Changes in fatigue, multiplanar knee laxity, and landing biomechanics during intermittent exercise.
Knee laxity increases during exercise. However, no one, to our knowledge, has examined whether these increases contribute to higher-risk landing biomechanics during prolonged, fatiguing exercise. To examine associations between changes in fatigue (measured as sprint time [SPTIME]), multiplanar knee laxity (anterior-posterior [APLAX], varus-valgus [VVLAX] knee laxity, and internal-external rotation [IERLAX]) knee laxity and landing biomechanics during prolonged, intermittent exercise. Descriptive laboratory study. Laboratory and gymnasium. A total of 30 male (age = 20.3 ± 2.0 years, height = 1.79 ± 0.05 m, mass = 75.2 ± 7.2 kg) and 29 female (age = 20.5 ± 2.3 years, height = 1.67 ± 0.08 m, mass = 61.8 ± 9.0 kg) competitive athletes. A 90-minute intermittent exercise protocol (IEP) designed to simulate the physiologic and biomechanical demands of a soccer match. We measured SPTIME, APLAX, and landing biomechanics before and after warm-up, every 15 minutes during the IEP, and every 15 minutes for 1 hour after the IEP. We measured VVLAX and IERLAX before and after the warm-up, at 45 and 90 minutes during the IEP, and at 30 minutes after the IEP. We used hierarchical linear modeling to examine associations between exercise-related changes in SPTIME and knee laxity with exercise-related changes in landing biomechanics while controlling for initial (before warm-up) knee laxity. We found that SPTIME had a more global effect on landing biomechanics in women than in men, resulting in a more upright landing and a reduction in landing forces and out-of-plane motions about the knee. As APLAX increased with exercise, women increased their knee internal-rotation motion (P = .02), and men increased their hip-flexion motion and energy-absorption (P = .006) and knee-extensor loads (P = .04). As VVLAX and IERLAX increased, women went through greater knee-valgus motion and dorsiflexion and absorbed more energy at the knee (P ≤ .05), whereas men were positioned in greater hip external and knee internal rotation and knee valgus throughout the landing (P = .03). The observed fatigue- and laxity-related changes in landing biomechanics during exercise often depended on initial knee laxity. Both exercise-related changes in fatigue and knee laxity were associated with higher-risk landing biomechanics during prolonged exercise. These relationships were more pronounced in participants with greater initial knee laxity.


Alpha-lipoic acid differently affects the reserpine-induced oxidative stress in the striatum and prefrontal cortex of rat brain.
Antioxidative properties of alpha-lipoic acid (LA) are widely investigated in different in vivo and in vitro models. The aim of this study was to examine whether LA attenuates oxidative stress induced in rats by reserpine, a model substance frequently used to produce Parkinsonism in animals. Male Wistar rats were treated with reserpine (5 mg/kg) and LA (50 mg/kg) separately or in combination. The levels of reduced glutathione (GSH), glutathione disulfide (GSSG), nitric oxide (NO) and S-nitrosothiols as well as activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and L-gamma-glutamyl transpeptidase (gamma-GT) were determined in the striatum and prefrontal cortex homogenates. In the striatum and prefrontal cortex a single dose of reserpine significantly enhanced levels of GSSG and NO but not that of S-nitrosothiols when compared with control. In the striatum, LA administered jointly with reserpine markedly increased the concentration of GSH and decreased GSSG level. In the prefrontal cortex, such treatment produced only an increasing tendency in GSH level but caused no changes in GSSG content. In both structures LA injected jointly with reserpine markedly decreased NO concentrations but did not cause significant changes in S-nitrosothiol levels when compared with control. Enzymatic activities of GPx and GST were intensified by LA in the striatum. In the prefrontal cortex, GPx activity was not altered, while that of GST was decreased. Gamma-GT activity was attenuated by reserpine in the striatum while LA reversed this effect. Such changes were not observed in the prefrontal cortex. The mode of LA action in the striatum during the reserpine-evoked oxidative stress strongly suggests that this compound may be of therapeutic value in the treatment of Parkinson's disease.


Splicing imbalances in basal-like breast cancer underpin perturbation of cell surface and oncogenic pathways and are associated with patients' survival.
Despite advancements in the use of transcriptional information to understand and classify breast cancers, the contribution of splicing to the establishment and progression of these tumours has only recently starting to emerge. Our work explores this lesser known landscape, with special focus on the basal-like breast cancer subtype where limited therapeutic opportunities and no prognostic biomarkers are currently available. Using ExonArray analysis of 176 breast cancers and 9 normal breast tissues we demonstrate that splicing levels significantly contribute to the diversity of breast cancer molecular subtypes and explain much of the differences compared with normal tissues. We identified pathways specifically affected by splicing imbalances whose perturbation would be hidden from a conventional gene-centric analysis of gene expression. We found that a large fraction of them involve cell-to-cell communication, extracellular matrix and transport, as well as oncogenic and immune-related pathways transduced by plasma membrane receptors. We identified 247 genes in which splicing imbalances are associated with clinical patients' outcome, whilst no association was detectable at the gene expression level. These include the signaling gene TGFBR1, the proto-oncogene MYB as well as many immune-related genes such as CCR7 and FCRL3, reinforcing evidence for a role of immune components in influencing breast cancer patients' prognosis.


The high burden of rheumatic heart disease found on autopsy in Fiji.
Rheumatic heart disease causes more than 200,000 deaths worldwide annually, with the vast majority of these deaths occurring in developing countries, yet there are few autopsy studies of rheumatic heart disease in these countries. We performed a retrospective review of 6218 autopsies performed during the period from 1990 through 2006, searching for cases of rheumatic heart disease based upon the macroscopic pathologic examination of the heart. We found 147 cases (2.4%) of rheumatic heart disease. There was an apparent increase in the number of cases in the past 5 years. There were 95 deaths that were directly attributable to rheumatic heart disease, with congestive cardiac failure being the most common cause of death in 75 cases. The mean age at death due to rheumatic heart disease was 38 years. There were more cases of rheumatic heart disease in Indigenous Fijians than Indo-Fijians, with an adjusted relative risk of 1.26 (95% confidence intervals from 0.87 to 1.86). Our findings reflect the high burden and early age of death due to rheumatic heart disease in Fiji and the Pacific region generally, and underline the need for early detection and adequate secondary penicillin prophylaxis in this region.


