Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue.
Many brain disorders, including epilepsy, migraine and depression, manifest with episodic symptoms that may last for various time intervals. Transient alterations of neuronal function such as related to serotonin homeostasis generally underlie this phenomenon. Several nucleotide polymorphisms (SNPs) in gene promoters associated with these diseases have been described. For obvious reasons, their regulatory roles on gene expression particularly in human brain tissue remain largely enigmatic. The rs6295 G-/C-allelic variant is located in the promoter region of the human HTR1a gene, encoding the G-protein-coupled receptor for 5-hydroxytryptamine (5HT1AR). In addition to reported transcriptional repressor binding, our bioinformatic analyses predicted a reduced binding affinity of the transcription factor (TF) c-Jun for the G-allele. In vitro luciferase transfection assays revealed c-Jun to (a) activate the rs6295 C- significantly stronger than the G-allelic variant and (b) antagonize efficiently the repressive effect of Hes5 on the promoter. The G-allele of rs6295 is known to be associated with aspects of major depression and migraine. In order to address a potential role of rs6295 variants in human brain tissue, we have isolated DNA and mRNA from fresh frozen hippocampal tissue of pharmacoresistant temporal lobe epilepsy (TLE) patients (n=140) after epilepsy surgery for seizure control. We carried out SNP genotyping studies and mRNA analyses in order to determine HTR1a mRNA expression in human hippocampal samples stratified according to the rs6295 allelic variant. The mRNA expression of HTR1a was significantly more abundant in hippocampal mRNA of TLE patients homozygous for the rs6295 C-allele as compared to those with the GG-genotype. These data may point to a novel, i.e., rs6295 allelic variant and c-Jun dependent transcriptional 5HT1AR 'receptoropathy'.


[Study on the experimental model of krypton laser-induced choroidal neovascularization in the rats].
To evaluate the feasibility of krypton laser-induced choroidal neovascularization (CNV) model in the Brown Norway rats in order to establish the foundation for studying the mechanism of CNV and for the development of treatment for CNV. Experimental eyes in 33 rats were received a series of 10 krypton red laser (647 nm) lesions per eye (360 mW, 50 micro m, 0.05 s). Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were performed, then the rats were sacrificed immediately, the eyes were enucleated and processed for histopathologic examination and transmission electron microscopy on days 3, 7, 14, 21, 28 and 56. CNV was firstly appeared on day 7 after photocoagulation, reaching the peak on day 21. The incidence of CNV was 76.0%. Disciform leakage staining appeared in the FFA. ICGA showed that the disciform area was filled with CNV. CNV was ascertained by light microscopy and electron microscopy. The thickness of laser-induced CNV was increased from day 7 to day 21 (P < 0.01) and no significant progress occurred after day 21 (P > 0.05). The present studies demonstrated that krypton laser photocoagulation could be used to produce choroidal neovascularization experimental model in the Brown Norway rat. CNV can be induced rapidly by the method, persists for a long period and at a high successful rate.


Preoperative Eccentric Aortic Regurgitation and Outcomes Following Valve-Sparing Root Replacement.
The David V valve-sparing root replacement (VSRR) is well-established for the treatment of aortic insufficiency (AI) and advanced root aortopathy. The impact of cusp repair in trileaflet aortic valve (TAV) patients, however, with preoperative moderate-severe AI and an eccentric jet is unclear. This study compares outcomes in TAV patients with pre-operative AI >2+ based on jet centricity and cusp repair status. Review of a single institutional database identified 309 consecutive patients undergoing VSRR from 2005 to 2018. Of these, 51 patients had TAV with AI >2+: 25 concentric and 26 eccentric jets. Mean follow-up was 58 (SD = 44) months. Echocardiographic parameters were compared pre- and post-operatively. Kaplan-Meier analysis, longitudinal mixed modeling, and cumulative incidence were used to compare long-term survival, recurrence of AI >1+, and valve specific re-intervention, respectively. The mean age was 48 (SD = 12) years and 84% were male. Differences in preoperative comorbidities and echocardiographic parameters between groups were not statistically significant. Postoperative outcomes were similar in concentric vs. eccentric and cusp vs. no cusp repair. Recurrence of AI>1+ was minimal and unrelated to jet centricity (concentric = 1, eccentric = 3) and cusp repair (no cusp repair = 1, cusp repair = 3) long-term. Aortic valve replacement cumulative incidence was 0% for central and 5% for eccentric at 3-, 5-, and 10-years, respectively. Long-term mortality was similar regardless of jet centricity and cusp repair. In appropriately selected TAV patients with preoperative AI >2+, current results suggest VSRR provides a durable repair regardless of jet centricity or the need for cusp repair based on low rates of reintervention reported.


Validation of the Brazilian Version of the Langer Mindfulness Scale.
Background and Purpose: The Langer Mindfulness Scale (LMS) is distinguished from other mindfulness scales by its dimensions, which are closely related to the awareness and experience of novelty, and by being a scale derived from a cognitive perspective of information processing. There are no mindfulness instruments of this type available in Brazil. Therefore, this study aimed to carry out a translation and cultural adaptation of the LMS into Brazilian Portuguese and to validate and assess the internal consistency and convergent construct validity of the translated instrument. Methods: The study had two distinct stages: (a) translation and cultural adaptation of the LMS into Brazilian Portuguese and (b) validation of the adapted instrument using a sample of 543 participants. Results: The Brazilian version of the LMS demonstrated acceptable internal consistency, with confirmatory factor analysis supporting the original four-factor model. Correlations between LMS, and the Five Facets of Mindfulness Questionnaire and the Mindfulness Attention Awareness Scale were statistically significant and in the expected directions. Conclusions: Our findings suggest that the Brazilian version of LMS, with its four dimensions, presents acceptable psychometric properties and seems to be a reliable and valid instrument for assessing the state of mindfulness in a Brazilian cultural context.


Metronidazole prophylaxis in colorectal surgery: the need for additional aminoglycoside?
A randomized double-blind trial was conducted in two phases to compare the efficacy of prophylactic oral and intravenous administration of kanamycin and metronidazole in preventing wound infection and other complications in patients undergoing colorectal surgery, and also to assess the need for inclusion of an aminoglycoside in the prophylactic regimen. Adequate prophylaxis did not depend on the route of antimicrobial administration, but wound infection rates were increased following exclusion of kanamycin.


Studies on the fat mass and obesity-associated (FTO) gene and its impact on obesity-associated diseases.
Obesity has become a major health crisis in the past ∼50 years. The fat mass and obesity-associated (FTO) gene, identified by genome-wide association studies (GWAS), was first reported to be positively associated with obesity in humans. Mice with more copies of the FTO gene were observed to be obese, while loss of the gene in mice was found to protect from obesity. Later, FTO was found to encode an m6A RNA demethylase and has a profound effect on many biological and metabolic processes. In this review, we first summarize recent studies that demonstrate the critical roles and regulatory mechanisms of FTO in obesity and metabolic disease. Second, we discuss the ongoing debates concerning the association between FTO polymorphisms and obesity. Third, since several small molecule drugs and micronutrients have been found to regulate metabolic homeostasis through controlling the expression or activity of FTO, we highlight the broad potential of targeting FTO for obesity treatment. Improving our understanding of FTO and the underlying mechanisms may provide new approaches for treating obesity and metabolic diseases.


Estrogen receptor-negative/progesterone receptor-positive and her-2-negative breast cancer might no longer be classified as hormone receptor-positive breast cancer.
The single progesterone receptor (PR)-positive phenotype (estrogen receptor (ER)-/PR + , sPR positive) is an infrequent and independent biological entity. However, the prognosis of patients with sPR-positive and her-2-negative phenotype is still controversial, and it is not always easy to decide treatment strategies for them. Patients during 2010-2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was used to evaluate cancer-specific survival (CSS). The propensity score matching (PSM) method was used to balance differences of characteristics in groups. The Life-Table method was used to calculate 5-year CSS rates and the annual hazard rate of death (HRD). A total of 97,527 patients were included, and only 745 (0.76%) patients were sPR-positive phenotype. The majority of sPR-positive breast cancer were basal-like subtype. Survival analysis showed that the sPR-positive breast cancer had similar prognosis comparing to double hormonal receptor-negative (ER-/PR-, dHoR-negative) breast cancer, and had the highest HRD during the initial 1-2 years of follow-up, then maintained the HRD of almost zero during the late years of follow-up. The patients with sPR-positive and her-2-negative breast cancer, similar to dHoR-negative breast cancer, had a worse survival, and could benefit from chemotherapy significantly. However, the escalating endocrine therapy was not recommended for sPR-positive patients. The patients with sPR positive should be excluded from future clinical trials concerning endocrine therapy.


HGT turbulence: Confounding phylogenetic influence of duplicative horizontal transfer and differential gene conversion.
Horizontal gene transfer (HGT) often leads to phylogenetic incongruence. When "duplicative HGT" introduces a second copy of a pre-existing gene, the two copies may then engage in gene conversion, leading to phylogenetically mosiac genes. When duplicative HGT is followed by differential gene conversion among descendant lineages, as under the DH-DC model, phylogenetic analysis is further complicated. To explore the effects of DH-DC on phylogeny reconstruction, we analyzed two sets of sequences: (1) an augmented set of plant mitochondrial atp1 sequences for which we recently published evidence of DH-DC; and (2) a set of simulated sequences for which we varied the extent of chimerism, the number of chimeric genes and nucleotide substitution rates. We show that the phylogenetic behavior of evolutionarily chimeric genes is highly volatile and depends on both the degree of chimerism and the number of differentially chimeric genes present in the analysis. Furthermore, we show that the presence of chimeric genes in gene trees can spuriously affect the phylogenetic position of purely native sequences, especially by attracting these sequences toward basal positions in trees. We propose the term "HGT turbulence" to describe these complex effects of evolutionarily chimeric genes on phylogenetic results.


Diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC).
Both bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. The prognosis may darken not infrequently, especially in the presence of intracardiac devices or methicillin-resistance. Indeed, the optimization of the antimicrobial therapy is a key step in the outcome of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates has led to the research of novel therapeutic schemes. Specifically, the interest raised in recent years on the new antimicrobials with activity against methicillin-resistant staphylococci has been also extended to infections caused by susceptible strains, which still carry the most important burden of infection. Recent clinical and experimental research has focused in the activity of new combinations of antimicrobials, their indication and role still being debatable. Also, the impact of an appropriate empirical antimicrobial treatment has acquired relevance in recent years. Finally, it is noteworthy the impact of the implementation of a systematic bundle of measures for improving the outcome. The aim of this clinical guideline is to provide an ensemble of recommendations in order to improve the treatment and prognosis of bacteremia and infective endocarditis caused by S. aureus, in accordance to the latest evidence published.


