Next-generation sequencing-based panel testing for myeloid neoplasms.
Our ability to interrogate a broad array of genetic alterations in myeloid neoplasm has increased significantly with the advance in next-generation sequencing (NGS). In addition to morphologic examination, flow cytometry, and cytogenetics, NGS-based testing can add additional information to the diagnostic workup. More than a dozen myeloid-focused NGS-based panels are now available from commercial and academic laboratories. In this review, we examine the content of these panels in the context of our current understanding of driver alterations in myeloid neoplasms. With improved turnaround time, decreasing costs, and an expanding knowledge of the therapeutic and prognostic significance of the detected variants, NGS-based panel testing is likely to play a major role in the management of patients with myeloid neoplasm in the coming decade.


Characterization of the bilin attachment sites in R-phycoerythrin.
The amino acid sequence around the sites of attachment of all the bilin prosthetic groups of Gastroclonium coulteri R-phycoerythrin, (alpha beta)6 gamma, have been determined. The sequences of tryptic peptides derived from the alpha and beta subunits are (Formula: see text) where the designations alpha and beta refer to the subunits from which the peptides derived. Cysteinyl residues involved in bilin attachment are indicated with an asterisk. Each peptide carries a single bilin, either phycoerythrobilin (PEB) or phycourobilin (PUB). Spectroscopic studies on the gamma subunit indicate the presence of one PEB and three PUB groups. However, five unique tryptic peptides, gamma-A through gamma-E, were characterized, indicating that Gastroclonium R-phycoerythrin is a mixture of at least two species, (alpha beta)6 gamma and (alpha beta)6 gamma', with gamma subunits differing in amino acid sequence. The sequences of the gamma subunit bilin peptides (see below) were not homologous to those from alpha and beta subunits of any biliprotein. (Formula: see text) The bilins in all these peptides are attached through single linkages to a cysteinyl residue, except for the phycourobilin on peptide beta-3 which is attached through two thioether linkages to cysteinyl residues 10 amino acids apart. The availability of small bilin peptides was exploited to obtain more accurate molar extinction coefficients for peptide-linked PEB and PUB groups. Application of these extinction coefficients in the calculation of the bilin content of R-, B-, and C-phycoerythrins shows that there are 5 bilins/alpha beta in each of these three biliprotein types.


Low-Field Combined Diffusion-Relaxation MRI for Mapping Placenta Structure and Function.
Demonstrating quantitative multi-parametric mapping in the placenta with combined T2∗-diffusion MRI at low-field (0.55T). We present 57 placental MRI scans performed on a commercially available 0.55T scanner. We acquired the images using a combined T2∗-diffusion technique scan that simultaneously acquires multiple diffusion preparations and echo times. We processed the data to produce quantitative T2∗ and diffusivity maps using a combined T2∗-ADC model. We compared the derived quantitative parameters across gestation in healthy controls and a cohort of clinical cases. Quantitative parameter maps closely resemble those from previous experiments at higher field strength, with similar trends in T2∗ and ADC against gestational age observed. Combined T2∗-diffusion placental MRI is reliably achievable at 0.55T. The advantages of lower field strength - such as cost, ease of deployment, increased accessibility and patient comfort due to the wider bore, and increased T2∗ for larger dynamic ranges - can support the widespread roll out of placental MRI as an adjunct to ultrasound during pregnancy.


Trapping of nitric oxide produced during denitrification by extracellular hemoglobin.
A spectrophotometric method has been developed that uses extracellular hemoglobin (Hb) to trap nitric oxide (NO) released during denitrification as nitrosyl hemoglobin (HbNO). The rate of complexation of NO with Hb is about at the diffusion controlled limit for protein molecules and the product, HbNO, is essentially stable. Hb was added to an anaerobic bacterial suspension and denitrification was initiated with either KNO2 or KNO3. HbNO formation was observed for six species of denitrifying bacteria and showed isosbestic points at 544, 568, and 586 nm. Cellular NO production, presumably by nitrite reductase, was kinetically distinct from the much slower chemical reaction of Hb with KNO2 to form methemoglobin and HbNO. The rate of HbNO formation was proportional to cell density, essentially independent of pH from 6.8 to 7.4, nearly zero order in [Hb] and, at least with Paracoccus denitrificans, strongly inhibited by rotenone and antimycin A. The Cu chelator, diethyldithiocarbamate, had no effect on HbNO formation by Pa. denitrificans, but abolished that by Achromobacter cycloclastes which uses a Cu-containing nitrite reductase known to be inactivated by the chelator. HbNO formation did not occur with non-denitrifying bacteria. The stoichiometry at high [Hb] for conversion of Hb to HbNO was 1.3-1.8 KNO2 per Hb for Pa. denitrificans, Pseudomonas aeruginosa, and A. cycloclastes and about 3.4 for Pseudomonas stutzeri. The former range of values corresponds to a partition of about 2 N atoms in 3 toward trapping and 1 in 3 toward reduction on the pathway to N2. Nitrogen not trapped appeared largely as N2O in presence of acetylene. The results are consistent with a model in which NO is a freely diffusible intermediate between nitrite and N2O, providing that nitric oxide reductase is or nearly is a diffusion controlled enzyme.


Shared molecular genetic factors influence subcortical brain morphometry and Parkinson's disease risk.
Parkinson's disease (PD) is a late-onset and genetically complex neurodegenerative disorder. Here we sought to identify genes and molecular pathways underlying the associations between PD and the volume of ten brain structures measured through magnetic resonance imaging (MRI) scans. We leveraged genome-wide genetic data from several cohorts, including the International Parkinson's Disease Genomics Consortium (IPDG), the UK Biobank, the Adolescent Brain Cognitive Development (ABCD) study, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the Enhancing Neuroimaging Genetics through Meta-Analyses (ENIGMA), and 23andMe. We observed significant positive genetic correlations between PD and intracranial and subcortical brain volumes. Genome-wide association studies (GWAS) - pairwise analyses identified 210 genomic segments with shared aetiology between PD and at least one of these brain structures. Pathway enrichment results highlight potential links with chronic inflammation, the hypothalamic-pituitary-adrenal pathway, mitophagy, disrupted vesicle-trafficking, calcium-dependent, and autophagic pathways. Investigations for putative causal genetic effects suggest that a larger putamen volume could influence PD risk, independently of the potential causal genetic effects of intracranial volume (ICV) on PD. Our findings suggest that genetic variants influencing larger intracranial and subcortical brain volumes, possibly during earlier stages of life, influence the risk of developing PD later in life.


A study on differentially expressed gene screening of Chrysanthemum plants under sound stress.
Environmental stress can induce differential expression of genes of flower plants. It had been found that sound stimulation had an obvious effect on the growth and development of flower plants, but it is not reported on the differentially expressed genes and their expressing characteristics under sound stimulation. This is one of the few reports in terms of using the DDRT-PCR technique for screening the differentially expressed cDNA fragments responding to sound-wave stress on Chrysanthemum. Six differentially expressed cDNA fragments were obtained. Molecular weight of fragments was from 200 to 600 bp, respectively. Among differential fragments acquired, three of them (SA3, SG7-1, and CA2) were found to be positive fragments by northern dot hybridization, whose molecular weight are 270, 580 and 370 bp, respectively. SA3 was differentially expressed and SG7-1 was preferably expressed, while CA2 was restrained by the sound wave. These results indicated that expression of some genes was turned on, meanwhile the stress restrained some genes from expression under the mode of sound-stress stimulation.


Proteasome-mediated cleavage of the Y-box-binding protein 1 is linked to DNA-damage stress response.
YB-1 is a DNA/RNA-binding nucleocytoplasmic shuttling protein whose regulatory effect on many DNA- and RNA-dependent events is determined by its localization in the cell. Distribution of YB-1 between the nucleus and the cytoplasm is known to be dependent on nuclear targeting and cytoplasmic retention signals located within the C-terminal portion of YB-1. Here, we report that YB-1 undergoes a specific proteolytic cleavage by the 20S proteasome, which splits off the C-terminal 105-amino-acid-long YB-1 fragment containing a cytoplasmic retention signal. Cleavage of YB-1 by the 20S proteasome in vitro appears to be ubiquitin- and ATP-independent, and is abolished by the association of YB-1 with messenger RNA. We also found that genotoxic stress triggers a proteasome-mediated cleavage of YB-1 in vivo and leads to accumulation of the truncated protein in nuclei of stressed cells. Endoproteolytic activity of the proteasome may therefore play an important role in regulating YB-1 functioning, especially under certain stress conditions.


Standardized magnetic resonance imaging acquisition and reporting in pediatric multiple sclerosis.
Magnetic resonance (MR) imaging is one of the most important paraclinical tools for the diagnosis of multiple sclerosis (MS), and monitoring of disease progression and treatment response. This article provides clinicians and neuroradiologists caring for children with demyelinating disorders with a suggested standard MR imaging acquisition and reporting protocol, and defines a standard lexicon for lesion features typical of MS in children. As there is considerable overlap between the MR imaging features of pediatric- and adult-onset MS, the recommendations provided herein may be of relevance to radiologists and clinicians caring for adults with multiple sclerosis.


Mothering a hospitalized child: it's the 'little things' that matter.
This article reports one aspect of a phenomenological study that described the lived experience of mothering a child hospitalized with acute illness or injury. The significance for mothers that nurses do the 'little things' emerged in considering the implications of this study's findings for nurses in practice. Seven mothers whose child had been hospitalized in the 12 months prior to the first interview agreed to share their stories. The resulting data were analysed and interpreted using van Manen's interpretation of phenomenology. This description of mothering in a context of crisis is useful in the potential contribution it makes to nurses' understanding of mothers' experience of the hospitalization of their children. It supports the philosophy of family-centred care and highlights the ability of individual nurses to make a positive difference to a very stressful experience by acknowledging and doing 'little things', because it is the little things that matter to the mothers of children in hospital.


