. The median energy-adjusted CC was 0.478, and the median ICC was 0.369. When we divided the athletes into quartiles, 65% (vitamin B1) to 86% (iron) of athletes were classified into the same or adjacent categories using the questionnaire and dietary records, with a median Kappa statistic of 0.32. In the reproducibility analysis, the median crude CC between the two completed questionnaires was 0.654, ranging from 0.582 (carbohydrate) to 0.743 (vitamin B2). The median energy-adjusted CC was 0.643, and the median ICC was 0.647. The new 62-item food frequency questionnaire is both reliable and valid and may be useful for assessing food intake in Japanese athletes.


Relating cell and tissue mechanics: implications and applications.
The Differential Adhesion Hypothesis (DAH) posits that differences in adhesion provide the driving force for morphogenetic processes. A manifestation of differential adhesion is tissue liquidity and a measure for it is tissue surface tension. In terms of this property, DAH correctly predicts global developmental tissue patterns. However, it provides little information on how these patterns arise from the movement and shape changes of cells. We provide strong qualitative and quantitative support for tissue liquidity both in true developmental context and in vitro assays. We follow the movement and characteristic shape changes of individual cells in the course of specific tissue rearrangements leading to liquid-like configurations. Finally, we relate the measurable tissue-liquid properties to molecular entities, whose direct determination under realistic three-dimensional culture conditions is not possible. Our findings confirm the usefulness of tissue liquidity and provide the scientific underpinning for a novel tissue engineering technology.


Measuring the year consumption of alcohol: the development of a questionnaire.
Most general alcohol consumption population surveys are meant to represent the year consumption, although they actually ask only for habitual drinking and/or frequencies and quantities of binge drinking in the past months. These surveys typically cover about half of the alcohol sales figures. In order to enhance sales coverage and to reduce seasonal bias, we developed a year consumption questionnaire on the basis of daily and weekly drinking adding 13 categories of less-than-weekly drinking occasions over the year. As a first test we offered the new questionnaire together with a traditional typical week questionnaire, in different modes to various groups adding up to a purposive high diversity sample of 101 drinking persons (56 women, 44 men, 16-69 years old, mean age 34 years). After correction for overlaps between weekly habits and less-than-weekly occasions, the new questionnaire produces considerably higher reports of annual consumption, compared with the typical-week-based estimates of year consumption. Limitations of the study are discussed.


Prevalence of erectile dysfunction and possible risk factors among men of South-Western Nigeria: a population based study.
Erectile dysfunction (ED) is currently one of the most common sexual dysfunctions worldwide but it is usually underestimated because it is not a life threatening condition. The associated stigma makes men who have it to suffer in silence. This study was conducted to determine the prevalence of erectile dysfunction and the possible associated risk factors among Nigerian men. The study was a descriptive cross-sectional population based survey among men aged 30-80 years in Ogbomoso, South-west, Nigeria. A multistage random sampling method was used. The instrument used was the International Index of Erectile Function Questionnaire-5 (IIEF-5). Unadjusted odds ratios of possible risk factors were calculated by univariate analyses. Binary logistic regression analysis was used to eliminate the effect of possible confounders on the risk factors to get the adjusted odds ratios. The general prevalence of ED in this study was 58.9%. Sixty-seven (47.2%), 16 (11.3%) and 59(41.5%) respondents had mild, moderate and severe ED respectively. Age, hypertension, use of anti-hypertensive drugs, diabetes mellitus and heart disease all had significant unadjusted associations with ED, but their adjusted associations were not statistically significant. Diabetes mellitus maintained a positive statistically significant relationship with ED after adjustment for potential confounders [OR= 8.31(95% CI 1.02 - 67.65), P= 0.048]. The prevalence of ED is high among south-western Nigeria male adults. Physicians, especially primary care ones, need to pay more attention to the sexual history of their patients in order to diagnose and manage ED more frequently.


Innervation of bat heart: cholinergic and adrenergic nerves innervate all chambers.
Adult Miniopterus schreibersii were anesthetized with chloroform, and in vitro preparations of cardiac chambers were prepared. Stimulation of intramural nerves in right ventricles paced at 6 Hz caused an inhibition (56.3 +/- 3.5% decrease on basal force) mediated by cholinergic nerves and an excitation (91.5 +/- 9.9% increase on basal force) mediated by adrenergic nerves. Mean pD2s (-log effective concentration, 50%) for ventricular beta-adrenoceptors and muscarinic cholinoceptors were 6.99 +/- 0.03 and 6.42 +/- 0.07, respectively. The inhibition of ventricular contractility, by nerve stimulation or exogenous acetylcholine, occurred even after blockade of beta-adrenoceptors. The results were comparable to those obtained on atria. In some experiments, the heart was perfused in situ and paced via electrodes on the ventricle: stimulation of the right vagus nerve decreased right ventricular contractility by up to 90%. The results show that, at least in this hibernating mammal, there is an adrenergic innervation of the ventricle. The presence of a cholinergic vagal innervation capable of inhibiting the basal force of ventricular contraction has not been shown in any other mammal.


