Efficacy of β-hydroxy-β-methylbutyric acid (HMB) for growing rate and its influence for health indicators in blood test of young early-weaning goats.
The study was conducted on 26 male, 30 days-old goats, separated from their mothers, divided into two equal groups: I - control and II - experimental, consisting of 13 animals each. All animals were fed with milk replacer, experimental group received additionally 50 g/kg body weight, additive of HMB, for 60 days. The following features were analyzed: body weight, daily increases of body weight, as well as hematological and biochemical blood features. Differences in body weight were found, between experimental and control group, after 60 days of experiment 0.57 kg (p≤0.01). The daily weight gain of experimental animals was higher in comparison with control group. Significant differences were also noted in results of hematological and biochemical blood parameters. Experimental animals showed a higher level of red blood cells as well as number of lymphocytes in comparison with the control group, (p≤0.01).Significant changes were also observed in the level of triglycerides, inorganic phosphorus and protein between both groups. The acid-base balance parameters and ionogram, showed a higher pH level (p≤0.05) HCO - act., HCO - std., BE, ctCO , O sat, K+, Cl- (p≤0.01), while the anion gap (AG) and Na+ were significantly lower in control group (p≤0.01).


Nuclear and mitochondrial genome sequencing of North-African Leishmania infantum isolates from cured and relapsed visceral leishmaniasis patients reveals variations correlating with geography and phenotype.
Although several studies have investigated genetic diversity of Leishmania infantum in North Africa, genome-wide analyses are lacking. Here, we conducted comparative analyses of nuclear and mitochondrial genomes of seven L. infantum isolates from Tunisia with the aim to gain insight into factors that drive genomic and phenotypic adaptation. Isolates were from cured (n=4) and recurrent (n=3) visceral leishmaniasis (VL) cases, originating from northern (n=2) and central (n=5) Tunisia, where respectively stable and emerging VL foci are observed. All isolates from relapsed patients were from Kairouan governorate (Centre); one showing resistance to the anti-leishmanial drug Meglumine antimoniate. Nuclear genome diversity of the isolates was analysed by comparison to the L. infantum JPCM5 reference genome. Kinetoplast maxi and minicircle sequences (1 and 59, respectively) were extracted from unmapped reads and identified by blast analysis against public data sets. The genome variation analysis grouped together isolates from the same geographical origins. Strains from the North were very different from the reference showing more than 34 587 specific single nucleotide variants, with one isolate representing a full genetic hybrid as judged by variant frequency. Composition of minicircle classes within isolates corroborated this geographical population structure. Read depth analysis revealed several significant gene copy number variations correlating with either geographical origin (amastin and Hsp33 genes) or relapse (CLN3 gene). However, no specific gene copy number variation was found in the drug-resistant isolate. In contrast, resistance was associated with a specific minicircle pattern suggesting Leishmania mitochondrial DNA as a potential novel source for biomarker discovery.


Improvements in memory after medial septum stimulation are associated with changes in hippocampal cholinergic activity and neurogenesis.
Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.


Evolutionary divergence in acoustic signals: causes and consequences.
Acoustic signals mediate mate choice, resource defense, and species recognition in a broad range of taxa. It has been proposed, therefore, that divergence in acoustic signals plays a key role in speciation. Nonetheless, the processes driving divergence of acoustic traits and their consequences in terms of speciation are poorly understood. A review of empirical and comparative studies reveals strong support for a role of sexual selection in acoustic divergence, but the possible concomitant influences of ecological context are rarely examined. We summarize a conceptual framework for testing the relative significance of both adaptive and neutral mechanisms leading to acoustic divergence, predictions for cases where these processes lead to speciation, and how their relative importance plays out over evolutionary time.


Quality indicators for the evaluation of patients with lung cancer.
Ideally, quality indicators are developed with the input of professional groups involved in the care of patients. This project, led by the Thoracic Oncology Network and Quality Improvement Committee of the American College of Chest Physicians (CHEST), had the goal of developing quality indicators related to the evaluation and staging of patients with lung cancer. Evidence-based guidelines were used to generate a list of process-of-care quality indicators, and project members revised the content and wording of this list. A survey of the Steering Committee of the Thoracic Oncology Network was performed to rate the validity, feasibility, and relevance of the indicators. Predefined thresholds were used to select indicators from the list. This process was repeated for the selected indicators through a survey available to all members of the Thoracic Oncology Network. Three academic medical centers determined if the surviving indicators were feasible and relevant within their practices. Eighteen quality indicators were drafted. Eleven survived the first round of voting, and seven survived the second round of voting. One was related to tissue acquisition for molecular testing, four were related to staging and stage documentation, one was related to smoking cessation counseling, and one was related to documentation of a performance status measure. The indicators were feasible and relevant within the practices assessed. We have defined seven process-of-care quality indicators related to the evaluation and staging of patients with lung cancer, which are felt to be valid, feasible, and relevant by lung cancer specialists.


Microcollinearity between autopolyploid sugarcane and diploid sorghum genomes.
Sugarcane (Saccharum spp.) has become an increasingly important crop for its leading role in biofuel production. The high sugar content species S. officinarum is an octoploid without known diploid or tetraploid progenitors. Commercial sugarcane cultivars are hybrids between S. officinarum and wild species S. spontaneum with ploidy at approximately 12x. The complex autopolyploid sugarcane genome has not been characterized at the DNA sequence level. The microsynteny between sugarcane and sorghum was assessed by comparing 454 pyrosequences of 20 sugarcane bacterial artificial chromosomes (BACs) with sorghum sequences. These 20 BACs were selected by hybridization of 1961 single copy sorghum overgo probes to the sugarcane BAC library with one sugarcane BAC corresponding to each of the 20 sorghum chromosome arms. The genic regions of the sugarcane BACs shared an average of 95.2% sequence identity with sorghum, and the sorghum genome was used as a template to order sequence contigs covering 78.2% of the 20 BAC sequences. About 53.1% of the sugarcane BAC sequences are aligned with sorghum sequence. The unaligned regions contain non-coding and repetitive sequences. Within the aligned sequences, 209 genes were annotated in sugarcane and 202 in sorghum. Seventeen genes appeared to be sugarcane-specific and all validated by sugarcane ESTs, while 12 appeared sorghum-specific but only one validated by sorghum ESTs. Twelve of the 17 sugarcane-specific genes have no match in the non-redundant protein database in GenBank, perhaps encoding proteins for sugarcane-specific processes. The sorghum orthologous regions appeared to have expanded relative to sugarcane, mostly by the increase of retrotransposons. The sugarcane and sorghum genomes are mostly collinear in the genic regions, and the sorghum genome can be used as a template for assembling much of the genic DNA of the autopolyploid sugarcane genome. The comparable gene density between sugarcane BACs and corresponding sorghum sequences defied the notion that polyploidy species might have faster pace of gene loss due to the redundancy of multiple alleles at each locus.


Value of 111 In-prostate-specific membrane antigen (PSMA)-radioguided surgery for salvage lymphadenectomy in recurrent prostate cancer: correlation with histopathology and clinical follow-up.
To evaluate the use of 111 In-labelled prostate-specific membrane antigen (PSMA)-I&T-based radioguided surgery (111 In-PSMA-RGS) for salvage surgery in recurrent prostate cancer (PCa) using comparison of intra-operative gamma probe measurements with histopathological results of dissected specimens. In addition, to determine the success of 111 In-PSMA-RGS with regard to postoperative prostate-specific antigen (PSA) responses, PCa-specific treatment-free survival rates and postoperative complication rates. A total of 31 consecutive patients with localized recurrent PCa undergoing salvage surgery with PSMA-targeted radioguided surgery using a 111 In-labelled PSMA ligand between April 2014 and July 2015 were retrospectively included in this study. The preoperative (interquartile range; range) median PSA level was 1.3 (0.57-2.53 ng/mL; 0.2-13.9 ng/mL). Results of ex vivo radioactivity rating (positive vs negative) of resected tissue specimens were compared with findings of postoperative histological analysis. Best PSA response without additional treatment was determined after 111 In-PSMA-RGS, and salvage-surgery-related postoperative complications and PCa-specific additional treatments were recorded. In 30/31 patients, 111 In-PSMA-RGS allowed intra-operative identification of metastatic lesions. In total, 145 surgical specimens were removed and 51 showed metastatic involvement at histological analysis. According to 111 In-PSMA-RGS ex vivo measurements, 48 specimens were correctly classified as metastatic and 87 as cancer-free, four were false-negative and six were false-positive compared with histological evaluation. Follow-up information was available for 30/31 patients. PSA declines of >50% and >90% were observed in 23/30 patients and in 16/30 patients, respectively. In 18/30 patients, a PSA decline to <0.2 ng/mL was observed. In 10/30 patients further PCa-specific treatment was given after a median (range) of 125 (48-454) days post-111 In-PSMA-RGS. The remaining 20 patients remained treatment-free at a median (range) follow-up of 337 (81-591) days. Of 30 patients, 10 presented with surgery-related complications (Clavien-Dindo grade 1, n = 6, Clavien-Dindo grade 3b, n = 4). 111 In-PSMA-RGS proved to be of high value for intra-operative detection of even small metastatic lesions in patients with PCa scheduled for salvage lymphadenectomy. It allows the exact localization and resection of metastatic tissue during 111 In-PSMA-RGS and is therefore anticipated to have a beneficial influence on further disease progression; however, identification of suitable patients on the basis of PSMA-positron-emission tomography imaging as well as clinical variables is essential for satisfactory results to be obtained.


Radical prostatectomy versus observation for localized prostate cancer.
The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).


