Long-term treatment with morphine increases the D-serine content in the rat brain by regulating the mRNA and protein expressions of serine racemase and D-amino acid oxidase.
Recent studies indicate that an endogenous co-agonist for an N-methyl-D-aspartate (NMDA) receptor-related glycine site, D-serine, is synthesized by serine racemase and is metabolized by D-amino acid oxidase (DAO) and that acute treatment with morphine augments the gene expression of serine racemase and DAO in rat brain. To further elucidate the mechanism underlying the activation of NMDA receptors following chronic opioid administration, we have evaluated the effects of the chronic administration of morphine on the mRNA and protein expressions of serine racemase and DAO and on the contents of D-serine in several areas of the rat brain. Repeated administration of morphine for 30 days produced a significant augmentation of both the mRNA and protein expressions of serine racemase in all the brain regions, whereas no significant change in the protein expression of DAO was observed in all the brain regions. Furthermore, the chronic administration caused a slight but significant elevation in the concentration of D-serine in the cortex, striatum, and hippocampus. These results indicate the elevated D-serine level following the chronic morphine treatment could at least in part be involved in the activation of NMDA receptors via the glycine site.


SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy.
Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Abnormal tau metabolism leads to neurodegenerative diseases named tauopathies, such as Alzheimer's disease and frontotemporal dementia. The alternative splicing of exon 10 (E10) in the primary transcript produces tau protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are found in equal amounts in the normal adult human brain. Several tauopathies are associated with abnormal E10 alternative splicing, leading to an imbalance between 3R and 4R isoforms, which underlies disease. Correction of such imbalance represents a potential disease-modifying therapy for those tauopathies. We have previously optimized a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau content in a mouse model of tauopathy related to tau mis-splicing (htau mice), and showed that local modulation of E10 inclusion in the prefrontal cortex prevents cognitive decline, neuronal firing impairments and hyperphosphorylated tau accumulation. Furthermore, local shifting of 3R-4R tau into the striatum of htau mice prevented motor coordination deficits. However, a major bottleneck of our previous work is that local splicing regulation was performed in young mice, before the onset of pathological phenotypes. Here we tested whether regulation of tau E10 splicing could rescue tau pathology phenotypes in htau mice, after the onset of cognitive and motor impairments, comparable to early stages of human tauopathies. To determine phenotypic time course and affected brain nuclei, we assessed htau mice using behavioural tests and microPET FDG imaging over time, similarly to diagnosis methods used in patients. Based on these analyses, we performed local delivery of pre-trans splicing molecules to regulate E10 inclusion either into the medial prefrontal cortex (mPFC) or the striatum at 6-month-old once behavioral phenotypes and metabolic changes were detected. Tau isoforms modulation into the mPFC restored cognitive performance in mice that previously showed mild to severe memory impairment while motor coordination deficit was rescued after striatal injection of trans-splicing molecules. Our data suggest that tau regulation could recover pathological phenotypes early after phenotypic onset, raising promising perspectives for the use of RNA based therapies in tauopathies related to MAPT abnormal splicing.


Design of dynamic ski motion capture and human posture detection model based on spatio-temporal Transformer and wireless device tracking technology.
As a result of significant advancements in living conditions, individuals have redirected their attention towards physical exercise. Skiing, as a widely popular sport, necessitates the real-time maintenance of correct posture during movement. Therefore, we present a dynamic skiing motion capture and human posture detection model that leverages wireless device tracking. Primarily, personnel tracking is enabled through the construction of service base stations and the utilization of wireless device tracking technology. Subsequently, a human posture detection model is formulated in the form of human posture key points, employing the image information of each frame obtained via wireless devices. Finally, we introduce a spatio-temporal Transformer structure that facilitates the detection and recognition of human posture in consecutive frames. Our results demonstrate that our approach can precisely locate and track the position of skiing personnel. Compared to the latest Blip and Conformer methods, our technique yields F values that surpass them by 1.20% and 4.51%, respectively. Moreover, our model can achieve convergent model parameters and accomplish training objectives more efficiently, thus enabling posture detection and dynamic capture of skiing personnel via image and video information.


Measurement and modeling of the mechanical impedance of human mastoid and condyle.
Bone conduction devices are used in audiometric tests, hearing rehabilitation, and communication systems. The mechanical impedance of the stimulated skull location affects the performance of the bone conduction devices. In the present study, the mechanical impedances of the mastoid and condyle were measured in 100 Chinese subjects aged from 22 to 67 years. The results show that the mastoid and condyle impedances within the same subject differ significantly and the impedance differences between subjects at the same stimulation position are mainly below the resonance frequency. The mechanical impedance of the mastoid is significantly influenced by age, and not related to gender or body mass index (BMI). While the mechanical impedance of the condyle is significantly affected by BMI, followed by gender, and not related to age. There are some differences in mastoid impedance between the Chinese and Western subjects. An analogy model predicts that the difference in mechanical impedance between the mastoid and condyle leads to a significant difference in the output force of the bone conduction devices. The results can be used to develop improved condyle and mastoid stimulators for the Chinese.


Erythropoietin and VEGF promote neural outgrowth from retinal explants in postnatal rats.
Recent studies have reported neuroprotective effects of erythropoietin (EPO) and vascular endothelial growth factor (VEGF). The purpose of the present study was to clarify their influence on neurite outgrowth and regeneration of rat retinal ganglion cells (RGCs) in vitro and to elucidate the expression of corresponding receptors in the rat retina in vivo. Retinal explants from postnatal rats were stimulated with VEGF alone; VEGF in combination with anti-VEGF-receptor (VEGF-R)-2 antibody or T-type Ca2+ channel blocker ethosuximide (ESX); EPO alone; or EPO in combination with anti-EPO-receptor antibody or ESX. The presence of the corresponding receptors in the rat retina was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and by immunohistochemistry. EPO induced a stable improvement of neurite outgrowth of RGCs in a dose-dependent manner (5 x 10(-15) M to 5 x 10(-13) M) up to 169% (P < 0.05). Treatment of the explants with anti-EPO-R antibody (1:80 dilution) and with ESX (5 microM) totally inhibited EPO-mediated effects on RGCs. In comparison, VEGF (50 ng/mL), induced neurite outgrowth of retina explants up to 167% (P < 0.05), which again was inhibited in the presence of anti-VEGF-R2 antibody or ESX. Transcripts of EPO-R, VEGF-R1, and VEGF-R2 were detected by RT-PCR. Intense immunoreactivity for VEGF-R1, VEGF-R2, and EPO-R were found in the RGC layer of the retina. The data demonstrate for the first time that EPO and VEGF have a significant and specific biological effect on neurite regrowth of axotomized RGCs. Therefore, these results imply that EPO and VEGF have not only a neuroprotective but also a neuroregenerative role in ischemic retinal conditions.


Pediatric acute leukemia: the effect of prognostic factors on clinical outcomes at Phramongkutklao Hospital, Bangkok, Thailand.
Leukemia is the most common malignancy in children. Multiple prognostic factors have been used in order to assist the clinician to decide appropriate risk-adjusted treatment for each patient; the current clinical outcomes of those patients have been significantly improved over the past decades. The purpose of this study was to examine survival outcome in children who were diagnosed with acute leukemia and treated in the Department of Pediatrics, Phramongkutklao Hospital during January 1, 2000 and July 31, 2013. The authors retrospectively reviewed the patients who were diagnosed with acute leukemia and treated at Phramongkutklao Hospital. Their clinical data were collected and analyzed based on clinicalfeatures inchluding age, initial WBC count at diagnosis, sex, immnunophenotype and cytogenetic abnormalities. Total 152 patients with acute leukemia, 123 patients were diagnosed with acute lymnphoblastic leukemia (ALL) and 29 patients were diagnosed with acute myeloid leukemia (AML). The 5-year survival rates of ALL and AML patients were 72.63% and 30.30%, respectively. In addition, we found a correlation between the ALL patients' clinical outcomes and several prognostic factors including initial white blood cell count, CNS status at diagnosis and ploidy. However, there was no correlation between those factors and clinical outcomes in AML patients. Our treatment outcomes on patients with acute leukemia were similar to the reports from other countries. The several prognostic factors especially initial WBC at diagnosis can assist the clinician to select appropriate treatment option for each patient.


Comparative Heating Efficiency of Cobalt-, Manganese-, and Nickel-Ferrite Nanoparticles for a Hyperthermia Agent in Biomedicines.
In this study, the ac magnetic hyperthermia responses of spinel CoFe2O4, MnFe2O4, and NiFe2O4 nanoparticles of comparable sizes (∼20 nm) were investigated to evaluate their feasibility of use in magnetic hyperthermia. The heating ability of EDT-coated nanoparticles which were dispersed in two different carrier media, deionized water and ethylene glycol, at concentrations of 1 and 2 mg/mL, was evaluated by estimating the specific loss power (SLP) (which is a measure of magnetic energy transformed into heat) under magnetic fields of 15, 25, and 50 kA/m at a constant frequency of 195 kHz. The maximum value of SLP has been found to be ∼315 W/g for CoFe2O4 and ∼295 W/g for MnFe2O4 and NiFe2O4 nanoparticles. We report very promising heating temperature rising characteristics of CoFe2O4, MnFe2O4, and NiFe2O4 nanoparticles under different applied magnetic fields that indicate the effectiveness of these nanoparticles as hyperthermia agents.


A procedure-specific systematic review and consensus recommendations for postoperative analgesia following laparoscopic cholecystectomy.
Laparoscopic cholecystectomy has advantages over the open procedure for postoperative pain. However, a systematic review of postoperative pain management in this procedure has not been conducted. A systematic review was conducted according to the guidelines of the Cochrane Collaboration. Randomized studies examining the effect of medical or surgical interventions on linear pain scores in patients undergoing laparoscopic cholecystectomy were included. Qualitative and quantitative analyses were performed. Recommendations for patient care were derived from review of these data, evidence from other relevant procedures, and clinical practice observations collated by the Delphi method among the authors. Sixty-nine randomized trials were included and 77 reports were excluded. Recommendations are provided for preoperative analgesia, anesthetic and operative techniques, and intraoperative and postoperative analgesia. A step-up approach to the management of postoperative pain following laparoscopic cholecystectomy is recommended. This approach has been designed to provide adequate analgesia while minimizing exposure to adverse events.