Readmissions After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: a US HIPEC Collaborative Study.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) results in significant morbidity and readmissions. Previous studies have been limited by single-institution design or lack of tumor details in the database used. The 12-institution US HIPEC Collaborative Database was queried between 1999 and 2017. Preoperative and intraoperative patient and tumor details were analyzed for associations with readmissions. A total of 2017 of 2372 cases were included in the analysis. The 30-day readmission rate was 15.9% (n = 321). Common indications for readmission included failure to thrive (29.9%), infection (23.6%), and ileus/bowel obstruction (15.1%). The readmitted cohort had more complications, including intra-abdominal abscess (21.2% vs 6.2%), ileus (28.0% vs 17.2%), anastomotic leak (11.2% vs 2.2%), enteric fistula (5.6% vs 1.5%), deep venous thrombosis (6.2% vs 2.5%), and pulmonary embolism (6.9% vs 2.5%). Factors independently associated with readmission (p < 0.05) included ECOG score ≥ 3 (OR 3.4), depression (OR 2.4), total parenteral nutrition (OR 3.6), low anterior resection or partial colectomy (OR 2.0), and stoma creation (OR 2.2). Factors not associated included neoadjuvant chemotherapy, peritoneal cancer index, and completeness of cytoreduction. Readmission rate between 31 and 90 days was 3.9% (n = 78). Independent predictors (p < 0.05) included operative time (OR 1.1), low anterior resection or partial colectomy (OR 1.7), and stoma creation (OR 2.2). In the largest study to date examining readmissions after CRS-HIPEC, 30-day readmission rate was 15.9%. Tumor factors failed to predict readmission, whereas preoperative functional status and depression along with individual cytoreductive procedures predicted readmission. Patients with these risk factors or postoperative complications may benefit from closer post-discharge monitoring.


Psychological strategies in the prevention and treatment of postnatal depression.
Prevention or treatment of most postnatal psychological disorders currently demands the manipulation of psychosocial not biological variables. How we treat women matters in terms of the emotional outcome of pregnancy and ultimately the family outcome. This is confirmed by two types of studies. Firstly, there are the controlled trials of psychological strategies aimed at the prevention or treatment of postnatal mood disturbance. Secondly, there are the studies of the relationship between the type of obstetric and midwifery care and emotional well-being following the birth. There have been far too few of either type of study. Since the rapid advances in medicine which relate to physical outcome have peaked, with mortality rates at an all-time low, the 1990s should see more clinical and research effort devoted to psychological outcomes. Perhaps some progress can now be made in reducing postnatal psychiatric and psychological morbidity.


Effects of threatening communications and mothers health beliefs on weight change in obese children.
A field experiment was designed to test the effects on weight change in obese children of (1) communications varying in threat and (2) health beliefs of the child's mother, in terms of perceived vulnerability to health threats, the efficacy of taking actions, and barriers to acting. Treatments involved messages containing more or less threatening material regarding obesity, plus a control (no communication) condition. Beliefs were assessed by means of personal interviews. All mothers and children received dietary counseling and were scheduled for four follow-up visits, which included weighing. The 182 participants were from low-income areas served by a large hospital pediatric clinic. High-threat messages yielded the most consistent weight loss, followed by low threat and control. In addition, both general beliefs concerning health and specific beliefs about obesity and dieting predicted weight loss. Both messages and mothers' beliefs acted together on keeping appointments and making efforts to comply. Results are discussed in terms of the effects of threats and health belief-behavior linkages.


Inhibition of testicular androgenesis by urinary gonadotropin-inhibiting substances in rats.
The effect of urinary gonadotropin-inhibiting substances (GIS) on the androgen synthesis in rat testes was studied in vitro and in vivo. GIS, which was added to the incubation medium containing tesased testicular tissues and injected into rats for 2 days, showed a suppressive effect on the formation of androstenedione from pregnenolone in the testis.


Suppressive effect of liposomes containing DNA coding for diphtheria toxin A-chain on cells transformed with bovine leukemia virus.
A recombinant plasmid which contained a gene for diphtheria toxin A-chain (DT-A) under the control of the long terminal repeat (LTR) of bovine leukemia virus (BLV) (BLV-LTR) was constructed to test a novel application of liposomes as antiviral agents. The promoter activity of BLV-LTR was estimated by the chloramphenicol acetyltransferase (CAT) assay using a plasmid which contains the coding sequence of CAT under the control of BLV-LTR (pBLVCAT). When BLV-infected cells were transfected with pBLVCAT, CAT activity was detected. BLV-uninfected cell lines, however, showed no detectable CAT activity. The plasmid DNA entrapped in liposomes was added to BLV-infected cells in culture. Syncytium formation induced by BLV-infected cells was effectively suppressed by the liposomes containing the gene for DT-A under the control of BLV-LTR. Conversely, liposomes containing the gene for DT-A without a promoter showed no such effect. DT-A gene-containing liposomes with BLV-LTR did not affect formation of syncytium induced by bovine immunodeficiency virus. These observations indicate that BLV-infected cells were readily targeted on the level of gene expression. This strategy could be applied to the treatment of BLV-induced B-cell proliferation of cattle, and further to other viral/neoplastic diseases where specific gene expression is exerted.


Molecular chaperones as regulators of cell death.
Molecular chaperones have been reported as multifunctional antistress molecules that can regulate diverse biological processes to maintain cellular homeostasis. Molecular chaperones have critical roles for maintaining proper protein folding, protein translocation, degradation of unfolded protein, regulating signal-transduction proteins and so on. Under pathological conditions, inducible or constitutively expressed molecular chaperones protect cells from stress. Non-dividing terminally differentiated cells accumulate abnormal proteins due to chronic environmental or physiological stress; thus, proper chaperone function is critical for maintaining homeostasis of those cells, such as neuronal and muscular cells. Cancer cells also have overexpression of molecular chaperone proteins for promoting survival from stress related to growth, cell cycle, hypoxia, metastasis and genetic mutations. Here, we will focus on the function of molecular chaperone proteins for the regulation of cell death in degenerative diseases, ischemic diseases and in cancer.


HL-37, a novel anthracene derivative, induces Ca(2+)-mediated apoptosis in human breast cancer cells.
HL-37, a novel anthracene derivative, exhibited potent anticancer activity in many kinds of cancer cells. However, the exact mechanism and signaling pathway involved in HL-37-induced apoptosis have not been fully elucidated. Therefore, we explored the mechanisms of HL-37-mediated apoptosis in MCF-7 and MDA-MB-435 human breast cancer cells. When MCF-7 cells or MDA-MB-435 cells were co-incubated with HL-37, the percentage of apoptotic cell and S phase of cell cycle was markedly increased. In addition, a rise in intracellular calcium levels, ROS production, phosphorylation of JNK and activation of calpain were found in both MCF-7 cells and MDA-MB-435 cells after exposure to HL-37. With the HL-37-mediated reduction of mitochondrial membrane potential, cytochrome c was released from mitochondria to cytosol. Moreover, HL-37 strongly induced cleavage of caspase-4, caspase-9, as well as caspase-3 in MDA-MB-435 cells, whereas, activation of caspase-4, caspase-9 and caspase-7 but not caspase-3 was detected in MCF-7 cells. These results suggested that HL-37 induced MDA-MB-435 and MCF-7 cells apoptosis via oxidative stress and Ca(2+)/calpain/caspase-4 pathway.


Cyclisation/fluorination of nitrogen containing dienes in superacid HF-SbF5: a new route to 3- and 4-fluoropiperidines.
Various N,N-diallylic amines and amides were rapidly converted to fluorinated piperidines after a novel cyclisation/fluorination reaction in superacid HF-SbF5.


Nonparametric covariate adjustment in estimating hazard ratios.
In randomized clinical trials with time-to-event outcomes, the hazard ratio is commonly used to quantify the treatment effect relative to a control. The Cox regression model is commonly used to adjust for relevant covariates to obtain more accurate estimates of the hazard ratio between treatment groups. However, it is well known that the treatment hazard ratio based on a covariate-adjusted Cox regression model is conditional on the specific covariates and differs from the unconditional hazard ratio that is an average across the population. Therefore, covariate-adjusted Cox models cannot be used when the unconditional inference is desired. In addition, the covariate-adjusted Cox model requires the relatively strong assumption of proportional hazards for each covariate. To overcome these challenges, a nonparametric randomization-based analysis of covariance method was proposed to estimate the covariate-adjusted hazard ratios for multivariate time-to-event outcomes. However, empirical evaluations of the performance (power and type I error rate) of the method have not been studied. Although the method is derived for multivariate situations, for most registration trials, the primary endpoint is a univariate outcome. Therefore, this approach is applied to univariate outcomes, and performance is evaluated through a simulation study in this paper. Stratified analysis is also investigated. As an illustration of the method, we also apply the covariate-adjusted and unadjusted analyses to an oncology trial.


Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process.
On the basis of three different models (namely: ddU, AZT and PMEA), mononucleotide phosphotriester derivatives were designed to be able to liberate the corresponding monophosphate (or phosphonate) inside the cell through a reductase-mediated activation process. It was demonstrated that the use of bis[S-(2-hydroxyethylsulfidyl)-2-thioethyl] esters of ddUMP (11), AZTMP (12) and PMEA (17) resulted in intracellular delivery of the parent monophosphate (or phosphonate). This point was corroborated by observation of an anti-HIV effect of, 11 in various cell lines, for 12 in CEM TK- cells and by the enhanced activity observed for 17. Furthermore, the reported decomposition data in cell extracts fully confirm the validity of this approach and show unambiguously the potential for intracellular reductase-mediated activation of the starting drug.


Effects of partial left ventriculectomy on left ventricular performance in patients with nonischemic dilated cardiomyopathy.
This study sought to assess the effects of partial left ventriculectomy (PLV) on left ventricular (LV) performance in a series of consecutive patients with nonischemic dilated cardiomyopathy. Reduction of LV systolic function in patients with heart failure is associated with an increase of LV volume and alteration of its shape. Recently, PLV, a novel surgical procedure, was proposed as a treatment option to alter this process in patients with dilated cardiomyopathy. We studied 19 patients with severely symptomatic nonischemic dilated cardiomyopathy, before and 13+/-3 days after surgery, and 12 controls. Single-plane left ventriculography with simultaneous measurements of femoral artery pressure was performed during right heart pacing. The LV end-diastolic and end-systolic volume indexes decreased after PLV (from 169 to 102 ml/m2, and from 127 to 60 ml/m2, respectively, p < 0.0001 for both). Despite a decrease in LV mass index (from 162 to 137 g/m2, p < 0.0001), there was a significant decrease in LV circumferential end-systolic and end-diastolic stresses (from 277 to 159 g/cm2, p < 0.0001 and from 79 to 39 g/cm2, p = 0.0014, respectively). Ejection fraction improved (from 24% to 41%, p < 0.0001); the stroke work index remained unchanged. The PLV improves LV performance by a dramatic reduction of ventricular end-systolic and end-diastolic stresses. Further studies are needed to assess whether this effect is sustained during long-term follow-up and to define the role of PLV in the treatment of patients with dilated cardiomyopathy.