Exploring Sirolimus Pharmacokinetic Variability Using Data Available from the Routine Clinical Care of Renal Transplant Patients - Population Pharmacokinetic Approach.
Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.


The current practice of family-centred care in Italian neonatal intensive care units: A multicentre descriptive study.
To explore family-centred care practices in Italian neonatal intensive care units and describe areas for improvement. A cross-sectional, multicentre, survey was conducted using the Italian language version of "Advancing family-centred new-born intensive care: a self-assessment inventory". The instrument is divided into 10 sections rating the status of family-centred care (1 = not at all, 5 = very well) and ranking the perceived priority for change/improvement (1 = low, 3 = high). A representative group of staff and parent for each unit were invited to complete the survey. Data was collected between January and June 2015. Correlations among unit characteristics and sections within the survey were explored. All Italian neonatal intensive care units (n = 105) were invited. Forty-six (43.8%) units returned the survey. The "Leadership" section scored highest in status of family-centred care (mean = 3.45; SD 0.78) and scored highest in priority for change (mean = 2.44; SD 0.49). Section "Families as Advisors and Leaders" scored lowest both in status (mean = 1.66; SD 0.67) and in priority for change (mean = 2.09; SD 0.59). The number of discharged infants was positively correlated with many sections in priority for change (r 0.402-0.421; p < .01). This study showed a variability in the organisation of family-centred care practices in Italian neonatal intensive care units and the need to involve parents as partners in the care team. Although family-centred care is considered important by Italian neonatology healthcare professionals, much remains to be done to improve family-centred care practices in neonatal intensive care units in Italy.


A confirmed case of toxic shock syndrome associated with the use of a menstrual cup.
Menstrual cups have been reported to be an acceptable substitute for tampons. These flexible cups have also been reported to provide a sustainable solution to menstrual management, with modest cost savings and no significant health risk. The present article documents the first case of toxic shock syndrome associated with the use of a menstrual cup in a woman 37 years of age, using a menstrual cup for the first time. Toxic shock syndrome and the literature on menstrual cups is reviewed and a possible mechanism for the development of toxic shock syndrome in the patient is described.


Marked aneuploidy and loss of multiple chromosomes are common in autosomal mutants isolated from normal mouse kidney epithelium.
Marked aneuploidy and loss of multiple chromosomes are hallmarks of cancer, but whether these events are only present in malignant cells is not known. In prior work, we showed that approximately half of spontaneous autosomal mutants isolated directly from normal kidney epithelium arose from loss of a marker chromosome 8 containing the wild type Aprt gene. Chromosome loss was detected by loss of heterozygosity (LOH) for all chromosome 8 polymorphic loci examined. To determine whether loss of chromosome 8 reflected a larger mitotic event, LOH was examined for polymorphic loci on 11 nonselected chromosomes in Aprt mutants that lost the selected chromosome 8 homologue. LOH events were detected for one or more nonselected chromosomes in 38% of these mutants. The additional LOH events also reflected apparent chromosome loss based on the molecular analysis. Metaphase spreads from mutants that lost chromosome 8 were markedly aneuploid, and chromosome painting revealed reduced levels for any chromosome shown to be lost with the LOH analysis. In contrast, LOH on nonselected chromosomes was infrequent in Aprt mutants exhibiting intragenic events or mitotic recombination for chromosome 8, and marked aneuploidy was absent. These observations suggest that the mechanism leading to chromosome loss in somatic mammalian cells is often not a simple nondisjunction event and instead could result from a single catastrophic event. They also suggest that cells with characteristics of malignancy are present in normal appearing tissue.


Parallel plumage colour evolution and introgressive hybridization in wheatears.
Genetic and phenotypic mosaics, in which various phenotypes and different genomic regions show discordant patterns of species or population divergence, offer unique opportunities to study the role of ancestral and introgressed genetic variation in phenotypic evolution. Here, we investigated the evolution of discordant phenotypic and genetic divergence in a monophyletic clade of four songbird taxa-pied wheatear (O. pleschanka), Cyprus wheatear (Oenanthe cypriaca), and western and eastern subspecies of black-eared wheatear (O. h. hispanica and O. h. melanoleuca). Phenotypically, black back and neck sides distinguish pied and Cyprus wheatears from the white-backed/necked black-eared wheatears. Meanwhile, mitochondrial variation only distinguishes western black-eared wheatear. In the absence of nuclear genetic data, and given frequent hybridization among eastern black-eared and pied wheatear, it remains unclear whether introgression is responsible for discordance between mitochondrial divergence patterns and phenotypic similarities, or whether plumage coloration evolved in parallel. Multispecies coalescent analyses of about 20,000 SNPs obtained from RAD data mapped to a draft genome assembly resolve the species tree, provide evidence for the parallel evolution of colour phenotypes and establish western and eastern black-eared wheatears as independent taxa that should be recognized as full species. The presence of the entire admixture spectrum in the Iranian hybrid zone and the detection of footprints of introgression from pied into eastern black-eared wheatear beyond the hybrid zone despite strong geographic structure of ancestry proportions furthermore suggest a potential role for introgression in parallel plumage colour evolution. Our results support the importance of standing heterospecific and/or ancestral variation in phenotypic evolution.


