Allosteric conformational change of a cyclic nucleotide-gated ion channel revealed by DEER spectroscopy.
Cyclic nucleotide-gated (CNG) ion channels are essential components of mammalian visual and olfactory signal transduction. CNG channels open upon direct binding of cyclic nucleotides (cAMP and/or cGMP), but the allosteric mechanism by which this occurs is incompletely understood. Here, we employed double electron-electron resonance (DEER) spectroscopy to measure intersubunit distance distributions in SthK, a bacterial CNG channel from Spirochaeta thermophila Spin labels were introduced into the SthK C-linker, a domain that is essential for coupling cyclic nucleotide binding to channel opening. DEER revealed an agonist-dependent conformational change in which residues of the B'-helix displayed outward movement with respect to the symmetry axis of the channel in the presence of the full agonist cAMP, but not with the partial agonist cGMP. This conformational rearrangement was observed both in detergent-solubilized SthK and in channels reconstituted into lipid nanodiscs. In addition to outward movement of the B'-helix, DEER-constrained Rosetta structural models suggest that channel activation involves upward translation of the cytoplasmic domain and formation of state-dependent interactions between the C-linker and the transmembrane domain. Our results demonstrate a previously unrecognized structural transition in a CNG channel and suggest key interactions that may be responsible for allosteric gating in these channels.


The association between C509T, T869C, G915C gene polymorphisms of transforming growth factor-β1 and systemic lupus erythematosus risk: A meta-analysis.
The relationship between transforming growth factor-β1 (TGF- β1) gene polymorphisms and systemic lupus erythematosus (SLE) has been reported in many studies, but there were still controversies with regard to their conclusions. Relevant documents were retrieved from 5 electronic databases such as PubMed, Embase, Cochrane Library, Wanfang, and China national knowledge infrastructure. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to assess the relationship between TGF-β1 genetic variation and SLE. The present meta-analysis included 12 case-control studies with 1308 SLE patients and 1714 healthy controls. The results of the combined analyses showed that TGF-β1 C509T polymorphism showed no association with SLE risk (TC vs CC: OR = 1.16, 95% CI = 0.91-1.48, PHeterogeneity (PH) = 0.579; TT vs CC: OR = 1.15, 95% CI = 0.63-2.09, PH = 0.003; T vs C: OR = 1.08, 95% CI = 0.8-1.45, PH = 0.003; TC/TT vs CC: OR = 1.17, 95% CI = 0.93-1.46, PH = 0.133; and TT vs TC/CC: OR = 1.06, 95% CI = 0.64-1.76, PH = 0.004). TGF-β1 G915C and T869C polymorphisms were not linked with SLE risk. Moreover, subgroup analysis stratified by ethnicity and Hardy-Weinberg equilibrium revealed no significant correlation of TGF-β1 T869C, C509T, G915C polymorphisms with SLE risk. TGF-β1 T869C, C509T, G915C polymorphisms might not be associated with the development of SLE.


Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: A meta-analysis.
Retrospective studies have suggested that capecitabine combined with temozolomide (CAPTEM) is effective for treating patients with advanced neuroendocrine neoplasms (NENs); however, the efficacy and safety of this regimen needs to be verified by high-quality evidence or results of randomized controlled trials.We carried out a meta-analysis to evaluate the safety and effectiveness of a CAPTEM protocol for patients with advanced NENs. Systematic electronic literature searches were conducted using PubMed, EMBASE, and the Cochrane Library, and among meeting abstracts of the American Society of Clinical Oncology, European Society for Medical Oncology, European Neuroendocrine Tumor Society, and North American Neuroendocrine Tumor Society, up to June 30, 2017. We selected studies describing CAPTEM regimens for treating advanced NENs and reported on tumor response and/or toxicities according to clear World Health Organization (WHO) grading of patients. Three reviewers independently and repeatedly identified studies, extracted data, and assessed the quality of the literature. A single-proportion meta-analysis was applied to included articles.Fifteen studies with a total of 384 individuals were included. Medium overall survival in most studies was more than 12 months, whereas medium progression-free survival was similar or slightly higher than that in studies using other treatment regimes. Disease control rate of CAPTEM administration for patients with NENs was 72.89% (95% confidence interval, 64.04-81.73%; I = 82.4%; P < .01). WHO grade 3 to 4 toxicities, such as thrombocytopenia (3.36%), neutropenia (0.69%), lymphopenia (0.65%), anemia (0.59%), mucositis (0.57%), fatigue (0.54%), diarrhea (0.49%), nausea (0.39%), and transaminase elevation (0.13%) were reported in the trials included.CAPTEM is effective and relatively safe for treating patients with advanced NENs.


Influence of the Phenological State of in the Antioxidant Potential and Chemical Composition of Ageratina havanensis. Effects on the P-Glycoprotein Function.
Ageratina havanensis (Kunth) R. M. King & H. Robinson is a species of flowering shrub in the family Asteraceae, native to the Caribbean and Texas. The aim of this work was to compare the quantitative chemical composition of extracts obtained from Ageratina havanensis in its flowering and vegetative stages with the antioxidant potential and to determine the effects on P-glycoprotein (P-gp) function. The quantitative chemical composition of the extracts was determined quantifying their major flavonoids by UPLC-ESI-MS/MS and by PCA analysis. The effects of the extracts on P-gp activity was evaluated by Rhodamine 123 assay; antioxidant properties were determined by DPPH, FRAP and inhibition of lipid peroxidation methods. The obtained results show that major flavonoids were present in higher concentrations in vegetative stage than flowering stage. In particular, the extracts obtained in the flowering season showed a significantly higher ability to sequester free radicals compared to those of the vegetative season, meanwhile, the extracts obtained during the vegetative stage showed a significant inhibitory effect against brain lipid peroxidation and a strong reductive capacity. This study also showed the inhibitory effects of all ethanolic extracts on P-gp function in 4T1 cell line; these effects were unrelated to the phenological stage. This work shows, therefore, the first evidence on: the inhibition of P-gp function, the antioxidant effects and the content of major flavonoids of Ageratina havanensis. According to the obtained results, the species Ageratina havanensis (Kunth) R. M. King & H. Robinson could be a source of new potential inhibitors of drug efflux mediated by P-gp. A special focus on all these aspects must be taking into account for future studies.


Extracorporeal Sorbent Technologies: Basic Concepts and Clinical Application.
Limitations imposed by the characteristics of some solutes and the structure of dialysis membranes have spurred new interest in the use of mechanisms beyond diffusion and convection for extracorporeal solute removal. Sorbents have been utilized for more than 50 years in extracorporeal blood treatments for specific purposes, and better understanding of their basic aspects may further expand the potential for their clinical application. In this chapter, the basic principles applying to sorbents are discussed, including composition and structure, along with the fundamental mechanisms of solute removal. The critical importance of sorbent biocompatibility is also highlighted. With these basic principles in mind, the clinical application of sorbents is discussed, with an emphasis on the use of hemoperfusion and coupled plasma filtration-adsorption for sepsis-related disorders. Finally, new sorbent-based clinical approaches for acute conditions and end-stage renal disease are presented, emphasizing that sorbent technologies may assume a larger role for a variety of clinical disorders in the future.


Septic discitis and septic pulmonary emboli: rare complications of Proteus mirabilis urinary tract infection.
Proteus mirabilis is a gram-negative bacterium frequently considered a pathogen of the urinary tract. Septic discitis and septic pulmonary emboli resulting from P. mirabilis urosepsis is a rare phenomenon. We report a 39-year-old woman who was admitted to our hospital with a complicated urinary tract infection resulting in bacteraemia, septic discitis, paraspinal abscesses and septic emboli. She was treated with a prolonged course of intravenous antibiotics resulting in the clinical resolution of her symptoms. Based on our PubMed search of the English literature, this is only the second reported case of septic discitis caused by P. mirabilis This paper illustrates that physicians should include septic discitis caused by P. mirabilis as a possible aetiology of low back pain in patients with active or recently treated urinary tract infection. Additionally, this article discusses the pathogenesis and other complications resulting from P. mirabilis bacteraemia.


Postpartum complicated by transverse myelitis.
Transverse myelitis is a very rare neurological condition associated with immunologic and infectious conditions causing interruption of the neuroanatomical pathways in a transverse plane in the spinal cord. Herein is described the fatal case of a patient that developed transverse myelitis after a Caesarean delivery, probably related to the epidural analgesia.


Genetic defects in the control of growth hormone secretion.
Since growth hormone deficiency (GHD) causes short stature and metabolic derangements, the processes which control its release are important physiologically. These processes can be illuminated by an understanding of genetically determined GHD. In 2 Indian Moslem cousins from a consanguineous family, GHD resistant to growth hormone releasing hormone (GHRH) stimulation was found. No mutations were found in the growth hormone gene (GH1) (J. Phillips). The receptor for GHRH (GHRHR), implicated in the dwarfism of the little mouse, thus becomes a candidate gene to explain their GHD. Amplification and sequencing a region of GHRHR homologous to that mutated in the little mouse showed a mutation (265G*T) leading to a stop codon at position 72 which would completely prevent GHRHR expression. Subsequently, Maheshwari et al. found an identical mutation in a multiplex kindred from Sindh, Pakistan, about 800 km from the place of origin of our patients. GHD is more commonly caused by recessive or dominant mutations of GH1. The latter are of great interest in understanding the mechanism of GH secretion. In a large kindred with dominant GHD we found a heterozygous 666G*A mutation replacing of Arg with His at amino acid 183. We speculate that the introduced histidine interferes with interactions necessary for correct GH secretion.


Sex differences in neurochemical effects of dopaminergic drugs in rat striatum.
Previous data indicate that dopamine neurotransmission is differently regulated in male and female rats. The purpose of the present study was to investigate the dopamine transporter and autoreceptor as potential loci responsible for this sex difference. Fast cyclic voltammetry at carbon-fiber microelectrodes was used to monitor changes in electrically evoked levels of extracellular dopamine in the striata of anesthetized male and female rats before and after administration of an uptake inhibitor, a dopamine D2 antagonist, or a D3/D2 agonist. Administration of 40 mg/kg cocaine ip increased electrically-evoked extracellular dopamine concentrations in both sexes, but to a significantly greater extent in female striatum at the higher stimulation frequencies. The typical antipsychotic, haloperidol, increased dopamine efflux in both sexes but the effect was twice as large in the female striatum. The D3/D2 agonist quinpirole induced an unexpected, transient increase in dopamine efflux following high-frequency stimulation only in females, and evoked dopamine was higher in females across this entire time course. More detailed analysis of cocaine effects revealed no fundamental sex differences in the interaction of cocaine with DAT in vivo or in synaptosomes. These results indicate that nigrostriatal dopamine neurotransmission in the female rat is more tightly regulated by autoreceptor and transporter mechanisms, perhaps related by greater autoreceptor control of DAT activity. Thus, baseline sex differences in striatal dopamine regulation induce different pharmacologic responses. These results contribute to understanding sex differences in stimulant-induced locomotor activity in rats and may have broader implications for neurologic disorders and their pharmacotherapies in humans.