The Dimension of Time in Host-Microbiome Interactions.
The intestinal microbiota contains trillions of commensal microorganisms that shape multiple aspects of host physiology and disease. In contrast to the host's genome, the microbiome is amenable to change over the course of an organism's lifetime, providing an opportunity to therapeutically modulate the microbiome's impact on human pathophysiology. In this Perspective, we highlight environmental factors that regulate the temporal dynamics of the intestinal microbiome, with a particular focus on the different time scales at which they act. We propose that the identification of transient and intermediate states of microbiome responses to perturbations is essential for understanding the rules that govern the behavior of this ecosystem. The delineation of microbiome dynamics is also helpful for distinguishing cause and effect in microbiome responses to environmental stimuli. Understanding the dimension of time in host-microbiome interactions is therefore critical for therapeutic strategies that aim at short-term or long-term engineering of the intestinal microbial community.


Atrial arrhythmogenesis in a rabbit model of chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) increases the risk of atrial fibrillation (AF), however, its arrhythmogenic mechanisms are unclear. This study investigated the effects of COPD on AF triggers (pulmonary veins, PVs) and substrates (atria), and their potential underlying mechanisms. Electrocardiographic, echocardiographic, and biochemical studies were conducted in control rabbits and rabbits with human leukocyte elastase (0.3 unit/kg)-induced COPD. Conventional microelectrode, Western blotting, and histological examinations were performed on PV, left atrium (LA), right atrium, and sinoatrial node (SAN) preparations from control rabbits and those with COPD. The rabbits with COPD had a higher incidence of atrial premature complexes, PV burst firing and delayed afterdepolarizations, higher sympathetic activity, larger LA, and faster PV spontaneous activity than did the control rabbits; but they exhibited a slower SAN beating rate. The LA of the rabbits with COPD had a shorter action potential duration and longer tachyarrhythmia induced by tachypacing (20 Hz) and isoproterenol (1 μM). Additionally, the rabbits with COPD had higher fibrosis in the PVs, LA, and SAN. H89 (10 μM), KN93 (1 μM), and KB-R7943 (10 μM) significantly suppressed burst firing and delayed afterdepolarizations in the PVs of the rabbits with COPD. Moreover, compared with the control rabbits, those with COPD had lower expression levels of the β1 adrenergic receptor, Cav 1.2, and Na+/Ca2+ exchanger in the PVs; Cav 1.2 in the LA; and hyperpolarization-activated cyclic nucleotide-gated K+ channel 4 in the SAN. COPD increases atrial arrhythmogenesis by modulating the distinctive electrophysiological characteristics of the PVs, LA, and SAN.


Predicting extended operative time and length of inpatient stay in cervical deformity corrective surgery.
It's increasingly common for surgeons to operate on more challenging cases and higher risk patients, resulting in longer op-time and inpatient LOS. Factors predicting extended op-time and LOS for cervical deformity (CD) patients are understudied. This study identified predictors of extended op-time and length of stay (LOS) after CD-corrective surgery. CD patients with baseline (BL) radiographic data were included. Patients were stratified by extended LOS (ELOS; >75th percentile) and normal LOS (N-LOS; <75th percentile). Op-time analysis excluded staged cases, cases >12 h. A Conditional Variable Importance Table used non-replacement sampling set of Conditional Inference trees to identify influential factors. Mean comparison tests compared LOS and op-time for top factors. 142 surgical CD patients (61 yrs, 62%F, 8.2 levels fused). Op-time and LOS were 358 min and 7.2 days; 30% of patients experienced E-LOS (14 ± 13 days). Overlapping predictors of E-LOS and op-time included levels fused (>7 increased LOS 2.7 days; >5 increased op-time 96 min, P < 0.001), approach (anterior reduced LOS 3.0 days; combined increased op-time 69 min, P < 0.01), BMI (>38 kg/m2 increased LOS 8.1 days; >39 kg/m2 increased op-time 17 min), and osteotomy (LOS 2.0 days, op-time 62 min, P < 0.005). BL cervical parameters increased LOS and op-time: cSVA (>42 mm increased LOS; >50 mm increased op-time, P < 0.030), C0 slope (>@-0.9° increased LOS, >0.3° increased op-time, P < 0.003.) Additional op-time predictors: prior cervical surgery (p = 0.004) and comorbidities (P = 0.015). Other predictors of E-LOS: EBL (P < 0.001), change in mental status (P = 0.001). Baseline cervical malalignment, levels fused, and osteotomy predicted both increased op-time and LOS. These results can be used to better optimize patient care, hospital efficiency, and resource allocation.


Etiology of Bronze Leaf Disease of Populus.
Bronze leaf disease is a potentially destructive disorder of the Populus section of the genus Populus. The causal agent has been reported to be Apioplagiostoma populi (anamorph: Discula sp.). Based on etiological and symptomological studies, field observations of symptom development suggest that the pathogen moves systemically in the host. This was verified by graft experiments where symptoms progressed from the scion into the elongating stem. A bronze-pigmented vascular discoloration was observed in symptomatic leaves and branches. Dieback of affected stems also was common. Spore-trap studies elucidated the timing and necessary weather conditions of A. populi ascospore dispersal in relation to infection and symptom development. Exposure-tree experiments revealed that ascospores of A. populi are the primary inoculum and resulting infection causes distinctive disease symptoms on affected trees. Perithecia of A. populi were observed on overwintered symptomatic leaves, but were not observed on asymptomatic leaves. Acervular conidiomata were observed on symptomatic leaves during August and September. Although A. populi ascospores germinated in vitro, A. populi was not recovered from symptomatic tissue. Isolations from diseased leaves consistently yielded Epicoccum nigrum, but the role of this species is unclear. Inoculations of susceptible plants with E. nigrum conidia failed to reproduce symptoms, but inoculations with ascospores of A. populi produced symptoms typical of bronze leaf disease and Koch's postulates were performed.


Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.
Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation. We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare. All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).


Data smashing: uncovering lurking order in data.
From automatic speech recognition to discovering unusual stars, underlying almost all automated discovery tasks is the ability to compare and contrast data streams with each other, to identify connections and spot outliers. Despite the prevalence of data, however, automated methods are not keeping pace. A key bottleneck is that most data comparison algorithms today rely on a human expert to specify what 'features' of the data are relevant for comparison. Here, we propose a new principle for estimating the similarity between the sources of arbitrary data streams, using neither domain knowledge nor learning. We demonstrate the application of this principle to the analysis of data from a number of real-world challenging problems, including the disambiguation of electro-encephalograph patterns pertaining to epileptic seizures, detection of anomalous cardiac activity from heart sound recordings and classification of astronomical objects from raw photometry. In all these cases and without access to any domain knowledge, we demonstrate performance on a par with the accuracy achieved by specialized algorithms and heuristics devised by domain experts. We suggest that data smashing principles may open the door to understanding increasingly complex observations, especially when experts do not know what to look for.


Multimorbidity and quality of life: Systematic literature review and meta-analysis.
Multimorbidity is typically defined as the co-existence of two or more chronic diseases within an individual. Its prevalence is highest among the elderly, with poor quality of life (QoL) being one of the major consequences. This study aims to: (1) understand the relationship between multimorbidity and QoL or health-related quality of life (HRQoL) through systematic literature review; (2) explore the strength of this association by conducting the first meta-analysis on the subject. Following PRISMA, Medline/PubMed, Embase, CINAHL and PsycINFO were searched for studies published through September 1st, 2018. Original studies with clear operationalization of multimorbidity and validated QoL (or HRQoL) measurement were retained. For random-effect meta-analysis, a minimum of three studies with the same multimorbidity tool (e.g. number of diseases or equal comorbidity index) and the same QoL tool were required. Number of diseases was most common and the only measure on which meta-analysis was carried out. The outcome of interest was the linear regression slope between increasing number of diseases and QoL. Heterogeneity was explored with meta-regression. Out of 25,890 studies initially identified, 74 studies were retained for systematic review (total of 2,500,772 participants), of which 39 were included in the meta-analysis. The mean decrease in HRQoL per each added disease, depending on the scale, ranged from: -1.55% (95%CI: -2.97%, -0.13%) for the mental component summary score of pooled SF-36, -12 and -8 scales to -4.37% (95%CI: -7.13%, -1.61%) for WHOQoL-BREF physical health domain. Additional studies considering severity, duration and patterns of diseases are required to further clarify this association.


The premature demise of public child and adolescent inpatient psychiatric beds : part I: overview and current conditions.
Current trends on the national landscape of available treatment and delivery systems for children and adolescents with serious emotional disturbance indicate a sharp decline in the availability of inpatient psychiatric services. These trends are troubling as six to nine million children and adolescents in the United States suffer from some serious emotional disturbance, and the majority in need of treatment do not receive behavioral health services. The consequences of untreated mental illness in children are grave, and the cost to society of children's mental health problems is high in both human and fiscal terms. This paper will describe national trends in behavioral health in general and specifically children's mental health, and will detail the experiences of many states to identify possible problems and pitfalls to downsizing and closing child and adolescent inpatient psychiatric beds.


