INNOVATIONS IN FOCUS: MECHANISTIC DISEASE THEORIES, CLIMATE DYNAMICS, AND HOST-PARASITE ADAPTATIONS.
Infectious illnesses are predicted to experience a range of intricate responses from climate change, with some likely to rise, others to fall and many expected to undergo changes in prevalence. The study uses extensive data on global temperature variations and infectious illness transmission in people and animals. We now know a lot more about how the temperature changes across the world and whether or not the spread of infectious diseases impacts people as well as animals. Three primary topics of research are investigated in this paper: improving mechanical disease modelling, investigating the role of environmental variation in sickness dynamics, and understanding the consequences of temperature imbalances between parasites and hosts. By incorporating the latest data stemming from these advancements into weather-disease models and bridging critical knowledge gaps, enhancing our ability to forecast the probable effect of rising temperatures on the prevalence of diseases among both human and animal communities is possible. Through the establishment of important information gaps and the incorporation of new findings into models of climate-disease relationships, it will be possible to predict the effects of changes in climatic averages, variations and extremes on people and wildlife health.


Generation of antibody responses to pneumococcal capsular polysaccharides is independent of CD1 expression in mice.
Streptococcus pneumoniae is a bacterial microorganism that frequently causes serious infection, particularly in children and the elderly. Protection against infection with S. pneumoniae is based mainly on the generation of antibodies to the pneumococcal capsular polysaccharides (caps-PS), but the mechanisms responsible for the generation of anticapsular antibodies remain incompletely understood. The aim of the present study was to evaluate the role of CD1-restricted T cells in the antibody response to caps-PS. When immunized with Pneumo23, wild-type mice and CD1 knockout mice on BALB/c and C57BL/6 backgrounds generated immunoglobulin M (IgM) and IgG antibody responses to soluble caps-PS that were comparable. Similar results were obtained after immunization with heat-inactivated S. pneumoniae. The IgM and IgG antibody response of wild-type mice to Pneumo23 was not affected by an antagonizing monoclonal anti-CD1 antibody treatment. In summary, our data provide evidence that the antibody response to caps-PS is generated independently of CD1 expression.


Injury and illness epidemiology in professional Asian football: lower general incidence and burden but higher ACL and hamstring injury burden compared with Europe.
While football injury and illness epidemiology surveillance at professional club level in Europe is available, epidemiological data from other continents are lacking. Investigating injury and illness epidemiology in professional Asian football. Descriptive prospective study. Professional teams from the Asian Football Confederation (AFC) league were followed prospectively for three consecutive AFC seasons (2017 through 2019, 13 teams per season, 322 team months). Time-loss injuries and illnesses in addition to individual match and training exposure were recorded using standardised digital tools in accordance with international consensus procedures. In total, 232 665 hours of exposure (88.6% training and 11.4% matches) and 1159 injuries were recorded; 496 (42.8%) occurred during matches, 610 (52.6%) during training; 32 (2.8%) were reported as 'not applicable' and for 21 injuries (1.8%) information was missing. Injury incidence was significantly greater during match play (19.2±8.6 injuries per 1000 hours) than training (2.8±1.4, p<0.0001), resulting in a low overall incidence of 5.1±2.2.The injury burden for match injuries was greater than from training injuries (456±336 days per 1000 hours vs 54±34 days, p<0.0001). The two specific injuries causing the greatest burden were complete ACL ruptures (0.14 injuries (95% CI 0.9 to 0.19) and 29.8 days lost (29.1 to 30.5) per 1000 hours) and hamstring strains (0.86 injuries (0.74 to 0.99) and 17.5 days (17.0 to 18.1) lost per 1000 hours).Reinjuries constituted 9.9% of all injuries. Index injuries caused 22.6±40.8 days of absence compared with 25.1±39 for reinjuries (p=0.62). The 175 illnesses recorded resulted in 1.4±2.9 days of time loss per team per month. Professional Asian football is characterised by an overall injury incidence similar to that reported from Europe, but with a high rate of ACL ruptures and hamstring injury, warranting further investigations.


Effects of Auditory and Visual Priming on the Identification of Spoken Words.
This study examined the effects of preceding contextual stimuli, either auditory or visual, on the identification of spoken target words. Fifty-one participants (29% males, 71% females; mean age = 24.5 years, SD = 8.5) were divided into three groups: no context, auditory context, and visual context. All target stimuli were spoken words masked with white noise. The relationships between the context and target stimuli were as follows: identical word, similar word, and unrelated word. Participants presented with context experienced a sequence of six context stimuli in the form of either spoken words or photographs. Auditory and visual context conditions produced similar results, but the auditory context aided word identification more than the visual context in the similar word relationship. We discuss these results in the light of top-down processing, motor theory, and the phonological system of language.


Nuclear RNA-seq of single neurons reveals molecular signatures of activation.
Single-cell sequencing methods have emerged as powerful tools for identification of heterogeneous cell types within defined brain regions. Application of single-cell techniques to study the transcriptome of activated neurons can offer insight into molecular dynamics associated with differential neuronal responses to a given experience. Through evaluation of common whole-cell and single-nuclei RNA-sequencing (snRNA-seq) methods, here we show that snRNA-seq faithfully recapitulates transcriptional patterns associated with experience-driven induction of activity, including immediate early genes (IEGs) such as Fos, Arc and Egr1. SnRNA-seq of mouse dentate granule cells reveals large-scale changes in the activated neuronal transcriptome after brief novel environment exposure, including induction of MAPK pathway genes. In addition, we observe a continuum of activation states, revealing a pseudotemporal pattern of activation from gene expression alone. In summary, snRNA-seq of activated neurons enables the examination of gene expression beyond IEGs, allowing for novel insights into neuronal activation patterns in vivo.


Fitness for work in health care workers from the prospective of ethics, science and good practices.
Fitness for work (FFW) is the final task of both risk assessment and health surveillance, aimed at protecting workers' health and working capacity. There are numerous specific concerns regarding health care workers. In particular: i) the frequent difficulty in determining at pre-employment/pre-placement examinations the specific task that the individual worker will perform; ii) the prevalence of female workers and the contemporary presence of numerous occupational risk factors that are a potential cause of harmful effects on women's reproductive health; iii) the progressive aging of the staff especially nurses; iv) the risk to third parties, with particular reference to the issues of biological risk and substance abuse, also in relation to shift work, fatigue and occupational stress; v) the increasing number of immigrant workers among support staff In such cases the occupational physician, respecting both ethical principles and regulations and with an appropriate balance between scientific evidence and the precautionary principle, should express a FFW judgment that allows both the adaptation of work to the worker and vice versa, as recommended by the World Health Organization (WHO) and the International Commission on Occupational Health (ICOH). Proper FFW judgment also permits the expected benefits to be achieved, not only for the workers but also for employers, companies and society.


Hope in Psychiatric Patients: An Observational Study in a Psychiatric Rehabilitation Centre.
The COVID-19 pandemic has led to the re-evaluation of some fundamental aspects for the management of emotions and psychological dynamics. Hope and its lack are important factors that have been especially evaluated in caregivers and HCWs. Instead, our study aimed to explore hopelessness among psychiatric rehabilitation center residents with Primary Psychosis. We recruited 116 inpatients affected by Primary Psychosis (schizophrenia, bipolar disorder, major depression disorder and personality disorder). Hopelessness was sought through the BHS, during the covid-19 pandemic period. They were compared with data from previous studies on HCWs (HealthCare Workers), in the same period, and in the same centre. The results obtained in this group of patients showed high total scores on the BHS scale (mean total score: 7.28±SD 3.73). These data are significantly higher than those found in HWs in the same pandemic period (mean total score: 3.74±SD 3.62). Among the different disorders the borderline personality disorder patients have presented the highest score (mean total score: 8.00±SD 3.50). Understanding resident - and HCWs- level variations in hopelessness may be important for targeting interventions to improve the outcome of residential psychiatric patients.


Leiomyomatosis peritonealis disseminata. Report of a case and review of the literature.
The eighth documented case of leimoyomatosis peritonealis disseminata (LPD) is presented. Histologic evidence for concomitant intravenous leiomyomatosis and early development of a leiomyoma in a vessel wal was noted in the present case. Electronmicroscopic studies proved the smooth muscle origin of the tumors in this case. Intriguing features of this disease are its grossly malignant appearance, relatively benign histology, and generally favorable clinical behavior. Because women of reproductive age, especially in the fourth decade, are affected, hormones may play a role in the etiology of LPD. Intraoperative diagnosis requires frozen-section examination and treatment has included extirpation of involved tissues, wherever possible. Also advocated is surgical castration which may remove the hormonal stimulus for the growth of any residual tumor. Since LPD bears a close resemblance to genital leiomyosarcoma, it warrants proper recognition and management.


The Effect of Fetal Heart Rate Segment Selection on Deep Learning Models for Fetal Compromise Detection.
Monitoring the fetal heart rate (FHR) is common practice in obstetric care to assess the risk of fetal compromise. Unfortunately, human interpretation of FHR recordings is subject to inter-observer variability with high false positive rates. To improve the performance of fetal compromise detection, deep learning methods have been proposed to automatically interpret FHR recordings. However, existing deep learning methods typically analyse a fixed-length segment of the FHR recording after removing signal gaps, where the influence of this segment selection process has not been comprehensively assessed. In this work, we develop a novel input length invariant deep learning model to determine the effect of FHR segment selection for detecting fetal compromise. Using this model, we perform five times repeated five-fold cross-validation on an open-access database of 552 FHR recordings and assess model performance for FHR segment lengths between 15 and 60 minutes. We show that the performance after removing signal gaps improves with increasing segment length from 15 minutes (AUC = 0.50) to 60 minutes (AUC = 0.74). Additionally, we demonstrate that using FHR segments without removing signal gaps achieves superior performance across signal lengths from 15 minutes (AUC = 0.68) to 60 minutes (AUC = 0.76). These results show that future works should carefully consider FHR segment selection and that removing signal gaps might contribute to the loss of valuable information.