Fast gene ontology based clustering for microarray experiments.
Analysis of a microarray experiment often results in a list of hundreds of disease-associated genes. In order to suggest common biological processes and functions for these genes, Gene Ontology annotations with statistical testing are widely used. However, these analyses can produce a very large number of significantly altered biological processes. Thus, it is often challenging to interpret GO results and identify novel testable biological hypotheses. We present fast software for advanced gene annotation using semantic similarity for Gene Ontology terms combined with clustering and heat map visualisation. The methodology allows rapid identification of genes sharing the same Gene Ontology cluster. Our R based semantic similarity open-source package has a speed advantage of over 2000-fold compared to existing implementations. From the resulting hierarchical clustering dendrogram genes sharing a GO term can be identified, and their differences in the gene expression patterns can be seen from the heat map. These methods facilitate advanced annotation of genes resulting from data analysis.


The Point Mutation G461S in the MfCYP51 Gene is Associated with Tebuconazole Resistance in Monilinia fructicola Populations in Brazil.
The ascomycete Monilinia fructicola is the causal agent of brown rot of stone fruit in Brazil, causing major pre- and postharvest losses. For many years, the demethylation inhibitor (DMI) fungicide tebuconazole has been used as the most effective active ingredient for controlling brown rot and, as a result, strains of M. fructicola resistant to this ingredient have emerged in many Brazilian states producing stone fruit. The aim of this study was to investigate the mechanisms associated with the resistance of M. fructicola to DMI tebuconazole. By sequencing the M. fructicola CYP51 (MfCYP51) gene, encoding the azole target sterol 14α-demethylase, a mutation was identified at the nucleotide position 1,492, causing the amino acid substitution from glycine to serine at the codon position 461, associated with reduced tebuconazole sensitivity. In addition, it was observed that MfCYP51 gene expression could play a secondary role in DMI fungicide resistance of M. fructicola strains in Brazil. However, for the specific isolate found to exhibit elevated expression levels of MfCYP51, no insertions that would trigger gene expression were found. Based on the point mutation associated with tebuconazole resistance, an allele-specific polymerase chain reaction method was developed to quickly identify resistant genotypes within the Brazilian population. This is the first report determining molecular mechanisms for DMI resistance identification for M. fructicola isolates from Brazil. This information provides an important advancement for risk assessment of DMI fungicides used to manage brown rot of stone fruit.


How well do hospital mortality rates reported in the New York State CABG report card predict subsequent hospital performance?
The use of mortality report cards as the basis for hospital choice assumes that a hospital's current performance is predicted by its past performance. To assess the accuracy of hospital risk-adjusted mortality rates reported in the New York State (NYS) coronary artery bypass graft (CABG) report card for predicting subsequent hospital mortality. We performed a retrospective study based on hospital mortality measures for CABG surgery (n = 37 hospitals) in NYS, which are publicly reported by the NYS Department of Health. Feasible generalized least squares was used to examine the association between a hospital's past quality ranking (high-quality, intermediate-quality, low-quality) and its subsequent performance, as measured using the ratio of the observed-to-expected mortality rate (O-to-E ratio). Hospitals identified as low-mortality hospitals using 2-year-old data had subsequent O-to-E ratios that were 16.8% lower (95% confidence interval, 8.9-24.8; P < 0.001) than average-mortality hospitals, whereas hospitals identified as high-mortality hospitals had subsequent O-to-E ratios that were 31.8% higher (95% confidence interval, 3.69-59.9; P < 0.05) compared with average-mortality hospitals. Hospitals identified as high-mortality hospitals using 3-year-old data were indistinguishable from average-mortality hospitals. Hospital ranking based on 2-year-old data is a strong predictor of future performance. Report cards based on 3-year-old data may not be useful for identifying low-performance hospitals. We recommend that the CABG report cards in NYS should be based on 2-year-old data, as opposed to the current practice of basing them on either 2- or 3-year-old data.


Oxidative stress enhances and modulates protein S-nitrosation in smooth muscle cells exposed to S-nitrosoglutathione.
Among S-nitrosothiols showing reversible binding between NO and -SH group, S-nitrosoglutathione (GSNO) represents potential therapeutics to treat cardiovascular diseases (CVD) associated with reduced nitric oxide (NO) availability. It also induces S-nitrosation of proteins, responsible for the main endogenous storage form of NO. Although oxidative stress parallels CVD development, little is known on the ability of GSNO to restore NO supply and storage in vascular tissues under oxidative stress conditions. Aortic rat smooth muscle cells (SMC) were stressed in vitro with a free radical generator (2,2'-azobis(2-amidinopropane) dihydrochloride, AAPH). The cellular thiol redox status was reflected through levels of reduced glutathione and protein sulfhydryl (SH) groups. The ability of GSNO to deliver NO to SMC and to induce protein S-nitrosation (investigated via mass spectrometry, MS), as well as the implication of two redox enzymes involved in GSNO metabolism (activity of gamma-glutamyltransferase, GGT, and expression of protein disulfide isomerase, PDI) were evaluated. Oxidative stress decreased both intracellular glutathione and protein -SH groups (53% and 32% respectively) and caused a 3.5-fold decrease of GGT activity, while PDI expression at the plasma membrane was 1.7-fold increased without any effect on extracellular GSNO catabolism. Addition of GSNO (50 μM) increased protein -SH groups and protein S-nitrosation (50%). Mass spectrometry analysis revealed a higher number of S-nitrosated proteins under oxidative stress (83 proteins, vs 68 in basal conditions) including a higher number of cytoskeletal proteins (15, vs 9 in basal conditions) related with cell contraction, morphogenesis and movement. Furthermore, proteins belonging to additional protein classes (cell adhesion, transfer/carrier, and transporter proteins) were S-nitrosated under oxidative stress. In conclusion, higher levels of GSNO-dependent S-nitrosation of proteins from the cytoskeleton and the contractile machinery were identified under oxidative stress conditions. The findings may prompt the identification of suitable biomarkers for the appraisal of GSNO bioactivity in the CVD treatment.


Perception of chirps by Sykes's monkeys (Cercopithecus albogularis) and humans (Homo sapiens).
Four Sykes's monkeys (Cercopithecus albogularis) and 4 humans (Homo sapiens) discriminated among 12 chirps presented in a repeating background paradigm. The test stimuli consisted of sets of 4 chirps recorded from Sykes's monkeys, red-tailed monkeys (C. ascanius), and small East African birds. Reaction times were submitted to a multidimensional scaling analysis. All monkey listeners perceived the bird chirps as similar to each other and distinct from the monkey calls, whereas 3 of the 4 human listeners had difficulty distinguishing the bird chirps from the monkey calls. Both human and monkey subjects tended to perceive Sykes's and red-tailed monkey calls as very similar to one another, but the degree of perceived similarity was greatest for the monkey listeners. The data suggest that the perceptual map of these calls is influenced by their biological significance in nature.


Pregnant women with opioid use disorder and their infants in three state Medicaid programs in 2013-2016.
Maternal opioid use disorder (OUD) has serious consequences for maternal and infant health. Analysis of Medicaid enrollee data is critical, since Medicaid bears a disproportionate share of costs. This study analyzes linked maternal and infant Medicaid claims data and infant birth records in three states in the year before and after a delivery in 2014-2015 (2013-2016) examining health, health care use, treatment, and neonatal outcomes. Diagnosis and procedure codes identify OUD and other substance use disorders (SUDs). In the year before and after delivery, 2.2 percent of the sample had an OUD diagnosis, and 5.9 percent had a SUD diagnosis other than OUD. Of the women with OUD, 72.8% had treatment for a SUD in the year before and after delivery, but most had none in an average enrolled month, and only 8.8% received any methadone treatment in a given month. Pregnant women with OUD had delayed and lower rates of prenatal care compared to women with other substance use disorders (SUDs). Infants of mothers with OUD did not differ from infants of mothers with other SUDs in rate of preterm or low birth weight but had higher NICU admission rates and longer birth hospitalizations. Health care costs for women with an OUD were higher than those with other SUDs. There is an urgent need for comprehensive, evidence-based OUD treatment integrated with maternity care. To fill critical gaps in care, workforce and infrastructure innovations can facilitate delivery of preventive and treatment services coordinated across settings.


Attention-deficit/hyperactivity disorder and obesity in US males and females, age 8-15 years: National Health and Nutrition Examination Survey 2001-2004.
Youth with ADHD may be at increased risk for obesity. Medications used to treat ADHD can affect weight. Few studies have investigated possible gender differences in associations between ADHD and obesity. Nationally representative of US youth aged 8-15 years. Height and weight were measured, and ADHD assessed by structured diagnostic interview and parent report. Associations between ADHD and obesity are reported for males and females to enable gender comparisons. To investigate how associations between attention-deficit/hyperactivity disorder (ADHD) and obesity differ by gender and medication use in a nationally representative sample of US youth in which height and weight were measured. Youth age 8-15 (n = 3050) studied in the National Health and Nutrition Examination Survey 2001-2004. Obesity was defined as ≥95th percentile of US body mass index-for-age reference. ADHD was determined by asking parents if child had been diagnosed and using the Diagnostic Interview Schedule for Children IV. Gender-stratified multivariable logistic regression was used to estimate odds of obesity for youth with ADHD (medicated and unmedicated) relative to youth without ADHD. Males with ADHD who were medicated had lower odds of obesity compared to males without ADHD (adjusted odds ratio [OR] = 0.42, 95% confidence interval [CI] = 0.23-0.78). Unmedicated males with ADHD were as likely as males without ADHD to be obese (adjusted OR = 1.02, 95% CI = 0.43-2.42). The odds of obesity for females taking medication for ADHD did not differ statistically from those of females without ADHD (adjusted OR = 1.21, 95% CI = 0.52-2.81). Females with ADHD not taking medication had odds of obesity 1.54 times those of females without ADHD; however, the 95% CI (0.79-2.98) was wide and not statistically significant at α = 0.05. Associations between ADHD and obesity are influenced by treatment of ADHD with medication and may differ by gender. Youth with ADHD who are not treated with medication are as or more likely than youth without ADHD to be obese.