Platelet-derived growth factor elicits cyclic AMP accumulation in Swiss 3T3 cells: role of prostaglandin production.
Partially purified porcine PDGF or purified human PDGF in the presence of phosphodiesterase inhibitors caused marked accumulation of cAMP in Swiss 3T3 cells. The responses were time- and dose-dependent; half-maximal effect was obtained at 0.6 nM PDGF. Indomethacin prevented the increase of cAMP levels in a dose-dependent manner; half-maximal effect was obtained at about 10 nM. Addition of PDGF increased (at least 25-fold) the production of E-type prostaglandins; PGE reached a concentration in the medium of 26 ng/ml 1 hr after treatment with human PDGF. This concentration of PGE produced a similar level of cAMP to that found with PDGF, suggesting that the PDGF-induced increase in cAMP is mediated by E-type prostaglandins released in the culture medium. Increased cAMP levels promoted by PDGF acting through stimulation of E-type prostaglandin synthesis may contribute to signal the initiation of cell proliferation in 3T3 cells.


A population-based study of the fractionation of palliative radiotherapy for bone metastasis in Ontario.
To describe the use of palliative radiotherapy (PRT) for bone metastases in Ontario between 1984 and 2001 and identify factors associated with the choice of fractionation. Electronic RT records from the nine provincial RT centers in Ontario were linked to the Ontario Cancer Registry to identify all courses of PRT for bone metastases. Between 1984 and 2001, 44,884 patients received 74,432 courses of PRT for bone metastases in Ontario. The mean number of courses per patient was 1.7, and 65% of patients received only a single course of PRT for bone metastasis. The mean number of fractions per course was 3.9. The proportion of patients treated with a single fraction increased from 27.2% in 1984-1986 to 40.3% in 1987-1992 and decreased thereafter. Single fractions were used more frequently in patients with a shorter life expectancy, in older patients, and in patients who lived further from an RT center. Single fractions were used more frequently when the prevailing waiting time for RT was longer. There were wide variations in the use of single fractions among the different RT centers (intercenter range, 11.8-62.3%). Intercenter variations persisted throughout the study period and were not explained by differences in case mix. Despite increasing evidence of the effectiveness of single-fraction PRT for bone metastases, most patients continued to receive fractionated PRT throughout the two decades of this study. Single fractions were used more frequently when waiting times were longer. There was persistent, unexplained variation in the fractionation of PRT among different centers.


Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer.
The dynamic regulation of alternative splicing requires coordinated participation of multiple RNA binding proteins (RBPs). Aberrant splicing caused by dysregulation of splicing regulatory RBPs is implicated in numerous cancers. Here, we reveal a frequently overexpressed cancer-associated protein, DAP3, as a splicing regulatory RBP in cancer. Mechanistically, DAP3 coordinates splicing regulatory networks, not only via mediating the formation of ribonucleoprotein complexes to induce substrate-specific splicing changes, but also via modulating splicing of numerous splicing factors to cause indirect effect on splicing. A pan-cancer analysis of alternative splicing across 33 TCGA cancer types identified DAP3-modulated mis-splicing events in multiple cancers, and some of which predict poor prognosis. Functional investigation of non-productive splicing of WSB1 provides evidence for establishing a causal relationship between DAP3-modulated mis-splicing and tumorigenesis. Together, our work provides critical mechanistic insights into the splicing regulatory roles of DAP3 in cancer development.


The anticonvulsant hypersensitivity syndrome.
Anticonvulsants can cause a characteristic hypersensitivity reaction. This multisystem reaction typically presents as fever, mucocutaneous eruptions, lymphadenopathy and hepatitis. There is cross-reactivity between different anticonvulsants, which complicates subsequent therapy. We report three cases to illustrate both the typical features, and less common complications, of this under-recognized and life-threatening syndrome.


StarD13 negatively regulates invadopodia formation and invasion in high-grade serous (HGS) ovarian adenocarcinoma cells by inhibiting Cdc42.
Metastasis remains the main challenge to overcome for treating ovarian cancers. In this study, we investigate the potential role of the Cdc42 GAP StarD13 in the modulation of cell motility, invasion in ovarian cancer cells. StarD13 depletion does not affect the 2D motility of ovarian cancer cells. More importantly, StarD13 inhibits matrix degradation, invadopodia formation and cell invasion through the inhibition of Cdc42. StarD13 does not localize to mature TKS4-labeled invadopodia that possess matrix degradation ability, while a Cdc42 FRET biosensor, detects Cdc42 activation in these invadopodia. In fact, StarD13 localization and Cdc42 activation appear mutually exclusive in invadopodial structures. Finally, for the first time we uncover a potential role of Cdc42 in the direct recruitment of TKS4 to invadopodia. This study emphasizes the specific role of StarD13 as a narrow spatial regulator of Cdc42, inhibiting invasion, suggesting the suitability of StarD13 for targeted therapy.


Protein kinase C-alpha inhibits the repair of oxidative phosphorylation after S-(1,2-dichlorovinyl)-L-cysteine injury in renal cells.
Previously, we showed that physiological functions of renal proximal tubular cells (RPTC) do not recover following S-(1,2-dichlorovinyl)-l-cysteine (DCVC)-induced injury. This study investigated the role of protein kinase C-alpha (PKC-alpha) in the lack of repair of mitochondrial function in DCVC-injured RPTC. After DCVC exposure, basal oxygen consumption (Qo(2)), uncoupled Qo(2), oligomycin-sensitive Qo(2), F(1)F(0)-ATPase activity, and ATP production decreased, respectively, to 59, 27, 27, 57, and 68% of controls. None of these functions recovered. Mitochondrial transmembrane potential decreased 53% after DCVC injury but recovered on day 4. PKC-alpha was activated 4.3- and 2.5-fold on days 2 and 4, respectively, of the recovery period. Inhibition of PKC-alpha activation (10 nM Go6976) did not block DCVC-induced decreases in mitochondrial functions but promoted the recovery of uncoupled Qo(2), oligomycin-sensitive Qo(2), F(1)F(0)-ATPase activity, and ATP production. Protein levels of the catalytic beta-subunit of F(1)F(0)-ATPase were not changed by DCVC or during the recovery period. Amino acid sequence analysis revealed that alpha-, beta-, and epsilon-subunits of F(1)F(0)-ATPase have PKC consensus motifs. Recombinant PKC-alpha phosphorylated the beta-subunit and decreased F(1)F(0)-ATPase activity in vitro. Serine but not threonine phosphorylation of the beta-subunit was increased during late recovery following DCVC injury, and inhibition of PKC-alpha activation decreased this phosphorylation. We conclude that during RPTC recovery following DCVC injury, 1). PKC-alpha activation decreases F(0)F(1)-ATPase activity, oxidative phosphorylation, and ATP production; 2). PKC-alpha phosphorylates the beta-subunit of F(1)F(0)-ATPase on serine residue; and 3). PKC-alpha does not mediate depolarization of RPTC mitochondria. This is the first report showing that PKC-alpha phosphorylates the catalytic subunit of F(1)F(0)-ATPase and that PKC-alpha plays an important role in regulating repair of mitochondrial function.


Gonadal and pituitary responses to progesterone antagonist ZK 98.299 during the follicular phase of the menstrual cycle in bonnet monkeys.
ZK 98.299 is a potent progesterone antagonist. Its effects on folliculogenesis, bioactive LH, ovulation and menstrual cycle (m.c.) length were studied in adult bonnet monkeys. ZK 98.299 (20 mg/day) was administered s.c., once daily on days 5 to 15 of m.c., to ten animals. The pretreatment m.c. was of 26.5 days (25 to 28 days, mean with 95% confidence limits) and on treatment it was significantly (p less than 0.001) prolonged to 46.9 days (39 to 54 days). The anticipated midcycle rise in estradiol and bioactive LH levels was completely blocked in six and attenuated in three animals during the treatment period. However, the levels did not drop below the early follicular phase levels. In one animal (#90), though the cycle length was prolonged by 5 days the midcycle rise in estradiol and bioactive LH levels was observed during the treatment period and this animal had normal luteal function. Seven animals had delayed ovulation whereas, two had anovulatory treatment cycles. The rise in estradiol and bioactive LH levels, prior to ovulation in the treatment cycles, was compatible with the midcycle rise observed in the pretreatment cycles. Serum progesterone levels during the luteal phase of the treatment cycles were normal in six animals whereas, in two they were indicative of luteal insufficiency. In two animals, the treatment cycles were anovulatory. ZK 98.299 had no effect on the duration of menses. The post-treatment cycles were of normal duration. This study suggests that the administration of ZK 98.299 during the follicular phase blocks estradiol and bioactive LH release and terminates the follicular phase in most of the animals. The follicular phase is reinitiated after the treatment is stopped.


B-type natriuretic peptide as an integrated risk marker in non-ST elevation acute coronary syndromes.
Elevated B-type natriuretic peptide (BNP) levels show prognostic significance in patients with non-ST elevation acute coronary syndromes, but the underlying pathophysiology remains unclear. Two hundred and eighteen consecutive patients with non-ST elevation acute coronary syndromes were studied retrospectively. We compared clinical characteristics between groups with plasma BNP levels above or below the median value, and performed multiple logistic regression analysis to identify independent predictors of supramedian BNP levels. Patients with supramedian BNP (>or=134 pg/ml) were more likely to be elderly (>or=75 years) with diabetes, prior myocardial infarction, and a history of coronary artery bypass grafting. They also had higher cardiac marker levels, a higher Killip class, a lower left ventricular ejection fraction, renal insufficiency (creatinine>or=1.5 mg/dl), and more 3-vessel disease. In multivariate analysis, the strongest independent predictor of supramedian BNP levels was 3-vessel disease (chi(2)=12.1), followed by old age (chi(2)=10.3), renal insufficiency (chi(2)=5.0), higher Killip class (chi(2)=4.2), and lower left ventricular ejection fraction (chi(2)=4.1). All 11 patients dying in hospital had supramedian BNP levels. Its elevation reflected the risk of 3-vessel disease and coronary artery bypass grafting regardless of troponin status. In unselected patients with non-ST elevation acute coronary syndromes, an increase of BNP is correlated with the extent of myocardial ischemia, age, renal insufficiency, and ventricular dysfunction. It may be a useful biomarker integrating conventional risk factors for risk stratification in this population.