Cloning and sequencing of Escherichia coli murZ and purification of its product, a UDP-N-acetylglucosamine enolpyruvyl transferase.
The Escherichia coli gene murZ, encoding the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase, has been cloned and sequenced. Identified by screening an E. coli genomic library for clones that conferred phosphomycin resistance, murZ encoded a 419-amino-acid polypeptide and was mapped to 69.3 min on the E. coli chromosome. MurZ protein was purified to near homogeneity and found to have the expected UDP-N-acetylglucosamine enolpyruvyl transferase activity. Sequence analysis of the predicted product revealed 44% identity to OrfR from Bacillus subtilis (K. Trach, J.W. Chapman, P. Piggot, D. LeCoq, and J.A. Hoch, J. Bacteriol. 170:4194-4208, 1988), suggesting that orfR may also encode a UDP-N-acetylglucosamine enolpyruvyl transferase enzyme. MurZ is also homologous to the aromatic amino acid biosynthetic enzyme enolpyruvyl shikimate phosphate synthase, the other enzyme known to catalyze an enolpyruvyl transfer.


Use of whole-genome sequencing to identify clusters of Shigella flexneri associated with sexual transmission in men who have sex with men in England: a validation study using linked behavioural data.
Since the 1970s, shigellosis has been reported as a sexually transmissible infection, and in recent years, genomic data have revealed the breadth of Shigella spp. transmission among global networks of men who have sex with men (MSM). In 2015, Public Health England (PHE) introduced routine whole-genome sequencing (WGS) of Shigella spp. to identify transmission clusters. However, limited behavioural information for the cases hampers interpretation. We investigated whether WGS can distinguish between clusters representing sexual transmission in MSM and clusters representing community (non-sexual) transmission to inform infection control. WGS data for Shigella flexneri from August 2015 to July 2017 were aggregated into single linkage clusters based on SNP typing using a range of SNP distances (the standard for Shigella surveillance at PHE is 10 SNPs). Clusters were classified as 'adult male', 'household', 'travel-associated' or 'community' using routine demographic data submitted alongside laboratory cultures. From August 2015 to March 2017, PHE contacted those with shigellosis as part of routine public-health follow-up and collected exposure data on a structured questionnaire, which for the first time included questions about sexual identity and behaviour. The questionnaire data were used to determine whether clusters classified as 'adult male' represented likely sexual transmission between men, thereby validating the use of the SNP clustering tool for informing appropriate public-health responses. Overall, 1006 S. flexneri cases were reported, of which 563 clustered with at least one other case (10-SNP threshold). Linked questionnaire data were available for 106 clustered cases, of which 84.0 % belonged to an 'adult male' cluster. At the 10-SNP threshold, 95.1 % [95 % confidence interval (CI) 88.0-98.1%] of MSM belonged to an 'adult male' cluster, while 73.2 % (95 % CI 49.1-87.5%) of non-MSM belonged to a 'community' or 'travel-associated' cluster. At the 25-SNP threshold, all MSM (95 % CI 96.0-100%) belonged to an 'adult male' cluster and 77.8 % (95 % CI 59.2-89.4%) of non-MSM belonged to a 'community' or 'travel-associated' cluster. Within one phylogenetic clade of S. flexneri, 9 clusters were identified (7 'adult male'; 2 'community') using a 10-SNP threshold, while a single 'adult male' cluster was identified using a 25-SNP threshold. Genotypic markers of azithromycin resistance were detected in 84.5 % (294/348) of 'adult male' cases and 20.9 % (9/43) of cases in other clusters (10-SNP threshold), the latter of which contained gay-identifying men who reported recent same-sex sexual contact. Our study suggests that SNP clustering can be used to identify Shigella clusters representing likely sexual transmission in MSM to inform infection control. Defining clusters requires a flexible approach in terms of genetic relatedness to ensure a clear understanding of underlying transmission networks.


Assessing the patterns of health-seeking behaviour and awareness among sleeping-sickness patients in eastern Uganda.
For those with sleeping sickness, the consequences of delayed diagnosis include poor prognosis at treatment and an increased risk of tsetse infection. Data on their socio-demographic and clinical characteristics, health-seeking behaviour and delays in presentation and diagnosis were collected from 119 diagnosed cases of rhodesiense sleeping sickness in eastern Uganda. The median total delay, from onset of the illness to diagnosis, was 60 days. The median service-provider delay (30 days) was markedly longer than the median patient delay (17 days). Each of these delays was, however, considerable and independently associated with patients presenting with late-stage sleepiness, giving odds ratios and (95% confidence intervals) of 7.29 (3.10-17.14) and 2.98 (1.38-6.43), respectively. A blood examination at the first visit was also associated with the service-provider delay (odds ratio = 0.45; 95% confidence interval = 0.22-0.95). Most of the patients (77.4%) had either been referred to the local sleeping-sickness hospital by other members of their community or presented at the hospital on their own initiative; few had been referred by other components of the local health system. The results are disappointing, not only in showing long delays in diagnosis (and therefore in treatment) but also in indicating that much of the delay is attributable to the service provider failing to diagnose sleeping sickness among symptomatic individuals.


Fundamentals of Clinical Pharmacology With Application for Pregnant Women.
Medication use is common in pregnancy, yet for most medications the optimal formulation and dosage have not been described specifically for pregnant women. Often, adverse effects are only discovered anecdotally or after extensive off-label use occurs. Since pharmacologic research that includes pregnant women is sparse and animal studies are often not applicable to the human fetus, providers must use knowledge of drug behavior and normal physiologic changes of pregnancy to personalize treatment for pregnant women. In this review, we present an overview of the basic concepts of clinical pharmacology: pharmacokinetics, pharmacodynamics, and pharmacogenomics. The normal physiologic changes of pregnancy are presented as a framework to understand alterations in drug behavior. A clinical vignette that addresses 4 pregnancy scenarios involving medications-preterm birth, vaccination, herpes simplex virus infection, and codeine toxicity-is provided to illustrate application of core clinical pharmacologic concepts. Discussion of relevant literature illustrates the challenges of offering individualized pharmacologic therapy in pregnancy.