Redefining "child-directed advertising" to reduce unhealthy television food advertising.
Food and beverage companies have pledged to reduce unhealthy marketing to children through the Children's Food and Beverage Advertising Initiative (CFBAI). However, public health experts question the initiative's effectiveness because pledges apply to only some types of marketing. For instance, the CFBAI covers only TV advertising that is "child-directed," defined as advertising during programs for which children make up 35% or more of the viewing audience. To quantify the proportion of food and beverage TV advertisements (ads) viewed by children that is covered by current CFBAI pledges and examine the potential impact of broader definitions of child-directed advertising. Nielsen data were used to quantify percentages of children (aged 2-11 years) in the audience (i.e., child-audience share), as well as absolute numbers of child viewers, for all national TV programs in 2009. Nielsen advertising data provided the number of food and beverage ads viewed by preschoolers (aged 2-5 years); older children (aged 6-11 years); and adults (aged 18-49 years) during programs with various child-audience compositions. Data were collected in 2010 and analyzed in 2011. Just 45%-48% of food ads viewed by children met current CFBAI definitions of child-directed advertising. Expanding this definition to include advertising during programs with a child-audience share of 20% or higher and/or 100,000 or more child viewers would cover 70%-71% of food advertising seen by children but just one third of ads seen by adults. Children viewed an estimated 35% fewer food ads during TV programs with a high child-audience share (≥50%) in 2009 compared with 2004. However, ensuring that nutrition standards apply to the majority of food ads viewed by children requires broader definitions of child-directed advertising.


[Acute massive thromboembolism after pulmonary wedge resection treated with open embolectomy: a case report].
Acute massive pulmonary thromboembolism after pneumonectomy usually results in death if not diagnosed early and treated aggressively. It was a case of acute embolism in the main pulmonary artery with thrombus following right pulmonary wedge resection. Diagnosis was made clinically and with computerized tomography before emergency surgery. Thromboembolectomy was successfully performed on cardiopulmonary bypass and the patient was subsequently discharged home after uneventful recovery. Although the patient had no previous history of thrombosis, he took high dose of warfarin for anticoagulating postoperatively, which suggested that the patient with pulmonary embolism attack may be associated with the hypercoagulable state of his own.


The role of risk avoidance and locus of control in workers' near miss experiences: Implications for improving safety management systems.
The process industry has made major advancements and is a leader in near-miss safety management, with several validated models and databases to track close call reports. However, organizational efforts to develop safe work procedures and rules do not guarantee that employees will behaviorally comply with them. Assuming that at some point, every safety management system will need to be examined and realigned to help prevent incidents on the job, it is important to understand how personality traits can impact workers' risk-based decisions. Such work has been done in the mining industry due to its characteristically high risks and the results can be gleaned to help the process industry realign goals and values with their workforce. In the current study, researchers cross-sectionally surveyed 1,334 miners from 20 mine sites across the United States, varying in size and commodity. The survey sought to understand how mineworkers' risk avoidance could impact their near miss incidents on the job - a common precursor to lost-time incidents. Multiple regressions showed that as a miner's level of risk avoidance increased by 1 unit in the 6-point response scale, the probability of experiencing a near miss significantly decreased by 30% when adjusting for relevant control variables. Additionally, a significant interaction between risk avoidance and locus of control suggested that the effect of risk avoidance on near misses is enhanced as a miner's locus of control increases. A one-unit increase in locus of control appends the base effect of risk avoidance on near misses with an additional 8% decrease in the probability. Findings are discussed from a near-miss safety management system perspective in terms of methods to foster both risk avoidance and locus of control in an effort to reduce the probability of near misses and lost time at the organizational level within the process industry and other high-hazard industries.


Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy.
Cysteine-rich 61 (Cyr61 or CCN1), a secreted protein from the CCN family, is an important proinflammatory cytokine. Migration and infiltration of mononuclear cells to inflammatory sites play a critical role in the pathogenesis of rheumatoid arthritis (RA). Monocyte chemoattractant protein-1 (MCP-1/CCL2) is the key chemokine that regulates migration and infiltration of monocytes. Here, we examined the role of CCN1 in monocyte migration, and CCL2 expression in osteoblasts. We found higher levels of CCN1 and CCL2 in synovial fluid from RA patients compared with levels from non-RA controls. We also found that the CCN1-induced increase in CCL2 expression is mediated by the MAPK signaling pathway and that miR-518a-5p expression was negatively regulated by CCN1 via the MAPK cascade. In contrast, inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA ameliorated articular swelling, cartilage erosion, and infiltration of monocytes in the ankle joints of mice with collagen-induced arthritis. Our study describes how CCN1 promotes monocyte migration by upregulating CCL2 expression in osteoblasts in RA disease. CCN1 could serve as a potential target for RA treatment.


Diagnostic accuracy study of multiplex PCR for detecting tuberculosis drug resistance.
To study the diagnostic accuracy of a multiplex real-time PCR (Anyplex II MTB/MDR/XDR, Seegene, Corea) that detects Mycobacterium tuberculosis resistant to isoniazid (INH), rifampicin (RIF), fluoroquinolones (FLQ) and injectable drugs (kanamycin [KAN], amikacin [AMK] and capreomycin [CAP]) in isolates and specimens. One hundred fourteen cultured isolates and 73 sputum specimens were retrospectively selected. Results obtained with multiplex PCR were compared with those obtained with BACTEC. Discordant results between multiplex PCR and BACTEC were tested by alternative molecular methods. Sensitivity and specificity of multiplex PCR for detecting drug resistance in isolates were 76.5% and 100%, respectively, for INH; 97.2% and 96.0%, respectively, for RIF; 70.4% and 87.9%, respectively, for FLQ; 81.5% and 84.8%, respectively, for KAN; 100% and 60%, respectively, for AMK, and 100% and 72.3%, respectively, for CAP. Sensitivity and specificity of Anyplex for detecting drug resistance in specimens were 93.3% and 100%, respectively, for INH; 100% and 100%, respectively, for RIF; 50.0% and 100%, respectively, for FLQ; and 100% and 94.4%, respectively, for both KAN and CAP. Among the discordant results, 87.7% (71/81) of results obtained with the multiplex PCR were concordant with at least one of the alternative molecular methods. This multiplex PCR may be a useful tool for the rapid identification of drug resistant tuberculosis in isolates and specimens, thus allowing an initial therapeutic approach. Nevertheless, for a correct management of patients, results should be confirmed by a phenotypic method.


Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression.
Accumulating evidence reveals that statins possess direct anti-inflammatory properties through inhibition of proinflammatory cytokine and chemokine secretion in addition to their antioxidant effects, which may contribute to amelioration of ischemia-reperfusion injury. This study tested the hypothesis that perioperative treatment of simvastatin suppresses the cardiac isograft ischemia-reperfusion injury by down-regulation of CC chemokine receptor-2 expression in an inbred rat model of cardiac transplantation. Donor hearts from Lewis rats were heterotopically transplanted to Lewis rat recipients. Recipients were orally treated with simvastatin (1 mg/kg) or vehicle every morning 3 days before the surgery until the harvest day. Rats were killed at 6 hours and at 1, 3, and 7 days after transplantation. Injury was assessed by infarct size measurement, histologic and immunohistochemical examination, and intragraft myeloperoxidase activity assay. Monocyte chemoattractant protein-1 levels in serum and graft were analyzed by enzyme-linked immunosorbent assay, and intragraft CC chemokine receptor-2 expression was measured by quantitative real-time polymerase chain reaction. The infarct size and macrophage infiltration were all significantly reduced in the simvastatin-treated group compared with those of the control group at 1 day after transplantation. Neutrophil accumulation was significantly suppressed until 3 days after transplantation, whereas myeloperoxidase activity had been significantly diminished at 1 day after transplantation. Both monocyte chemoattractant protein-1 concentrations in serum and graft were remarkably decreased at 6 hours after transplantation. Intragraft CC chemokine receptor-2 expression was also down-regulated at 1 day and 3 days after transplantation. Perioperative treatment of simvastatin could suppress the isograft ischemia-reperfusion injury through retarding intragraft monocyte chemoattractant protein-1 accumulation and CC chemokine receptor-2 expression.


Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life.
MDC9 (ADAM9/meltrin gamma) is a widely expressed and catalytically active metalloprotease-disintegrin protein that has been implicated in the ectodomain cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and as an alpha secretase for the amyloid precursor protein. In this study, we evaluated the expression of MDC9 during development and generated mice lacking MDC9 (mdc9(-/-) mice) to learn more about the function of this protein during development and in adults. During mouse development, MDC9 mRNA is ubiquitously expressed, with particularly high expression levels in the developing mesenchyme, heart and brain. Despite the ubiquitous expression of MDC9, mdc9(-/-) mice appear to develop normally, are viable and fertile, and do not have any major pathological phenotypes compared to wild-type mice. Constitutive and stimulated ectodomain shedding of HB-EGF is comparable in embryonic fibroblasts isolated from mdc9(-/-) and wild-type mice, arguing against an essential role of MDC9 in HB-EGF shedding in these cells. Furthermore, there were no differences in the production of the APP alpha and gamma secretase cleavage product (p3) and of beta- and gamma-secretase cleavage product (A beta) in cultured hippocampal neurons from mdc9(-/-) or wild-type mice, arguing against an essential major role of MDC9 as an alpha-secretase in mice. Further studies, including functional challenges and an evaluation of potential compensation by, or redundancy with, other members of the ADAM family or perhaps even with other molecules will be necessary to uncover physiologically relevant functions for MDC9 in mice.


Autosomal suppressors of sex-ratio in Drosophila mediopunctata.
The sex-ratio trait has been described as the production of progenies with excess of females due to X-linked meiotic drive in the parental males. This trait has a variable expression in Drosophila mediopunctata. We describe here the existence and chromosomal localization of autosomal suppressors of sex-ratio in this species. There are at least four such genes (one on each major autosome) and the strongest effect is localized on chromosome IV. These genes possibly result from the operation of 'Fisher's Principle'; a mechanism of Natural Selection leading to a 1:1 sex ratio.


