Cytotoxicity of Piper aduncum (Piperaceae) essential oil in brown stink bug Euschistus heros (Heteroptera: Pentatomidae).
Euschistus heros (F.) (Hemiptera: Pentatomidae) is a soybean pest in Brazil, controlled with synthetic chemical insecticides, which may be harmful to the environment and humans, as well as to select pest resistant strains. The research for new pest control strategies such as the use of plant essential oils has been increased due to the selectivity and biodegradation of these molecules. The objective was to evaluate the cytological changes in the salivary glands, fat body and midgut of E. heros exposed to different concentrations of essential oil of Piper aduncum L. (Piperales: Piperaceae), which the main compounds were identified as myristicin 30.03%, aromadendrene 9.20%, dillapiole 8.43%, α-serinene 7.31%, tridecane 6.26%, γ-elemene 4.58% and o-cymene 4.20%. The essential oil of P. aduncum was toxic for E. heros with LD50 = 36.23 mg per insect and LD90 = 50.42 mg per insect. Cytological changes such as tissue disruption, increase in mitochondria population, and glycogen and lipid depletion occur in the fat body cells, whereas salivary glands and midgut are not affected by this essential oil. Results suggest that P. aduncum essential oil causes fat body cellular stress, which may compromise some physiological processes for the insect survival.


Work-family conflict, perceived organizational support, and organizational commitment among employed mothers.
This study investigated the impact of work interfering with family (WIF) and family interfering with work (FIW) on women's organizational commitment and examined both the direct and moderating effects of their perceived organizational support. Participants were 143 professional employed mothers with at least 1 preschool-age child. The study found that WIF was positively related to continuance organizational commitment but unrelated to affective commitment, and FIW was not related to either form of organizational commitment. Results also indicated that perceived organizational support exhibited a main effect on both types of commitment.


An open trial of risperidone in young autistic children.
To assess the benefits and side effects of risperidone in young autistic children. In this open, prospective trial, subjects were treated with risperidone for 12 weeks. All subjects were started at 0.5 mg daily with individual titration to a maximum of 6 mg or 0.1 mg/kg daily. Behavioral ratings, completed by the investigators and the children's parents, included the Clinical Global Impressions (CGI), Children's Psychiatric Rating Scale, Conners Parent-Teacher Questionnaire, Childhood Autism Rating Scale, and Abnormal Involuntary Movement Scale. Ten boys, aged 4.5 to 10.8 years, were enrolled in the study and all completed the 12-week protocol. The mean final dose was 1.3 mg/day (range = 1 to 2.5 mg/day). On the basis of CGI-rated improvement, 8 of the 10 children were considered to be responders. Improvement was also demonstrated on the other scales. Transient sedation was common, and the children gained an average of 3.5 kg over the 12 weeks of the study. There was no evidence of either extrapyramidal symptoms or tardive dyskinesia. These results suggest that risperidone may be safe and leads to improvements in several behavioral symptoms in young children with autism. Controlled studies of risperidone in young autistic children are warranted.


Eurados review of retrospective dosimetry techniques for internal exposures to ionising radiation and their applications.
This work presents an overview of the applications of retrospective dosimetry techniques in case of incorporation of radionuclides. The fact that internal exposures are characterized by a spatially inhomogeneous irradiation of the body, which is potentially prolonged over large periods and variable over time, is particularly problematic for biological and electron paramagnetic resonance (EPR) dosimetry methods when compared with external exposures. The paper gives initially specific information about internal dosimetry methods, the most common cytogenetic techniques used in biological dosimetry and EPR dosimetry applied to tooth enamel. Based on real-case scenarios, dose estimates obtained from bioassay data as well as with biological and/or EPR dosimetry are compared and critically discussed. In most of the scenarios presented, concomitant external exposures were responsible for the greater portion of the received dose. As no assay is available which can discriminate between radiation of different types and different LETs on the basis of the type of damage induced, it is not possible to infer from these studies specific conclusions valid for incorporated radionuclides alone. The biological dosimetry assays and EPR techniques proved to be most applicable in cases when the radionuclides are almost homogeneously distributed in the body. No compelling evidence was obtained in other cases of extremely inhomogeneous distribution. Retrospective dosimetry needs to be optimized and further developed in order to be able to deal with real exposure cases, where a mixture of both external and internal exposures will be encountered most of the times.


Improvement of physical fitness and muscle strength in polymyositis/dermatomyositis patients by a training programme.
In the present investigation, the benefit of physical training in patients with inflammatory myopathy was studied. In this prospective, randomized, controlled study, 14 patients with polymyositis (PM) or dermatomyositis (DM) were investigated. The training, consisting of bicycle exercise and step aerobics, took place over a 6 week period. Baseline and endpoint measurements included an 'activities of daily living' (ADL) score, peak isometric torque (PIT) generated by muscle groups in the lower extremities, peak oxygen consumption (VO2max), and creatine phosphokinase (CPK) levels. There was no significant rise in disease activity in the training group in comparison to the controls. The ADL score for the treatment group, in comparison to the control group, improved (P < 0.02), PIT rose (P < 0.05) and there was a statistically significant increase in oxygen uptake relative to body weight (P < 0.05). No rise in inflammatory activity, but significant improvement in muscle strength, oxygen uptake and well-being, were found in patients with inflammatory myopathy as a result of physical training. Besides medication, a physical training programme consisting mainly of concentric muscle contractions should therefore be an integral part of therapy, particularly in view of the cardiopulmonary risk of these patients.


A rhythmic modulatory gating system in the stomatogastric nervous system of Homarus gammarus. I. Pyloric-related neurons in the commissural ganglia.
1. Operation of the pyloric neural network in the crustacean stomatogastric ganglion (STG) depends on constant firing of modulatory inputs from anterior ganglia. We have identified two bilaterally symmetrical pairs of these inputs in the commissural ganglia (COGs) of the European rock lobster Homarus gammarus. During operation of the pyloric CPG, they fired in pyloric time, out of phase with the pyloric pacemakers. 2. One of the pair was the commissural pyloric (CP) neuron and the other was homologous to the P neuron described in the spiny lobster Panulirus interruptus. We describe their morphology and location in the COG. The CP neuron projected to the STG via the superior esophageal nerve (son) and the stomatogastric nerve (stn), whereas the P neuron projected via the inferior esophageal nerve (ion) and stn. 3. To determine the total number of commissural neurons projecting to the STG, we used cobalt and Lucifer yellow backfilling from their cut axons in the stn. With the ion cut, there were between 8 to 12 labeled somata in each COG including CP cell body, whereas only 2 somata (including P) were labeled with the son cut. Among these neurons, CP and P appeared to be the only commissural neurons that fired in pyloric time and projected in the STG on the pyloric network. 4. The CP neuron produced monosynaptic excitatory postsynaptic potentials (EPSPs) on the pyloric dilator (PD), lateral pyloric (LP), and inferior cardiac (IC) neurons, whereas the P neuron produced monosynaptic EPSPs on all pyloric motoneurons but IC. The P neuron was gamma-aminobutyric acid immunoreactive, and the P-derived EPSPs in pyloric neurons were reversibly blocked by bicuculline, picrotoxin, and D-tubocurarine. 5. The CP and P neurons were electrically coupled, and modification of membrane potential in either one of them appreciably changed the firing frequency of the coupled neuron. 6. A negative-feedback loop from the pyloric anterior burster (AB) interneuron provoked simultaneous rhythmic inhibitions in the P and CP neurons. Together with the electrical coupling, the rhythmic inhibition contributed to synchronize firing of the two commissural neurons. 7. The following papers in the series of describe the modulatory and rhythmic control exerted by the P and CP neurons over the pyloric pattern generator.


Acetyl-coenzyme A carboxylases: versatile targets for drug discovery.
Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in humans and most other living organisms. They are attractive targets for drug discovery against a variety of human diseases, including diabetes, obesity, cancer, and microbial infections. In addition, ACCs from grasses are the targets of herbicides that have been in commercial use for more than 20 years. Significant progresses in both basic research and in drug discovery have been made over the past few years in the studies on these enzymes. At the basic research level, the crystal structures of the biotin carboxylase (BC) and the carboxyltransferase (CT) components of ACC have been determined, and the molecular basis for ACC inhibition by small molecules are beginning to be understood. At the drug discovery level, a large number of nanomolar inhibitors of mammalian ACCs have been reported and the extent of their therapeutic potential is being aggressively explored. This review summarizes these new progresses and also offers some prospects in terms of the future directions for the studies on these important enzymes.


Metabolism, bioenergetics and thermal physiology: influences of the human intestinal microbiota.
The micro-organisms which inhabit the human gut (i.e. the intestinal microbiota) influence numerous human biochemical pathways and physiological functions. The present review focuses on two questions, 'Are intestinal microbiota effects measurable and meaningful?' and 'What research methods and variables are influenced by intestinal microbiota effects?'. These questions are considered with respect to doubly labelled water measurements of energy expenditure, heat balance calculations and models, measurements of RMR via indirect calorimetry, and diet-induced energy expenditure. Several lines of evidence suggest that the intestinal microbiota introduces measurement variability and measurement errors which have been overlooked in research studies involving nutrition, bioenergetics, physiology and temperature regulation. Therefore, we recommend that present conceptual models and research techniques be updated via future experiments, to account for the metabolic processes and regulatory influences of the intestinal microbiota.


Melatonin in Tuberous Sclerosis Complex Analysis Using Modern Mathematical Modeling Methods.
Purpose. The aim of the study was to assess melatonin secretion pattern in children with TSC and to compare it with the secretion patterns in children with and without epilepsy. Material and Methods. Melatonin secretion was measured every three hours using the RIA method in four children with recognized TSC. The parameters of the melatonin secretion models were interpreted and compared with those obtained for the patients with epilepsy (n = 76) and the children from the control, nonepileptic group (n = 36). To describe the diurnal melatonin secretion, mathematical model was constructed and nonlinear least squares method with the Levenberg-Marquardt optimization algorithm was applied to approximate its parameters. The dim light melatonin onset (DLMO) parameters were also estimated from the model. Results and Conclusions. Statistically significant differences were found between the TSC melatonin secretion profiles and the nonepileptic control group. The profiles for the epileptic and TSC groups were found to be similar. For the TSC group, though a small one, the variations in the MLT release amplitudes seem to be independent of the total number of seizures; however, the MLT release shift appears to depend on the number of seizures.