Neisseria prophage repressor implicated in gonococcal pathogenesis.
Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea, can infect and colonize multiple mucosal sites in both men and women. The ability to cope with different environmental conditions requires tight regulation of gene expression. In this study, we identified and characterized a gonococcal transcriptional regulatory protein (Neisseria phage repressor [Npr]) that was previously annotated as a putative gonococcal phage repressor protein. Npr was found to repress transcription of NGNG_00460 to NGNG_00463 (NGNG_00460-00463), an operon present within the phage locus NgoΦ4. Npr binding sites within the NGNG_00460-00463 promoter region were found to overlap the -10 and -35 promoter motifs. A gonococcal npr mutant demonstrated increased adherence to and invasion of human endocervical epithelial cells compared to a wild-type gonococcal strain. Likewise, the gonococcal npr mutant exhibited enhanced colonization in a gonococcal mouse model of mucosal infection. Analysis of the gonococcal npr mutant using RNA sequence (RNA-seq) analysis demonstrated that the Npr regulon is limited to the operon present within the phage locus. Collectively, our studies have defined a new gonococcal phage repressor protein that controls the transcription of genes implicated in gonococcal pathogenesis.


Immune responses against sexual stages of Plasmodium vivax during human malarial infections in Sri Lanka.
During natural infections of P. vivax malaria a variety of immune responses to the infection affect infectivity of the parasites to mosquitoes. Sexual stage antigens present in the blood stage parasites induce antibodies which may either enhance or suppress the infectivity of the sexual parasites to mosquitoes. Subsequent infections of P. vivax do not, unless occurring within less than 4 months, boost this response indicating a very short immune memory for the relevant antigens. Blood infection also results in the release of cytokines and other non-antibody factors which together can mediate death of the blood stage sexual parasites. These factors are associated with paroxysm in non-immune individuals. In individuals from an endemic area with age-acquired anti-disease immunity clinical symptoms are mild and the parasite killing factors are not induced.


Pyrosequencing revealed highly microbial phylogenetic diversity in ferromanganese nodules from farmland.
There is renewed interest in the origin and makeup of ferromanganese nodules (FMNs), long known to soil mineralogists as unusual secondary minerals. However, new evidence suggests that microorganisms play a significant role in the generation of FMNs. The biogenic origin of nodules has remained elusive because until recently, little has been known about the overall microbial community structure in their microbiota. To learn more about the microbial community and to determine the relative abundance, diversity, and composition of the microbial communities present in FMNs and their surrounding soil, we used pyrosequencing to investigate 16S rRNA genes obtained from vertical soil profiles of both paddy fields and sugarcane fields. Using pyrotaq 16S rRNA gene sequencing, we show that the microbial phylogenetic diversity of nodules was higher than those reported in previous studies of this biosphere, and we identified many previously unidentified microorganisms. Here, we show that the microbial community of these nodules is dominated by Burkholderiales, Rhodocyclales, Acidobacteriales, Desulfuromonales, and Clostridiales, and there were no statistically significant differences found when comparing the microbial community structures of FMNs obtained from vertical soil sequences. Although the microbial composition was markedly different between the surrounding soil and the FMNs, the microbes found within the FMNs were very similar to other FMNs from both field types examined here. In addition to their geochemical properties and the microbial community composition of FMNs, we found that the levels of iron (Fe), manganese (Mn), and SiO2 greatly impact the microbial diversity among FMN communities. Our results indicate that the FMN microbial communities from different land-use types are very similar and suggest that natural selection of these microbes is based on the oligotrophic conditions and the high metal content. Researching FMNs in these two land-use patterns, which represent two different redox potentials, deepens our understanding of Fe-Mn biogeochemical cycling in these oligotrophic biospheres and suggests a biogenetical origin for these nodules.


RNA-sequencing and bioinformatics analysis of long noncoding RNAs and mRNAs in the asthenozoospermia.
Asthenozoospermia is one of the major causes of human male infertility. Long noncoding RNAs (lncRNAs) play critical roles in the spermatogenesis processes. The present study aims to investigate the intricate regulatory network associated with asthenozoospermia. The lncRNAs expression profile was analyzed in the asthenozoospermia seminal plasma exosomes by RNA-sequencing, and the functions of differentially expressed genes (DEGs) were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and DO (Disease Ontology) enrichment analyses. Pearson's correlation test was utilized to calculate the correlation coefficients between lncRNA and mRNAs. Moreover, the lncRNA-miRNA-mRNA co-expression network was constructed with bioinformatics. From the co-expression analyses, we identified the cis regulated correlation pairs lncRNA-mRNA. To confirm sequencing results with five of the identified DElncRNAs were verified with quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We identified 4228 significantly DEGs, 995 known DElncRNAs, 2338 DEmRNAs and 11,706 novel DElncRNAs between asthenozoospermia and normal group. GO and KEGG analyses showed that the DEGs were mainly associated with metabolism, transcription, ribosome and channel activity. We found 254,981 positive correlations lncRNA-mRNA pairs through correlation analysis. The detailed lncRNA-miRNA-mRNA regulatory network included 11 lncRNAs, 35 miRNAs and 59 mRNAs. From the co-expression analyses, we identified 7 cis-regulated correlation pairs lncRNA-mRNA. Additionally, the qRT-PCR analysis confirmed our sequencing results. Our study constructed the lncRNA-mRNA-miRNA regulation networks in asthenozoospermia. Therefore, the study findings provide a set of pivotal lncRNAs for future investigation into the molecular mechanisms of asthenozoospermia.


Inactivation of NMB0419, Encoding a Sel1-Like Repeat (SLR) Protein, in Neisseria meningitidis Is Associated with Differential Expression of Genes Belonging to the Fur Regulon and Reduced Intraepithelial Replication.
Neisseria meningitidis is a commensal microbe that colonizes the human nasopharynx but occasionally invades the bloodstream to cause life-threatening infection. N. meningitidis MC58 NMB0419 encodes a Sel1-like repeat (SLR)-containing protein, previously implicated in invasion of epithelial cells. A gene-regulatory function was revealed in Escherichia coli expressing plasmid-borne NMB0419 and showing significantly increased epithelial adherence compared to the wild type, due to increased expression of mannose-sensitive type 1 pili. While a meningococcal NMB0419 mutant did not have altered epithelial adherence, in a transcriptome-wide comparison of the wild type and an NMB0419 mutant, a large proportion of genes differentially regulated in the mutant were involved in iron acquisition and metabolism. Fifty-one percent and 38% of genes, respectively, up- and downregulated in the NMB0419 mutant had previously been identified as being induced and repressed by meningococcal Fur. An in vitro growth defect of the NMB0419 mutant under iron restriction was consistent with the downregulation of tbpAB and hmbR, while an intraepithelial replication defect was consistent with the downregulation of tonB, exbB, and exbD, based on a known phenotype of a meningococcal tonB mutant. Disruption of the N-terminal NMB0419 signal peptide, predicted to export the protein beyond the cytoplasmic membrane, resulted in loss of functional traits in N. meningitidis and E. coli Our study indicates that the expression of NMB0419 is associated with transcriptional changes counterbalancing the regulatory function of Fur, offering a new perspective on regulatory mechanisms involved in meningococcal interaction with epithelial cells, and suggests new insights into the roles of SLR-containing genes in other bacteria.


[Female student of a visible minority].
This article is the second on visible minority groups in schools of nursing and the profession. The survey was conducted in three institutions in the Ottawa region. The goal was to discover whether statistics reflect the current college and university nursing population. Of this population, 73.7 per cent participated. Results show clearly that the following questions must be answered by health professionals responsible for community services: Is the goal of equal representation of all ethnic groups at the college and university level realistic? How can educators identify reasons why certain ethnic groups lean toward nursing? Will it be necessary to consider several factors in order to clearly identify the visible minority representation? These questions and others will guide the authors in their subsequent surveys of minority representation in the health care professions.


Antigen-specific human T lymphocyte clones: induction, antigen specificity, and MHC restriction of influenza virus-immune clones.
Human peripheral blood lymphocytes from an HLA-Dw1,3 individual were primed in vitro with influenza A virus (A/Texas/1-77/x-49) and subsequently cloned by limiting dilution in TCGF. Of the 96 TLCs originally obtained, nine were characterized in detail. TLCs were antigen specific, responding to influenza A virus, not to influenza B, TGAL, GAT, tetanus toxoid, or KLH, and only when antigen was presented by cells unable to form rosettes with AET-treated SRBC. Presentation of antigen by unseparated PBL often resulted in significant "back stimulation," probably via production of growth factors. The MHC requirements for the induction of TLC proliferation were analyzed. Of four representative clones analyzed, three required Dw1;DR1 compatibility for successful presentation of viral antigens by a panel of antigen-presenting cells. In contrast, one TLC showed an unusual pattern of response that could not be correlated to a particular HLA haplotype. Monoclonal anti-T cell antibody analysis of the surface phenotype of two TLCs maintained in continuous culture for 5 mo indicated that they were OKT3+, 4+, and 8-, consistent with an inducer/helper phenotype. To confirm the clonal nature of TLCs, data on the functional properties of TLC subclones are also presented.