Hydrogel bowls for cleaning oil spills on water.
We demonstrate a hydrogel bowl capable of selectively and rapidly collecting spilled oil while floating on water. The bowl has macroscopic openings in its sidewall, and its surface is first coated with octadecyltrichlorosilane (OTS) and then with diffusion pump oil, which imparts exceptional hydrophobic, oleophilic, and high oil wettability properties. The use of a hydrogel makes it possible to obtain surface hydrophobicity and oleophilicity, while also being inexpensive, eco-friendly, and easy to fabricate. Using a prototype of the bowl and a small pump system, we demonstrate that oils with a broad range of viscosities (2.7-2000.0 cSt at 20-40 °C) are more rapidly and efficiently collected from the surface of both pure water and seawater than with any other reported technique. The hydrogel bowl can collect oil for more than one month without losing its efficiency and can be stored in oil for reuse. Therefore, such hydrogel bowls represent a new alternative to conventional oil spill remediation techniques.


Altered excitability of afferent C-fibres of the rat distal to a nerve site exposed to capsaicin.
Excitability of afferent C-fibres in saphenous and coccygeal nerves of rats was studied distal to a nerve site treated with 1% capsaicin for half an hour one day before. This treatment induced the following changes. (a) Fewer C-fibres than in control nerves were excited by natural skin stimulation among those driven by electrical nerve stimulation. Comparison of compound action potentials derived from capsaicin-treated and from untreated contralateral coccygeal nerves indicated that the total number of excitable C-fibres was also diminished. (b) Whereas in a normal rat nerve virtually all unmyelinated nociceptors responding to heat stimulation are also driven by strong mechanical stimuli (MH-nociceptors, polymodal nociceptors), most of them were found to respond only to heat stimulation after local capsaicon treatment of the nerve.


A passive isolation of sensor faults from un-stealthy attacks in uncertain nonlinear systems.
In this paper, a novel nonlinear observer-based approach is established to cast light on the problem of isolating sensor faults from un-stealthy attacks for Lipschitz affine nonlinear systems subjected to unknown uncertainties and disturbances. A structure consisting of a multi-line transmission mechanism, a random number generator (RNG), and Dedicated Observer Scheme is developed to make the abnormal behaviors distinguishable. A group of two interlinked nonlinear Luenberger-Like observers is designed in nonlinear coordinates to detect abnormal behaviors. Two banks of detection observers and an incidence matrix are introduced to make the final decisions. Adaptive threshold techniques are exploited to guarantee the robustness against the model uncertainties and disturbances. Compared with the existing results, the proposed approach isolates the abnormal behaviors without the need for any redundant hardware components. Finally, the performance of the proposed approach is evaluated on a continuous stirred tank reactor (CSTR).


Detection of anti-colon antibodies in inflammatory bowel disease using human cultured colonic cells.
Investigation of anti-colon antibodies may be simplified if a sensitive method and homogeneous source of antigen were available. To examine the anti-colon antibody response using human colonic carcinoma cell lines as antigen. Patients with inflammatory bowel disease and other gastrointestinal disorders and healthy controls were studied. Comparative enzyme linked immunosorbent assays (ELISAs) were performed to assess the value of whole Caco-2, HT-29, and LS-180 cells as antigen. The antigenic determinants of the immune response were characterised by western blot analysis. Sera demonstrated immunoreactivity against each of the cell lines, but different epitopes were recognised. Applying whole Caco-2 cells as antigen in an ELISA, the prevalence of anti-colon antibodies was significantly greater in patients with ulcerative colitis (36%) than Crohn's disease (13%), other gastrointestinal disorders (13%) and healthy controls (0) (p<0. 05). The immune response was not associated with one predominant antigen. Fixed whole cell ELISA is a simple and feasible method for studying the anti-colon antibody response. This response is non-specific, being directed against multiple antigens, and is likely to be an epiphenomenon of inflammatory bowel disease, more so for ulcerative colitis than Crohn's disease.


Analysis of B-lymphocyte differentiation in patients infected with hepatitis C virus.
To clarify whether some of the functions of B lymphocytes could be affected during hepatitis C virus (HCV) infection, phenotypic characteristics of B lymphocytes from HCV-infected patients and their capacity to differentiate into immunoglobulins (Ig)-secreting cells were studied. B lymphocytes differentiation was investigated for patients untreated and non-responders (n=9), treated and non-responders (n=6), responders (n=6), long-term responders (n=9) to therapy and seronegative controls (n=14) following in vitro stimulation with S. aureus strain Cowan I mitogen. HCV sequences in purified B lymphocytes were detected by RT-PCR. It was found that HCV-patients harbor a similar mean percentage of B cells and a normal level of naïve B cells (% IgM+/IgD+ cells=79.7 +/- 15.4 for untreated non-responders, 57.1 +/- 22.9 for treated non-responders, 44.3 +/- 29.1 for responders, 75.7 +/- 16 for long-term responders) as compared with controls. It was also found that peripheral blood mononuclear cells (PBMCs) of patients or controls produced similar amounts of IgG, A, and M in vitro. A total of 57% of untreated non-responders versus 17% of treated non-responders were able to produce HCV-specific antibodies. Interestingly, B lymphocytes from PBMCs able to secrete anti-HCV antibodies contained HCV positive strand RNA, although no systematic detection of the negative strand was found. These data suggest that signaling through the B cell receptor (BCR) in B lymphocytes of HCV-infected patients appears normal whatever their response to therapy. The capacity to secrete HCV-specific IgG seemed to be linked to the presence of positive strand RNA rather than virus replication.


Left hemisphere specialization for duration discrimination of musical and speech sounds.
Hemispheric asymmetries for processing duration of non-verbal and verbal sounds were investigated in 60 right-handed subjects. Two dichotic tests with attention directed to one ear were used, one with complex tones and one with consonant-vowel syllables. Stimuli had three possible durations: 350, 500, and 650 ms. Subjects judged whether the duration of a probe was same or different compared to the duration of the target presented before it. Target and probe were part of two dichotic pairs presented with 1s interstimulus interval and occurred on the same side. Dependent variables were reaction time and accuracy. Results showed a significant right ear advantage for both dependent variables with both complex tones and consonant-vowel syllables. This study provides behavioural evidence of a left hemisphere specialization for duration perception of both musical and speech sounds in line with the current view based on a parameter--rather than domain-specific structuring of hemispheric perceptual asymmetries.


Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell Carcinoma.
Treatment intensification either by using concurrent chemoradiotherapy (CCRT) or altered fractionation radiotherapy (AFRT) improves outcomes of locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The superiority of one approach over the other, however, remains to be firmly established. The aim of the present study was to compare outcomes of CCRT versus AFRT in the definitive non-surgical management of locoregionally advanced HNSCC for evidence-based decision making. An electronic search of Medline via PubMed was conducted with no language, year, or publication status restrictions. The Cochrane Central Register of Controlled Trials (CENTRAL) and Database of Abstracts of Reviews of Effectiveness (DARE) were also searched electronically. Only randomised controlled trials assigning HNSCC patients randomly to conventionally fractionated CCRT or AFRT alone were included. Data were extracted independently by two reviewers and pooled using the Cochrane methodology for meta-analysis and expressed as a hazard ratio with 95% confidence intervals. Overall survival was the primary outcome of interest, whereas disease-free survival, locoregional control and toxicity were secondary end points. Five randomised controlled trials (involving 1117 patients and 627 deaths) directly comparing conventionally fractionated CCRT with AFRT alone were included. The risk of bias in included studies was low for efficacy outcomes, but high for toxicity outcomes. The overall pooled hazard ratio of death was 0.73 (95% confidence interval = 0.62-0.86), which significantly favoured conventionally fractionated CCRT over AFRT alone (P < 0.0001). Similarly, disease-free survival (hazard ratio = 0.79, 95% confidence interval = 0.68-0.92; P = 0.002) and locoregional control (hazard ratio = 0.71, 95% confidence interval = 0.59-0.84; P < 0.0001) were significantly improved with CCRT. There were no significant differences in the incidence of severe acute toxicity (dermatitis and mucositis) between the two approaches of treatment intensification. Late xerostomia was significantly increased with CCRT. Significant haematological toxicity and nephrotoxicity were seen exclusively with chemotherapy. There is moderate quality evidence that conventionally fractionated CCRT improves survival outcomes compared with AFRT alone in the definitive radiotherapeutic management of locoregionally advanced HNSCC. No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy.


A review of antidepressant-induced hypomania in major depression: suggestions for DSM-V.
To determine if the classification of 'antidepressant-induced hypomania' in DSM-IV is supported by available data. We reviewed the available scientific literature to examine the incidence of mania and hypomania in non-bipolar patients who were treated with antidepressants. Eighty-nine per cent of studies of antidepressants in major depressive disorder patients reported no cases of treatment-induced hypomania. No instances of treatment-induced hypomania were reported in three large studies of patients with chronic forms of depression. The rate of antidepressant-induced hypomania in major depressive disorder is within the rate of misdiagnosis of bipolar depression as unipolar. Depressed patients who experience antidepressant-associated hypomania are truly bipolar.


A nursing intervention to increase compliance in otitis media patients.
This study was conducted to evaluate two forms of a clinical nursing intervention based on the Health Belief Model (HBM) and designed to increase compliance among 59 otitis media (OM) patients (14 adults and 45 children) visiting an emergency department (ED). Subjects (adult patients or caretakers of child patients) who received an HBM clinical intervention administered by a nurse in the ED, and HBM phone intervention 2 to 4 days after the ED visit, or both interventions were much more likely than control subjects to comply with a follow-up referral appointment. Both the clinical and phone interventions were designed to increase perceived susceptibility to complications of the OM, seriousness of the complications, and benefits and costs of action. Other factors predicting compliance included subjects' unmet needs for child care, perceived seriousness of the OM, and degree of knowledge of the etiology, pathophysiology, and management of OM.