Communication Network Structures and Content of Men with Prostate Cancer: Models for Explaining Health-Related Quality of Life.
Communication networks contribute to health-related quality of life (HRQOL) for men living with prostate cancer. However, the mechanisms for understanding how communication networks shape HRQOL are not well understood. The purpose of this study was to test three models explaining the communication networks and related communication variables for HRQOL. A total of 214 men with prostate cancer in New Zealand completed a survey questionnaire describing aspects of their networks including opportunities for connection, social support/undermining, status disclosure, communication efficacy, and HRQOL. The findings support a mediating model of communication networks where social undermining has a direct and negative impact on HRQOL, and an indirect effect mediated through communication efficacy, which has a direct and positive impact on HRQOL. Contrary to previous studies, social support and disclosure did not significantly impact HRQOL in this sample. The benefits of developing communication efficacy and reducing social undermining for enhancing long-term psychosocial health in this cohort of men are two key findings.


Hydroxypropyl-modified potato starch increases fecal bile acid excretion in rats.
The effects of hydroxypropyl potato starches (HPS) of three different degrees of substitution (DS) on concentration of plasma cholesterol, apparent digestibility of protein, fecal excretion of bile acids, fecal output and cecal pool of organic acids such as acetic, propionic, butyric, lactic and succinic acid were studied in rats in Experiment 1. In Experiment 2, the effects of hydroxypropyl distarch phosphate (HDP) of three different degrees of cross-linking (DC) on the same indexes were studied. Gelatinized potato starch that was not modified chemically (PS) was used as a control. Rats were fed a fiber-free, purified diet containing either HPS, HDP or PS (100 g/kg) for 21 d. In each experiment, fecal output was greater and fecal excretion of bile acids was higher in rats fed the HPS diets with higher DS and the HDP diets compared with control rats fed the PS diet. Apparent protein digestibility in rats fed the HPS diets with higher DS and the HDP diets with higher DC was lower than that in control rats fed the PS diet. The pool size of cecal organic acids was not affected by diet. In Experiment 1, apparent protein digestibility, fecal output and fecal bile acids excretion were significantly correlated with DS (r = -0.994, P = 0.0059; r = 0.976, P = 0.0236; and r = 0.899, P = 0.0077, respectively). The plasma cholesterol concentration was significantly lower in rats fed the HPS diets than in control rats fed the PS diet. The HPS diets resulted in higher proportions of propionic acid, lactic acid and succinic acid and a lower proportion of n-butyric acid than the PS diet. In Experiment 2, apparent protein digestibility was significantly correlated with DSP (r = 0.996, P = 0.0028), which was inversely related to DC. The HDP diets did not affect the plasma cholesterol concentration. The HDP diets resulted in higher proportions of acetic acid, lactic acid and succinic acid and a lower proportion of n-butyric acid than the PS diet. These results suggest that the physiological effects of chemically modified starches are affected by the type of modification.


Inverse relationship between P-glycoprotein expression and its proliferative activity in hepatocellular carcinoma.
Hepatocellular carcinomas (HCCs) from 31 patients, cirrhotic livers from 7 patients and normal liver from 8 patients were immunohistochemically assessed in frozen sections using anti-P-glycoprotein (Pgp) monoclonal antibody C219. Immunohistochemical staining with anti-Ki-67 monoclonal antibody MIB-1 was performed for 22 HCCs to assess proliferative activity. Tumor tissues expressed Pgp on the biliary surface and on the luminal surface of cancer cells, which was less extensive than in normal and cirrhotic liver hepatocytes. Expression of Pgp was closely associated with the degree of histological differentiation and the histological type of HCC. Labeling indices (LI) of Pgp expression were 0.68 +/- 0.06 (mean +/- SD) in well, 0.51 +/- 0.14 in moderately and 0.04 +/- 0.06 in poorly differentiated HCC (significant differences among the three groups). LI of Pgp expression in the trabecular (0.55 +/- 0.15) and in the pseudoglandular types (0.44 +/- 0.10) were remarkably higher than in the compact type (0.04 +/- 0.06). The extent of Pgp expression in HCC was significantly inversely related to the extent of Ki-67 expression, in which Pgp expression decreased in highly proliferating tumors. In conclusion, Pgp expression in HCC was clearly related to its proliferative activity.


Full Genome Sequence of the Western Reserve Strain of Vaccinia Virus Determined by Third-Generation Sequencing.
The vaccinia virus is a large, complex virus belonging to the Poxviridae family. Here, we report the complete, annotated genome sequence of the neurovirulent Western Reserve laboratory strain of this virus, which was sequenced on the Pacific Biosciences RS II and Oxford Nanopore MinION platforms.


Modeling obesity and its associated disorders in Drosophila.
In recent years, obesity has been recognized as a major public health problem due to its increased prevalence in both children and adults and its association with numerous life-threatening complications including diabetes, heart disease, hypertension, and cancer. Obesity is a complex disorder that is the result of the interaction between predisposing genetic and environmental factors. However, the precise nature of these gene-gene and gene-environment interactions remains unclear. Here, we will describe recent studies demonstrating how fruit flies can be used to identify and characterize the mechanisms underlying obesity and to establish models of obesity-associated disorders.


Astereognosis. Tactile discrimination after localized hemispheric lesions in man.
The specific object of this study was to determine which cortical areas have to be damaged or disconnected to cause an impairment of somatosensory discrimination (astereognosis). Ninety-three patients with verified unilateral and circumscribed lesions took part in a somatosensory two-alternative forced-choice discrimination of size and shape. The results failed to support earlier views of astereognosis. Only direct damage to or an undercutting of the anterior part of the middle third of the postcentral gyrus caused impairment of size and shape discrimination (astereognosis) contralateral to the lesion. When the hand is used for stereognostic discrimination, the integration of somatosensory impulse patterns into spatial information about the objects is believed to take place in the contralateral somatosensory hand area.


Platelet Integrin αIIbβ3 Activation is Associated with 25-Hydroxyvitamin D Concentrations in Healthy Adults.
Cardiovascular events are associated with low circulating vitamin D concentrations, although the underlying mechanisms are poorly understood. This study investigated associations between 25-hydroxyvitamin D concentrations, platelet function, and single-nucleotide polymorphisms (SNPs) in genes influencing vitamin D biology in the 500 Functional Genomics (500FG) cohort. In this observational study, platelet activation and function were measured by flow cytometry by binding of fibrinogen to the activated fibrinogen receptor integrin αIIbβ3 and expression of P-selectin, markers of platelet aggregation and degranulation, respectively. These parameters were correlated to serum 25-hydroxyvitamin D and genotyping was performed to investigate SNPs in genes important for vitamin D biology. Circulating 25-hydroxyvitamin D concentrations correlated inversely with baseline platelet binding of fibrinogen to integrin αIIbβ3 (Pearson's r= -0.172, p = 0.002) and platelet responses to platelet agonist cross-linked collagen-related peptide (CRP-XL) (Pearson's r= -0.196,p = 0.002). This effect was due to circulating vitamin D levels ≤50nmol/L, since no differences in platelet fibrinogen binding were observed between subjects with normal 25-hydroxyvitamin D concentrations (>75nmol/L) and a 25-hydroxyvitamin D insufficiency (50-75 nmol/L). No correlations between 25-hydroxyvitamin D concentrations and platelet P-selectin expression were found. Several SNPs in the GC region of the vitamin D binding proteingene were associated with platelet responses to CRP-XL. Low circulating vitamin D concentrations are associated with increased platelet fibrinogen binding to integrin αIIbβ3 in unstimulated samples and after stimulation with CRP-XL. These findings may contribute to the increased incidence of cardiovascular events in vitamin D deficient adults and its seasonal variation. Further studies are needed to investigate causality.


Effect of Fire-Extinguishing Agents on Combustion of Sucrose.
Although sucrose and cellulose are both carbohydrates of basically similar composition, the very materials which have been found to be most effective in preventing flaming combustion of cellulose are also effective in causing sugar cubes to support flame.


Cumulative effects of several nonenzymatic mechanisms on the resistance of Pseudomonas aeruginosa to aminoglycosides.
Screening of a Tn5-Hg insertional library (12,000 clones) constructed in wild-type Pseudomonas aeruginosa strain PAO1 identified four genes (namely, galU, nuoG, mexZ, and rplY) whose disruption individually led to increased resistance to aminoglycosides (means of twofold). Inactivation of these genes was associated with (i) impaired outer membrane uptake, (ii) reduced active transport, (iii) increased MexXY-OprM-mediated active efflux, and (iv) alteration of target of aminoglycosides, respectively. In addition, suppression of the gene rplY, which codes for ribosomal protein L25, was found to result in both moderate upregulation of the efflux system MexXY-OprM and hypersusceptibility to beta-lactam antibiotics. Construction of double, triple, and quadruple mutants demonstrated cumulative effects of the different mechanisms on aminoglycoside resistance, with MICs increasing from 16- to 64-fold in the quadruple mutant compared to the wild-type strain PAO1. Altogether, these results illustrate how P. aeruginosa may gradually develop high resistance to these antibiotics via intrinsic (i.e., nonenzymatic) mechanisms, as in cystic fibrosis patients.


Prenatal diagnosis of a bundle branch block based on the fetal ECG.
A non-invasive fetal ECG was performed on a 36-year-old pregnant woman at 24+6 weeks of gestation as part of ongoing clinical research. A paediatric cardiologist suspected an incomplete bundle branch block based on the averaged ECGs from the recording. The characteristic terminal R' wave was present in multiple leads of the fetal ECGs. A fetal anomaly scan had been performed at 20 weeks of gestation and showed no abnormalities. An incomplete right bundle branch block was confirmed on an ECG recorded at the age of 2 years. This case shows the possibility of novel non-invasive fetal ECG technology as an adjunct to the diagnosis of fetal cardiac anomalies in the future.


Neurobehavioral Effects of Organic Solvents Exposure Among Wood Furniture Makers in Ile-Ife, Osun State, Southwestern Nigeria.
Furniture making industries are small scale businesses that commonly use organic solvents. There has been minimal focus on the health effects of this chemical hazard on the nervous system among furniture makers in Nigeria. The present study aimed to assess the association between organic solvents exposure and neurobehavioral status of furniture makers, using electronic technicians as a comparison group. A comparative cross-sectional study design was employed. A sample size of 108 was calculated for each group. A semi-structured interviewer-administered questionnaire was used to obtain data on the socio-demographic variables and use of personal protective equipment (PPE). A proforma was developed to collect neurobehavioral assessment data. A checklist was used to assess the furniture makers' workshops. Air was sampled from all of the workshops in both the study and comparison groups to determine the concentration of total volatile organic compounds (TVOCs). The use of PPE was poor in both the study and comparison groups, with no significant difference between them (34.4% and 37.7% respectively). Total volatile organic compound and formaldehyde (HCHO) concentrations were significantly higher at the furniture makers' workshops compared with electronic technicians (p<0.001) for both chemicals. The 8-hour time-weighted average of TVOC was also higher in the furniture makers' workshops (4.4±0.6 mg/m3) compared with the control group (0.3±0.3 mg/m3). The neurobehavioral symptoms score was significantly higher among the study group relative to the comparison group (p<0.001). There was a significant difference in the outcome of the auditory verbal learning test, total recall (p=0.005), and delayed recall (p=0.003). There was no significant association between solvent exposure index and findings from the simple reaction time test. Poor compliance with the use of PPE among furniture makers may increase their exposure to organic solvents. There were more neurobehavioral changes in the furniture makers with a higher exposure index. Measures are needed to educate artisans about workrelated chemical hazards and ensure compliance with basic occupational safety and hygiene standards. Obtained. Ethics approval was obtained from the Health Research and Ethics Committee of the Institute of Public Health, Obafemi Awolowo University (IPH/OAU/12/1049). The authors declare no competing financial interests.