Signalling pathways involved in the direct effects of IGFBP-5 on breast epithelial cell attachment and survival.
We have demonstrated previously that IGFBP-5 can confer survival against apoptosis induced by ceramide, C2, or a small synthetic arginine-glycine-aspartic acid (RGD)-containing peptide in a direct manner. The endogenous ceramide-induced pathway is normally counter-balanced by survival signals mediated by sphingosine kinase (SK) and protein kinase C (PKC). In order to investigate whether these pathways are involved in the IGFBP-5 survival effect, we have used inhibitors of SK (N, N-di-methyl sphingosine, DMS) and PKC (chelerythrine chloride, CC). The effect of pre-incubating Hs578T breast cancer cells with IGFBP-5 on cell adhesion or on subsequent cell death induced by C2 or RGD was investigated with and without the presence of DMS or CC. Cell death was determined by trypan blue cell counts and apoptosis confirmed by morphological assessment and flow cytometry. Cell attachment was determined by a cell adhesion assay. The presence of IGFBP-5 significantly inhibited cell death induced by C2 or RGD, compared to the triggers of apoptosis alone (P<0.01 in both cases). In the presence of either IGFBP-5, CC or DMS, there was no significant effect on cell death compared to the control. IGFBP-5 in the presence of either inhibitor resulted in a significant increase in cell death; IGFBP-5 also lost its ability to confer survival on C2 and RGD-induced apoptosis and in contrast significantly increased cell death. In the cell adhesion assay, IGFBP-5 significantly increased cell attachment over basal levels. In the presence of either inhibitor the IGFBP-5 effect on cell adhesion was reversed and cell attachment was reduced to below basal levels. These data suggest that IGFBP-5 promotes the attachment and survival of Hs578T cells by modulating the balance between ceramide and opposing survival signals.


Intratumoral VEGF and FGF1 administration alters tumor growth, vascular density, oxygenation, and expression of MCP-1 and interleukins.
The biological and physiological effects of exogenous FGF 1 and VEGF were measured using the KHT murine fibrosarcoma tumor model. Tumor-bearing C3H mice were treated intratumorally with either one or six daily doses of 6 microg/mouse FGF1, VEGF, or saline. Tumors were excised 24 hrs after the final injection. Compared to controls, only FGF1 treatment significantly increased tumor weight and size, and only in the 6 dose group. Both FGF1 and VEGF administration (6 dose) decreased tumor cell hypoxia as detected by EF5 uptake: 85% +/- 5% for FGF1 and 82% +/- 6% for VEGF versus 100% +/- 6% for controls. Decreased tumor cell EF5 staining, however, was not associated with changes in numbers of structural or angiogenic vessels. DiOC7 staining showed a slight decrease in perfused vessel numbers in tumors treated with daily VEGF. Intratumoral injections of FGF1 or VEGF also slightly decreased the tumor tissue chemokine MCP-1, interleukins (IL-1beta, IL-6, and IL-18) mRNA expression, and increased NFkappaB binding without altering Ap-1 binding of IkappaB protein expression. In summary, single pulse exposures of tumors to angiogenic factors had little or no effects on tumor growth or perfusion, while daily exposures stimulated tumor growth through improved tumor oxygenation. This improved vascular function occurs without an increase in vascular density.


Ni-catalyzed asymmetric hydrogenation of N-aryl imino esters for the efficient synthesis of chiral α-aryl glycines.
Chiral α-aryl glycines play a key role in the preparation of some bioactive products, however, their catalytic asymmetric synthesis is far from being satisfactory. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of N-aryl imino esters, affording chiral α-aryl glycines in high yields and enantioselectivities (up to 98% ee). The hydrogenation can be conducted on a gram scale with a substrate/catalyst ratio of up to 2000. The obtained chiral N-p-methoxyphenyl α-aryl glycine derivatives are not only directly useful chiral secondary amino acid esters but can also be easily deprotected by treatment with cerium ammonium nitrate for further transformations to several widely used molecules including drug intermediates and chiral ligands. Formation of a chiral Ni-H species in hydrogenation is detected by 1H NMR. Computational results indicate that the stereo selection is determined during the approach of the substrate to the catalyst.


Effect of pregnenolone-16alpha-carbonitrile (PCN) on drug response in man.
Pregnenolone-16alpha-carbonitrile (PCN), which alters drug responses and induces hepatic microsomal drugs-metabolizing enzymes in experimental animals, is well-tolerated in man. There were no marked changes in the concentrations of blood sugar and urea; marked changes in the concentrations of blood sugar and urea; bromsulphophthalein (BSP) clearance; serum alkaline phosphatase activity; hematocrit, erythrocyte and leukocyte counts; as well as in ecg patterns. When the steroid was given by mouth for 4 days to patients treated with electroshock for psychiatric disorders, it decreased suxamethonium-induced skeletal muscle fasciculation and shortened thiopentone as well as propanidid anaesthesia. Breathing was resumed more rapidly than in control subjects. The protective effect of PCN is probably mediated through induction of activation or hepatic drug-metabolizing enzymes, or both.


Bioassay-based detection of Toxoplasma gondii in free-range chickens from Khorramabad, Iran: comparison of direct microscopy and semi-nested PCR.
This study aimed to investigate the occurrence of anti-Toxoplasma gondii antibodies in free-range chickens from Khorramabad, western Iran, and also to compare the performance of direct microscopy and semi-nested PCR in mice bioassayed with tissues from seropositive chickens. We investigated 97 serum samples from free-range chickens, using the modified agglutination test (MAT). Tissues from all seropositive chickens (MAT ≥ 1:10) were bioassayed in mice. All inoculated mice were examined by direct microscopy and a semi-nested PCR targeting the 529 bp repeat element (RE) of the parasite. Anti-T. gondii antibodies were detected in 21.6% of chicken sera. Eighteen of 21 (85.7%) seropositive chickens were positive in mouse bioassay using molecular DNA detection. However, biological forms of the parasite were isolated only from 11 (52.3%) seropositive chickens. Compared with semi-nested PCR, the sensitivity of direct microscopy was 62.1%. It can be concluded that although direct microscopy is a rapid and specific method for the detection of T. gondii, it does not detect the parasite in all experimentally infected mice. The low sensitivity of direct microscopy highlights the need for molecular techniques, such as RE-based semi-nested PCR, to increase the sensitivity of the mouse bioassay.


Bell's palsy--Varicella Zoster and meningitis.
Two cases with Bell's palsy due to Varicella Zoster virus in children are reported. It is suggested that pyogenic meningitis resulting in lowered body resistance reactivated the latent V.Z. virus.


Japanese dace (Tribolodon hakonensis) fish freshness estimation using front-face fluorescence spectroscopy coupled with chemometric analysis.
Although fish and its related products are good sources of protein and unsaturated fatty acids, like omega-3 in the human diet, their shelf-life is limited by biochemical and microbial changes. In this study, a front-face fluorescence spectroscopy technique was used to acquire Excitation-emission matrices (EEM) to monitor Japanese dace (Tribolodon hakonensis) fish freshness degradation during storage. EEM of Japanese dace fish parts (intact eyeball and surface-containing scales), excitation from 220 to 585 nm and emissions from 250 to 600 nm, were measured at different times during storage. To simplify the acquired complex spectra datasets from each fish part, the variables were reduced to those that were only significant/important (those with higher positive or negative correlation) for K value prediction, and as an index of freshness. Partial least square regression (PLSR) results demonstrated that combining the fluorescence EEM of the eyeball and surface-containing scales the best monitoring of fish freshness; excitation at 280 and 350 nm for both the eyeball and surface-containing scales, with 2.84 and 0.96 as RMSE and R2, respectively. These findings demonstrate that multiple excitation fluorescence approaches can be convenient for the freshness evaluation of fish.


Estimation of sweat rates during cycling exercise by means of the closed chamber condenser technology.
Knowledge of local sweating patterns is of importance in occupational and exercise physiology settings. The recently developed closed chamber condenser technology (Biox Aquaflux® ) allows the measurement of evaporative skin water loss with a greater measurement capacity (up to 1325 g/h/m2 ) compared to traditional evaporimeters. The aim of this study was to evaluate the applicability of the Biox Aquaflux® to estimate sweat production during exercise. Fourteen healthy subjects performed a 20-min cycle ergometer trial at respectively 55% heart rate (HRreserve and 75% HRreserve . Sweat production was estimated by measuring body weight before and after exercise, by calculating the amount of sweat collected in a patch, and by measuring the water flux (in g/h/m2 ) with the Biox Aquaflux® instrument. The Biox Aquaflux® instrument allowed the follow up of sweat kinetics at both intensities. Correlations between the measurement methods were all significant for the 75% HRreserve trial (with r ranging from 0.68 to 0.76) whilst for the 55% HRreserve a significant relation was detected between the patch method and the Biox Aquaflux® only (with r ranging from 0.41 to 0.79). The Biox Aquaflux® instrument is a practical and direct method for the estimation of local sweat rates under field conditions.


The foraging behaviour of a nectar feeding marsupial, Petaurus australis.
The foraging behaviour of non-flying nectar feeding mammals has been examined rarely. The exudivorous yellow-bellied glider (Petaurus australis) was observed to feed extensively (70% of the total feeding observation time) on the nectar of all species of Eucalyptus present at a site in southeastern Australia. Gliders harvested nectar, and presumably pollen also, whenever eucalypt flowers were available and selected trees with 2-3 times as many flowers as that on trees randomly selected along a transect. The abundance of flowering trees varied temporally and, at times when few flowering trees were present, gliders chose trees with fewer flowers than at times when flowering trees were abundant. When flowering trees were superabundant or scarce, there was no relationship between the number of flowers in a tree and the duration of visits by gliders. However, at intermediate levels of abundance, the amount of time a glider spent in a tree was related to the number of flowers in a tree. Gliders devoted 90% of the time outside their dens to foraging and the above relationship is suggested to reflect two foraging options which maximize net energy gain for different abundances of flowering trees. Although gliders spent considerable lengths of time in individual trees feeding, initial deposition of cross pollen when gliders first arrive in a tree may be substantial and thus, may provide significant amounts of outcrossing for these eucalypts.


