Conservation and divergence of microRNAs and their functions in Euphorbiaceous plants.
MicroRNAs (miRNAs) are approximately 21 nt non-coding RNAs which regulate post-transcriptional gene expression. miRNAs are key regulators of nearly all essential biological processes. Aiming at understanding miRNA's functions in Euphorbiaceae, a large flowering plant family, we performed a genome-scale systematic study of miRNAs in Euphorbiaceae, by combining computational prediction and experimental analysis to overcome the difficulty of lack of genomes for most Euphorbiaceous species. Specifically, we predicted 85 conserved miRNAs in 23 families in the Castor bean (Ricinus communis), and experimentally verified and characterized 58 (68.2%) of the 85 miRNAs in at least one of four Euphorbiaceous species, the Castor bean, the Cassava (Manihot esculenta), the Rubber tree (Hevea brasiliensis) and the Jatropha (Jatropha curcas) during normal seedling development. To elucidate their function in stress response, we verified and profiled 48 (56.5%) of the 85 miRNAs under cold and drought stresses as well as during the processes of stress recovery. The results revealed some species- and condition-specific miRNA expression patterns. Finally, we predicted 258 miRNA:target partners, and identified the cleavage sites of six out of ten miRNA targets by a modified 5' RACE. This study produced the first collection of miRNAs and their targets in Euphorbiaceae. Our results revealed wide conservation of many miRNAs and diverse functions in Euphorbiaceous plants during seedling growth and in response to abiotic stresses.


Coordinated expression of UT-A and UT-B urea transporters in rat testis.
The blood-seminiferous tubule barrier is responsible for maintaining the unique microenvironment conducive to spermatogenesis. A key feature of the blood-testis barrier is selective permeability to solutes and water transport, conferred by the Sertoli cells of the seminiferous tubules (SMTs). Movement of fluid into the lumen of the seminiferous tubule is crucial to spermatogenesis. By Northern analysis, we have shown that 4.0-, 3.3-, 2.8-, and ~1.7-kb UT-A mRNA transcripts and a 3.8-kb UT-B mRNA transcript are detected within rat testis. Western analysis revealed the expression of both characterized and novel UT-A and UT-B proteins within the testis. Immunolocalization studies determined that UT-A and UT-B protein expression are coordinated with the developmental stage of the SMT. UT-A proteins were detected in Sertoli cell nuclei at all stages of tubule development and in residual bodies of stage VIII tubules. UT-B protein was expressed on Sertoli cell membranes of stage II-III tubules. Using in vitro perfusion, we determined that a phloretin-inhibitable urea pathway exists across the SMTs of rat testis and conclude that UT-B is likely to participate in this pathway.


A brief description of the Bethesda System for reporting thyroid fine needle aspirates.
Fine needle aspiration has become the most prominent, and the easiest way, to morphologically evaluate lesions of the thyroid. When done correctly, the sensitivity and specificity of thyroid aspirates for detecting malignancy is very high. Unfortunately, clinicians are sometimes confused by the terminology used in thyroid cytopathology reports. One way to mitigate confusion is for all pathologists to use the same diagnostic criteria and terminology. Standardized terminology for thyroid cytopathology reports has recently been proposed. The following article introduces the concept of the Bethesda System for reporting thyroid aspirates. Sample diagnoses are given to illustrate how thyroid cytopathology reports may appear using the Bethesda System.


Kinesin-3 mediated axonal delivery of presynaptic neurexin stabilizes dendritic spines and postsynaptic components.
The functional properties of neural circuits are defined by the patterns of synaptic connections between their partnering neurons, but the mechanisms that stabilize circuit connectivity are poorly understood. We systemically examined this question at synapses onto newly characterized dendritic spines of C. elegans GABAergic motor neurons. We show that the presynaptic adhesion protein neurexin/NRX-1 is required for stabilization of postsynaptic structure. We find that early postsynaptic developmental events proceed without a strict requirement for synaptic activity and are not disrupted by deletion of neurexin/nrx-1. However, in the absence of presynaptic NRX-1, dendritic spines and receptor clusters become destabilized and collapse prior to adulthood. We demonstrate that NRX-1 delivery to presynaptic terminals is dependent on kinesin-3/UNC-104 and show that ongoing UNC-104 function is required for postsynaptic maintenance in mature animals. By defining the dynamics and temporal order of synapse formation and maintenance events in vivo, we describe a mechanism for stabilizing mature circuit connectivity through neurexin-based adhesion.


A comprehensive clinical and biochemical functional study of a novel RPE65 hypomorphic mutation.
Later onset and progression of retinal dystrophy occur with some RPE65 missense mutations. The functional consequences of the novel P25L RPE65 mutation was correlated with its early-childhood phenotype and compared with other pathogenic missense mutations. In addition to typical clinical tests, fundus autofluorescence (FAF), optical coherence tomography (OCT), and two-color threshold perimetry (2CTP) were measured. RPE65 mutations were screened by SSCP and direct sequencing. Isomerase activity of mutant RPE65 was assayed in 293F cells and quantified by HPLC analysis of retinoids. A very mild phenotype was detected in a now 7-year-old boy homozygous for the P25L mutation in RPE65. Although abnormal dark adaptation was noticed early, best corrected visual acuity was 20/20 at age 5 years and 20/30 at age 7 years. Nystagmus was absent. Cone electroretinogram (ERG) was measurable, rod ERG severely reduced, and FAF very low. 2CTP detected mainly cone-mediated responses in scotopic conditions, and light-adapted cone responses were approximately 1.5 log units below normal. High-resolution spectral domain OCT revealed morphologic changes. Isomerase activity in 293F cells transfected with RPE65/P25L was reduced to 7.7% of wild-type RPE65-transfected cells, whereas RPE65/L22P-transfected cells had 13.5%. The mild clinical phenotype observed is consistent with the residual activity of a severely hypomorphic mutant RPE65. Reduction to <10% of wild-type RPE65 activity by homozygous P25L correlates with almost complete rod function loss and cone amplitude reduction. Functional survival of cones is possible in patients with residual RPE65 isomerase activity. This patient should profit most from gene therapy.


Hypothesis: is lactose a dietary risk factor for ischaemic heart disease?
The prevalence of primary adult lactose malabsorption (LM) in 23 ethnic groups was matched with national data on milk consumption and mortality rates from ischaemic heart disease (HD). In 6 other ethnic groups prevalence of LM was related to unquantified assessments of milk consumption and frequency of IHD. On the available data, populations with a prevalence of LM over 30%, and whose consumption of milk is low or is largely in low lactose form, have a lower risk of IHD mortality than populations with a prevalence of LM under 30% and a high milk consumption. There is evidence against attributing these findings to genetic linkage between susceptibility to IHD mortality and persistent lactose absorption, or to differences in socio-economic development, cigarette consumption or intake of animal fats. The findings are compatible with an hypothesis that, if the correlation reported previously between milk consumption and IHD mortality is causal, lactose could be the responsible dietary factor.


Progress and promise in understanding the genetic basis of common diseases.
Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations. Although most efforts have focused on identifying and interpreting genetic variants that are irrefutably associated with disease, it is increasingly clear that--even at large sample sizes--these represent only the tip of the iceberg of genetic signal, motivating polygenic analyses that consider the effects of genetic variants throughout the genome, including modest effects that are not individually statistically significant. As data from an increasingly large number of diseases and traits are analysed, pleiotropic effects (defined as genetic loci affecting multiple phenotypes) can help integrate our biological understanding. Looking forward, the next generation of population-scale data resources, linking genomic information with health outcomes, will lead to another step-change in our ability to understand, and treat, common diseases.


Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages.
Children with congenital adrenal hyperplasia (CAH) provide us an opportunity to study the clinical effects of androgen excess in humans. We studied the sequence of pubertal development in girls with congenital adrenal hyperplasia initiated on treatment at different ages, to assess the effects of androgen exposure on the Hypothalamic-Pituitary-Ovarian (HPO) axis. Girls more than 18 years of age, with CAH, on follow-up at this hospital were the subjects for this study. Details of history, physical findings, laboratory evaluation, and medication were noted from their case records and verified from the patients and their / parents, in addition to assessment of their present health status. We studied 24 patients of classical CAH (SW-2, SV-22, average age - 24.5 ± 6.6 years). All had varying degrees of genital ambiguity (Prader stage 3 (n = 13), Prader stage 2 (n = 10), Prader stage 1 (n = 1). Among them were13 girls, who were started on steroids after eight years of age. Girls who received treatment from infancy and early childhood had normal pubertal development (mean age at menarche 11.4 ± 1.7 years). Hirsutism was not a problem among them. Untreated children had progressive clitoral enlargement throughout childhood, developed pubic hair at around three to six years of age, and facial hair between nine and eleven years. Plasma testosterone ranged from 3 to 6 ng / ml prior to treatment. Six of the 13 untreated CAH girls had subtle breast development starting at ages 11 - 16 years and three had spontaneous infrequent vaginal bleeding starting at ages 11 - 17. Steroid supplementation initiated pubertal changes in older girls in two-to-six months' time. There was a delay in HPO axis maturation (as evidenced by delayed pubertal development) in the absence of treatment in girls with CAH. This could be corrected with steroid supplementation.


What Is the Key for Older People to Show Interest in Playing Digital Learning Games? Initial Qualitative Findings from the LEAGE Project on a Multicultural European Sample.
Learning digital games can influence both older adults' health condition and their capacity to carry on activities in their actual environment. The goal of the current study was to explore and define the user requirements for developing digital learning games for older Europeans, focusing on types of learning games, motivational and social aspects, and preferences on game controllers. For this initial stage, a qualitative focus group study was performed in three participating countries (Spain, The Netherlands, and Greece) where both games existing in the market and others developed in other European Commission projects like HERMES were presented to them, both on video presentations and also with the possibility to actually test some of them. Challenge, socialization, fun, providing learning opportunities, and escape from daily routine were extracted as the main keys why older people would be interested in playing digital games. Users described themselves as active and participating in many leisure activities, and this level of activity appeared to be related with the contents proposed for digital games, such as physical activity, culture, arts, and other human sciences (history, geography, traveling, foreign languages, music), and daily life skills (cooking, computer use, first aid). The knowledge gathered from the focus groups will be used as input for the design of a learning game that will be largely compatible with the needs and abilities of a wide range of older Europeans.