[miRNA in regulation of skin and hair follicle development].
Epidermal development and cyclic hair follicle regeneration are governed by well-balanced programs of gene activation and silencing. Recent researches demonstrated that the expression profiles of miRNA showed tissue-specific expression patterns in the epidermis and hair follicles and stage-specific in cyclical development of hair follicles. Furthermore, a large number of miRNAs are involved in the development of epidermis and hair follicles, pigmentation, and the cyclical development of hair follicles. miRNAs in different cell types formed a comprehensive, multi-level network system through interaction with signal pathway and regulation factors. This review summarizes the available progress on how miRNAs are involved in the control of epidermal homeostasis and hair follicle development to enrich the research of gene regulatory networks and contribute to disease treatment and molecular breeding.


The immunocytochemical detection of protein hormones in human prostatic tissues.
The immunocytochemical detection of four pituitary protein hormones in tissue from 13 patients with benign prostatic hyperplasia has been described. There have been marked differences in the distribution and intensity of reaction product attributable to the various hormonal antisera. The intracellular presence of endogenous prolactin and FSH in the epithelial cytoplasm has been suggested together with the stromal localization of growth hormone and prolactin. Minimal diffuse staining over most cellular components was observed with the LH antiserum. This technique has provided an invaluable means of studying the potential involvement of pituitary protein hormones in the control of prostatic function and disease.


Determining the energetic and informational components of speech-on-speech masking.
Identification of target speech was studied under masked conditions consisting of two or four independent speech maskers. In the reference conditions, the maskers were colocated with the target, the masker talkers were the same sex as the target, and the masker speech was intelligible. The comparison conditions, intended to provide release from masking, included different-sex target and masker talkers, time-reversal of the masker speech, and spatial separation of the maskers from the target. Significant release from masking was found for all comparison conditions. To determine whether these reductions in masking could be attributed to differences in energetic masking, ideal time-frequency segregation (ITFS) processing was applied so that the time-frequency units where the masker energy dominated the target energy were removed. The remaining target-dominated "glimpses" were reassembled as the stimulus. Speech reception thresholds measured using these resynthesized ITFS-processed stimuli were the same for the reference and comparison conditions supporting the conclusion that the amount of energetic masking across conditions was the same. These results indicated that the large release from masking found under all comparison conditions was due primarily to a reduction in informational masking. Furthermore, the large individual differences observed generally were correlated across the three masking release conditions.


The central role of provider training in implementing resource-stratified guidelines for palliative care in low-income and middle-income countries: Lessons from the Jamaica Cancer Care and Research Institute in the Caribbean and Universidad Católica in Latin America.
Individuals in low-income and middle-income countries (LMICs) account for approximately two-thirds of cancer deaths worldwide, and the vast majority of these deaths occur without access to essential palliative care (PC). Although resource-stratified guidelines are being developed that take into account the actual resources available within a given country, and several components of PC are available within health care systems, PC will never improve without a trained workforce. The design and implementation of PC provider training programs is the lynchpin for ensuring that all seriously ill patients have access to quality PC services. Building on the Breast Health Global Initiative's resource-stratified recommendations for provider education in PC, the authors report on efforts by the Jamaica Cancer Care and Research Institute in the Caribbean and the Universidad Católica in successfully developing and implementing PC training programs in the Caribbean and Latin America, respectively. Key aspects of this approach include: 1) fostering strategic academic partnerships to bring additional expertise and support to the effort; 2) careful adaptation of the curriculum to the local context and culture; 3) early identification of feasible metrics to facilitate program evaluation and future outcomes research; and 4) designing PC training programs to meet local health system needs.


Localized cyclotron mode driven by fast alpha particles under a nonuniform magnetic field.
Resonance requires precise synchronization. Surprisingly, relativistic cyclotron instability can survive under a magnetic field with its nonuniformity larger than the requirement of synchronism. Localized eigenmode observed in a hybrid simulation is found to be consistent with that predicted by an analytical theory including both profile and eigenvalue. Half of the spatial area of the wave profile is located where the frequency mismatch is negative as against to the positive requirement generally believed. The consequence on the alpha dynamics is also demonstrated.


[Less common variants association study and statistical analysis].
In the past decade, based on the "common disease-common variant" hypothesis, genomewide association studies (GWAS) have been extensively used to dissect the genetic components of complex diseases and quantitative traits. However, the identified disease-associated common variants by GWASs can only explain small part of the corresponding disease heritability. "Common disease-rare variant" hypothesis has been proposed to explore the missed heritability. With the development of the next generation sequencing technology, various association studies of less common variants are ongoing. This paper provides an overview of the study designs and statistical tests of these variants.


Plasma lipidomic profiling of thiopurine-induced leukopenia after NUDT15 genotype-guided dosing in Chinese IBD patients.
Thiopurines, azathiopurine (AZA) and mercaptopurine (6-MP) have been regularly used in the treatment of inflammatory bowel disease (IBD). Despite optimized dosage adjustment based on the NUDT15 genotypes, some patients still discontinue or change treatment regimens due to thiopurine-induced leukopenia. We proposed a prospective observational study of lipidomics to reveal the lipids perturbations associated with thiopurine-induced leukopenia. One hundred and twenty-seven IBD participants treated with thiopurine were enrolled, twenty-seven of which have developed thiopurine-induced leucopenia. Plasma lipid profiles were measured using Ultra-High-Performance Liquid Chromatography-Tandem Q-Exactive. Lipidomic alterations were validated with an independent validation cohort (leukopenia n = 26, non-leukopenia n = 74). Using univariate and multivariate analysis, there were 16 lipid species from four lipid classes, triglyceride (n = 11), sphingomyelin (n = 1), phosphatidylcholine (n = 1) and lactosylceramide (n = 3) identified. Based on machine learning feature reduction and variable screening strategies, the random forest algorithm established by six lipids showed an excellent performance to distinguish the leukopenia group from the normal group, with a model accuracy of 95.28% (discovery cohort), 79.00% (validation cohort) and an area under the receiver operating characteristic (ROC) curve (ROC-AUC) of 0.9989 (discovery cohort), 0.8098 (validation cohort). Our novel findings suggested that lipidomic provided unique insights into formulating individualized medication strategies for thiopurines in IBD patients.


Dyslipidemia in HIV-infected individuals: from pharmacogenetics to pharmacogenomics.
HIV-infected individuals may have accelerated atherogenesis and an increased risk for premature coronary artery disease. Dyslipidemia represents a key pro-atherogenic mechanism. In HIV-infected patients, dyslipidemia is typically attributed to the adverse effects of antiretroviral therapy. Nine recent genome-wide association studies have afforded a comprehensive, unbiased inventory of common SNPs at 36 genetic loci that are reproducibly associated with dyslipidemia in the general population. Genome-wide association study-validated SNPs have now been demonstrated to contribute to dyslipidemia in the setting of HIV infection and antiretroviral therapy. In a Swiss HIV-infected study population, a similar proportion of serum lipid variability was explained by antiretroviral therapy and by genetic background. In the individual patient, both antiretroviral therapy and the cumulative effect of SNPs contribute to the risk of high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol and hypertriglyceridemia. Genetic variants presumably contribute to additional major metabolic complications in HIV-infected individuals, including diabetes mellitus and coronary artery disease. In an effort to explain an increasing proportion of the heritability of complex metabolic traits, ongoing large-scale gene resequencing studies are focusing on the effects of rare SNPs and structural genetic variants.


Bioavailability to rats of calcium in meat products prepared from hand or mechanically deboned beef shank.
Mechanical deboning yields meat containing approximately 0.5% calcium. The bioavailability of the calcium in mechanically deboned meat ( MDM ) was compared to that from calcium carbonate fed in hand deboned meat ( HDM ) diets. Processing calcium carbonate with HDM into bologna, Thuringer or canned meat improved calcium bioavailability but did not increase the bioavailability of the calcium from MDM . The calcium absorptions were 62.7, 60.4 and 60.6%, respectively, from raw MDM , MDM bologna, MDM Thuringer and canned MDM . However, the percentage of calcium absorbed from calcium carbonate was increased slightly from 65.3, 65.9 and 65.6%, respectively, when it was processed as raw HDM , HDM bologna and Thuringer to 69.0% when processed as canned HDM . The bioavailability of the calcium in MDM was similar to that of calcium carbonate, whether expressed as apparent absorption or as relative biological value.


The mystery bridges of Martin Bormann's alleged Berlin skull--key clues for forensic identification or another Piltdown case?
Dental records prepared by Martin Bormann's dentist Dr Hugo Blaschke in 1945 have been examined in the Captured Military Record Branch of the US National Archives in 1972 and compared with the direct evidence from examination of skeletal remains unearthed in Berlin in 1972 at a site next to Lehrter RR station where Bormann is known to have been seen alive for the last time on May 2, 1945. There is adequate qualitative and quantitative concurrence between all available antemortem and postmortem dental data to ascertain that the forensic identification of Martin Bormann can be considered established.


Application of an innovative ridge-ladder-shaped polycrystalline diamond compact cutter to reduce vibration and improve drilling speed.
Polycrystalline diamond compact bits have been widely used in the Oil and Gas drilling industry, despite the fact that they may introduce undesired vibration into the drilling process, for example, stick-slip and bit bounce, which accelerate the failure rate and lead to higher drilling costs. First, we develop an innovative ridge-ladder-shaped polycrystalline diamond compact cutter, which has ridge-shaped cutting faces and multiple cutting edges with stepped distribution, in the hope of reducing vibration and improving drilling speed. Then, the scrape tests of ridge-ladder-shaped and general polycrystalline diamond compact cutters are carried out in a laboratory, indicating that the cutting, lateral, and longitudinal forces on ridge-ladder-shaped polycrystalline diamond compact cutters are smaller and with minor fluctuations. Due to different rock-breaking mechanisms, ridge-ladder-shaped polycrystalline diamond compact cutters have higher cutting efficiency compared to general polycrystalline diamond compact cutters, which is also verified experimentally. Finally, the drilling characteristics of a new polycrystalline diamond compact bit fitted with some ridge-ladder-shaped polycrystalline diamond compact cutters are compared to those of a general polycrystalline diamond compact bit by means of finite element simulation. The results show that introducing ridge-ladder-shaped polycrystalline diamond compact cutters can not only reduce the stick-slip vibration, bit bounce, and backward rotation of drill bits effectively, but also improve their rate of penetration.