Endothelial function in the forearm circulation of patients with the metabolic syndrome--effect of different lipid-lowering regimens.
We compared the effect of statin therapy (either alone or combined with ezetimibe) on the inhibition of cholesterol resorption and endothelial function by measuring forearm blood flow in male patients with the metabolic syndrome. Compared to 40 mg atorvastatin alone, combination therapy with 10 mg ezetimibe and 10 mg atorvastatin for 8 weeks resulted in significantly decreased total serum cholesterol and triglycerides levels (n = 14). Endothelium-dependent, acetylcholine-mediated vasodilation was significantly better with combination therapy (p < 0.05). In contrast, endothelium-independent forearm blood flow response to sodium nitroprusside was comparable in both groups. Our data suggest a more effective restoration of endothelial function with the statin/ezetimibe combination compared to statin monotherapy in patients with the metabolic syndrome.


LEARNS Model as Perioperative Education Strategy for Patients with Laryngeal Tumors.
To evaluate LEARNS model as a perioperative strategy for health education and nursing supervision of patients with laryngeal tumors. LEARNS scheme based on the best practice guidelines was applied to patients in the observation group: (1) analyze the needs of patients (Listen_L); (2) establish therapeutic partnership (Establish_E); (3) adopt intentional intervention (Adopt_A); (4) reinforce health awareness (Reinforce_R); (5) implement feedback assessment of knowledge (Name_N); (6) strengthen self-management based on community resources (Strengthen_S). In the control group, traditional medical care instructions were provided to the patients by medical staff. Parameters such as anxiety status, treatment compliance, nursing satisfaction, self-care ability, and life quality were compared between the observation and control groups. Upon admission, there was no significant difference in self-care ability and anxiety level between two groups. However, the anxiety level of observation group was significantly lower than that of the control group 1 day before operation and 7 days after operation. Postoperative treatment compliance and nursing satisfaction were also improved in the observation group. In addition, self-care ability and life quality in the observation group were significantly enhanced as compared to the control group. As a mutual learning process between nurses and patients, LEARNS model motivates nurses to assess the needs of patients voluntarily. Furthermore, evidence-based education reinforces the self-care ability and health awareness of the patients. Our data suggests that LEARNS model is of great value in improving the life quality of the patients with laryngeal tumors and nursing satisfaction.


Triphenylphosphine oxide-1-naphthoic acid (1/1).
In the title compound, C18H15OP.C11H8O2, co-crystallization of triphenylphosphine oxide with 1-naphthoic acid yields a supramolecular structure held together by one O-H...O and three C-H...O hydrogen bonds. The O-H...O hydrogen bond [O...O = 2.592 (2) A] has little effect on the O=P bond distance.


[The Projet PIE: a promising strategy to reach elders with a mental health problem].
Approximately fifty percent of older adults with a mental health problem do not receive services. A proactive outreach strategy, Project PIE (Prevention-Intervention-Education) relies upon the assistance of non-traditional referral sources, namely community liaisons, to identify and refer to the CSSS vulnerable or isolated elders with a mental health problem. An evaluation of this project reveals encouraging results. The project appears useful, relevant and efficient to detect elders with a mental health problem and offer the required assistance. This project also appears to be a means to foster social solidarity.


A critical role for the regulated wnt-myc pathway in naive T cell survival.
Wnt signaling is involved in T cell development, activation, and differentiation. However, the role for Wnt signaling in mature naive T cells has not been investigated. In this article, we report that activation of Wnt signaling in T cell lineages by deletion of the Apc (adenomatous polyposis coli) gene causes spontaneous T cell activation and severe T cell lymphopenia. The lymphopenia is the result of rapid apoptosis of newly exported, mature T cells in the periphery and is not due to defects in thymocyte development or emigration. Using chimera mice consisting of both wild-type and Apc-deficient T cells, we found that loss of naive T cells is due to T cell intrinsic dysregulation of Wnt signaling. Because Apc deletion causes overexpression of the Wnt target gene cMyc, we generated mice with combined deletion of the cMyc gene. Because combined deletion of cMyc and Apc attenuated T cell loss, cMyc overexpression is partially responsible for spontaneous T cell apoptosis and lymphopenia. Cumulatively, our data reveal a missing link between Wnt signaling and survival of naive T cells.


Quantitative trait locus dissection in congenic strains of the Goto-Kakizaki rat identifies a region conserved with diabetes loci in human chromosome 1q.
Genetic studies in human populations and rodent models have identified regions of human chromosome 1q21-25 and rat chromosome 2 showing evidence of significant and replicated linkage to diabetes-related phenotypes. To investigate the relationship between the human and rat diabetes loci, we fine mapped the rat locus Nidd/gk2 linked to hyperinsulinemia in an F2 cross derived from the diabetic (type 2) Goto-Kakizaki (GK) rat and the Brown Norway (BN) control rat, and carried out its genetic and pathophysiological characterization in BN.GK congenic strains. Evidence of glucose intolerance and enhanced insulin secretion in a congenic strain allowed us to localize the underlying diabetes gene(s) in a rat chromosomal interval of approximately 3-6 cM conserved with an 11-Mb region of human 1q21-23. Positional diabetes candidate genes were tested for transcriptional changes between congenics and controls and sequence variations in a panel of inbred rat strains. Congenic strains of the GK rats represent powerful novel models for accurately defining the pathophysiological impact of diabetes gene(s) at the locus Nidd/gk2 and improving functional annotations of diabetes candidates in human 1q21-23.


Renal outcomes of transient proteinuria in patients with systemic lupus erythematosus treated with corticosteroid therapy alone.
To examine the long-term renal outcomes of systemic lupus erythematosus (SLE) patients with transient proteinuria. The medical records of SLE patients who showed improvement in proteinuria (urine protein/creatinine ratio < 500 mg/g) after receiving corticosteroid therapy without immunosuppressants were reviewed. A total of 38 patients (mean creatinine: 0.74 ± 0.33 mg/dl) showed an improvement of proteinuria (1361 ± 1053 mg/g to 289 ± 125 mg/g) after receiving corticosteroid therapy alone for a median of 25 days (IQR, 10-55). After follow-up (median, 23 months [IQR, 15-121]), 25 (65%) patients maintained the resolution of proteinuria without renal dysfunction. The remaining 13 (34%) patients experienced a relapse of proteinuria during a median follow-up of 13.9 months from baseline (IQR, 1.6-25). There was no significant difference in the baseline laboratory data according to the occurrence of proteinuria relapse, but longer SLE disease duration at baseline was associated with the risk of proteinuria relapse (HR, 1.007; p = 0.033). Of the patients who underwent renal biopsy with proteinuria relapse, class II (53%) lupus nephritis was the most common pathology. None progressed to end-stage renal disease during an additional long-term further follow-up of median 33 months (IQR, 22-49) after proteinuria relapse. Two-thirds of SLE patients who showed improvement in proteinuria after corticosteroid alone maintained the non-proteinuric state without renal dysfunction. Thus, performing a kidney biopsy at the first onset of proteinuria could be delayed in patients who show an improvement in proteinuria after treatment with corticosteroids.


Hepatotoxicity of antimicrobial agents.
Antimicrobial agents are a common and important cause of hepatotoxicity. As a class, the antimicrobials contain many and varied structures, leading to a wide clinical spectrum of hepatotoxicity. Minor liver injury, manifest only as liver enzyme elevations, is common with some antimicrobials. Clinically significant injury is unusual but can adopt almost any form. Classical acute hepatocellular, cholestatic, or mixed reactions are most often seen. Other forms of hepatotoxicity including granulomatous reactions, steatosis, chronic hepatitis, and cirrhosis have also been described. Generally, antimicrobial-associated hepatotoxicity is mild and self-limited; most cases resolve after withdrawal of the offending medication. Occasionally, however, liver injury presents as a fulminant life-threatening condition or may develop into a chronic illness with significant morbidity. This article presents a summary of reported hepatotoxicity associated with the major classes of antimicrobials and, where possible, identifies potential risk factors and management strategies to assist clinical practice.


Left ventricular function in atrial fibrillation during overdrive pacing.
Our purpose was to measure the effect of ventricular pacing in patients with atrial fibrillation (AF) on stroke volume and cardiac output. Unceasing variation in cycle length in AF decreases stroke volume and cardiac output. Because ventricular-inhibited pacing after atrioventricular node ablation has been reported to improve left ventricular performance, we tested the hypothesis that overdrive pacing would produce a similar benefit by regularizing cycle length. We studied 18 patients with chronic AF and permanent pacemakers. The aortic time velocity integral (TVI) was measured with continuous-wave Doppler and was used as a surrogate measure of stroke volume (stroke volume = TVI x aortic valve area, and aortic valve area is constant whether in AF or during pacing). For each patient, the linear relation between preceding cycle length and TVI in AF was used to estimate relative stroke volume (TVI compared within each patient) at a preceding cycle length of 666 ms in AF, and a similar comparison between AF and pacing was made at the minimum allowable pacing rate. Relative stroke volume in AF was then compared with relative stroke volume at both the fixed cycle (666 ms) and the minimum allowable rate. During pacing at 666 ms, relative stroke volume increased significantly by 18% (t = 2.8, P =.048), but there was no difference in cardiac output during pacing at the minimum possible rate and the corresponding preceding cycle length in AF. Our data suggest that regularization of ventricular rhythm by overdrive pacing in patients with AF only improves stroke volume (and by extension, cardiac output) at pacing rates at the outer limit of and above the normal physiologic range.


Mitochondrial replacement: from basic research to assisted reproductive technology portfolio tool-technicalities and possible risks.
Mitochondrial DNA (mtDNA) mutations are a relatively common cause of progressive disorders that can be severe or even life-threatening. There is currently no cure for these disorders; therefore recent research has been focused on attempting to prevent the transmission of these maternally inherited mutations. Here we highlight the challenges of understanding the transmission of mtDNA diseases, discuss current genetic management options and explore the use of germ-line reconstruction technologies to prevent mtDNA diseases. In particular we discuss their potential, indications, limitations and possible safety concerns.