The extracardiac lateral tunnel Fontan, constructed with bovine pericardium: comparison with the extracardiac conduit Fontan.
The Fontan procedure performed with an extracardiac conduit (ECC) has gained wide acceptance as an alternative to the intracardiac lateral tunnel because it avoids placement of extensive atrial suture lines and use of prosthetic material in the systemic circulation. The extracardiac lateral tunnel (ELT) is a modification of the Fontan procedure which uses pericardium and the external surface of the atrium to create a conduit from the inferior vena cava to the pulmonary artery. This surgery theoretically avoids disruption of intra-atrial conduction by eschewing endocardial suturing while maintaining conduit growth potential and the ability to easily create a fenestration to the systemic circulation. We retrospectively analyzed the short-term outcome of 96 consecutive patients who underwent an extracardiac Fontan procedure. An ELT using bovine pericardium was performed in 59 patients, whereas 37 patients received a traditional ECC. The 2 groups were similar with respect to age (P = .96), body surface area (P = .54), number of preoperative Fontan risk factors (P = .43), and ventricular morphology (P = .72). There were no significant differences in the following outcome variables between the ELT and the traditional ECC: length of hospitalization (P = .73), duration of chest tube drainage (P = .48), abnormal rhythm at time of discharge (P = .27), and mortality (P = .63). The ELT Fontan can be performed with a low risk of mortality and complications. The results are equivalent to the traditional ECC procedure. The theoretical advantages of the procedure suggest that it should be considered a useful modification of Fontan surgery.


Resistance development in Escherichia coli to delafloxacin at pHs 6.0 and 7.3 compared to ciprofloxacin.
Understanding the resistance mechanisms of antibiotics in the micro-environment of the infection is important to assess their clinical applicability and potentially prevent resistance development. We compared the laboratory resistance evolution of Escherichia coli to delafloxacin (DLX) compared to ciprofloxacin (CIP), the co-resistance evolution, and underlying resistance mechanisms at different pHs. Three clones from each of the eight clinical E. coli isolates were subjected to subinhibitory concentrations of DLX or CIP in parallel at either pH 7.3 or 6.0. Minimum inhibitory concentrations (MICs) were regularly tested (at respective pHs), and the antibiotic concentration was adjusted accordingly. After 30 passages, MICs were determined in the presence of the efflux pump inhibitor phenylalanine-arginine-β-naphthylamide. Whole genome sequencing of the parental isolates and their resistant derivatives (n = 54) was performed. Complementation assays were carried out for selected mutations. Quantitative PCR and efflux experiments were carried out for selected derivatives. For DLX-challenged strains, resistance to DLX evolved much slower in acidic than in neutral pH, whereas for CIP-challenged strains, the opposite was the case. Mutations in the quinolone resistance-determining region were mainly seen in CIP-challenged E. coli, whereas a multifactorial mechanism including mutations in efflux-related genes played a role in DLX resistance evolution (predominantly at pH 6.0). This work provides novel insights into the resistance mechanisms of E. coli to delafloxacin and highlights the importance of understanding micro-environmental conditions at the infection site that might affect the true clinical efficacy of antibiotics and challenges our current antibiotic susceptibility-testing paradigm.


Severe Covid-19 in pregnant and postpartum women admitted to an intensive care unit: A retrospective cohort study.
SARS-CoV-2 infection is associated with worse maternal and fetal outcomes. This study aims to describe the characteristics of pregnant and postpartum women with severe Covid-19 admitted to ICU. It's a retrospective cohort study evaluating pregnant and postpartum women referenced to a specialized ICU between May 2020 and June 2022. Covid-19 was confirmed with RT-PCR or rapid antigen test on a nasopharyngeal swab. Variables were described by median and IQR when numerical, and by frequency and percentage when categorical. OR with 95% CI were calculated for the evaluation of factors related to death. P-values were calculated using Pearson's ꭓ2-test, Fisher's exact test, Wilcoxon rank sum test, and Kruskall-Wallis test, and statistical significance was established as < 0·05. Missing data were excluded. All statistical analysis were performed using R software version 4.2.2. Of the 101 admissions, 85 (84·2%) were of pregnant women. Obesity (23·0%) and systemic arterial hypertension (13·0%) were the most prevalent medical conditions. Sixty-six (65·3%) were admitted using some type of oxygen support. Forty-seven (46·5%) evolved to mechanical ventilation. There were 61 events considered obstetric complications, with 8 stillbirths/fetal losses. The overall lethality was 15·8%. Pregnancy interruption, need for non-invasive mechanical ventilation, level of oxygen support at admission, prone maneuver, hemodialysis, and healthcare-related infections were factors associated with death. Evaluating the WHO 7-category ordinary scale, there was a trend of increase in the risk of death with higher punctuation, with a statistically significant difference of women with 5 (OR = 7·27; 95% IC = 1·17-194; p = 0·031) or 6 points (OR = 12·0; 95% IC = 1·15-391; p = 0·038) when compared to the ones with 3 points, i.e., of women admitted with a high-flow non-rebreathing mask or invasive mechanical ventilation, compared with the ones admitted at room air, respectively. The main limitations of this study are the relatively small number of participants, and the use of data derived of medical records-which are susceptible to misclassification and variable amounts of missing data. Pregnant and postpartum women with severe Covid-19 have high lethality and a high incidence of clinical and obstetric complications. These findings support that this population should be prioritized in public health strategies that address Covid-19.


Neuronal organization in the dorsal horn of the spinal cord.
Two major output systems from the dorsal horn, the spinocervical tract (SCT) and the post-synaptic dorsal column (PSDC) pathway, have been characterized by electrophysiological methods and the injection of horseradish peroxidase into single neurones. Neurones of both systems have somata in laminae III, IV and V but they differ in their physiology and anatomy. SCT neurones have few inputs and their receptive fields are simple. PSDC neurones show several patterns of excitatory convergent input and have more complex receptive fields. Structurally, SCT cells are fairly homogeneous with dendrites mainly in laminae III and IV; input is from two major types of boutons - 2/3 contain round clear vesicles and 1/3 contain flattened clear vesicles and these latter are located more proximally on the dendritic tree. PSDC cells have a more varied anatomy: the dorsal cells send their dendrites through lamina III into II where they receive a variety of contacts including the central element of the glomerular complexes; deeper neurones have dendrites in laminae V - VII and these receive large synaptic boutons, often on long-necked spines. Thus even though SCT and PSDC neurones occupy the same parts of the dorsal horn they constitute separate populations of cells differing in axonal projection, receptive field organization, light microscopical appearance and the ultrastructure of the synaptic contacts they receive.


Impact of cell source on human cornea reconstructed by tissue engineering.
To investigate the effect of the tissue origin of stromal fibroblasts and epithelial cells on reconstructed corneas in vitro. Four types of constructs were produced by the self-assembly approach using the following combinations of human cells: corneal fibroblasts/corneal epithelial cells, corneal fibroblasts/skin epithelial cells, skin fibroblasts/corneal epithelial cells, skin fibroblasts/skin epithelial cells. Fibroblasts were cultured with ascorbic acid to produce stromal sheets on which epithelial cells were cultured. After 2 weeks at the air-liquid interface, the reconstructed tissues were photographed, absorption spectra were measured, and tissues were fixed for histologic analysis. Cytokine expression in corneal- or skin-fibroblast-conditioned media was determined with the use of protein array membranes. The effect of culturing reconstructed tissues with conditioned media, or media supplemented with a cytokine secreted mainly by corneal fibroblasts, was determined. The tissue source from which epithelial and mesenchymal cells were isolated had a great impact on the macroscopic and histologic features (epithelium thickness and differentiation) and the functional properties (transparency) of the reconstructed tissues. The reconstructed cornea had ultraviolet-absorption characteristics resembling those of native human cornea. The regulation of epithelial differentiation and thickness was mesenchyme-dependent and mediated by diffusible factors. IL-6, which is secreted in greater amounts by corneal fibroblasts than skin fibroblasts, decreased the expression of the differentiation marker DLK in the reconstructed epidermis. The tissue origin of fibroblasts and epithelial cells plays a significant role in the properties of the reconstructed tissues. These human models are promising tools for gaining a thorough understanding of epithelial-stromal interactions and regulation of epithelia homeostasis.


Ranibizumab combined with low-dose sorafenib for exudative age-related macular degeneration.
Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered.


Relationship of child IQ to parental IQ and education in children with fetal antiepileptic drug exposure.
Clinical trial designs need to control for genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude randomization. However, the contributions of maternal and paternal IQ and education to pediatric cognitive outcomes are uncertain in disease populations. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs. Here, we examined the relationship of IQ and education in both parents to child IQ at age 3 years. IQ and education for both parents were statistically correlated to child IQ. However, paternal IQ and education were not significant after accounting for maternal IQ effects. Because maternal IQ and education are independently related to child cognitive outcome, both should be assessed in studies investigating the effects of fetal drug exposures or other environmental factors that could affect the child's cognitive outcome.


Comparison of the TEMPO Binocular Perimeter and Humphrey Field Analyzer.
This study compared between TEMPO, a new binocular perimeter, with the Humphrey Field Analyzer (HFA). Patients were tested with both TEMPO 24 - 2 AIZE-Rapid and HFA 24 - 2 SITA-Fast in a randomized sequence on the same day. Using a mixed-effects model, visual field (VF) parameters and reliability indices were compared. Retinal nerve fiber layer (RNFL) thickness was measured using Cirrus OCT, and coefficient of determinations for visual field and OCT parameters were calculated and compared using Akaike information criteria. 740 eyes (including 68 healthy, 262 glaucoma suspects, and 410 glaucoma) of 370 participants were evaluated. No significant differences were seen in mean deviation and visual field index between the two perimeters (P > 0.05). A stronger association between VF mean deviation and circumpapillary RNFL was found for TEMPO (adjusted R2 = 0.28; AIC = 5210.9) compared to HFA (adjusted R2 = 0.26; AIC = 5232.0). TEMPO had better reliability indices (fixation loss, false positive, and false negative) compared to HFA (all P < 0.05). Measurement time was faster for TEMPO compared to HFA (261sec vs. 429sec, P < 0.001). Further investigations are needed to assess the long-term monitoring potential of this binocular VF test.