Nutritional risk of high-carbohydrate, guar gum dietary supplementation in non-insulin-dependent diabetes mellitus.
Dietary supplementation with high-carbohydrate, guar gum fiber (HCF) is effective in acutely blunting postprandial blood glucose levels. We report the effect of such supplementation on the diet and nutritional status of a group of 16 subjects with non-insulin-dependent diabetes mellitus (NIDDM) who incorporated either HCF bars (35.7 g carbohydrate and 6.6 g guar gum/bar) or placebo bars (identical except for the absence of guar gum) into the diet for 6 mo as part of a double-blind, randomized clinical trial. The HCF subjects achieved mean daily intake of 4.8 +/- 0.4 bars, constituting 51.2 +/- 3.1% of total calories and providing 29.7 +/- 2.6 g guar gum daily. Energy intakes and body weight did not change significantly in either group. Food consumption patterns and nutrient intakes did change, although not enough to impair the nutritional integrity of the diet because the bars themselves served as a source of nutrients. The bars were rich in thiamin, B6, folacin, phosphorus, iron, zinc, and copper, adequately replacing any decrease in nutrient intake as a result of foods being dropped from the diet. In fact, daily intakes of B6, folacin, and copper actually increased due to contributions from the bars. Nutrients in which the bars were poor (vitamins A, C and B12) resulted in suboptimal intakes (less than 66% RDA). Although no significant change in nutritional status of the HCF group occurred as determined by arm muscle area, arm fat area, hemoglobin, hematocrit, or serum albumin, transferrin, iron, ferritin, calcium, phosphate, B12, and magnesium levels, these indicators of nutritional status are rather insensitive.(ABSTRACT TRUNCATED AT 250 WORDS)


Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells.
Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or Mdivi-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with Mdivi-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient-specific cardiac regenerative medicine.


Update: Public Health Response to the Coronavirus Disease 2019 Outbreak - United States, February 24, 2020.
An outbreak of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) began in Wuhan, Hubei Province, China in December 2019, and has spread throughout China and to 31 other countries and territories, including the United States (1). As of February 23, 2020, there were 76,936 reported cases in mainland China and 1,875 cases in locations outside mainland China (1). There have been 2,462 associated deaths worldwide; no deaths have been reported in the United States. Fourteen cases have been diagnosed in the United States, and an additional 39 cases have occurred among repatriated persons from high-risk settings, for a current total of 53 cases within the United States. This report summarizes the aggressive measures (2,3) that CDC, state and local health departments, multiple other federal agencies, and other partners are implementing to slow and try to contain transmission of COVID-19 in the United States. These measures require the identification of cases and contacts of persons with COVID-19 in the United States and the recommended assessment, monitoring, and care of travelers arriving from areas with substantial COVID-19 transmission. Although these measures might not prevent widespread transmission of the virus in the United States, they are being implemented to 1) slow the spread of illness; 2) provide time to better prepare state and local health departments, health care systems, businesses, educational organizations, and the general public in the event that widespread transmission occurs; and 3) better characterize COVID-19 to guide public health recommendations and the development and deployment of medical countermeasures, including diagnostics, therapeutics, and vaccines. U.S. public health authorities are monitoring the situation closely, and CDC is coordinating efforts with the World Health Organization (WHO) and other global partners. Interim guidance is available at https://www.cdc.gov/coronavirus/index.html. As more is learned about this novel virus and this outbreak, CDC will rapidly incorporate new knowledge into guidance for action by CDC, state and local health departments, health care providers, and communities.


Revision of unstable capitellocondylar (unlinked) total elbow replacement.
Instability is a recognized complication associated with unlinked total elbow implants. The best form of treatment of this problem is uncertain as very little has been written about it. Twelve patients underwent operative treatment of instability at the site of a capitellocondylar unlinked total elbow replacement, and the results were reviewed retrospectively. The study group included ten women and two men with an average age of fifty-eight years. Ten patients had rheumatoid arthritis. Three elbows underwent conversion to a semi-constrained hinged prosthesis. In the other nine elbows, an attempt was made to continue with an unlinked prosthesis: three had reconstruction of one or both collateral ligaments, four had component revision, and two had both ligament reconstruction and component revision. After an average duration of follow-up of six years (range, two to fifteen years) only three patients had retained a functioning unlinked prosthesis. Of the remaining nine patients, three had had a conversion to a semi-constrained arthroplasty at the time of the index procedure, four had had a conversion to a semi-constrained prosthesis at the time of a salvage procedure, one had had a resection arthroplasty, and one had a painfully dislocated elbow and had declined revision. Thus, seven elbows eventually underwent conversion to a semi-constrained prosthesis; these conversion procedures were technically difficult, with perforation of the humerus occurring in six patients and perforation of the ulna occurring in four. After all procedures, the average elbow flexion was 132 degrees and the average flexion contracture was 25 degrees. According to the Mayo Elbow Performance Index, there were four excellent results, three good results, three fair results, and one poor result. Revision of an unlinked total elbow prosthesis to a linked total elbow prosthesis is difficult, but it restores elbow function. Although the present series documents the unpredictability of attempts to salvage an unstable unlinked prosthesis, it seems reasonable to attempt at least one soft-tissue procedure before converting to a linked prosthesis.


[Serum antibody profiles against gangliosides and sulfatide in peripheral neuropathies: evaluation of a new immunoassay].
We evaluated the analytical performances of a new line immunoassay (LIA) for the simultaneous detection of twelve anti-ganglioside and anti-sulfatide autoantibodies from Generic Assays, in comparison with our dot immunoassay. The LIA detected IgG and/or IgM autoantibodies against human GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b and sulfatide. Forty sera of patients with IgG autoantibody profiles in acute autoimmune neuropathies and 39 sera of patients with IgM autoantibody profiles in chronic autoimmune neuropathies were tested. To have a better sensitivity, 20 μL of sera instead of 10 μL were used. In these conditions, we observed a good concordance of IgG and IgM autoantibody profiles by both immunoassays. The test including novel gangliosides was easy to perform and superior for identifying autoimmune neuropathies. The data indicate that the test provides reliable simultaneous detection of autoantibodies against a large panel of human gangliosides and sulfatide with a good diagnostic usefulness in combination with clinical and electrophysiological data.


[Microrelief of the coronary artery intima in sudden death].
Scanning electron microscopy was used to study the microrelief of the intima of coronary arteries in 11 cases of sudden death due to acute coronary insufficiency. In areas of macroscopically intact intima and in zones of minimal atherosclerotic lesions in patients dying of acute coronary insufficiency there were disorganization of intima microrelief with zones of flattening of folds of the first order, the appearance of microplaques with ulceration, dystrophic calcification which reflect early manifestations of coronary artery atherosclerosis. Another group of lesions (diendothelization of the intima with initial signs of parietal thrombus formation) characterizes the functional state of the vessel and serves an indirect criterion of acutely developing spasm of the coronary artery.


Peripheral defocus as it relates to myopia progression: A mini-review.
Myopia is the most common refractive error in the world and has reached a pandemic level. The potential complications of progressive myopia have inspired researchers to attempt to understand the sources of myopia and axial elongation and to develop modalities to arrest progression. Considerable attention has been given over the past few years to the myopia risk factor known as hyperopic peripheral blur, which is the focus of this review. It will discuss the primary theories believed to be the cause of myopia and the parameters considered to contribute to and influence the effect of peripheral blur, such as the surface retinal area of blur or the depth of blur. The multitude of optical devices designed to provide peripheral myopic defocus will be mentioned, including bifocal and progressive addition ophthalmic lenses, peripheral defocus single-vision ophthalmic lenses, orthokeratology lenses, and bifocal or multifocal center distance soft lenses, as well as their effectivity as discussed in the literature to date.


Temperature and the vertical movements of oceanic whitetip sharks, Carcharhinus longimanus.
Large-bodied pelagic ectotherms such as sharks need to maintain internal temperatures within a favourable range in order to maximise performance and be cost-efficient foragers. This implies that behavioural thermoregulation should be a key feature of the movements of these animals, although field evidence is limited. We used depth and temperature archives from pop-up satellite tags to investigate the role of temperature in driving vertical movements of 16 oceanic whitetip sharks, Carcharhinus longimanus, (OWTs). Spectral analysis, linear mixed modelling, segmented regression and multivariate techniques were used to examine the effect of mean sea surface temperature (SST) and mixed layer depth on vertical movements. OWTs continually oscillated throughout the upper 200 m of the water column. In summer when the water column was stratified with high SSTs, oscillations increased in amplitude and cycle length and sharks reduced the time spent in the upper 50 m. In winter when the water column was cooler and well-mixed, oscillations decreased in amplitude and cycle length and sharks frequently occupied the upper 50 m. SSTs of 28 oC marked a distinct change in vertical movements and the onset of thermoregulation strategies. Our results have implications for the ecology of these animals in a warming ocean.


Two to five year follow-up of Harris-Galante cementless total hip arthroplasty.
One hundred and forty-nine hips (125 patients) underwent cementless Harris-Galante primary total hip arthroplasty from September 1987 to June 1990 at the Taichung Veterans General Hospital. Seventy hips (61 patients) have been followed up for at least 2 years (range, 26-55 months, mean 36 months). The primary diagnoses included osteoarthritis (42.9%) and avascular necrosis (57.1%). All the hips were evaluated using Harris hip score and Mayo Clinic hip score. The average Harris hip score was 36.5 points (23-73) preoperatively, and 95 points (80-100) postoperatively. When evaluated by the Harris hip score, 94.3% were excellent, and 5.7% had good results; and 90% were excellent, 10% had good results when evaluated by Mayo Clinic hip score. No fair or poor results were noted by either evaluating system. Fifty-seven femoral components (81.4%) appeared to have stable bone ingrowth fixation, ten components (14.3%) had stable fibrous ingrowth, and three (4.3%) were unstable. Fifty-five hips (78.6%) showed radiolucent lines around the femoral component in follow-up roentgenogram; most were at the non-porous, fiber-mesh part. It seemed that there was no correlation between these radiolucent lines and clinical outcome, according to this short-term study.