Clinical Research Abstracts of the British Equine Veterinary Association Congress 2015.
In cases of laminitis, an increased muscle force or contracture of the deep digital flexor muscle (DDFM) is suggested, but evidence-based research is lacking. To test if the DDFM of laminitic equines shows an increased muscle force detectable by needle-EMG including Interference Pattern Analysis (IPA). Cross-sectional study. Three groups consisted of Group 0 (control): 6 Royal Dutch Sport horses, 3 Shetland ponies and one Welsh pony (healthy, sound adults, mean ± s.d. weight 411 ± 217 kg). Group 1: 3 Royal Dutch Sport horses, one Friesian, one Haflinger, one Icelandic horse, 2 Welsh ponies, one miniature Appaloosa and 6 Shetland ponies (adults, mean ± s.d. weight 310 ± 172 kg) suffering from acute or chronic laminitis. EMG measurements including firing frequency (F) and IPA parameters Turns/Second (T), Amplitude/Turn (M) and Ratio M/T (R) were performed. ANOVA was used to analyse data. P values of P<0.05 were considered significant. Mean ± s.d. F of Group 0 and Group 1 was 53 ± 11 and 72 ± 21 Hz, mean ± s.d. T was 112 ± 57 and 106 ± 42, mean ± s.d. M was 284 ± 51 and 254 ± 38 μV and mean ± s.d. R was 0.39 ± 0.17 and 0.42 ± 0.16%, respectively. The firing frequency of Group 1 was significantly higher compared to Group 0 (P = 0.02), whereas other differences were not significant. In human medicine, an increased firing frequency is a characteristic of increased muscle force [1,2]. Thus, the increased firing frequency of the DDFM in case of laminitis suggests an elevated muscle force. As all parameters show a high variance, a repeated study including a larger test group is advised. Ethical animal research: Data collection from controls was approved by the Animal Welfare Committee of Utrecht University, approval number 2008.III.07.061 and 2013.III.01.012. Clinical cases were privately owned and written owner consent was obtained. None. Competing interests: None declared.


Experimental Assessment of the Degradation of "Unbiodegradable" Organic Solids in Activated Sludge.
In current process models activated sludge consists of biodegradable and unbiodegradable organic fractions. Recent evidence suggests that this approach may not be accurate because some of this "unbiodegradable" material may indeed be degradable. To improve sludge production predictions, it is important to know to what extent the "unbiodegradable" organic fraction is degradable. Assuming that volatile suspended solids (VSS) is a measure of the sum of biodegradable and unbiodegradable organic solids and the integral of the oxygen uptake rate (OUR) is representative of the biodegradable organics, the combination of these measurements can be used to predict the change of unbiodegradable organic solids within an aerobic digestion batch experiment. This procedure was used to estimate degradation rates of "unbiodegradable" VSS between 0.006 to 0.029 d(-1). The advantage of the proposed method is that the degradation rate can be determined directly based on measurements and relies on a limited number of assumptions.


The influence of parasitic water mites on the instantaneous death rate of their hosts.
The effect of 2 species of water mites on the instantaneous death rate of their hosts was measured on the basis of laboratory experiments. In both parasite-host association - the parasitic water mite Hydryphantes tenuabilis on the aquatic insect host Hydrometra australis and the parasitic water mite Arrenurus pseudotenuicollis on the mosquito Anopheles crucians - the effect of mite load on the instantaneous death rate of the host appeared to be linear. Also, the impact of a single parasite on the host's death rate was apparently related to the ratio of parasite to host body weight. The results of this study are in general agreement with recent theoretical investigations of the regulation of host populations by parasites.


PERSIST platform provides programmable RNA regulation using CRISPR endoRNases.
Regulated transgene expression is an integral component of gene therapies, cell therapies and biomanufacturing. However, transcription factor-based regulation, upon which most applications are based, suffers from complications such as epigenetic silencing that limit expression longevity and reliability. Constitutive transgene transcription paired with post-transcriptional gene regulation could combat silencing, but few such RNA- or protein-level platforms exist. Here we develop an RNA-regulation platform we call "PERSIST" which consists of nine CRISPR-specific endoRNases as RNA-level activators and repressors as well as modular OFF- and ON-switch regulatory motifs. We show that PERSIST-regulated transgenes exhibit strong OFF and ON responses, resist silencing for at least two months, and can be readily layered to construct cascades, logic functions, switches and other sophisticated circuit topologies. The orthogonal, modular and composable nature of this platform as well as the ease in constructing robust and predictable gene circuits promises myriad applications in gene and cell therapies.


FLOWERING LOCUS C in monocots and the tandem origin of angiosperm-specific MADS-box genes.
MADS-domain transcription factors have been shown to act as key repressors or activators of the transition to flowering and as master regulators of reproductive organ identities. Despite their important roles in plant development, the origin of several MADS-box subfamilies has remained enigmatic so far. Here we demonstrate, through a combination of genome synteny and phylogenetic reconstructions, the origin of three major, apparently angiosperm-specific MADS-box gene clades: FLOWERING LOCUS C- (FLC-), SQUAMOSA- (SQUA-) and SEPALLATA- (SEP-)-like genes. We find that these lineages derive from a single ancestral tandem duplication in a common ancestor of extant seed plants. Contrary to common belief, we show that FLC-like genes are present in cereals where they can also act as floral repressors responsive to prolonged cold or vernalization. This opens a new perspective on the translation of findings from Arabidopsis to cereal crops, in which vernalization was originally described.


Production of tricarballylic acid by rumen microorganisms and its potential toxicity in ruminant tissue metabolism.
1. Rumen microorganisms convert trans-aconitate to tricarballylate. The following experiments describe factors affecting the yield of tricarballylate, its absorption from the rumen into blood and its effect on mammalian citric acid cycle activity in vitro. 2. When mixed rumen microorganisms were incubated in vitro with Timothy hay (Phleum pratense L.) and 6.7 mM-trans-aconitate, 64% of the trans-aconitate was converted to tricarballylate. Chloroform and nitrate treatments inhibited methane production and increased the yield of tricarballylate to 82 and 75% respectively. 3. Sheep given gelatin capsules filled with 20 g trans-aconitate absorbed tricarballylate and the plasma concentration ranged from 0.3 to 0.5 mM 9 h after administration. Feeding an additional 40 g potassium chloride had little effect on plasma tricarballylate concentrations. Between 9 and 36 h there was a nearly linear decline in plasma tricarballylate. 4. Tricarballylate was a competitive inhibitor of the enzyme, aconitate hydratase (aconitase; EC 22.214.171.124), and the inhibitor constant, KI, was 0.52 mM. This KI value was similar to the Michaelis-Menten constant (Km) of the enzyme for citrate. 5. When liver slices from sheep were incubated with increasing concentrations of tricarballylate, [14C]acetate oxidation decreased. However, even at relatively high concentrations (8 mM), oxidation was still greater than 80% of the maximum. Oxidation of [14C]acetate by isolated rat liver cells was inhibited to a greater extent by tricarballylate. Concentrations as low as 0.5 mM caused a 30% inhibition of citric acid cycle activity.


Application of the general linear model for smoothing gas exchange data.
The precision of an interpretation of gas exchange records in progressive exercise is limited by the typical breath-to-breath variation in the data. Recently, two procedures have been proposed for minimizing the "noise" in the estimates of alveolar gas exchange time series data. One approach utilizes an estimate of pulmonary blood flow (Q) for smoothing purposes. The other approach utilizes an estimate of effective lung volume (V'L) for smoothing purposes. In this paper, we formulate the smoothing problem as a general linear model and demonstrate the concurrent estimates of both V'L and Q. Furthermore, we investigate the interaction between V'L and Q. Specifically, when a high value of lung volume is used (such as the subject's resting functional residual capacity) in the alveolar gas exchange algorithm, the estimate of Q is biased low and the result is a less effective smoothing of the data. In addition, we demonstrate how the Q estimate can be improved by utilizing more appropriate estimates of arterial carbon dioxide tension.


Functional analysis of selenok, selenot and selenop promoters and their regulation by selenium in yellow catfish Pelteobagrus fulvidraco.
The selenok, selenot and selenop are three key selenoproteins involved in stress response. Our study, using the yellow catfish Pelteobagrus fulvidraco as the experimental animal, obtained the 1993-bp, 2000-bp and 1959-bp sequences of selenok, selenot and selenop promoters, respectively, and predicted the binding sites of several transcriptional factors on their promoters, such as Forkhead box O 4 (FoxO4), activating transcription factor 4 (ATF4), Kruppel-like factor 4 (KLF4) and nuclear factor erythroid 2-related factor 2 (NRF2). Selenium (Se) increased the activities of the selenok, selenot and selenop promoters. FoxO4 and Nrf2 can directly bind with selenok promoter and controlled selenok promoter activities positively; KLF4 and Nrf2 can directly bind with selenot promoter and controlled selenot promoter activities positively; FoxO4 and ATF4 can directly bind to selenop promoter and regulated selenop promoter activities positively. Se promoted FoxO4 and Nrf2 binding to selenok promoter, KLF4 and Nrf2 binding to selenot promoter, and FoxO4 and ATF4 binding to selenop promoter. Thus, we provide the first evidence for FoxO4 and Nrf2 bindnig elements in selenok promoter, KLF4 and Nrf2 binding elements in selenot promoter, and FoxO4 and ATF4 binding elements in selenop promoter, and offer novel insight into regulatory mechanism of these selenoproteins induced by Se.


Combined rs-fMRI study on brain functional imaging and mechanism of RAGE-DAMPs of depression: Evidence from MDD patients to chronic stress-induced depression models in cynomolgus monkeys and mice.
More and more evidence show that major depressive disorder (MDD) is closely related to inflammation caused by chronic stress, which seriously affects human physical and mental health. However, the inflammatory mechanism of depression and its effect on brain function have not been clarified. Based on resting-state functional magnetic resonance imaging (rs-fMRI), we investigated change of brain functional imaging and the inflammatory mechanism of damage-related molecular patterns (DAMPs)-receptor of advanced glycation protein end product (RAGE) in MDD patients and depressive-like cynomolgus monkeys and mice models induced by chronic stress. The regional homogeneity (ReHo) and functional connectivity (FC) were analyzed using MATLAB and SPM12 software. We detected the expression of DAMPs-RAGE pathway-related proteins and mRNA in MDD peripheral blood and in serum and brain tissue of cynomolgus monkeys and mice. Meanwhile, RAGE gene knockout mice, RAGE inhibitor, and overexpression of AVV9RAGE adeno-associated virus were used to verify that RAGE is a reliable potential biomarker of depression. The results showed that the ReHo value of prefrontal cortex (PFC) in MDD patients and depressive-like cynomolgus monkeys was decreased. Then, the PFC was used as a seed point, the FC of ipsilateral and contralateral PFC were weakened in depressive-like mice. At the same time, qPCR showed that RAGE and HMGB1 mRNA were upregulated and S100β mRNA was downregulated. The expression of RAGE-related inflammatory protein in PFC of depressive-like monkeys and mice were consistent with that in peripheral blood of MDD patients. Moreover, the results were confirmed in RAGE-/- mice, injection of FPS-ZM1, and overexpression of AAV9RAGE in mice. To sum up, our findings enhance the evidence that chronic stress-PFC-RAGE are associated with depression. These results attempt to establish the links between brain functional imaging, and molecular targets among different species will help to reveal the pathophysiological mechanism of depression from multiple perspectives.