SU-E-T-410: Spine Radiosurgery Imaging Guidance Using ExacTrac and CT on rails.
To evaluate the patient setup accuracy and effectiveness using ExacTrac and CT_on_rails systems. We used Brainlab's Exactrac system and Varian/GE's CT_on_rails for spine radiosurgery patient setup. Once the patient was setup using the ExacTrac and couch position was recorded, fiducially markers were placed on stable surfaces based on the room laser to indicate the linac iso for the CT images. CT images were acquired using the on-rail CT with the couch rotated 180 degrees. The couch was returned to 0 degree position, and verification X-ray images were taken and corrections were made by ExacTrac. The treatment CT images were registered with the planning CT using the in-house CAT software and it displays the correct couch position based on CT which can be compared with ExacTrac setup. The corrected couch positions from CT registration are compared to those from ExacTrac. The translational discrepancies needed to be within 2 mm for confirmation. If a discrepancy was greater than 2 mm, investigation or re-setup was required. The rotation deviations were also evaluated by ExacTrac and confirmed by the treatment CT images. We would also re-setup patient if Exactrac detected more than 3 degree rotation, or treatment CT images showed significant target rotation compared to planning CT. The use of the CTonrails took little extra time, but make the overall evaluation process easier, faster and with more confidence. for 171 treatment sessions using this approach, the mean discrepancies between CTonrails and ExacTrac setup is: x=0.0±1.0 mm, y=-0. 1±0.9 mm, z=0.2±0.9 mm; for rotations, about 3% of the cases required re-setup patient due to significant rotation displayed by the treatment CT on the CAT system. The combined use of ExacTrac and CT_on_Rails systems can improve the overall setup accuracy and increase the confidence in setup for spine radiosurgery treatments.


Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma: A Phase 2 Randomized Clinical Trial.
Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer. To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine. In a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020. In the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle. The primary end point of the study was progression-free survival. The analysis was on all patients who started therapy. Of the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001). The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine. ClinicalTrials.gov Identifier: NCT02567409.


Men who have sex with men, risk behavior, and HIV infection: integrative analysis of clinical, epidemiological, and laboratory databases.
Centralized data collection and analytic tools facilitate tracing HIV transmission trends at the patient-population level with increasing resolution, complementing behavioral studies while avoiding sampling biases. By several measures, the rate of HIV infection among men who have sex with men (MSM) in Israel increased in the past several years more rapidly than was expected. We describe features of the data that connect this increase to behavioral changes. We retrospectively analyzed data from the national HIV reference laboratory and the national HIV and sexually transmitted infections registries. We examined changes in selected epidemiologic and clinical parameters and in the pattern of drug-resistant virus transmission among MSM in Israel. In particular, virus isolates from 296 MSM (23.8% of all MSM who received a diagnosis) were genotyped, drug-resistance conferring mutations were characterized, and phylogenetic trees were constructed. Compared with earlier years, during 2007-2009 MSM were more often infected with drug-resistant virus before treatment initiation, were coinfected with syphilis, and received a diagnosis during acute retroviral syndrome. Phylogenetic analysis suggested frequent transmission of drug-resistant HIV by drug-treated individuals to >1 partner. Secondary transmission of resistant virus by drug-naive patients is also consistent with the phylogenetic patterns. In addition, non-B HIV subtypes began to appear among MSM. Together, our findings suggest that the sexual behavior of MSM, both HIV-infected and uninfected, has become riskier, contributing to the number of those seeking early clarification of status, to syphilis comorbidity, and to the spread of drug resistance. These findings call for action by public health planners and community-based organizations aimed at increasing awareness of the risks, bringing a change in attitude and establishing safe sex norms.


Magnetic Anomalies over the Pacific-Antarctic Ridge.
Four magnetic profiles across the Pacific-Antarctic Ridge reveal magnetic anomalies that show trends parallel with the ridge axis and symmetry about the ridge axis. The distribution of bodies that could cause these anomalies supports the Vine and Matthews hypothesis for the generation of patterns of magnetic anomalies associated with the midocean ridge system. The geometry of the bodies accords with the known reversals of the geomagnetic field during the last 3.4 million years, indicating a spreading rate of the ocean floor of 4.5 centimeters per year. If one assume that the spreading rate within 500 kilometers of the ridge axis has been constant, reversals of the geomagnetic field during the last 10.0 million years can be determined. This new, detailed history of field reversals accords with observed anomalies over Reykjanes Ridge in the North Atlantic if a spreading rate of 1 centimeter per year is assumed there.


AKAP79/150 signal complexes in G-protein modulation of neuronal ion channels.
Voltage-gated M-type (KCNQ) K+ channels play critical roles in regulation of neuronal excitability. Previous work showed A-kinase-anchoring protein (AKAP)79/150-mediated protein kinase C (PKC) phosphorylation of M channels to be involved in M current (I(M)) suppression by muscarinic M1, but not bradykinin B2, receptors. In this study, we first explored whether purinergic and angiotensin suppression of I(M) in superior cervical ganglion (SCG) sympathetic neurons involves AKAP79/150. Transfection into rat SCG neurons of ΔA-AKAP79, which lacks the A domain necessary for PKC binding, or the absence of AKAP150 in AKAP150(-/-) mice, did not affect I(M) suppression by purinergic agonist or by bradykinin, but reduced I(M) suppression by muscarinic agonist and angiotensin II. Transfection of AKAP79, but not ΔA-AKAP79 or AKAP15, rescued suppression of I(M) by muscarinic receptors in AKAP150(-/-) neurons. We also tested association of AKAP79 with M(1), B(2), P2Y(6), and AT(1) receptors, and KCNQ2 and KCNQ3 channels, via Förster resonance energy transfer (FRET) on Chinese hamster ovary cells under total internal refection fluorescence microscopy, which revealed substantial FRET between AKAP79 and M1 or AT1 receptors, and with the channels, but only weak FRET with P2Y(6) or B2 receptors. The involvement of AKAP79/150 in G(q/11)-coupled muscarinic regulation of N- and L-type Ca2+) channels and by cAMP/protein kinase A was also studied. We found AKAP79/150 to not play a role in the former, but to be necessary for forskolin-induced upregulation of L-current. Thus, AKAP79/150 action correlates with the PIP(2) (phosphatidylinositol 4,5-bisphosphate)-depletion mode of I(M) suppression, but does not generalize to G(q/11)-mediated inhibition of N- or L-type Ca2+ channels.


Outpatient Cervical and Lumbar Spine Surgery is Feasible and Safe: A Consecutive Single Center Series of 1449 Patients.
There is an increasing demand for surgery of degenerative spinal disease. Limited healthcare resources draw attention to the need for cost-effective treatments. Outpatient surgery, when safe and feasible, is more cost effective than inpatient surgery. To study types and rates of complications after outpatient lumbar and cervical spine decompressions. Complications were recorded prospectively in 1449 (1073 lumbar, 376 cervical) outpatients undergoing microsurgical decompression for degenerative spinal disease at the private Oslofjord Clinic from 2008 to 2013. Surgical mortality was 0%. A total of 51 (3.5%) minor and major complications were recorded in 51 patients. Three (0.2%) patients had to be admitted to a hospital the day of surgery. Twenty-two (1.5%) patients were admitted to a hospital within 3 months due to surgery-related events. The encountered complications were postoperative hematoma (0.6%), neurological deterioration (0.3%), deep wound infection (0.9%), dural lesions with cerebrospinal fluid leakage (1.0%), persistent dysphagia (0.1%), persistent hoarseness (0.1%), and severe pain/headache (0.4%). All of the life-threatening hematomas were detected within 6 and 3 hours after cervical and lumbar surgery, respectively. This series of 1449 consecutive outpatient microsurgical spine decompressions adds to the growing literature in favor of outpatient spinal surgery in properly selected patients. In our study, 99.8% of the patients were successfully discharged either to their homes or to a hotel on the day of surgery. The overall complication rate was 3.5%, surgical mortality was 0%, and only 1.5% had to be admitted to a hospital within 3 months after surgery.


Microbiome-Gut-Brain Axis: A Pathway for Improving Brainstem Serotonin Homeostasis and Successful Autoresuscitation in SIDS-A Novel Hypothesis.
Sudden infant death syndrome (SIDS) continues to be a major public health issue. Following its major decline since the "Back to Sleep" campaign, the incidence of SIDS has plateaued, with an annual incidence of about 1,500 SIDS-related deaths in the United States and thousands more throughout the world. The etiology of SIDS, the major cause of postneonatal mortality in the western world, is still poorly understood. Although sleeping in prone position is a major risk factor, SIDS continues to occur even in the supine sleeping position. The triple-risk model of Filiano and Kinney emphasizes the interaction between a susceptible infant during a critical developmental period and stressor/s in the pathogenesis of SIDS. Recent evidence ranges from dysregulated autonomic control to findings of altered neurochemistry, especially the serotonergic system that plays an important role in brainstem cardiorespiratory/thermoregulatory centers. Brainstem serotonin (5-HT) and tryptophan hydroxylase-2 (TPH-2) levels have been shown to be lower in SIDS, supporting the evidence that defects in the medullary serotonergic system play a significant role in SIDS. Pathogenic bacteria and their enterotoxins have been associated with SIDS, although no direct evidence has been established. We present a new hypothesis that the infant's gut microbiome, and/or its metabolites, by its direct effects on the gut enterochromaffin cells, stimulates the afferent gut vagal endings by releasing serotonin (paracrine effect), optimizing autoresuscitation by modulating brainstem 5-HT levels through the microbiome-gut-brain axis, thus playing a significant role in SIDS during the critical period of gut flora development and vulnerability to SIDS. The shared similarities between various risk factors for SIDS and their relationship with the infant gut microbiome support our hypothesis. Comprehensive gut-microbiome studies are required to test our hypothesis.