Quantum chemical study of the reactivity of C60HR and C60(CHR) derivatives.
In the present work a quantum chemical study of a series of substituted hydrofullerenes, C(60)HR, and a series of methanofullerenes, C(60)(CHR), is presented. Their reactivity and geometrical, energetic, electronic, and magnetic properties, as well as the influence of the substituent, are discussed. As a probe of the reactivity, the acidic properties of these fullerene derivatives were predicted, based on the calculated deprotonation energies, with a previously set up scheme. The electronic delocalization upon deprotonation was described, and the global (magnetizabilities) and local aromaticity (nucleus-independent chemical shifts) was analyzed and compared with respect to the group properties for the series of functional groups. The geometries of both acidic and basic forms were fully optimized at the AM1 level, and all property calculations were performed at the HF/3-21G and the B3LYP/6-31G* level of theory.


Isolation and characterization of mutants of Streptococcus mutans using selective removal of wild-type cells by agglutination with an agglutinin from Persea americana.
Persea americana agglutinin (PAA), a substance known to bind basic proteins and inhibit the sucrose-independent adherence of Streptococcus mutants to saliva = coated hydroxyapatite (Staat et al., 1980) was used to selectively enrich for mutants defective in a variety of cell surface associated virulence characteristics from cultures UAB62 (PS14 Riff, serotype c), UAB66 (6715 Strr Spcr, serotype g) and UAB77 (GS5, serotype c). Following mutagenesis and growth for segregation and phenotypic expression, washed cells of each strain were exposed to PAA overnight at 37 degrees C. Aggregated cells were removed by low-speed centrifugation and cells remaining in the supernatant fluids were concentrated, grown to stationary phase and the enrichment with PAA repeated. Mutants isolated following enrichment were phenotypically diverse and included strains defective in one or more of the following characteristics: adherence to glass in a sucrose-containing medium, aggregation with sucrose, dextran or PAA. dextranase production, colony morphology, cell or chain morphology, fermentation of sorbitol, lactose, galactose, raffinose, melibiose, or fructose, and production of surface protein antigen A (SpaA). The diversity of mutant phenotypes identified along with the observation that PAA could still cause aggregation (with a lower efficiency) of all mutants leads us to infer that the interaction of this agglutinin with proteins on the S. mutans cell surface is relatively nonspecific and that the observed inhibition of S. mutants attachment to saliva-coated hydroxyapatite caused by PAA is not due to a highly specific unique interaction of PAA with the protein(s) responsible for sucrose-independent adherence.


Tolerance to acetic acid is improved by mutations of the TATA-binding protein gene.
Screening a library of overexpressing mutant alleles of the TATA-binding gene SPT15 yielded two Saccharomyces cerevisiae strains (MRRC 3252 and 3253) with enhanced tolerance to acetic acid. They were also tolerant to propionic acid and hydrogen peroxide. Transcriptome profile analysis identified 58 upregulated genes and 106 downregulated genes in MRRC 3252. Stress- and protein synthesis-related transcription factors were predominantly enriched in the upregulated and downregulated genes respectively. Eight deletion mutants for some of the highly downregulated genes were acetic acid-tolerant. The level of intracellular reactive oxygen species was considerably lessened in MRRC 3252 and 3253 upon exposure to acetic acid. Metabolome profile analysis revealed that intracellular concentrations of 5 and 102 metabolites were increased and decreased, respectively, in MRRC 3252, featuring a large increase of urea and a significant decrease of amino acids. The dur1/2Δmutant, in which the urea degradation gene DUR1/2 is deleted, displayed enhanced tolerance to acetic acid. Enhanced tolerance to acetic acid was also observed on the medium containing a low concentration of amino acids. Taken together, this study identified two SPT15 alleles, nine gene deletions and low concentration of amino acids in the medium that confer enhanced tolerance to acetic acid.


Improving the Process of Adjusting the Parameters of Finite Element Models of Healthy Human Intervertebral Discs by the Multi-Response Surface Method.
The kinematic behavior of models that are based on the finite element method (FEM) for modeling the human body depends greatly on an accurate estimate of the parameters that define such models. This task is complex, and any small difference between the actual biomaterial model and the simulation model based on FEM can be amplified enormously in the presence of nonlinearities. The current paper attempts to demonstrate how a combination of the FEM and the MRS methods with desirability functions can be used to obtain the material parameters that are most appropriate for use in defining the behavior of Finite Element (FE) models of the healthy human lumbar intervertebral disc (IVD). The FE model parameters were adjusted on the basis of experimental data from selected standard tests (compression, flexion, extension, shear, lateral bending, and torsion) and were developed as follows: First, three-dimensional parameterized FE models were generated on the basis of the mentioned standard tests. Then, 11 parameters were selected to define the proposed parameterized FE models. For each of the standard tests, regression models were generated using MRS to model the six stiffness and nine bulges of the healthy IVD models that were created by changing the parameters of the FE models. The optimal combination of the 11 parameters was based on three different adjustment criteria. The latter, in turn, were based on the combination of stiffness and bulges that were obtained from the standard test FE simulations. The first adjustment criteria considered stiffness and bulges to be equally important in the adjustment of FE model parameters. The second adjustment criteria considered stiffness as most important, whereas the third considered the bulges to be most important. The proposed adjustment methods were applied to a medium-sized human IVD that corresponded to the L3-L4 lumbar level with standard dimensions of width = 50 mm, depth = 35 mm, and height = 10 mm. Agreement between the kinematic behavior that was obtained with the optimized parameters and that obtained from the literature demonstrated that the proposed method is a powerful tool with which to adjust healthy IVD FE models when there are many parameters, stiffnesses, and bulges to which the models must adjust.


Brain state monitoring for the future prediction of migraine attacks.
Migraine attacks are unpredictable, precluding preemptive interventions and leading to lack of control over individuals' lives. Although there are neurophysiological changes 24-48 hours before migraine attacks, so far, they have not been used in patients' management. This study evaluates the applicability and the ability to identify pre-attack changes of daily "at home" electroencephalography obtained with a portable system for migraine patients. Patients with episodic migraine fulfilling ICHD-3 beta criteria used a mobile system composed of a wireless EEG device (BrainStation®, Neuroverse®, Inc., USA) and mobile application (BrainVitalsM®, Neuroverse®, Inc., USA) to self-record their neural activity daily at home while resting and while performing an attention task, over the course of 2 weeks. Standard EEG spectral analysis and event-related brain potentials (ERP) methods were used and recordings were grouped by time from migraine attacks (i.e. "Interictal day", "24 h Before Migraine", "Migraine day" and "Post Migraine"). Twenty-four patients (22 women) recorded an average of 13.3 ± 1.9 days and had 2 ± 0.9 attacks. Twenty-four hours before attack onset, there was a statistically significant modulation of relative power in the delta (decrease) and beta (increase) frequency bands, at rest, and a significant reduction of the amplitude and inter-trial coherence measures of an attention event-related brain potential (P300). This proof-of-concept study shows that brain state monitoring, utilising an easy-to-use wearable EEG system to track neural modulations at home, can identify physiological changes preceding a migraine attack enabling valuable pre-symptom prediction and subsequent early intervention.


A pilot-study of Paclitaxel in previously treated patients with metastatic unknown primary carcinomas.
We enrolled 12 patients in a pilot phase II study to evaluate the efficacy and toxicity of paclitaxel as a single agent in the salvage treatment of patients with metastatic unknown primary carcinoma (UPC). Patients were given 175 mg/m(2) of paclitaxel as a three-hour infusion. One patient was enrolled into the study with a diagnosis of poorly differentiated carcinoma but was found after another biopsy to have a soft tissue sarcoma and was therefore not included in this study. All patients had progressive disease after receiving at least one prior chemotherapy regimen containing cisplatin. Two patients had also received radiation therapy. Seven patients had adenocarcinomas, two patients had poorly differentiated adenocarcinomas and two had poorly differentiated carcinomas (PDC). Four patients experienced grade IV granulocytopenia and two patients experienced grade II nausea and vomiting. No responses were observed, and the study was terminated without enrolling more patients. At the dose level used in this study, paclitaxel was inactive in the treatment of patients with UPC whose cancer was resistant to cisplatin.


Arbitrary Microphone Array Optimization Method Based on TDOA for Specific Localization Scenarios.
Various microphone array geometries (e.g., linear, circular, square, cubic, spherical, etc.) have been used to improve the positioning accuracy of sound source localization. However, whether these array structures are optimal for various specific localization scenarios is still a subject of debate. This paper addresses a microphone array optimization method for sound source localization based on TDOA (time difference of arrival). The geometric structure of the microphone array is established in parametric form. A triangulation method with TDOA was used to build the spatial sound source location model, which consists of a group of nonlinear multivariate equations. Through reasonable transformation, the nonlinear multivariate equations can be converted to a group of linear equations that can be approximately solved by the weighted least square method. Then, an optimization model based on particle swarm optimization (PSO) algorithm was constructed to optimize the geometric parameters of the microphone array under different localization scenarios combined with the spatial sound source localization model. In the optimization model, a reasonable fitness evaluation function is established which can comprehensively consider the positioning accuracy and robustness of the microphone array. In order to verify the array optimization method, two specific localization scenarios and two array optimization strategies for each localization scenario were constructed. The optimal array structure parameters were obtained through numerical iteration simulation. The localization performance of the optimal array structures obtained by the method proposed in this paper was compared with the optimal structures proposed in the literature as well as with random array structures. The simulation results show that the optimized array structure gave better positioning accuracy and robustness under both specific localization scenarios. The optimization model proposed could solve the problem of array geometric structure design based on TDOA and could achieve the customization of microphone array structures under different specific localization scenarios.


Approximate model of cooperative activation and crossbridge cycling in cardiac muscle using ordinary differential equations.
We develop a point model of the cardiac myofilament (MF) to simulate a wide variety of experimental muscle characterizations including Force-Ca relations and twitches under isometric, isosarcometric, isotonic, and auxotonic conditions. Complex MF behaviors are difficult to model because spatial interactions cannot be directly implemented as ordinary differential equations. We therefore allow phenomenological approximations with careful consideration to the relationships with the underlying biophysical mechanisms. We describe new formulations that avoid mean-field approximations found in most existing MF models. To increase the scope and applicability of the model, we include length- and temperature-dependent effects that play important roles in MF responses. We have also included a representation of passive restoring forces to simulate isolated cell shortening protocols. Possessing both computational efficiency and the ability to simulate a wide variety of muscle responses, the MF representation is well suited for coupling to existing cardiac cell models of electrophysiology and Ca-handling mechanisms. To illustrate this suitability, the MF model is coupled to the Chicago rabbit cardiomyocyte model. The combined model generates realistic appearing action potentials, intracellular Ca transients, and cell shortening signals. The combined model also demonstrates that the feedback effects of force on Ca binding to troponin can modify the cytosolic Ca transient.


Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila.
Methionine restriction (MetR) extends lifespan in various organisms, but its mechanistic understanding remains incomplete. Whether MetR during a specific period of adulthood increases lifespan is not known. In Drosophila, MetR is reported to extend lifespan only when amino acid levels are low. Here, by using an exome-matched holidic medium, we show that decreasing Met levels to 10% extends Drosophila lifespan with or without decreasing total amino acid levels. MetR during the first four weeks of adult life only robustly extends lifespan. MetR in young flies induces the expression of many longevity-related genes, including Methionine sulfoxide reductase A (MsrA), which reduces oxidatively-damaged Met. MsrA induction is foxo-dependent and persists for two weeks after cessation of the MetR diet. Loss of MsrA attenuates lifespan extension by early-adulthood MetR. Our study highlights the age-dependency of the organismal response to specific nutrients and suggests that nutrient restriction during a particular period of life is sufficient for healthspan extension.


Exogenous Melatonin Promotes Cold Tolerance in Grape Seedlings: Physiological, Transcriptomic, and Functional Evidence.
Melatonin (MEL) is an antioxidant molecule that enhances plant tolerance to environmental stress. However, the mechanisms by which MEL regulates cold signaling pathways in grapes under cold stress remain elusive. Here, we investigated the physiological and transcriptomic changes in grape seedlings treated with exogenous MEL to determine their protective role under cold stress. Results showed that 150 μM MEL effectively attenuated cold-induced cell damage by reducing reactive oxygen species (ROS) and preserving the chloroplast structure and function. MEL also inhibited tannin degradation, which contributed to its protective effect. Exogenous MEL promoted the synthesis of endogenous MEL, abscisic acid, auxin, and cytokinin while inhibiting gibberellin. Transcriptomic profiling revealed 776 differentially expressed transcripts in MEL-treated samples compared to controls. Functional analysis of a candidate hub gene, VvHSFA6b, showed that its overexpression in grape calli enhances cold tolerance by activating jasmonic acid synthesis pathway genes, promoting JA accumulation, and inhibiting JAZ-repressed transcription factors.


Correlation of Serum Endocan Level With Apoptosis Indicators and Severity of Atherosclerotic Lesions of Coronary Arteries in Patients With Coronary Heart Disease.
Aim To study the relationship of blood serum concentration of endocan with indexes of apoptosis and clinical and instrumental characteristics of patients with ischemic heart disease (IHD).Material and methods The study included 176 subjects (105 men and 71 women). 150 of them were diagnosed with IHD and 26 were healthy volunteers. Anthropometric measurements, coronary angiography, echocardiography, duplex ultrasound scanning of extracranial parts of the brachiocephalic arteries were performed for all patients. Concentrations of endocan (ng / ml), glucose (mmol / l), and apoptotic markers Bcl-2 (ng / ml), Bax (ng / ml), Bcl-2 / Bax, TRAIL (pg / ml), and p53 (ng / ml) were measured in blood serum. Patients were divided into groups based on their SYNTAX scores: group 1 with moderate atherosclerotic lesions of the coronary arteries (CA) (score < 22, 78 patients); group 2 with severe CA atherosclerosis (score 23-32, 37 patients); and group 3 with extremely severe CA lesions (score >33, 35 patients). The control group consisted of healthy volunteers (26 subjects). All groups were age- and sex-matched. Differences were considered statistically significant at p<0.05.Results A correlation was found between endocan concentration and IHD severity (r=0.32, p<0.001). In group 1, the median endocan concentration was 14.57 ng / ml [8.21; 23.66], in group 2, 19.34 ng / ml [8.425; 26.645], in group 3, 32.13 ng / ml [18.2; 39.12], and in the control group, 6.92 ng / ml [4.62; 9.18]. Correlations of varying strength and significance were observed between the endocan concentration and a number of clinical and instrumental characteristics. Endocan concentrations significantly differed in groups of patients with multifocal atherosclerosis (p<0.01), angina pectoris (p<0.01), a history of myocardial infarction (p<0.001), and obesity (p<0.05) from patients without these signs. Also, a correlation was found between serum endocan concentration and apoptotic markers: TRAIL (r= -0.448, p<0.001); BCL-2 (r= -0.552, p<0.001), Bax (r= -0.519, p<0.001), Bcl-2 / Bax (r= -0.576, p<0.001) and p53 (r= -0.520, p <0.001).Conclusion The study demonstrated a potential role of endocan as a promising biomarker for risk stratification, prognosis and therapeutic monitoring of IHD patients.


[Multilayer dermatoplasty by means of autodermal strip in inguinal hernia].
The author suggests the method of plastic reconstruction of the posterior wall of the inguinal canal by means of an autodermal strip, the lower edges of the internal oblique and transverse abdominal muscle together with the transverse fascia being laced by an autodermal strip. Then, stitches of the latter are sutured to the ilio-pubic band posterior to the testicular cord with a simultaneous constriction of the inguinal canal deep ring. A medial aponeurotic leaf of the external oblique abdominal muscle is sutured to the inguinal ligament anterior to the testicular cord, while a lateral aponeurotic leaf of the former muscle is sutured to the medial one as a duplicature. Since 1971 eighty eight operations have been performed after the technic described. Late results up to 3 years were followed up in 80 cases. No recurrences were noted.


Central control of cardiovascular function during sleep.
There is increasing evidence that cardiovascular control during sleep is relevant for cardiovascular risk. This evidence warrants increased experimental efforts to understand the physiological mechanisms of such control. This review summarizes current knowledge on autonomic features of sleep states [non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS)] and proposes some testable hypotheses concerning the underlying neural circuits. The physiological reduction of blood pressure (BP) during the night (BP dipping phenomenon) is mainly caused by generalized cardiovascular deactivation and baroreflex resetting during NREMS, which, in turn, are primarily a consequence of central autonomic commands. Central commands during NREMS may involve the hypothalamic ventrolateral preoptic area, central thermoregulatory and central baroreflex pathways, and command neurons in the pons and midbrain. During REMS, opposing changes in vascular resistance in different regional beds have the net effect of increasing BP compared with that of NREMS. In addition, there are transient increases in BP and baroreflex suppression associated with bursts of brain and skeletal muscle activity during REMS. These effects are also primarily a consequence of central autonomic commands, which may involve the midbrain periaqueductal gray, the sublaterodorsal and peduncular pontine nuclei, and the vestibular and raphe obscurus medullary nuclei. A key role in permitting physiological changes in BP during sleep may be played by orexin peptides released by hypothalamic neurons, which target the postulated neural pathways of central autonomic commands during NREMS and REMS. Experimental verification of these hypotheses may help reveal which central neural pathways and mechanisms are most essential for sleep-related changes in cardiovascular function.


Secondary glaucoma associated with advanced acanthamoeba keratitis.
To describe the association of acanthamoeba keratitis and glaucoma, to establish an incidence of glaucoma in patients with acanthamoeba keratitis, to discuss treatment options and outcomes in these patients, and to describe the histopathologic findings and pathogenesis of glaucoma secondary to acanthamoeba keratitis. After Institutional Review Board approval, the charts of all patients suspected of having acanthamoeba keratitis at Aston Ambulatory Center at The University of Texas Southwestern Medical Center were reviewed. Inclusion criteria were as follows: diagnosis of acanthamoeba keratitis by positive confocal microscopy or culture, diagnosis of glaucoma or ocular hypertension secondary to acanthamoeba keratitis, and at least 6 months of follow-up. Exclusion criteria included a previous diagnosis of glaucoma or ocular hypertension and any history of intraocular surgery before the development of glaucoma. The date of keratitis development, pneumotonometry on initial and follow-up examinations, glaucoma medications used, and surgical procedures performed were tabulated. Twenty patients (20 eyes) were included. Six (30%) eyes developed secondary glaucoma during the review period. Of the patients treated for glaucoma with medication alone, the visual acuity of three (75%) of four became light perception or no light perception. Three of six patients required glaucoma drainage device implantation for intraocular pressure control. Of these, the vision of one eye became no light perception, and the other two eyes maintained better than 20/100 vision. Histopathologic examination showed chronic inflammation of the trabecular meshwork and angle closure. No acanthamoeba organisms were found in the angle structures. The development of secondary glaucoma is not uncommon in acanthamoeba keratitis and is a poor prognostic sign in patients with acanthamoeba keratitis, because most progress to light perception or no light perception vision. Histopathologic findings suggest an inflammatory angle-closure mechanism, apparently without direct infiltration of the organism. The glaucoma associated with acanthamoeba keratitis is often severe and frequently requires surgical intervention for intraocular pressure control and vision preservation.


Prevalence of CARD15/NOD2 mutations in Caucasian healthy people.
Crohn's disease (CD) has been associated with CARD15/NOD2 mutations in Caucasians. The R702W, G908R, and 1007fs mutations represent 82% of the mutated chromosomes. The relative risk of developing CD in homozygous or compound heterozygous people has been estimated as between 10 and 40 times that of the general population. This high risk may support the opinion that CARD15/NOD2 variants are strong CD risk factors at the individual and population levels. The allele and genotype frequencies were calculated for the R702W, G908R, and 1007fs mutations in 3,575 Caucasian healthy controls recruited by 15 groups distributed on three continents. Geographic homogeneity was tested and the observed proportion of double mutants was compared with the expected value using chi2 tests. The allele frequencies of the R702W, G908R, and 1007fs mutations were 4.3% (3.6-4.9), 1.2% (0.8-1.6), and 2.3% (1.8-2.8), respectively, with large geographic fluctuations of the G908R, 1007fs, and wild-type alleles (P<0.0001). At the population level, no simple relationship was observed between mutation frequencies and the disease incidences in the studied populations. At the individual level, no significant deficit of double-dose mutation carriers among healthy controls was found, providing strong evidence that the penetrances of the most at-risk genotypes are low. Altogether, these data confirm that CARD15/NOD2 acts in interaction with other unknown risk cofactors.