Sucrose analgesia for heel-lance procedures in neonates.
Sucrose has been examined for calming and pain-relieving effects in neonates for invasive procedures such as heel lance. To assess the effectiveness of sucrose for relieving pain from heel lance in neonates in terms of immediate and long-term outcomes SEARCH METHODS: We searched (February 2022): CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and three trial registries. We included randomised controlled trials where term and/or preterm neonates received sucrose for heel lances. Comparison treatments included water/placebo/no intervention, non-nutritive sucking (NNS), glucose, breastfeeding, breast milk, music, acupuncture, facilitated tucking, and skin-to-skin care. We used standard Cochrane methods. We reported mean differences (MD) with 95% confidence intervals (CI) using the fixed-effect model for continuous outcome measures. We assessed heterogeneity by the I2 test. We used GRADE to assess certainty of evidence. We included 55 trials (6273 infants): 29 included term neonates, 22 included preterm neonates, and four included both. Heel lance was investigated in 50 trials; 15 investigated other minor painful procedures in addition to lancing. Sucrose vs control The evidence suggests that sucrose probably results in a reduction in PIPP scores compared to the control group at 30 seconds (MD -1.74 (95% CI -2.11 to -1.37); I2 = 62%; moderate-certainty evidence) and 60 seconds after lancing (MD -2.14, 95% CI -3.34 to -0.94; I2 = 0%; moderate-certainty evidence). The evidence is very uncertain about the effects of sucrose on DAN scores compared to water at 30 seconds after lancing (MD -1.90, 95% CI -8.58 to 4.78; heterogeneity not applicable (N/A); very low-certainty evidence). The evidence suggests that sucrose probably results in a reduction in NIPS scores compared to water immediately after lancing (MD -2.00, 95% CI -2.42 to -1.58; heterogeneity N/A; moderate-certainty evidence). Sucrose vs NNS The evidence is very uncertain about the effect of sucrose on PIPP scores compared to NNS during the recovery period after lancing (MD 0.60, 95% CI -0.30 to 1.50; heterogeneity not applicable; very low-certainty evidence) and on DAN scores at 30 seconds after lancing (MD -1.20, 95% CI -7.87 to 5.47; heterogeneity N/A; very low-certainty evidence). Sucrose + NNS vs NNS The evidence is very uncertain about the effect of sucrose + NNS on PIPP scores compared to NNS during lancing (MD -4.90, 95% CI -5.73 to -4.07; heterogeneity not applicable; very low-certainty evidence) and during recovery after lancing (MD -3.80, 95% CI -4.47 to -3.13; heterogeneity N/A; very low-certainty evidence). The evidence is very uncertain about the effects of sucrose + NNS on NFCS scores compared to water + NNS during lancing (MD -0.60, 95% CI -1.47 to 0.27; heterogeneity N/A; very low-certainty evidence). Sucrose vs glucose The evidence suggests that sucrose results in little to no difference in PIPP scores compared to glucose at 30 seconds (MD 0.26, 95% CI -0.70 to 1.22; heterogeneity not applicable; low-certainty evidence) and 60 seconds after lancing (MD -0.02, 95% CI -0.79 to 0.75; heterogeneity N/A; low-certainty evidence). Sucrose vs breastfeeding The evidence is very uncertain about the effect of sucrose on PIPP scores compared to breastfeeding at 30 seconds after lancing (MD -0.70, 95% CI -0.49 to 1.88; I2 = 94%; very low-certainty evidence). The evidence is very uncertain about the effect of sucrose on COMFORTneo scores compared to breastfeeding after lancing (MD -2.60, 95% CI -3.06 to -2.14; heterogeneity N/A; very low-certainty evidence). Sucrose vs expressed breast milk The evidence suggests that sucrose may result in little to no difference in PIPP-R scores compared to expressed breast milk during (MD 0.3, 95% CI -0.24 to 0.84; heterogeneity not applicable; low-certainty evidence) and at 30 seconds after lancing (MD 0.3, 95% CI -0.11 to 0.71; heterogeneity N/A; low-certainty evidence). The evidence suggests that sucrose probably may result in slightly increased PIPP-R scores compared to expressed breast milk 60 seconds after lancing (MD 1.10, 95% CI 0.34 to 1.86; heterogeneity N/A; low-certainty evidence). The evidence is very uncertain about the effect of sucrose on DAN scores compared to expressed breast milk 30 seconds after lancing (MD -1.80, 95% CI -8.47 to 4.87; heterogeneity N/A; very low-certainty evidence). Sucrose vs laser acupuncture There was no difference in PIPP-R scores between sucrose and music groups; however, data were reported as medians and IQRs. The evidence is very uncertain about the effect of sucrose on NIPS scores compared to laser acupuncture during lancing (MD -0.86, 95% CI -1.43 to -0.29; heterogeneity N/A; very low-certainty evidence). Sucrose vs facilitated tucking The evidence is very uncertain about the effect of sucrose on total BPSN scores compared to facilitated tucking during lancing (MD -2.27, 95% CI -4.66 to 0.12; heterogeneity N/A; very low-certainty evidence) and during recovery after lancing (MD -0.31, 95% CI -1.72 to 1.10; heterogeneity N/A; very low-certainty evidence). Sucrose vs skin-to-skin + water (repeated lancing) The evidence suggests that sucrose results in little to no difference in PIPP scores compared to skin-to-skin + water at 30 seconds after 1st (MD 0.13, 95% CI -0.70 to 0.96); 2nd (MD -0.56, 95% CI -1.57 to 0.45); or 3rd lancing (MD-0.15, 95% CI -1.26 to 0.96); heterogeneity N/A, low-certainty evidence for all comparisons. The evidence suggests that sucrose results in little to no difference in PIPP scores compared to skin-to-skin + water at 60 seconds after 1st (MD -0.61, 95% CI -1.55 to 0.33); 2nd (MD -0.12, 95% CI -0.99 to 0.75); or 3rd lancing (MD-0.40, 95% CI -1.48 to 0.68); heterogeneity N/A, low-certainty evidence for all comparisons. Minor adverse events required no intervention. Sucrose compared to control probably results in a reduction of PIPP scores 30 and 60 seconds after single heel lances (moderate-certainty evidence). Evidence is very uncertain about the effect of sucrose compared to NNS, breastfeeding, laser acupuncture, facilitated tucking, and the effect of sucrose + NNS compared to NNS in reducing pain. Sucrose compared to glucose, expressed breast milk, and skin-to-skin care shows little to no difference in pain scores. Sucrose combined with other nonpharmacologic interventions should be used with caution, given the uncertainty of evidence.


A comparison of parent and child perspectives about barriers to and facilitators of bicycle helmet and booster seat use.
To date, little work has compared similarities and differences between parent and young people's perceptions of barriers to and facilitators of bicycle helmet and booster seat usage. Our goal was to conduct such a comparison in order to inform future safety campaigns. Eleven focus groups with a total of 68 parents and 11 focus groups with a total of 76 young people were conducted. Recruitment was conducted and focus groups were held in diverse neighbourhoods to facilitate participation by families from a variety of cultural, linguistic, and socioeconomic backgrounds. Overall, parents and their children agreed on 50% of the barriers identified for bicycle helmet use and approximately 40% of the barriers for booster seats. Barriers common to both types of equipment for parents and children included comfort, style and design, and fear of teasing. Common facilitators included perceived safety, and comfort. While there was considerable overlap between the perspectives of parents and young people, there were also differences, underscoring the importance of addressing both perspectives. The barriers and facilitators identified were modifiable to a large extent; based on these, recommendations for future injury prevention campaigns were outlined.


Design and feasibility of a randomized behavioral intervention to reduce distributive injection risk and improve health-care access among hepatitis C virus positive injection drug users: the Study to Reduce Intravenous Exposures (STRIVE).
Hepatitis C virus (HCV) is hyperendemic among injection drug users (IDUs). However, few scientifically proven interventions to prevent secondary transmission of HCV from infected IDUs to others exist. This report describes the design, feasibility, and baseline characteristics of participants enrolled in the Study to Reduce Intravenous Exposure (STRIVE). STRIVE was a multisite, randomized-control trial to test a behavioral intervention developed to reduce distribution of used injection equipment (needles, cookers, cottons, and rinse water) and increase health-care utilization among antibody HCV (anti-HCV) positive IDUs. STRIVE enrolled anti-HCV positive IDU in Baltimore, New York City, and Seattle; participants completed behavioral assessments and venipuncture for HIV, HCV-RNA, and liver function tests (LFTs) and were randomized to attend either a six-session, small-group, peer-mentoring intervention workshop or a time-matched, attention-control condition. Follow-up visits were conducted at 3 and 6 months. At baseline, of the 630 HCV-positive IDUs enrolled (mean age of 26 years, 60% white, 76% male), 55% reported distributive needle sharing, whereas 74, 69, and 69% reported sharing cookers, cottons, and rinse water, respectively. Health-care access was low, with 41% reporting an emergency room as their main source of medical care. Among those enrolled, 66% (418/630) were randomized: 53% (222/418) and 47% (196/418) to the intervention and control conditions, respectively. Follow-up rates were 70 and 73% for the 3- and 6-month visits, respectively. As distributive sharing of used injection equipment was common while reports of receiving HCV care were low, these findings indicate an urgent need for HCV-related interventions with IDUs and demonstrate the acceptability and feasibility to do so.


Nucleolar necklaces in chick embryo myoblasts formed by lack of arginine.
The round nucleoli of chick embryo myoblasts, when grown in a culture medium devoid of arginine, unravel in several days into 5-20 micro long, beaded strands termed nucleolar necklaces (NN). Addition of arginine reverses this change. The NN contain protein, RNA, and traces of DNA as determined cytochemically by enzyme digestion and by acridine-orange fluorescent staining. When a cell containing the beaded strand is treated with agents, such as actinomycin D, that prevent rRNA polymerase action, the strand collapses and condenses into a small dense nucleolus with segregated regions of ribonucleoprotein (RNP) and deoxyribonucleoprotein (DNP). The properties of the NN appear to resemble those of the nucleolar necklaces of amphibian oocytes. Cycloheximide or puromycin inhibition of general protein synthesis does not lead to NN formation. We suggest that NN formation during arginine starvation may be a result of a singular depletion of some rapidly turning over, arginine-rich proteins that normally attach to ribosomal RNA precursor molecules during their synthesis in the processing towards maturation of the ribosomes.