Pharmacological and molecular biological (RT-PCR) characterization of functional TP prostanoid receptors in immortalized human non-pigmented ciliary epithelial cells.
Immortalized human non-pigmented ciliary epithelial (NPE) cells (ODM-2) were shown to express the mRNA for the prostanoid TPalpha but not the TPbeta receptor using reverse transcription-polymerase chain reaction (RT-PCR). These TPalpha receptors were coupled to phospholipase C (PLC) and, thus, promoted phosphoinositide (PI) turnover. TP receptor agonists yielded the following potencies (EC50S) in the PI turnover assays: I-BOP = 8.2 +/- 1.1 nM; carbocyclic TA2 = 87.5 +/- 25.3 nM; U-44069 = 1.16 +/- 0.32 microM; U-46619 = 1.2 +/- 0.2 microM (n = 4-17). Agonists selective for other prostanoid receptor subtypes (e.g., fluprostenol and sulprostone) were inactive. The agonist effects of U-44619 and I-BOP were potently blocked, in an apparent non-competitive manner (ki = 53.9 +/- 12 nM; pA2s = 7.6-7.8; pKbs = 7.38), by the TP receptor-selective antagonist, SQ29,548, but were unaffected by other prostanoid receptor antagonists (e.g., AH6809, AL-8810). The PLC inhibitor (U73122) inhibited U-46619-induced PI turnover (IC50 = 4.3 +/- 0.6 microM). The functional potencies of the compounds stimulating or inhibiting the TP receptor-mediated PI turnover in the NPE cells correlated well with the TP receptor binding affinities of these compounds at human platelet TP receptors (r = 0.98). These studies have shown the presence of the mRNA for and the expression of functional TPalpha receptors coupled to PLC in human NPE cells. The TPalpha receptors on NPE cells may be responsible for inhibiting aqueous humor production and may help explain the intraocular pressure-lowering effects of certain TP agonists.


Return to treatment after assessment in a community children's mental health clinic.
Most people who receive mental health assessments do not follow up on needed treatment. The authors examined factors that predicted return for at least one treatment visit among 113 children who presented for treatment at a rural community mental health center, using predictors of return for adults from a previous study. Sixty-four percent of the children, compared with 46 percent of the adults, returned at least once. Time until the first appointment predicted whether patients returned for treatment. The age of the child was the only other variable that predicted initial treatment engagement. The results strongly suggest that community mental health agencies can improve treatment acceptance rates by providing rapid response to requests for treatment.


Winning and losing: an evolutionary approach to mood disorders and their therapy.
To advance a new evolutionary model that examines the effects of winning and losing on mood and physiological variables. Previous studies have focused on the involuntary defeat strategy in de-escalating conflict. Here, we propose that there also exists an involuntary winning strategy (IWS) that is triggered by success and characterized by euphoria and increased self-confidence. It motivates efforts to challenge, and promotes reconciliation. Previous studies are presented, including data on student athletes, demonstrating the impact of winning and losing on mood. Winning is consistently shown to be related to physiological changes such as increased testosterone and serotonin levels in primates. It reliably leads to mood changes that serve to motivate winners to continue their competitive efforts. When the IWS functions optimally, success leads to success in an adaptive cycle. Over time, the initial differences between the winners and losers of agonistic encounters become magnified in a process known as difference amplification. As a result of assortative mating, the children of people who have entered into an adaptive cycle will inherit traits from both parents that will, in turn, give them an increased competitive advantage. In this manner, difference amplification could have accelerated human evolution by natural selection. Vignettes of clinical interventions are also used to illustrate therapeutic strategies designed to disrupt maladaptive cycles and promote adaptive behaviour.


Maternal Dietary Patterns during Pregnancy Are Associated with Newborn Body Composition.
Background: Maternal dietary intake during pregnancy may influence offspring growth and adiposity. Specific dietary patterns associated with newborn adiposity have not been identified.Objective: We aimed to identify patterns of maternal dietary intake associated with gestational weight gain (GWG) and fasting glucose during pregnancy and to evaluate whether adherence to these patterns is associated with newborn adiposity.Methods: In the Healthy Start prospective cohort, dietary intake during pregnancy was assessed via 24-h recalls. Reduced-rank regression identified dietary patterns predictive of GWG and fasting glucose. Associations between dietary patterns and newborn fat mass, fat-free mass, and adiposity were estimated by using linear regression models among 764 ethnically diverse mother-infant pairs.Results: Two dietary patterns were identified. Pattern 1, correlated with greater GWG (r = 0.22, P < 0.01), was characterized by a higher consumption of poultry, nuts, cheese, fruits, whole grains, added sugars, and solid fats. Greater adherence to pattern 1 (upper compared with lower tertile) predicted a greater newborn fat-free mass (61 g; 95% CI: 12, 110 g) but no difference in fat mass or adiposity. Pattern 2, correlated with greater maternal fasting glucose (r = 0.16, P < 0.01), was characterized by a higher consumption of eggs, starchy vegetables, solid fats, fruits, and nonwhole grains and a lower consumption of dairy foods, dark-green vegetables, and whole grains. Greater adherence to pattern 2 was associated with a greater newborn birth weight (80 g; 95% CI: 15, 145 g), fat mass (33 g; 95% CI: 8, 59 g), and adiposity (0.9%; 95% CI: 0.3%, 1.6%).Conclusions: Among pregnant women, adherence to a dietary pattern characterized by an intake of poultry, nuts, cheese, and whole grains was associated with greater GWG but not maternal fasting glucose or newborn adiposity. Adherence to a pattern characterized by an intake of eggs, starchy vegetables, and nonwhole grains was associated with higher maternal fasting glucose and greater newborn adiposity. Maternal dietary patterns during pregnancy may influence newborn body composition.


Diagnostic and therapeutic problems of pulmonary tuberculosis in elderly patients.
To identify differences in the clinical, radiologic, and microbiologic features of pulmonary tuberculosis (TB) in the young (<64 yr) and elderly (> or =65 yr), we performed a retrospective analysis of the medical charts and chest radiographs of 207 young and 119 elderly pulmonary TB patients. Hemoptysis and a febrile sense were more frequent in the young, whereas weakness, dyspnea, anorexia, and mental change were more frequent in the elderly. Elderly patients showed higher frequencies of cardiovascular and chronic lung diseases, whereas the young showed a higher proportion of underlying liver disease. In addition, chest radiography showed a significantly higher frequency of mid or lower lung involvement by TB lesions in the elderly (10.6% vs. 22.7%, p<0.05). Lesions were frequently misdiagnosed as pneumonia or lung cancer in the elderly. However, there was no difference between these two groups in terms of sputum acid-fast bacilli positivity. The elderly showed a higher frequency of adverse drug reactions (18.5% vs. 40.7%, p<0.05), and higher TB-related mortality (1.3% vs. 11.1%, p<0.05). In conclusion this study showed that young and elderly pulmonary TB patients have similar microbiologic features; however, the elderly showed higher frequencies of atypical clinical and radiologic presentations, adverse drug reactions, and higher TB-related mortality.


[Effects of mixed carbon sources in cultivation of recombinant Pichia pastoris for polygalacturonate lyase production].
In order to increase the production and productivity of alkaline polygalacturonate lyase (PGL), we studied the mixed carbon sources feeding strategies during the induction phase by recombinant Pichia pastoris GS 115. Glycerol, sorbitol or lactic acid co-feeding with methanol all enhanced the PGL production. Among all the feeding strategies, the sorbitol co-feeding strategy was most significant. By using this strategy, the PGL activity and productivity reached 1593 U/mL and 16.7 U/(mL-h). Compared to the control, the enhancements of PGL activity and productivity were 84.6% and 45.2% respectively, when we set the sorbitol feeding rate at 3.6 g/(h x L).


Scarred for life.
Thousands of girls in the UK are at risk of female genital mutilation. A multi-agency safeguarding group in Bristol, established after a school nurse became concerned that pupils were at risk, is preventing girls from being taken out of the country to have the procedure. It raises awareness among professionals and supports families in the Sudanese and Somalian communities to speak out against the practice.


GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis.
Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.


Antimicrobial Susceptibility of Mycobacterium abscessus Complex Clinical Isolates from a Chinese Tertiary Hospital.
Mycobacterium abscessus complex (MABC) is a group of important infectious agents that are highly associated with drug resistance, and antibiotic treatment is usually ineffective. This study investigated the characteristics of antimicrobial susceptibility of MABC isolates and the synergy between certain β-lactam combinations against MABC infection. We collected 129 MABC isolates from patients with lower respiratory tract infections and categorized them into three subspecies. The minimum inhibitory concentrations (MICs) of 15 antimicrobials for the MABC isolates were determined using commercial Sensititre RAPMYCOI MIC plates and the broth microdilution method, as recommended in the CLSI (M24-A2). In addition, the MICs of imipenem, alone and with ceftazidime and/or avibactam, were assessed in vitro for all isolates. The erm(41) and rrl genes were also sequenced. The MABC isolates exhibited >80% resistance to 11 of the 15 antimicrobials. Regarding the remaining four antimicrobials, the isolates were least resistant to tigecycline (12.4%) and amikacin (3.9%), and only partially resistant to two cefoxitin (39.5%) and imipenem (40.3%). Compared with M. massiliense isolates, M. abscessus and M. bolletii isolates were more resistant to amikacin and imipenem, whereas M. abscessus was significantly less resistant to tigecycline relative to M. massiliense and M. bolletii isolates. The clarithromycin inducible resistance rate was 68.4% and 74.3% among M. bolletii and M. abscessus isolates. Furthermore, 88.7% of the M. abscessus isolates carried a T at position 28 of erm(41), which is associated with inducible clarithromycin resistance. In addition, compared to imipenem with avibactam only, the MIC50 and MIC90values of imipenem after adding ceftazidime plus avibactam were decreased fourfold. The antimicrobial resistance rates and the characteristics of the erm(41) gene associated with inducible clarithromycin resistance were different among the three MABC subspecies. There was also synergy between imipenem and 100μg/mL ceftazidime against MABC isolates.


BFPTool: a software tool for analysis of Biomembrane Force Probe experiments.
The Biomembrane Force Probe is an approachable experimental technique commonly used for single-molecule force spectroscopy and experiments on biological interfaces. The technique operates in the range of forces from 0.1 pN to 1000 pN. Experiments are typically repeated many times, conditions are often not optimal, the captured video can be unstable and lose focus; this makes efficient analysis challenging, while out-of-the-box non-proprietary solutions are not freely available. This dedicated tool was developed to integrate and simplify the image processing and analysis of videomicroscopy recordings from BFP experiments. A novel processing feature, allowing the tracking of the pipette, was incorporated to address a limitation of preceding methods. Emphasis was placed on versatility and comprehensible user interface implemented in a graphical form. An integrated analytical tool was implemented to provide a faster, simpler and more convenient way to process and analyse BFP experiments.