Can morbidity associated with untreated asthma in primary school children be reduced?: a controlled intervention study.
To determine whether an intervention programme based on existing school and community resources can reduce school absence and improve participation in games lessons and sport in children with unrecognised or undertreated asthma. Parallel group controlled intervention study. 102 primary schools in Nottingham: 49 were randomised to receive the intervention and 53 to be control schools. All children aged 5 to 10 years with parent reported absence from school because of wheezing in the previous year and taking no treatment or beta agonists only. Children with asthma were referred to their general practitioner for assessment of symptoms and treatment. Teachers were given education on asthma by the school nurse in 44 of the 49 intervention schools. Changes in school absence and missed games and swimming lessons because of wheezing, and schools' policy towards management of asthma in school. Of 17,432 children screened, 451 met the entry criteria--228 in intervention schools and 223 in control schools. 152 (67%) children in intervention schools visited their general practitioner, of whom 39 (26%) were given a new diagnosis of asthma and 58 (38%) had treatment for asthma increased or changed. Over the next academic year mean (SE) parent reported school absence due to wheezing fell significantly, but to a similar extent, in both intervention and control schools (0.82 (0.11) and 1.09 (0.21) weeks respectively). There was little change in school recorded absence or participation in games lessons and swimming lessons in either group. At the end of the study intervention schools were more likely to have improved aspects of management of asthma in school. The intervention resulted in a majority of children being assessed by their general practitioner and improved teachers' understanding and management of asthma, but it did not result in any appreciable reduction in morbidity.


Toxicity and tissue accumulation of copper in chicks fed casein and soy-based diets.
Experiments were conducted to study Cu toxicity in chicks fed casein or soy-containing diets containing graded levels of excess CuSO4.5H2O. Differences between diets in measures of Cu toxicity were pronounced. Addition of 800 mg of Cu/kg to a casein-dextrose semipurified diet decreased weight gains by 63%, but the same addition of Cu to a corn-soybean meal complex diet decreased gains by only 8%. At all levels of Cu supplementation (100, 200, 400 or 800 mg/kg), Cu deposition in the liver was increased markedly in chicks fed casein diets compared with those fed the complex diet. Substituting soy-protein concentrate for casein in the semipurified diet resulted in a marked decrease in Cu toxicity as measured by weight gain reductions and tissue accumulation of Cu.


Cultural and ethnic barriers in conducting research. Factors influencing menarche in the United Arab Emirates.
The objective of this cross sectional survey was to study the feasibility of conducting research on issues related to physical and sexual maturation in a predominantly Islamic society and to identify the factors influencing menarche in this multi ethnic community. This study was conducted in Al-Ain, United Arab Emirates (UAE) between January 1999 through to February 1999. Fifteen female secondary schools located in different geographical regions in Al-Ain were chosen in consultation with the District Education Department. All girls aged 12-16-years were selected. Information regarding whether they had attained menarche including month and the year, age at menarche and the factors influencing it such as height and weight, diet, physical activity were gathered. Univariate and multiple linear regressions were used in analysis. Of the 1500 questionnaires distributed, 1416 questionnaires were returned but only 890 had the required information and were used in the analysis. Ninety-three (10.4%) had not attained menarche and as expected these girls were younger (p<0.0001) than those who had attained menarche. Mean age at menarche was 12.68 (SD 1.27) years. In the univariate analysis UAE nationality, vegetarians (p=0.001), higher income group (p=0.008), low body weight (p=0.009) and a diagnosis of anemia (p<0.05) in the year before menarche were all positively associated with the age at menarche. Only anemia achieved borderline significance (p=0.056) in multivariate analysis and no other variables were significant. This study highlights the difficulties of conducting research on issues considered to be sensitive by the community and provide data on factors influencing menarche in a multi ethnic community.


Evaluation of transobturator tension-free vaginal tapes in the surgical management of mixed urinary incontinence: 3-year outcomes of a randomized controlled trial.
We evaluate the clinical effectiveness of transobturator tension-free vaginal tape procedures in the surgical management of mixed urinary incontinence in women at 3-year followup. In this secondary analysis of a prospective, single-blind, randomized controlled trial 83 of 341 women (24%) with mixed urinary incontinence were randomized to undergo an outside-in (Aris® transobturator sling system 42) or inside-out (TVT™-O 41) transobturator tension-free vaginal tape procedure. Patients were contacted by postal questionnaire at a minimum of 3 years postoperatively. The primary outcome was the patient reported success rate, defined as very much improved/much improved on the PGI-I (Patient Global Impression of Improvement). Secondary outcomes included improvement in quality of life, impact on preoperative urgency/urgency incontinence and repeat surgical treatment for stress urinary incontinence. Outcomes at 3 years were compared between groups (outside-in vs inside-out) and to 1-year outcomes. Analysis was performed using SPSS® version 20 with significance levels set at p = 0.05. A total of 66 women with mixed urinary incontinence completed the 3-year followup (outside-in 35 vs inside-out 31). In each group 2 women underwent further continence surgery. The patient reported success rate was 73.8% with no significant differences between the groups (OR 1.035, 95% CI 0.342-3.134, p = 0.951). Overall 34 (50.1%) and 26 women (56.5%) reported cure of preoperative urgency and urgency incontinence, respectively, and 52 women (86.7%) had a clinically significant improvement in quality of life (18 points or more in total KHQ [King's Health Questionnaire] score) compared to baseline. Transobturator tape procedures are associated with a good (73.8%) patient reported success rate at a minimum of 3 years of followup in the surgical management of mixed urinary incontinence in women with predominant stress urinary incontinence symptoms. Nearly half of the women reported cure of urgency/urgency incontinence.


Default and Executive Network Coupling Supports Creative Idea Production.
The role of attention in creative cognition remains controversial. Neuroimaging studies have reported activation of brain regions linked to both cognitive control and spontaneous imaginative processes, raising questions about how these regions interact to support creative thought. Using functional magnetic resonance imaging (fMRI), we explored this question by examining dynamic interactions between brain regions during a divergent thinking task. Multivariate pattern analysis revealed a distributed network associated with divergent thinking, including several core hubs of the default (posterior cingulate) and executive (dorsolateral prefrontal cortex) networks. The resting-state network affiliation of these regions was confirmed using data from an independent sample of participants. Graph theory analysis assessed global efficiency of the divergent thinking network, and network efficiency was found to increase as a function of individual differences in divergent thinking ability. Moreover, temporal connectivity analysis revealed increased coupling between default and salience network regions (bilateral insula) at the beginning of the task, followed by increased coupling between default and executive network regions at later stages. Such dynamic coupling suggests that divergent thinking involves cooperation between brain networks linked to cognitive control and spontaneous thought, which may reflect focused internal attention and the top-down control of spontaneous cognition during creative idea production.


Probing the mechanism of cellulosome attachment to the Clostridium thermocellum cell surface: computer simulation of the Type II cohesin-dockerin complex and its variants.
The recalcitrance of lignocellulosic biomass to hydrolysis is the bottleneck in cellulosic ethanol production. Efficient degradation of biomass by the anaerobic bacterium Clostridium thermocellum is carried out by the multicomponent cellulosome complex. The bacterial cell-surface attachment of the cellulosome is mediated by high-affinity protein-protein interactions between the Type II cohesin domain borne by the cell envelope protein and the Type II dockerin domain, together with neighboring X-module present at the C-terminus of the scaffolding protein (Type II coh-Xdoc). Here, the Type II coh-Xdoc interaction is probed using molecular dynamics simulations, free-energy calculations and essential dynamics analyses on both the wild type and various mutants of the C. thermocellum Type II coh-Xdoc in aqueous solution. The simulations identify the hot spots, i.e. the amino acid residues that may lead to a dramatic decrease in binding affinity upon mutation and also probe the effects of mutations on the mode of binding. The results suggest that bulky and hydrophobic residues at the protein interface, which make specific contacts with their counterparts, may play essential roles in retaining a rigid cohesin-dockerin interface. Moreover, dynamical cross-correlation analysis indicates that the X-module has a dramatic effect on the cohesin-dockerin interaction and is required for the dynamical integrity of the interface.


Accurate representation of B-DNA double helical structure with implicit solvent and counterions.
High-resolution nuclear magnetic resonance (NMR) and crystallographic data have been taken to refine the force field used in the torsion angle space nucleic acids molecular mechanics program DUPLEX. The population balance deduced from NMR studies of two carcinogen-modified DNA conformers in equilibrium was used to fine tune a sigmoidal, distance-dependent dielectric function so that reasonable relative energies could be obtained. In addition, the base-pair and backbone geometry from high-resolution crystal structures of the Dickerson-Drew dodecamer was used to re-evaluate the deoxyribose pseudorotation profile and the Lennard-Jones nonbonded energy terms. With a modified dielectric function that assumes a very steep distance-dependent form, a deoxyribose pseudorotation profile with reduced energy barriers between C2'- and C3'-endo minima, and a shift of the Lennard-Jones potential energy minimum to a distance approximately 0.4 A greater than the sum of the van der Waals' radii, the sequence-dependent conformational features of the Dickerson-Drew dodecamer in both the solid state and the aqueous liquid crystalline phase are well reproduced. The robust performance of the revised force field, in conjunction with its efficiency through implicit treatment of solvent and counterions, provides a valuable tool for elucidating conformations and structure-function relationships of DNA, including those of molecules modified by carcinogens and other ligands.