Gold-catalyzed synthesis of chroman, dihydrobenzofuran, dihydroindole, and tetrahydroquinoline derivatives.
Different furans containing an ynamide or alkynyl ether moiety in the side chain were prepared. The gold-catalyzed transformation of these compounds delivered dihydroindole, dihydrobenzofuran, chroman, and tetrahydroquinoline derivatives at room temperature through very fast reactions. Furthermore, the stabilizing effect of the heteroatom directly attached to the intermediate arene oxides led to highly selective reactions, even in the case of only mono-substituted furans, which is quite different from previous results obtained with non-heteroatom-substituted alkynes.


Direct algorithm for digital image restoration.
In this paper we report some experimental results of a direct algorithm for the solution of digital image restoration problems. The solution is obtained directly from the system of linear equations that result from the discretization of the Fredholm integral equation of the first kind. This algorithm uses a simple regularized least-squares technique. Also, the regularization parameter for the optimum solution is calculated by a direct (noniterative) method. A computer simulated example using both space invariant and space variant spatially separable point spread functions is presented. We show that this method compares favorably with other known direct methods.


Fermi-Pasta-Ulam auto recurrence in the description of the electrical activity of the heart.
The authors proposed and mathematically described model of a new type of the Fermi-Pasta-Ulam recurrence (the FPU auto recurrence) and hypothesized an adequate description of the heart's electrical dynamics within the observed phenomenon. The dynamics of the FPU auto recurrence making appropriate electrical dynamics of the normal functioning of the heart in the form of an electrocardiogram (ECG) was obtained by a computer model study. The model solutions in the form of the FPU auto recurrence - ECG Fourier spectrum were evaluated for resistance to external disturbances in the form of random effects, as well as periodic perturbation at a frequency close to the heart beating rate of about 1Hz. In addition, in order to simulate the dynamics of myocardial infarction model, studied the effect of the surface area of the myocardium on the stability and shape of the auto recurrence - ECG spectrum. It has been found that the intense external disturbing periodic impacts at a frequency of about 1Hz lead to a sharp disturbance spectrum shape FPU auto recurrence - ECG structure. In addition, the decrease in the surface of the myocardium by 50% in the model led to the destruction of structures of the auto recurrence - ECG, which corresponds to the state of atrial myocardium. Research models have revealed a hypothetical basis of coronary heart disease in the form of increasing the energy of high-frequency harmonics spectrum of the auto recurrence by reducing the energy of low-frequency harmonic spectrum of the auto recurrence, which ultimately leads to a sharp decrease in myocardial contractility. In order to test the hypothesis has been studied more than 20,000 ECGs both healthy people and patients with cardiovascular disease. As a result of these studies, it was found that the dynamics of the electrical activity of normal functioning of the heart can be interpreted by the display of the detected by authors the FPU auto recurrence, and coronary heart disease is a violation of the energy ratio between the low and high frequency harmonics of the FPU auto recurrence Fourier spectrum equal to the ECG spectrum. Thus, the hypothesis has been confirmed.


A fatal case of multicentric Kikuchi's histiocytic necrotizing lymphadenitis.
Kikuchi's histiocytic necrotizing lymphadenitis (Kikuchi's disease) is a histologically alarming but self-limiting lesion typically affecting the cervical lymph nodes of young adults. The authors report the first case of fatality occurring during the active phase of Kikuchi's disease. The 38-year-old patient presented with fever and generalized lymphadenopathy. During hospitalization, he developed abrupt onset of heart failure and died. Postmortem examination revealed enlarged lymph nodes all over the body showing typical histologic changes of Kikuchi's disease, but there was no encroachment on vital structures. The heart was dilated and flabby, with multiple microscopic foci of necrosis and mild fatty change. There were no other significant findings, and all cultures were negative. The authors speculate that large amounts of cytokines produced by the histiocytes or high endogenous catecholamines resulting from the stress response might be responsible for the myocardial damage. Alternatively, infection by an as yet uncharacterized microbial might be the underlying cause for both the lymphadenitis and myocardial disease.


1-Benzyl-3,5-bis-(4-chloro-benzyl-idene)piperidin-4-one.
The title compound, C(26)H(21)Cl(2)NO, crystallizes with two symmetry-independent mol-ecules (A and B) in the asymmetric unit. In both mol-ecules, the central heterocyclic ring adopts a sofa conformation. The dihedral angles between the planar part of this central heterocyclic ring [maximum deviations of 0.011 (1) and 0.036 (1) Å in mol-ecules A and B, respectively] and the two almost planar [maximum deviations of 0.020 (1) and 0.008 (1) Å in A and 0.007 (1) and 0.011 (1) in B] side-chain fragments that include the aromatic ring and bridging atoms are 20.1 (1) and 31.2 (1)° in mol-ecule A, and 26.4 (1) and 19.6 (1)° in mol-ecule B. The dihedral angles between the planar part of the heterocyclic ring and the benzyl substituent are 79.7 (1) and 53.2 (1)° in mol-ecules A and B, respectively. In the crystal, weak inter-molecular C-H⋯O hydrogen bonds link the two independent mol-ecules into dimers.


Untargeted analysis in post-COVID-19 patients reveals dysregulated lipid pathways two years after recovery.
Introduction: Similar to what it has been reported with preceding viral epidemics (such as MERS, SARS, or influenza), SARS-CoV-2 infection is also affecting the human immunometabolism with long-term consequences. Even with underreporting, an accumulated of almost 650 million people have been infected and 620 million recovered since the start of the pandemic; therefore, the impact of these long-term consequences in the world population could be significant. Recently, the World Health Organization recognized the post-COVID syndrome as a new entity, and guidelines are being established to manage and treat this new condition. However, there is still uncertainty about the molecular mechanisms behind the large number of symptoms reported worldwide. Aims and Methods: In this study we aimed to evaluate the clinical and lipidomic profiles (using non-targeted lipidomics) of recovered patients who had a mild and severe COVID-19 infection (acute phase, first epidemic wave); the assessment was made two years after the initial infection. Results: Fatigue (59%) and musculoskeletal (50%) symptoms as the most relevant and persistent. Functional analyses revealed that sterols, bile acids, isoprenoids, and fatty esters were the predicted metabolic pathways affected in both COVID-19 and post-COVID-19 patients. Principal Component Analysis showed differences between study groups. Several species of phosphatidylcholines and sphingomyelins were identified and expressed in higher levels in post-COVID-19 patients compared to controls. The paired analysis (comparing patients with an active infection and 2 years after recovery) show 170 dysregulated features. The relationship of such metabolic dysregulations with the clinical symptoms, point to the importance of developing diagnostic and therapeuthic markers based on cell signaling pathways.


[Successful induction of tolerance in an epilepsy patient with phenobarbital allergy].
We report on a 32-year-old female patient who had had a history of complex partial seizures since the age of 14. Phenobarbital was the most effective anticonvulsant drug in this patient. However, the drug treatment was complicated by a phenobarbital-induced exanthematous eruption. Reintroduction of the phenobarbital some years later resulted in a skin rash again; therefore, treatment with this substance had to be discontinued a second time. Because of the satisfactory antiepileptic efficacy, phenobarbital was introduced a third time using a desensitization procedure with increased oral doses, starting with a dose of 1 mg. After a daily dose of 90 mg phenobarbital, on day 6 an exanthematous eruption appeared. The exanthem disappeared parallel to a dose reduction of phenobarbital and with a gradually increasing dosage up to a maintenance dose of 200 mg. Tolerance to the allergic effect of phenobarbital was preserved and the seizure frequency was significantly reduced by phenobarbital monotherapy with a daily dose of 200-175 mg.


Necrotizing Fasciitis: A Side Effect of Rituximab Administration in Steroid-Dependent Nephrotic Syndrome.
Steroid-dependent nephrotic syndrome (SDNS) is a common type of childhood nephrotic syndrome. Remission following steroid therapy is achieved in 80-90% of the patients, while the remainder show steroid-resistant nephrotic syndrome (SRNS). Rituximab is an anti-CD20 chimeric monoclonal antibody with proven therapeutic effects in several diseases and has been used with great success in the treatment of NS since its discovery. We report a case of a 4-year-old girl diagnosed with SDNS at the age of 3. As treatment with steroids, enalapril, and mycophenolate failed to produce complete remission, rituximab was initiated, and remission was successfully achieved after administration of the first dose. Due to this response, rituximab therapy was continued; however, a day after being admitted to the nephrology ward for the second dose, she started to develop a high fever, which reached up to 40°C. In addition, she also displayed symptoms of upper respiratory tract infection and an ulcerated wound on her left cheek. The patient became drowsy with reactive pupils, cold peripheries, and weak peripheral pulses. The capillary refill time was prolonged to 3-4 seconds and it was decided to withhold the second dose of rituximab. The patient was shifted to the PICU as a case of septic shock secondary to facial cellulitis and started on inotropes (epinephrine and norepinephrine), meropenem, vancomycin, and hydrocortisone 15 mg. Thereafter, surgical debridement of the wound was carried out. The patient remained in remission with regard to nephrotic syndrome and was discharged in a healthy condition. In conclusion, rituximab used in conjunction with steroids and other immunosuppressants may increase the risk of serious infections like necrotizing fasciitis (NF). Further studies are needed to explore the relationship between rituximab and NF.


Outcomes of concurrent endoscopic sinus surgery and rhinoplasty: a case control study.
To evaluate results of concurrent functional endoscopic sinus surgery (FESS) and nasal plastic surgery in terms of safety, efficacy and patient satisfaction, and compare them with the results of single procedures. We conducted a prospective case control study in three groups of patients with chronic sinusitis and nasal deformity; 25 cases had concurrent FESS and rhinoplasty, 25 controls had FESS, and 25 controls had rhinoplasty alone. The patients preoperative and postoperative sino-nasal outcome test (SNOT22) and also patients' satisfaction using the visual analogue scale were evaluated after one year. There were no significant differences between aesthetic indexes of concurrent surgery and control groups. Also, we found no significant inter-group difference between SNOT22 scores. There was no major complication in the studied patients. Conducting nasal plastic surgery and FESS concurrently can be a feasible surgery with functional and aesthetic results comparable to those with individual FESS or rhinoplasty.