The effects of extracorporeal shock wave therapy on the pain and function of patients with degenerative knee arthritis.
[Purpose] The purpose of this study was to identify the effects of extracorporeal shock wave therapy on the pain and function of patients with degenerative knee arthritis. [Subjects and Methods] Twenty patients with degenerative knee arthritis were divided into a conservative physical therapy group (n=10) and an extracorporeal shock wave therapy group (n=10). Both groups received general conservative physical therapy, and the extracorporeal shock wave therapy was additionally treated with extracorporeal shock wave therapy after receiving conservative physical therapy. Both groups were treated three times a week over a four-week period. The visual analogue scale was used to evaluate pain in the knee joints of the subjects, and the Korean Western Ontario and McMaster Universities Osteoarthritis Index was used to evaluate the function of the subjects. [Results] The comparison of the visual analogue scale and Korean Western Ontario and McMaster Universities Osteoarthritis Index scores within each group before and after the treatment showed statistically significant declines in scores in both the conservative physical therapy group and extracorporeal shock wave therapy group. A group comparison after the treatment showed statistically significant differences in these scores in the extracorporeal shock wave therapy group and the conservative physical therapy group. [Conclusion] extracorporeal shock wave therapy may be a useful nonsurgical intervention for reducing the pain of patients with degenerative knee arthritis and improving these patients' function.


Cost-effectiveness of measuring fractional flow reserve to guide coronary interventions.
Most patients come to the catheterization laboratory without prior functional tests, which makes the cost-effective treatment of patients with intermediate coronary lesions a practical challenge. We developed a decision model to compare the long-term costs and benefits of 3 strategies for treating patients with an intermediate coronary lesion and no prior functional study: 1) deferring the decision for percutaneous coronary intervention (PCI) to obtain a nuclear stress imaging study (NUC strategy); 2) measuring fractional flow reserve (FFR) at the time of angiography to help guide the decision for PCI (FFR strategy); and 3) stenting all intermediate lesions (STENT strategy). On the basis of the literature, we estimated that 40% of intermediate lesions would produce ischemia, 70% of patients treated with PCI and 30% of patients treated medically would be free of angina after 4 years, and the quality-of-life adjustment for living with angina was 0.9 (1.0 = perfect health). We estimated the cost of FFR to be 761 dollars, the cost of nuclear stress imaging to be 1093 dollars, and the cost of medical treatment for angina to be 1775 dollars per year. The extra cost of splitting the angiogram and PCI as dictated by the NUC strategy was 3886 dollars by use of hospital cost-accounting data. Sensitivity and threshold analyses were performed to determine which variables affected our results. The FFR strategy saved 1795 dollars per patient compared with the NUC strategy and 3830 dollars compared with the STENT strategy. Quality-adjusted life expectancy was similar among the 3 strategies (NUC-FFR = 0.8 quality-adjusted days, FFR-STENT = 6 quality-adjusted life days). Compared with the FFR strategy, the NUC strategy was expensive (>800,000 dollars per quality-adjusted life year gained). Both screening strategies were superior to (less cost, better outcomes) the STENT strategy. Sensitivity analysis indicated that the NUC strategy would only become attractive (<50,000 dollars/quality-adjusted life years compared with FFR) if the specificity of nuclear stress imaging was >25% better than FFR. Our results were not altered significantly by changing the other assumptions. In patients with an intermediate coronary lesion and no prior functional study, measuring FFR to guide the decision to perform PCI may lead to significant cost savings compared with performing nuclear stress imaging or with simply stenting lesions in all patients.


IGF-1R nuclear import and recruitment to chromatin involves both alpha and beta subunits.
Mature type 1 insulin-like growth factor receptors (IGF-1Rs) are heterotetrameric structures comprising two extracellular α-subunits disulphide-bonded to two transmembrane β-subunits with tyrosine kinase activity. IGF-1R is a well-known cell surface mediator of malignant growth, with an incompletely understood role upon nuclear import as a transcriptional regulator. Previous characterisation of nuclear IGF-1R focused on IGF-1Rβ. Here, we aimed to clarify the source of nuclear IGF-1R and investigate whether α-subunits contribute to nuclear IGF-1R function. Using prostate cancer cell lines DU145 and 22Rv1 we detected nuclear α- and β-subunits, with increase in nuclear signal upon IGF-treatment and reduction in response to IGF-1R inhibitor BMS-754807. Following biotinylation of cell surface proteins, biotinylated α- and β-subunits were detected in nuclear extracts of both cell lines. Furthermore, α- and β-subunits reciprocally co-precipitated from nuclear extract. Finally, we detected recruitment of both subunits to regulatory regions of chromatin, including the promoter of the oncogene JUN, that we previously identified in ChIP-seq as sites of IGF-1Rβ enrichment. These data confirm the cell surface origin of nuclear IGF-1R, suggest the presence of nuclear αβ complexes and reveal that both IGF-1Rα- and β-subunits contribute to pro-tumorigenic functions of nuclear IGF-1R. The online version contains supplementary material available at 10.1007/s12672-021-00407-8.


The multifaceted role of Th17 lymphocytes and their associated cytokines in cancer.
While the role of T helper 17 lymphocytes (Th17) in the pathogenesis of autoimmune diseases and in infectious immunity has been relatively well defined, the impact of these cells and their associated cytokines on cancer development is still under debate. Although multiple reports have indicated that Th17 can promote anticancer immunity, others have argued that these cells may exhibit tumor-promoting properties. This dichotomy in the function of Th17 lymphocytes in cancer may be related to the versatile nature of these cells, being capable of differentiating into either proinflammatory Th1 or suppressive FoxP3-expressing Treg cells or hybrid T cell subsets depending on the underlying environmental conditions. In the current review, we examine the role of Th17 lymphocytes and Th17-associated cytokines in cancer and discuss how factors that control their final lineage commitment decision may influence the balance between their tumor-promoting versus tumor-suppressing properties.


A randomized, double-blind, placebo-controlled exploratory study to evaluate the potential of pycnogenol for improving allergic rhinitis symptoms.
The potential of Pycnogenol for relieving allergic rhinitis (birch pollen) symptoms was explored in a double-blind, placebo-controlled trial. In 2008 19 subjects started treatment 3 weeks prior to the onset of birch pollen season in Ontario, Canada. While there was an improvement of eye and nasal symptoms with Pycnogenol, there was no significance versus placebo. It was postulated that Pycnogenol may require a lag-time between the start of therapy and the onset of action. Therefore 39 subjects were treated 5-8 weeks prior to the 2009 birch allergy season. The evaluation of subjects in 2009 showed much lower scores for eye (-35%) and nasal (-20.5%) symptoms with Pycnogenol compared with placebo. In succession of the allergy season birch specific IgE increased by 31.9% in the placebo group compared with only 19.4% in the Pycnogenol group. Detailed analysis suggested that symptom-relief was better the longer subjects were on Pycnogenol prior to the allergen exposure. The best results were found with subjects who took Pycnogenol 7-8 weeks ahead of the allergy season. With the limited number of 39 patients statistical predications were unattainable. In conclusion, Pycnogenol improved allergic rhinitis symptoms when supplementation was started at least 5 weeks before the onset of the allergy season.


Anterior choroidal artery territory infarcts. Study of presumed mechanisms.
A previous study suggested that occlusive diseases of small penetrating arteries account for most anterior choroidal artery (AChA) territory infarcts, but half of the patients did not have an echocardiogram. Cases of AChA territory infarcts associated with internal carotid artery stenosis or atrial fibrillation suggest that this hypothesis may be wrong. The aim of this study was to determine the mechanism of 16 nonselected consecutive AChA territory infarcts. The study population consisted of 8 men and 8 women aged 17 to 89 years. They underwent a computed tomographic scan at the acute stage, Doppler ultrasonography and B-mode echotomography of the cervical arteries, bidimensional transthoracic echocardiography, and cerebral magnetic resonance imaging, replaced by a second computed tomographic scan in 3 patients. Ten patients underwent cerebral angiography. We defined the presumed cause of stroke according to the criteria used in the trial of Org 10172 in acute stroke treatment. The presumed cause of stroke was definite cardio-embolism in 4 patients (atrial fibrillation in 2, paradoxical embolism in 1, and left ventricular akinesia in 1); definite large-vessel atherosclerosis in 2; dissection of the internal carotid artery in 2; and definite small-vessel occlusion in 1. Seven patients had a negative diagnostic workup. Six patients had no risk factors for small-vessel occlusion. The AChA was not visible on angiography in 4 patients. One patient had two arterial cutoffs, suggestive of emboli in other cerebral arteries. This study suggests that AChA territory infarcts are rarely related to small-vessel occlusion and therefore require a complete diagnostic workup.


The Biomechanics of Standing Start and Initial Acceleration: Reliability of the Key Determining Kinematics.
The reliability of the key determining kinematic variables associated with short sprint performance provide insight into how and why movement may vary between individual trials. Currently, literature surrounding these determinants is scarce when investigating the first three strides of a sprint. The purpose of this study was to investigate the reliability of sprint acceleration and the key kinematic determinants involved during the first three steps of the movement. The aim was to use a practical method of kinematic analysis to help explain why changes may occur in sprint performance via the use of correlative statistics and to provide reference values for intervention research to make conclusions about their change scores. Ten male volunteers from various team sports attended two separate testing sessions, a minimum of 48 hours apart. They performed three maximal sprint trials over a 10m distance from a standing start, where researchers captured 5m and 10m sprint times alongside high speed camera footage, from which the key kinematic variables were measured. Results demonstrated that although 5m and 10m sprint times depicted moderate to large levels of similarity between sessions, neither of these variables met the criteria to be classified as adequately, or highly reliable. Kinematic measures typically produced ICC values > 0.70 and CV% < 10%, demonstrating all relevant statistical traits to be categorised as reliable measures. Step frequency and flight time during the third step showed the largest correlation with performance, exhibiting 'r' values of -0.386 and 0.396, respectively. These findings demonstrate that kinematic variables may not have an influential role with sprint times; therefore suggesting kinetic concepts may in fact be the key determinants of speed. Future research is required investigating the interaction of kinetic and kinematic variables associated with sprinting and how the variability in these concepts effects the reliability of performance.