D609-mediated inhibition of ATP synthesis in neural progenitor cells.
Tricyclodecan-9-yl-xanthogenate (D609) is an antioxidative molecule with antiproliferative and neuroprotective properties in a variety of cells. Previously, we have shown that D609 decreased the proliferation of neural progenitor cells. In this study, we examined the antioxidative property of D609 on neural progenitor cells isolated from the subventricular zone of the rat brain. Cellular oxidation was assessed by measuring the ATP content of the cells. Our results show that D609 decreased the ATP content of the neural progenitor cells by ∼40%, suggesting the possible inhibition of cellular metabolic activity. Cytochrome c oxidase (Cox), also known as complex IV of the electron transport chain, is a terminal enzyme involved in the oxidation of substrates resulting in the generation of energy required for the cellular activity. Therefore, regulating the activity of Cox could interfere with the generation of ATP, consequently affecting the proliferation of cells. Consistent with this hypothesis, we also observed a decrease in the Cox activity following the incubation of neural progenitor cells with D609. These results suggest that D609 could inhibit the activity of Cox and subsequent ATP synthesis in the neural progenitor cells.


IL4I1: an inhibitor of the CD8⁺ antitumor T-cell response in vivo.
The L-phenylalanine oxidase IL4I1 inhibits T-cell proliferation in vitro through H(2) O(2) production, and is highly expressed in tumor-associated macrophages. IL4I1 is also detected by immunohistochemistry in neoplastic cells from several B-cell lymphomas and some non-lymphoid tumors. To evaluate IL4I1's effect on tumor growth, we developed a mouse melanoma model constitutively coexpressing IL4I1 and the GP33 epitope. After GP33 vaccination, tumors developed more frequently in mice injected with IL4I1-expressing cells in comparison with mice receiving control cells. Tumor escape was preceded by a rapid diminution of IFN-γ-producing cytotoxic antitumor CD8(+) T cells. Moreover, tumor incidence was already increased when only 20% of the injected cells expressed IL4I1. The minimal IL4I1 activities leading to tumor escape were close to those detected in human melanoma and mesothelioma. Thus, we demonstrate the immunosuppressive functions of IL4I1 in vivo and suggest that IL4I1 facilitates human tumor growth by inhibiting the CD8(+) antitumor T-cell response.


A new approach to toxicity determination by respirometry.
Respirometry, as used in wastewater treatment, is the measurement and interpretation of the respiration rate of microorganisms in activated sludge. The respiration rate is the amount of the oxygen per unit of volume and time that is consumed by the microorganisms. For a long time respirometry has been recognized as a valuable basis for controlling the activated sludge process. The reason for this is that respiration rate is directly linked to two important biochemical processes that must be controlled in a wastewater treatment plant: biomass growth and substrate consumption. This paper shows different experiments to quantify toxic or inhibitory effects as determined by the toxicity protocol for respirometry. The protocol used was based on the utilization of the respiration of activated sludge to measure and quantify toxic effects of compounds. Our purpose was for both the protection and treatment ability determination of wastewater plants, depending on the problems (e.g. pollution), needs of customers and possibilities for biodegradation of the tested products.


Long-term results of spinal accessory nerve transfer to the suprascapular nerve in upper-type paralysis of brachial plexus injury.
In the management of upper type of brachial plexus injury, reconstruction to restore shoulder function is accomplished by multiple nerve transfers. We used the accessory nerve to neurotize the suprascapular nerve in 12 patients (11 men, 1 woman) from 1989 to 2003. The average age at the time of operation was 28.1 years (range 16 to 53). The mean preoperative time was 3.6 months. The type of paralysis was C5-C6 type in four cases, C5-C7 type in five cases, and C5-C8 type in three cases. The average time of follow-up was 28.5 months. All the patients showed reinnervation of the supraspinatus and infraspinatus muscles that was confirmed by electromyogram. At the time of final followup, the average shoulder flexion was 70.4 degrees and abduction was 77.1 degrees. However, average shoulder external rotation was only 16.7 degrees. We compared the shoulder flexion and abduction in patients with or without paralysis of the serratus anterior muscle and found significantly better functional outcome in the latter group of patients. We, therefore, conclude that repair of long thoracic nerve is mandatory for achieving optimum shoulder function.


Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery.
Detection, comparison and analyses of binding pockets are pivotal to structure-based drug design endeavors, from hit identification, screening of exosites and de-orphanization of protein functions to the anticipation of specific and non-specific binding to off- and anti-targets. Here, we analyze protein-ligand complexes and discuss methods that assist binding site identification, prediction of druggability and binding site comparison. The full potential of pockets is yet to be harnessed, and we envision that better understanding of the pocket space will have far-reaching implications in the field of drug discovery, such as the design of pocket-specific compound libraries and scoring functions.


[A mathematical study of the mortality curve of Escherichia coli exposed to aminoglycosides].
The time killing curves of three strains of E. coli (CIP54117, ATCC25922 and ATCC29194) exposed to kanamycin, amikacin, netilmicin and dibekacin are decreasing exponentials. The absolute value of the killing rate m is related to the antibiotic concentration through a Michaelis-Henry equation. A maximum killing rate m max and an affinity constant Kc between bacteria and antibiotic can thus be estimated. m max is mainly strain dependent. On the contrary, Kc is related to the antibiotic. Kc is much higher (i.e. the affinity is much lower) for kanamycin and amikacin than for netilmicin or dibekacin. The dose-effect curve is a saturation curve. Increasing doses of antibiotic do not increase the mortality proportionally.


Evaluating Robustness and Sensitivity of the NanoString Technologies nCounter Platform to Enable Multiplexed Gene Expression Analysis of Clinical Samples.
Analysis of clinical trial specimens such as formalin-fixed paraffin-embedded (FFPE) tissue for molecular mechanisms of disease progression or drug response is often challenging and limited to a few markers at a time. This has led to the increasing importance of highly multiplexed assays that enable profiling of many biomarkers within a single assay. Methods for gene expression analysis have undergone major advances in biomedical research, but obtaining a robust dataset from low-quality RNA samples, such as those isolated from FFPE tissue, remains a challenge. Here, we provide a detailed evaluation of the NanoString Technologies nCounter platform, which provides a direct digital readout of up to 800 mRNA targets simultaneously. We tested this system by examining a broad set of human clinical tissues for a range of technical variables, including sensitivity and limit of detection to varying RNA quantity and quality, reagent performance over time, variability between instruments, the impact of the number of fields of view sampled, and differences between probe sequence locations and overlapping genes across CodeSets. This study demonstrates that Nanostring offers several key advantages, including sensitivity, reproducibility, technical robustness, and utility for clinical application.


Photoinduced rearrangement of aromatic N-chloroamides to chloroaromatic amides in the solid state: inverted Π(N)-Σ(N) occupational stability of amidyl radicals.
We report a solid-state photochemical rearrangement reaction by which aromatic N-chloroamides exposed to UV light or sunlight are rapidly and efficiently converted to chloroaromatic amides. The course, the intermediate (nascent chlorine vs dichlorine) and the outcome of the reaction depend on the excitation (exposure time, wavelength, and intensity) and on inherent structural factors (the directing role of the substituents and, as demonstrated by the different reactivity of two polymorphs of N-chlorobenzanilide, the supramolecular structure). The photolysis of the chloroamides provides facile photochemical access to arylamidyl radicals as intermediates, which in the absence of strong hydrogen bond donors are stabilized in the reactant crystals by C-H/N-Cl···π interactions, thus, providing insight into their structure and chemistry. Thorough theoretical modeling of the factors determinant to the stability and the nature of the spin-hosting orbital evidenced that although the trans-Π(||) state (Np spin) of the amidyls is normally preferred over the trans-Σ(⊥) configuration (Nsp(2) spin), stabilization by aromatic conjugation, steric and geometry factors, as well as by electronic effects from the substituents can decrease the Π-Σ gap in these intermediates significantly, resulting in similar and, in the case of the orthogonal amide-phenyl disposition, even reversed population of the unpaired electron in the two orbitals. Quantitative correlation established that the inverted occupational spin stability and the Π(N)-Σ(N) crossover are collectively facilitated by the conformation, valence angle, and disposition of the amide group relative to the aromatic system. The stabilization and detection of a trans-Σ(⊥) radical was experimentally accomplished by steric locking of the orthogonal trans-amide conformation with double ortho-tert-butyl substitution at the phenyl ring. The effects of the single para-phenyl substituents on the relative occupational stability of the arylamidyl radical states point out to non-Hammett behavior. By including cumulative electronic effects from multiple substitutions, four distinct families of the aromatic amidyl radicals were identified. The Π(∥) state is the most stable structure of the N-phenylacetamidyl radical and of most of the substituted arylamidyls, although the Σ(⊥) and Π(⊥) states can also be stabilized by introducing tert-butyl and nitro groups, respectively.


RNAi screening of Drosophila (Sophophora) melanogaster S2 cells for ricin sensitivity and resistance.
The ribosome-inhibiting toxin ricin binds exposed β1→4 linked galactosyls on multiple glycolipids and glycoproteins on the cell surface of most eukaryotic cells. After endocytosis, internal cell trafficking is promiscuous, with only a small proportion of ricin proceeding down a productive (cytotoxic) trafficking route to the endoplasmic reticulum (ER). Here, the catalytic ricin A chain traverses the membrane to inactivate the cytosolic ribosomes, which can be monitored by measuring reduction in protein biosynthetic capacity or cell viability. Although some markers have been discovered for the productive pathway, many molecular details are lacking. To identify a more comprehensive set of requirements for ricin intoxication, the authors have developed an RNAi screen in Drosophila S2 cells, screening in parallel the effects of individual RNAi treatments alone and when combined with a ricin challenge. Initial screening of 806 gene knockdowns has revealed a number of candidates for both productive and nonproductive ricin trafficking, including proteins required for transport to the Golgi, plus potential toxin interactors within the ER and cytosol.