The bidirectional longitudinal association between health-related quality of life and academic performance in adolescents: DADOS study.
Although previous evidence has suggested a relationship between health-related quality of life (HRQoL) and academic performance, the directionality of this association is understudied and remains to be clarified. Thus, the primary objective of this study was to explore the bidirectional association between HRQoL and academic performance in adolescents between two timepoints with a 24-month interval. A secondary aim was to analyze whether this association varies between boys and girls. This is a bidirectional longitudinal analysis with 257 adolescents (13.9 ± 0.3 years at baseline) from the DADOS study. HRQoL was measured using the KIDSCREEN-10 questionnaire. Academic performance was assessed through academic grades and the Spanish version of the Science Research Associates Test of Educational Ability. Cross-lagged analyses revealed that HRQoL at baseline was not associated with academic performance 24 months later, while all the academic grades and the overall score of academic abilities at baseline were positively associated with HRQoL at follow-up in adolescents. Results of the stratified analyses by sex were largely similar. Specifically, in girls, math, language, physical education, and grade point average at baseline were positively associated with HRQoL 24 months later, while in boys, all the academic grades indicators (except physical education), numeric ability, and the overall score of academic abilities at baseline were positively associated with HRQoL at follow-up. These findings suggest that academic performance in early adolescence may predict HRQoL 24 months later. Health and education professionals could benefit from collaborating to achieve both improved academic performance and HRQoL in youth.


Assessment of Groundwater Quality and Human Health Risk (HHR) Evaluation of Nitrate in the Central-Western Guanzhong Basin, China.
To investigate the quality of domestic groundwater and assess its risk to inhabitants of the Guanzhong Basin, China, 191 groundwater samples were collected to analyze major ions, nitrate, pH, total dissolved solids (TDS), total hardness (TH), and electrical conductivity (EC). The physiochemical parameters, hydrochemical facies, and sources of major ions were analyzed using Durov diagrams, bivariate diagrams, and chloro-alkaline indices (CAI-I and CAI-II). The suitability of groundwater for drinking, the nitrate distribution, and human health risk (HHR) for different age groups were evaluated. The results showed that the relative abundance of cations in the groundwater samples was K++Na+ > Ca2+ > Mg2+, while that of anions was HCO3- > SO42- > Cl- > NO3-. Groundwater samples mainly contained HCO3-Na and HCO3-Ca, which were introduced mainly by rock weathering and ion exchange. The groundwater in the Guanzhong Basin contained mainly good and medium water, and the groundwater in the southern part of the Wei River was better than that north of the Wei River. Areas containing high nitrate concentrations were mainly located in the central and western parts of the Guanzhong Basin. The percentages of low risk (<45 mg/L), high risk (45-100 mg/L), and very high risk (>100 mg/L) of nitrate pollution in the study area were 90.58%, 8.9%, and 0.52%, respectively. The HHR assessment results indicated that people in the 6-12 month age group were more likely to suffer from health complications due to a higher nitrate concentration, followed by 6-11 years, 21-65 years, 18-21 years, ≥65 years, 11-16 years, and 16-18 years age groups, which was mainly due to the different exposure parameters. The results of this study will be useful in regional groundwater management and protection.


Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer.
Although mammary gland tumors (MT) are the most-common type of tumor in intact female dogs, there is little information about their incidence in dog population. Data on MT in female dogs was retrieved from the Animal Tumor registry of dogs and cats of Venice and Vicenza provinces during 2005-2013 and was analyzed to visualize crude incidence rates by breed and across age categories. Overall, 2744 mammary tumors were reported accounting for 54% of all tumors in female dogs. The annual incidence rate (IR) was 250 cases per 100,000 dogs. The most frequent malignant tumors were complex carcinomas, consisting of both epithelial and myoepithelial tissues (IR=71.89), and simple carcinomas (IR=62.59). The MT incidence rate increased through the study period; particularly in the last 4 years, and malignant neoplasms occurred more frequently (70%) than the benign counterparts (30%). Seventy-four percent of tumors were diagnosed in intact females, and the mean age at diagnosis was significantly higher for spayed dogs than for intact ones. MT were less frequent in dogs younger than 6 years and increased up to approximately 60% for ages between 8 and 13 years. The purebred dogs had a higher probability to have a malignant neoplasm than mixed-breed dogs, particularly in dogs younger than 7 years, and the Samoyed, Dobermann, Schnauzer and Yorkshire Terrier breeds were more inclined to develop malignant MT. The incidence of MT in dogs is increasing, and IRs are comparable to that in women. The epidemiological similarities between dogs and women support the validity of canine MT as a model for human breast cancer.


Different developmental changes in latency for two functions of a single membrane bound enzyme: glucose-6-phosphatase activities as a function of age.
(1). The capacity for the synthesis of glucose 6-phosphate from PPi and glucose as well as for glucose-6-P hydrolysis, catalyzed by rat liver microsomal glucose-6-phosphatase, increases rapidly from low prenatal levels to a maximum between the second and fifth day, then slowly decreases to reach adult levels. When measured in enzyme preparations optimally activated by hydroxyl ions, the maximum neonatal activities were 4--5-fold higher than in adult animals and several-fold higher than had previously been observed for the unactivated enzyme. (2) The latencies of two catalytic activities associated with the same membrane-bound enzyme show strikingly different age-related changes. The latency of PPi-glucose phosphotransferase activity reaches high levels (60--80% latent) soon after birth and remains high throughout life, while the latency of glucose-6-P phosphohydrolase decreases with age. The phosphohydrolase is 2--3 times more latent in the liver of the neonatal animal than in the adult. (3). The well established neonatal overshoot of liver glucose-6-phosphatase is almost entirely due to changes in the enzyme in the rough microsomal membranes. The enzyme activity in the rough membrane reaches a maximum and then decreases after day 2, while that in the smooth membrane is still slowly increasing. Despite the great differences in absolute specific activities and in the pattern of early enzyme development between the rough and smooth microsomes, enzyme latency in the two subfractions remains parallel, glucose-6-P phosphohydrolase being only slightly more latent, while PPi-glucose phospho-transferase is much more latent in smooth than in rough membranes throughout life. (4). Kidney glucose-6-P phosphohydrolase and PPi-glucose phosphotransferase activities were found to change in a parallel fashion with age, showing a small neonatal peak between days 2 and 7 before rising to adult levels. Kidney phosphotransferase activity, like that of liver, remained highly latent throughout life. In contrast to liver, the glucose-6-P phosphohydrolase of kidney did not show a characteristic decrease in latency with age and in the adult remained appreciably more latent than in liver. (5). An improved method was devised for the separation of smooth microsomes from liver homogenates.


Effectiveness of a low dose testosterone undecanoate to improve sexual function in postmenopausal women.
Adding testosterone to hormonal therapy could improve sexual function and general well-being among women during climacteric. We evaluated the effectiveness of testosterone undecanoate on sexual function in postmenopausal women utilizing the standardized questionnaire FSFI score. Postmenopausal women with sexual complaints and Female Sexual Function Index (FSFI) ≤ 26.5 were enrolled in to this randomized, double-blinded, placebo-controlled trial. Participants were randomly assigned to 8-week treatment with either oral testosterone undecanoate 40 mg or placebo twice weekly with daily oral estrogen. The FSFI scores before and after treatment were compared to assess any improvement of sexual function. Seventy women were recruited of which each group had 35 participants. The baseline characteristics and baseline FSFI scores were comparable between both groups. After 8 weeks of treatment, the FSFI scores significantly improved in both groups when compared to the baseline but the FSFI scores from the testosterone group were significantly higher than in the placebo group post-treatment (28.6 ± 3.6, 25.3 ± 6.7, respectively, p = 0.04). There was no difference in adverse effect between the two groups The twice weekly addition of testosterone undecanoate to daily oral estrogen was associated with a significant improvement in sexual function among postmenopausal women than the use of the estrogen alone. ClinicalTrials.gov Identifier NCT01724658 (February 17, 2012).


Host specificity dynamics: observations on gyrodactylid monogeneans.
The directly transmitted viviparous gyrodactylids have high species richness but low morphological and biological diversity, and many species are recorded from only a single host. They therefore constitute a guild of species ideal for studies of the evolutionary significance of host specificity. The group has the widest host range of any monogenean family, being found on 19 orders of bony fish. However, individual species range from narrowly specific (71% of 402 described species recorded from a single host) to extremely catholic (Gyrodactylus alviga recorded from 16 hosts). Gyrodactylid-host interactions extend from 60 mya (G. lotae, G. lucii) down to 150 years (G. derjavini on Oncorhynchus mykiss). Co-evolution with the host is comparatively rare within the gyrodactylids, but host switching or ecological transfer is common, and has been facilitated by the mixing of fish strains that followed glaciation. In this review, we consider the factors responsible for gyrodactylid specificity patterns, using examples from our work on salmonid gyrodactylids including G. salaris, responsible for major epidemics on wild Atlantic salmon (Salmo salar) in Norway since 1975, and G. thymalli from grayling and G. derjavini from trout.G. salaris has a wide host range with highest population growth rates on Norwegian salmon strains. However, growth rates are variable on both host strains and species, because of the multitude of micro- and macro-environmental factors influencing parasite mortality and fecundity. A better predictor of performance is the proportion of fishes of a strain which are innately resistant to the parasite, a measure which is negatively correlated with the time to peak infection in a host strain. Population growth rate is also negatively correlated with age of infection; the initial rate, therefore, predicts best the suitability of a fish as host for G. salaris. The host response to gyrodactylids appears to be the same mechanism in all salmonids with innate resistance as one end of a spectrum, but influenced by stress and probably under polygenic control. Hybrid experiments show that performance of G. salaris on a host is heritable, and usually intermediate between that of the parents. This host response mechanism, coupled with the initial parasite population growth on a fish, determines the host specificity, i.e. whether the fish will be susceptible, a responder or innately resistant. The use of population growth rate parameters allows comparison of different hosts as a resource for a gyrodactylid. In the case of G. salaris, East Atlantic and Baltic strains of Atlantic salmon are core hosts, but other salmonids can physiologically sustain infections for considerable periods, and may be important in parasite dispersal and transmission. A further group of non-salmonid fishes are unable to sustain G. salaris reproduction, but can act as transport hosts.Population growth parameters are very labile to stressors and environmental factors, particularly temperature and salinity, and also other aspects of host ecology and water quality. These factors may also influence the spectrum of hosts that can be infected under particular conditions, and probably favoured ecological transfer of gyrodactylids between host species in periglacial conditions. G. salaris may still be undergoing post-glacial range expansion (aided by anthropogenic spread) as shown by the increase in the species range over the last 25 years. The origin of G. salaris, G. teuchis and G. thymalli is discussed in relation to glacial refugiums during the last ice age.