Rapid and accurate genotyping of human SNP rs671 in aldehyde dehydrogenase 2 gene using one-step CRISPR/Cas12b assay without DNA amplification.
The SNP rs671 of Human aldehyde dehydrogenase (ALDH) is G-A transition at 1510th nucleotides, which is an important clinical indicator of alcoholic liver disease, digestive tract cancer and some drug efficiency. The commonly used genotyping assay of this polymorphism is relatively time-consuming and costly. This study develops a rapid and accurate one-step CRISPR/Cas12b assay to distinguish the G1510A polymorphism of human ALDH2 free of DNA amplification. The method we established requires only one step of adding 1 μl genomic DNA sample to premixed system, and waiting for the acquisition of fluorescent signal, taking approximate 30 min. This method provides a potential tool for more accurate and reliable nucleic acid detection with a single base difference and supports the relevant disease diagnosis and personalized medicine.


Cardiovascular Pharmacology.
Pharmacologic therapy is an integral component in the management of most cardiovascular emergencies. This article reviews the pharmacotherapy involved in the treatment of acute coronary syndromes, acute heart failure, and various arrhythmias. The focus will be to provide practical pearls that can be applied at the bedside in the Emergency Department.


Antibodies against human parvovirus B19 in pregnant women in Ogbomoso, Oyo State Nigeria.
Infection caused by Human parvovirus B19 (HPVB19) during pregnancy has been associated with adverse effects on fetus such as intrauterine fetal death but there is dearth information about the seroprevalence and risk factors among pregnant women. This study was carried out to determine the incidence of specific IgM antibodies to HPVB19 among pregnant women attending Bowen University Teaching Hospital, Ogbomoso, Oyo State. A total of 185 participants, in the age range 18-49 years, who consented voluntarily after thorough explanation of the purpose of the study were recruited for the study. Specific IgM antibodies were detected using commercially available third-generation ELISA kits. Data on socio-demographic characteristics and potential risk factors were collected using structured questionnaires. Chi-square (χ2) test was utilized to assess the association between the socio-demographic variables and HPVB19 status (P ˂ 0.05). Logistic regression was done to determine the strength of association between the potential risk factors and HPVB19 status (P ˂ 0.05). The overall incidence of IgM antibody recorded was 2.70% (5/185). Pregnant women in the age group 36-45 (7.7%) years had the highest record. None of the socio-demographic characteristics and risk factor considered were significantly associated with acquiring HPVB19. However, a one-fold risk was observed among those who had previous history of blood transfusion (95% CI = 0.949-0.997, OR = 1.0) The findings in this study confirmed the presence of antibodies to HPVB19 among pregnant women in Ogbomoso. Public awareness, enlightenment, and screening for the virus should be encouraged to prevent fetal complications during pregnancy.


Interleukin-10 plays a crucial role in suppression of experimental autoimmune encephalomyelitis by Bowman-Birk inhibitor.
The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor with anti-inflammatory properties. Experimental autoimmune encephalomyelitis (EAE) serves as an animal model of the central nervous system (CNS) inflammatory disorder multiple sclerosis (MS). EAE is mediated by Th1 and Th17 cells which migrate into the CNS and initiate inflammation directed against myelin components, resulting in CNS pathology and neurological clinical deficit. We have shown previously that oral treatment with BBI delays onset of EAE and reduces its severity. These beneficial effects were associated with an increase in IL-10 secretion by immune cells of BBI-treated mice. It is not known, however, whether this was a causal relationship or simply an epiphenomenon. In the present study we provide evidence that BBI regulates CD4+ T cell immune responses in EAE. BBI administration delayed the onset of EAE and reduced its severity in an IL-10-dependent manner, as BBI-mediated suppression of EAE was abrogated in IL-10 knockout mice. The beneficial effects were accompanied by reduced IFN-γ, IL-17 and increased IL-10 production, as well as increased Foxp3 expression. CD4+ T cells were the major source of IL-10 in the periphery and in the CNS during BBI treatment. Furthermore, BBI-treated mice had reduced numbers of infiltrated cells in the CNS, including Th17 cells, as compared with PBS-treated control animals. In conclusion, our data provide clear evidence for the essential role of IL-10 in BBI-mediated suppression in EAE, and indicate that BBI may be a promising candidate for the development of a novel MS therapy.


Evidence for modification of lamin B by a product of mevalonic acid.
Previous work from this laboratory has shown that a derivative of mevalonic acid is post-translationally incorporated into a number of specific proteins in Swiss 3T3 cells. Neither the nature of the modification nor the identities of the modified proteins have been determined to date. Here we describe results concerning modified proteins of approximately 67 kDa from HeLa cells and Chinese hamster ovary cells. We show that these proteins are specific to the nucleus and remain associated with a Triton/salt-insoluble nuclear fraction. Furthermore, immunological studies demonstrate that one of the modified proteins comigrates on two-dimensional gels with lamin B, a structural protein associated with the nuclear envelope. Using antibodies directed against lamin B in an immunoprecipitation experiment, we further show that this mevalonic acid-modified protein specifically coprecipitates with lamin B. These results support the hypothesis that lamin B is modified by a derivative of mevalonic acid.


A cluster-randomised controlled trial to test the efficacy of facemasks in preventing respiratory viral infection among Hajj pilgrims.
Cost-effective interventions are needed to control the transmission of viral respiratory tract infections (RTIs) in mass gatherings. Facemasks are a promising preventive measure, however, previous studies on the efficacy of facemasks have been inconclusive. This study proposes a large-scale facemask trial during the Hajj pilgrimage in Saudi Arabia and presents this protocol to illustrate its feasibility and to promote both collaboration with other research groups and additional relevant studies. A cluster-randomised controlled trial is being conducted to test the efficacy of standard facemasks in preventing symptomatic and proven viral RTIs among pilgrims during the Hajj season in Mina, Mecca, Saudi Arabia. The trial will compare the 'supervised use of facemasks' versus 'standard measures' among pilgrims over several Hajj seasons. Cluster-randomisation will be done by accommodation tents with a 1:1 ratio. For the intervention tents, free facemasks will be provided to be worn consistently for 7days. Data on flu-like symptoms and mask use will be recorded in diaries. Nasal samples will be collected from symptomatic recruits and tested for nucleic acid of respiratory viruses. Data obtained from questionnaires, diaries and laboratory tests will be analysed to examine whether mask use significantly reduces the frequency of laboratory-confirmed respiratory viral infection and syndromic RTI as primary outcomes. This trial will provide valuable evidence on the efficacy of standard facemask use in preventing viral respiratory tract infections at mass gatherings. This study is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: ACTRN12613001018707 (http://www.anzctr.org.au).


The Changing Epidemiology of Viral Hepatitis in a Post-Soviet Country-The Case of Kyrgyzstan.
Historically, viral hepatitis has been a considerable public health problem in Central Asian countries, which may have worsened after the dissolution of the Soviet Union. However, up-to-date seroepidemiological studies are lacking. The aim of the present study was, therefore, to provide current estimates of the seroprevalence of viral hepatitis in Kyrgyzstan, one of the economically least developed countries in the region. We conducted a population-based cross-sectional study in 2018 in the capital of Kyrgyzstan, Bishkek (n = 1075). Participants, children and adults, were recruited from an outpatient clinic. The data were collected during face-to-face interviews. A blood sample (6 mL) was collected from each participant and tested with ELISA for the presence of serological markers for five viral hepatitides (A, B, C, D, and E). Post-stratification weighing was performed to obtain nationally representative findings. The overwhelming majority of the study participants were positive for anti-HAV (estimated seroprevalence, 75.3%; 95% confidence interval, 72.5-77.9%). The weighted seroprevalence estimates of HBsAg, anti-HCV, and anti-HDV were 2.2% (1.5-3.3%), 3.8% (2.8-5.1%), and 0.40% (0.15-1.01%), respectively. Anti-HEV seropositivity was 3.3% (2.4-4.5%). Of the 33 HBsAg-positive participants, five (15%) were anti-HDV-positive. Our study confirms that Kyrgyzstan remains a highly endemic country for hepatitis virus A and C infections. However, seroprevalences of HBV and HDV were lower than previously reported, and based on these data, the country could potentially be reclassified from high to (lower) intermediate endemicity. The observed anti-HEV seroprevalence resembles the low endemicity pattern characteristic of high-income countries.


RGS9-2 is a negative modulator of mu-opioid receptor function.
Regulators of G-protein signaling (RGS) 9-2 is a striatal enriched protein that controls G protein coupled receptor signaling duration by accelerating Galpha subunit guanosine triphosphate hydrolysis. We have previously demonstrated that mice lacking the RGS9 gene show enhanced morphine analgesia and delayed development of tolerance. Here we extend these studies to understand the mechanism via which RGS9-2 modulates opiate actions. Our data suggest that RGS9-2 prevents several events triggered by mu-opioid receptor (MOR) activation. In transiently transfected PC12 cells, RGS9-2 delays agonist induced internalization of epitope HA-tagged mu-opioid receptor. This action of RGS9-2 requires localization of the protein near the cell membrane. Co-immunoprecipitation studies reveal that RGS9-2 interacts with HA-tagged mu-opioid receptor, and that this interaction is enhanced by morphine treatment. In addition, morphine promotes the association of RGS9-2 with another essential component of MOR desensitization, beta-arrestin-2. We also show that over-expression of RGS9-2 prevents opiate-induced extracellular signal-regulated kinase phosphorylation. Our data indicate that RGS9-2 plays an essential role in opiate actions, by negatively modulating MOR downstream signaling as well as the rate of MOR endocytosis.


Virtual Touch quantification using acoustic radiation force impulse (ARFI) technology for the evaluation of focal solid renal lesions: preliminary findings.
To evaluate potential value of Virtual Touch quantification (VTQ) of acoustic radiation force impulse (ARFI) imaging for characterising focal solid renal lesions. Two independent operators performed 10 and five measurements of each lesion and adjacent renal cortex, respectively. Mean shear wave velocity (SWV) and shear wave velocity ratio (SWR) of histotypes were compared. One hundred and ninety-seven renal lesions were evaluated, including 155 renal cell carcinomas (RCCs; 129 clear-cell RCCs [ccRCCs], 14 papillary RCCs [pRCCs], and 12 chromophobe RCCs [cRCCs]) and 42 angiomyolipomas (AMLs). The interoperator reproducibility of SWV of renal tumours and renal cortex were good (ICC=0.852, and 0.903, respectively). SWV of the renal cortex at a depth of <4 cm was significant higher than that at a depth of >4 cm. Regardless of the subtypes of RCC, SWV and SWR of RCCs differed significantly from those of AMLs (2.28±0.85 versus 1.98±0.85; 1.09±0.56 versus 0.78±0.34; p=0.045 and p<0.001, respectively). At cut-off points of SWV >1.87 m/s or SWR >0.84 to differentiate RCCs from AMLs, the sensitivity and specificity were 47.5%, 33.2% or 47.5%, 30.2%, respectively. When the subtypes of RCCs were taken into account, SWV and SWR of ccRCCs were significantly higher than those of pRCCs, cRCCs, and AMLs, while there was no significant difference among the latter. With SWV >1.98 m/s or SWR >0.80 as the cut-off point to differentiate ccRCCs from other renal tumours, the sensitivity and specificity were 69.8%, 65% or 76.8%, 73.4%, respectively. The ARFI technique offers additional information regarding renal tumour elasticity with good reproducibility. SWV and SWR are potential biomarkers in this setting, helping to differentiate ccRCC from other renal tumour histotypes.