Electret Modulation Strategy to Enhance the Photosensitivity Performance of Two-Dimensional Molybdenum Sulfide.
Due to the limited light absorption efficiency of atomic thickness layers and the existence of quenching effects, photodetectors solely made of transition metal dichalcogenides (TMDs) have exhibited an unsatisfactory detection performance. In this article, electret/TMD hybridized devices were proposed by vertically coupling a MoS2 channel and the PTFE film, which reveals an optimized photodetection behavior. Negative charges were generated in the PTFE layer through the corona charging method, akin to applying a negative bias on the MoS2 channel in lieu of a traditional voltage-driven back gate. Under a charging voltage of -6 kV, PTFE/MoS2 devices reveal improved photodetection performance (Rhybrid = 67.95A/W versus Ronly = 3.37 A/W, at 470 nm, 1.20 mW cm-2) and faster recovery speed (τd(hybrid) = 2000 ms versus τd(only) = 2900 ms) compared to those bare MoS2 counterparts. The optimal detection performance (2 orders of magnitude) was obtained when the charging voltage was -2 kV, limited by the minimum of the carrier density in MoS2 channels. This study provides an alternative strategy to optimize optoelectronic devices based on the 2D components through non-voltage-driven gating.


Potassium channel modulation: a new drug principle for regulation of smooth muscle contractility. Studies on isolated airways and arteries.
K+ channels play a key role in regulation of membrane potential and cell excitability. Several different types of K+ channels have been identified and the presence, characteristics and functions of these channels vary among different tissues. The 3 most important K+ channels in smooth muscle are the KATP (activated by a fall in intracellular ATP and a rise in nucleotide diphosphates and blocked by glibenclamide), BKCa (activated by a rise in intracellular Ca2+) and Kv (activated by depolarization). Cromakalim, pinacidil and nicorandil are members of a rapidly increasing group of novel drugs which open K+ channels. Opening of such channels leads to K+ efflux, membrane hyperpolarization, reduced excitability and smooth muscle relaxation. The purpose of the studies included in this thesis was to investigate this novel drug principle of K+ channel modulation on smooth muscle contractility of isolated airways and arteries and on neuroeffector transmission in airways. Smooth muscle contractility was measured in airway and vascular ring preparations suspended in isometric myographs. Neurotransmitter release was elicited by transmural electrical field stimulation. The major findings were: 1) Membrane depolarization by high extracellular K+ concentrations induced contraction of airway smooth muscle that was easily relaxed by Ca2+ antagonists and abolished in a Ca2+ free medium indicating that K+ contraction is triggered by Ca2+ influx through voltage-operated Ca2+ channels. Indomethacin was required to obtain reproducible responses upon repeated exposure to K+ suggesting that endogenous prostaglandins are released by K+ and interferes with its contractile effect. K+ depolarization was shown to be a valuable pharmacological tool for detection of drugs acting by K+ channel opening. The prototype K+ channel opener cromakalim relaxed contractions induced by 20-30 mM K+ but had no effect against contraction induced by 124 mM K+. This was a unique profile of action not shared by other types of airway and vascular smooth muscle relaxants. As the extracellular K+ concentration is raised the outward directed electrochemical gradient for K+ is reduced and at high K+ concentrations the effect of K+ channel opening is negligible. Although the K+ channel opener pinacidil had a higher relaxant potency against contraction induced by 30 mM K+ than by 124 mM K+, it still relaxed the latter contraction indicating an additional K+ channel independent mechanism of action of the drug. When K+ depolarization is used as a pharmacological tool, it is essential to maintain osmolarity. Addition of KCI directly to the tissue bath solution, which previously was a commonly applied technique, produced confounding and unwanted effects due to hyperosmolarity per se. 2) Pinacidil and cromakalim relaxed guinea-pig trachea either tone was spontaneous or induced by a range of airway spasmogens (histamine, PGF2 alpha, LTC4/LTD4 or carbachol) of relevance as asthma mediators. The relaxant effectiveness of the drugs was reduced when tone was elicited by carbachol. The airway smooth muscle relaxation produced by pinacidil and cromakalim was selectively blocked by the antidiabetic sulfonylureas glibenclamide, glipizide and glibornuride and also by phentolamine. These drugs are blockers of KATP which therefore indicates that this channel is the target for cromakalim and pinacidil in airway smooth muscle. Additional to the antagonistic action against K+ channel openers the sulfonylurea KATP blockers and phentolamine at higher concentrations relaxed airway smooth muscle by yet unknown mechanisms that seemed unrelated to KATP. 3) Cromakalim and pinacidil inhibited nerve-mediated e-NANC contractile responses in guinea-pig bronchi. Such responses are due to release of SP and related tachykinins from sensory nerve endings. These neuropeptides cause bronchoconstriction and airway inflammation and may possibly play an important role in the pathophysiology of asthma.


Electrophysiologic changes in workers with "low" blood lead levels.
In spite of numerous studies, the minimum level of lead exposure at which "sub-clinical" electrophysiologic abnormalities appear is still under discussion. Furthermore, it has not been clarified whether the electrophysiologic changes are directly related to PbB levels or to duration of exposure. This study was conducted on a group of 62 subjects occupationally exposed to lead with average blood lead levels below 50 microgram/100 ml and durations of exposure of less than 10 years. A reduction of motor and sensory nerve conduction velocities and sensory action potential amplitude of the median nerve was found in the subjects exposed to lead, as compared with a control group. Such abnormalities were already present in workers with the lowest blood lead levels, but were more severe in workers whose blood lead levels had exceeded 70 microgram/100 ml, even if this occurred only once in the last two years. The electrophysiologic changes did not correlate with duration of exposure but occurred very soon after initial exposure to lead.


[Evidence of occult systemic hypoperfussion in head injured patients. Preliminary study].
To determine the correlation between blood lactic acid levels in the first 48 hours and outcome, in hemodynamically stable patients, with moderate or severe head injury (HI), and to investigate the risk factors associated with abnormal lactate levels. A prospective observational study, in 210 adults patients with moderate or severe head injury. When the patients were hemodynamically stable, blood lactate concentrations were measured once on admission, twice daily during the first 2 days and once daily until lactate levels were normalized. The whole group 210 patients were divided into 2 groups. Group 1: (LA < 2.2 mmol/L) patients without occult hypoperfussion (OH), and group 2: (LA >or= 2.2 mmol/L) patients with OH. One hundred and fifteen patients (57.76%) were categorized as group 1, and 95 patients (45.24%) as group 2. In the univariate analysis of risk factors for blood lactate >or=2.2 mmol/L the following variables showed statistical significance: severity of the head injury measured by several scales [Glasgow Coma Scale (GCS), Injury Severity Score (ISS), Revised Trauma Score (RTS) and Acute Physiology and Chronic Health Evaluation (APACHE) II], arterial hypotension, hypoxemia, anaemia, hyperglucemia, hypothermia, a greater incidence of norepinephrine infusion, and the higher percentage of type II lesions in the head computerized tomography at admission showed in the group 1 (53.91% vs. 38.94%) (p<0.03). In the multiple logistic regression analysis only two variables were risk independently associated with elevated blood lactate concentration: APACHE II in the first 24 hours: OR 1.12 (95% IC 1.06--1.196; p<0.0001) and the first 48-hours total fluid infusion volumes: OR 1.09 (95% IC 1.021,16; p < 0.0001). The infection rate (63.2% vs 47.8%, p=0.026), and length of ICU stay [mediana (percentil 25--75)] [13.29 (7.11--21.22) days vs. 8.78 (4.40--16.72) days; p<0.018] were significantly higher in patients with blood lactate >or=2.2 mmol/L (group 2). Although, the percentage of intracranial hypertension and mortality was higher in the group 2, there was no significant difference. In the multivariate analysis, the increase of blood lactate concentration, was not independently associated as a risk factor with studied complications. The presence of OH in patients with moderate or severe head injury, with postres uscitation arterial pressure, according to present recommendations, is associated with a more severe head injury, showed by APACHE II and the total fluid infusion volumes in the first 48 hours. OH in head injury increases the infection rate and length of ICU stay.


Rate and equilibrium constants for the addition of N-heterocyclic carbenes into benzaldehydes: a remarkable 2-substituent effect.
Rate and equilibrium constants for the reaction between N-aryl triazolium N-heterocyclic carbene (NHC) precatalysts and substituted benzaldehyde derivatives to form 3-(hydroxybenzyl)azolium adducts under both catalytic and stoichiometric conditions have been measured. Kinetic analysis and reaction profile fitting of both the forward and reverse reactions, plus onwards reaction to the Breslow intermediate, demonstrate the remarkable effect of the benzaldehyde 2-substituent in these reactions and provide insight into the chemoselectivity of cross-benzoin reactions.


Cases of alleged asbestos-related disease: a radiologic re-evaluation.
Chest radiographs were re-evaluated from 439 active and retired tireworkers previously designated as having a condition consistent with an asbestiform mineral exposure. The review was performed in an independent manner by three board-certified radiologists according to guidelines from an international classification system. The percentage of cases with abnormalities consistent with an asbestiform mineral exposure found separately by the three radiologists was 3.7, 3.0, and 2.7%. Application of an algorithm to form a consensus evaluation indicated that approximately 3.6% (16) of the subjects evaluated may have a condition consistent with an asbestos exposure. A more detailed review, however, revealed that only 11 workers, or 2.5% of the total, would have a reasonable likelihood of having such a condition. Most cases were normal and the majority of abnormalities present on the radiographs evaluated were nonoccupational in origin. Prevalent conditions identified included healed tuberculosis, histoplasmosis, emphysema, discoid atelectasis, effusions, healed rib fractures, scarring due to infection or old inflammatory disease, possible cancer, miscellaneous nonspecific linear markings consistent with cigarette smoking and aging, and heart and vascular system diseases--the latter evidenced by an abnormally large number of subjects with healed coronary artery bypass surgery and pacemaker implants. In summary, the best estimate from this study indicates that possibly 16 (3.6%), but more realistically 11 (2.5%), of the 439 tireworkers evaluated may have a condition consistent with exposure to an asbestiform mineral. This represents a 40-fold difference between the re-evaluation results and the original survey work.


Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans.
Human lymphocytes from elderly and young donors were cultured with phytohemagglutinin (PHA) or concanavalin A. Cultures from old donors produced less T cell growth factor (TCGF) and incorporated less tritiated thymidine (3H-Tdr) than did similar cultures from young donors in the presence of either mitogen. Furthermore, the response of lymphocytes from elderly donors to TCGF was impaired. Thus, PHA-activated T cells from aged donors showed no increase tritiated thymidine incorporation when incubated with exogenous human TCGF. In contrast, addition of exogenous human TCGF to PHA-activated peripheral blood leukocytes from younger individuals increased tritiated thymidine incorporation by 30-50%. The impaired response to TCGF was associated with decreased binding of TCGF by PHA-activated cells from old donors. TCGF production or responsiveness was not associated with the presence of "suppressor" activity in elderly T cell preparations. These studies suggest a possible molecular mechanism for the impaired proliferative response of elderly human T cells. These data lend support to the hypothesis that defects in the capacity to either produce or respond to TCGF may be a fundamental cause of immune deficiency.


Mental and motor development correlates in patients with end-stage biliary atresia awaiting liver transplantation.
We measured mental and motor development in 27 infants and 14 children with end-stage biliary atresia who were awaiting liver transplantation, and we measured disease-related variables (physical growth, liver function, and severity and duration of disease) that may relate to development. We then determined the relationship between development and the disease-related variables. Infants were assessed with the Bayley scales, and children were assessed with the Stanford-Binet scales of intelligence and the Minnesota Child Development Inventory. The mean +/- SD mental and motor scores for infants were 79.5 +/- 19.6 and 69.7 +/- 17.6, respectively. The mean +/- SD IQ and motor development scores for children were 76.1 +/- 16.6 and 56.9 +/- 18.1, respectively. For infants, mental and motor development were related significantly to height and weight (r values ranged from .42 to .72). Mental development in infants was also related significantly to serum vitamin E levels (P = .03). Multiple regression analyses combining growth and disease-related indices predicted 70% of the variance in mental and motor development in infants (P = .001). For children, development was related to measures of liver function (ie, to serum bilirubin, r = -.51, P = -.08, and to serum albumin, r = .54, P = .06) but not to growth. Careful nutritional support during infancy and aggressive management of liver disease prior to transplantation may be important in optimizing the development of children with biliary atresia who subsequently undergo liver transplantation.


[Mechanism for subcellular localization of nuclear receptor CAR].
Animals including human beings have defense mechanisms against the toxicity of xenobiotics such as medicinal compounds and environmental pollutants. Receptor-type transcriptional factors, such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR), play important roles in the defense against xenobiotic toxicities. In the absence of stimuli, these receptors are distributed predominantly in the cytoplasmic compartment. Following xenobiotic stimuli, receptors translocate into the nucleus and transactivate its target genes. However, the exogenously expressed CAR translocates spontaneously into the nucleus in immortal cells. Previously, we identified subcellular localization signals in rat CAR: nuclear localization signal (NLS), nuclear export signal (NES) and cytoplasmic retention region (CRR). Lack of CRR function might be responsible for the spontaneous nuclear accumulation of CAR in immortal cells. Further, the nuclear import of CAR is regulated by the importin-Ran system, which is required for maintaining an intact microtubule network. Clarifying the mechanisms underlying the nuclear translocation of CAR would be useful for the establishment of novel assay systems for the screening of ligands and activators of CAR using immortal cells without sacrificing animals.


Graph Laplacian tomography from unknown random projections.
We introduce a graph Laplacian-based algorithm for the tomographic reconstruction of a planar object from its projections taken at random unknown directions. A Laplace-type operator is constructed on the data set of projections, and the eigenvectors of this operator reveal the projection orientations. The algorithm is shown to successfully reconstruct the Shepp-Logan phantom from its noisy projections. Such a reconstruction algorithm is desirable for the structuring of certain biological proteins using cryo-electron microscopy.


Endoscopic papillotomy (EPT) in acute obstructive suppurative cholangitis.
Eight high risk patients, median age 79 years, with a distal obstruction of the common bile duct and serious clinical symptoms of acute obstructive cholangitis were treated by EPT. In seven patients, impaction of a stone in the common bile duct was found and in one patient, an obstructing cancer. EPT was performed without immediate complications and followed by obvious drainage of purulent bile in all patients. Repapillotomy with stone extraction was necessary in three patients 5, 6, and 10 days after the first EPT. The papillotomy was followed by immediate symptom relief, normalization of body temperature, and a decrease in leukocytes and bilirubin and alkaline phosphatase values within the first several postoperative days. Average hospitalization time was 8 days, ranging from 4-17 days. The patient with pancreatic cancer died 3 months after the EPT. One other patient died in pseudomonas sepsis 17 days after an uncomplicated EPT. ERCP controls in the other six patients have been normal and they all remain symptom free. Since early decompression is mandatory in these patients and laparotomy with internal decompression is associated with a high morbidity and mortality, endoscopic decompression should probably be the recommended treatment in patients with obstructive, septic cholangitis prior to employing this therapeutic option.


A Multipronged Comparative Study of the Ultraviolet Photochemistry of 2-, 3-, and 4-Chlorophenol in the Gas Phase.
The S1((1)ππ*) state of the (dominant) syn-conformer of 2-chlorophenol (2-ClPhOH) in the gas phase has a subpicosecond lifetime, whereas the corresponding S1 states of 3- and 4-ClPhOH have lifetimes that are, respectively, ∼2 and ∼3-orders of magnitude longer. A range of experimental techniques-electronic spectroscopy, ultrafast time-resolved photoion and photoelectron spectroscopies, H Rydberg atom photofragment translational spectroscopy, velocity map imaging, and time-resolved Fourier transform infrared emission spectroscopy-as well as electronic structure calculations (of key regions of the multidimensional ground (S0) state potential energy surface (PES) and selected cuts through the first few excited singlet PESs) have been used in the quest to explain these striking differences in excited state lifetime. The intramolecular O-H···Cl hydrogen bond specific to syn-2-ClPhOH is key. It encourages partial charge transfer and preferential stabilization of the diabatic (1)πσ* potential (relative to that of the (1)ππ* state) upon stretching the C-Cl bond, with the result that initial C-Cl bond extension on the adiabatic S1 PES offers an essentially barrierless internal conversion pathway via regions of conical intersection with the S0 PES. Intramolecular hydrogen bonding is thus seen to facilitate the type of heterolytic dissociation more typically encountered in solution studies.


Polyunsaturated fatty acids n-3: new data on heart disease, cancer, immune resistance and mental depression.
Attention to the role of n-3 long-chain polyunsaturated fatty acids from fish (n-3) in human health has remarkably increased during recent decades. Many clinical and epidemiologic studies have shown a positive role for n-3 in cardiovascular diseases, cancer, infant development and more recently, in various mental illnesses, especially in depression. These fatty acids are known to have pleiotropic effects, especially against hypertriglyceridemia and platelet aggregation. These may be mediated through several distinct mechanisms, including alterations in cell membrane composition and function, gene expression, or eicosanoid production. A number of authorities have recently recommended an increase in intakes of n-3 by the general population, because "western" diets are deficient in n-3 and have excessive amounts of n-6 fatty acids. The target EPA + DHA consumption was recommended to be at least 500 mg/day for individuals without heart disease and at least 800 to 1000 mg/day for patients with known coronary heart disease. To comply with this recommendation, a variety of food products, most notably eggs, yogurt, milk and spreads have been enriched with n-3. Additional controlled clinical trials are needed to document whether long-term consumption or supplementation with eicosapentaenoic (EPA) or docosahexaenoic (DHA) acids results in better quality of life (Fig. 4, Ref. 47).


Cost-effectiveness of the anti-vascular endothelial growth factor intravitreal injection and panretinal photocoagulation for patients with proliferative diabetic retinopathy in South Korea.
We determined the cost-effectiveness of the anti-vascular endothelial growth factor (VEGF) intravitreal injection versus panretinal photocoagulation (PRP) for patients with proliferative diabetic retinopathy (PDR) in South Korea. We simulated four treatment strategies using PRP and the anti-VEGF injection by constructing a Markov model for a hypothetical cohort of 50-year-old PDR patients: (1) PRP only; (2) anti-VEGF injection only; (3) PRP first; and (4) anti-VEGF injection first. In this cost-effectiveness analysis, compared with only-PRP, the incremental cost-effectiveness ratio was $95,456 per quality-adjusted life-year (QALY) for PRP first, $34,375 per QALY for anti-VEGF injection first, and $33,405 per QALY for anti-VEGF injection only from a healthcare perspective. From the societal and payer perspective, strategy (2) was more cost-saving and effective than (1). In the probabilistic sensitivity analysis, only-PRP was cost-effective up to the willingness-to-pay (WTP) of about $42,000, while anti-VEGF injection only was cost-effective from a healthcare perspective. From the societal and payer perspectives, regardless of the value of WTP, anti-VEGF injection only was the most cost-effective strategy. In our study, the anti-VEGF injection for PDR was cost-effective from the payer and societal perspectives.