Inhibiting PKCβ2 protects HK-2 cells against meglumine diatrizoate and AGEs-induced apoptosis and autophagy.
Contrast induced diabetic nephropathy (CIN) is an important cause of hospital-acquired acute renal failure. Our aim was to observe the effect of protein kinase C β2 (PKCβ2) knockdown on human proximal tubular epithelial cells (HK-2 cells) against meglumine diatrizoate and advanced glycation end products (AGEs)-induced apoptosis and autophagy. Cell viability was detected using cell counting kit-8 (CCK-8) assay in HK-2 cells after disposal with meglumine diatrizoate and AGEs with or without PKCβ2 siRNA/inhibitor LY333531. Flow cytometry and western blot were used to test cell apoptosis and the related protein levels in meglumine diatrizoate and AGEs co-treated HK-2 cells with or without PKCβ2 siRNA/inhibitor LY333531. Autophagy related proteins were detected using western blot. Immunofluorescence staining was used to examine the autophagy-specific protein light chain 3 (LC3), and autophagosome and autolysosome formation was observed under a transmission electron microscopy. CCK-8 assay results showed that meglumine diatrizoate inhibited AGEs-induced HK-2 cell viability. Furthermore, meglumine diatrizoate promoted cell apoptosis and the expression level of caspase3 in AGEs-induced HK-2. Western blot results showed that meglumine diatrizoate elevated the expression levels of PKCβ2 and p-PKCβ2 in AGEs-induced HK-2 cells, and up-regulated the expression level of Beclin-1 and the ratio of LC3 II/LC3 I, and down-regulated the expression level of p62 in AGEs-induced HK-2 cells. We found that PKCβ2 knockdown alleviated meglumine diatrizoate and AGEs-induced HK-2 cell apoptosis and autophagy. Intriguingly, PKCβ2 inhibitor LY333531 reversed 3-methyladenine (3-MA)-induced autophagy inhibition in meglumine diatrizoate and AGEs-induced HK-2 cells. Our findings reveal that inhibiting PKCβ2 protects HK-2 cells against meglumine diatrizoate and AGEs-induced apoptosis and autophagy, which provide a novel therapeutic insight for CIN in diabetic patients.


A novel miRNA produced during lytic HSV-1 infection is important for efficient replication in tissue culture.
The influence of miRNAs on the host-pathogen environment is largely unknown and under intensive investigation. Whether produced by the pathogen or by the host cell, these miRNAs will sculpt the intracellular landscape, as their activity will ultimately affect levels of target proteins. Using a high-throughput sequencing approach, we identified 19 novel small RNAs produced during the early hours of herpes simplex virus type 1 (HSV-1) infection in epithelial cells. Six of the novel RNAs had predicted folds characteristic of miRNAs. One of the six, miR-92944, which resides in the 5' UTR of the ul42 gene in the sense orientation, was confirmed as a bona fide miRNA by RT-PCR and stem-loop PCR analysis. Northern blot analysis was used to observe the precursor forms of miR-92944. Viral mutants that do not produce miR-92944 exhibited significant reductions in viral titers in both single and multi-step growth analysis and a fourfold reduction in plaque size. The miR-92944 mutants produce wild-type levels of ICP4, UL42, VP5, and gC proteins contain no additional changes in the DNA sequence surrounding the site of mutagenesis. The defective phenotype of miR-92944 mutants was complemented in V42.3 cells, which contain the 5'UTR of ul42. We also found that miR-H1 expression was diminished in cells infected with the miR-92944 mutant virus. This study provides new information on the miRNA landscape during the early stages of HSV-1 infection and reveals novel targets for antagonistic molecules that may curtail the establishment of lytic or latent virus infection.


Telomere shortening triggers a feedback loop to enhance end protection.
Telomere homeostasis is controlled by both telomerase machinery and end protection. Telomere shortening induces DNA damage sensing kinases ATM/ATR for telomerase recruitment. Yet, whether telomere shortening also governs end protection is poorly understood. Here we discover that yeast ATM/ATR controls end protection. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this regulation is stimulated by DNA damage and telomere shortening. Compromised Rap1 phosphorylation hampers the interaction between Rap1 and its interacting partner Rif1, which thereby disturbs the end protection. As expected, reduction of Rap1-Rif1 association impairs telomere length regulation and increases telomere-telomere recombination. These results indicate that ATM/ATR DNA damage checkpoint signal contributes to telomere protection by strengthening the Rap1-Rif1 interaction at short telomeres, and the checkpoint signal oversees both telomerase recruitment and end capping pathways to maintain telomere homeostasis.


Practical use of insulin degludec/insulin aspart in a multinational setting: beyond the guidelines.
Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec, which provides long-lasting basal insulin coverage, and insulin aspart, which targets postprandial glycaemia. This review provides expert opinion on the practical clinical use of IDegAsp, including: dose timings relative to meals, when and how to intensify treatment from once-daily (OD) to twice-daily (BID) dose adjustments, and use in special populations (including hospitalized patients). IDegAsp could be considered as one among the choices for initiating insulin treatment, preferential to starting on basal insulin alone, particularly for people with severe hyperglycaemia and/or when postprandial hyperglycaemia is a major concern. The recommended starting dose of IDegAsp is 10 units with the most carbohydrate-rich meal(s), followed by individualized dose adjustments. Insulin doses should be titrated once weekly in two-unit steps, guided by individualized fasting plasma glucose targets and based on patient goals, preferences and hypoglycaemia risk. Options for intensification from IDegAsp OD are discussed, which should be guided by HbA1c, prandial glucose levels, meal patterns and patient preferences. Recommendations for switching to IDegAsp from basal insulin, premixed insulins OD/BID, and basal-plus/basal-bolus regimens are discussed. IDegAsp can be co-administered with other antihyperglycaemic drugs; however, sulphonylureas frequently need to be discontinued or the dose reduced, and the IDegAsp dose may need to be decreased when sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists are added. Considerations around the initiation or continuation of IDegAsp in hospitalized individuals are discussed, as well as in those undergoing medical procedures.


[Diagnostic problems before specific immunotherapy in patients with late-summer seasonal allergic rhinitis].
Skin prick tests were performed on 245 patients with late summer seasonal allergic rhinitis, and of these patients, 135 specific serum IgE test were performed. On the basis of skin prick test results, 94% of the patients were found to be sensitive to Ragweed: 18% of these patients had monosensitisation to Ragweed, and 56% were sensitive not only to Ragweed but also to Mugwort. The correlation between results of skin prick tests and specific serum IgE tests was found to be very good (95%) with Ragweed antigen experiencing no problem in the diagnostic process before immunotherapy. However, in 48% of patients with positive skin prick tests to Mugwort the specific serum IgE was found to be negative. Before immunotherapy, a specific nasal provocation test was performed on 12 of these patients with Mugwort to examine the real sensitivity of the shock-organ. This careful allergen research will demonstrate which components of allergen extract should be used for immunotherapy in late summer seasonal allergic rhinitis patients.


Pharmacological evaluation of phytochemicals from South Indian Black Turmeric (Curcuma caesia Roxb.) to target cancer apoptosis.
Curcuma caesia Roxb. (Black turmeric), a perennial herb of the family Zingiberaceae is indigenous to India. C. caesia is used as a spice, food preservative and coloring agent commonly in the Indian subcontinent. Functional parametric pharmacological evaluations like drug ability and toxicity profile of this endangered species is poorly documented. In our present study, among all the extracts of dried C. caesia rhizome viz- hexane, ethyl acetate, methanol and water tested for free radical scavenging capacity by total antioxidant activity (TAO) method, Hexane Rhizome Extract (HRE) was found to possess remarkable activity (1200mg ascorbic acid equivalent/100g). In MTT assay across three cancer cell lines and a control cell line, HRE exhibited a dose-dependent inhibition only in cancer cells, with notable activity in HepG2 cell lines (IC50: 0976µg/mL). Further, western blotting and flow cytometry experiments proved that HRE induces cell arrest at G2/M phase along with cellular apoptosis as suggestive by multiple-point mitochondrial mediated intrinsic pathway of Programmed Cell Death (PCD). Gas Chromatography-Mass Spectrophotometry (GC-MS) analysis of HRE suggested twenty compounds that when docked in silico with Tubulin (1SA0) and Epidermal Growth Factor Receptor/ EGFR (1XKK) showed very intimate binding with the original ligands. Our results provided significant evidence of the toxicity mechanisms of HRE that may be beneficial for more rational applications of drug discovery for slowing down cancer progression.


Serum Level of Matrix Metalloproteinase-2 and -9 in Patients with Laryngeal Squamous Cell Carcinoma and Clinical Significance.
Laryngeal cancer is an important malignancy in head and neck area and squamous cell carcinoma (SCC) is the most common type accounting for 95% of cases. Increase in matrix metalloproteinases (MMPs) in different tumors and their correlation with tumor invasiveness has been documented. However, most studies have evaluated MMP-2 and MMP-9 expression and few have evaluated serum levels. The aim of current study was to evaluate serum levels in patients with laryngeal SCC compared to normal subjects and assess any relation with tumor clinicopathological findings. In this case control study, 20 patients with oral SCC and 20 healthy subjects were included. Serum levels of MMP-2 and MMP-9 were compared between groups and correlations with findings including grade (T) and node involvement (N) were evaluated. Patients with laryngeal SCC had significantly higher serum levels of MMP-2 (p=0.01) and MMP-9 (p=0.03) compared to healthy subjects. Patients with higher T stage (T3,4) had significantly higher MMP-2 (p=0.04) and MMP-9 (p=0.01). There was significant positive correlation between serum levels of MMP-2 with T stage (r=0.45, p=0.04) and lymph node involvement (r=0.563, p=0.01) and between levels of MMP-9 with T stage (r=0.527, p=0.01). Our results showed that compared to healthy subjects, both MMP-2 and MMP-9 are significantly increased in serum of laryngeal SCC cases. MMP-2 was correlated with lymph node involvement while MMP-9 has stronger correlation with T stage compared to MMP-2.