Comparison of phosphorylation of two polyoma virus middle T antigens in vivo and in vitro.
Two species of polyoma virus middle T antigen were detected in both lytically infected and transformed cells by in vitro kinase assay of immunoprecipitates. A minor species with an apparent molecular weight of 58,000 (58K) represented less than 10% of the total middle T protein. This species was roughly 10 times more active as a phosphate acceptor than was the predominant 56K form. Partial proteolytic mapping experiments showed that the same site was phosphorylated in both species. Mapping of the middle T antigens from a series of deletion mutants suggested that the major site of phosphorylation is tyrosine residue 315. Phosphorylation occurred on both middle T species in vivo, involving sites predominantly other than the tyrosine labeled in vitro. The 56K and 58K middle T forms differed from each other in their in vivo phosphorylation patterns. Some phosphate was incorporated into the 58K species in a region of the molecule to which at least part of the apparent molecular weight different could be mapped. hr-t mutant NG-59, which codes for a slightly altered middle T, produced only a single species (56K) which was inactive in the in vitro kinase reaction. Moreover, no 58K species appeared in vivo with this mutant. hr-t mutants are therefore defective in both aspects of phosphorylation. Phenotypically normal revertant cells of a polyoma transformed line failed to express any middle T antigens or associated kinase activity.


Transgenic proteins in agricultural biotechnology: The toxicology forum 40th annual summer meeting.
During the 40th Annual Meeting of The Toxicology Forum, the current and potential future science, regulations, and politics of agricultural biotechnology were presented and discussed. The range of current commercial crops and commercial crop traits related to transgenic proteins were reviewed and example crop traits discussed, including insecticidal resistance conferred by Bt proteins and the development of nutritionally enhanced food such as Golden Rice. The existing regulatory framework in the USA, with an emphasis on US FDA's role in evaluating the safety of genetically engineered crops under the regulatory umbrella of the FD&C Act was reviewed. Consideration was given to the polarized politics surrounding agricultural biotechnology, the rise of open access journals, and the influence of the internet and social media in shaping public opinion. Numerous questions related to misconceptions regarding current products and regulations were discussed, highlighting the need for more scientists to take an active role in public discourse to facilitate public acceptance and adoption of new technologies and to enable science-based regulations.


Scientific basis and development of internal dosimetry models (BIODOS).
Assessments of doses and risks to workers and members of the public exposed to radionuclides require biokinetic and dosimetric models which describe the behaviour of the radionuclides and provide tools for dose calculations. The overall objective of BIODOS is to improve the scientific basis of existing models and to provide new or improved models. One part aims to provide models targeting specific uncertainties, including estimates of doses and risks from radionuclides ingested by adults and children; estimates of the transfer of radionuclides to breast milk and doses to infants; development of systemic models to improve the interpretation of bioassays; and studies of the importance of heterogeneous distribution of dose within tissues and cells. The other part forms a comprehensive research programme on the inhalation of radionuclides and addresses four areas of uncertainty, namely ultrafine particles, inter-subject variation, absorption into blood and clearance mechanisms.


A post-synthetic approach for the synthesis of 2'-O-methyldithiomethyl-modified oligonucleotides responsive to a reducing environment.
Based on a novel concept, a Reducing-Environment-Dependent Uncatalyzed Chemical Transforming RNA, "REDUCT RNA", we established a post-synthetic approach for the synthesis of 2'-O-methyldithiomethyl-modified oligonucleotides from 2'-O-(2,4,6-trimethoxybenzylthiomethyl)-oligonucleotides by treatment with dimethyl(methylthio)sulfonium tetrafluoroborate. 2'-O-methyldithiomethyl oligonucleotides were easily converted into 2'-hydroxy oligonucleotides under reducing conditions, such as those found in the intracellular environment.


Schizophrenia and impulsive aggression: a heuristic inquiry with forensic and clinical implications.
Assessment of a violent act committed by an offender with schizophrenia typically focuses on whether the act was due to distortions in thought or perception, i.e., delusions or hallucination. An important but less appreciated feature is the impulsivity of the act, which can have forensic and therapeutic implications. Here a modification of Barratt's classification of aggressive behavior is presented that includes premeditated (instrumental), medical (secondary), impulsive (expressive), and compulsive (instrumental and expressive) aggression. Violence due to a mental condition such as schizophrenia is considered medical, but even aggression motivated by delusions or hallucinations can also be characterized as impulsive, premeditated, or compulsive.Although research on aggression and schizophrenia is limited with regard to the impulsivity-premeditation dimension and difficult to compare, current evidence suggests this to be an important consideration in the assessment of aggression in individuals with schizophrenia, important both forensically and therapeutically. Future research on the impulsive-premeditated quality of aggressive acts by offenders with schizophrenia--research wherein aggressive behavior is defined, situational context is clarified, and diagnostic criteria are explicitly followed--should further refine our understanding of the nature of aggressive acts associated with schizophrenia. Findings from such research will undoubtedly inform assessment, treatment, and forensic relevance of schizophrenia-related physical aggression.


Combinatorial Fgf and Bmp signalling patterns the gastrula ectoderm into prospective neural and epidermal domains.
Studies in fish and amphibia have shown that graded Bmp signalling activity regulates dorsal-to-ventral (DV) patterning of the gastrula embryo. In the ectoderm, it is thought that high levels of Bmp activity promote epidermal development ventrally, whereas secreted Bmp antagonists emanating from the organiser induce neural tissue dorsally. However, in zebrafish embryos, the domain of cells destined to contribute to the spinal cord extends all the way to the ventral side of the gastrula, a long way from the organiser. We show that in vegetal (trunk and tail) regions of the zebrafish gastrula, neural specification is initiated at all DV positions of the ectoderm in a manner that is unaffected by levels of Bmp activity and independent of organiser-derived signals. Instead, we find that Fgf activity is required to induce vegetal prospective neural markers and can do so without suppressing Bmp activity. We further show that Bmp signalling does occur within the vegetal prospective neural domain and that Bmp activity promotes the adoption of caudal fate by this tissue.


Evaluation of Spontaneous Bone Regeneration after Enucleation of Large Cysts of the Jaws using Radiographic Computed Software.
Spontaneous regeneration of bone is commonly seen in the small surgical defects caused by enucleation of cysts. However, in case of large surgical defects caused by the enucleation, spontaneous regeneration of bone is a rare phenomenon and it depends on factors, such as age of the patient, intact periosteum, and proper stabilization. The study included 16 patients, who reported to the department of oral and maxillofacial surgery with the complaint of pain and swelling in the jaws diagnosed as cyst. The sample included equal numbers of male and female subjects aged between 15 and 40 years. Panoramic radiographs were taken pre- and postoperatively on day 2 of the enucleation. The dimensions of the cyst were evaluated on the radiograph according to the proforma. Subsequent radiographs were taken at regular intervals of 1.5, 3, and 6 months using standard parameters and were analyzed using MCID™ analysis software of imaging research. Mean reduction was seen in up to 39 and 60% in the cystic cavity size and increase in the mean density up to 59 and 90.2% at 3 and 6 months intervals respectively. Spontaneous bone regeneration was seen even after primary closure of the large cystic defect without the need for placement of foreign substances or grafts and it also eliminated the complications resulting from placement of foreign substance. Further studies are required in a larger sample with longer follow-up durations to confirm the outcome of the present work for the benefit of patients. The present study depicted that spontaneous bone regeneration can occur with accepted results after simple enucleation of jaw cyst without the aid of any graft material. Hence, simple enucleation may be considered as a first line of treatment modality for cystic lesion of the jaws. This simplifies the surgical procedure, decreases the economic and biologic costs, and reduces the risk of postoperative complications. Follow-up is necessary along with patient's compliance for the success of treatment.


Barriers and Mitigating Strategies to Healthcare Access in Indigenous Communities of Canada: A Narrative Review.
The objective of this review is to document contemporary barriers to accessing healthcare faced by Indigenous people of Canada and approaches taken to mitigate these concerns. A narrative review of the literature was conducted. Barriers to healthcare access and mitigating strategies were aligned into three categories: proximal, intermediate, and distal barriers. Proximal barriers include geography, education attainment, and negative bias among healthcare professionals resulting in a lack of or inadequate immediate care in Indigenous communities. Intermediate barriers comprise of employment and income inequities and health education systems that are not accessible to Indigenous people. Distal barriers include colonialism, racism and social exclusion, resulting in limited involvement of Indigenous people in policy making and planning to address community healthcare needs. Several mitigation strategies initiated across Canada to address the inequitable health concerns include allocation of financial support for infrastructure development in Indigenous communities, increases in Indigenous education and employment, development of culturally sensitive education and medical systems and involvement of Indigenous communities and elders in the policy-making system. Indigenous people in Canada face systemic/policy barriers to equitable healthcare access. Addressing these barriers by strengthening services and building capacity within communities while integrating input from Indigenous communities is essential to improve accessibility.


The transformational power of IT: Experience from patient safety leaders.
Late last year, David J. Brailer, M.D., Ph.D., National Health Information Technology Coordinator for the Department of Health and Human Services, visited Evanston (IL) Northwestern Hospital (ENH) to observe its electronic medical record system. ENH is the first in the nation to put such a system into an acute care setting, including all three of its hospitals and its 70 medical offices and ambulatory sites. "It's been truly transformational for our processes, our delivery of care, our communications, and our way of doing business," says Mark R. Neaman, FACHE, ENH's president and chief executive officer. What's more, ENH has demonstrated at least a 20 percent reduction in medication errors, and the remaining errors have shifted from wrong medication and wrong patient to errors of timing, which are almost always less severe.