Attenuated cardiac function degradation in ex vivo pig hearts.
Isolated hearts offer the opportunity to evaluate heart function, treatments, and diagnostic tools without in vivo factor interference. However, the early loss of cardiac function and edema occur over time and do limit the duration of the experiment. This research focuses on delaying these limitations using optimal blood control. This study examines whether blood conditioning by means of the combination of blood predilution and hemodialysis can significantly reduce cardiac function degradation. Slaughterhouse porcine hearts were revived in the PhysioHeart™ platform to restore physiological cardiac performance. Twelve hearts were divided into a control group and a dialysis group; in the latter group, hemodialysis was attached to the blood reservoir. Cardiac hemodynamics and blood parameters were recorded and evaluated. Blood conditioning significantly reduced the loss of cardiac pump function (control group vs dialysis group, -14.9 ± 6.3%/h vs -9.7 ± 2.7%/h) and loss of cardiac output (control group vs dialysis group, -11.8 ± 3.4%/h vs -5.9 ± 2.0%/h). Hemodialysis resulted in physiological and stable blood parameters, whereas in the control group ions reached pathological values, while interstitial edema still occurred. The combination of blood predilution and hemodialysis significantly attenuated ex vivo cardiac function degradation and delayed the loss of cardiac hemodynamics. We hypothesized that besides electrolyte and metabolic control, the hemodialysis-accompanied increase in hematocrit resulted in improved oxygen transport. This could have temporarily compensated the deleterious effect of an increased oxygen-diffusion distance due to edema in the dialysis group and resulted in less progression of cell decay. Clinically validated measures delaying edema might improve the effectiveness of the PhysioHeart™ platform.


Regular exercise during pregnancy to prevent gestational diabetes: a randomized controlled trial.
To assess whether exercise during pregnancy can prevent gestational diabetes and improve insulin resistance. A total of 855 women in gestational week 18-22 were randomly assigned to receiving a 12-week standard exercise program (intervention group) or standard antenatal care (control group). The exercise program followed standard recommendations and included moderate-intensity to high-intensity activity 3 or more days per week. Primary outcomes were gestational diabetes and insulin resistance estimated by the homeostasis model assessment method. For the power calculation, we assumed a gestational diabetes prevalence of 9% in the control group and a prevalence of 4% in the exercise group (risk difference of 5%). Under these assumptions, a two-sample comparison with a 5% level of significance and power of 0.80 gave a study population of 381 patients in each group. At 32-36 weeks of gestation there were no differences between groups in prevalence of gestational diabetes: 25 of 375 (7%) in the intervention group compared with 18 of 327 (6%) in the control group (P=.52). There were no differences in insulin resistance between groups when adjusting for baseline values. Only 55% of women in the intervention group managed to follow the recommended exercise protocol. No serious adverse events related to physical exercise were seen, and the outcomes of pregnancy were similar in the two groups. There was no evidence that offering women a 12-week standard exercise program during the second half of pregnancy prevents gestational diabetes or improves insulin resistance in healthy pregnant women with normal body mass indexes. : ClinicalTrials.gov, www.clinicaltrials.gov, NCT00476567.


Management of laboratory data and information exchange in the electronic health record.
In the era of the electronic health record, the success of laboratories and pathologists will depend on effective presentation and management of laboratory information, including test orders and results, and effective exchange of data between the laboratory information system and the electronic health record. In this third paper of a series that explores empowerment of pathology in the era of the electronic health record, we review key elements of managing laboratory information within the electronic health record and examine functional issues pertinent to pathologists and laboratories in the exchange of laboratory information between electronic health records and both anatomic and clinical pathology laboratory information systems. Issues with electronic order-entry and results-reporting interfaces are described, and considerations for setting up these interfaces are detailed in tables. The role of the laboratory medical director as mandated by the Clinical Laboratory Improvement Amendments of 1988 and the impacts of discordance between laboratory results and their display in the electronic health record are also discussed.