One-Step Preparation of Highly Hydrophobic and Oleophilic Melamine Sponges via Metal-Ion-Induced Wettability Transition.
Hydrophobic and oleophilic absorbent materials have received wide attention in recent years for potential applications in pollutant removal from accidental spills of oil or organic chemicals. In this work, we report a metal-ion-induced hydrophobic melamine sponge (MII-HMS) prepared by a one-step solution immersion process. The commercial melamine sponge (intrinsically superhydrophilic with a water contact angle of ∼0°) is immersed in an aqueous solution of transition metal ions (e.g., FeCl3, Fe(NO3)3, Zn(NO3)2, Ni(NO3)2, and Co(NO3)2) for a short period, followed by drying. This simple process renders the transition of the superhydrophilic melamine sponge to become highly hydrophobic (a water contact angle of ∼130°). Results from X-ray photoelectron spectroscopy and infrared spectroscopy suggest that the unprecedented transition is likely due to the formation of metal complexes during immersion. The MII-HMS is also oleophilic, exhibiting excellent oil absorption capabilities, ∼71-157 times of its weight, for a wide range of oils and organic solvents. Our work offers a simple, scalable, and economical approach to fabricate highly efficient absorbent materials for potential applications in oil spill recovery and environmental remediation.


Recent influenza activity in tropical Puerto Rico has become synchronized with mainland US.
We used data from the Sentinel Enhanced Dengue Surveillance System (SEDSS) to describe influenza trends in southern Puerto Rico during 2012-2018 and compare them to trends in the United States. Patients with fever onset ≤ 7 days presenting were enrolled. Nasal/oropharyngeal swabs were tested for influenza A and B viruses by PCR. Virologic data were obtained from the US World Health Organization (WHO) Collaborating Laboratories System and the National Respiratory and Enteric Virus Surveillance System (NREVSS). We compared influenza A and B infections identified from SEDSS and WHO/NREVSS laboratories reported by US Department of Health and Human Services (HHS) region using time series decomposition methods, and analysed coherence of climate and influenza trends by region. Among 23,124 participants, 9% were positive for influenza A and 5% for influenza B. Influenza A and B viruses were identified year-round, with no clear seasonal patterns from 2012 to 2015 and peaks in December-January in 2016-2017 and 2017-2018 seasons. Influenza seasons in HHS regions were relatively synchronized in recent years with the seasons in Puerto Rico. We observed high coherence between absolute humidity and influenza A and B virus in HHS regions. In Puerto Rico, coherence was much lower in the early years but increased to similar levels to HHS regions by 2017-2018. Influenza seasons in Puerto Rico have recently become synchronized with seasons in US HHS regions. Current US recommendations are for everyone 6 months and older to receive influenza vaccination by the end of October seem appropriate for Puerto Rico.


Promoting Behavioral Health Equity Through Implementation of the Incredible Years Within Primary Care.
Mental health disparities continue to be a concern for racial and ethnic minorities in the United States. Further, approximately 20% of children in the United States have a mental health disorder with less than half of these youth receiving mental health treatment (Polanczyk, Salum, Sugaya, Caye, & Rohde, 2015; Stancin & Perrin, 2014; U.S. Surgeon General, 1999). Integrated primary care has been identified as an ideal place where youth and families can receive mental health services. There is evidence supporting that when psychologists are in primary care, behavioral health outcomes improve and the costs per patient are reduced (Chiles, Lambert, & Hatch, 1999). The objective of this paper is to describe the steps taken to colocate The Incredible Years Parenting Program (IY; Webster-Stratton & Reid, 2010) an evidence-based parenting group, in a pediatric primary care setting at a major metropolitan children's hospital. The parenting group was delivered as a prevention and early intervention program for an underserved population, specifically focused on parents of children ages 3-6 years, to reduce health disparities and improve access to needed behavioral health care. A case study illustrates the potential benefits to mental health and physical health outcomes through colocation, and ultimately integration, of behavioral health services in primary care. Policy implications for sustainability of group parenting interventions in primary care, the impact on decreasing health disparities, and future directions along this line of research are discussed.


[Continuous peridural application of sufentanil for postoperative analgesia].
Efficacy and side effects of a continuous infusion of sufentanil following epidural administration of a single dose of 30 micrograms of the opioid were studied in 28 patients undergoing laparotomy. Patients were divided into two groups treated with either 10 micrograms/h (n = 13) or 15 micrograms/h (n = 15) and compared with regard to sufentanil plasma levels, side effects and changes in blood gases. The analgesic effect of 15 micrograms/h was slightly better than that of 10 micrograms/h. There were few side effects during continuous administration of the high- or low-dose sufentanil: in some cases nausea (4/13 and 1/15) and vomiting (3/13 and 1/15) occurred. After the injection of a bolus of 30 micrograms sufentanil, a dose chosen according to current recommendations, a quick onset of analgesia was noted, but also sedation and respiratory depression with apneic intervals lasting up to 30 s, demonstrating both the efficacy and the possibility of unwanted and even harmful side effects associated with this kind of administration. During long-term infusion, after about 20 h PaCO2 and respiratory rate were significantly different between the two groups, which could be explained by differences in sufentanil plasma levels and a somewhat higher level of postoperative pain in the group receiving 10 micrograms/h.


Second malignancies after allogeneic hematopoietic cell transplantation.
Allogeneic hematopoietic cell transplantation (allo-HCT) may prolong life and cure patients suffering from otherwise fatal diseases. However, the growing population of long-term survivors has led to the realization of multiple long-term complications, including the risk of second malignancies. Compared to the autologous setting, allo-HCT carries a much higher risk of posttransplant lymphoproliferative disorder (PTLD), which usually occurs within the first year after allo-HCT and is strongly associated with the Epstein-Barr virus (EBV). Treatment-related myelodysplastic syndromes (tMDS) and second leukemias are extremely rare. Both autologous and allo-HCT carry increased risks for second solid malignancies (SSM). The cumulative incidence of SSM continues to increase in each of the largest studies with as much as 20 years of follow-up, likely related to the long latency of radiation-related SSM. Systematic, prospective monitoring, vigilant screening processes, and well-maintained survivorship clinics and databases are absolute necessities, and should be included in the infrastructure of individual transplant centers and networks, with mandatory periodic reporting of second malignancy incidences. Primary care and transplant physicians alike must be aware of the risk of second malignancies after allo-HCT. Most importantly, guidelines should be developed in regard to screening and prevention of second malignancies, so that physicians can provide state-of-the-art counsel and care for the benefit of our patients.


Deguelins, Natural Product Modulators of NF1-Defective Astrocytoma Cell Growth Identified by High-Throughput Screening of Partially Purified Natural Product Extracts.
A high-throughput screening assay for modulators of Trp53/NF1 mutant astrocytoma cell growth was adapted for use with natural product extracts and applied to a novel collection of prefractionated/partially purified extracts. Screening 68 427 samples identified active fractions from 95 unique extracts, including the terrestrial plant Millettia ichthyotona. Only three of these extracts showed activity in the crude extract form, thus demonstrating the utility of a partial purification approach for natural product screening. The NF1 screening assay was used to guide purification of active compounds from the M. ichthyotona extract, which yielded the two rotenones deguelin (1) and dehydrodeguelin (2). The deguelins have been reported to affect growth of a number of cancer cell lines. They potently inhibited growth of only one of a panel of NF1/Trp53 mutant murine astrocytoma cell lines, possibly related to epigenetic factors, but had no effect on the growth of normal astrocytes. These results suggest the potential utility of deguelins as tools for further investigating NF1 astrocytoma cell growth. These bioprobes were identified only as a result of screening partially purified natural product extracts.


Magnetic Resonance Neurography of the Pelvic Nerves.
Chronic pelvic pain syndrome is commonly caused by nerve injury, inflammation, or entrapment. Owing to the complex anatomy and branching patterns of pelvic nerves, pelvic neuropathies are often difficult to illustrate and diagnose. High-resolution 3-T magnetic resonance neurography is a promising technique for the evaluation of peripheral neuropathy. In this article, the authors discuss the normal anatomy of major pelvic nerves, technical considerations of high-resolution imaging, and normal and abnormal imaging appearances with relevant case examples.


Adequate Anesthesia and More Effective Analgesia by Adjusted Doses of Bupivacaine during Cesarean Section: A Randomized Double-blind Clinical Trial.
Several adjuvants, added to local anesthetics, were suggested to induce an ideal regional block with high-quality analgesia. The purpose of this study was to evaluate the particular blocking properties of low-dose bupivacaine in combination with meperidine and fentanyl in spinal anesthesia during Cesarean sections. A randomized, double-blind clinical trial was conducted at Hafez Hospital affiliated with Shiraz University of Medical Sciences (Shiraz, Iran) from February 2015 to February 2016. A total of 120 pregnant women, who underwent spinal anesthesia during elective Cesarean section were enrolled in the study. Based on block-wise randomization, the patients were randomly assigned to three groups, namely "B" group received 2 mL bupivacaine 0.5% (10 mg), "BM" group received 8 mg bupivacaine and 10 mg meperidine, and "BF" group received 8 mg bupivacaine and 15 µg fentanyl intrathecally. The block onset, the duration of analgesia, and the time of discharge from the post-anesthesia care unit (PACU) were all assessed. Data were analyzed using SPSS software version 21, and P<0.05 were considered statistically significant. The mean duration of motor blocks in the B group (150 min) were significantly higher than the BM (102 min) and BF (105 min) groups (P<0.0001). In both the BM and BF groups, the duration of sensory and motor blocks was the same. The length of stay in the PACU was significantly longer in the B group (P<0.001) than the BM and BF groups. When meperidine or fentanyl was added to bupivacaine, the duration of the analgesia lengthened (P<0.001). Intrathecal low-dose spinal anesthesia induced by bupivacaine (8 mg) in combination with meperidine and/or fentanyl for Cesarean section increased maternal hemodynamic stability, while ensuring effective anesthetic conditions, extending effective analgesia, and reducing the length of stay in PACU.Trial Registration Number: IRCT2015013119470N14.


Paediatric sedation in emergency department: what is our practice?
The aim of the present study was to document the use of sedation in paediatric patients in emergency departments within Australia and New Zealand. A questionnaire was sent to 54 emergency departments throughout Australia and New Zealand. A total of 45 departments (83%) responded to the survey. Because the adult departments (n 5) reported few paediatric attendances, they were not included in the analysis. Thirty-nine of 40 departments (97.50%) reported using sedation in children. Midazolam was used most frequently (77%) for sedation. There was marked variation in the route of delivery and the dose of midazolam used. Ketamine was reported as the most efficacious agent used, but it was used only in 12% of cases. Formal guidelines existed in all paediatric departments but only in 58% of mixed departments, and formal discharge criteria were used in only 52% of all departments. The use of topical anaesthesia in wound closure was reported in only 3,000 of departments. There exists wide variation in practice regarding the use of sedation in children in emergency departments throughout Australia and New Zealand. Thus, the development of adequate guidelines, including discharge instructions and the use of topical agents, will improve sedation for children.