Cinnamaldehyde is a biologically active compound for the disinfection of removable denture: blinded randomized crossover clinical study.
Fungal infections associated with the use of dentures, like denture stomatitis, are difficult to prevent and treat. This in situ study aimed to investigate the efficacy of cinnamaldehyde for the disinfection of complete removable dentures, and the effect on the physical and mechanical properties (Vickers microhardness, color, and surface roughness) of the acrylic resin. Acrylic resin disks were inserted into the dentures of a probabilistic sample of 33 complete denture users, that used cinnamaldehyde (27 μg/mL) and 0.5% sodium hypochlorite solutions in a 20 min/7-days protocol of dentures immersion in each solution, with a wash-out period of 7 days, to constitute a crossover-study. The disks were analyzed before and after the immersion, for the presence of microorganisms (CFU/mL) and by scanning electron microscope (SEM). Also, the surface roughness (Ra) and Vickers microhardness were measured, and color parameters were analyzed using the National Bureau of Standards (NBS) method. Data was analyzed by Wilcoxon and Friedman (microbiological evaluation), paired t-test (color and roughness) and independent t-test (Vickers hardness) (α = 0.05). A significant reduction (P < 0.05) in the number of microorganisms was observed for each species (total microorganisms, Streptococcus mutans, and Candida spp.), with no significant differences (P > 0.05) between hypochlorite and cinnamaldehyde. There was an increase in the roughness and a decrease in the hardness of the test specimens, with no difference between the two disinfectant substances (P > 0.05). Both hypochlorite and cinnamaldehyde also caused changes in color, considered as "perceptible" by the NBS classification, but with no significant difference between disinfectant substances (P < 0.05), and under the clinically acceptable limit (ΔE ≤ 3.7). The 27 μg/mL cinnamaldehyde solution was effective against all evaluated microorganisms and caused minor alterations in hardness, surface roughness, and color parameters, with no clinical relevance.


Systematic literature review of cold-formed steel at elevated temperature scenario.
Cold-formed steels (CFS) or light gauge steels (LGS) are steel sections created through processes without heat application, such as roll forming or press-braking. In the past few decades, the utilization of CFS as a structural material has expanded due to its advantages over the other materials used in the construction industry, consequently increasing the number of studies conducted by many researchers. CFS studies have focused on many research areas, including designing, and analyzing members and systems, connections, sustainability, residual stresses, and post-fire data. As a result, several authors have also conducted a literature review involving these areas. However, a literature review for more recent studies involving elevated temperature exposure of CFS has not been conducted. This paper seeks to compile and review the recent publications regarding CFS behavior and performance at high temperatures events. Sixty-nine (69) journal articles published from 2017 to 2023 were retrieved from the Scopus database and systematically reviewed through text mining with the aid of VOS Viewer. Prior studies utilizing finite element analysis and experimental methods to investigate the performance at elevated temperature events of varying CFS sections, systems, and steel grades have been summarized. In addition, this paper also briefly discussed the findings of the recent research works involving member connections of CFS. Key points from the literature review have been emphasized such as the outcome of experimental and numerical validation of existing design rules from different codes such as American Iron and Steel Institute (AISI), Eurocodes, and Australian codes which could vary depending on the CFS section and steel grades. Important points of previous studies regarding the CFS walls, insulations, and screwed connections have also been noted in this paper. Based on the review, research gaps in the prior studies involving elevated temperature exposure of CFS have been identified, such as lack of CFS investigation under fatigue and cyclic loading. These were then recommended as future direction and concentration of CFS at elevated temperatures research works.


Investigation of vitamin D levels in patients with Sudden Sensory-Neural Hearing Loss and its effect on treatment.
Due to high prevalence of vitamin D deficiency and the possible association with Sudden Sensory-Neural Hearing Loss (SSNHL) finding the main causes and appropriate treatments are highly essential. This study aimed to investigate vitamin D levels in patients suffering SSNHL and its effect on response to treatment. This cross-sectional study was performed on two groups of case (34 SSNHL patients) and control (34 healthy subjects without risk of hearing loss). All patient information such as age, sex, audiogram illustration of hearing frequency and the level of vitamin D were recorded at baseline. Patients with SSNHL received routine treatments such as 10 days of 1 mg/kg/day steroid and the response or lack of complete response to treatment was recorded and analyzed according to the audiometry. Vitamin D level in SSNHL group with a mean of 19.28 ± 9.56 ng/ml was significantly less than the control group (25.71 ± 11.21 ng/ml; P value < 0.001). After treatment, 76.5% were completely recovered and 23.5% did not recover completely. Factors such as age, sex and level of initial hearing loss did not have a significant effect on the response to treatment, but the level of vitamin D in these patients had a significant relationship with the response to treatment (P value = 0.004); so that all patients with sufficient vitamin D level had completely recovered, versus 87.5% of patients with vitamin D deficiency and 12.5% of insufficient vitamin D had no response to treatment. According to the results of the present study, the prevalence of vitamin D deficiency in patients with SSNHL was more than healthy people. SSNHL patients with deficient vitamin D had the highest percentage of no response to treatment.


Pulmonary hypertension in the critical care setting: classification, pathophysiology, diagnosis, and management.
Pulmonary hypertension (PH) is common in the critical care setting, and may be a target for specific therapy. Moderate degrees of pulmonary hypertension are most often the consequence of acute or chronic heart failure, hypoxemia, or acute pulmonary embolism, and may be relatively rapidly reversible. The consequences of more severe forms of PH, both acute and chronic, can include hypotension; low cardiac output; right heart failure with congestion of the liver, gut, and kidneys; and varying degrees of hypoxemia, each of which can lead to death or severe disability. We review the physiology, definitions, classification, pathogenesis, diagnostic tools, and algorithms for diagnosis and specific treatments for the various causes of PH as seen in the critical care setting.


Interdigitating cell sarcoma. A morphologic, immunohistologic, and enzyme-histochemical study.
A 58-year-old man presented with an unusual sarcoma of the cervical lymph node. The tumor also involved the mesenteric lymph node and jejunum. Tumor cells possessed intracytoplasmic S100 protein, Leu-3a (T4), and HLA-DR antigens. The neoplastic cells also showed membranous ATPase activity. LeuM1, T6, Leu1, Leu2a, B1, lysozyme, and immunoglobulin were not recognized. Their fine structure was similar to that of interdigitating cells. These data are consistent with derivation from lymph node interdigitating reticulum cell.


Dynamic processes of indigenous microorganisms from a low-temperature petroleum reservoir during nutrient stimulation.
Compared to medium-high temperature petroleum reservoirs (30°C-73°C), little is known about microbial regulation by nutrients in low-temperature reservoirs. In this study, we report the performance (oil emulsification and biogas production) and community structure of indigenous microorganisms from a low-temperature (22.6°C) petroleum reservoir during nutrient stimulation. Culture-dependent approaches indicated that the number of hydrocarbon-oxidizing bacteria (HOB), nitrate-reducing bacteria (NRB) and methane-producing bacteria (MPB) increased by between 10- and 1000-fold, while sulfate-reducing bacteria (SRB) were observed at low levels during stimulation. Phylogenetic analysis of the 16S rRNA gene indicated that Pseudomonas, Ochrobactrum, Acinetobacter, Halomonas and Marinobacter, which have the capability to produce surfactants, were selectively enriched. Methanoculleus, Methanosaeta, Methanocorpusculum and Methanocalculus showed the largest increase in relative abundance among archaea. Micro-emulsion formed with an average oil droplet diameter of 14.3 μm (ranging between 4.1 μm and 84.2 μm) during stimulation. Gas chromatographic analysis of gas production (186 mL gas/200 mL medium) showed the levels of CO2 and CH4 increased 8.97% and 6.21%, respectively. Similar to medium-high temperature reservoirs, HOB, NRB, SRB and MPB were ubiquitous in the low-temperature reservoir, and oil emulsification and gas production were the main phenomena observed during stimulation. Oil emulsification required a longer duration of time to occur in the low-temperature reservoir.


A quarter century of decline of autopsies in the Netherlands.
Autopsy rates have been declining worldwide. The present study reports the outcome of a retrospective analysis of all non-forensic autopsies in the Netherlands over a course of 25 years, and compares these with the most recent Dutch study. Retrospectively, 25 years of data on clinical autopsies from the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA) was paired with the mortality registry (Statistics Netherlands). The crude prevalence of autopsies declined from 7.07% in 1991 to 2.73% in 2015. After adjusting for age at death, there was no difference in autopsy rate between males and females. An increasing age significantly decreased the autopsy rate. In the Netherlands, clinical autopsies have been declining over the last quarter century. Age at death, but not sex, was associated with the autopsy rate. These different results stress the importance of correct collection and analysis methods of data.


Discriminating Coercive from Sadomasochistic Sexuality.
Sadomasochistic (SM) sexual interest is reported by a wide range of individuals. Within the sex offender literature, the presence of SM interest is often viewed as a herald of criminal sexual behavior; however, research indicates that SM interests are not predictive of coercive sexual behavior. In the current study, we measured a range of sexual fantasies and behaviors, and then applied cluster analyses to determine (1) if individuals endorsed elevated SM interests also endorsed coercive fantasies and, (2) to explore cluster membership correlates using measures of sensation seeking, externalizing and antisocial behaviors, attitudes toward rape, and empathic capacity. A total of 550 participants were recruited through a variety of on-line discussion areas. A four cluster solution best fit the data with distinct clusters observed for those endorsing SM behaviors and those reporting coercive sexual behavior. Additional analyses revealed greater endorsement of victim blaming attitudes and lower empathic concern among members of the coercive sexual behavior cluster. Elevated sensation seeking and externalizing behaviors were reported by members of clusters marked by SM and coercive sexual behavior. Results provide further support for the differentiation between SM and coercive sexual behaviors as representative of individuals with divergent attitudes, traits, and behaviors.