Testing the abuse liability of anxiolytic and hypnotic drugs in humans.
This paper represents a comprehensive review of laboratory studies investigating the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective effects of these drugs, most of which are either barbiturates or benzodiazepines, have been measured using various self-report questionnaires and their reinforcing effects have been studied using self-administration and choice procedures. Studies using both subjective and reinforcing effects reveal orderly relations between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates are associated with higher abuse liability than benzodiazepines), between different doses of the drugs (e.g. higher doses are usually associated with higher abuse liability) and among different compounds within a class. The subjective and reinforcing effects of barbiturates and benzodiazepines depend critically upon the subject populations that are tested and it is argued that individuals with histories of drug abuse provide a more sensitive indicator of abuse liability than healthy volunteers. Several principles of abuse liability testing are discussed, including the selection of an appropriate subject population, the use of blind drug administration procedures, the comparison of a test compound to an appropriate standard, the inclusion of a placebo and a wide range of doses of the test drug and the use of multiple measures of likelihood of abuse.


[Management of 42 complex intracranial aneurysms in hybrid operating room].
Objective: To analyze the efficacy and methods of hybrid operation in the treatment of complex intracranial aneurysms. Methods: Fourty-two patients with complex intracranial aneurysms were treated in hybrid operation room of Qilu Hospital of Shandong University between July 2011 and October 2016. Twenty-one cases of aneurysm clipping guided by intraoperative angiography, 10 cases of aneurysm clipping assisted by endovascular therapy, and 11 cases of aneurysm occlusion assisted by bypass surgery. Results: Thirty-five patients were followed up 6-36 months.Thirty-three (94.3%) cases were completely occlusion, 2 (5.7%) cases were recurrent in follow-up.One of the recurrence case was performed interventional embolization treatment, and the other was continuous follow-up. Conclusion: Hybrid operating room is beneficial to evaluate the surgical curative effect immediately. It could increase the occlusion rate of complicated aneurysms, and could provide an ideal platform for complicated intracranial aneurysm treatment.


The small-molecule kinase inhibitor D11 counteracts 17-AAG-mediated up-regulation of HSP70 in brain cancer cells.
Many types of cancer express high levels of heat shock proteins (HSPs) that are molecular chaperones regulating protein folding and stability ensuring protection of cells from potentially lethal stress. HSPs in cancer cells promote survival, growth and spreading even in situations of growth factors deprivation by associating with oncogenic proteins responsible for cell transformation. Hence, it is not surprising that the identification of potent inhibitors of HSPs, notably HSP90, has been the primary research focus, in recent years. Exposure of cancer cells to HSP90 inhibitors, including 17-AAG, has been shown to cause resistance to chemotherapeutic treatment mostly attributable to induction of the heat shock response and increased cellular levels of pro-survival chaperones. In this study, we show that treatment of glioblastoma cells with 17-AAG leads to HSP90 inhibition indicated by loss of stability of the EGFR client protein, and significant increase in HSP70 expression. Conversely, co-treatment with the small-molecule kinase inhibitor D11 leads to suppression of the heat shock response and inhibition of HSF1 transcriptional activity. Beside HSP70, Western blot and differential mRNA expression analysis reveal that combination treatment causes strong down-regulation of the small chaperone protein HSP27. Finally, we demonstrate that incubation of cells with both agents leads to enhanced cytotoxicity and significantly high levels of LC3-II suggesting autophagy induction. Taken together, results reported here support the notion that including D11 in future treatment regimens based on HSP90 inhibition can potentially overcome acquired resistance induced by the heat shock response in brain cancer cells.


Affinity-based methods in drug-target discovery.
Target discovery using the molecular approach, as opposed to the more traditional systems approach requires the study of the cellular or biological process underlying a condition or disease. The approaches that are employed by the "bench" scientist may be genetic, genomic or proteomic and each has its rightful place in the drug-target discovery process. Affinity-based proteomic techniques currently used in drug-discovery draw upon several disciplines, synthetic chemistry, cell-biology, biochemistry and mass spectrometry. An important component of such techniques is the probe that is specifically designed to pick out a protein or set of proteins from amongst the varied thousands in a cell lysate. A second component, that is just as important, is liquid-chromatography tandem massspectrometry (LC-MS/MS). LC-MS/MS and the supporting theoretical framework has come of age and is the tool of choice for protein identification and quantification. These proteomic tools are critical to maintaining the drug-candidate supply, in the larger context of drug discovery.


Effects of isoproterenol and norepinephrine on regional ocular blood flows.
The effects of norepinephrine and isoproterenol on regional ocular blood flows were studied by the labeled microspheres using the reference sample method in pigs. Total and regional ocular flows increased in response to norepinephrine and isoproterenol infusions. Increase in flows during norepinephrine infusion may be due to increased ocular perfusion pressure induced by the drug, thereby masking its reported direct vasoconstrictor effect in isolated perfused ocular vessels. Increase in flows during isoproterenol infusion occurred despite a decrease in arterial pressure suggesting the existence of vasodilatory beta-adrenergic receptors in the ocular circulation of the pig.


P(3HB-co-4HB) as high value polyhydroxyalkanoate: its development over recent decades and current advances.
Polyhydroxyalkanoate (PHA) is a biogenic polymer that has the potential to substitute synthetic plastic in numerous applications. This is due to its unique attribute of being a biodegradable and biocompatible thermoplastic, achievable through microbial fermentation from a broad utilizable range of renewable resources. Among all the PHAs discovered, poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] stands out as a next generation healthcare biomaterial for having high biopharmaceutical and medical value since it is highly compatible to mammalian tissue. This review provides a critical assessment and complete overview of the development and trend of P(3HB-co-4HB) research over the last few decades, highlighting aspects from the microbial strain discovery to metabolic engineering and bioprocess cultivation strategies. The article also outlines the relevance of P(3HB-co-4HB) as a material for high value-added products in numerous healthcare-related applications.


[Therapeutic possibilities for the diabetic and ischemic foot].
The prognosis and treatment of a diabetic foot depend on the extent of the lesions. If infected, these lesions are always mixed, secondary to aerobic and anaerobic bacteroides. The antibiotic treatment must be well adjusted and applied for a long enough time. It is absolutely necessary, for the treatment to be effective, to know the level of the ischemia in order to decide whether a lesion or an amputation scar will heal without revascularization. The author discusses various non-invasive examinations. Today, distal revascularization if possible due to new surgical techniques. But, one must emphasize that the patency of an adequate by-pass is definitely longer than the survival of a diabetic patient, in general. A accurate diagnosis and a multiudiscipline treatment will therefore improve the quality of the survival of the patient.


Trends in COVID-19-related in-hospital mortality in women and men.
Whether political, scientific and medical development in a country is associated with better clinical results according to gender in patients with COVID-19 has not yet been clearly elucidated. To determine the trends of COVID-19-related in-hospital mortality in women and men from March 2020 to February 2022. Clinical data of all patients with COVID-19 cared for at 21 Spanish hospitals were used, both of those who were discharged and of those who died during hospitalization. The association between hospital length of stay and mortality was analyzed with logistic regression models. Out of 7,974 patients that were included, 3,234 were women; 928 patients died. A significant decreasing trend in mortality was identified. When the analysis was carried out by gender, no significant mortality trend was found in women (OR = 0.96 [0.90-1.03], p = 0.239), while in men there was a significant decreasing trend identified (OR = 0.87 [0.82-0.92], p < 0.001). Health policies, together with clinical and preventive interventions, may explain these results. Response to treatment and behavioral differences may explain why mortality does not decrease for women.


Interobserver and Intraobserver Reliability of Cone-beam Computed Tomography in Identification of Apical Periodontitis.
Accurate radiographic interpretation is of the utmost importance in the diagnosis and treatment of patients. Previous studies have indicated subjectivity in the radiographic interpretation of periapical tissues irrespective of using conventional radiography, digital radiography, or cone-beam computed tomographic (CBCT) imaging. No studies to date have evaluated the reliability of the interpretation of periapical tissues based on the size of periapical radiolucency (PAR). The purpose of this study was to assess the interobserver and intraobserver reliability of CBCT interpretation by observers from different specialties and different levels of experience when identifying PARs of various sizes. Limited field of view CBCT scans were selected such that a variety of PARs with various sizes were included. Six observers with different levels of experience and fields of specialty evaluated periradicular tissues of 28 roots on the CBCT scans at 3 separate sittings each a month apart. The overall Fleiss kappa coefficient for interobserver reliability and intraobserver reliability was 0.88 and 0.85; the larger the PAR, the more reliable the radiographic interpretation. Increased experience level improved the intraobserver reliability. CBCT imaging appears to be a reliable method for the interpretation of PAR. The larger the PAR is the more reliable the radiographic interpretation.


Entrepreneurship Education and Health-Stress Analysis of College Teachers and Students Using Backpropagation Neural Network Model.
The purpose is to solve the problem of college students' employment difficulties. It is the development trend of the times to master the basic psychological pressure state of students and analyze students' problems by using modern technology and science. First, based on Marxist theory, the theory of entrepreneurship education and the characteristics of teachers and students in colleges are expounded, and the principle and algorithms of Backpropagation Neural Network (BPNN) are introduced. Second, from the perspective of entrepreneurship education and mental health factors of college students, the sample set of the BPNN model is collected using a Questionnaire Survey (QS). Then, the sample set is normalized to analyze the current college entrepreneurship education and the health and stress of college students. The results show that the comprehensive BPNN output of entrepreneurship education is 0.726, indicating that entrepreneurship education in colleges is at a moderate level. The proposed BPNN model can perform better than the traditional prediction methods in predicting college students' mental health, and the data fitting results are satisfactory. Overall, college students' entrepreneurship education should be improved, and schools should take more incentives to help adjust college students' mentality.