[Protective effect of Oviductus Ranae capsules on the reproductive organs of aged mice].
To observe the protective effect of Oviductus Ranae (OR) capsules on the reproductive organs in an aged mouse model established by D-galactose injection. Forty-eight female Kunming mice were randomly divided into 4 equal groups, namely the high- and low-dose OR groups, diethylstilbestrol (DT) group, and model group. The mice received subcutaneous injection of D-galactose for 6 weeks to establish aging models. Another 12 mice were injected daily with normal saline (NS) to serve as the normal control group. From the third week of the experiment, the mice were given oral OR at low or high doses (in the OR groups) or vegetable oil (in the model or control groups) till the sixth week. In the last two weeks, the vaginal smears were obtained from the mice for evaluating the changes of the vaginal keratinocytes and counting the days of estrus. After completion of drug administration, all the mice were sacrificed and the serum content of estradiol (E(2)) was detected by radioimmunoassay, with the ovarian and uterine indices determined. The ovarian and uterine pathologies were observed using HE staining, and SOD and MDA activities in the ovary and uterus were also assessed. OR obviously increased E(2) level and the ovarian and uterine indices in the aged mice, also alleviating the pathological change of the ovary and uterus. OR substantially depressed MDA content and enhanced SOD activity in the ovary and uterus. OR has definite antioxidative effects and ameliorates the degenerative changes of the reproductive organs in mouse models of aging.


Mycobacterial Cell Wall Stimulant in the Treatment of Squamous Cell Carcinoma: A Case Series Regarding Treatment in Equine, Bovine and Caprine Patients.
Squamous cell carcinoma (SCC) is a common dermatological neoplasia found in large animal species. Treatment options, such as surgery and cryotherapy may be difficult or not feasible. Alternative therapies, such as immunomodulating drugs, can potentially be used for companion large animals. The hypothesis of the following retrospective study is: following multiple intravenous and intralesional injections of a mycobacterial cell wall stimulant (MCW) regression of SCC in equine, bovine and caprine patients will be observed. In this observational-retrospective case series, patients included are 2 bovine, 2 caprine and 3 equine patients. The medical records at two different teaching veterinary hospitals were searched for cases with a positive histopathological diagnosis of squamous cell carcinoma that were subsequently treated with MCW, as either the sole therapy, or in conjunction with other therapies. Seven cases were included in this retrospective study. The median duration of therapy was 56.5 days, with 3 of the 7 patients being euthanized. Significant complications were seen in 3/7 patients. Repeated injections of a MCW may lead to reduction in lesion size of SCC in some cases, but long-term resolution is unlikely and the risk of significant complications is high; due to limited sample size and the variety in species, it is difficult to conclude if MCW is an effective therapy for SCC.


Alpha-1-antitrypsin suppresses oxidative stress in preeclampsia by inhibiting the p38MAPK signaling pathway: An in vivo and in vitro study.
This present study was designed to investigate the effects of alpha-1-antitrypsin (AAT) on oxidative stress in preeclampsia (PE) by regulating p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. HTR8/SVneo cells were randomly assigned into normal, hypoxia/reoxygenation (H/R), HR + AAT and HR + siRNA-AAT groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the mRNA and protein expressions of p-p38MAPK, AAT, signal transducer and activator of transcription 1 (STAT1) and activating transcription factor2 (ATF2). Flow cytometry, scratch test, cell counting kit-8 (CCK-8) assay and the 3-(4,5)-dimethylthiazol (-z-y1)-3,5-di- phenyltetrazolium bromide (MTT) assay were conducted to detect reactive oxygen species (ROS) and cell apoptosis, cell migration, proliferation and cytotoxicity, respectively. Mouse models in PE were established, which were divided into normal pregnancy (NP), PE and PE + AAT groups with blood pressure and urine protein measured. Chromatin immunoprecipitation (ChIP) and enzyme-linked immunosorbent assay (ELISA) were conducted to detect the activity of oxidative stress-related kinases and expressions of inflammatory cytokines and coagulation-related factors in cells and mice placenta. Immunohistochemistry, Western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect AAT and p38MAPK expressions, apoptosis-related protein expressions, and apoptosis rate in mice placenta. Compared with the normal group, the H/R group had decreased expression of AAT, activity of superoxide dismutase (SOD) and GSH-Px, cell proliferation and migration, but increased p38MAPK, STAT1, ATF2, MDA, H2O2, inflammatory cytokines, coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate. Compared with the H/R group, the HR + ATT group had increased expressions of AAT, activity of SOD and GSH-Px, cell proliferation and migration but decreased p38MAPK, STAT1, ATF2, malonyldialdehyde (MDA), H2O2, inflammatory cytokines and coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate, while opposite results were observed in the HR + siRNA-ATT group. Compared with the NP group, the PE group had decreased activity of SOD and GSH-Px but increased MDA, H2O2, AAT, p38MAPK, inflammatory cytokines, coagulation-related factors and apoptosis rate. The indexes in the PE + AAT group were between the NP and PE groups. Thus, we concluded that AAT suppressed oxidative stress in PE by inhibiting p38MAPK signaling pathway.


Origin of clay minerals in Early Eocene volcanic paleosols on King George Island, Maritime Antarctica.
The paleoclimate during the Early Eocene in Maritime Antarctica is characterized by cool conditions without a pronounced dry season. Soils formed on volcanic material under such climate conditions in modern analogue environments are usually Andosols rich in nanocrystalline minerals without pedogenic smectite. The paleosols formed on volcanic material on King Georges Island are covered by basalts, dated by 6 new 40Ar/39Ar datings to 51-48 Ma, and are rich in smectite. A pedogenic origin of the smectites would suggest a semi-arid rather than a wet non-seasonal humid paleoclimate. To investigate the origin of the smectites in these paleosols we used X-ray diffraction and microscopic techniques. Minor mineralogical changes between the volcanic parent material and the paleosols and a homogenous distribution of smectites throughout the paleosol horizons indicate that these smectites were mainly inherited from the pyroclastic parent material, which was altered prior to surficial weathering. Nevertheless, the mineralogical properties, such as degree of crystallinity and octahedral site occupancy, of these smectites were modified during the ancient soil formation. Our findings highlight that trioctahedral smectites were a product of deuteric alteration of pyroclastic rocks and were progressively transformed to dioctahedral smectites during weathering in a soil environment on King George Island.


Pre-hospital advanced airway management by experienced anaesthesiologists: a prospective descriptive study.
We report data from the first Utstein-style study of physician-provided pre-hospital advanced airway management. Anaesthesiologists from eight pre-hospital critical care teams in the Central Denmark Region (a mixed rural and urban region with 1.27 million inhabitants) prospectively registered data according to the template for reporting data from pre-hospital advanced airway management. Data collection took place from February 1st 2011 to October 31st 2012. Included were patients of all ages on whom pre-hospital advanced airway management was performed. The objective was to estimate the incidences of failed and difficult pre-hospital endotracheal intubation, and complications related to pre-hospital advanced airway management. The overall incidence of successful pre-hospital endotracheal intubation among 636 intubation attempts was 99.7%, even though 22.4% of pre-hospital endotracheal intubations required more than one intubation attempt. The overall incidence of complications related to pre-hospital advanced airway management was 7.9%. Following rapid sequence intubation, the incidence of first pass success was 85.8%, the overall incidence of complications was 22.0%, the incidence of hypotension 7.3% and that of hypoxia 5.3%. Multiple endotracheal intubation attempts were associated with an increased overall incidence of complications. No airway management related deaths occurred. The overall incidence of successful pre-hospital endotracheal intubations compares to those found in other physician-staffed pre-hospital systems. The incidence of pre-hospital endotracheal intubations requiring more than one attempt is higher than suspected. The incidence of hypotension or hypoxia after pre-hospital rapid sequence intubation compares to those found in UK emergency departments. Pre-hospital advanced airway management including pre-hospital endotracheal intubation performed by experienced anaesthesiologists is associated with high success rates and relatively low incidences of complications. An increased first pass success rate following pre-hospital endotracheal intubation may further reduce the incidence of complications and enhance patient safety in our system.


Partial involvement of group I metabotropic glutamate receptors in the neurotoxicity of 3-N-oxalyl-L-2,3-diaminopropanoic acid (L-beta-ODAP).
Neurolathyrism is a human motoneuron disease caused by the overconsumption of grass pea (Lathyrus sativus) that contains a toxic non-protein amino acid, 3-N-oxalyl-L-2,3-diaminopropanoic acid (L-beta-ODAP). The preventive activities of various glutamatergic agents from acute neuronal death caused by L-beta-ODAP were studied using rat primary cortical neuron/glia culture. Nearly 80% of the rat primary cortical neurons were killed by 300 microM L-beta-ODAP within 24 h. Though antagonists acting on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor prevented most of the toxicity, antagonists acting on group I metabotropic glutamatergic receptors (mGluRs), including (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), (S)-alpha-methyl-4-carboxyphenylglycine (MCPG), and 2-methyl-6-(2-phenylethenyl)pyridine (SIB1893) partially and significantly prevented neuronal death due to L-beta-ODAP. These antagonists, within limited concentrations, did not have any inhibitory effects on the currents through AMPA receptors expressed in Xenopus oocytes. L-beta-ODAP itself did not induce the currents through group I mGluRs expressed in Xenopus oocytes. These results suggest that the neurotoxicity induced by L-beta-ODAP is partially mediated by the activation of group I mGluRs by an indirect mechanisms.


Jarisch‒Herxheimer reaction.
Syphilis is caused by a spirochete, Treponema pallidum. Diagnosis of syphilis is made with a venereal disease research laboratory test. Treatment of choice is intramuscular injection benzathine Penicillin. The Jarisch‒Herxheimer reaction (JHR) is a transient immunological phenomenon that can occur in patients during treatment for syphilis with penicillin. It is a rare phenomenon but can be a potentially severe one. It manifests clinically with short-term constitutional symptoms such as fever, chills, headache, and myalgia, besides exacerbation of existing cutaneous lesions. We report the case of a 24-year-old man presenting with JHR posttreatment with benzathine penicillin.


[Impact of FDG-PET in therapeutic management of patients with suspected recurrence of head and neck cancer].
This study aims to evaluate the impact of Positron Emission Tomography on therapeutic decisions in patients with suspicion of recurrence of head and neck cancers. The diagnostic and therapeutic impact of FDG-PET was evaluated in 59 of 60 studies performed in a sample of 54 patients. The impact was graded on five levels (high, moderate, low, no impact and negative impact) following the Hicks et al. classification modified by us. The FDG-PET impact was high in 28 studies (47.46 %), moderate in 7 (11.86 %), low in 20 (33.90 %), no impact in 3 (5.09 %) and finally negative impact in 1 study (1.69 %). FDG-PET is useful in the management of patients in 59.32 % of the studies with indeterminate physical examination and conventional imaging tests. This paper supplies new data since we did not find any studies showing statistical results on therapeutic impact of FDG-PET in head and neck cancers in a systematic review of the literature made by our group.