Increased risk of cigarette smoking among immigrant children and girls in Hong Kong: an emerging public health issue.
Despite global progress in tobacco control, data are needed for subgroups with increased risk of tobacco use for more effective smoking prevention. Survey data from a random sample of 6,486 youth in grades 7, 8 and 9 were derived from the project Chinese Student Health Survey. Prevalence and hazards of smoking onset were compared by gender and immigrant status. Mediation analysis was used to assess factors that may mediate the impact of immigrant status on smoking. Immigrant students had a much higher risk of hazards of smoking initiation than non-immigrant students. Parental monitoring and parental smoking significantly mediated the effect of immigrant status on early smoking onset. In addition, gender differences in the prevalence of smoking and hazards of smoking onset in our study were smaller than those reported by others targeting non-Hong Kong Chinese youth. Findings of this study imply that immigrant children and girls in Hong Kong are at increased risk to tobacco use. Special attention should be paid to these subgroups for prevention intervention. Prevention intervention for immigrant children should address parental smoking and parental monitoring. Reduced gender difference in smoking among Hong Kong youth suggests an emerging trend for more Chinese girls on the Mainland to smoke along with the rapid socioeconomic development.


Embodiment as procedures: Physical cleansing changes goal priming effects.
Physical cleansing reduces the influence of numerous psychological experiences, such as guilt from immoral behavior, dissonance from free choice, and good/bad luck from winning/losing. How do these domain-general effects occur? We propose an integrative account of cleansing as an embodied procedure of psychological separation. By separating physical traces from a physical target object (e.g., detaching dirt from hands), cleansing serves as the embodied grounding for the separation of psychological traces from a psychological target object (e.g., dissociating prior experience from the present self). This account predicts that cleansing reduces the accessibility of psychological traces and their consequences for judgments and behaviors. Testing these in the context of goal priming, we find that wiping one's hands (vs. not) decreases the mental accessibility (Experiment 1), behavioral expression (Experiment 2), and judged importance (Experiments 3-4) of previously primed goals (e.g., achievement, saving, fitness). But if a goal is primed after cleansing, its importance gets amplified instead (Experiment 3). Based on the logic of moderation-of-process, an alternative manipulation that psychologically separates a primed goal from the present self produces the same effects, but critically, the effects vanish once people wipe their hands clean (Experiment 4), consistent with the notion that cleansing functions as an embodied procedure of psychological separation. These findings have implications for the flexibility of goal pursuit. More broadly, our procedural perspective generates novel predictions about the scope and mechanisms of cleansing effects and may help integrate embodied and related phenomena. (PsycINFO Database Record


Gaussian-like dual-wavelength prescaled clock recovery with simultaneous frequency-doubled clock recovery using an optoelectronic oscillator.
A novel multifunctional frequency-doubling optoelectronic oscillator (FD-OEO) mainly based on a Mach-Zehnder modulator (MZM) cascaded with a phase modulator (PM) and a subsequent optical bandpass filter (OBPF) is proposed. We experimentally demonstrate simultaneous operations of frequency-doubled optical clock (FD-OC) recovery, low-duty-cycle dual-wavelength prescaled OC recovery and error-free fourfold time division demultiplexing with the proposed OEO injected with a 4 × 25-Gb/s optical time-division-multiplexing (OTDM) signal. We show that the proposed FD-OEO operates well for both the differential phase shift keying (DPSK) and on-off keying (OOK) modulation formats. The extracted dual-wavelength prescaled OC is proved to be nearly transform-limited with Gaussian-like shape. Furthermore, all four 25-Gb/s tributaries can be selectively demultiplexed by adjusting the phase shifters in the OEO loop. The power penalty at a bit error rate (BER) of 10(-9) is measured to be 2.4 dB, 1.2 dB for the best channel for DPSK signal and to be 2.5 dB, 1.1 dB for the best channel for OOK signal. In addition, as an extra benefit of the OEO, low-phase-noise prescaled electrical clock (EC) is also extracted.


Methylation of inorganic arsenic in different mammalian species and population groups.
Thousands of people in different parts of the world are exposed to arsenic via drinking water or contaminated soil or food. The high general toxic of arsenic has been known for centuries, and research during the last decades has shown that arsenic is a potent human carcinogen. However, most experimental cancer studies have failed to demonstrate carcinogenicity in experimental animals, indicating marked variation in sensitivity towards arsenic toxicity between species. It has also been suggested that there is a variation in susceptibility among human individuals. One reason for such variability in toxic response may be variation in metabolism. Inorganic arsenic is methylated in humans as well as animals and micro-organisms, but there are considerable differences between species and individuals. In many, but not all, mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are more rapidly excreted in urine than is the inorganic arsenic, especially the trivalent form (AsIII, arsenite) which is highly reactive with tissue components. Absorbed arsenate (AsV) is reduced to trivalent arsenic (AsIII) before the methyl groups are attached. It has been estimated that as much as 50-70% of absorbed AsV is rapidly reduced to AsIII, a reaction which seems to be common for most species. In most experimental animal species, DMA is the main metabolite excreted in urine. Compared to human subjects, very little MMA is produced. However, the rate of methylation varies considerably between species, and several species, e.g. the marmoset monkey and the chimpanzee have been shown not to methylate inorganic arsenic at all. In addition, the marmoset monkey accumulates arsenic in the liver. The rat, on the other hand, has an efficient methylation of arsenic but the formed DMA is to a large extent accumulated in the red blood cells. As a result, the rat shows a low rate of excretion of arsenic. In both human subjects and rodents exposed to DMA, about 5% of the dose is excreted in the urine as trimethylarsine oxide. It is obvious from studies on human volunteers exposed to specified doses of inorganic arsenic that the rate of excretion increases with the methylation efficiency, and there are large inter-individual variations in the methylation of arsenic. Recent studies on people exposed to arsenic via drinking water in northern Argentina have shown unusually low urinary excretion of MMA. Furthermore, children had a lower degree of methylation of arsenic than adults. Some studies indicate a lower degree of arsenic methylation in men than in women, especially during pregnancy. Whether the observed differences in methylation of arsenic are associated with variations in the susceptibility of arsenic remains to be investigated.


Enhanced dispersibility and deposition of spray-dried powders for pulmonary gene therapy.
Spray-drying represents a viable alternative to freeze-drying for preparing dry powder dispersions for delivering macromolecules to the lung. The dispersibility of spray-dried powders is limited however, and needs to be enhanced to improve lung deposition and subsequent biological activity. In this study, we investigate the utility of leucine as a dry powder dispersibility enhancer when added prior to spray-drying a model non-viral gene therapy formulation (lipid:polycation:pDNA, LPD). Freeze-dried lactose-LPD, spray-dried lactose-LPD and spray-dried leucine-lactose-LPD powders were prepared. Scanning electron microscopy showed that leucine increased the surface roughness of spray-dried lactose particles. Particle size analysis revealed that leucine-containing spray-dried powders were unimodally dispersed with a mean particle diameter of 3.12 microm. Both gel electrophoresis and in vitro cell (A549) transfection showed that leucine may compromise the integrity and biological functionality of the gene therapy vector. The deposition of the leucine containing powder was however significantly enhanced as evidenced by an increase in gene expression mediated by dry powder collected at lower stages of a multistage liquid impinger (MSLI). Further studies are required to determine the potential of leucine as a ubiquitous dispersibility enhancer for a variety of pulmonary formulations.


Heterogeneous distribution of basal cyclic guanosine monophosphate within distinct neuronal populations in the hypothalamic paraventricular nucleus.
The supraoptic (SON) and the paraventricular (PVN) hypothalamic nuclei constitute major neuronal substrates underlying nitric oxide (NO) effects on autonomic and neuroendocrine control. Within these nuclei, constitutively produced NO restrains the firing activity of magnocellular neurosecretory and preautonomic neurons, actions thought to be mediated by a cGMP-dependent enhancement of GABAergic inhibitory transmission. In the present study, we expanded on this knowledge by performing a detailed anatomical characterization of constitutive NO-receptive, cGMP-producing neurons within the PVN. To this end, we combined tract-tracing techniques and immunohistochemistry to visualize cGMP immunoreactivity within functionally, neurochemically, and topographically discrete PVN neuronal populations in Wistar rats. Basal cGMP immunoreactivity was readily observed in the PVN, both in neuronal and vascular profiles. The incidence of cGMP immunoreactivity was significantly higher in magnocellular (69%) compared with preautonomic ( approximately 10%) neuronal populations (P < 0.01). No differences were observed between oxytocin (OT) and vasopressin (VP) magnocellular neurons. In preautonomic neurons, the incidence of cGMP was independent of their subnuclei distribution, innervated target (i.e., intermediolateral cell column, nucleus tractus solitarii, or rostral ventrolateral medulla) or their neurochemical phenotype (i.e., OT or VP). Finally, high levels of cGMP immunoreactivity were observed in GABAergic somata and terminals within the PVN of eGFP-GAD67 transgenic mice. Altogether, these data support a highly heterogeneous distribution of basal cGMP levels within the PVN and further support the notion that constitutive NO actions in the PVN involve intricate cell-cell interactions, as well as heterogeneous signaling modalities.