Cellular basis of prolactin action: involvement of cyclic nucleotides, polyamines, prostaglandins, steroids, thyroid hormones, Na/K ATPases and calcium: relevance to breast cancer and the menstrual cycle.
The mechanisms of prolactin action are uncertain. Prolactin effects are characterised by great variability in the prolactin concentration required to produce a response and by the frequent occurrence of "bell-shaped" dose response curves. Relationships between prolactin and thyroid hormones and steroids are difficult to understand: both steroids and thyroid hormones may potentiate or inhibit prolactin effects in different situations. At the second messenger level, claims have been made that cyclic nucleotides, polyamines, Na/K ATPases and prostaglandins are involved. There is evidence that prostaglandin E1 may be an important second messenger and it is proposed that this is the clue to understanding the complexity. At low concentrations PGE1 enhances intracellular calcium release and at high concentrations PGE1 inhibits calcium release. The other second messengers proposed are all probably dependent upon calcium. Many prolactin effects may involve both PGE1 and another second messenger: at low prolactin concentrations PGE1 will potentiate the other messenger whereas at high concentrations the PGE1 effect will be inhibitory leading to a bell-shaped response. Thryoid hormones seem to enhance while glucocorticoids inhibit PGE1 synthesis. PGE1 dependent effects will thus be enhanced by thyroid hormone and blocked by cortisol. The reverse will be true of effects dependent on other second messengers.


[Elective cesarean section is preferred after the completion of a minimum of 38 weeks of pregnancy].
To determine the frequency of neonatal respiratory morbidity following elective caesarean delivery at term and to identify prognostic factors for this morbidity. Retrospective. Academic Hospital Utrecht/Wilhelmina Children's Hospital Neonatal Intensive Care Unit, Utrecht, the Netherlands. All elective caesarean deliveries in the Academic Hospital Utrecht from the period 1990-1995 were studied. Also, neonates were included who were admitted for intensive neonatal care because of respiratory insufficiency following elective caesarean delivery in the region surrounding Utrecht. An elective caesarean delivery was defined as a delivery performed after 37 weeks of gestation without any complicating factor that might influence the timing of delivery. Prognostic factors for neonatal morbidity after caesarean delivery were identified by multivariate logistic regression analysis. During 1990-1995, 272 elective caesarean deliveries after 37 weeks of gestation were performed that fulfilled the inclusion criteria; 5.1% of the neonates were admitted to the medium care unit because of respiratory problems. The relative risk of respiratory morbidity after delivery by caesarean section with a gestational age of 39-42 weeks compared with a gestational age of 37-38 weeks, was 0.14 (95% confidence interval: 0.03-0.64; p < 0.001). Male sex was a cofactor. Nine neonates of whom 8 (90%) had a gestational age of less than 39 weeks were admitted to the intensive care unit. Most of neonatal respiratory morbidity could have been avoided by postponement of the at-term elective caesarean section until a certain gestational age of at least 38 complete weeks. An elective caesarean section should not be performed before that period.


Cloning and expression of a puromycin N-acetyl transferase gene from Streptomyces alboniger in Streptomyces lividans and Escherichia coli.
A gene (pac) encoding a puromycin N-acetyl transferase (PAC) of Streptomyces alboniger ATCC12461 was cloned in the Streptomyces plasmid pIJ702 and expressed in S. lividans 1326. Several clones resistant to puromycin were isolated and shown to carry pIJ702 with different inserts of S. alboniger DNA. They were classified as of low and high activity according to the levels of enzymatic activity expressed by them. The different levels of expression were related to the two possible orientations of the S. alboniger DNA inserts in the pIJ702 vector. Six of the recombinant plasmids contain a common 1.6-kb DNA sequence which, by subcloning experiments, was shown to carry a pac gene encoding PAC activity. The pac gene was subcloned next to the lac promoter of Escherichia coli plasmid pUC19. Only one of the two possible orientations of insertion expressed PAC activity, suggesting that it was dependent on the lac promoter. Accordingly, isopropylthio-beta-D-galactoside (IPTG) was able to stimulate the expression of the enzyme activity. These results allowed the direction of transcription of the pac gene to be determined.


Systematic review and meta analysis of randomized controlled trials on Tianmagouteng decoction in treatment of primary hypertension with liver Yang hyperactivity syndrome.
To assess the efficacy of Tianmagouteng decoction in the treatment of primary hypertension with liver yang hyperactivity syndrome. The databases of MEDLINE (1950-2012), EMbase (1980-2012), China biology medicine (CBM) (1994-2012), China national knowledge infrastructure (CNKI) (1989-2012), Weipu (VIP) (1995-2012) and Wanfang (1989-2012) were searched and we performed manual searches for conference proceedings to select randomized controlled trials (RCTs) on Tianmagouteng decoction for the treatment of primary hypertension with liver Yang hyperactivity syndrome. Studies were enrolled according to the study-selecting criteria. The methodological quality was evaluated, data were extracted and meta-analyses were conducted with RevMan 4.2 software. Nine RCTs were selected involving 784 patients with no significant difference in decrease in systolic blood pressure (SBP) [OR = 1.02, 95% CI (-0.24, 2.29), P = 0.10] and diastolic blood pressure (DBP) [OR = 0.56, 95% CI (-0.10,1.23), P = 0.11] between the Tianmagouteng group and the control group. While there was a significantly larger increase in serum superoxide dismutase (SOD) [OR = 6.26, 95% CI (1.27,11.66), P = 0. 01] in the Tianmagouteng group than that in the control group. Tianmagouteng decoction can decrease both systolic and diastolic blood pressure and greatly increase serum SOD. Due to poor quality of included studies, the efficacy needs to be further assessed.


Prophylactic influences of prebiotics on gut microbiome and immune response of heat-stressed broiler chickens.
Climatic changes and elevated ambient temperature are significant environmental stressors with a negative impact on birds' physiological, immunological, and behavioral status, increasing their susceptibility to stressors and immunosuppression and consequently increasing intestinal permeability (leaky gut). Prebiotics have been utilized to stop or diminish the harmful effects of stress in chickens. We aimed to evaluate the role of mannan-oligosaccharides, and beta-D-glucan prebiotics supplements in drinking water against experimentally induced heat stress (HS) on broiler chickens and study their impact on birds' performance, gut microbiome, and immune response. A total of 120 1-day-old Ross broiler chicks were allocated into four groups (30 birds/group), and each group was subdivided into triplicates (10 birds each). The experimental groups were classified as follows; the 1st (G1) control birds, the 2nd (G2) birds exposed experimentally to HS, the 3rd (G3) birds administered prebiotics in drinking water without exposure to HS, and the 4th (G4) birds exposed to HS and administered prebiotics in drinking water. After each vaccination, blood samples and serum samples were collected to evaluate the birds' immune status. Fecal samples were also collected for the molecular evaluation of the gut microbiome based on the genetic analyses and sequencing of 16S rRNA gene. The results showed that HS has reduced the birds' performance and badly affected the birds' immune response and gut microbiome. However, the addition of prebiotics to drinking water, with or without stress, enhanced the growth rate, maintained a normal gut microbiome, and improved immune parameters. Moreover, the usage of prebiotics improved the chicken gut microbiome and alleviated the negative effect of heat stress. Administering prebiotics significantly (p < 0.05) increased the relative abundance of beneficial bacteria and eradicated pathogenic ones in the birds' gut microbiome. Prebiotics showed a positive effect on the gut microbiome and the immune status of chickens under HS in addition to their efficacy as a growth promoter.


Vascular complications (splenic and hepatic artery aneurysms) in the occipital horn syndrome: report of a patient and review of the literature.
We report an 18-year-old boy with occipital horn syndrome who developed aneurysms of the splenic and hepatic arteries. Occipital horn syndrome, also called X-linked cutis laxa or Ehlers-Danlos syndrome (EDS) type IX, is characterised by a skeletal dysplasia which includes occipital horns, broad clavicles, deformed radii, ulnae and humeri, narrow rib cage, undercalcified long bones and coxa valga. Distinctive features common to all patients are unusual facial appearance, hypermobility of finger joints, limitation of extension of elbows, chronic diarrhoea and genitourinary abnormalities. In this case report we describe the difficulties encountered in the diagnostic management of patients with EDS-related vascular lesions.


Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders.
Olanzapine is a widely used atypical antipsychotic, with well known metabolic side effects such as weight gain, insulin resistance and blood glucose abnormalities. It has been previously shown in a phase II clinical trial that BGP-15, an amidoxim derivative has insulin-sensitizing effects. The aim of this study was to investigate the efficacy of BGP-15 for the treatment of olanzapine-induced metabolic side effects, in healthy volunteers. Thirty-seven (37) subjects (ages 18-55 years) with normal glucose metabolism were randomly assigned to 17 days of once-daily treatment with 400mg of BGP-15 or placebo and 5mg of olanzapine for 3 days followed by 10mg for 14 days. Total body and muscle tissue glucose utilization was determined by hyperinsulinemic-euglycemic clamp technique. As expected the 17-day olanzapine treatment provoked insulin resistance and body weight gain (p<0.05) in both groups. Administration of BGP-15 significantly reduced olanzapine-induced insulin resistance. The protective effect of BGP-15 on insulin stimulated glucose utilization had the highest magnitude in the values calculated for the muscle tissue (p=0.002). In healthy individuals BGP-15 was safe and well tolerated during the whole study period. It is suggested that BGP-15 can be a successful insulin sensitizer agent to prevent side effects of olanzapine treatment.