[Association of MMP14 gene polymorphisms and osteoporosis in Zhuang men from Baise region of Guangxi].
To assess the association between membrane type 1 matrix metalloproteinase gene (MT1-MMP, MMP14) polymorphisms and osteoporosis in Zhuang men from Baise region of Guangxi. Genotypes of 5 loci (rs1003349, rs3751488, rs2269213, rs2236303 and rs743257) of MMP14 gene in 301 Zhuang men were determined with single base extension methods, and bone mineral density (BMD) at left calcaneus was evaluated with quantitative ultrasound with measured values of broadband ultrasonic attenuation (BUA). The subjects were divided according to BMD into osteoporosis group, osteopenia group and normal bone density group. All selected loci were in Hardy-Weinberg equilibrium (P> 0.05). By multiple linear stepwise regression analysis, polymorphisms of the five loci were not associated with BUA. But a significant higher risk of osteoporosis was found in individuals with MMP14 rs1003349 GT genotype (vs. GG genotype; P<0.05) and rs2236303 CC and CT genotypes (vs. TT genotype; P<0.05). Genetic linkage between rs1003349 and rs2236303 was also discovered (D'= 0.839, r(2) = 0.458, P<0.01). Compared with the normal bone density group, the frequency of a G-T haplotype of rs1003349 and rs2236303 was significantly lower in the osteoporosis group (P<0.05). And the risk of osteoporosis for individuals with G-C and T-C haplotypes was 2.556 (95% CI: 1.029-6.349, P = 0.038) and 5.111 (95% CI: 1.341-19.485, P = 0.011) compared with G-T haplotype. Polymorphisms of rs1003349 and rs2236303 loci of MMP14 gene are associated with the susceptibility of osteoporosis in Zhuang men in Guangxi. G-C and T-C haplotypes for loci rs1003349 and rs2236303 may increase the disease risk.


Treatment program planning by speech therapists in Taiwan.
Speech-language pathology is a rapidly growing profession in Taiwan. To assess its autonomy and maturity, a survey on the treatment program with the help of a 14-item questionnaire was conducted among 90 speech therapists from health care settings. Questions about the planning of the treatment program, its components, and the employed therapeutic methods were addressed in the study. The survey findings helped clarify the current role of speech therapists in Taiwan.


At what age does iron supplementation become necessary in low-birth-weight infants?
Prevention of iron deficiency in low-birth-weight infants requires iron supplementation before neonatal iron stores are exhausted. In order to accurately determine when this depletion occurs, we measured the hemoglobin, mean corpuscular volume, serum iron/iron-binding capacity, and serum ferritin in 117 low-birth-weight infants (1,000 to 2,000 gm) from 0.5 until 6 months of age. All infants received banked breast milk in the hospital and breast milk or cow milk formula later; those with odd birth dates received 2 mg iron as ferrous sulfate/kg/day starting at 0.5 months; those with even birth dates received no additional iron unless they developed anemia. The results indicate that low-birth-weight infants who receive no supplemental iron may develop iron deficiency by three months of age and that a dose of iron of 2 mg/kg/day started at two weeks of age prevents iron deficiency without providing excess.


Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms.
ADAM10 (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological alpha-secretase in neurons, responsible for cleaving APP in a non-amyloidogenic manner. This cleavage results in the production of a neuroprotective APP-derived fragment, APPs-alpha, and an attenuated production of neurotoxic A-beta peptides. An increase in ADAM10 activity shifts the balance of APP processing toward APPs-alpha and protects the brain from amyloid deposition and disease. Thus, increasing ADAM10 activity has been proposed an attractive target for the treatment of neurodegenerative diseases and it appears to be timely to investigate the physiological mechanisms regulating ADAM10 expression. Therefore, in this article, we will (1) review reports on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or protein interactions, (2) describe conditions, which change ADAM10 expression in vitro and in vivo, (3) report how neuronal ADAM10 expression may be regulated in humans, and (4) discuss how this knowledge on the physiological and pathophysiological regulation of ADAM10 may help to preserve or restore brain function.


Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice.
Polychlorinated biphenyls (PCBs) are environmental contaminants that can cause neurotoxicity. PCBs, such as PCB 95 (2,2',3,5',6-pentachlorobiphenyl), can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites. To better understand how the metabolism of PCB 95 affects neurotoxic outcomes, we conducted a study on the disposition of PCB 95 in transgenic mouse models. The mice were given a single oral dose of PCB 95 (1.0 mg/kg) and were euthanized 24 h later for analysis. PCB 95 levels were highest in adipose tissue, followed by the liver, brain, and blood. Adipose tissue levels were significantly higher in wild-type (WT) mice than in Cyp2abfgs-null (KO) or CYP2A6-transgenic (KI) mice. We also observed genotype-dependent differences in the enrichment of aS-PCB 95 in female mice, with a less pronounced enrichment in KO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detected in blood and tissue across all exposure groups. The metabolite profiles differed across tissues, while sex and genotype-dependent differences were less pronounced. Total OH-PCB levels were highest in the blood, followed by the liver, adipose tissue, and brain. Total OH-PCB blood levels were lower in KO than in WT mice, while the opposite trend was observed in the liver. In male mice, total OH-PCB metabolite levels were significantly lower in KI than in WT mice in blood and the liver, while the opposite trend was observed in female mice. In conclusion, the study highlights the differences in the atropselective disposition of PCB 95 and its metabolites in different types of mice, demonstrating the usefulness of these transgenic mouse models for characterizing the role of PCB metabolism in PCB neurotoxicity.


New-Onset Seizures in Patients With COVID-19: A Case Series From a Single Public Hospital in Korea.
Seizure is an uncommon complication of coronavirus disease 2019 (COVID-19). The frequency and characteristics of new-onset seizures in hospitalized patients with COVID-19 were investigated. Of a total of 1,487 patients with confirmed COVID-19, six (0.4%) developed new-onset seizures. All six had severe or critical COVID-19 requiring intensive care and mechanical ventilation or high-flow oxygen therapy. Among COVID-19 patients admitted to the intensive care unit (n = 169), the incidence of new-onset seizures was 3.6%. Underlying structural lesions (acute infarction and remote hemorrhage), hypoxia, sepsis, and metabolic derangements were associated with the development of seizures. Of the six patients, three patients died, and, at the time of discharge, one patient had a severe disability, while the remaining two were well recovered.


Mesenchymal chondrosarcomas showing immunohistochemical evidence of rhabdomyoblastic differentiation: a potential diagnostic pitfall.
The diagnosis of mesenchymal chondrosarcoma, a distinctive biphasic malignant neoplasm harboring the HEY1-NCOA2 gene fusion and consisting of primitive round to spindled cells admixed with foci of relatively mature hyaline cartilage, is usually straightforward by morphologic evaluation alone. However, in the setting of a limited biopsy, specimens lacking cartilage generate a broad differential diagnosis, encompassing a variety of other primitive sarcomas, including spindle cell/sclerosing rhabdomyosarcoma. Although a small number of cases of mesenchymal chondrosarcoma with aberrant skeletal muscle marker expression have been reported, pathologists are largely unaware of this potential diagnostic pitfall. We report 6 additional cases of mesenchymal chondrosarcoma showing expression of multiple skeletal muscle markers, including one case initially misdiagnosed as "spindle cell/sclerosing rhabdomyosarcoma" on needle biopsy. Awareness of this phenomenon and judicious application of molecular diagnostic testing for the HEY1-NCOA2 fusion are critical to avoid misclassification of mesenchymal chondrosarcoma as rhabdomyosarcoma, with potentially adverse patient impact.


Clinical evaluation of a quaternary ammonium-containing mouthrinse.
This was a double-blind, radomized, crossover study of adult subjects to evaluate the effect of a test mouthrinse (Cepacol) on plaque accumulation. The study was divided into two parts, four weeks each, one in which only a mouthwash was used (part I) and the other in which a mouthwash and toothbrushing were used (part II). 1. The test mouthrinse produced a satistically significant reduction in dental plaque when compared to a placebo rinse. 2. The GI averaged approximately 1.0 throughout the study regardless of which mouthrinse was used. 3. A possible carryover effect of the test mouthrinse was noted. 4. A lower plaque score was seen in 67 to 75% of all patients during the period in which the test mouthrinse was used as compared to the placebo. 5. Ten subjects reported a burning sensation of the tongue with the test mouthrinse. No objective adverse effects were seen.


A quantitative relationship between Cl- enhanced [3H]flunitrazepam and [35S]t-butylbicyclophosphorothionate binding to the benzodiazepine/GABA receptor chloride ionophore complex.
A quantitative relationship between the efficacy (i.e. maximum enhancement) of Cl- to increase [3H]flunitrazepam binding and the density of [35S]t-butylbicyclophosphorothionate binding sites was observed in well-washed membrane fragments of rat cerebral cortex previously exposed to phospholipase A2. This relationship (described by the equation y = ABx) was maintained when [3H]flunitrazepam was assayed at Cl- concentrations between 100 and 600 mM, and was not qualitatively altered by the presence of 100 microM pentobarbital. However, under experimental conditions that reduced the ratio of [35S]TBPS binding sites/benzodiazepine receptors, the effects of pentobarbital suggest that the conductance state of benzodiazepine receptor-coupled chloride channels may be the primary determinant of Cl- enhanced [3H]flunitrazepam binding.


Acute Kidney Injury in Children with Plasmodium falciparum Malaria: Determinants for Mortality.
♦ Acute kidney injury (AKI) in P. falciparum malaria infection is an important morbidity in children. The purpose of the present study was done to observe the renal involvement, associated morbidities and outcome. ♦ Out of 156 patients with severe P. falciparum malaria, diagnosed on the basis of compatible clinical presentations and positive malarial parasites in the peripheral blood smear and/or histidine rich protein 2 antigen, 31 had AKI at presentation and were analyzed. ♦ Of 31 (19.9%) patients with AKI, 4 were classified at risk, 11 injury, and 16 failure stage, as per pRIFLE criteria (pediatric version of RIFLE [R = risk, I = injury, F = failure, L = loss E = end-stage kidney disease]). Mean age of children with AKI was 7.7 ± 3.2 years. A significantly higher proportion of patients with AKI had hypoglycemia (41.9%), pulmonary edema (32.2%), and disseminated intravascular coagulation (DIC) (29.0%) compared to those without AKI (18.4%, 4.8%, and 3.2%, respectively). Twelve patients (38.7%) required peritoneal dialysis (PD), 8 (25.8%) died, and all were in failure stage. The non-survivors had significantly higher blood urea (p = 0.005) and serum creatinine levels (p = 0.042), lower glomerular filtration rate (p < 0.001), longer duration of illness (p = 0.003), and oliguria/anuria (p = 0.001) than survivors at admission. On logistic regression analysis, the disseminated intravascular coagulation (DIC), jaundice and parasite density (≥ 3+) were found to be significant factors contributing to mortality in children with AKI. ♦ Acute kidney injury in falciparum malaria is one of the severe systemic complications. Duration of illness and presence of comorbidities adversely affected the outcome.