Identification of the Main Intermediate Precursor of l-Ergothioneine Biosynthesis in Human Biological Specimens.
A capillary electrophoresis coupled to tandem mass spectrometry (CE-MS/MS) has been used to make a qualitative determination of hercynine-the main precursor of l-ergothioneine biosynthesis-in some key human biological specimens, such as urine, whole blood, plasma, and saliva. From semiquantitative analysis results, the highest concentrations of hercynine were detected in saliva and whole blood, whereas much lower concentrations were measured in urine and plasma. Whole blood was the biological matrix with the highest concentration of l-ergothioneine followed by plasma, saliva, and urine. The antioxidant effects attributed to l-ergothioneine, along with its peculiar antioxidant mechanism, offer a possible explanation for the presence of the hercynine, as well as its concentration, in the considered biological matrices.


Initial clinical experience with the GORE septal occluder for the treatment of atrial septal defects and patent foramen ovale.
To describe the initial experience with the GORE® septal occluder (GSO), a new septal occluder for the treatment of atrial septal defects (ASD) and patent foramen ovale (PFO). This was a prospective single-centre review of patients undergoing percutaneous closure for a PFO or ASD with the GSO. A clinical evaluation and follow-up echocardiography were performed at three months with transoesophageal echocardiography (TEE) in case of PFO and transthoracic echocardiography (TTE) in ASDs. Between July 2011 and February 2012, thirty-eight patients underwent PFO (n=29) or ASD (n=9) closure with the GSO using TEE (n=36, 94.7%) or intracardiac echocardiography (n=2, 5.3%) guidance. In PFOs, three-month TEE was available in 24 patients and showed no residual shunt in 18 (75%), bubble shunt in two (8.3%) and bubble shunt after Valsalva in four (16.7%). In ASDs, three-month TTE showed no shunt in eight patients (88.8%) and residual shunt in one patient (11.2%). There was no device embolisation, air embolism, procedure-related stroke or pericardial effusion. No neurological events occurred during the follow-up period. This initial experience with the new GSO device has demonstrated acceptable safety with no procedural complications and acceptable efficacy with low rates of residual shunting at three-month follow-up.


Cofactor specificity motifs and the induced fit mechanism in class I ketol-acid reductoisomerases.
Although most sequenced members of the industrially important ketol-acid reductoisomerase (KARI) family are class I enzymes, structural studies to date have focused primarily on the class II KARIs, which arose through domain duplication. In the present study, we present five new crystal structures of class I KARIs. These include the first structure of a KARI with a six-residue β2αB (cofactor specificity determining) loop and an NADPH phosphate-binding geometry distinct from that of the seven- and 12-residue loops. We also present the first structures of naturally occurring KARIs that utilize NADH as cofactor. These results show insertions in the specificity loops that confounded previous attempts to classify them according to loop length. Lastly, we explore the conformational changes that occur in class I KARIs upon binding of cofactor and metal ions. The class I KARI structures indicate that the active sites close upon binding NAD(P)H, similar to what is observed in the class II KARIs of rice and spinach and different from the opening of the active site observed in the class II KARI of Escherichia coli. This conformational change involves a decrease in the bending of the helix that runs between the domains and a rearrangement of the nicotinamide-binding site.


Ex vivo diffusion tensor MRI of human hearts: relative effects of specimen decomposition.
Recently, diffusion tensor MRI has been utilized as a tool to reconstruct, with high resolution, the three-dimensional myofiber orientation of hearts ex vivo. However, because of limited availability of human hearts, it is common to recover specimens postmortem, after some degree of decomposition has occurred. In this study, we describe the ability to reconstruct local fiber orientation within a unique set of human hearts using diffusion tensor MRI; relative effects of specimen decomposition were also assessed. The mean diffusivity, fractional anisotropy, and principal eigenvalues (E1, E2, and E3) were measured in hearts with varying postmortem intervals from 0 to 27 days (n = 17), and local fiber orientations were reconstructed. Mean diffusivities and principal eigenvalues nonlinearly increased as a function of postmortem interval, while fractional anisotropies nonlinearly decreased. There were good correlations between postmortem intervals and changes in diffusion properties after linear transformation of the data (R(2) > 0.7). Thus, we determined that there were regional discontinuities in the reconstruction of local fiber orientation in hearts where postmortem intervals were greater than 3 days. Therefore, any delay in tissue fixation after death (if not properly preserved using organ transplantation techniques) will compromise measurement of fiber orientation and delineation of diseased pathology, e.g., based, in part, on fractional anisotropy.


Unique processing during a period of high excitation/inhibition balance in adult-born neurons.
The adult dentate gyrus generates new granule cells (GCs) that develop over several weeks and integrate into the preexisting network. Although adult hippocampal neurogenesis has been implicated in learning and memory, the specific role of new GCs remains unclear. We examined whether immature adult-born neurons contribute to information encoding. By combining calcium imaging and electrophysiology in acute slices, we found that weak afferent activity recruits few mature GCs while activating a substantial proportion of the immature neurons. These different activation thresholds are dictated by an enhanced excitation/inhibition balance transiently expressed in immature GCs. Immature GCs exhibit low input specificity that switches with time toward a highly specific responsiveness. Therefore, activity patterns entering the dentate gyrus can undergo differential decoding by a heterogeneous population of GCs originated at different times.


Genes encoding two Theileria parva antigens recognized by CD8+ T-cells exhibit sequence diversity in South Sudanese cattle populations but the majority of alleles are similar to the Muguga component of the live vaccine cocktail.
East Coast fever (ECF), caused by Theileria parva infection, is a frequently fatal disease of cattle in eastern, central and southern Africa, and an emerging disease in South Sudan. Immunization using the infection and treatment method (ITM) is increasingly being used for control in countries affected by ECF, but not yet in South Sudan. It has been reported that CD8+ T-cell lymphocytes specific for parasitized cells play a central role in the immunity induced by ITM and a number of T. parva antigens recognized by parasite-specific CD8+ T-cells have been identified. In this study we determined the sequence diversity among two of these antigens, Tp1 and Tp2, which are under evaluation as candidates for inclusion in a sub-unit vaccine. T. parva samples (n = 81) obtained from cattle in four geographical regions of South Sudan were studied for sequence polymorphism in partial sequences of the Tp1 and Tp2 genes. Eight positions (1.97%) in Tp1 and 78 positions (15.48%) in Tp2 were shown to be polymorphic, giving rise to four and 14 antigen variants in Tp1 and Tp2, respectively. The overall nucleotide diversity in the Tp1 and Tp2 genes was π = 1.65% and π = 4.76%, respectively. The parasites were sampled from regions approximately 300 km apart, but there was limited evidence for genetic differentiation between populations. Analyses of the sequences revealed limited numbers of amino acid polymorphisms both overall and in residues within the mapped CD8+ T-cell epitopes. Although novel epitopes were identified in the samples from South Sudan, a large number of the samples harboured several epitopes in both antigens that were similar to those in the T. parva Muguga reference stock, which is a key component in the widely used live vaccine cocktail.


Growth arrest-specific protein 6 (Gas6) attenuates inflammatory injury and apoptosis in iodine-induced NOD.H-2h4 mice.
Growth arrest-specific protein 6 (Gas6) is a vitamin K-dependent protein that plays an important role in the pathogenesis of autoimmune diseases. The purpose of this study was to explore the expression of Gas6 and its effects on autoimmune thyroiditis (AIT). A total of 24 male NOD.H-2h4 mice were randomly assigned to three groups: (1) a control group supplied with regular water; (2) a sodium iodide (NaI) group supplied with 0.005% sodium iodide water; and (3) a group treated with recombinant mouse Gas6 (rmGas6) after iodine supplementation (NaI + Gas6 group). The severity of lymphocytic infiltration in the thyroid was measured through histopathology. Serum levels of tumor necrosis factor α (TNF-α), interleukin (IL) 6 and IL-1β, as well as anti-thyroglobulin antibody (TgAb) titers were measured using an enzyme-linked immunosorbent assay. In addition, the expression of Gas6, Caspase 3, TAM receptors (Axl and MerTK), nuclear factor κB (NF-κB) and I-kappa-B α (IκB-α) were measured by Western blotting. Finally, the proportions of T cells were determined in the splenocytes of NOD.H-2h4 mice by flow cytometry. The mRNA and protein expression of Gas6 was significantly lower in the NaI group compared to the control group. Serum levels of TgAb, TNF-α, IL-6 and IL-1β were also significantly higher in the NaI group but were dramatically reduced after rmGas6 injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly lower in the NaI + Gas6 group compared to the NaI group. The protein expression of cleaved-Caspase 3, phosphorylation of MerTK, and NF-κB and IκB-α in the thyroid gland were significantly reduced after rmGas6 administration. The proportion of Th1, Th2 and Th17 cells in splenocytes were also significantly reduced after rmGas6 treatment, whereas there was a dramatic increase in the proportion of Treg cells. Gas6 exerts an anti-inflammatory effect in a mouse model of AIT and may therefore be a potential therapeutic target.


Mortality and causes of death in autism spectrum disorders: an update.
This study compared mortality among Danish citizens with autism spectrum disorders (ASDs) with that of the general population. A clinical cohort of 341 Danish individuals with variants of ASD, previously followed over the period 1960-93, now on average 43 years of age, were updated with respect to mortality and causes of death. Standardized mortality ratios (SMRs) were calculated for various times after diagnosis. In all, 26 persons with ASD had died, whereas the expected number of deaths was 13.5. Thus the mortality risk among those with ASD was nearly twice that of the general population. The SMR was particularly high in females. The excess mortality risk has remained unchanged since our first study in 1993. Eight of the 26 deaths were associated with epilepsy and four died from epilepsy. Future staff education should focus on better managing of the complex relationships between ASD and physical illness to prevent avoidable deaths.


Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium.
The mammalian main olfactory epithelium (MOE) recognizes and transduces olfactory cues through a G protein-coupled, cAMP-dependent signaling cascade. Additional chemosensory transduction mechanisms have been suggested but remain controversial. We show that a subset of MOE neurons expressing the orphan receptor guanylyl cyclase GC-D and the cyclic nucleotide-gated channel subunit CNGA3 employ an excitatory cGMP-dependent transduction mechanism for chemodetection. By combining gene targeting of Gucy2d, which encodes GC-D, with patch clamp recording and confocal Ca2+ imaging from single dendritic knobs in situ, we find that GC-D cells recognize the peptide hormones uroguanylin and guanylin as well as natural urine stimuli. These molecules stimulate an excitatory, cGMP-dependent signaling cascade that increases intracellular Ca2+ and action potential firing. Responses are eliminated in both Gucy2d- and Cnga3-null mice, demonstrating the essential role of GC-D and CNGA3 in the transduction of these molecules. The sensitive and selective detection of two important natriuretic peptides by the GC-D neurons suggests the possibility that these cells contribute to the maintenance of salt and water homeostasis or the detection of cues related to hunger, satiety, or thirst.


The role of nitric oxide in the cardiovascular response to physical training.
Introduction. In 1980 Furchgort and Zawadzki [1] showed that the vascular endothelium is capable of releasing a potent short-acting vasodilating substance in response to the application of acetylcholine (ACh). This substance, initially defined as endothelium-derived relaxing factor, was subsequently identified with nitric oxide (NO) [2]. Since then a wealth of research has demonstrated the involvement of this molecule not only in the regulation of vascular resistance but also in immunological processes, neuronal transmission, platelet function, growth of smooth muscle cells and cardiac mechanical and electrophysiological properties [3-5].


[Formula: see text]Children's sense of reality: The development of orbitofrontal reality filtering.
Orbitofrontal reality filtering denotes a memory control mechanism necessary to keep thought and behavior in phase with reality. In adults, it is mediated by the orbitofrontal cortex and subcortical connections and its failure induces reality confusion, confabulations, and disorientation. Here we investigated for the first time the development of this mechanism in 83 children from ages 7 to 11 years and 20 adults. We used an adapted version of a continuous recognition task composed of two runs with the same picture set but arranged in different order. The first run measures storage and recognition capacity (item memory), the second run measures reality filtering. We found that accuracy and reaction times in response to all stimulus types of the task improved in parallel across ages. Importantly, at no age was there a notable performance drop in the second run. This means that reality filtering was already efficacious at age 7 and then steadily improved as item memory became stronger. At the age of 11 years, reality filtering dissociated from item memory, similar to the pattern observed in adults. However, performance in 11-year-olds was still inferior as compared to adults. The study shows that reality filtering develops early in childhood and becomes more efficacious as memory capacity increases. For the time being, it remains unresolved, however, whether this function already depends on the orbitofrontal cortex, as it does in adults, or on different brain structures in the developing brains of children.


Isokinetic Dynamometry and 1RM Tests Produce Conflicting Results for Assessing Alterations in Muscle Strength.
The purpose of this study was to compare strength gains in the lower limbs, assessed by one maximum repetition (1RM) and isokinetic peak torque (PT), in young men undergoing a resistance training (RT) program. Twenty-seven young men performed resistance training twice a week for 11 weeks. Training involved two exercises for the lower body, two for the upper body and one for the midsection performed with three sets of 8-12 repetitions to momentary muscle failure. Before and after the training period, participants performed the 1RM test in the 45° leg press and knee extension PT in isokinetic dynamometry. The Pearson correlation coefficient was used to assess the relationship between the changes in 1RM and PT, and the Bland-Altman test was performed to check for agreement between the strength changes of both tests. There were significant changes in 1RM and PT of 23.98% and 15.96%, respectively (p < 0.05). The changes in leg press 1RM were significantly higher than the ones in PT. The Bland-Altman analysis revealed that the tests were not equivalent. In conclusion, professionals and researchers involved in strength assessment should be aware that the results obtained by PT and 1RM are not equivalent when evaluating individual responsiveness and/or the efficacy of an intervention on muscle strength, as the results obtained show large variations and can be even conflicting.


Dynamic Protein Acylation: New Substrates, Mechanisms, and Drug Targets.
Post-translational attachment of lipids to proteins is found in all organisms, and is important for many biological processes. Acylation with myristic and palmitic acids are among the most common lipid modifications, and understanding reversible protein palmitoylation dynamics has become a particularly important goal. Linking acyltransferase enzymes to disease states can be challenging due to a paucity of robust models, compounded by functional redundancy between many palmitoyl transferases; however, in cases such as Wnt or Hedgehog signalling, small molecule inhibitors have been identified, with some progressing to clinical trials. In this review, we present recent developments in our understanding of protein acylation in human health and disease through use of chemical tools, global profiling of acylated proteomes, and functional studies of specific protein targets.


Salvage chemotherapy with docetaxel and epirubicin for advanced/metastatic gastric cancer.
We conducted a phase II study to assess the efficacy and tolerability of docetaxel and epirubicin as salvage chemotherapy in advanced/metastatic gastric cancer patients with documented progression after 5-fluorouracil/platinum-based combination chemotherapy. Docetaxel 75 mg/m(2) and epirubicin 50 mg/m(2) were administered on days 1 and 2, respectively, every 3 weeks. Treatment continued until progression of disease or until a life-threatening adverse event occurred. The primary objectives of this study were to evaluate the safety profile and response rate to this treatment regimen. Thirty-four patients were enrolled in the study. Twenty-six patients had locally advanced or metastatic disease at the time of diagnosis, and 8 patients had recurrent disease after surgical resection of the primary tumor. A total of 157 chemotherapy cycles were administered. Seven (21.8%) patients had a partial response and 12 (37.5%) patients had stable disease. The median time to progression and overall survival were 4.1 and 13.4 months, respectively. Grade III/IV hematologic toxicities included neutropenia in 16 patients (47%) and febrile neutropenia in 8 patients (24%). Nonhematologic toxicities were rare. A combination of chemotherapy with docetaxel and epirubicin showed moderate activity as salvage treatment in advanced/metastatic gastric cancer, especially in patients who had responded to prior chemotherapy.


Near-normal-incidence extreme-ultraviolet efficiency of a flat crystalline anisotropically etched blazed grating.
We have measured the extreme-ultraviolet (EUV) efficiency at an angle of incidence of 10 degrees of a flat crystalline anisotropically etched blazed grating. The measured efficiencies are high for uncoated gratings and agree well with a calculated model derived from a reasonable estimate of the groove profile. The highest groove efficiencies derived from the measurements are 48.8% at 19.07 nm and 64.1% at 16.53 nm for the -2 and -3 orders, respectively, which are comparable to the best values obtained yet from a holographic ion-etched blazed grating. This presents opportunities to instrument designs for high-resolution EUV spectroscopy in astrophysics where high efficiency in high orders is desirable.


Poor clinical outcomes among pneumonia patients with schizophrenia.
Despite the recent attention to patient safety and quality of care, no prior studies have addressed outcomes of hospitalization for pneumonia among patients with schizophrenia. This study investigated the extent to which clinical outcomes of pneumonia were different among patients with schizophrenia. This study used data from the Taiwan National Health Insurance Research Database. Of the total of 81,599 patients admitted with a principal diagnosis of pneumonia from 2002 to 2004, 949 had previously been admitted with a principal or secondary diagnosis of schizophrenia within the 2 years of their index pneumonia admission. We randomly selected 2847 pneumonia patients matched with the study group in terms of gender, age, year of admission, length of stay, and Charlson Comorbidity Index score as the comparison cohort. Conditional logistic regression models were used for analysis. Findings indicated a higher prevalence of adverse outcomes among patients with schizophrenia. Patients with schizophrenia were independently associated with a 1.81 times greater risk of intensive care unit admission (95% confidence interval [CI] = 1.37-2.40), a 1.37 times greater risk of acute respiratory failure (95% CI = 1.08-1.88), and a 1.34-fold greater risk of mechanical ventilation (95% CI = 1.04-1.92) after adjusting for characteristics of patients, physicians, hospitals, and potential clustering effects. Adjusted odds ratios were further evident among those treated in private hospitals and in regional/district hospitals. Significant barriers to prompt and appropriate medical care for pneumonia persist for patients with schizophrenia. Careful monitoring of physical health and proper integration between psychiatrists and physicians should be stressed to reduce poor clinical outcomes in this vulnerable population.


Heterogeneity in the association between socioeconomic position in early life and adult self-rated health in two birth cohorts of Spanish adults.
The purpose of this work was to evaluate the association between socioeconomic circumstances in early life and poor self-rated health in adulthood, and to determine whether this association varies depending on birth cohort. Using data from the 2005 Living Conditions Survey carried out in a Spanish population sample, separate analyses were made for persons born between 1941 and 1959 who lived their childhood and adolescence in a period marked by absence of economic growth in Spain, and those born between 1960 and 1980. The authors estimated of the relation of financial difficulties in adolescence, occupation of father, education of father and education of mother with poor self-reported health, adjusted for the measures of socioeconomic position in adulthood. Also evaluated was the possibility of interaction between early and adult socioeconomic position and the cumulative effect of low socioeconomic position across the life course. In the two cohorts, the presence of financial difficulties in adolescence showed an association with an increased risk of poor self-rated health; in contrast, the relation of occupation and education of parents with poor self-rated health varied depending on the birth cohort and gender of the study subjects. The effect of family financial situation was shown to accumulate over the life course, whereas the effect of socioeconomic position across the life course was heterogeneous when occupation and education of parents were used. The importance of financial difficulties in the household has probably not varied over time; in contrast, the heterogeneity of the findings regarding occupation and education of parents suggests that the importance of these indicators and, consequently, their aetiological pathways may differ depending on the gender and birth cohort of the study subjects.