Plant Cytogenetics: From Chromosomes to Cytogenomics.
Chromosomes have been studied since the late nineteenth century in the disciplines of cytology and cytogenetics. Analyzing their numbers, features, and dynamics has been tightly linked to the technical development of preparation methods, microscopes, and chemicals to stain them, with latest continuing developments described in this volume. At the end of the twentieth and beginning of the twenty-first centuries, DNA technology, genome sequencing, and bioinformatics have revolutionized how we see, use, and analyze chromosomes. The advent of in situ hybridization has shaped our understanding of genome organization and behavior by linking molecular sequence information with the physical location along chromosomes and genomes. Microscopy is the best technique to accurately determine chromosome number. Many features of chromosomes in interphase nuclei or pairing and disjunction at meiosis, involving physical movement of chromosomes, can only be studied by microscopy. In situ hybridization is the method of choice to characterize the abundance and chromosomal distribution of repetitive sequences that make up the majority of most plant genomes. These most variable components of a genome are found to be species- and occasionally chromosome-specific and give information about evolution and phylogeny. Multicolor fluorescence hybridization and large pools of BAC or synthetic probes can paint chromosomes and we can follow them through evolution involving hybridization, polyploidization, and rearrangements, important at a time when structural variations in the genome are being increasingly recognized. This volume discusses many of the most recent developments in the field of plant cytogenetics and gives carefully compiled protocols and useful resources.


Neurodevelopmental outcome among multiples and singletons: a regional neonatal intensive care unit's experience in Turkey.
The aim of this study was to compare the neurodevelopmental outcome at 12-18 months' corrected age between multiples and singleton preterm infants. We designed a prospective study of preterm infants (≤32 weeks gestation) born and hospitalized in the neonatal intensive care unit between November 2008 and November 2009, whose assessments were performed at 12-18 months' corrected age. Neurodevelopmental impairment was defined as the presence of any one of the following: moderate or severe cerebral palsy, severe bilateral hearing loss or bilateral blindness, mental developmental index score, or psychomotor developmental index score less than 70. Results were compared for both multiples and singleton infants. One hundred and fifty-nine multiples and 211 singleton infants were assessed at 12-18 months' corrected age. The neurodevelopmental outcome including all parameters at 12-18 months' corrected age in multiples was not significantly different from singleton preterm infants. Multiple gestation in preterm infants is not associated with an increased risk of neurodevelopmental impairment at 12-18 months' corrected age compared with singleton preterm infants. For further information, long term and high participation in neurodevelopmental follow-up and evaluation at pre-school age will be needed.


Gene therapy of chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder which results from absence or malfunction of the respiratory burst oxidase normally expressed in neutrophils and other phagocytic leukocytes. Two-thirds of the patients are males hemizygous for mutations in the X-linked gene coding for gp91-phox. As a therapeutic approach towards the X-linked form of CGD bicistronic retroviral vectors containing the gp91-phox gene and a selectable marker gene were constructed. The ability of these vectors to restore NADPH oxidase activity was tested in a human myeloid leukemic cell line that is defective in superoxide production, as well as in primary CD34+ cells obtained from X-CGD patients. Under optimal conditions 80% of the CD34+ cells derived from bone marrow of one X-CGD patient were transduced. The level of superoxide production, in phagocytes derived from transduced cells was 68.9% of normal levels. Considering that low levels of superoxide generating activity are sufficient for normal host defense, the present experiments provide the basis for the development of a gene replacement therapy for the X-linked form of CGD.


Hydrogen peroxide-induced translocation of glycolipid-anchored (c)AMP-hydrolases to lipid droplets mediates inhibition of lipolysis in rat adipocytes.
The insulin-independent inhibition of lipolysis by palmitate, the anti-diabetic sulphonylurea glimepiride and H2O2 in rat adipocytes involves stimulation of the glycosylphosphatidylinositol (GPI)-specific phospholipase-C (GPI-PLC) and subsequent translocation of the GPI-anchored membrane ectoproteins (GPI-proteins), Gce1 and cluster of differentiation antigen (CD73), from specialized plasma membrane microdomains (DIGs) to cytosolic lipid droplets (LDs). This results in cAMP degradation at the LD surface and failure to activate hormone-sensitive lipase. Reactive oxygen species (ROS) may trigger this sequence of events in response to palmitate and glimepiride. The effects of various inhibitors of ROS production on the release of H2O2, GPI anchor cleavage and translocation of the photoaffinity-labelled or metabolically labelled Gce1 and CD73 from DIGs to LD and inhibition of lipolysis by different fatty acids and sulphonylureas were studied with primary rat adipocytes. Glimepiride and palmitate induced the production of H2O2 via the plasma membrane NADPH oxidase and mitochondrial complexes I and III, respectively. Inhibition of ROS production was accompanied by the loss of (i) GPI-PLC activation, (ii) Gce1 and CD73 translocation and (iii) lipolysis inhibition in response to palmitate and glimepiride. Non-metabolizable fatty acids and the sulphonylurea drug tolbutamide were inactive. NADPH oxidase and GPI-PLC activities colocalized at DIGs were stimulated by glimepiride but not tolbutamide. The data suggest that ROS mediate GPI-PLC activation at DIGs and subsequent GPI-protein translocation from DIGs to LD in adipocytes which leads to inhibition of lipolysis by palmitate and glimepiride. This insulin-independent anti-lipolytic mechanism may be engaged by future anti-diabetic drugs.


Synergistic activation of peroxydisulfate with magnetite and copper ion at neutral condition.
Magnetite is known to exhibit high catalytic reactivity in Fenton-like reactions merely at low pH conditions. Here we report the association of Cu2+ ion can significantly enhance peroxydisulfate (PDS) activation with magnetite under environmental aquatic conditions (near neutral pH). Cu2+ is able to synergistically activate PDS with magnetite to generate radicals, e.g., SO4·-, at neutral or slightly alkaline pH, and such synergistic activation of PDS is promising to degrade various contaminants in groundwater. In-depth study reveals Cu2+ ion adsorbed on magnetite plays a crucial role in PDS activation. The adsorbed Cu2+ is labile to be reduced by the structural Fe(II) on magnetite to generate Cu+, which is relatively stable in the presence of magnetite at neutral or alkaline pH, but extremely unstable at acidic pH. The generated Cu+ on magnetite surface, rather than Cu2+, contributes to PDS activation in the reaction system, and the recycling of Cu+/Cu2+ sustains continuous activation of PDS. This study is among the first to report the synergistic activation of PDS by magnetite and Cu2+ ion at neutral pH, and unambiguously discern the role of Cu+ in PDS activation. The new mechanistic knowledge provides a more accurate understanding of PDS activation by natural minerals in environmental remediation.


Contralateral effects and binaural interactions in dorsal cochlear nucleus.
The dorsal cochlear nucleus (DCN) receives afferent input from the auditory nerve and is thus usually thought of as a monaural nucleus, but it also receives inputs from the contralateral cochlear nucleus as well as descending projections from binaural nuclei. Evidence suggests that some of these commissural and efferent projections are excitatory, whereas others are inhibitory. The goals of this study were to investigate the nature and effects of these inputs in the DCN by measuring DCN principal cell (type IV unit) responses to a variety of contralateral monaural and binaural stimuli. As expected, the results of contralateral stimulation demonstrate a mixture of excitatory and inhibitory influences, although inhibitory effects predominate. Most type IV units are weakly, if at all, inhibited by tones but are strongly inhibited by broadband noise (BBN). The inhibition evoked by BBN is also low threshold and short latency. This inhibition is abolished and excitation is revealed when strychnine, a glycine-receptor antagonist, is applied to the DCN; application of bicuculline, a GABAA-receptor antagonist, has similar effects but does not block the onset of inhibition. Manipulations of discrete fiber bundles suggest that the inhibitory, but not excitatory, inputs to DCN principal cells enter the DCN via its output pathway, and that the short latency inhibition is carried by commissural axons. Consistent with their respective monaural effects, responses to binaural tones as a function of interaural level difference are essentially the same as responses to ipsilateral tones, whereas binaural BBN responses decrease with increasing contralateral level. In comparison to monaural responses, binaural responses to virtual space stimuli show enhanced sensitivity to the elevation of a sound source in ipsilateral space but reduced sensitivity in contralateral space. These results show that the contralateral inputs to the DCN are functionally relevant in natural listening conditions, and that one role of these inputs is to enhance DCN processing of spectral sound localization cues produced by the pinna.


A Selective Activity-Based Approach for Analysis of Enzymes with an OmpG Nanopore.
Many enzymatic activity assays are based on either (1) identifying and quantifying the enzyme with methods such as western blot or enzyme-linked substrate assay (ELISA) or (2) quantifying the enzymatic reaction by monitoring the changing levels of either product or substrate. We have generated an outer membrane protein G (OmpG)-based nanopore approach to distinguish enzyme identity as well as analyze the enzyme's catalytic activity. Here, we engineered an OmpG nanopore with a peptide cut site inserted into one of its loops to detect proteolytic behavior. In addition, we generated an OmpG nanopore with a single-stranded DNA attached to a loop for analyzing nucleolytic cleavage. This OmpG nanopore approach may be highly useful in analyzing specific enzymes in complex biological samples, or in directly determining kinetics of enzyme-substrate complex association and dissociation.


Midface skeletal enhancement.
Alloplastic malar augmentation offers a reliable means of achieving a permanent, yet reversible, form of midfacial volume enhancement that serves to correct the changes associated with facial aging, hypoplasia, and congenital malar asymmetry. The degree of augmentation depends on the severity of existing malar bony hypoplasia, soft tissue volume loss/ptosis, or both. Facial aesthetic surgeons have a multitude of implant designs and shapes and implant materials available. The transoral surgical approach with transcutaneous implant suture stabilization is the most commonly used surgical protocol in alloplastic midface augmentation and is, therefore, the technique specifically chosen for review in this article.


Outcome of pregnancies with spontaneous PPROM before 24+0 weeks' gestation.
To examine the contemporary outcome in women with rupture of membranes (PPROM) before 24+0 weeks' gestation. Retrospective analysis of women with spontaneous PPROM before 24+0 weeks that were treated at the University of Tuebingen/Germany. The search of the database included common maternal and pregnancy characteristics as well as the neonatal outcomes. One hundred and one pregnancies fulfilled the inclusion criteria. 32 (31.7%) women opted for termination of pregnancy, which were excluded from further analysis. The gestational age at PPROM in the 69 women with an expectant management was 21.3 (IQR 19.1-22.6) weeks. 40 (58.0%) pregnancies carried on beyond 24+0 weeks. Multiple regression analysis indicated that the time of PPROM and the absence of oligo-/anhydramnios were associated with a prolongation beyond 24+0 weeks. In the 40 pregnancies that remained intact beyond 24+0 weeks' gestation, the fetuses were born at 27.7 (IQR 25.3-30.9) weeks. Survival without major complications was observed in 22 (55.0%) fetuses. Multiple regression analysis indicated that only the gestational age at the time of delivery was significantly associated with such an intact survival. In cases with PPROM there is a 60% chance of a prolongation beyond 24+0 weeks. About half of these fetuses will be discharged alive without major complications.