27 T ultra-high static magnetic field changes orientation and morphology of mitotic spindles in human cells.
Purified microtubules have been shown to align along the static magnetic field (SMF) in vitro because of their diamagnetic anisotropy. However, whether mitotic spindle in cells can be aligned by magnetic field has not been experimentally proved. In particular, the biological effects of SMF of above 20 T (Tesla) have never been reported. Here we found that in both CNE-2Z and RPE1 human cells spindle orients in 27 T SMF. The direction of spindle alignment depended on the extent to which chromosomes were aligned to form a planar metaphase plate. Our results show that the magnetic torque acts on both microtubules and chromosomes, and the preferred direction of spindle alignment relative to the field depends more on chromosome alignment than microtubules. In addition, spindle morphology was also perturbed by 27 T SMF. This is the first reported study that investigated the cellular responses to ultra-high magnetic field of above 20 T. Our study not only found that ultra-high magnetic field can change the orientation and morphology of mitotic spindles, but also provided a tool to probe the role of spindle orientation and perturbation in developmental and cancer biology.


The case for prescribing PrEP in community mental health settings.
Pre-exposure prophylaxis (PrEP) is a biomedical HIV prevention modality that is up to 99% effective in preventing HIV acquisition through sex if taken as directed. People with serious mental illness (eg, schizophrenia and bipolar disorder) are at high risk of acquiring HIV due to sexual behaviours, injection drug use, social factors, and structural discrimination that limits access to all types of preventive health services. We seek to show the importance of prioritising access to PrEP for people living with serious mental illness treated in community mental health settings. We describe barriers to prescribing PrEP, including provider attitudes and provider knowledge gaps, patient attitudes and knowledge, and systems issues. We also address the concerns that community mental health clinic administrators might have about taking on the responsibility of offering PrEP. In summary, despite the barriers to prescribing PrEP in these settings, we believe that there is a unique opportunity for community mental health settings to help address the HIV epidemic by facilitating the prescribing of PrEP to the at-risk populations they currently serve.


Decreasing lead levels in Swedish biota revealed by 36 years (1969-2004) of environmental monitoring.
Since the 1980s, lead levels decreased significantly in most marine biota from the Baltic Sea, the Kattegatt and the Skagerrack and in terrestrial biota from south and central Sweden, analysed in the National Swedish Environmental Monitoring Programme. In herring and cod liver, the decrease was 4.2-7.1% annually 1981-2003 and in perch liver and guillemot eggs analysed since the middle of the 1990s the decrease was 10-13%. In kidneys of young starlings from south and central Sweden, lead levels decreased 6.2-12% annually and the annual decrease in liver and kidney from young moose was 8.8% and 6.5%, respectively. In northern Sweden, lead levels decreased in pike liver by 2.8% between 1969 and 1994 and in reindeer liver by 3.5% annually while a significant increase (5% annually 1981-1994) has been detected in arctic char. In some marine biota, there were indications of a larger decrease during the last ten years compared to the whole period. The large decline in lead emission to the atmosphere during the last twenty years, mainly because of decreasing use of leaded gasoline has obviously resulted in decreasing lead levels in biota.


Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study. A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point. At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457-0.704; log-rank P = 9.63 × 10-8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity. The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy. NCT01958021.


Comparison of the Polar S810i monitor and the ECG for the analysis of heart rate variability in the time and frequency domains.
The aim of the present study was to compare heart rate variability (HRV) at rest and during exercise using a temporal series obtained with the Polar S810i monitor and a signal from a LYNX(R) signal conditioner (BIO EMG 1000 model) with a channel configured for the acquisition of ECG signals. Fifteen healthy subjects aged 20.9 +/- 1.4 years were analyzed. The subjects remained at rest for 20 min and performed exercise for another 20 min with the workload selected to achieve 60% of submaximal heart rate. RR series were obtained for each individual with a Polar S810i instrument and with an ECG analyzed with a biological signal conditioner. The HRV indices (rMSSD, pNN50, LFnu, HFnu, and LF/HF) were calculated after signal processing and analysis. The unpaired Student t-test and intraclass correlation coefficient were used for data analysis. No statistically significant differences were observed when comparing the values analyzed by means of the two devices for HRV at rest and during exercise. The intraclass correlation coefficient demonstrated satisfactory correlation between the values obtained by the devices at rest (pNN50 = 0.994; rMSSD = 0.995; LFnu = 0.978; HFnu = 0.978; LF/HF = 0.982) and during exercise (pNN50 = 0.869; rMSSD = 0.929; LFnu = 0.973; HFnu = 0.973; LF/HF = 0.942). The calculation of HRV values by means of temporal series obtained from the Polar S810i instrument appears to be as reliable as those obtained by processing the ECG signal captured with a signal conditioner.


VDAC2 inhibits BAK activation and mitochondrial apoptosis.
The multidomain proapoptotic molecules BAK or BAX are required to initiate the mitochondrial pathway of apoptosis. How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown. In viable cells, we found BAK complexed with mitochondrial outer-membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate "BH3-only" molecules such as tBID, BIM, or BAD, which displace VDAC2 from BAK, enabling homo-oligomerization of BAK and apoptosis. Thus, VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.