Smoky coal, tobacco smoking, and lung cancer risk in Xuanwei, China.
Lung cancer rates in Xuanwei are the highest in China. In-home use of smoky coal has been associated with lung cancer risk, and the association of smoking and lung cancer risk strengthened after stove improvement. Here, we explored the differential association of tobacco use and lung cancer risk by the intensity, duration, and type of coal used. We conducted a population-based case-control study of 260 male lung cancer cases and 260 age-matched male controls. Odds ratios (OR) and 95% confidence interval (CI) for tobacco use was calculated by conditional logistic regression. Use of smoky coal was significantly associated with an increased risk of lung cancer, and tobacco use was weakly and non-significantly associated with lung cancer risk. When the association was assessed by coal use, the cigarette-lung cancer risk association was null in hazardous coal users and elevated in less hazardous smoky coal users and non-smoky coal users. The risk of lung cancer per cigarette per day decreased as annual use of coal increased (>0-3 tons: OR: 1.09; 95% CI: 1.03-1.17; >3 tons: OR: 0.99; 95% CI: 0.95-1.03). Among more hazardous coal users, attenuation occurred at even low levels of usage (>0-3 tons: OR: 1.02; 95% CI: 0.91-1.14; >3 tons: OR: 0.94; 95% CI: 0.97-1.03). We found evidence that smoky coal attenuated the tobacco and lung cancer risk association in males that lived in Xuanwei, particularly among users of hazardous coal where even low levels of smoky coal attenuated the association. Our results suggest that the adverse effects of tobacco may become more apparent as China's population continues to switch to cleaner fuels for the home, underscoring the urgent need for smoking cessation in China and elsewhere.


Effects of physiotherapy combined with sirolimus in a patient with vascular malformation: A case report.
The aim of the present case report was to investigate the effects of a physiotherapy program combined with sirolimus in a child patient with upper extremity edema and joint limitation due to low-flow vascular malformation. This case report included an 11-year-old male patient (26 kg, 130 cm) diagnosed with congenital lymphovascular malformation on the left and right chest. The patient, who had edema on the upper left extremity and experienced joint limitations, was administered complete decongestive therapy (CDT) and manual therapy in combination with sirolimus. Physiotherapy included a total of 24 sessions, 3 sessions a week for 8 weeks. Following the physiotherapy, the patient was assigned to a home therapy program, and then the maintenance phase of the CDT was initiated. Evaluations were carried out at baseline, at the end of week 8, and after 12 months. Following the physiotherapy program combined with sirolimus, a decrease in extremity volume, an increase in joint movement range, and an improvement in disease-related complaints were observed. Physiotherapy methods combined with sirolimus may be an effective treatment method in patients with vascular malformations. However, further studies with larger sample size are warranted.


Development of house flies (Diptera:Muscidae) in sand containing varying amounts of manure solids and moisture.
House flies, Musca domestica L., developed in 200 cm3 of coarse sand containing just 1 ml (0.47%) of dairy manure solids and 10 ml (4.74%) of moisture. At these levels, development was slow (21.5 d from 1st instar to adult), adult survival was low (7.5%), but successful development did occur. At higher manure and moisture levels, rates of development and survival were similar to those reported previously. All soil samples collected from a feedlot dairy contained higher levels of manure solids than the highest level tested in the laboratory. The implications for fly control in soil/manure mixtures and the need for additional studies are discussed.


Eating disorder examination questionnaire: norms for young adolescent girls.
This paper reports young adolescent female norms for the Eating Disorder Examination Questionnaire (EDE-Q). The standardization sample was comprised of 808 girls aged between 12 and 14 years from three single-sex schools (one private and two state schools). Means, standard deviations and percentile ranks for raw EDE-Q subscale scores are presented. Prevalence figures for key eating disorder behaviors over the previous two weeks were as follows: 4% self-induced vomiting; 1% laxative misuse; 0.4% diuretic misuse; and 8% regular binge eating.


Continuous Optical Monitoring of Red Blood Cells During a Photosensitization Reaction.
Background: An oxygen-enriched photosensitizer solution was created by the addition of red blood cells (RBCs) as an investigative tool for photosensitization reactions (PRs). Although the oxygen levels and reaction progress can be monitored using the optical characteristics of hemoglobin, previously this has only been done using intermittent measurements. An increase in methemoglobin concentration with irradiation time was reported. Objective: We constructed a continuous optical measurement system to study the dynamics of the PR in a photosensitizer solution containing RBCs. We also measured the relationship between hemolysis and methemoglobin production in the solution. Materials and methods: A 664 nm wavelength continuous laser beam at 60 mW/cm2 was used to drive the PR, and a broadband (475-650 nm) light beam was used to monitor the absorption spectra during the PR. The light sources were arranged perpendicularly to cross at a 1 × 10 mm cuvette. The sample in this cuvette was prepared from a low-hematocrit rabbit RBC suspension medium containing 30 μg/mL talaporfin sodium, a chlorine photosensitizer. The concentrations of oxygenated hemoglobin, deoxygenated hemoglobin, and methemoglobin were obtained using a multiple regression analysis of the measured spectra. Results: The oxygen saturation decreased continuously during the PR. The relationship between the degree of hemolysis and produced methemoglobin concentration was confirmed. Conclusions: We determined the dynamics of the oxidation and oxygen desorption of hemoglobin, as well as RBC hemolysis, during the PR. Our measurement system, which uses the properties of hemoglobin contained in RBCs, might be useful for continuous monitoring of PR dynamics.


A facile solvent-free synthesis route for the assembly of a highly CO2 selective and H2S tolerant NiSIFSIX metal-organic framework.
The development of materials for CO2 capture with high selectivity and high tolerance to H2S is of prime importance for various industrially relevant gas streams (e.g. natural gas and biogas upgrading as well as pre-combustion capture). Here, we report the successful fabrication of a MOF with combined exceptional CO2 capture properties and H2S tolerance, namely the NiSIFSIX-based MOF using both solvothermal and solvent-free methodologies.


MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity.
The role of major histocompatibility complex (MHC) class I expression in natural killer (NK) cell target recognition is controversial. Normal T cell blasts from MHC class I-deficient mutant mice were found to serve as target cells for NK cells in vitro, which suggests that MHC class I molecules are directly involved in NK cell recognition. Spleen cells from the mutant mice were deficient in their ability to lyse MHC class I-deficient target cells or NK-susceptible tumor targets, and mutant mice could not reject allogeneic bone marrow. Thus, class I molecules may participate in the positive selection or tolerance induction of NK cells.


Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection.
Zika virus (ZIKV), a mosquito-borne flavivirus with homology to Dengue virus (DENV), has become a public health emergency. By characterizing memory lymphocytes from ZIKV-infected patients, we dissected ZIKV-specific and DENV-cross-reactive immune responses. Antibodies to nonstructural protein 1 (NS1) were largely ZIKV-specific and were used to develop a serological diagnostic tool. In contrast, antibodies against E protein domain I/II (EDI/II) were cross-reactive and, although poorly neutralizing, potently enhanced ZIKV and DENV infection in vitro and lethally enhanced DENV disease in mice. Memory T cells against NS1 or E proteins were poorly cross-reactive, even in donors preexposed to DENV. The most potent neutralizing antibodies were ZIKV-specific and targeted EDIII or quaternary epitopes on infectious virus. An EDIII-specific antibody protected mice from lethal ZIKV infection, illustrating the potential for antibody-based therapy.


Serum magnesium levels and its correlation with level of control in patients with asthma: A hospital-based, cross-sectional, prospective study.
Magnesium (Mg) is an intracellular cation which takes part in various functions including smooth muscle contractility. Studies have shown that serum Mg level has no significant effect on asthma severity. There are only sparse data on the effect of serum Mg level on asthma control. The aim of this study was to evaluate the effect of serum Mg level on asthma control. This hospital-based cross-sectional study was conducted at the Department of Respiratory Medicine, Kasturba Medical College, Manipal. Our participants were adult asthma patients over 18 years of age. Asthma control was assessed using a questionnaire. Serum Mg level was estimated. The study was approved by the Institutional Ethics Committee, and informed consent was obtained from the participants. Welch's ANOVA test was used to analyze the correlation between serum Mg level and level of control of asthma. We screened 256 patients who met the inclusion criteria. After 96 patients were removed based on exclusion criteria, 160 patients were grouped into three based on the level of symptom control. Forty-eight patients belonged to the "well controlled" group, 59 in "partly controlled" group, and the remaining 53 in "uncontrolled" group. The mean serum Mg level (mg/dl) was 2.08 ± 0.37, 2.07 ± 0.28, and 1.83 ± 0.34 in well, partly, and uncontrolled groups, respectively. As the level of control of asthma decreased from well controlled to uncontrolled, the level of mean serum Mg also decreased. Serum Mg levels have a positive correlation with the level of symptom control in asthma. In uncontrolled asthma, serum Mg is significantly low. Hence, it might be useful as a biomarker in assessing control or severity of asthma.