Fever induced in rabbits by intravenous injection of bovine serum albumin.
1. Bovine serum albumin injected into conscious rabbits produced a dose-dependent fever of short latency and duration of at least 2 1/2 hr. 2. The fever was not due to contamination by other proteins nor due to contamination by bacterial endotoxin. 3. The fever following albumin injection had characteristics similar to endogenous pyrogen fever. 4. Some traditional ways of distinguishing bacterial endotoxin fever from other types of fever need to be reassessed.


Toxicological effects of paracetamol on the clam Ruditapes philippinarum: exposure vs recovery.
Exposure of wild organisms to anthropogenic substances never follows a definite time-course and pulsed events can often determine biological responses to such chemicals, confounding the interpretation of toxicological data. This is the case of specific chemicals such as pharmaceutical drugs, which are commonly released by sewage systems into sensitive areas, including estuaries. The presence and amount of these chemicals in the wild can be modulated by events such as dilution due to heavy rain, floods, or by varying patterns of domestic water use (daily vs. seasonal). The present study aimed to obtain additional data about the toxicity of paracetamol towards the marine clam species Ruditapes philippinarum, following realistic modes of exposure. Thus, the toxicity assessment was made after an acute exposure to different concentrations of paracetamol, followed by a recovery period. The adopted toxicological endpoints included energy-related parameters (glycogen content, GLY; protein content, PROT; electron transport system activity, ETS), activity of antioxidant and biotransformation enzymes (superoxide dismutase, SOD; glutathione peroxidase, GPx; Glutathione-S-transferases, GSTs), levels of reduced glutathione (GSH), neurotoxicity (cholinesterases activity, ChEs), and indicators of oxidative damage (lipid peroxidation, LPO). The here obtained results showed an increase in SOD and GPx activities after exposure. In organisms exposed to the highest concentration tested it was also possible to observe a significant increase in GSTs activity. However, these alterations in the antioxidant defence system were not able to prevent the occurrence of oxidative stress in exposed organisms. Furthermore, exposure to paracetamol induced neurotoxicity in clams, with a concentration-dependent ChEs inhibition along the exposure concentrations. Exposure to paracetamol also led to an increase of GLY content which resulted from metabolic activity depression along the increasing exposure gradient. In recovering organisms the activities of SOD, GPx and GSTs decreased back towards control values presenting lower values than the ones observed in organisms after acute exposure to paracetamol. No LPO was registered in organisms after the recovery period. In addition, after recovery, clams showed no signs of neurotoxicity, with ChEs activities in previously exposed organisms similar to control clams. After recovery clams seemed to re-establish their metabolic capacity, especially evidenced in clams previously exposed to the highest paracetamol concentration as demonstrated by the increase of ETS activity up to control values. Furthermore, the decrease of GLY content after recovery may indicate that clams increased their metabolic activity and started to use their energetic reserves to re-establish their oxidative status. This set of data shows that an acute exposure to paracetamol can exert deleterious effects that may compromise specific biochemical pathways in sensitive aquatic species, such as R. philippinarum, but organisms can re-establish their biochemical status to control levels after a recovery period.


Alcohol consumption induces hepatocyte apoptosis in patients with chronic hepatitis C infection.
Epidemiological studies have established that heavy alcohol consumption in persons with chronic hepatitis C infection is associated with advanced liver disease, including cirrhosis. The cellular mechanisms underlying this process, which appear to occur over decades, are unknown. Increased hepatocyte apoptosis has been observed in association with hepatitis C infection. The aim of this study was to evaluate the relationship between alcohol consumption and hepatocyte apoptosis in hepatitis C-infected patients. Liver tissue from 20 hepatitis C-infected patients with variable alcohol consumption, and 10 normal control subjects was examined for hepatocyte apoptosis, proliferation and bcl-2 expression. Hepatocyte apoptosis was significantly greater in hepatitis C-infected patients than in controls. In hepatitis C-infected patients, significantly more hepatocyte apoptosis was seen in those consuming at least 30 g per day of alcohol compared with those drinking less than 10 g daily. Bcl-2, an inhibitor of apoptosis, was not detected in liver tissue from patients with the highest ethanol intake and rate of hepatocyte apoptosis. In contrast, patients drinking lesser amounts of ethanol had lower rates of hepatocyte apoptosis and more frequent bcl-2 expression. This study confirms that both hepatitis C infection and ethanol consumption induce hepatocyte apoptosis in humans. Ethanol-induced hepatocyte apoptosis has previously been shown only in animal models of alcohol-related liver injury. The precise role of apoptosis in the pathogenesis of hepatitis C-related liver injury remains unclear, but its induction may be related to downregulation of bcl-2 expression associated with ethanol consumption.


Impact of prodromal angina pectoris and white blood cell count on outcome of patients with acute myocardial infarction.
Elevation of white blood cell (WBC) count at admission is associated with adverse outcome after acute myocardial infarction (AMI). Prodromal angina, by the mechanism of ischemic preconditioning, improves left ventricular (LV) function and survival after reperfusion therapy in patients with AMI. Recent experimental studies have reported that preconditioning has anti-inflammatory effect. This study consisted of 598 patients with first anterior wall AMI who underwent coronary angiography within 12 h after symptom onset. WBC count was measured at the time of hospital admission. Prodromal angina was defined as angina occurring within 24 h before the onset of AMI. Serial measurements of LV ejection fraction (EF) were obtained before reperfusion therapy and before discharge in 421 patients (71%). High WBC count (>10.2 x 103/mm3, n=297) was associated with higher 30-day mortality (8% vs. 4%, p=0.02) and lower predischarge LVEF (51+/-15% vs. 57+/-14%, p<0.001), although there was no significant difference in acute LVEF (47+/-10% vs. 49+/-11%, p=0.07). High WBC count was an independent predictor of 30-day mortality (p=0.009) and predischarge LVEF (p=0.002). Prodromal angina was associated with lower 30-day mortality (3% vs. 7%, p=0.02) and preserved predischarge LVEF (57+/-15% vs. 53+/-14%, p=0.006). Patients with prodromal angina had lower WBC count (10.0+/-3.3 x 10(3)/mm3 vs. 11.0+/-3.9 x 10(3)/mm3, p=0.001) and prodromal angina was an independent predictor of WBC count (p<0.001). Elevation of WBC count and lack of prodromal angina were associated with impaired LV function and mortality after reperfusion in patients with AMI. Prodromal angina might have contributed to favorable outcome after AMI through its anti-inflammatory effect.


Effectiveness of virtual reality in reducing preoperative anxiety in adults: A systematic review and meta-analysis.
To evaluate the impact of a virtual reality (VR) intervention on adult patients' preoperative anxiety, heart rate, respiration rate and blood pressure. A systematic review and meta-analysis of randomized controlled trials (RCTs). A librarian-designed search of the Cochrane Library, PubMed, Web of Science, EMBASE, CINAHL, CBM, CNKI and Wanfang databases was conducted to identify research studies in English or Chinese on RCTs from their inception to 31 May 2022. Detailed search strategies and the checklist are provieded in Supplementary files S1 and S2. Two researchers independently screened eligible studies. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias in the included studies. A fixed- or random-effects meta-analysis model was used to determine the pooled mean difference based on the results of the heterogeneity test. This study included 11 articles with a total of 892 participants. VR distraction comprised five studies, and VR exposure consisted of six studies. The results indicated that VR could reduce preoperative anxiety in adult patients and VR exposure seems to be more effective. The results also indicated that VR intervention can effectively reduce patients' heart rate and blood pressure compared to traditional intervention methods, but had no significant effect on respiration rate. VR technology could relieve preoperative anxiety in adult patients through distraction or exposure. More well-designed RCTs containing a wider range of surgical types are needed to verify our findings before we can make strong recommendations. Our systematic review and meta-analysis show a positive effect of VR distraction and exposure interventions in reducing preoperative anxiety in adult patients. We suggest incorporating VR into preoperative procedures as an auxiliary way to reduce negative emotions in eligible patients. Our paper is a systematic review and meta-analysis and such details do not apply to our work.


Tauopathies: new perspectives and challenges.
Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics. Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.


Combined carotid endarterectomy and coronary artery bypass: immediate and long-term results.
Data from 213 cases of simultaneous carotid endarterectomy and coronary artery bypass grafting (CEN/CABG) were analyzed (1980-1996). There were 154 males (72.3%), and 59 females (27.7%), (mean age: 65. 6 years, range: 42-83). One hundred and thirty-two patients (62.0%) had angina, 58 (37.2%) had myocardial infarction, and 23 (10.8%) had congestive heart failure. Symptomatic cerebrovascular disease was present in 89 patients (41.7%). One hundred and twenty-two patients (57.2%) had three-vessel coronary artery disease, 41 (19.2%) had left main disease, and 27 (12.6%) had a low ejection fraction (ejection fraction </=30%). Significant (>/=75% diameter reduction) stenosis was present in 168 (78.8%) of the operated carotid arteries. The contralateral internal carotid artery was severely stenosed or occluded in 35 patients (16.4%). The hospital mortality rate was 5. 6% (12 patients). The cause of death was cardiac in ten patients (4. 6%), and neurologic in two (1%). Eleven patients (5.1%) developed a stroke postoperatively; eight strokes were ipsilateral to the operated artery, and six were permanent. Myocardial infarction occurred in five patients (2.3%). Independent predictors of early mortality were age >62 years, hypertension, and postoperative stroke (p < 0.05). Male sex was the only independent predictor of neurologic morbidity (p < 0.05). Late follow-up data were obtained for 163 (81.0%) patients (mean: 54.8 months, range: 1-168). Four (9. 3%) out of the 43 late deaths were attributed to strokes. There were three (1.8%) late ipsilateral strokes, and five (3.1%) contralateral strokes. The 5- and 10-year survival probabilities were 75 +/- 4%, and 52 +/- 6.9%. The freedom from late ipsilateral neurologic morbidity at 5 and 10 years were 97 +/- 1.7% and 90 +/- 4.0%, respectively. Taken together, the results indicate that combined carotid endarterectomy and coronary artery bypass grafting can be performed safely in this high-risk group of patients. Excellent long-term freedom from stroke can be expected.