Joining Forces: The Status of Military and Veteran Health Care in Nursing Curricula.
According to the Department of Veterans Affairs, there are approximately 23 million veterans living in the United States. In 2012, the Joining Forces initiative highlighted the need to enhance nursing education for the military and veteran population. With the drawdown of 2 long, large-scale conflicts, a young cohort of veterans presented new challenges in health care. Although not necessarily a traditional vulnerable population, given their emergent health care needs, they are vulnerable. Purnell's Model for Cultural Competence provided a framework for this exploratory descriptive study. A national on-line survey of 123 nursing programs that pledged to support Joining Forces responded as to how they addressed the initiatives, curricular content, and facilitators and barriers to the process. The findings suggest that some schools/colleges of nursing have exceeded the initiative goals, some who have implemented little, whereas most are in the process. Respondents shared approaches used to enhance courses and curricula. Faculty who were veterans were a strength to program enhancement. The majority felt that incorporating this content was important, although lack of time and a content-laden curriculum were common barriers. Nurse educators have an ethical obligation to teach culturally sensitive care. Making the pledge was only the first step.


Oscillations-free PID control of anesthetic drug delivery in neuromuscular blockade.
The PID-control of drug delivery or the neuromuscular blockade (NMB) in closed-loop anesthesia is considered. The NMB system dynamics portrayed by a Wiener model can exhibit sustained nonlinear oscillations under realistic PID gains and for physiologically feasible values of the model parameters. Such oscillations, also repeatedly observed in clinical trials, lead to under- and over-dosing of the administered drug and undermine patient safety. This paper proposes a tuning policy for the proportional PID gain that via bifurcation analysis ensures oscillations-free performance of the control loop. Online estimates of the Wiener model parameters are needed for the controller implementation and monitoring of the closed-loop proximity to oscillation. The nonlinear dynamics of the PID-controlled NMB system are studied by bifurcation analysis. A database of patient models estimated under PID-controlled neuromuscular blockade during general anesthesia is utilized, along with the corresponding clinical measurements. The performance of three recursive algorithms is compared in the application at hand: an extended Kalman filter, a conventional particle filter (PF), and a PF making use of an orthonormal basis to estimate the probability density function from the particle set. It is shown that with a time-varying proportional PID gain, the type of equilibria of the closed-loop system remains the same as in the case of constant controller gains. The recovery time and frequency of oscillations are also evaluated in simulation over the database of patient models. Nonlinear identification techniques based on model linearization yield biased parameter estimates and thus introduce superfluous uncertainty. The bias and variance of the estimated models are related to the computational complexity of the identification algorithms, highlighting the superiority of the PFs in this safety-critical application. The study demonstrates feasibility of the proposed oscillation-free control strategy combining bifurcation theory based design and online parameter estimation by PF.


Toxinology of venoms from five Australian lesser known elapid snakes.
Research into Australian elapid venoms has mainly focused on the seven genera of greatest clinical significance: Acanthophis, Hoplocephalus, Notechis, Oxyuranus, Pseudechis, Pseudonaja and Tropidechis. However, even small species represent a potential for causing severe clinical envenoming. Further, owing to taxonomic distinctiveness, these species are a potential source of novel toxins for use in drug design and development. This is the first study to characterize the venoms of Cryptophis boschmai, Denisonia devisi, Echiopsis curta, Hemiaspis signata and Vermicella annulata. MALDI analysis of each venom, over the range of 4-40 kDa, indicated components in the weight range for three finger toxins (6-8 kDa) and phospholipase A(2) (PLA(2) ; 12-14 kDA). Interestingly, C. boschmai venom was the only venom, which contained components > 25 kDa. All venoms (10 μg/ml) demonstrated in vitro neurotoxicity in the chick biventer cervicis nerve-muscle preparation, with a relative rank order of: H. signata ≥ D. devisi ≥ V. annulata = E. curta > C. boschmai. CSL polyvalent antivenom neutralized the inhibitory effects of C. boschmai venom but only delayed the inhibitory effect of the other venoms. All venoms displayed PLA(2) activity but over a wide range (i.e. 1-621 μmol/min./mg). The venoms of C. boschmai (60 μg/kg, i.v.), D. devisi (60 μg/kg, i.v.) and H. signata (60 μg/kg, i.v.) produced hypotensive effects in vivo in an anaesthetized rat preparation. H. signata displayed moderate pro-coagulant activity while the other venoms were weakly pro-coagulant. This study demonstrated that these understudied Australian elapids have varying pharmacological activity, with notable in vitro neurotoxicity for four of the venoms, and may produce mild to moderate effects following systemic envenoming.


[The role of substance P in electroacupuncture analgesia and its relation to enkephalins in the rat brain].
In order to understand the role of substance P (SP) in the brain and the relationship between SP and enkephalins in the electroacupuncture analgesia (EA), we have observed the influence of SP-antagonist, (D-Arg', D-Phe5, D-Trp7.9, Leu11) -SP (DADPDTL) injected intracerebroventricularly (icv) on EA and the change of the level of SP in the brain regions of the rat during EA. We have made a further observations on the influences of the naloxone (NX) on the che change of the content of SP induced by EA and DADPDTL on the increase in Leu-enkephalins (LEK) induced by EA. The Wistar rats were used in the experiment. The latency of the tail flick, immersing the tip of rat tail (4 cm) into hot-water of 50 degrees C, was taken as the pain threshold. The drugs were injected icv via plastic cannulae implanted in the bilateral ventricles. The EA was applied to the point of "Zusanli" (S36). The contents of SP and LEK were determined radioimmunoassay in the hypothalamus, mid-brain, striatum and pons-medulla-oblongata. The pain threshold was increased by 48 +/- 9% (P less than 0.01) after EA. But icv injection of DADPDTL decreased the pain threshold by 14 +/- 7% after EA. The result suggests that DADPDTL can antagonize the effect of EA and that SP in the brain is involved in EA. After EA the contents of SP in the hypothalamus and mid-brain of the rats were decreased by 29% and 28% in comparison with that of the control group respectively (both of them, P less than 0.05), but the contents of SP in the striatum and pons-medulla-oblongata had no significant change.(ABSTRACT TRUNCATED AT 250 WORDS)


Pentobarbital inhibits glucose uptake, but not water transport by glucose transporter type 3.
To understand the mechanisms underlying the neuroprotective efficacy of barbiturates, the effect of pentobarbital on glucose uptake and water transport was determined in Xenopus oocytes expressing glucose transporter type 3 (GLUT3). Pentobarbital induced a 50% concentration-dependent inhibition in glucose uptake, but exerted no effect on water transport by GLUT3. Eadie-Hofstee analysis showed that pentobarbital decreased Vmax significantly, but not Km of GLUT3 for 2-deoxy-D-glucose. Although the protein kinase C (PKC) activator significantly decreased glucose uptake by GLUT3, no additive or synergistic interactions were observed between the PKC activator and pentobarbital. Our results suggest that pentobarbital may play an important role in neuroprotection by inhibition of glucose uptake by GLUT3 by a mechanism involving PKC.


LncRNA SNHG6 is Associated with Poor Prognosis of Gastric Cancer and Promotes Cell Proliferation and EMT through Epigenetically Silencing p27 and Sponging miR-101-3p.
Background/Amis: Long non-coding RNAs (lncRNAs), a novel class of transcripts, have been shown to play critical roles in diverse cellular biological processes, including tumorigenesis. Small nucleolar RNA host gene 6 (SNHG6) regulates various biological processes in cancer cells. However, the biological role of SNHG6 in gastric cancer still remains to be explored. The aim of this study is to investigate the characteristic of the SNHG6 in gastric cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of SNHG6 in gastric cancer tissues and cell lines. MTT assays, colony formation assays were used to determine the impact of SNHG6 on tumorigenesis . Flow cytometric analysis of cell cycle and apoptosis was performed to measure the effect of SNHG6 on cell cycle and apoptosis rate. Transwell assay was performed to measure the effect of SNHG6 on cell migration. Western blotting and immunofuorescence were utilized to examine the effect of SNHG6 on epithelial-mesenchymal transition (EMT) of GC cells. Chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), RNA-pulldown and luciferase reporter assays were employed to dissect molecular mechanisms. In this study, we revealed that SNHG6 was overexpressed in gastric cancer tissues and cell lines. High expression levels of SNHG6 wereassociated with invasion depth, lymph node metastasis, distant metastasis and tumor/node/metastasis (TNM) stage, and predicted poor prognosis. Loss-of-function assays revealed that silenced SNHG6 obviously inhibited gastric cancer cell growth, weakened cell migration capacity and suppressed the EMT processes of gastric cancer cells. Additionally, ChIP, RIP, RNA-pulldown and luciferase reporter assays evidenced that SNHG6 could epigenetically silenced p27 and could competitively sponging miR-101-3p thereby regulating zinc finger E-box-binding homeobox 1 (ZEB1). In summary, our findings demonstrated that SNHG6 acted as an oncogene in gastric cancer cells through regulating miR-101-3p/ZEB1 at a post-transcriptional level and silencing expression at a transcriptional level by recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p27. SNHG6 might serve as a candidate prognostic biomarker and a target for novel therapies of gastric cancer patients.


Growth stimulus-mediated differential translocation of casein kinase 2 to the nuclear matrix. Evidence based on androgen action in the prostate.
Recently, we documented that a significant amount of nuclear casein kinase 2 (CK2) (a ubiquitous multipotential messenger-independent serine/threonine protein kinase) is associated with the nuclear matrix (NM), where it may be involved in the phosphorylation of several intrinsic proteins (Tawfic, S., and Ahmed, K. (1994) J. Biol. Chem. 269, 7489-7493). Both CK2 and NM have been implicated in cell growth and proliferation. To examine whether CK2 in the NM was regulated in relation to a growth stimulus, we employed androgen action in the prostate as a model of growth control. In rats, androgen deprivation leads to a differential loss of CK2 activity and protein from the NM fraction in the prostate. At 24 h after androgen deprivation, the NM-associated CK2 activity as well as immunoreactive protein decline by about 80%. By comparison, total nuclear CK2 activity decreased by only 37%. Androgen administration to the castrated rats evokes a rapid differential increase in CK2 activity in the NM, so that within 1 h following the androgenic stimulus, the CK2 activity increases by 110% in the NM fraction versus 45% in the total nuclei. We propose that the stimulus-mediated differential translocation of CK2 to NM may play a role in the transduction of growth signal.


[Clinical risk factors for the occurrence of tobacco dependence].
In order to formulate a biosocial conception of tobacco dependence essential for fundamental grounding of smoking prevention, the authors examined 1106 subjects with smoking habits, smoking dependence and nonsmokers. A combination of internal and external factors is determined underlying the onset and maintenance of tobacco dependence. Risk factors responsible for consolidation of tobacco addiction are listed.