Therapeutic management of skin hemangiomas in children.
Hemangiomas are benign, self-involuting tumors of endothelial cells that are common in childhood. To evaluate the treatment of 122 patients with skin hemangiomas treated at a teaching hospital in Brasilia, Brazil between March 2000 and December 2006. Data were collected from the patients' medical records and questionnaires were applied to the children's parents. Variables analyzed were: gender, pre- and perinatal factors, clinical characteristics of the lesions, type of treatment and outcome. A male-to-female ratio of 1.5:1 was found. In 42 patients, hemangiomas were superficial, while in 13 cases they were deep and in 67 patients lesions were mixed. In 7 patients, the lesions were associated with syndromes. In 79 patients, hemangiomas were in the cephalic region. Of the 122 patients, 98 were submitted to one single treatment, while 24 required multiple forms of treatment. In the first group, expectant management was the conduct in 38 patients, compression in 3 cases, systemic corticotherapy in 18 patients, intralesional corticotherapy in 13, topical steroids in 4 cases, conventional surgery in 12 patients, cryosurgery in 7, pulsed light in one case and imiquimod in 2 patients. In the second group of 24 patients submitted to multiple treatment modalities, 15 required two types of treatment and 9 needed three or more. The data obtained in this study were in agreement with results in the literature with respect to gender and the site of the lesions. The incidence of hemangiomas present at birth was higher than rates published in the literature. The therapeutical results obtained were comparable with data from other published studies. Identification of hemangiomas that require treatment, as well as the right moment for intervention and the best therapeutic option for each case, are factors that need to be taken into consideration.


The Cost-Effectiveness of Visual Triage of Human Papillomavirus-Positive Women in Three Low- and Middle-Income Countries.
Background: World Health Organization guidelines support human papillomavirus (HPV) testing alone (followed by treatment with cryotherapy) or in conjunction with visual inspection with acetic acid (VIA) triage testing. Our objective was to determine the cost-effectiveness of VIA triage for HPV-positive women in low-resource settings.Methods: We calibrated mathematical simulation models of HPV infection and cervical cancer to epidemiologic data from India, Nicaragua, and Uganda. Using cost and test performance data from the START-UP demonstration projects, we assumed screening took place either once or three times in a lifetime between ages 30 and 40 years. Strategies included (i) HPV alone, followed by cryotherapy for all eligible HPV-positive women; and (ii) HPV testing with VIA triage for HPV-positive women, followed by cryotherapy for eligible women who were also VIA-positive (HPV-VIA). Model outcomes included lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs; international dollars/year of life saved).Results: In all three countries, HPV alone was more effective than HPV-VIA. In Nicaragua and Uganda, HPV alone was also less costly than HPV-VIA; ICERs associated with screening three times in a lifetime (HPV alone) were below per capita GDP. In India, both HPV alone and HPV-VIA had ICERs below per capita GDP.Conclusions: VIA triage of HPV-positive women is not likely to be cost-effective in settings with high cervical cancer burden. HPV alone followed by treatment may achieve greater health benefits and value for public health dollars.Impact: This study provides early evidence on the cost-effectiveness of HPV testing followed by VIA triage versus an HPV screen-and-treat strategy. Cancer Epidemiol Biomarkers Prev; 26(10); 1500-10. ©2017 AACR.


The multiple facets of homology and their use in comparative genomics to study the evolution of genes, genomes, and species.
The incredible development of comparative genomics during the last decade has required a correct use of the concept of homology that was previously utilized only by evolutionary biologists. Unhappily, this concept has been often misunderstood and thus misused when exploited outside its evolutionary context. This review brings back to the correct definition of homology and explains how this definition has been progressively refined in order to adapt it to the various new kinds of analysis of gene properties and of their products that appear with the progress of comparative genomics. Then, we illustrate the power and the proficiency of such a concept when using the available genomics data in order to study the evolution of individual genes, of entire genomes and of species, respectively. After explaining how we detect homologues by an exhaustive comparison of a hundred of complete proteomes, we describe three main lines of research we have developed in the recent years. The first one exploits synteny and gene context data to better understand the mechanisms of genome evolution in prokaryotes. The second one is based on phylogenomics approaches to reconstruct the tree of life. The last one is devoted to reminding that protein homology is often limited to structural segments (SOH=segment of homology or module). Detecting and numbering modules allows tracing back protein history by identifying the events of gene duplication and gene fusion. We insist that one of the main present difficulties in such studies is a lack of a reliable method to identify genuine orthologues. Finally, we show how these homology studies are helpful to annotate genes and genomes and to study the complexity of the relationships between sequence and function of a gene.


Trans-biopolitics: Complexity in interspecies relations.
This article introduces the concept of trans-biopolitics to account for complexity in the intermingling of animal and human bodies, with particular attention to diseases capable of crossing the species divide from animals to humans. While zoonotic diseases never disappeared, they had re-emerged as pressing concerns by the 21st century. The concept of trans-biopolitics takes into account the power relations inherent in human and nonhuman lives in contemporary global, industrial, and technological formations. More specifically, trans-biopolitics revolves around practices determining whose lives are possible or legitimate to prolong, whose bodies are sacrificed in order to preserve the vitality of other bodies, and whose bodies are sustained yet ultimately rendered insignificant. To illustrate, we examine connections between bovine spongiform encephalopathy and feline spongiform encephalopathy, to show how certain bodies (humans, livestock) are taken into consideration in terms of health and food regulations, whereas other bodies (pets) remain at the periphery. Acknowledging human-animal relations in contemporary technological and global contexts challenges us to rethink ways in which the politics of health continues to evolve.


The fourth dimension of life: fractal geometry and allometric scaling of organisms.
Fractal-like networks effectively endow life with an additional fourth spatial dimension. This is the origin of quarter-power scaling that is so pervasive in biology. Organisms have evolved hierarchical branching networks that terminate in size-invariant units, such as capillaries, leaves, mitochondria, and oxidase molecules. Natural selection has tended to maximize both metabolic capacity, by maximizing the scaling of exchange surface areas, and internal efficiency, by minimizing the scaling of transport distances and times. These design principles are independent of detailed dynamics and explicit models and should apply to virtually all organisms.