Comparison of serum testosterone levels in prostate cancer patients receiving LHRH agonist therapy with or without the removal of the prostate.
: The prostate secretes enzymes and nutrients to promote sperm motility. Recent reports suggest that the prostate may also secrete testosterone, which is believed to be a fuel for prostate tumour growth. The aim of this study was to determine if a difference in serum testosterone levels exists between men on luteinizing hormone releasing-hormone (LHRH) agonists who have undergone radical prostatectomy, radiation or hormone therapy as primary prostate cancer treatment. : Serum testosterone levels were evaluated in 165 consecutive prostate cancer patients using LHRH analogues for >3 months. We excluded patients receiving either radiation or chemotherapy at time of time of testosterone measurement. Patients were classified based on primary treatment: (1) radical prostatectomy; (2) radiation; or (3) primary hormone therapy. We used one-way ANOVA to compare testosterone levels. Pearson correlation was used to correlate testosterone with prostate-specific antigen (PSA) and time on LHRH agonists. Multivariable linear regression was used to predict serum testosterone levels. : The median (interquartile range) serum testosterone levels were 1.4 (1-1.9), 1.3 (1-1.625) and 1.25 (0.9-1.525) nmol/L for radical prostatectomy, radiation and primary hormone therapy groups, respectively. There was no statistically significant difference in testosterone levels between the groups (p = 0.3). No correlation was found between testosterone and PSA levels or time on LHRH (r = 0.02 and r = 0.01), respectively. Multivariable linear regression showed that none of the clinical variables were predictors of serum testosterone levels. : Our study suggests that primary treatment does not affect serum testosterone levels among men using LHRH analogues.


Creation of a fully functional human chimeric DNA repair protein. Combining O6-methylguanine DNA methyltransferase (MGMT) and AP endonuclease (APE/redox effector factor 1 (Ref 1)) DNA repair proteins.
A dose-limiting toxicity of certain chemotherapeutic alkylating agents is their toxic effects on nontarget tissues such as the bone marrow. To overcome the myelosuppression observed by chemotherapeutic alkylating agents, one approach is to increase the level of DNA repair proteins in hematopoietic stem and progenitor cells. Toward this goal, we have constructed a human fusion protein consisting of O6-methylguanine DNA methyltransferase coupled with an apurinic endonuclease, resulting in a fully functional protein for both O6-methylguanine and apurinic/apyrimidinic (AP) site repair as determined by biochemical analysis. The chimeric protein protected AP endonuclease-deficient Escherichia coli cells against methyl methanesulfonate and hydrogen peroxide (H2O2) damage. A retroviral construct expressing the chimeric protein also protected HeLa cells against 1,3-bis(2-chloroethyl)-1-nitrosourea and methyl methanesulfonate cytotoxicity either when these agents were used separately or in combination. Moreover, as predicted from previous analysis, truncating the amino 150 amino acids of the apurinic endonuclease portion of the O6-methylguanine DNA methyltransferase-apurinic endonuclease protein resulted in the retention of O6-methylguanine DNA methyltransferase activity but loss of all AP endonuclease activity. These results demonstrate that the fusion of O6-methylguanine DNA methyltransferase and apurinic endonuclease proteins into a combined single repair protein can result in a fully functional protein retaining the repair activities of the individual repair proteins. These and other related constructs may be useful for protection of sensitive tissues and, therefore, are candidate constructs to be tested in preclinical models of chemotherapy toxicity.


Opioid Prescribing Trends and Geographic Variation After Anterior Cruciate Ligament Reconstruction.
Opioid prescribing patterns play an important role in the opioid epidemic in the United States. The purpose of this study is to examine the trends and geographic variation in opioid prescribing patterns after anterior cruciate ligament (ACL) reconstruction. Regional differences in opioid prescribing patterns after ACL reconstruction are present. Descriptive epidemiology study. Level 4. The Truven Health MarketScan Commercial Claims database was used to analyze all patients with perioperative private insurance coverage who underwent ACL reconstruction from January 1, 2010, to November 31, 2017. Total number and morphine milligram equivalents per day (MMED) of opioid prescriptions were examined, and regional and statewide variation was assessed. A total of 90,068 ACL reconstruction patients who underwent surgery between 2010 and 2017 were included in the study. Overall, 67% received an opioid prescription within 30 days of surgery and 17% received an opioid prescription ≥90 MMED. The West (20%) had the highest proportion of patients with an opioid prescription ≥90 MMED and the Northeast had the lowest (12%), P < 0.001. The number of opioid prescriptions as well as proportion of opioid prescriptions ≥90 MMED varied significantly by state, P < 0.001. There was a significant increase in number of opioid prescriptions from 2010 to 2017 (62% in 2010 and 83% in 2017; P < 0.001). A significant change in the proportion of patients being prescribed ≥90 MMED was also present (P = 0.04; 15% in 2010, 17% in 2011, 17% 2012, 17% in 2013, 15% in 2014, 20% in 2015, 18% in 2016, and 15% in 2017). This study shows a trend of increasing opioid prescriptions and geographic variations in the amount and MMED of opioid prescriptions for patients undergoing ACL reconstruction. These data highlight several areas of improvement that state officials and national entities can use to help curb the opioid epidemic and underscore the importance of national guidelines for opioid prescribing. Knowledge of prescribing patterns after specific procedures may help provide more direct insight and guidance to surgeons and patients regarding postoperative pain management.


In Vivo Aroma Release and Dynamic Sensory Perception of Composite Foods.
Condiments such as spreads, dressings, or sauces are usually consumed together with carrier foods such as breads or vegetables. Dynamic interactions between condiments and carriers occur during consumption, which can influence aroma release and perception. This study investigated in vivo aroma release (PTR-MS) and dynamic sensory perception (time-intensity) of mayonnaises spiked with lemon aroma (limonene, citral). Mayonnaises were assessed without and with carrier foods (bread, potato). When different mayonnaises were consumed and assessed alone, aroma release and intensity perception were positively correlated. Interestingly, when mayonnaises were combined with carriers, aroma release and perception were no longer positively correlated. Addition of carriers increased release of limonene and citral into the nasal cavity during consumption but decreased perceived aroma intensity of condiments. The increase in aroma release induced by the carriers can be explained by differences in oral processing behaviors and by the increased surface area of mayonnaise-carrier combinations. Carrier addition is likely to modulate aroma perception of composite foods by cross-modal texture-aroma interactions. This work demonstrates that not only physicochemical characteristics of foods but also cross-modal interactions play a role in influencing flavor perception of composite foods.


Investigating thought disorder in schizophrenia: evidence for pathological activation.
Previous research has yielded evidence for enhanced semantic priming in formal thought-disordered schizophrenia patients, a result that fits well with the hypothesis of disinhibited processes of spreading activation in this population. The current study examined whether hyper priming among schizophrenia patients is an outcome of further spreading of activation of a node or a result of farther activation of nodes in the semantic network. We also try to shed light on the fate of this activation. The present study tested this hypothesis by using semantic and identical priming in two different experiments. SOA (stimulus onset asynchrony) was manipulated (240 ms vs. 740 ms) within block. It is assumed that among healthy individuals, performance relies on a balance between activation and inhibition processes, contrary to in schizophrenic individuals. In order to examine this hypothesis, we compared formal thought-disordered schizophrenia patients, non thought-disordered schizophrenia patients, and healthy controls. For thought-disordered schizophrenia patients, we found a large positive semantic effect and identical priming effect (129 ms and 154 ms, respectively) only with short SOA. SOA and type of priming did not modulate priming effects in the control groups. This result supports the claim that there is a lack of inhibitory processes among thought-disordered patients. Hyper priming in the thought-disorder group may be an outcome of hyper activation followed by rapid decay below baseline threshold.


Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE.
S100A8/A9, a proinflammatory protein, is upregulated in inflammatory diseases, and also has a tumor-promoting activity by the recruitment of myeloid cells and tumor cell invasion. However, whether the expression of S100A8/A9 in tumors predicts a good or poor prognosis is controversial in the clinical setting. In this study, to clarify the in vivo role of S100A8/A9 in the tumor microenvironment, we s.c. inoculated Pan02 cells stably expressing S100A8 and S100A9 proteins (Pan02-S100A8/A9) in syngeneic C57BL/6 mice. Unexpectedly, after small tumor nodules were once established, they rapidly disappeared. Flow cytometry showed that the number of NK cells in the tumors was increased, and an administration of anti-asialoGM1 Ab for NK cell depletion promoted the growth of Pan02-S100A8/A9 s.c. tumors. Although the S100A8/A9 proteins alone did not change the IFN-γ expression of NK cells in vitro, a coculture with Pan02 cells, which express Rae-1, induced IFN-γ production, and Pan02-S100A8/A9 cells further increased the number of IFN-γ(+) NK cells, suggesting that S100A8/A9 enhanced the NK group 2D ligand-mediated intracellular activation pathway in NK cells. We then examined whether NK cell activation by S100A8/A9 was via their binding to receptor of advanced glycation end product (RAGE) by using the inhibitors. RAGE antagonistic peptide and anti-RAGE Ab inhibited the IFN-γ production of NK cells induced by S100A8/A9 proteins, and an administration of FPS-ZM1, a RAGE inhibitor, significantly enhanced the in vivo growth of Pan02-S100A8/A9 tumors. We thus found a novel activation mechanism of NK cells via S100A8/A9-RAGE signaling, which may open a novel perspective on the in vivo interaction between inflammation and innate immunity.


Sevoflurane induces inflammation in primary hippocampal neurons by regulating Hoxa5/Gm5106/miR-27b-3p positive feedback loop.
Postoperative cognitive dysfunction (POCD) is a normal condition that develops after surgery with anesthesia, leading to deterioration of cognitive functions. However, the mechanism of POCD still remains unknown. To elucidate the POCD molecular mechanism, sevoflurane was employed in the present study to generate neuroinflammation mice model. Sevoflurane treatment caused inflammatory markers IL6, IL-10 and TNF-α high expression in primary hippocampal neurons and blood samples. Long non-coding RNA Gm5106 was found to be increased after being stimulated with sevoflurane. Silencing Gm5106 inhibited neuron inflammation. In the meanwhile, Gm5106 was identified as a direct target of miR-27b-3p that was inhibited by sevoflurane and related to inflammation suppression. In addition, transcription factor (TF) Hoxa5 was validated to activate Gm5106 through two binding motifs in the promoter region after sevoflurane exposure. Furthermore, miR-27b-3p also directly targeted Hoxa5 3'UTR, which affected nuclear Hoxa5 protein served as TF. Hoxa5 protein instead of 3'UTR reduced miR-27b-3p, in which Gm5106 knocking down abrogated this effect. In conclusion, sevoflurane induces neuroinflammation through increasing long non-coding RNA Gm5106, which is transcriptionally activated by Hoxa5 and directly targeted by miR-27-3p. Apart from that, Hoxa5, Gm5106, and miR-27b-3p form a positive feedback loop in sevoflurane stimulation.