Epstein-Barr virus related opsoclonus-myoclonus-ataxia does not rule out the presence of occult neuroblastic tumors.
Opsoclonus-myoclonus-ataxia (OMA) secondary to Epstein-Barr virus (EBV) infection has only been described in three pediatric patients. Previous reports suggested that evidence for a recent EBV infection in the absence of an occult neoplasm would predict a favorable prognosis for OMA as well as no tumor development. We present the case of a 20-month-old child with OMA associated with a microbiologically documented acute EBV infection and an occult thoracic ganglioneuroblastoma diagnosed 5 months later.


The pathogenesis and pathway into the central nervous system after intraocular infection of herpes simplex virus type I in rabbits.
Herpes simplex virus (HSV) type I was injected into the right eye of 18-day-old New Zealand albino rabbits and the animals were killed on the fourth and eighth days after inoculation. Longitudinal section of the optic nerves and chiasma showed that both myelinated axons and neuroglial cells crossed at the chiasma. Semi-serial (1 micrometer) and ultrathin sections showed the presence of HSV in both astrocytes and oligodendrocytes, although no particles were seen in the myelinated axons; the infected cells were confined to the medial side of the right optic nerve. HSV travels centropetally along the optic pathway and slowly spreads laterally by cell-to-cell infection. The virus does not appear to kill the astrocytes and oligodendrocytes, and also does not directly damage the myelin sheath.


Nature and properties of ionomer assemblies. II.
The principle subject in the current paper is to summarize and characterize the ionomers based on polymers and copolymers such as polystyrene (PSt), polyisoprene (PIP), polybutadiene (PB), poly(styrene-b-isobutylene-b-styrene) (PSt-PIB-PSt), poly(butadiene-styrene) (PB-PSt), poly(ethylene terephthalate) (PET), poly(butylene adipate) (PBA), poly(butylene succinate) (PBSi), poly(dimethylcarbosiloxanes), polyurethane, etc. The self-assembly of ionomers, models concerning ionomer morphologies, physical and rheological properties of ionomer phase and percolation behavior of ionomers were discussed. The ionomer phase materials and dispersions have been characterized by differential scanning calorimetry (DSC), small-angle X-ray catering (SAXS), small-angle neutron scattering (SANS), Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), etc. The wide range of compositions, molecular architectures, and morphologies present in ionomeric disperse systems are of great interest. The research is particularly devoted to the potential application of these materials and an understanding of the fundamental principles of the ionomers. They are extremely complex systems, sensitive to changes in structure and composition, and therefore not easily amenable to modeling and to the derivation of general patterns of behavior. The reviewed data indicate that a large number of parameters are important in influencing multiplet formation and clustering in random ionomers. Among these are the ion content, size of the polyion and counterion, dielectric constant of the host, T(g) of the polymer, rigidity or persistence length of the backbone, position of the ion pair relative to the backbone, steric constraints, amount and nature of added additive (plasticizer), thermal history, etc.


Splenectomy for massive splenomegaly.
Twenty-four patients who underwent resection of giant spleen (spleen weight greater than 1.5 kg) have been reviewed to determine the difficulties and benefits of the procedure and, in particular, whether the use of adrenaline injection into the splenic artery could safely reduce technical difficulty. Although morbidity was higher in patients with giant spleens compared with those undergoing resection of smaller spleens the incidence of serious complications was small, and there were no operative or in-hospital deaths. In addition, virtually all patients benefited either on the basis of minimized haematological defect, or palliation of symptoms. Further, the injection of 1 ml of 1:10,000 adrenaline into the splenic artery before splenic mobilization reduced the splenic volume by approximately 40 per cent on average, and resulted in improved exposure, thereby facilitating the procedure.


Cellular morphogenesis: slow-as-molasses accelerates polarized membrane growth.
Cellularization of the early Drosophila embryo is a modified form of cytokinesis that gives rise to the blastoderm epithelium through polarized membrane growth. The gene slow-as-molasses encodes a novel protein essential for the formation of a plasma membrane domain that initiates membrane growth during cellularization.


Psoriatic arthritis successfully treated with second-line anti-interleukin-6 treatment: a case report and review of the literature.
Psoriatic arthritis treatment with antitumor necrosis factor has been shown to reduce disease activity. Nonetheless, more than 30% of patients do not achieve a sufficient response to tumor necrosis factor blockers. Currently, treatment with interleukin-6 inhibitors is expected to be effective and suppress the joint destruction in patients with psoriatic arthritis; however, evidence regarding their efficacy is limited to a few reports. A 78-year-old Japanese woman with psoriatic arthritis associated with rapid joint destruction was successfully treated with a second-line anti-interleukin-6 receptor agent. In this case, a tumor necrosis factor inhibitor induced an inadequate response, and the right knee and left hip joints required artificial joint replacement surgery. However, second line treatment with anti-interleukin-6 treatment was effective, and the right elbow joint function was preserved. We experienced a case of psoriatic arthritis, in which anti-interleukin-6 treatment repaired a bone cyst in the lateral epicondyle of the humerus and enthesitis of the distal interphalangeal joints. The patient is currently in clinical remission with no restrictions in daily life activities. Anti-interleukin-6 treatment may address the unmet needs of patients with psoriatic arthritis who are resistant or intolerant to antitumor necrosis factor treatment, with rapidly destructive large joints but with well-managed skin manifestations.


Dynamic radioisotope study of the internal carotid region of the neck in cerebrovascular disease.
The results of radionuclide angioscintigraphy were evaluated in patients with stricture or occlusion of the extracranial part of the internal carotid artery. Time-activity curves for the first 13 s were generated from left and right internal carotid regions of interest of the neck. The differences between the counts from symmetric regions of interest were measured. We observed decreased activity in regions of interest in cases with stricture of the internal carotid. The first 13 s were significant for evaluation of the extracranial part of the internal carotid.


Evolution of helotialean fungi (Leotiomycetes, Pezizomycotina): a nuclear rDNA phylogeny.
The highly divergent characters of morphology, ecology, and biology in the Helotiales make it one of the most problematic groups in traditional classification and molecular phylogeny. Sequences of three rDNA regions, SSU, LSU, and 5.8S rDNA, were generated for 50 helotialean fungi, representing 11 out of 13 families in the current classification. Data sets with different compositions were assembled, and parsimony and Bayesian analyses were performed. The phylogenetic distribution of lifestyle and ecological factors was assessed. Plant endophytism is distributed across multiple clades in the Leotiomycetes. Our results suggest that (1) the inclusion of LSU rDNA and a wider taxon sampling greatly improves resolution of the Helotiales phylogeny, however, the usefulness of rDNA in resolving the deep relationships within the Leotiomycetes is limited; (2) a new class Geoglossomycetes, including Geoglossum, Trichoglossum, and Sarcoleotia, is the basal lineage of the Leotiomyceta; (3) the Leotiomycetes, including the Helotiales, Erysiphales, Cyttariales, Rhytismatales, and Myxotrichaceae, is monophyletic; and (4) nine clades can be recognized within the Helotiales.


Comparative effectiveness of preoperative, postoperative and perioperative treatments for resectable gastric cancer: A network meta-analysis of the literature from the past 20 years.
Different preoperative, postoperative or perioperative treatment strategies, including chemotherapy or chemoradiotherapy, are available for patients with gastric cancer, but conventional meta-analyses that assess two alternative treatments are unable to compare differences in overall survival. Thus, we performed a network meta-analysis to identify the best treatment strategy. We systematically searched and assessed studies for eligibility and extracted data. We then pooled the data and conducted a Bayesian network meta-analysis to combine direct comparisons with indirect evidence. The node-splitting method was used to assess the inconsistency. Rank probabilities were assessed by the probability of treatment rankings. Thirty-three eligible randomized controlled trials were included in the network meta-analysis. Four treatments that had significantly improved prognoses when compared with surgery only were postoperative chemotherapy [HR = 0.80 with 95% CrI: (0.73, 0.88)], postoperative chemoradiotherapy [HR = 0.73 with 95% CrI: (0.61, 0.87)], preoperative chemoradiotherapy [HR = 0.77 with 95% CrI: (0.62, 0.98)] and perioperative chemotherapy [HR = 0.69 with 95% CrI: (0.55, 0.84)]. Preoperative chemotherapy, however, did not significantly improve survival when compared with surgery alone [HR = 0.94 with 95% CrI: (0.71, 1.2)]. There was no statistically significant difference between postoperative chemotherapy, postoperative chemoradiotherapy, preoperative chemoradiotherapy and perioperative chemotherapy in terms of overall survival. Chemoradiotherapy after D2 lymphadenectomy did not significantly improve OS when compared with postoperative chemotherapy [HR = 0.95 with 95% CrI: (0.73, 1.3)]. Among patients with operable gastric cancer, perioperative chemotherapy had the highest probability of being the best treatment. Further clinical resources may be required to assess the efficacy and safety of perioperative chemotherapy for patients with gastric cancer.


Microfluidic-based fluorescent electronic eye with CdTe/CdS core-shell quantum dots for trace detection of cadmium ions.
Cadmium ions (Cd2+) greatly threat human health and the environment due to its extremely severe toxicity. Therefore, it is of paramount importance to establish a sensitive and portable platform for monitoring Cd2+ on site. In this work, a novel microfluidic-based fluorescent electronic eye (E-eye) combined with tetrasodium iminodisuccinate (IDS)-etched CdTe/CdS quantum dots (QDs) was developed for portable and sensitive detection of trace Cd2+ in water environment. The fluorescent E-eye consists of a microfluidic chip for miniaturized flow analysis, an ultraviolet light excitation module for fluorescent excitation, an optical lens for device miniaturization and a smartphone for portable photographing and analysis. The IDS was added in the CdTe/CdS QDs to cause fluorescence quenching due to the chemical etching. Subsequently added Cd2+ will be recognized by etched QDs, thus inducing the fluorescence changes that can be directly captured by the E-eye for quantitative detection of Cd2+. With the optimization of all parameters including pH, reaction time and the concentration of IDS, the proposed platform could detect Cd2+ with a low detection limit of 0.26 μg/L in the range of 1-250 μg/L. It is worth noting that the performance of the developed fluorescent E-eye is quite comparable to a commercial microplate reader with a detailed comparison in linearity, sensitivity and detection limit. In summary, the proposed microfluidic-based fluorescent E-eye provides a promising platform for portable and high sensitive detection of trace cadmium in water environment.