[Computer simulation of high frame rate ultrasonic imaging system based on the angular spectrum concept].
A high frame rate (HFR) ultrasonic imaging method developed by Jianyu Lu has been attracting attention in the related imaging area. Because a special weighting on the received signal is needed to implement this method, the imaging system is complicated. This paper presents a new kind of theroetical analysis for the HFR imaging system in view of the angular spectrum concept. Based on the study, the special weighting process can be replaced by Fourier transform. Computer simulation demonstrates the correctness of the analysis. It shows that the constructed images by the new method have the same high quality as those obtained by using the original HFR method while the system implementation is greatly simplified.


Should the Dose of Antiplatelet Drugs Be Adjusted for Body Weight? The Example of Vorapaxar.
In contrast to the vast majority of pharmaceuticals on the market, antiplatelet agents are widely prescribed in a uniform, 'one size fits all' manner, without conventional dose adjustments. However, strong evidence yielded from clinical trials repeatedly suggests that patients with a low body weight (LBW), the elderly and those with renal or hepatic impairment may benefit from reduced doses, while younger, heavier patients, males and diabetics may benefit from a dose escalation. Vorapaxar, a thrombin protease-activated receptor-1 inhibitor, has been tested in the TRA2P and TRACER clinical trials, but its efficacy and safety in patients with a LBW is unclear. To determine the impact of LBW on primary end point rates (PER) and bleeding risk after vorapaxar, as yielded from the TRA2P and TRACER secondary FDA review. The LBW (<60 kg) groups in TRA2P (n = 1,852; 7%) and TRACER (n = 1,046; 8%) were small. However, the PER repeatedly suggested inferiority of vorapaxar over placebo in both the successful TRA2P study (10.6 vs. 8.4%; p = 0.012) and the failed TRACER study (19.3 vs. 18.2%; p = not significant). In TRA2P, the PER monotonically escalated with increasing weight for placebo, while those in the vorapaxar arm formed a flat U- or J-shaped distribution across the weight quintiles. In TRACER, the PER by weight quintile appear much higher, but also more random than in TRA2P. The bleeding rates in TRA2P were higher for the 2 lowest-weight quintiles with both placebo and vorapaxar. In TRACER, bleeding rates were more than doubled when compared to TRA2P, and they varied little by weight quintile, with a slight decrease for the heaviest patients in the placebo population and being the highest in the 2 lowest-weight quintiles after vorapaxar. The FDA analyses revealed no definite proof that LBW is associated with reduced efficacy of vorapaxar. While these data are striking, they can be explained by better outcomes in LBW placebo patients already sufficiently treated with dual-antiplatelet therapy. In contrast to efficacy, both TRA2P and TRACER definitely suggest that bleeding rates after vorapaxar are higher in patients with LBW. Dose adjustment for antiplatelet agents may soon become a reality.


Who decides the "best interests" of the child?
B was a frail 15-year-old girl who was brought to the hospital by the police. She had met a 22-year-old boy on a social networking site a few months earlier. They had fallen in love and she had started living with him. On finding his daughter missing, B's father reported the matter to the police station. The police caught the couple and brought them to the police station. The boy was arrested. The father sent B to a shelter home lest she run away from home again. The police registered a complaint of rape.


IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.
An excess of aldosterone results in cardiac remodelling and fibrosis. Interleukin-6 (IL-6) is a key mediator in the fibrotic process; however, the effect of aldosterone on the expression of IL-6 remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the fibrotic process. In this clinical study, we prospectively enrolled 25 patients with primary aldosteronism (PA) and 26 patients with essential hypertension (EH). The PA patients had higher plasma IL-6 levels, left ventricular mass index, degree of myocardial fibrosis, and more impaired diastolic function than the EH patients. In addition, plasma IL-6 levels were positively correlated with 24-h urinary aldosterone and echocardiographic parameters. In cell studies, we investigated the possible molecular mechanism how aldosterone-induced IL-6 secretion and the further effects of collagen production. Aldosterone significantly induced IL-6 protein and mRNA production in human umbilical vein endothelial cells. Intracellular signalling occurred through the mineralocorticoid receptor/PI3K/Akt/NF-kB pathway. In cardiac fibroblasts, IL-6 trans-signalling played a critical role in aldosterone-induced IL-6-enhanced fibrosis-related factor expression. To further investigate the role of IL-6 trans-signalling in aldosterone-induced cardiac fibrosis, we measured the severity of myocardial fibrosis in aldosterone infusion mice models including an IL-6 chemical inhibitor and Sgp130 Knockin Transgenic Mice. Mice receiving recombinant soluble gp130 and Sgp130 Knockin Transgenic Mice prevented myocardial fibrosis and cardiac hypertrophy by aldosterone infusion. IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.


The molecular structures of pentaborane(9) with halogen substituents in apical and basal positions, determined by electron diffraction and theoretical calculations.
The molecular structures of 1-bromo-pentaborane(9) and 2-bromo-pentaborane(9) in the gas phase have been determined by electron diffraction and ab initio and DFT computational methods. Computational methods have also been applied to the fluoro and chloro analogues, to 1,2-dibromo-pentaborane(9), and to the parent unsubstituted borane. The electronic effects of halogen substitution on the borane cage are remarkably small, particularly for chlorine and bromine substituents, and steric effects are also minimal, even in the compound with two bromine atoms. The largest effects are (a) lengthening of B((base))-B((apex)) bonds adjacent to the halogen in the 2-isomers, with an associated shortening of the opposite base-apex bond, (b) shortening of the B((base))-B((apex)) bond in the 1-fluoro compound, and (c) increase of the B((base))-B((apex))-F angle in 1-F-B(5)H(8), but a decrease in this angle in the 2-bromo compounds.


AtSLP2 is an intronless protein phosphatase that co-expresses with intronless mitochondrial pentatricopeptide repeat (PPR) and tetratricopeptide (TPR) protein encoding genes.
Shewanella-like PPP family phosphatases (SLPs) are a unique lineage of eukaryote PPP-family phosphatases of bacterial origin which are not found in metazoans. 1,2 Their absence in metazoans is marked by their ancient bacterial origins and presence in plants. 1 Recently, we found that the SLP2 phosphatase ortholog of Arabidopsis thaliana localized to the mitochondrial intermembrane space (IMS) where it was determined to be activated by mitochondrial intermembrane space protein 40 (MIA40) to regulate seed germination. 3 Through examination of atslp2 knockout (accelerated germination) and 35S::AtSLP2 over-expressing (delayed germination) plants it was found that AtSLP2 influences Arabidopsis thaliana germination rates via gibberellic acid (GA) biosynthesis. 3 However, the exact mechanism by which this occurs remains unresolved. To identify potential partners of AtSLP2 in regulating germination through GA, we undertook a gene co-expression network analysis using RNA-sequencing data available through Genevestigator ( https://genevestigator.com/gv/ ).


Entropic ratchet transport of interacting active Brownian particles.
Directed transport of interacting active (self-propelled) Brownian particles is numerically investigated in confined geometries (entropic barriers). The self-propelled velocity can break thermodynamical equilibrium and induce the directed transport. It is found that the interaction between active particles can greatly affect the ratchet transport. For attractive particles, on increasing the interaction strength, the average velocity first decreases to its minima, then increases, and finally decreases to zero. For repulsive particles, when the interaction is very weak, there exists a critical interaction at which the average velocity is minimal, nearly tends to zero, however, for the strong interaction, the average velocity is independent of the interaction.


PET/CT imaging in invasive endometriosis: a way to minimize missed diagnosis and reduce invasive interventions.
Heterogeneous and nonspecific symptoms make invasive endometriosis a difficult entity to diagnose. Small lesions with absent associated changes can be easily missed in cross-sectional imaging. Even when the lesions satisfy the thresholds for various investigations, their appearance changes with cyclical fluctuations in the hormonal levels. Therefore, newer approaches are needed to achieve correct diagnosis. Six females in reproductive age group (mean age = 32.5 ± 4.3 years) were retrospectively selected, wherein the diagnosis of invasive endometriosis was confirmed after 18F-FDG-PET/CT. Indications for PET/CT were staging in 4 patients, suspected progression in 1 and suspected inflammatory bowel disease in one patient. The study was repeated in proliferative phase in two patients and in the menstrual phase in another patient. FNAC was available in two patients and a drop in CA125 was documented in the last patient. In five patients metabolically active lesions were seen in PET/CT and in the last, activity was absent despite symptoms. Repeat menstrual phase imaging in the last patient confirmed the diagnosis. In two patients with metabolically active lesions at baseline, resolution was seen in proliferative phase PET/CT. In the other two patients, repeat study was not indicated as FNAC revealed normal endometrial tissue and in the last patient, significant drop in CA125 was documented after just 2 weeks. In all of these patients, the final diagnosis was of invasive endometriosis. In reproductive-age women, PET/CT acquisition should be optimized in the context of menstrual cycle. This approach can be used to non-invasively rule in/rule out endometriosis, especially with repeat imaging in proper menstrual phase.


Graduate nursing students' precourse and postcourse perceptions and preferences concerning completely web-based courses.
Web-based nursing courses have proliferated rapidly in recent years, but few data are available about course outcomes. A pretest/posttest survey design of student perceptions and preferences was used to evaluate two graduate-level on-line nursing courses (required research and elective aging issues courses; N = 31 and N = 29, respectively) on the basis of Billings' outcomes evaluation framework for nursing Web-based courses. Students in both courses were favorable or at least neutral in their perceptions of outcomes at both pretest and posttest, but favorable shifts in perceptions also occurred from pretest to posttest. Most students remained stable in their preferences for format of instruction (on-line or classroom), and most favored an on-line format. Almost all students indicated they would take the course they took if they had the decision to make over again. Students who took the elective aging issues course had somewhat more favorable perceptions overall at posttest, compared to the required research course, but some differences were accounted for by pretest score differences between the groups. While outcomes were positive for both courses, the results also highlight specific needs for adequate socialization and support of students, particularly for first-year graduate students who are taking Web-based courses.