The Role of Religiousness/Spirituality in Health-Related Quality of Life Among Adolescents with HIV: A Latent Profile Analysis.
The purpose of this study was to determine whether distinct latent profiles of religiousness/spirituality exist for ALWH, and if so, are latent profile memberships associated with health-related quality of life (HRQoL). Latent profile analysis of religiosity identified four profiles/groups. Compared to the other three groups, higher levels of emotional well-being were found among young perinatally infected adolescents who attended religious services, but who did not pray privately, feel God's presence or identify as religious or spiritual. Social HRQoL was significantly higher among the highest overall religious/spiritual group. Understanding adolescent profiles of religiousness/spirituality on HRQoL could inform faith-based interventions. Trial registration NCT01289444.


Treatment with recombinant growth hormone is associated with modest improvement in CD4 lymphocyte reconstitution in HIV-infected persons on antiretroviral therapy: results of ACTG A5174.
Pilot studies have suggested that treatment with recombinant human growth hormone (rhGH) is associated with increased T-lymphocyte restoration and enhanced thymic output. We evaluated the immunologic effects of rhGH on HIV(+) subjects with incomplete immune reconstitution on antiretroviral therapy (ART). Sixty subjects were randomized to receive rhGH 1.5 mg scqd and ART for 48 weeks (Arm A) or continue ART alone for 24 weeks then add rhGH 3.0 mg scqd for 24 weeks (Arm B). Median baseline CD4 for Arms A and B were 223 and 219, respectively. There was little difference between Arm A and Arm B in change in total or naive CD4 cells or percentage from baseline to week 24. Only one subject in Arm A met the primary endpoint, an increase in naive CD4 percentage of at least 10 percentage points. By week 48 both Arms had statistically significant increases in naive CD4 cell count and percentage and thymus size. Within Arm B, treatment with rhGH was associated with significant increases in naive CD4(+) cell count and percentage compared with ART alone. Treatment with rhGH +ART may be associated with modest increases in CD4 lymphocytes over ART alone in subjects with CD4 <350, yet the origin of these naive cells and their impact on immune function require further investigation.


HLA in the Azores Archipelago: possible presence of Mongoloid genes.
The HLA profile of the Azoreans has been compared with those of other world populations in order to provide additional information regarding the history of their origins. The allele frequencies, genetic distances between populations, correspondence analyses and most frequent haplotypes were calculated. Our results indicate that the Azorean population most likely contains an admixture of high-frequency Caucasoid, Mongoloid and, to a lesser degree, Negroid HLA genes. The middle Atlantic Azores Archipelago was officially colonized by the Portuguese after 1439 and historical records are concordant with the existence of Caucasoid and Negroid population. However, Mongoloid genes were not suspected, but the Oriental HLA haplotypes A24-B44-DR6-DQ1, A29-B21-DR7-DQ2 and A2-B50-DR7-DQ2 are the fourth, fifth and sixth most frequent ones in Azores. A correspondence analysis shows that the Azorean population is equidistant from Asian and European populations and genetic distances are in some cases closer to the Asian than to European ethnic groups, and never are significantly different; also, B*2707 subtype is found in Asians and Azoreans (but not in Europeans) and the same Machado-Joseph Disease founder haplotypes (Chr 14) are found in both Japanese and Azoreans. It is proposed that a Mongoloid population exists in Azores; whether, the arrival occurred prior to discovery is undetermined.


Evidence of nonthermal particles in coronal loops heated impulsively by nanoflares.
The physical processes causing energy exchange between the Sun's hot corona and its cool lower atmosphere remain poorly understood. The chromosphere and transition region (TR) form an interface region between the surface and the corona that is highly sensitive to the coronal heating mechanism. High-resolution observations with the Interface Region Imaging Spectrograph (IRIS) reveal rapid variability (~20 to 60 seconds) of intensity and velocity on small spatial scales (≲500 kilometers) at the footpoints of hot and dynamic coronal loops. The observations are consistent with numerical simulations of heating by beams of nonthermal electrons, which are generated in small impulsive (≲30 seconds) heating events called "coronal nanoflares." The accelerated electrons deposit a sizable fraction of their energy (≲10(25) erg) in the chromosphere and TR. Our analysis provides tight constraints on the properties of such electron beams and new diagnostics for their presence in the nonflaring corona.


Effects of a Cycling Dual Task on Emotional Word Choice in Parkinson's Disease.
Purpose Individuals with Parkinson's disease (PD) demonstrate language- and emotion-related impairments; however, emotional language production has received little attention within the literature despite the fact that deficits could significantly impact one's daily interactions with loved ones and others. Multitasking (i.e., dual tasking), specifically while completing language tasks, is a common everyday occurrence and typically impacts performance on 1 or both tasks. This study compared emotional word use during discourse production in individuals with PD and healthy older adults (HOAs) under single- and dual-task conditions. Method Participants completed a discourse task while sitting in a quiet room and while stationary cycling. Discourse output was analyzed along several emotional and intellectual language dimensions obtained from the Linguistic Inquiry and Word Count program (Pennebaker, Booth, & Francis, 2007 ). Results Groups did not differ on any outcome measure in the single-task condition. However, HOAs produced a higher percentage of words associated with affective processes and positive emotion while completing the dual-task condition, whereas the PD group exhibited a decrease in production of these words. Compared to the single-task condition, during cycling, individuals with PD also produced a lower percentage of inhibition-related words. Conclusions These results suggest that cycling, like other types of exercise, improves mood as manifested in discourse word choice in HOAs; however, it may lead to reduced use of emotional words in individuals with PD. Expressing emotion may also be more difficult in those with PD than in HOAs and, therefore, easily disrupted in distracting circumstances.