Increased platelet adenylate cyclase activity ion diabetic patients with microangiography.
Platelet aggregation, beta-thromboglobulin levels and the platelet adenylate cyclase activity (expressed as increase of cAMP levels) were determined in blood samples from healthy control subjects and from diabetic patients with and without microangiopathy. Patients with diabetic microangiography showed significantly higher beta-thromboglobulin levels, an increased tendency to platelet aggregation, and higher cAMP levels in platelet-rich plasma after incubation with PGI2. The findings were interrupted by the assumption of an increased turn-over of platelets which might be a consequence of the microvascular disease.


Changes in the dynamic compliance coefficient of the lungs and breathing mechanics during administration of diethyl ether and halothane for general anaesthesia with spontaneous respiration.
Changes of the dynamic compliance coefficient of lungs were studied during diethyl ether and halothane anaesthesia. Determining lung compliance at the same time it was possible to show the effect of these agents on changes in the magnitude of breathing work necessary to overcome elastic and non-elastic resistances. The investigations were carried out on 31 patients during general anaesthesia with spontaneous respiration. The determinations revealed that the tidal volume (TV) was decreased in relation to the initial values (before anaesthesia) indicating a depressing effect of these agents on the processes of respiration. Changes in the tidal volume and intrapulmonary pressure decided on the changes of the pulmonary compliance coefficient and the magnitude of breathing work. The coefficient of pulmonary compliance decreased during diethyl ether administration by 18.8% and during halothane by 30.9%. On the other hand the work necessary to overcome respiratory resistances increased mainly during ether anaesthesia owing to a significant rise in the non-elastic resistance (bronchial secretion).


Nutritional scientist or biochemist?
When invited by the editors to provide a prefatory article for the Annual Review of Nutrition, I attempted to decide what might be unique about my experiences as a nutritional biochemist. Although a large proportion of contemporary nutritional scientists were trained as biochemists, the impact of the historical research efforts related to nutrition within the Biochemistry Department at the University of Wisconsin 50 to 60 years ago was, I think, unique, and I have tried to summarize that historical focus. My scientific training was rather standard, but I have tried to review the two major, but greatly different, areas of research that I have been involved in over my career: inorganic fluorides as an industrial pollutant and the metabolic role of vitamin K. I have also had the opportunity to become involved with the activities of the societies representing the nutritional sciences (American Society for Nutrition), biochemistry (American Society for Biochemistry and Molecular Biology), Federation of American Societies for Experimental Biology, the Food and Nutrition Board, the Board on Agriculture and Natural Resources, and the U.S. Department of Agriculture National Agricultural Research, Extension, Education, and Economics. These interactions can be productive or frustrating but are always time-consuming.


Percutaneous Endoscopic Gastrostomy: A Practical Overview on Its Indications, Placement Conditions, Management, and Nursing Care.
Percutaneous endoscopic gastrostomy (PEG) feeding represents the most effective and safest option for feeding patients with an impaired or diminished swallowing ability, despite having a functioning digestive system. The use of PEG has evolved to be useful in many situations beyond degenerative neuromuscular disorders, with an increasing body of evidence supporting the advantages of PEG tubes in oncologic and pediatric patients. Risk factors for complications after PEG tube placement include acute and chronic conditions associated with malnutrition and several organic disorders. Patients suitable for PEG tube placement should be individually identified to implement the advantages of this technique while minimizing risk events. The safety of placing a PEG tube in patients under antithrombotic medication has been investigated, as well as the advantages of antibiotic prophylaxis in reducing peristomal infection. Evidence supports the safety of early feeding after placement, thus resulting in lower costs. Percutaneous endoscopic gastrostomy-related complications are rare and mostly prevented by appropriate nursing care. Best medical practice and nursing care will ensure optimal performance leading to a wider acceptance, and greater utility of PEG by healthcare professionals, patients, and caregivers. This review aims to update knowledge relating to PEG tube indications, placement, management, and care in order to reinforce PEG feeding as the most valuable access for patients with a functional gastrointestinal system who have abnormalities in swallowing mechanisms.


Mercury (micro)biogeochemistry in polar environments.
The contamination of polar regions with mercury that is transported as inorganic mercury from lower latitudes has resulted in the accumulation of methylmercury in the food chain of polar environments, risking the health of humans and wildlife. This problem is likely to be particularly severe in coastal marine environments where active cycling occurs. Little is currently known about how mercury is methylated in polar environments. Relating observations on mercury deposition and transport through polar regions to knowledge of the microbiology of cold environments and considering the principles of mercury transformations as have been elucidated in temperate aquatic environments, we propose that in polar regions (1) variable pathways for mercury methylation may exist, (2) mercury bioavailability to microbial transformations may be enhanced, and (3) microbial niches within sea ice are sites where active microorganisms are localized in proximity to high concentrations of mercury. Thus, microbial transformations, and consequently mercury biogeochemistry, in the Arctic and Antarctic are both unique and common to these processes in lower latitudes, and understanding their dynamics is needed for the management of mercury-contaminated polar environments.


Response of genes associated with mitochondrial function to mild heat stress in yeast Saccharomyces cerevisiae.
The genome-wide expression pattern of budding yeast Saccharomyces cerevisiae in response to mild heat treatment in a non-fermentable carbon source was analyzed using DNA microarrays. Of 5,870 open reading frames (nuclear genome transcripts) examined, 104 genes were upregulated and 287 genes were downregulated upon shifting of the cells from 25 degrees C to 37 degrees C. Forty upregulated genes and 235 downregulated genes encoded localization-assigned proteins. Of 113 heat-repressible genes (excluding 122 heat-repressible ribosomal genes), 36 were mitochondria-related genes, whereas only 2 of 40 heat-inducible genes were mitochondria-related. In particular, 9 genes involved in the mitochondrial respiratory chain and 7 genes involved in mitochondrial protein translocation were significantly repressed, suggesting that mitochondrial respiratory function and biogenesis were downregulated. Consistent with these findings, the growth of yeast cells in a non-fermentable carbon source was repressed at 37 degrees C and the mitochondria isolated from heat-stressed cells exhibited compromised preprotein-import activity compared with those from unstressed cells. In contrast, many genes involved in glycolysis and the metabolic pathway to produce glutamate via the tricarboxylic acid cycle, which is essential for biosynthetic reactions, were upregulated. Yeast cells might downregulate mitochondrial function to circumvent heat-induced oxidative stress, upregulate stress-related genes, and remodel genes for metabolic pathways in response to mild heat stress: an adaptive response at the expense of cell growth.


An analysis of the outcomes of cervical cone biopsies performed in a low resource setting.
Following skills transfer to this low resource setting, we carried out a descriptive analysis of the outcomes of all cone biopsies performed for women with cervical intra-epithelial neoplasia 3 (CIN 3). We also compared two methods of cone biopsy. All the women had follow-up smear tests at 6 and 18 months. There were no cases of CIN 3 at follow-up. 80% had normal smears at 18 months and 20% had CIN 1. Compared with knife cone biopsy, women who had an electric knife (hand-held diathermy blade) cone biopsy had a significantly smaller volume of mean blood loss (55.5mls ± 15.9 vs 153.3ml ± 40, p < 0.001). With appropriate skills transfer, women with CIN 3 in a low resource setting can be effectively treated with conisation procedures. The diathermy knife is preferred to cold knife because of its associated low blood loss.


Validating HONO as an Intermediate Tracer of the External Cycling of Reactive Nitrogen in the Background Atmosphere.
In the urban atmosphere, nitrogen oxide (NOx═NO + NO2)-related reactions dominate the formation of nitrous acid (HONO). Here, we validated an external cycling route of HONO and NOx, i.e., formation of HONO resulting from precursors other than NOx, in the background atmosphere. A chemical budget closure experiment of HONO and NOx was conducted at a background site on the Tibetan Plateau and provided direct evidence of the external cycling. An external daytime HONO source of 100 pptv h-1 was determined. Both soil emissions and photolysis of nitrate on ambient surfaces constituted likely candidate mechanisms characterizing this external source. The external source dominated the chemical production of NOx with HONO as an intermediate tracer. The OH production was doubled as a result of the external cycling. A high HONO/NOx ratio (0.31 ± 0.06) during the daytime was deduced as a sufficient condition for the external cycling. Literature review suggested the prevalence of high HONO/NOx ratios in various background environments, e.g., polar regions, pristine mountains, and forests. Our analysis validates the prevalence of external cycling in general background atmosphere and highlights the promotional role of external cycling regarding the atmospheric oxidative capacity.


Profiles of DES performance in inmate and student samples.
Despite the finding of a recent review of the literature (Moskowitz, 2004) that at least 25% of offenders demonstrated pathological levels of dissociation, very little empirical research has been conducted that examines dissociation in samples of prison inmates. This study examined the profiles of dissociative experiences reported in a sample of 42 prison inmates, when compared to 119 students on the Dissociative Experiences Scale. Profile analysis indicated that overall DES performances differed significantly for the two samples. Using Hotelling's criterion, DES items were found to deviate significantly from flatness, and using Wilks's criterion, the profiles also found to differ significantly from parallelism (p < .01). Specific items contributing to these differences were examined. It is hypothesized that some of these items may be reflective of past criminal activities rather than dissociation. As DES-taxon item content reflects less susceptibility to alternative interpretations, it is recommended that both researchers and clinicians consider using the DES-taxon, rather than DES total scores when examining dissociation in forensic samples.