Increasing capitation in mixed remuneration schemes: Effects on service provision and process quality of care.
Many health systems apply mixed remuneration schemes for general practitioners, but little is known about the effects on service provision of changing the relative mix of fee for services and capitation. We apply difference-in-differences analyses to evaluate a reform that effectively reversed the mix between fee for services and capitation from 80/20 to 20/80 for patients with type 2 diabetes. Our results show reductions in provision of both the contact services that became capitated and in other non-capitated (still-billable) services. Reduced provision also occurred for guideline-recommended process quality services. We find that the effects are mainly driven by patients with co-morbidities and by general practitioners with high income, relatively many diabetes patients, and solo practitioners. Thus, increasing capitation in a mixed remuneration schemes appears to reduce service provision for patients with type 2 diabetes monitored in general practice with a risk of unwanted quality effects.


Solution structure of the d(T-C-G-A) duplex at acidic pH. A parallel-stranded helix containing C+ .C, G.G and A.A pairs.
The solution structure of the d(T-C-G-A) sequence at acidic pH has been determined by a combination of NMR and molecular dynamics calculations including NOE intensity based refinements. This sequence forms a right-handed parallel-stranded duplex with C+ .C (three hydrogen bonds along Watson-Crick edge), G.G (two symmetry related N2-H.. N3 hydrogen bonds) and A.A (two symmetry related N6-H..N7 hydrogen bonds) homo base-pair formation at acidic pH. The duplex is stabilized by intra-strand base stacking at the C2-G3 step and cross-strand base stacking at the G3-A4 step. The thymine residues on partner strands are directed towards each other and are positioned over the C+ .C base-pair. All four residues adopt anti glycosidic torsion angles and C2'-endo type sugar conformations in the parallel-stranded d(T-C-G-A) duplex which exhibits large changes in twist angles between adjacent steps along the duplex. This study rules out previously proposed models for the structure of the d(T-C-G-A) duplex at acidic pH and supports earlier structural contributions, which established that d(C-G) and d(C-G-A) containing sequences at acidic pH pair through parallel-stranded alignment. We have also monitored hydration patterns in the symmetry related grooves of the parallel-stranded d(T-C-G-A) duplex.


A cross-sectional study of associations between kinesiophobia, pain, disability, and quality of life in patients with chronic low back pain.
Low back pain is a significant health problem condition due to high prevalence among the general population. Emotions and physical factors are believed to play a role in chronic low back pain. Kinesiophobia is one of the most extreme forms of fear of pain due to movement or re-injury. The purpose of this study was to investigate the association between kinesiophobia and pain intensity, disability and quality of life in people with chronic low back pain. The study included 132 individuals with chronic back pain, with ages between 18 and 65 years old. Kinesiophobia was assessed using the Tampa Scale of Kinesiophobia, pain intensity was measured using the Numeric Rating Scale with a cut-off more than 3 for inclusion in the study, disability was assessed using the Roland Morris questionnaire, quality of pain was assessed using the McGill questionnaire, and quality of life was assessed using the Quality of Life questionnaire SF-36. The results are statistically significant, but with weak associations were found between kinesiophobia and pain intensity (r = 0.187), quality of pain (sensory, r = 0.266; affective, r = - 0.174; and total r = 0.275), disability (r = 0.399) and physical quality of life (emotional r = - 0.414). Kinesiophobia is an important outcome to assess in patients with chronic low back pain. The results suggest that correlations between kinesiophobia and disability and quality of life are statistically significant.


High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes.
As more mutations are identified in genes of known sequence, there is a crucial need in the areas of medical genetics and genome analysis for rapid, accurate and cost-effective methods of mutation detection. We have developed a multiplex allele-specific diagnostic assay (MASDA) for analysis of large numbers of samples (> 500) simultaneously for a large number of known mutations (> 100) in a single assay. MASDA utilizes oligonucleotide hybridization to interrogate DNA sequences. Multiplex DNA samples are immobilized on a solid support and a single hybridization is performed with a pool of allele-specific oligonucleotide (ASO) probes. Any probes complementary to specific mutations present in a given sample are in effect affinity purified from the pool by the target DNA. Sequence-specific band patterns (fingerprints), generated by chemical or enzymatic sequencing of the bound ASO(s), easily identify the specific mutation(s). Using this design, in a single diagnostic assay, we tested samples for 66 cystic fibrosis (CF) mutations, 14 beta-thalassemia mutations, two sickle cell anemia (SCA) mutations, three Tay-Sachs mutations, eight Gaucher mutations, four mutations in Canavan disease, four mutations in Fanconi anemia, and five mutations in BRCA1. Each mutation was correctly identified. Finally, in a blinded study of 106 of these mutations in > 500 patients, all mutations were properly identified. There were no false positives or false negatives. The MASDA assay is capable of detecting point mutations as well as small insertion or deletion mutations. This technology is amenable to automation and is suitable for immediate utilization for high-throughput genetic diagnostics in clinical and research laboratories.


A multicompartmental model of cholesterol metabolism in rats.
A complete model of the cholesterol system was developed in the rat. It synthesizes several partial models previously developed under different isotopic conditions. It contains 16 compartments and 40 parameters. It specifically describes the intestine (mucosa and contents), liver and plasma cholesterol subsystems. The model was validated by the similarity between the simulated and experimental values in all the compartments during the 48 hours following the single introduction of an isotopic label in two different parts of the system (single ingestion of 14C-cholesterol, intravenous injection of red cells containing 3H-cholesterol). The similarity between the simulations and the experimental values was also observed up to 4 months following labelled cholesterol ingestion as well as under other different isotopic conditions for shorter periods. The parameter values identified and the resulting fluxes agree with the already published data.


About the involvement of deoxyribonuclease I in apoptosis.
Cell death by apoptosis is involved in a large variety of developmental events and physiological processes requiring a reduction in cell count. Nuclear collapse, one of the first visible changes denoting irreversible commitment to cell death by apoptosis, is frequently accompanied by chromatin degradation into nucleosome-sized fragments of multiples thereof. The identity of the endonuclease responsible for this DNA digestion has attracted some interest in recent years and several candidate endonucleases have been proposed. The scope of this article is to summarise the present knowledge about deoxyribonuclease I, one of the candidate enzymes.


Association between ADAMTS-4 gene polymorphism and lumbar disc degeneration in Chinese Han population.
Low back pain (LBP) is a common health problem and many LBP are caused by lumbar disc degeneration (LDD). ADAMTS-4 (a disintegrin and metalloprotease with thrombospondin motifs-4), also known as aggrecanse-1, plays a core role in degeneration of extracellular matrix in LDD. To investigate the association between ADAMTS-4 genetic polymorphism and LDD, we genotyped SNPs in and around ADAMTS-4. We recruited 482 sporadic cases of LDD and 496 healthy controls from Chinese Han population. Five SNPs were selected and phenotyped by the Sequenom MassARRAY system. Allelic, genotypic, and haplotypic association was performed. Rs4233367 (c.1877 C>T), which located in exon of ADAMTS-4 showed significant association with LDD. The T allele conferred a lower risk of LDD with an OR of 0.69 and TT genotype is at nearly one-fifth of the risk compared to CC genotype. Other tested SNPs didn't show significant difference between the case and control groups. The SNP rs4233367 in the exon of ADAMTS-4 gene may be associated with lumbar disc degeneration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:860-864, 2016.


Are children with clinical obesity at increased risk of inpatient hospital admissions? An analysis using linked electronic health records in the UK millennium cohort study.
Few studies have examined health service utilization of children with overweight or obesity by using linked electronic health records (EHRs). We analysed EHRs from 3269 children (1678 boys; 51.3% [weighted]) participating in the Millennium Cohort Study, living in Wales or Scotland at age seven whose parents consented to record linkage. We used height and weight measurements at age five to categorize children as obese (>98th centile) or overweight (>91st centile) (UK1990 clinical reference standards) and linked to hospital admissions, up to age 14 years, in the Patient Episode Database for Wales and Scottish Morbidity Records. Negative binomial regression models compared rates of inpatient admissions by weight status at age five. At age five, 11.5% and 6.7% of children were overweight or obese, respectively; 1221 (38%) children were subsequently admitted to hospital at least once. Admissions were not increased among children with overweight or obesity (adjusted rate ratio [RR], 95% confidence interval [CI]: 0.87, 0.68-1.10 and 1.16, 0.87-1.54, respectively). In this nationally representative cohort of children in Wales and Scotland, those with overweight or obesity at entry to primary school did not have increased rates of hospital admissions in later childhood and early adolescence.


Conventional vs invert-grayscale X-ray for diagnosis of pneumothorax in the emergency setting.
Pneumothorax is a pathologic condition in which air is accumulated between the visceral and parietal pleura. After clinical suspicion, in order to diagnose the severity of the condition, imaging is necessary. By using the help of Picture Archiving and Communication Systems (PACS) direct conventional X-rays are converted to gray-scale and this has become a preferred method among many physicians. Our study design was a case-control study with cross-over design study. Posterior-anterior chest X-rays of patients were evaluated for pneumothorax by 10 expert physicians with at least 3years of experience and who have used inverted gray-scale posterior anterior chest X-ray for diagnosing pneumothorax. The study included posterior anterior chest X-ray images of 268 patients of which 106 were diagnosed with spontaneous pneumothorax and 162 patients used as a control group. The sensitivity of Digital-conventional X-rays was found to be higher than that of inverted gray-scale images (95% CI (2,08-5,04), p<0,01). There was no statistically significant difference between the gold standard and digital-conventional images (95% CI (0,45-2,17), p=0,20), while the evaluations of the gray-scale images were found to be less sensitive for diagnosis (95% CI (3,16-5,67) p<0,01). Inverted gray-scale imaging is not a superior imaging modality over digital-conventional X-ray for the diagnosis of pneumothorax. Prospective studies should be performed where diagnostic potency of inverted gray-scale radiograms is tested against gold standard chest CT. Further research should compare inverted grayscale to lung ultrasound to assess them as alternatives prior to CT.