Knowledge and work performance of multi-purpose workers under national leprosy eradication programme in Satara district, Maharashtra.
After integration of leprosy services into general health care services, peripheral health care workers played important role in leprosy elimination. The objectives of present study are to assess the knowledge and work performance of multi-purpose workers and it's correlation towards eradication of leprosy under national leprosy eradication programme in Satara district. The cross sectional study was conducted over a period of 6 months includes 71 Primary health centres (PHCs) and 6 Urban leprosy centres (ULCs) providing leprosy services to whole Satara district, Maharashtra. Random sampling technique was used to select study subjects (Multi-purpose workers, MPWs) and data was collected by using pre-tested semi structured proforma by personal interview method. Percentage distribution and statistical association between knowledge and work performance was analysed. More than 88.31% MPWs had good knowledge about leprosy and National leprosy eradication programme (NLEP), similarly more than 88.42% showed good work performance under NLEP in Satara district. Significant statistical association was existed between age and work experience of MPWs with their work performance under NLEP (chi2=11.2, p=0.023* and chi2=10.1, p=0.038*). Significant correlation was also observed between knowledge of MPWs about leprosy and NLEP with their work performance under NLEP (r=0.66, p=0.001*). Satara district achieved leprosy elimination which was mainly due to very good knowledge and quality work performance by multi-purpose workers.


Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema.
Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male smokers or ex-smokers and it has a mortality rate of 55% and a median survival of 5 years. Pulmonary hypertension (PH) is a frequently fatal complication of CPFE. Despite this dismal prognosis, no curative therapies exist for patients with CPFE outside of lung transplantation and no therapies are recommended to treat PH. This highlights the need to develop novel treatment approaches for CPFE. Studies from our group have demonstrated that both adenosine and its receptor ADORA2B are elevated in chronic lung diseases. Activation of ADORA2B leads to elevated levels of hyaluronan synthases (HAS) and increased hyaluronan, a glycosaminoglycan that contributes to chronic lung injury. We hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE lung tissue, we characterized expression levels of ADORA2B and HAS. Next, using a unique mouse model of experimental lung injury that replicates features of CPFE, namely airspace enlargement, PH and fibrotic deposition, we investigated whether 4MU, a HAS inhibitor, was able to inhibit features of CPFE. Increased protein levels of ADORA2B and HAS3 were detected in CPFE and in our experimental model of CPFE. Treatment with 4MU was able to attenuate PH and fibrosis but not airspace enlargement. This was accompanied by a reduction of HAS3-positive macrophages. We have generated pre-clinical data demonstrating the capacity of 4MU, an FDA-approved drug, to attenuate features of CPFE in an experimental model of chronic lung injury.This article has an associated First Person interview with the first author of the paper.


Food pricing strategies, population diets, and non-communicable disease: a systematic review of simulation studies.
Food pricing strategies have been proposed to encourage healthy eating habits, which may in turn help stem global increases in non-communicable diseases. This systematic review of simulation studies investigates the estimated association between food pricing strategies and changes in food purchases or intakes (consumption) (objective 1); Health and disease outcomes (objective 2), and whether there are any differences in these outcomes by socio-economic group (objective 3). Electronic databases, Internet search engines, and bibliographies of included studies were searched for articles published in English between 1 January 1990 and 24 October 2011 for countries in the Organisation for Economic Co-operation and Development. Where ≥ 3 studies examined the same pricing strategy and consumption (purchases or intake) or health outcome, results were pooled, and a mean own-price elasticity (own-PE) estimated (the own-PE represents the change in demand with a 1% change in price of that good). Objective 1: pooled estimates were possible for the following: (1) taxes on carbonated soft drinks: own-PE (n = 4 studies), -0.93 (range, -0.06, -2.43), and a modelled -0.02% (-0.01%, -0.04%) reduction in energy (calorie) intake for each 1% price increase (n = 3 studies); (2) taxes on saturated fat: -0.02% (-0.01%, -0.04%) reduction in energy intake from saturated fat per 1% price increase (n = 5 studies); and (3) subsidies on fruits and vegetables: own-PE (n = 3 studies), -0.35 (-0.21, -0.77). Objectives 2 and 3: variability of food pricing strategies and outcomes prevented pooled analyses, although higher quality studies suggested unintended compensatory purchasing that could result in overall effects being counter to health. Eleven of 14 studies evaluating lower socio-economic groups estimated that food pricing strategies would be associated with pro-health outcomes. Food pricing strategies also have the potential to reduce disparities. Based on modelling studies, taxes on carbonated drinks and saturated fat and subsidies on fruits and vegetables would be associated with beneficial dietary change, with the potential for improved health. Additional research into possible compensatory purchasing and population health outcomes is needed.