Determination of copper and zinc in serum by derivative atomic absorption spectrometry using the microsampling technique.
A method has been developed for the determination of copper and zinc in the serum of rats by derivative microsampling flame atomic absorption spectrometry (D-MFAAS). The microsampling volume, solution uptake rate and other figures of merit of the proposed methodology were studied. For a 100 microl volume, the characteristic concentrations and detection limits (3s) of D-MFAAS were 0.023 and 0.013 microg ml(-1) for copper and 0.0066 and 0.0080 microg ml(-1) for zinc, which were 4.5-6.5-fold better than those of microsampling flame atomic absorption spectrometry (MFAAS). The detection limits and sensitivities of D-MFAAS were 6.4- and 16-fold for 300 microl volume for copper, 14- and 13-fold for 250 microl volume for zinc, better than those of MFAAS. The method demonstrates high tolerance to interferences, and the analytical results obtained for a certified reference material, GBW 08551 Pork Liver, were in good agreement with the certified values. The recovery with the standard additions method was good, in the range 97.6-101.5%, and precisions (relative standard deviations) obtained for a diluent sample containing 0.5 microg ml(-1) copper and 0.7 microg ml(-1) zinc were 4.0% and 3.5% (n = 15) for copper and zinc, respectively.


A new model for risk stratification and delivery of cardiovascular rehabilitation services in the long-term clinical management of patients with coronary artery disease.
This model for risk stratification includes variables that classify patients for Risk of Event similar to current models of risk stratification, as well as variables that stratify patients for Risk of Progression of Atherosclerosis by established risk factors. Categories of risk are established using accepted data from the literature for each risk factor that targets regression or plaque stabilization as the goal for Low Risk. A case-rate charging system and the proposed removal of time restrictions for length of cardiovascular rehabilitation fit neatly into the present climate for health care. Health maintenance organizations will be seeking programs that use similar models to address cost issues inherent in cardiovascular rehabilitation programs under current fee-for-service models. Improved outcomes will also be targets for these programs and case-management lends itself to disease management, thus, improved outcomes. Tracking outcomes becomes even more important to both the provider and the insurer because results drive referrals. Likewise, removal of the time restriction for cardiovascular rehabilitation allows programs to individualize care and to target risk factors that are not only most deleterious, but also where patients show readiness for change. The changing environment of health care virtually mandates change in cardiovascular rehabilitation. It is imperative that programs manage the disease process, are effective in achieving outcomes that affect both patient function and the disease process, and are cost effective. This model for risk stratification and delivery of services addresses these requirements and provides a beginning for implementing these changes in cardiovascular rehabilitation.


Silencing of CREB Inhibits HDAC2/TLR4/NF-κB Cascade to Relieve Severe Acute Pancreatitis-Induced Myocardial Injury.
The purpose of the present study is to investigate the role of CREB in cardiomyocytes proliferation in regulation of HDAC2-dependent TLR4/NF-κB pathway in severe acute pancreatitis (SAP)-induced myocardial injury. The SAP rat model was developed by injecting sodium touracholate into SD rats and then infected with lentivirus vectors expressing sh-CREB in the presence/absence of LPS. The pathological alterations of rat pancreatic and cardiac tissues were observed by HE staining. TUNEL assay was used to study apoptosis of cardiomyocytes. Next, the loss- and gain-function assay was conducted in LPS-induced myocardial injury cardiomyocytes to define the roles of CREB, HDAC2, and TLR4 in cardiomyocyte proliferation, apoptosis, inflammation, and myocardial injury in vitro. ChIP assay was used to study the enrichment of CREB bound to HDAC2 promoter. RT-qPCR and Western blot analysis were used to detect the expressions of related mRNA and proteins in the NF-κB pathway, respectively. CREB was found to be overexpressed in both SAP tissues and cells. CREB directly bound to the promoter of HDAC2 and activated its expression. Overexpressed CREB or HDAC2 inhibited proliferation and promoted apoptosis of cardiomyocytes. Suppression of CREB inhibited the HDAC2/TLR4/NF-κB cascade to promote proliferation and inhibit apoptosis of cardiomyocytes. The in vitro results were validated in vivo experiments. Coherently, suppression of CREB can inhibit HDAC2/TLR4/NF-κB cascade to promote cardiomyocyte proliferation, thus ameliorating SAP-induced myocardial injury.


Late listeriosis after fludarabine plus prednisone treatment.
Fludarabine plus prednisome treatment in patients with chronic lymphocytic leukaemia has recently been correlated with an increased incidence of Listeria monocytogenes infections. We observed a patient with chronic lymphocytic leukaemia who received fludarabine plus prednisone and developed a fatal listeriosis 7 months later. A further case of listeriosis has recently been described in a man who developed the infection 2 years after successful fludarabine treatment while he had a normal CD4 lymphocyte count. These cases suggest that the risk period for the development of such an unusual infection could be unexpectedly and unpredictably long. This data could be important in the evaluation of a possible antibacterial prophylaxis schedule and in the wariness about the potential danger of food known to contain L. monocytogenes.


Recombinant probiotic therapy in experimental colitis in mice.
Recently, high interest has been attracted to the research of inflammatory bowel diseases (IBD). Recombinant probiotic bacteria may represent an interesting way to influence the course of IBD. Their benefits include cheap and simple production and easy manipulation of the genetic material. Several gene therapy and probiotic approaches already showed promising results in the past. The aim of this study was to test the probiotic potential of IL-10-expressing Escherichia coli Nissle 1917 in a mouse model of IBD and to compare it with control bacterial strains. The dextran sulphate sodium (DSS) model of colitis was examined for this purpose. Animals received control probiotic bacteria or modified probiotics (expressing IL-10) via gastric gavage. Body weight, stool consistency, food and water consumption were monitored. At the end of the experiment, the parameters of inflammation, oxidative stress and carbonyl stress were analysed in the samples and statistical analysis was performed. We prepared an anti-inflammatory probiotic Escherichia coli strain that we designated Nissle 1917/pMEC-IL10 and proved its anti-inflammatory properties, which are similar to those of the control probiotic strains Nissle 1917 and Lactococcus lactis/pMEC-IL10 in vivo. The probiotic therapy was successful according to several parameters, including colon length, and oxidative and carbonyl stress. Bacterially produced IL-10 was detected in the plasma. The potential of bacterial anti-inflammatory therapy of IBD using modified probiotics was outlined. The results opened a way for upcoming studies using modified probiotics for therapy of systemic diseases.


A pilot trial using topical regular crystalline insulin vs. aqueous zinc solution for uncomplicated cutaneous wound healing: Impact on quality of life.
When wounds are treated with regular insulin, they are also being treated with zinc; used in the formula to crystallize insulin molecules. It is not clear if regular insulin-accelerated wound healing is due to insulin, the zinc it contains, or both. Thus, we aimed to compare topical regular crystalline insulin (containing zinc) vs. aqueous zinc chloride solution to controls, on healing of open uncomplicated cutaneous wounds. In this randomized controlled pilot study, 90 nondiabetic patients were randomly assigned to one of three groups depending on the twice daily applications received; group I: regular insulin; group II: aqueous zinc chloride solution, and group III: 0.9% saline (control). A questionnaire was used to determine the effect of wounds on the quality of life. Both topical regular crystalline insulin (containing zinc) and aqueous zinc chloride solution enhanced healing of uncomplicated cutaneous wounds of nondiabetic patients, than control (p < 0.001), and hence improved patients' quality of life. However, regular insulin showed better results than aqueous zinc solution (p = 0.015), probably due to synergistic effect between insulin and zinc of its formulation. Healing rate was significantly higher in acute than chronic wounds (p < 0.001), in those ≤40 years than those >40 (p = 0.004), and in upper body wounds than lower body (p = 0.015).


Comparison of Primary B/NKT Non-Hodgkin Lymphomas in Nasopharynx, Nasal Cavity, and Paranasal Sinuses.
We aimed to compare clinical and survival differences between B-cell (B-NHL) and NKT-cell non-Hodgkin lymphomas (NKT-NHL) located in the nasal cavity (NC), nasopharynx, and paranasal sinuses, which are always categorized as one sinonasal type. Patients diagnosed with primary B-NHL and NKT-NHL in the nasal cavity, nasopharynx, and paranasal sinuses from Surveillance, Epidemiology, and End Results (SEER) database were included (1975-2017). Population-based cohort study. We conducted univariate and multivariate Cox regressions and Kaplan-Meier analysis to examine survival outcomes of B/NKT-NHL in the nasal cavity, nasopharynx, and paranasal sinuses, respectively. Overall, most B-NHL cases originated from the nasopharynx, while the majority of NKT-NHL cases occurred in the nasal cavity. Notably, the cancer-special survival (CSS) outcomes improved significantly in all sinonasal B-NHL cases over time, whereas no such improvement trend was observed in each sinonasal NKT-NHL type. Additionally, increasing age was linked with an elevated risk of death in B-NHL, particularly in the nasal cavity (Hazard ratio [HR]: 3.37), rather than in NKT-NHL. Compared with B-NHL, the adverse effect of a higher stage on CSS was more evident in NKT-NHL, particularly in its nasopharynx site (HR: 5.12). Furthermore, radiotherapy was beneficial for survival in patients with sinonasal B-NHL and NKT-NHL, except in the nasopharynx NKT-NHL. However, chemotherapy has only been beneficial for CSS in patients with paranasal sinuses B-NHL (HR: 0.42) since 2010, rather than in other types of B/NKT-NHL. Although B-NHL and NKT-NHL in the nasal cavity, nasopharynx and paranasal sinuses have similar anatomical locations, their clinicodemographics and prognoses are largely different and should be treated and studied as distinct diseases.


The effects of metformin treatment of gestational diabetes on maternal weight and glucose tolerance postpartum--a prospective follow-up study.
Metformin seems to reduce gestational weight gain compared with insulin in women with gestational diabetes (GDM). Women with GDM requiring insulin are more likely to develop abnormal glucose tolerance postpartum than women treated with diet only. In this prospective follow-up study of a randomized clinical trial, we investigated the effect of metformin treatment in women with GDM on weight gain and glucose tolerance postpartum. Women with GDM with two or more pathologic glucose values at 2-h 75-g oral glucose tolerance test (OGTT) were recruited. Those needing medication to achieve sufficient glycemic control were randomized at 22-34 weeks of gestation to either metformin (n = 110) or insulin (n = 107) treatment until delivery. A third GDM group (n = 128) requiring no medication had only diet treatment. Weight, OGTT and glycosylated hemoglobin (HbA1c) were determined at 6-8 weeks and 1 year postpartum. At least one postpartum visit was attended by 104, 101 and 120 women in the metformin, insulin and diet-only groups, respectively. No significant differences were found in the change of weight, HbA1c or OGTT glucose values between the groups during the study (p ≥ 0.121 in all comparisons). One year postpartum the diet-only group had less impaired glucose tolerance compared with the metformin and insulin groups (7.1%, 19.1% and 15.6%, respectively; overall p = 0.039) and a lower incidence of diabetes (p = 0.027). Short-term metformin therapy does not affect weight, HbA1c or OGTT glucose values postpartum compared with insulin or diet-only treatments. Women with GDM requiring no medication are least likely to develop impaired glucose tolerance or diabetes postpartum.