Lycopene protects pancreatic acinar cells against severe acute pancreatitis by abating the oxidative stress through JNK pathway.
This study investigated the anti-oxidative and anti-inflammatory effects of lycopene on severe acute pancreatitis (SAP) in both in vivo and in vitro models. Utilizing a rat model, we found that lycopene administration protected against SAP, as indicated by the decreased levels of serum amylase and C-reactive protein. Pathological changes were alleviated by pretreatment with lycopene. The serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein-1α, and monocyte chemotactic protein-1 were decreased by lycopene. The decreased reactive oxygen species (ROS) content in the pancreatic tissues of the lycopene-treated group were indirectly evaluated by measuring the levels of myeloperoxidase, lipid peroxidase, and superoxide dismutase. Lycopene protected acinar cells against necrosis and apoptosis by relieving the mitochondrial and endoplasmic stress caused by ROS which was shown in electron microscopy and immunohistochemistry staining of active nuclear factor-κB p65. The protective effect was also observed in a simulated SAP model in a rat acinar cell line. ROS and apoptotic staining were compared between groups. Lycopene exerts protective effects against SAP in rats that may be related to its anti-inflammatory property through inhibiting the expression of damage-associated molecular patterns, and anti-oxidative property which can thus maintain cellular homeostasis and prevent the phosphorylation of JNK pathway.


CD4+ T Cells Play a Critical Role in Mediating Hypertension in Response to Placental Ischemia.
Similar to preeclamptic women, hypertension in the chronic Reduced Uterine Perfusion Pressure Rat Model Of Preeclampsia (RUPP) is associated with increased CD4+ T cells, cytokines, sFlt-1 and agonistic autoantibodies to the AngII receptor (AT1-AA). We examined the effect inhibition of T cell co-stimulation in RUPP rats treated with (A) (abatacept, 250 mg/kg, infused i.v. at gestation day 13), on hypertension and sFlt-1, TNF-α and AT1-AA. RUPP surgical procedure was performed on day 14. On day 19 MAP increased from 94+2 mmHg in Normal Pregnant (NP) to 123 ± 3 mmHg in RUPP control rats. This response was attenuated by Abatacept, MAP was 104 ± 2 mmHg in RUPP ± A, and 96 ± 2 mmHg NP ± A. Percent circulating CD4+ T cells were 66 ± 3% in RUPPs compared to 55 ± 3% NP rats (p<0.04) but were normalized in RUPP ± A rats (54 ± 3%). The twofold increase in TNF alpha seen in RUPPs (277 ± 47 pg/ml) was decreased to 80 ± 18 pg/ml in RUPP+A. Placental sFlt-1 was reduced 70 % to 151 ± 28 in RUPP ± A compared 488 ± 61 pg/ml in RUPP (p<0.001). AT1-AA decreased from 20 ± 0.8 bpm in control RUPP to 6 ± 0.7 bpm in RUPP ± A. We next determined the effect of RUPP in causing hypertension in pregnant T cell deficient rats by examining MAP in NP (123 ± 5 mmHg) and RUPP athymic nude rats (123 ± 7 mmHg). In the absence of T cells, hypertension in response to placental ischemia was completely abolished. Collectively these data indicate that CD4+ Tcells in response to placental ischemia play an important role in the pathophysiology of hypertension associated with preeclampsia.


Growth Hormone, Insulin-Like Growth Factor-1, Insulin Resistance, and Leukocyte Telomere Length as Determinants of Arterial Aging in Subjects Free of Cardiovascular Diseases.
Background: Increased arterial stiffness (AS), intima-media thickness (IMT), and the presence of atherosclerotic plaques (PP) have been considered as important aspects of vascular aging. It is well documented that the cardiovascular system is an important target organ for growth hormone (GH) and insulin-like growth factor (IGF)-1 in humans, and GH /IGF-1 deficiency significantly increases the risk for cardiovascular diseases (CVD). The telomere length of peripheral blood leukocytes (LTL) is a biomarker of cellular senescence and that has been proposed as an independent predictor of (CVD). The aim of this study is to determine the role of GH/IGF-1, LTL and their interaction cardiovascular risk factors (CVRF) in the vascular aging. Methods: The study group included 303 ambulatory participants free of known CVD (104 males and 199 females) with a mean age of 51.8 ± 13.3 years. All subjects had one or more CVRF [age, smoking, arterial hypertension, obesity, dyslipidemia, fasting hyperglycemia, insulin resistance-HOMA (homeostatic model assessment) >2.5, or high glycated hemoglobin]. The study sample was divided into the two groups according to age as "younger" (m ≤ 45 years, f ≤ 55 years) and "older" (m > 45 years, f > 55 years). IMT and PP were determined by ultrasonography, AS was determined by measuring the carotid-femoral pulse wave velocity (c-f PWV) using the SphygmoCor system (AtCor Medical). LTL was determined by PCR. Serum IGF-1 and GH concentrations we measured by immunochemiluminescence analysis. Results: Multiple linear regression analysis with adjustment for CVRF indicated that HOMA, GH, IGF-1, and LTL had an independent relationship with all the arterial wall parameters investigated in the younger group. In the model with c-f PWV as a dependent variable, p < 0.001 for HOMA, p = 0.03 for GH, and p = 0.004 for LTL. In the model with IMT as a dependent variable, p = 0.0001 for HOMA, p = 0.044 for GH, and p = 0.004 for IGF-1. In the model with the number of plaques as a dependent variable, p = 0.0001 for HOMA, and p = 0.045 for IGF-1. In the older group, there were no independent significant associations between GH/IGF-1, LTL, HOMA, and arterial wall characteristics. Conclusions: GH/IGF-1, IR, HOMA, and LTL were the important parameters of arterial aging in younger healthy participants.


Management and outcome of hepatocellular adenoma with massive bleeding at presentation.
To evaluate outcome of acute management and risk of rebleeding in patients with massive hemorrhage due to hepatocellular adenoma (HCA). This retrospective cohort study included all consecutive patients who presented to our hospital with massive hemorrhage (grade II or III) due to ruptured HCA and were admitted for observation and/or intervention between 1999-2016. The diagnosis of HCA was based on radiological findings from contrast-enhanced magnetic resonance imaging (MRI) or pathological findings from biopsy or resection of the HCA. Hemorrhage was diagnosed based on findings from computed tomography or MRI. Medical records were reviewed for demographic features, clinical presentation, tumor features, initial and subsequent management, short- and long-term complications and patient and lesion follow-up. All patients were female (n = 23). Treatment in the acute phase consisted of embolization (n = 9, 39.1%), conservative therapy (n = 13, 56.5%), and other intervention (n = 1, 4.3%). Median hemoglobin level decreased significantly more on days 0-3 in the intervention group than in the patients initially treated conservatively (0.9 mmol/L vs 2.4 mmol/L respectively, P = 0.006). In total, 4 patients suffered severe short-term complications, which included hypovolemic shock, acute liver failure and abscess formation. After a median follow-up of 36 mo, tumor regression in non-surgically treated patients occurred with a median reduction of 76 mm down to 25 mm. Four patients underwent secondary (elective) treatment (i.e., tumor resection) to address HCA size of > 5 cm and/or desire for future pregnancy. One case of rebleeding was documented (4.3%). None of the patients experienced long-term complication (mean follow-up time: 36 mo). With a 4.3% risk of rebleeding, secondary (elective) treatment of HCA after massive hemorrhage may only be considered in patients with persistent HCA > 5 cm.


Studies on glycopeptide released by trypsin from sheep erythrocytes.
Pretreatment of sheep erythrocytes with trypsin abolishes their specific binding and rosette formation with human T lymphocytes. A glycopeptide containing sialic acid is released from the intact sheep erythrocytes by incubation with trypsin and purified. This glycopeptide contains activity that can be bound to T lymphocytes and produces inhibition of rosette formation. This component with a m.w. of about 10,000 contains galactose, acetylglucosamine, acetylgalactosamine, sialic acid, and serine. These results suggest that the glycopeptide released by trypsin treatment may contain the site of the T cell receptor of sheep erythrocytes.


Unraveling the solvent stability on the cathode surface of Li-O2 batteries by using in situ vibrational spectroscopies.
In aprotic lithium-oxygen (Li-O2) batteries, solvent properties are crucial in the charge/discharge processes. Therefore, a thorough understanding of the solvent stability at the cathode surface during the oxygen reduction/evolution reactions (ORR/OER) is essential for the rational design of high-performance electrolytes. In this study, the stability of typical solvents, a series of glyme solvents with different chain lengths, has been investigated during the ORR/OER by in situ vibrational spectroscopy measurements of sum frequency generation (SFG) spectroscopy and infrared reflection absorption spectroscopy (IRRAS). The structural evolution and decomposition mechanism of the solvents during ORR/OER have been discussed based on the observations. Our results demonstrate that superoxide (O2-) generated during the ORR plays a critical role in the stability of the solvents.


Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs.
A wide array of molecular pathways has been investigated during the past decade in order to understand the mechanisms by which the practice of physical exercise promotes neuroprotection and reduces the risk of developing communicable and non-communicable chronic diseases. While a single session of physical exercise may represent a challenge for cell homeostasis, repeated physical exercise sessions will improve immunosurveillance and immunocompetence. Additionally, immune cells from the central nervous system will acquire an anti-inflammatory phenotype, protecting central functions from age-induced cognitive decline. This review highlights the exercise-induced anti-inflammatory effect on the prevention or treatment of common chronic clinical and experimental settings. It also suggests the use of pterins in biological fluids as sensitive biomarkers to follow the anti-inflammatory effect of physical exercise.


Can patents deter innovation? The anticommons in biomedical research.
The "tragedy of the commons" metaphor helps explain why people overuse shared resources. However, the recent proliferation of intellectual property rights in biomedical research suggests a different tragedy, an "anticommons" in which people underuse scarce resources because too many owners can block each other. Privatization of biomedical research must be more carefully deployed to sustain both upstream research and downstream product development. Otherwise, more intellectual property rights may lead paradoxically to fewer useful products for improving human health.


Investigation of Age Polyethism in Food Processing of the Fungus-Growing Termite Odontotermes formosanus (Blattodea: Termitidae) Using a Laboratory Artificial Rearing System.
Laboratory rearing systems are useful models for studying Rhinotermitid behavior. Information on the biology of fungus-growing termites, however, is limited because of the difficulty of rearing colonies in the laboratory settings. The physical structure of termite nests makes it impossible to photograph or to observe colonies in the field. In this study, an artificial rearing system for field-collected colonies of the fungus-growing termite Odontotermes formosanus (Shiraki) was developed to facilitate observation in the laboratory. We recorded colony activity within the artificial rearing system and documented a variety of social behaviors that occurred throughout the food processing of the colony. This complex miniature ecosystem was cooperatively organized via division of labor in the foraging and processing of plant materials, and the observed patterns largely resembled the caste and age-based principles present in Macrotermes colonies. This work extends our insights into polyethism in the subfamily Macrotermitinae.