Erratum: [Corrigendum] Lidocaine inhibits the invasion and migration of TRPV6‑expressing cancer cells by TRPV6 downregulation.
[This corrects the article DOI: 10.3892/ol.2016.4709.].


Epiglottic reconstruction after supraglottic laryngectomy.
It has been well established that supraglottic laryngectomy is an effective treatment of laryngeal cancer arising above the vocal cords with cure rates equaling total laryngectomy. Although there is preservation of a near normal voice after supraglottic laryngectomy, chronic aspiration occurs in some patients particularly after extended supraglottic laryngectomy or when there is associated compromised pulmonary function. During normal deglutition, the epiglottis serves to divert food to the pyriform fossae and partially covers the inlet to the airway. These important functions can be accomplished after supraglottic laryngectomy by reconstructing a neoepiglottis from an epiglottic remnant whenever one third or more of the epiglottis can be preserved which is microscopically free of tumor. Our results in 14 patients have shown no clinically significant aspiration after epiglottic reconstruction.


Infrared evidence of azide binding to iron, copper, and non-metal sites in heart cytochrome c oxidase.
Interactions of azide ion with bovine heart cytochrome c oxidase (CcO) at five redox levels (IV) to (0), obtained by zero to four electron reduction of fully oxidized enzyme CcO(IV), were monitored by infrared and visible/Soret spectra. Partially reduced CcO gave three azide asymmetric stretch band at 2040, 2016, and 2004 cm-1 for CcO(III)N3 and two at 2040 and 2016 cm-1 for CcO(II)N3 and CcO(I)N3. Resting CcO(IV) reacts with N3- to give one band at 2041 cm-1 assigned to CuB2+N3 and another at 2051 cm-1 to N3- that is associated with protein but is not bound to a metal ion. At high azide concentrations the weak association of many azide molecules with non-metal protein sites was observed at all redox levels. These findings provide direct evidence for 1) N3- binding to CuB as well as Fea3 in partially reduced enzyme, but no binding to Fea3 in fully oxidized enzyme and no binding to either metal in fully reduced enzyme; 2) a long range effect of the oxidation state of Fea or CuA on ligand binding at heme a3, but not at CuB; and 3) an insensitivity of either Fea3 or CuB ligand site to changes in ligand or oxidation state at the other site. The observed independence of the Fea3 and CuB sites provides further support for Fea3(3)+ OOH, rather than Fea3(3)+ OOCuB2+, as an intermediate in the reduction of O2 to water by the oxidase.


Identifying the Appropriate FISH Criteria for Defining MET Copy Number-Driven Lung Adenocarcinoma through Oncogene Overlap Analysis.
Mesenchymal-epithelial transition factor gene (MET) gene copy number gain may be a predictive biomarker for mesenchymal-epithelial transition factor (MET) inhibition in lung cancer, but the most appropriate method and criteria for defining MET positivity are uncertain. MET copy number was assessed by fluorescence in situ hybridization in lung adenocarcinoma. Positivity criteria included mean MET per cell values greater than 5 (low [≥5 to <6], intermediate [≥6 to <7], and high [≥7]) and mean MET-to-chromosome 7 centromere ratios (MET/CEP7) of at least 1.8 (low [≥1.8 to ≤2.2], intermediate [>2.2 to <5], and high [≥5]). Associated clinical and molecular characteristics were captured. Of 686 cases, 99 (14%) had a mean MET per cell value of 5 or greater, 52 of 1164 (4.5%) had a MET/CEP7 ratio of 1.8 or higher. Other oncogenic drivers (in EGFR, KRAS, anaplastic lymphoma receptor tyrosine kinase gene [ALK], erb-b2 receptor tyrosine kinase 2 gene [ERBB2], BRAF, NRAS, ROS1, or ret proto-oncogene [RET]) were detectable in 56% of the group with a mean MET per cell value of 5 or higher and 47% of the group with a MET/CEP7 ratio of 1.8 or higher, suggesting that many MET-positive cases are not truly MET addicted. The rates of concomitant drivers in the groups of patients in the low, indeterminate, and high categories of mean MET per cell were 32 of 52 (62%), 12 of 19 (63%), and 11 of 27 (41%) (p = 0.2), and the rates of concomitant drivers in the low, intermediate, and high categories of MET/CEP7 ratios were 15 of 29 (52%), 9 of 18 (50%), and 0 of 4 (0%), respectively (p = 0.04). A MET/CEP7 ratio of 1.8 or higher in the absence of other oncogenes was associated with a higher rate of adrenal metastases (p = 0.03) but not with never-smoking status. A fluorescence in situ hybridization MET/CEP7 ratio of 5 or higher defined a "MET-positive" group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition, it represents the clearest definition of a MET copy number gain-addicted state. However, a MET-associated phenotype may also exist across cases with a MET/CEP7 of 1.8 or higher when no other oncogene overlap occurs.


Anterior pituitary function and growth hormone use in the elderly.
Age-related changes in GH and IGF-I secretion occur in both men and women and may partially contribute to the body compositional changes of decreased lean body mass, increased adiposity, alterations in bone density, and increased cardiovascular risk, all of which can affect adversely on functional capacity. hGH, GHRH, GHRP and other trophic factors hold promise as therapeutic strategies to improve the functional status of frail elderly subjects. In addition, there is potential for hGH use in elderly patients in various catabolic states because of its anabolic effects with nitrogen retention. However, careful long-term clinical trials are necessary with development of specific targeting criteria before conclusions regarding efficacy and benefits can be decided.


The role of computer-assisted radiographer reporting in lung cancer screening programmes.
Successful lung cancer screening delivery requires sensitive, timely reporting of low-dose computed tomography (LDCT) scans, placing a demand on radiology resources. Trained non-radiologist readers and computer-assisted detection (CADe) software may offer strategies to optimise the use of radiology resources without loss of sensitivity. This report examines the accuracy of trained reporting radiographers using CADe support to report LDCT scans performed as part of the Lung Screen Uptake Trial (LSUT). In this observational cohort study, two radiographers independently read all LDCT performed within LSUT and reported on the presence of clinically significant nodules and common incidental findings (IFs), including recommendations for management. Reports were compared against a 'reference standard' (RS) derived from nodules identified by study radiologists without CADe, plus consensus radiologist review of any additional nodules identified by the radiographers. A total of 716 scans were included, 158 of which had one or more clinically significant pulmonary nodules as per our RS. Radiographer sensitivity against the RS was 68-73.7%, with specificity of 92.1-92.7%. Sensitivity for detection of proven cancers diagnosed from the baseline scan was 83.3-100%. The spectrum of IFs exceeded what could reasonably be covered in radiographer training. Our findings highlight the complexity of LDCT reporting requirements, including the limitations of CADe and the breadth of IFs. We are unable to recommend CADe-supported radiographers as a sole reader of LDCT scans, but propose potential avenues for further research including initial triage of abnormal LDCT or reporting of follow-up surveillance scans. • Successful roll-out of mass screening programmes for lung cancer depends on timely, accurate CT scan reporting, placing a demand on existing radiology resources. • This observational cohort study examines the accuracy of trained radiographers using computer-assisted detection (CADe) software to report lung cancer screening CT scans, as a potential means of supporting reporting workflows in LCS programmes. • CADe-supported radiographers were less sensitive than radiologists at identifying clinically significant pulmonary nodules, but had a low false-positive rate and good sensitivity for detection of confirmed cancers.


Accuracy of intraoral scanners for static virtual articulation: A systematic review and meta-analysis of multiple outcomes.
Static virtual articulation with intraoral scanners (IOSs) can eliminate the human errors related to conventional articulation methods and enhance accuracy. A systematic review and meta-analysis based on multiple accuracy outcomes can combine the available literature and provide an evidence-based conclusion. The purpose of this systematic review and meta-analysis was to investigate whether static virtual articulation with IOSs has acceptable accuracy for completely dentate and partially edentulous patients. An electronic search was conducted on the PubMed, Web of Science, and Scopus databases. In addition, a manual search through reference lists of selected articles was performed. Clinical and in vitro studies evaluating the accuracy of static virtual articulation with IOSs based on diagnostic accuracy, trueness, precision, and occlusion of fabricated fixed restorations were included. The pooled results included sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR), diagnostic odds ratios (DORs), mean values, and 95% confidence intervals (CIs). Results were presented as forest plots. The summary receiver operator characteristic (SROC) was displayed to summarize the diagnostic test performance. The initial search resulted in a total of 5061 articles, of which 29 articles were included in the analysis. The virtual interocclusal records (VIRs) with IOSs showed acceptable pooled results for diagnostic accuracy (sensitivity: 0.76; specificity: 0.80; DOR: 14.77, area under the SROC (AUC): 0.87; cut off point Q∗: 80; +LR: 3.66; -LR: 0.31). The pooled data for trueness and precision were within the acceptable limits. The pooled mean (95% CI) for trueness based on linear deviations was 243.53 (144.90, 342.17). The pooled mean (95% CI) for precision based on 3D deviation of articulated models was 54.97 (43.49, 66.46). In addition, the included studies reported accurate occlusion for fixed restorations fabricated by using VIRs with IOSs. Moreover, most of the studies on trueness based on virtual occlusal contact area reported acceptable accuracy. VIRs with IOSs had acceptable accuracy for static virtual articulation.


Compound 48/80 and substance P induced release of histamine and serotonin from rat peritoneal mast cells.
The effect of substance P and compound 48/80 on histamine and serotonin release from not isolated and isolated mast cells have been compared in experiments in vitro. The response of not isolated and isolated mast cells were virtually identical. The release of both amines, in response to 48/80 and substance P, was dose-dependent. The percentage of histamine released by 48/80 was significantly higher than the percentage of serotonin, the difference being higher at lower concentrations of compound 48/80 after 15 min of incubation. Substance P also showed a tendency to higher efficiency for histamine than for serotonin release. In contrast to 48/80, the dose-response curves for histamine and serotonin release were parallel. These results support the view that the ratio between histamine and serotonin release depends on the liberator used. They also showed that this ratio can depend on the concentration of the agent inducing secretion. The results indicate that substance P as well as 48/80 act rather selectively as histamine liberators and that there is some difference in releasing properties of 48/80 and substance P.


Compounds with potential anticancer activity. Benzenesulfonamido-pyrimidine derivatives.
Some derivatives of N-(5-pyrimidinyl)benzenesulfonamide, variously substituted at the benzene and pyrimidine ring, and variously methylated at ring and/or sulfonamidic nitrogens, were re-prepared. The activity of these compounds against lymphocytic leukemia P388 was evaluated and proved to be negligible or completely absent.