Can Additional Homeopathic Treatment Save Costs? A Retrospective Cost-Analysis Based on 44500 Insured Persons.
The aim of this study was to compare the health care costs for patients using additional homeopathic treatment (homeopathy group) with the costs for those receiving usual care (control group). Cost data provided by a large German statutory health insurance company were retrospectively analysed from the societal perspective (primary outcome) and from the statutory health insurance perspective. Patients in both groups were matched using a propensity score matching procedure based on socio-demographic variables as well as costs, number of hospital stays and sick leave days in the previous 12 months. Total cumulative costs over 18 months were compared between the groups with an analysis of covariance (adjusted for baseline costs) across diagnoses and for six specific diagnoses (depression, migraine, allergic rhinitis, asthma, atopic dermatitis, and headache). Data from 44,550 patients (67.3% females) were available for analysis. From the societal perspective, total costs after 18 months were higher in the homeopathy group (adj. mean: EUR 7,207.72 [95% CI 7,001.14-7,414.29]) than in the control group (EUR 5,857.56 [5,650.98-6,064.13]; p<0.0001) with the largest differences between groups for productivity loss (homeopathy EUR 3,698.00 [3,586.48-3,809.53] vs. control EUR 3,092.84 [2,981.31-3,204.37]) and outpatient care costs (homeopathy EUR 1,088.25 [1,073.90-1,102.59] vs. control EUR 867.87 [853.52-882.21]). Group differences decreased over time. For all diagnoses, costs were higher in the homeopathy group than in the control group, although this difference was not always statistically significant. Compared with usual care, additional homeopathic treatment was associated with significantly higher costs. These analyses did not confirm previously observed cost savings resulting from the use of homeopathy in the health care system.


Caution Should be Taken in Performing Surgical Hip Dislocation for the Treatment of Femoroacetabular Impingement in Patients Over the Age of 40.
Open and arthroscopic procedures are treatment options for patients with femoroacetabular impingement (FAI). Age has been found to be a predictive factor in the outcome of patients undergoing periacetabular osteotomy (PAO) for hip dysplasia. It is unclear if older age contraindicates joint preservation through a surgical hip dislocation (SHD). The purpose of this retrospective case series was to evaluate the short-term outcomes of patients over 40 years of age without radiographic evidence of end-stage arthritis who underwent SHD for the treatment of FAI and to determine whether older age should be a contraindication for joint-preserving procedures in these patients. Our specific aims included (1) documenting the intraoperative findings and procedures, (2) assessing pain relief provided, and (3) assessing treatment failures and postoperative complications, noting the number of patients that ultimately required total hip arthroplasty (THA). All patients at age 40 and older who had SHD for the treatment of FAI were identified from a series of patients treated with SHD. Clinical notes, radiographs, and operative reports were reviewed to determine clinical results, complications, and the need for additional procedures. The minimum follow-up was 1 year (mean 3.9 years; range 1-8 years). At final follow-up, 11/22 (50%) of hips had pain relief, while 11/22 (50%) either continued having significant symptoms or required THA. Five (23%) reported nontrochanteric pain symptoms that were the same or worse than before surgery, and six hips (27%) underwent subsequent THA). The average time between SHD and THA was 1.9 years (0.9-6.2). The average age of patients who went on to require THA was 45 (42-50) years. Surgical hip dislocation can be used for the treatment of FAI in patients over age 40, but strict selection criteria should be adhered to, as only half of the patients experienced significant improvement in their hip pain. THA was required in one-third of hips for continued pain and radiographic progression of arthritis. SHD for treatment of pathology that is not amenable to hip arthroscopy should remain a surgical option in older patients with FAI only if joint degeneration is not present.


Sources of Resistance to Stem Rust Race Ug99 in Spring Wheat Germplasm.
Wheat stem rust (Puccinia graminis f. sp. tritici) race TTKSK (Ug99), with virulence to the majority of the world's wheat (Triticum aestivum) cultivars, has spread from Uganda throughout eastern Africa, Yemen, and Iran. The identification and spread of variants of race TTKSK with virulence to additional stem rust resistance genes has reminded breeders and pathologists of the danger of deploying major resistance genes alone. In order to protect wheat from this rapidly spreading and adapting pathogen, multiple resistance genes are needed, preferably from improved germplasm. Preliminary screening of over 700 spring wheat breeding lines and cultivars developed at least 20 years ago identified 88 accessions with field resistance to Ug99. We included these resistant accessions in the stem rust screening nursery in Njoro, Kenya for two additional seasons. The accessions were also screened with a bulk of North American isolates of P. graminis f. sp. tritici in the field in St. Paul, MN. In order to further characterize the resistance in these accessions, we obtained seedling phenotypes for 10 races of P. graminis f. sp. tritici, including two races from the race TTKSK complex. This phenotyping led to the identification of accessions with either adult-plant or all-stage resistance to race TTKSK, and often North American races of P. graminis f. sp. tritici as well. These Ug99 resistant accessions can be obtained by breeders and introgressed into current breeding germplasm.


Effects of subchronic simazine exposure on some biometric, biochemical, hematological and histopathological parameters of common carp (Cyprinus carpio L.).
This study assessed the subchronic effects of a triazine compound, simazine, on common carp (Cyprinus carpio L.) though, via by means of biometric, biochemical, hematological, and histological examination. One-year-old fish were exposed to simazine at four concentrations, 0.06, (reported concentration in Czech rivers), 4, 20, and 50 microg L-1 for 28 days and compared to carp in a non-treated control group. Exposure of fish to simazine at 0.06 microg L-1 had no effect on measured parameters. However, exposure to simazine at the concentrations of 4, 20, 50 microg L-1 showed significant differences in biochemical, hematological, and histopathological profiles of fish compared to controls. Our data suggest that simazine in the recorded environmental concentration 0.06 microg L-1 had no effect on common carp. Subchronic exposure to 4, 20, and 50 microg L-1 of simazine was associated with alterations in biochemical and hematological indices and in fish organ tissues.