Investigations on the mechanism of the hypocholesterolemic action of 1-ethoxysilatrane.
Intraperitoneal administration of the nontoxic silicon compound, 1-ethoxysilatrane, to the rat did not cause proliferation of hepatic mitochondria or of endoplasmic reticulum, nor did it affect mitochondrial oxidative phosphorylation. The activities of cholesterol 7 alpha-hydroxylase in hepatic microsomes and of cholesterol oxidase in mitochondria respectively were unaffected by silatrane treatment. The rate of release of bile, whose composition remained unchanged, also was not increased in silatrane-treated animals. The results indicated that the compound did not affect the pathway of cholesterol degradation. A progressive decrease in the activity of hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase was observed on administration of the compound over a period of three weeks. Consistent with this, cholesterol biosynthesis in liver as measured by incorporation of radioactive precursors, acetate and water but not mevalonate, was significantly decreased in silatrane-treated animals. However, enzyme-linked immunosorbent assay revealed that the concentration of HMGCoA reductase protein was not decreased by the treatment indicating that inactivated enzyme was also present in such microsomes. Addition of silatrane to microsomes in the assay system did not cause inhibition indicating that the inactivation is by an indirect mechanism. It is concluded that the hypocholesterolemic action of the compound rested entirely on the inhibition of cholesterol biosynthesis in vivo by inactivation of the rate-limiting enzyme HMGCoA reductase.


Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement.
Despite the high prevalence of performance-enhancing drug (PED) use, media attention has focused almost entirely on PED use by elite athletes to illicitly gain a competitive advantage in sports, and not on the health risks of PEDs. There is a widespread misperception that PED use is safe or that adverse effects are manageable. In reality, the vast majority of PED users are not athletes but rather nonathlete weightlifters, and the adverse health effects of PED use are greatly underappreciated. This scientific statement synthesizes available information on the medical consequences of PED use, identifies gaps in knowledge, and aims to focus the attention of the medical community and policymakers on PED use as an important public health problem. PED users frequently consume highly supraphysiologic doses of PEDs, combine them with other PEDs and/or other classical drugs of abuse, and display additional associated risk factors. PED use has been linked to an increased risk of death and a wide variety of cardiovascular, psychiatric, metabolic, endocrine, neurologic, infectious, hepatic, renal, and musculoskeletal disorders. Because randomized trials cannot ethically duplicate the large doses of PEDs and the many factors associated with PED use, we need observational studies to collect valid outcome data on the health risks associated with PEDs. In addition, we need studies regarding the prevalence of PED use, the mechanisms by which PEDs exert their adverse health effects, and the interactive effects of PEDs with sports injuries and other high-risk behaviors. We also need randomized trials to assess therapeutic interventions for treating the adverse effects of PEDs, such as the anabolic-androgen steroid withdrawal syndrome. Finally, we need to raise public awareness of the serious health consequences of PEDs.


A novel rhodamine-based Hg2+ sensor with a simple structure and fine performance.
An excellent spectral sensor for Hg2+ named 2-(2-((2-aminoethyl)thio)ethyl)-3',6'-bis(diethylamino)spiro[isoindoline-1,9'-xanthen]-3-one (RMTE) was achieved by a one-step reaction between rhodamine B and thiobisethylamine. RMTE could detect Hg2+ in nearly pure water reversibly and highly selectively, indicated by a new increasing absorption peak at 561 nm and 170-fold enhanced fluorescence at 578 nm coupled with remarkable visual and fluorescence color changes. When the Hg2+ concentration ([Hg2+]) varied from 0 to 120 μM, the absorbance and fluorescence intensity of the RMTE solution responded linearly to [Hg2+] with the detection limits of 2.08 and 0.14 μM, respectively. RMTE could work in ecologically and biologically favorable pH values of 6.41-8.33. The binding mode of RMTE toward Hg2+ was 1 : 1. RMTE could monitor Hg2+ in environmental water and living cells effectively with low cytotoxicity.


Use of Eye-Tracking Technology by Medical Students Taking the Objective Structured Clinical Examination: Descriptive Study.
The objective structured clinical examination (OSCE) is a test used throughout Spain to evaluate the clinical competencies, decision making, problem solving, and other skills of sixth-year medical students. The main goal of this study is to explore the possible applications and utility of portable eye-tracking systems in the setting of the OSCE, particularly questions associated with attention and engagement. We used a portable Tobii Glasses 2 eye tracker, which allows real-time monitoring of where the students were looking and records the voice and ambient sounds. We then performed a qualitative and a quantitative analysis of the fields of vision and gaze points attracting attention as well as the visual itinerary. Eye-tracking technology was used in the OSCE with no major issues. This portable system was of the greatest value in the patient simulators and mannequin stations, where interaction with the simulated patient or areas of interest in the mannequin can be quantified. This technology proved useful to better identify the areas of interest in the medical images provided. Portable eye trackers offer the opportunity to improve the objective evaluation of candidates and the self-evaluation of the stations used as well as medical simulations by examiners. We suggest that this technology has enough resolution to identify where a student is looking at and could be useful for developing new approaches for evaluating specific aspects of clinical competencies.


A20 ameliorates advanced glycation end products-induced melanogenesis by inhibiting NLRP3 inflammasome activation in human dermal fibroblasts.
Advanced glycation end products (AGEs) promote melanogenesis through activating NLRP3 inflammasome in fibroblasts. Although A20 has been highlighted to inhibit NLRP3 inflammasome activation, its roles and mechanisms remain elusive in photoaging-associated pigmentation. To determine the significance of fibroblast A20 in AGEs-induced NLRP3 inflammasome activation and pigmentation. The correlation between A20 and AGEs or melanin was studied in sun-exposed skin and lesions of melasma and solar lentigo. We then investigated A20 level in AGEs-treated fibroblast and the effect of fibroblast A20 overexpression or knockdown on AGEs-BSA-induced NLRP3 inflammasome activation and pigmentation, respectively. Finally, the severity of NLRP3 inflammasome activation and pigmentation was evaluated after mice were injected intradermally with A20-overexpression adeno-associated virus and AGEs-BSA. Dermal A20 expression was decreased and exhibited negative correlation with either dermal AGEs deposition or epidermal melanin level in sun-exposed skin and pigmentary lesions. Moreover, both AGEs-BSA and AGEs-collagen robustly decreased A20 expression via binding to RAGE in fibroblasts. Further, A20 overexpression or depletion significantly decreased or augmented AGEs-BSA-induced activation of NF-κB pathway and NLRP3 inflammasome and IL-18 production and secretion in fibroblasts, respectively. Importantly, fibroblast A20 potently repressed AGEs-BSA-stimulated melanin content,tyrosinase activity,and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes. Particularly, fibroblast A20 significantly abrogated AGEs-BSA-promoted melanogenesis in ex vivo skin and mouse models. Additionally, fibroblast A20 inhibited AGEs-BSA-activated MAPKs in melanocytes and the epidermis of ex vivo skin. Fibroblast A20 suppresses AGEs-stimulate melanogenesis in photoaging-associated hyperpigmentation disorders by inhibiting NLRP3 inflammasome activation.


Protein Expression Modifications in Phage-Resistant Mutants of Aeromonas salmonicida after AS-A Phage Treatment.
The occurrence of infections by pathogenic bacteria is one of the main sources of financial loss for the aquaculture industry. This problem often cannot be solved with antibiotic treatment or vaccination. Phage therapy seems to be an alternative environmentally-friendly strategy to control infections. Recognizing the cellular modifications that bacteriophage therapy may cause to the host is essential in order to confirm microbial inactivation, while understanding the mechanisms that drive the development of phage-resistant strains. The aim of this work was to detect cellular modifications that occur after phage AS-A treatment in A. salmonicida, an important fish pathogen. Phage-resistant and susceptible cells were subjected to five successive streak-plating steps and analysed with infrared spectroscopy, a fast and powerful tool for cell study. The spectral differences of both populations were investigated and compared with a phage sensitivity profile, obtained through the spot test and efficiency of plating. Changes in protein associated peaks were found, and these results were corroborated by 1-D electrophoresis of intracellular proteins analysis and by phage sensitivity profiles. Phage AS-A treatment before the first streaking-plate step clearly affected the intracellular proteins expression levels of phage-resistant clones, altering the expression of distinct proteins during the subsequent five successive streak-plating steps, making these clones recover and be phenotypically more similar to the sensitive cells.


A National Survey of Stress and Burnout in Critical Care Nurses: A Prepandemic Study.
Critical care nurses (CCNs) experience a higher level of stress and burnout than nurses in other specialties. Approximately 50% of CCNs are mildly stressed, and almost 20% are moderately stressed. Prolonged periods of stress can lead to burnout, which has been shown to have deleterious effects on quality and patient safety. The purpose of this study is to determine the prevalence of burnout among a national sample of CCNs and the association with environmental factors. A national survey of CCNs working in the United States was implemented using an exploratory descriptive design. The anonymous survey was developed iteratively according to best practices of survey design. The survey included the Perceived Stress Scale and the Copenhagen Burnout Inventory tool. Pretesting and pilot testing were conducted with CCN specialists, and the survey was revised based on their feedback. An anonymous link was distributed to respondents using convenience sampling through social media and further disseminated via snowball sampling. Two hundred seventy nurses responded to the survey. The mean (SD) Perceived Stress Scale score in the study population was 18.5 (6.4), indicating moderate stress. The mean (SD) Copenhagen Burnout Inventory score was 61.9 (16.5), indicating moderate burnout. Our study found that the overall health of the work environment was one of the most important factors associated with both stress and burnout. This study has demonstrated the relationship between the health of the work environment and burnout among CCNs. It is imperative that health care organizations evaluate and implement strategies to optimize the health of the work environment to mitigate burnout and its negative sequelae on the nurse, patient, and system.