Global analysis of translation termination in E. coli.
Terminating protein translation accurately and efficiently is critical for both protein fidelity and ribosome recycling for continued translation. The three bacterial release factors (RFs) play key roles: RF1 and 2 recognize stop codons and terminate translation; and RF3 promotes disassociation of bound release factors. Probing release factors mutations with reporter constructs containing programmed frameshifting sequences or premature stop codons had revealed a propensity for readthrough or frameshifting at these specific sites, but their effects on translation genome-wide have not been examined. We performed ribosome profiling on a set of isogenic strains with well-characterized release factor mutations to determine how they alter translation globally. Consistent with their known defects, strains with increasingly severe release factor defects exhibit increasingly severe accumulation of ribosomes over stop codons, indicative of an increased duration of the termination/release phase of translation. Release factor mutant strains also exhibit increased occupancy in the region following the stop codon at a significant number of genes. Our global analysis revealed that, as expected, translation termination is generally efficient and accurate, but that at a significant number of genes (≥ 50) the ribosome signature after the stop codon is suggestive of translation past the stop codon. Even native E. coli K-12 exhibits the ribosome signature suggestive of protein extension, especially at UGA codons, which rely exclusively on the reduced function RF2 variant of the K-12 strain for termination. Deletion of RF3 increases the severity of the defect. We unambiguously demonstrate readthrough and frameshifting protein extensions and their further accumulation in mutant strains for a few select cases. In addition to enhancing recoding, ribosome accumulation over stop codons disrupts attenuation control of biosynthetic operons, and may alter expression of some overlapping genes. Together, these functional alterations may either augment the protein repertoire or produce deleterious proteins.


Firearms in New Mexico.
To determine the prevalence of firearm ownership and storage practices in New Mexico, we did a random-digit-dialing survey of New Mexico residents in October 1991. Of 200 households surveyed, 79 (40%) had 1 or more firearms in the home. Rural households were more likely than urban households to have firearms (44% versus 30%), and households with annual incomes of greater than $25,000 were more likely to have a firearm than households with incomes of $25,000 or less (41% versus 33%). Household firearm ownership did not vary with the presence of young (< 15 years old) children (38% with children versus 41% without). Handguns were generally owned for self-protection, and rifles were owned for hunting. Of households with firearms, 24% stored them unsafely (unlocked and loaded or unloaded but with ammunition nearby), including 21% of households with young children. Of the households with handguns only, 40% stored these firearms unsafely compared with 13% of those with rifles only. The prevalence of gun ownership in New Mexico is similar to that reported in national surveys; handguns are stored less safely than rifles; and the presence of young children in the home does not appear to improve firearm storage safety.


Clinical competency development with handmade simulator in highly realistic paediatric dentistry scenarios.
The use of simulation is extremely useful in pregraduate students. However, there is a very small number of simulators adapted to paediatric dentistry. A paediatric simulator was created to use in simulated scenarios for paediatric dentistry using an actress in the role of mother. The objectives of the present study were three. First, to analyse the perception of clinical competencies acquired by the students. Second, to examine the realism perceived by the students. Finally, to analyse the influence on the perception of clinical competencies after the integration of a handmade simulator in the Paediatric Dentistry III course. Eight clinical scenarios were carried out with a modified Erler Zimmer simulator for children, a professional actress in the role of the mother and two students (in the roles of dentist and assistant) on a paediatric dentistry case of pulpal pathology. The educational intervention was evaluated on 114 students by means of questionnaires with Likert-type answers applied pre- and post-simulation. The perception of clinical competence in the students increased an average of 0.956 points in relation with the initial clinical evaluation, finding a strong correlation between the perception of subsequent competence and all the perceived realism, with significant statistical differences in all cases. The realism of the simulated participant (professional actress) was the best rated by the students, although not significantly. The realism of the mannequin was positively and strongly correlated with the perceived realism of the cabinet. Simulation using a handmade mannequin with a professional actress in a simulated dental office increased the perception of clinical competence in 4th year dental students and raised the level of overall realism perceived by the student.


Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets
In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.


Racial Inequities in Access to Ventricular Assist Device and Transplant Persist After Consideration for Preferences for Care: A Report From the REVIVAL Study.
Racial disparities in access to advanced therapies for heart failure (HF) patients are well documented, although the reasons remain uncertain. We sought to determine the association of race on utilization of ventricular assist device (VAD) and transplant among patients with access to care at VAD centers and if patient preferences impact the effect. We performed an observational cohort study of ambulatory chronic systolic HF patients with high-risk features and no contraindication to VAD enrolled at 21 VAD centers and followed for 2 years in the REVIVAL study (Registry Evaluation of Vital Information for VADs in Ambulatory Life). We used competing events cause-specific proportional hazard methodology with multiple imputation for missing data. The primary outcomes were (1) VAD/transplant and (2) death. The exposures of interest included race (Black or White), additional demographics, captured social determinants of health, clinician-assessed HF severity, patient-reported quality of life, preference for VAD, and desire for therapies. The study included 377 participants, of whom 100 (26.5%) identified as Black. VAD or transplant was performed in 11 (11%) Black and 62 (22%) White participants, although death occurred in 18 (18%) Black and 36 (13%) White participants. Black race was associated with reduced utilization of VAD and transplant (adjusted hazard ratio, 0.45 [95% CI, 0.23-0.85]) without an increase in death. Preferences for VAD or life-sustaining therapies were similar by race and did not explain racial disparities. Among patients receiving care by advanced HF cardiologists at VAD centers, there is less utilization of VAD and transplant for Black patients even after adjusting for HF severity, quality of life, and social determinants of health, despite similar care preferences. This residual inequity may be a consequence of structural racism and discrimination or provider bias impacting decision-making. URL: https://www. gov; Unique identifier: NCT01369407.


Cavopulmonary anastomosis without cardiopulmonary bypass.
There is an increasing trend to perform the bidirectional superior cavopulmonary (Glenn) anastomosis without cardiopulmonary bypass. In this report, we present our results of off-pump bidirectional Glenn operation done without using a venoatrial shunt to decompress the superior vena cava during clamping. [corrected]. A prospective, non-randomized comparative study was conducted in 50 patients with functional single ventricle anomalies who underwent bidirectional Glenn anastomosis without cardiopulmonary bypass. The patients were divided into two groups: Group I (n = 25), where it was done without a veno-atrial shunt, and Group II (n = 25), where it was done with a veno-atrial shunt. Two patients in Group I and 4 patients in Group II had a bilateral bidirectional Glenn shunt. Five patients in Group I and three patients in Group II had a previous left modified Blalock-Taussig shunt. All patients underwent a complete neurological examination both preoperatively as well as postoperatively. The early hospital mortality was 4% (2/50), one in each group. The median follow-up was 14 months. The mean internal venous pressure on clamping the superior vena cava was 37.07 ± 7.12 mmHg in Group I and 24 ± 4.4 mmHg in Group II. The mean clamp time was 9.85 ± 3.52 min in Group I and 21.3 ± 4.4 min in Group II. The transcranial pressure gradient was 62.37 ± 15.01 mmHg in Group I, while 65.08 ± 13.89 in Group II. The mean intensive care unit stay was 2.57 ± 75 days in Group I, 3.3 ± 1.09 in Group II. There were no major neurological complications apart from treatable convulsions in one case in Group I (4%), 2 cases in Group II (8%), and delayed recovery in one case (4%) in Group I. Off-pump bidirectional Glenn operation without caval decompression is a safe, simple and more economic procedure.


Immunotherapy With Apitopes Blocks the Immune Response to TSH Receptor in HLA-DR Transgenic Mice.
We have combined major histocompatibility complex-binding assays with immunization and tolerance induction experiments in HLA-DR3 transgenic mice to design apitopes (antigen-processing independent epitopes) derived from thyrotropin receptor (TSHR) for treatment of patients with Graves' disease (GD). A challenge model was created by using an adenovirus-expressing part of the extracellular domain of the thyrotropin receptor (TSHR289). This model was used to test whether current drug treatments for GD would have an impact on effective antigen-specific immunotherapy using the apitope approach. Furthermore, selected peptides were assessed for their antigenicity using peripheral blood mononuclear cell samples from patients with GD. A mixture of two immunodominant apitopes was sufficient to suppress both the T-cell and antibody response to TSHR when administered in soluble form to HLA-DR transgenic mice. Tolerance induction was not disrupted by current drug treatments. These results demonstrate that antigen-specific immunotherapy with apitopes from TSHR is a suitable approach for treatment of GD.


Microstructural characterization of a foil crown system.
In this study, the microstructural nature of the Renaissance crown system has been characterized in an effort to understand its reported properties and performance. Intergranular cavitation was characteristic of the foil surface. The brazed area joining various pleats was porous and exhibited an equiaxial grain structure. Particles of the interfacial alloy sintered with each other and bonded to the foil. Flow of porcelain into intergranular grooves of the foil and within the porous interfacial alloy network was observed. Tags that formed as a result contributed to the micromechanical retention of porcelain on the foil. No evidence of foil-porcelain chemical bonding was found, nor was there any indication of substantial interlayer diffusion.


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The author discusses her experiences with first generation patients with academic degree. In Hungary, the social-political changes, the ideological pressure, and the accelerated social mobility caused severe problems for the young persons who left their social background. The author outlines similarities among the therapies, and illustrates with case vignettes the special difficulties in the working through of transference-counter-trancferene relating the before mentioned processes. She concludes that the most pathogenic factors are the preodipal trauma, and the ineffectivness of the shame regulation.