Inner workings and biological impact of phospholipid flippases.
The plasma membrane, trans-Golgi network and endosomal system of eukaryotic cells are populated with flippases that hydrolyze ATP to help establish asymmetric phospholipid distributions across the bilayer. Upholding phospholipid asymmetry is vital to a host of cellular processes, including membrane homeostasis, vesicle biogenesis, cell signaling, morphogenesis and migration. Consequently, defining the identity of flippases and their biological impact has been the subject of intense investigations. Recent work has revealed a remarkable degree of kinship between flippases and cation pumps. In this Commentary, we review emerging insights into how flippases work, how their activity is controlled according to cellular demands, and how disrupting flippase activity causes system failure of membrane function, culminating in membrane trafficking defects, aberrant signaling and disease.


Thermal expansion of vitrified blood vessels permeated with DP6 and synthetic ice modulators.
This study provides thermal expansion data for blood vessels permeated with the cryoprotective cocktail DP6, when combined with selected synthetic ice modulators (SIMs): 12% polyethylene glycol 400, 6% 1,3-cyclohexanediol, and 6% 2,3-butanediol. The general classification of SIMs includes molecules that modulate ice nucleation and growth, or possess properties of stabilizing the amorphous state, by virtue of their chemical structure and at concentrations that are not explained on a purely colligative basis. The current study is part of an ongoing effort to characterize thermo-mechanical effects on structural integrity of cryopreserved materials, where thermal expansion is the driving mechanism to thermo-mechanical stress. This study focuses on the lower part of the cryogenic temperature range, where the cryoprotective agent (CPA) behaves as a solid for all practical applications. By combining results obtained in the current study with literature data on the thermal expansion in the upper part of the cryogenic temperature range, unified thermal expansion curves are presented.


Kinship Verification Based on Cross-Generation Feature Interaction Learning.
Kinship verification from facial images has been recognized as an emerging yet challenging technique in many potential computer vision applications. In this paper, we propose a novel cross-generation feature interaction learning (CFIL) framework for robust kinship verification. Particularly, an effective collaborative weighting strategy is constructed to explore the characteristics of cross-generation relations by corporately extracting features of both parents and children image pairs. Specifically, we take parents and children as a whole to extract the expressive local and non-local features. Different from the traditional works measuring similarity by distance, we interpolate the similarity calculations as the interior auxiliary weights into the deep CNN architecture to learn the whole and natural features. These similarity weights not only involve corresponding single points but also excavate the multiple relationships cross points, where local and non-local features are calculated by using these two kinds of distance measurements. Importantly, instead of separately conducting similarity computation and feature extraction, we integrate similarity learning and feature extraction into one unified learning process. The integrated representations deduced from local and non-local features can comprehensively express the informative semantics embedded in images and preserve abundant correlation knowledge from image pairs. Extensive experiments demonstrate the efficiency and superiority of the proposed model compared to some state-of-the-art kinship verification methods.


Characterization of a low-methoxyl pectin extracted from red radish (Raphanus sativus L.) pomace and its gelation induced by NaCl.
There is an increasing demand for obtaining pectin from new sources. Red radish (Raphanus sativus L.) pomace pectin extracted by alkali was low-methoxyl pectin with esterification degree of 10.17 %, galacturonic acid content of 69.71 % (wt), and average molar weight of 78.59 kDa. The pectin primarily consisted of rhamnogalacturonan I and homogalacturonan domains. The predominant monosaccharides of the pectin were galacturonic acid (46.32 mol%), arabinose (16.03 mol%), galactose (10.46 mol%), and rhamnose (10.28 mol%), respectively. The red radish pomace pectin solution exhibited a shear-thinning behavior. NaCl could induce gelation of red radish pomace pectin, and the gel properties of red radish pomace pectin were considerably affected by the NaCl concentration. As the NaCl concentration (0.25-0.50 mol/L) increased, the rate of gelation accelerated, and the time to gelation point appeared earlier. There was an optimal NaCl concentration (0.50 mol/L) for the pectin to form a gel with the greatest solid-like properties, gel hardness (33.84 g) and water-holding capacity (62.41 %). Gelation force analysis indicated gel formation mainly caused by electrostatic shielding effect of Na+ and hydrogen bonding. This research could facilitate the applications of the red radish pomace pectin in the realm of edible hydrocolloids.


Neurologic injury in cardiac surgery: aortic atherosclerosis emerges as the single most important risk factor.
With older and sicker patients undergoing cardiac surgery, neurologic injury has emerged as an increasingly important cause of rising costs, morbidity and mortality. Several studies investigating the relationship between atherosclerotic aortic disease and subsequent adverse clinical outcomes have demonstrated that the single most important risk factor for neurologic injury following cardiac surgery is the presence of aortic atheromatous disease. The results of these studies suggest that atheroemboli are correlated with neurologic injury following cardiac surgery. Surgical techniques to avoid and prevent particulate debris during cardiac surgery may be a major step in preventing severe neurologic injury.


Results of a survey of pediatric clerkship programs in American medical schools.
Pediatric clerkship coordinators from 119 medical schools responded to a questionnaire about administration, resources, goals, instructional design, evaluation, and perceived strengths and weaknesses of their own programs. Problems were reported in the definition of objectives, the evaluation of students' knowledge, interviewing and physical-examination skills, and problem-solving ability. A dedicated faculty and house staff interested in teaching and a large and varied patient population were perceived as strengths of many programs. Weaknesses cited included a lack of uniformity in students' experience, insufficient time spent on the pediatric clerkship, too many students with decreased faculty contact, overemphasis on tertiary care, an inadequate ambulatory experience, lack of specific objectives, and unsystematic evaluation methods. It is hoped that this survey will provide an impetus for further fruitful exchanges among clerkship directors.


Transcriptome Analysis of Dnmt3l Knock-Out Mice Derived Multipotent Mesenchymal Stem/Stromal Cells During Osteogenic Differentiation.
Multipotent mesenchymal stem/stromal cells (MSCs) exhibit great potential for cell-based therapy. Proper epigenomic signatures in MSCs are important for the maintenance and the subsequent differentiation potential. The DNA methyltransferase 3-like (DNMT3L) that was mainly expressed in the embryonic stem (ES) cells and the developing germ cells plays an important role in shaping the epigenetic landscape. Here, we report the reduced colony forming ability and impaired in vitro osteogenesis in Dnmt3l-knockout-mice-derived MSCs (Dnmt3l KO MSCs). By comparing the transcriptome between undifferentiated Dnmt3l KO MSCs and the MSCs from the wild-type littermates, some of the differentially regulated genes (DEGs) were found to be associated with bone-morphology-related phenotypes. On the third day of osteogenic induction, differentiating Dnmt3l KO MSCs were enriched for genes associated with nucleosome structure, peptide binding and extracellular matrix modulation. Differentially expressed transposable elements in many subfamilies reflected the change of corresponding regional epigenomic signatures. Interestingly, DNMT3L protein is not expressed in cultured MSCs. Therefore, the observed defects in Dnmt3l KO MSCs are unlikely a direct effect from missing DNMT3L in this cell type; instead, we hypothesized them as an outcome of the pre-deposited epigenetic signatures from the DNMT3L-expressing progenitors. We observed that 24 out of the 107 upregulated DEGs in Dnmt3l KO MSCs were hypermethylated in their gene bodies of DNMT3L knock-down ES cells. Among these 24 genes, some were associated with skeletal development or homeostasis. However, we did not observe reduced bone development, or reduced bone density through aging in vivo. The stronger phenotype in vitro suggested the involvement of potential spreading and amplification of the pre-deposited epigenetic defects over passages, and the contribution of oxidative stress during in vitro culture. We demonstrated that transient deficiency of epigenetic co-factor in ES cells or progenitor cells caused compromised property in differentiating cells much later. In order to facilitate safer practice in cell-based therapy, we suggest more in-depth examination shall be implemented for cells before transplantation, even on the epigenetic level, to avoid long-term risk afterward.


Treatment Efficacy of PD-1 Inhibitor Therapy in Patients With Recurrent and/or Metastatic Salivary Gland Carcinoma.
The efficacy of programmed cell death 1 (PD-1) inhibitor therapy for patients with recurrent and/or metastatic salivary gland carcinoma (R/M SGC) remains unclear. We retrospectively analyzed 36 patients with R/M SGC treated with PD-1 inhibitor. The expression of programmed cell death ligand 1 (PD-L1) and mismatch repair (MMR) proteins was also analyzed. The objective response rate (ORR) was 11.1%. The histopathological subtypes of patients who achieved complete response or partial response were salivary duct carcinoma (SDC) in three patients and poorly differentiated carcinoma in one patient, all of whom showed a positive PD-L1 expression. The expression of MMR proteins was not associated with the efficacy of PD-1 inhibitors. Although the efficacy of PD-1 inhibitor therapy in R/M SGC is limited, certain patients may respond and achieve long-term disease control. There is a potential therapeutic effect in SDC patients with positive PD-L1 expression.


Deep venous thrombosis: behaviour of the polymorphonuclear leukocyte integrin pattern at baseline and after in vitro activation.
In a group of 18 subjects with acute deep venous thrombosis (DVT), evidenced by clinical examination and echo-color-Doppler, we examined the phenotypical expression of the polymorphonuclear leukocyte (PMN) beta2-integrins (CD11a, CD11b, CD11c, CD18), obtained by using a flow cytofluorimeter. The evaluation was performed before and after in vitro activation (prolonged for 5 and 15 minutes) with 4-phorbol 12-myristate 13-acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (fMLP). In DVT subjects, at baseline, the phenotypical expression of CD11b was decreased and that of CD11c was increased when compared with normal controls; no difference was found in CD11a and CD18 expression. In normal subjects PMN activation with both activators led to a constant increase of all PMN adhesion molecules; in DVT subjects CD11b, CD11c and CD18 increased, while CD11a expression did not show any change. These data indicate the presence of a functional alteration in circulating PMN cells from patients with DVT.