A molecular study of hemotropic mycoplasmas (hemoplasmas) in cats in Iran.
Three feline hemoplasma species are recognized: Mycoplasma haemofelis, 'Candidatus Mycoplasma haemominutum', and 'Candidatus Mycoplasma turicensis'. These species can cause anemia in cats and have a worldwide distribution. There was no previous information on hemotropic mycoplasma spp in cats in Iran and the Middle East. Accordingly, we investigated the molecular presence, and clinical signs and hematological profile in cats infected with these microorganisms in Iranian cats. Polymerase chain reaction (PCR) assays and cytology were performed on 100 blood samples collected from Iranian Shorthair cats. ACBC and case history were also collected for each sample. By PCR, 22 (22%; 14-30%, 95% CI) samples were positive. The prevalence of M haemofelis, 'Ca M haemominutum', and 'Ca M turicensis' was 63.63% (14/22), 54.54% (12/22), and 18.18% (4/22), respectively. Some double and triple co-infections were also found. Using PCR as the reference method, cytology had poor sensitivity (27%) and reasonable specificity (89.74%). Male cats were at a higher risk of infection (P = .001). Cats older than 8 years were more frequently infected than the younger cats (P = .0018). Lower HCT (P = .018), RBC count (P = .028) and HGB concentration (P = .003) were also associated with hemoplasma PCR-positive status. Based on this study, the most prevalent feline hemoplasma species in Iranian cats was M haemofelis, but double and triple co-infections are also documented. Age and sex, as well as reduced RBC parameters, were predisposing factors for hemoplasma infection.


LAGO on the unit sphere.
LAGO is an efficient kernel algorithm designed specifically for the rare target detection problem. However, unlike other kernel algorithms, LAGO cannot be easily used with many domain-specific kernels. We solve this problem by first providing a unified framework for LAGO and clarifying its basic principle, and then applying that principle on the unit sphere instead of in the Euclidean space.


Genetic screening for colorectal cancer and intervention.
There is a complex interaction between environmental/dietary factors and genetics underlying the pathogenesis of colon carcinogenesis. Little data exist concerning the impact of diet on the phenotypic expression of genetically linked colon cancer. As a result, it has been difficult to develop rationally designed dietary intervention studies in first-degree relatives of patients with established familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and other familial colon cancer syndromes. Only 2 double-blinded, placebo-controlled trials have been published concerning the use of preventive strategies in patients with genetically inherited colorectal cancer syndromes, both in patients with FAP. One study evaluated the effects of vitamin C plus vitamin E with or without a high-dose wheat bran fiber supplement on the recurrence of rectal adenomas. Over a 48-month intervention period, only the wheat bran fiber intervention significantly reduced polyp growth. A second study reported that intervention with the NSAID sulindac for 9 months in young patients with FAP resulted in a significant reduction in both polyp number and size in the rectosigmoid colon. All of the large-scale (i.e., >500 randomized participants) phase III nutrient or chemopreventive agent intervention studies thus far have targeted participants with a history of non-familial, sporadic colorectal adenomas. Current clinical adenoma trials do not measure whether the regimen being tested can prevent genotoxic events occurring in early stages of abnormal cell development that contribute to the eventual formation of adenomas nor whether the agent(s) can inhibit events occurring during the progression of adenomas to carcinomas. Therefore, future clinical trial designs may have to consider (i) lengthening the clinical trial period before adenomas develop, (ii) testing at early patient ages and/or (iii) measuring the growth of adenomas as they progress to carcinomas.


Production of ochratoxin A by Aspergillus ochraceus isolated in Japan from moldy rice.
A simple thin-layer chromatography-fluorodensitometric method for quantitative analysis of ochratoxin A was developed. This method proved to be of use in investigating the production of the toxin and the nutritional factors affecting the toxin production by two strains of Aspergillus ochraceus isolated from moldy rice in Japan. These fungi produced large amounts of ochratoxin A in a nutrient solution containing 1% l-phenylalanine and 2% yeast extract.


Malaria severity: Possible influence of the E670G PCSK9 polymorphism: A preliminary case-control study in Malian children.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promotes the degradation of low-density lipoprotein receptors leading to reduced hepatic uptake of plasma cholesterol. Non-synonymous single-nucleotide polymorphisms in its gene have been linked to hypo- or hyper- cholesterolemia, depending on whether they decrease or increase PCSK9 activity, respectively. Since the proliferation and the infectivity of Plasmodium spp. partially depend on cholesterol from the host, we hypothesize that these PCSK9 genetic polymorphisms could influence the course of malaria infection in individuals who carry them. Here we examined the frequency distribution of one dominant (C679X) and two recessive (A443T, I474V) hypocholesterolemic polymorphisms as well as that of one recessive hypercholesterolemic polymorphism (E670G) among healthy and malaria-infected Malian children. Dried blood spots were collected in Bandiagara, Mali, from 752 age, residence and ethnicity-matched children: 253 healthy controls, 246 uncomplicated malaria patients and 253 severe malaria patients. Their genomic DNA was extracted and genotyped for the above PCSK9 polymorphisms using Taqman assays. Associations of genotype distributions and allele frequencies with malaria were evaluated. The minor allele frequency of the A443T, I474V, E670G, and C679X polymorphisms in the study population sample was 0.12, 0.20, 0.26, and 0.02, respectively. For each polymorphism, the genotype distribution among the three health conditions was statistically insignificant, but for the hypercholesterolemic E670G polymorphism, a trend towards association of the minor allele with malaria severity was observed (P = 0.035). The association proved to be stronger when allele frequencies between healthy controls and severe malaria cases were compared (Odd Ratio: 1.34; 95% Confidence Intervals: 1.04-1.83); P = 0.031). Carriers of the minor allele of the E670G PCSK9 polymorphism might be more susceptible to severe malaria. Further investigation of the cholesterol regulating function of PCSK9 in the pathophysiology of malaria is needed.


Ablation of brainstem C1 neurons improves cardiac function in volume overload heart failure.
Activation of the sympathetic nervous system is a hallmark of heart failure (HF) and is positively correlated with disease progression. Catecholaminergic (C1) neurons located in the rostral ventrolateral medulla (RVLM) are known to modulate sympathetic outflow and are hyperactivated in volume overload HF. However, there is no conclusive evidence showing a contribution of RVLM-C1 neurons to the development of cardiac dysfunction in the setting of HF. Therefore, the aim of this study was to determine the role of RVLM-C1 neurons in cardiac autonomic control and deterioration of cardiac function in HF rats. A surgical arteriovenous shunt was created in adult male Sprague-Dawley rats to induce HF. RVLM-C1 neurons were selectively ablated using cell-specific immunotoxin (dopamine-β hydroxylase saporin [DβH-SAP]) and measures of cardiac autonomic tone, function, and arrhythmia incidence were evaluated. Cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction were present in HF rats and improved after DβH-SAP toxin treatment. Most importantly, the progressive decline in fractional shortening observed in HF rats was reduced by DβH-SAP toxin. Our results unveil a pivotal role played by RVLM-C1 neurons in cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction in volume overload-induced HF.


Neuronal calcium spikes enable vector inversion in the Drosophila brain.
A typical neuron signals to downstream cells when it is depolarized and firing sodium spikes. Some neurons, however, also fire calcium spikes when hyperpolarized. The function of such bidirectional signaling remains unclear in most circuits. Here we show how a neuron class that participates in vector computation in the fly central complex employs hyperpolarization-elicited calcium spikes to invert two-dimensional mathematical vectors. When cells switch from firing sodium to calcium spikes, this leads to a ∼180° realignment between the vector encoded in the neuronal population and the fly's internal heading signal, thus inverting the vector. We show that the calcium spikes rely on the T-type calcium channel Ca-a1T, and argue, via analytical and experimental approaches, that these spikes enable vector computations in portions of angular space that would otherwise be inaccessible. These results reveal a seamless interaction between molecular, cellular and circuit properties for implementing vector math in the brain.


TAT-mediated delivery of Bcl-xL protein is neuroprotective against neonatal hypoxic-ischemic brain injury via inhibition of caspases and AIF.
Systemic delivery of recombinant Bcl-xL fusion protein containing the TAT protein transduction domain attenuated neonatal brain damage following hypoxic ischemia (H-I). Within 30 min after intraperitoneal injection of TAT-Bcl-xL protein into 7-day-old rats, substantially enhanced levels of Bcl-xL were found in several brain regions. Administration of TAT-Bcl-xL at the conclusion of the H-I insult decreased cerebral tissue loss in a dose-dependent manner measured 1 and 8 weeks later. Neuroprotection provided by TAT-Bcl-xL was significantly greater than that of the pan-caspase inhibitor BAF, suggesting that protection is only partially attributable to caspase inhibition by TAT-Bcl-xL. TAT-Bcl-xL not only inhibited caspases-3 and -9 activities after H-I but also prevented nuclear translocation of AIF. Taken together, these results substantiate the feasibility of peripheral delivery of an anti-apoptotic factor into the brain of neonatal animals to reduce H-I-induced brain injury.


[Hydrolases of the digestive and nondigestive organs in rhesus macaque monkeys].
Distribution of activity of a wide range of hydrolases was characterised in the duodenum, ileum, jejunum, and colon, as well as in the liver, kidney and spleen in Macaca rhesus. The findings suggest presence of a complex enzyme system performing the membrane and intracellular hydrolysis of nutritional substances, in the small intestine of the primates as well as other mammals. This system, along with the hydrolases of the colon and non-digestive organs, seems to function as an enzymatic barrier.


Online Mental Health Survey for Addressing Psychosocial Condition During the COVID-19 Pandemic in Indonesia: Instrument Evaluation.
Regular monitoring of the pandemic's psychosocial impact could be conducted among the community but is limited through online media. This study aims to evaluate the self-rating questionnaire commonly used for online monitoring of the psychosocial implications of the coronavirus disease 2019 (COVID-19) pandemic. The data were taken from the online assessment results of two groups, with a total of 765 participants. The instruments studied were Self-Rating Questionnaire (SRQ-20), post-traumatic stress disorder (PTSD), and Center for Epidemiological Studies Depression Scale-10 (CESD-10), used in the online assessment. Data analysis used Rasch modeling and Winsteps applications. Validity and reliability were tested, and data were fit with the model, rating scale, and item fit analysis. All the scales for outfit mean square (MnSq) were very close to the ideal value of 1.0, and the Chi-square test was significant. Item reliability was greater than 0.67, item separation was greater than 3, and Cronbach's alpha was greater than 0.60; all the instruments were considered very good. The raw variance explained by measures for the SRQ-20, PTSD, and CESD-10 was 30.7%, 41.6%, and 47.6%, respectively. The unexplained eigenvalue variances in the first contrast were 2.3, 1.6, and 2.0 for the SRQ-20, PTSD, and CESD-10, respectively. All items had positive point-measure correlations. The internal consistency of all the instruments was reliable. Data were fit to the model as the items were productive for measurement and had a reasonable prediction. All the scales are functionally one-dimensional.


Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea.
Because fetal hemoglobin contains gammaglobin chains instead of beta chains, it is not affected by the genetic defect that causes sickle cell disease. Increased levels of fetal hemoglobin decrease the tendency toward intracellular polymerization of sickle hemoglobin that characterizes this disease. Hydroxyurea is one of several cytostatic agents that have been shown to increase the production of fetal hemoglobin in some patients with sickle cell disease. We studied the effects of hydroxyurea administration in 10 hospitalized patients with sickle cell disease, each of whom was treated for three months. Seven patients responded with a 2- to 10-fold increase in fetal hemoglobin, from a mean (+/- SD) of 1.6 +/- 1.6 percent of total hemoglobin to 6.8 +/- 4.7 percent; three patients had fetal-hemoglobin levels of 10 to 15 percent of total hemoglobin. Three did not respond to treatment. Four of the patients who responded were retreated with hydroxyurea after one to four months without treatment and were found to have larger increases in fetal-hemoglobin levels. In most patients, levels were still rising at the end of the study, even after 90 days of therapy. Fetal-hemoglobin levels tended to peak at dosages of hydroxyurea that were myelosuppressive. In the patients who responded to treatment, there were significant increases in the percentage of reticulocytes and erythrocytes containing fetal hemoglobin and in the amount of fetal hemoglobin within these cells. The percentage of dense red cells decreased in the patients who responded to treatment. The tendency toward intracellular polymerization at physiologic oxygen saturation was reduced by about 33 percent in the cells containing fetal hemoglobin, whereas there was no change in the other cells. We conclude that hydroxyurea is effective in increasing the production of fetal hemoglobin, which in this study was found to be associated with a small decrease in hemolysis and an increase in hemoglobin levels despite myelosuppression. Controlled, prospective trials are necessary to establish whether these effects will lead to clinical benefit.


Recombinant A(H6N1)-H274Y avian influenza virus with dual drug resistance does not require permissive mutations to retain the replicative fitness in vitro and in ovo.
The possible emergence of drug-resistant avian flu raises concerns over the limited effectiveness of currently approved antivirals (neuraminidase inhibitors - NAIs) in the hypothetical event of a zoonotic spillover. Our study demonstrated that the recombinant avian A(H6N1) viruses showed reduced inhibition (RI) by multiple NAI drugs following the introduction of point mutations found predominantly in the neuraminidase gene (NA) of NAI-resistant human influenza strains (E119V, R292K and H274Y; N2 numbering). Moreover, A(H6N1)-H274Y showed increased replication efficiency in vitro, and a fitness advantage over wild-type (WT) when co-inoculated into embryonated hen's eggs. The results presented in our study together with the zoonotic potential of the A(H6N1) virus as evidenced by the human infection from 2013, highlight the need for enhanced monitoring of NAI resistance-associated signatures in circulating LPAI (low pathogenic avian influenza) globally.


Relationship Between Violence Against Women, Social Support, Self-Esteem, and Mental Health in Riyadh, Saudi Arabia.
The objectives of this study were to measure the prevalence of mental distress and to explore the relationship between violence against women (VAW), social support, self-esteem, and mental distress in women in Riyadh, Saudi Arabia. A questionnaire-guided, cross-sectional, interview-based study was conducted with 1,932 women, in primary healthcare centers. Around 29% reported moderate to severe distress levels, whereas 40% of women reported lifetime exposure to at least one type of violence. Linear regression analysis found that VAW was positively associated with mental distress with a unit increase associated with a 0.13 (0.58, 1.15) increase in distress level, whereas, for both social support and self-esteem, a unit increase in violence was associated with -0.23 (-0.47, -0.32) and -0.22 (-0.49, -0.33) unit decrease in the mental distress. Structural equation modeling found that violence had direct significant negative effects on social support (β = -.156, p < .001) and self-esteem (β = -.135, p < .001). Both social support (β = -.266, p < .001) and self-esteem (β = -.183, p < .001) had direct significant negative effects on distress. VAW exerted a direct significant positive effect on distress (β = .171, p < .001) as well as an indirect effect (β = .068, p < .001). Both social support (β = .044, p < .001) and self-esteem (β = .025, p < .001) were significant mediators of the effect of violence on mental distress. VAW can lead to mental distress and low self-esteem. Identification, counseling, and social support for women are important to improve their self-confidence and reduce the adverse effects of violence.


[Comparative evaluation of protein hydrolysates in designing their based universal culture medium for the diagnosis of plague and cholera].
Various protein hydrolysates made in Russia and foreign countries were comparatively evaluated to use them to design a universal agarized culture medium for the diagnosis of plague and cholera. Pancreatic baker's yeast broth was found to be most effective among the test media.


Enhanced protocol for real-time transmission of echocardiograms over wireless channels.
This paper presents a methodology to transmit clinical video over wireless networks in real-time. A 3-D set partitioning in hierarchical trees compression prior to transmission is proposed. In order to guarantee the clinical quality of the compressed video, a clinical evaluation specific to each video modality has to be made. This evaluation indicates the minimal transmission rate necessary for an accurate diagnosis. However, the channel conditions produce errors and distort the video. A reliable application protocol is therefore proposed using a hybrid solution in which either retransmission or retransmission combined with forward error correction (FEC) techniques are used, depending on the channel conditions. In order to analyze the proposed methodology, the 2-D mode of an echocardiogram has been assessed. A bandwidth of 200 kbps is necessary to guarantee its clinical quality. The transmission using the proposed solution and retransmission and FEC techniques working separately have been simulated and compared in high-speed uplink packet access (HSUPA) and worldwide interoperability for microwave access (WiMAX) networks. The proposed protocol achieves guaranteed clinical quality for bit error rates higher than with the other protocols, being for a mobile speed of 60 km/h up to 3.3 times higher for HSUPA and 10 times for WiMAX.


Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure.
Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.


Perceptions of healthy eating amongst Indian adolescents in India and Canada.
Dietary patterns have contributed to the rising prevalence of overweight and obesity among Indian adolescents. Yet there are limited studies on their perspectives on healthy eating. The purpose of this study was to understand perceptions and attitudes of Indian-origin adolescents in India and Canada that may contribute to healthy eating behaviour. Qualitative data collection and analysis of 13 focus group discussions (FGD) was conducted among 34 boys and 39 girls (total number of participants: 73) of different weight and socioeconomic status (SES) in rural and urban India, and urban Canada aged 11-18 years. All adolescents perceived homemade foods, and foods high in vitamins, minerals and fiber as healthy. Rural Indian adolescents also identified contaminant-free food as important. Opinions differed regarding the health value of consuming meat, and amongst Canadian adolescents, the health impact of Western versus Indian diets. Identified benefits of healthy eating included improved energy for Indians, and disease prevention for Canadians and urban Indians. Identified barriers across all settings included peers; and availability, access and affordability of unhealthy foods. Urban Indians and Canadian girls also reported academic stress and lack of time as barriers. Canadian girls reported limited parental supervision during mealtimes as an additional barrier. Facilitators to healthy eating included parents, friends and personal preferences for healthy foods. This study suggests potential targets for family-based and school-based education programs and policies to improve dietary habits of Indian and Indo-Canadian adolescents which include, culturally focused nutrition education and guidelines, academic stress management strategies, parental education, food hygiene regulations and restriction on the sale and advertising of unhealthy foods.


HIV mortality and infection in India: estimates from nationally representative mortality survey of 1.1 million homes.
To determine the rates of death and infection from HIV in India. Nationally representative survey of deaths. 1.1 million homes in India. Population 123,000 deaths at all ages from 2001 to 2003. HIV mortality and infection. HIV accounted for 8.1% (99% confidence interval 5.0% to 11.2%) of all deaths among adults aged 25-34 years. In this age group, about 40% of deaths from HIV were due to AIDS, 26% were due to tuberculosis, and the rest were attributable to other causes. Nationally, HIV infection accounted for about 100,000 (59,000 to 140,000) deaths or 3.2% (1.9% to 4.6%) of all deaths among people aged 15-59 years. Deaths from HIV were concentrated in the states and districts with higher HIV prevalence and in men. The mortality results imply an HIV prevalence at age 15-49 years of 0.26% (0.13% to 0.39%) in 2004, comparable to results from a 2005/6 household survey that tested for HIV (0.28%). Collectively, these data suggest that India had about 1.4-1.6 million HIV infected adults aged 15-49 years in 2004-6, about 40% lower than the official estimate of 2.3 million for 2006. All cause mortality increased in men aged 25-34 years between 1997 and 2002 in the states with higher HIV prevalence but declined after that. HIV prevalence in young pregnant women, a proxy measure of incidence in the general population, fell between 2000 and 2007. Thus, HIV mortality and prevalence may have fallen further since our study. HIV attributable death and infection in India is substantial, although it is lower than previously estimated.


Microcystic adnexal carcinoma. Electron microscopic and immunohistochemical study.
We present a patient with microcystic adnexal carcinoma. The lesion was an indurated plaque on the skin of the right upper lip of a 58-year-old woman which was slowly growing during 27 years. Carcinoembryonic antigen was immunoreactive in the luminal contents of the tumor ducts and in the cytoplasm of cells surrounding ducts. S-100 protein was positive in the cytoplasm of a few cells at the lower dermis. These observations suggested that this tumor was related to sweat glands. Furthermore, electron microscopy revealed that tumor cells had features of eccrine ductal cells. These observations confirm that this tumor appeared at least capable of eccrine duct differentiation.