Contraindications for percutaneous transluminal coronary angioplasty in treatment of unstable angina pectoris.
In recent years, the indications for percutaneous transluminal coronary angioplasty have expanded to include multivessel disease, unstable angina pectoris, stenosis of coronary bypass grafts, and recent total coronary occlusion. To evaluate our experience in using percutaneous transluminal coronary angioplasty to treat unstable angina, we reviewed the records of the patients who underwent this procedure at our hospital between January 1983 and December 1986. Of the 689 patients who underwent balloon angioplasty during the study period, 454 had stable angina and 235 had unstable angina; of the latter group, 34 (14.5%) required emergency coronary artery bypass grafting after balloon angioplasty failed. This outcome was associated with 2 risk factors: previous myocardial infarction and triple-vessel disease. Our data suggest that, in cases of unstable angina pectoris, percutaneous transluminal coronary angioplasty should be reserved for patients with single-vessel disease and no evidence of previous myocardial infarction. They also lend credence to the conclusion that the disease process in unstable angina is different from that in stable angina, and that therapy should be directed towards reducing platelet aggregation and correcting global ischemia, rather than towards balloon angioplasty of "culprit lesions."


The Hedgehog signaling pathway as a target for anticancer drug discovery.
The Hedgehog (Hh) signaling pathway directs the development of multiple tissues during embryonic development, and contributes to tissue homeostasis in adults. Deficient Hh signaling results in defective embryogenesis; conversely, excessive Hh signaling is associated with an inherited cancer predisposition syndrome (Gorlin Syndrome), and a growing list of sporadic human cancers. It is now clear that multiple components of "The Hh Pathway" can be altered in tumors. The Hhs are morphogens that signal through effectors that are largely unprecedented in drug discovery, with many key concepts derived from studies in Drosophila melanogaster. However, studies in tumor cell lines have recently identified targets that can be exploited for the discovery of human Hh antagonists, with additional targets likely to emerge as the human pathway is further defined. Here, we review basic aspects of Hh signal transduction, with an emphasis on molecular targets for drug discovery. The use of first-generation Hh antagonists such as cyclopamine will also be discussed; such agents remain invaluable in ongoing efforts to validate drug discovery assays and survey tumor lines for Hh dependence. The various types and frequencies of Hh signaling defects in different human tumors will also be reviewed, as will the status of medicinal chemistry efforts to discover novel Hh antagonists. In section VI, we review assays from the literature that could be utilized to discover new Hh antagonists for the treatment of cancer.


IgA and/or IgG subclass deficiency in children with recurrent respiratory infections and its relationship with chronic pulmonary damage.
Most patients with IgA and/or IgG subclass deficiency are asymptomatic but some may suffer from frequent mainly respiratory infections. The aim of our study was to determine the frequency of IgA and/or IgG subclass deficiencies and the rate of chronic pulmonary damage secondary to recurrent pulmonary infections in these children. Serum IgA and IgG subclass levels were measured in 225 children aged 6 months to 6 years with recurrent sinopulmonary infections (44 with recurrent upper respiratory tract infections, 100 with recurrent pulmonary infections and 81 with recurrent bronchiolitis). In order to determine chronic pulmonary damage due to recurrent infections in patients with recurrent pulmonary infections CT scans of thorax were also obtained. The overall frequency of antibody defects was found to be 19.1%. IgA deficiency was observed in 9.3%, IgG subclass deficiency in 8.4% and IgA + IgG subclass deficiency in 1.4%. The prevalance of IgA and/or IgG subclass deficiency was 25% in patients with recurrent upper respiratory tract infections, 22% in patients with recurrent pulmonary infections and 12.3% in patients with recurrent bronchiolitis (p>0.05). Chronic pulmonary damage in lungs was determined radiologically in 17 of 100 cases with recurrent pulmonary infection. In IgG subclass deficiencies sequel changes, although not statistically significant, were observed five times more frequently than that of IgA deficiencies. CT scans revealed pulmonary sequels in 5 of the 22 (22.7%) patients with recurrent pulmonary infections and immunodeficiency (bronchiectasis in 2 patients with IgG3 deficiency, fibrotic changes in one with IgA deficiency and in one with IgG3 deficiency, bronchiolitis obliterans in one with IgG2 + IgG3 deficiency). On the other hand, pulmonary sequels were observed in 12 patients (15.4%) with normal immunoglobulin levels. Eight of them were bronchiolitis obliterans, 2 of them were atelectasia and 1 of them was bronchiectasia. We therefore suggest that determination of antibody levels and evaluation of pulmonary alterations is crucial in patients with recurrent sinopulmonary infections since the deficiency of antibodies is associated with a greater pulmonary damage.


Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells.
Acute myeloid leukemia (AML) is a highly lethal hematological malignancy in adults and children. Abnormal proliferation of leukemia stem cells (LSC) with CD34+ and CD38- phenotypes are the main clinical features of AML. Patients with AML face drug resistance and treatment failure due to a default in stem and progenitor cells. Therefore, defining LSC properties is necessary for targeting leukemia-initiating cells. Mitochondrial mass and activity increase in AML initiating cells compared with normal stem cells. This idea has offered the inhibition of the mitochondrial translation machinery to reduce the number of leukemia-initiating cells in patients with AML Tigecycline is an FDA-approved microbial antibiotic that inhibits oxidative phosphorylation in mitochondria, resulting in the suppression of leukemia cell proliferation with little toxicity to normal cells. Thus, the present study was conducted to evaluate whether LSC is influenced by mitochondrial inhibition. We measured the IC50 of tigecycline in KG-1a AML cell lines. KG-1a AML cell lines were separated into CD34+ and CD34- cells by MACS. In the following, these cells were treated with 20 µM (IC50) tigecycline. The expression of Annexin/PI, Caspase 3, apoptotic genes (BCL2, BCLX, BAX, BAD, and P53) and proteins (P53, BAX, BCL2 and Caspase 9) was evaluated in CD34+ , CD34- and KG-1a AML cells. In addition, the telomere length and expression of hTERT were evaluated in this study. The results indicated that BCl2 (gene and protein) and BCLX gene dramatically decreased. In addition, BAD, BAX, and P53 gene and protein expression significantly increased in CD34+ AML cells compared to CD34- AML cells. The results also suggested that tigecycline induced intrinsic (Cleaved-caspase 9/Pro-Caspase 9 ratio) and p53-mediated apoptosis. Furthermore, hTERT gene expression and telomere length decreased in the tigecycline-treated groups. Taken together, our findings indicate that inhibition of mitochondrial activity with tigecycline can induce apoptosis in cancer stem cells and can be used as a novel method for cancer therapy.


The Academic Achievement of Limited English Proficient (LEP) Youth in New and Established Immigrant States: Lessons from the National Assessment of Educational Progress (NAEP).
The dramatic growth and dispersal of immigrant families has changed the face of public education at a time when states are experiencing increased school accountability pressures under the No Child Left Behind (NCLB) and its recent successor the Every Student Succeeds Act. Of particular concern is how these demographic shifts affect the academic well-being of Limited English Proficient (LEP) youth, the protected sub-group that most directly targets children from immigrant families. Using individual-level data from the National Association of Educational Progress, we examine how 8th grade test scores of LEP youth differ across new and established immigrant destination states. Results show that achievement for LEP youth is higher in new than in established immigrant states but that this advantage is not consistent across ethnic/racial groups. LEP youth in new immigrant states benefit from more favorable demographic characteristics and more family and school resources, but these differences only explain a small portion of the achievement gap.


Contractile function, energy metabolism and myocardial structure at graded restriction of coronary blood flow.
In closed-chest dogs, 30, 50 and 70% restriction of coronary blood flow was carried out by catheterization and autoperfusion of the circumflex branch of the left coronary artery. At 70% restriction, a mild decrease in most contractility indices was observed, without simultaneous impairment of the indices of systemic haemodynamics. Changes in energy metabolism appeared already in the initial stage of coronary insufficiency. A characteristic features at suppression of aerobic oxidation was an increase of the cAMP level of glycolytic activity of the pentoso-phosphate cycle, which ensured a sufficiently high ATP level in the myocardium. A limiting factor were disturbances in the system of energy transport (creatine phosphate, creatine phosphokinase) and of the calcium pump (Ca++-ATPase of the sarcoplasmic reticulum, SPR), which evidently led to a decrease of the inotropic properties of the myocardium at 70% restriction of coronary blood flow. Signs were found of structural lesions of the myofibrils and the SPR.


Prophylaxis of DVT with enoxaparin in patients undergoing total knee replacement.
To evaluate the efficacy and safety of the low molecular weight heparin as prophylaxis against thromboembolism following total knee replacement surgery. Post-operative bilateral lower extremity colour duplex scan was performed on 55 patients subjected to total knew arthroplasty. The scan was performed 7 days after surgery for detection of DVT. All patients were given Enoxaparin 40mg subcutaneous daily for 2 weeks as prophylaxis against DVT. Two patients were diagnosed as DVT by color duplex scanning and both were distal but only one was asymptomatic. Another patient developed pulmonary embolism and died subsequently. The major and minor wound problems were seen in two and six patients respectively; nearly all complications were seen in obese patients. DVT is not a nonexistent entity in our population. Low molecular weight heparins are safe drugs but apparently the bleeding complications are more as compared to Western literature. Larger case control studies are required to determine the true efficacy and safety of LMWH.


Improvements in child resistant containers.
The numbers of children under 5 years in South Glamorgan admitted to hospital because of accidental poisoning have been analysed for 1980-4. There has been no significant fall in those taking solid dose, prescribable medications since the voluntary agreement between the government and the pharmaceutical profession in 1981 on child resistant containers. Most children still take these poisons from containers of an ordinary, non-child resistant type. Aspirin poisoning has remained at the same low level since the introduction of regulations on child resistant containers in 1976, but there has been a rise in paracetamol liquid poisoning largely due to one preparation. The advent of 'original pack' dispensing in 1987-8 provides an ideal opportunity to ensure that child resistant containers are used for all medications that are toxic if taken by children.