Transcranial magnetic stimulation to dorsolateral prefrontal cortex affects conflict-induced behavioural adaptation in a Wisconsin Card Sorting Test analogue.
A substantial body of literature has proposed a role for dorsolateral prefrontal cortex (dlPFC) in supporting behavioural adaptation during conflict tasks. The vast majority of the evidence in support of this interpretation comes from neuroimaging studies. However, in order to unequivocally ascribe such a role to dlPFC, it is important to determine whether or not it is essential for this mechanism, and this can only be achieved by lesioning the area or interfering with its activity. In this study, we investigated the effects of repeated Transcranial Magnetic Stimulation (rTMS) to dlPFC on performance on a conflict version of a Wisconsin Card Sorting Test analogue (used previously in circumscribed lesion studies in monkeys) in neurologically healthy human participants. Our results supported the view of dlPFC as a fundamental structure for optimal conflict-induced behavioural adaptation, as stimulation cancelled out the adaptation effect normally observed on control trials. We show that there is some indication of differential modulation of trial types by stimulation and we hypothesize that this might suggest a role for dlPFC in conflict-induced adaptation that is more specifically concerned with the maintenance of conflict-history information online across trials.


Substituent Effects on the Reactivity of the 2,4,6-Tridehydropyridinium Cation, an Aromatic σ,σ,σ-Triradical.
2,4,6-Tridehydropyridinium cation (7) undergoes three consecutive atom or atom group abstractions from reagent molecules in the gas phase. By placing a π-electron-donating hydroxyl group between two radical sites, their reactivity can be quenched by enhancing their through-space coupling via a favorable resonance structure. Indeed, 3-hydroxy-2,4,6-tridehydropyridinium cation (8) abstracts only one atom or group of atoms from reagents. On the other hand, an electron-withdrawing cyano group between two of the radical sites (9) destabilizes the analogous resonance structure and diminishes through-space coupling between the radical sites, resulting in abstraction of three atoms, just like 7. However, the cyano-substituent also increases acidity to the point that 9 reacts pre-dominantly via proton transfer instead of undergoing radical reactions. Therefore, acidic triradicals may undergo nonradical, barrierless proton transfer reactions faster than radical reactions, which are usually accompanied by barriers. Examination of the analogous cyano-substituted mono-and biradicals revealed behavior similar to that of the corresponding unsubstituted species, with the exception of substantially greater reactivities due to their greater (calculated) vertical electron affinities. Finally, the 3-cyano-2,6-didehydropyridinium cation with a singlet ground state (S-T splitting: -11.9 kcal mol-1) was found to react exclusively from the lowest-energy triplet state by fast proton transfer reactions.


Bartonella spp. bacteremia and rheumatic symptoms in patients from Lyme disease-endemic region.
Bartonella spp. infection has been reported in association with an expanding spectrum of symptoms and lesions. Among 296 patients examined by a rheumatologist, prevalence of antibodies against Bartonella henselae, B. koehlerae, or B. vinsonii subsp. berkhoffii (185 [62%]) and Bartonella spp. bacteremia (122 [41.1%]) was high. Conditions diagnosed before referral included Lyme disease (46.6%), arthralgia/arthritis (20.6%), chronic fatigue (19.6%), and fibromyalgia (6.1%). B. henselae bacteremia was significantly associated with prior referral to a neurologist, most often for blurred vision, subcortical neurologic deficits, or numbness in the extremities, whereas B. koehlerae bacteremia was associated with examination by an infectious disease physician. This cross-sectional study cannot establish a causal link between Bartonella spp. infection and the high frequency of neurologic symptoms, myalgia, joint pain, or progressive arthropathy in this population; however, the contribution of Bartonella spp. infection, if any, to these symptoms should be systematically investigated.


Effects of Whole-Body Vibration Training Combined With Cyclic Hypoxia on Bone Mineral Density in Elderly People.
Prevention and treatment of osteoporosis are an issue of great concern in public health so that the increase/maintenance of whole-body bone mineral density (BMD) is clinically relevant and could reduce the financial burden. Whole-body vibration (WBV) has been recently proposed as a potential alternative to bone stimulation, which combined with therapies, could provide a new treatment for osteoporosis prevention. In this sense, moderate cyclic hypoxia protocols may help to restrain osteoclastic activity and/or stimulate osteoblastic activity, enhance the effects of whole-body vibration alone. So, the present study investigated the effects of cyclic hypoxic exposure combined with WBV training on BMD of the elderly. Healthy elderly persons (n = 30) were randomly assigned to a (1) Hypoxia-Whole Body Vibration group (HWBV; n = 10), (2) Normoxic-Whole Body Vibration group (NWBV; n = 10) or (3) Control group (CON; n = 10). During 18 weeks, HWBV performed WBV treatment under normobaric hypoxic conditions (16.1% FiO2). A vibration session included 4 bouts of 30 s (12.6 Hz-4 mm) with 1 min rest between bouts. NWBV performed the same vibration treatment as HWBV but under normoxic conditions. Whole-body and proximal femur BMD (g⋅cm-2) were measured using dual-energy X-ray absorptiometry. Two-way ANOVA indicated a borderline significant (p = 0.07) time x group interaction for total BMD; post hoc analysis revealed a slight but significant (p = 0.021) increase of BMD after treatment in the HWBV group. In conclusion, 18-week WBV training with hypoxic stimuli has shown positive effects for the participants of the current study. As changes did not differ significantly between groups, future large-scale studies will be necessary to confirm these findings.


Renal oncocytoma: a comparative clinicopathologic study and fluorescent in-situ hybridization analysis of 73 cases with long-term follow-up.
Clinical studies have confirmed that renal oncocytoma (RO) is a benign neoplasm with excellent prognosis. In diagnostically challenging cases of renal oncocytic epithelial neoplasms, fluorescent in-situ hybridization (FISH) is increasingly being used and its ability to distinguish RO from chromophobe renal cell carcinoma (ChRCC) has been documented. In this study, we evaluated the differential diagnostic contribution of FISH in cases of RO.Clinicopathologic data and glass slides from 73 patients with RO were reviewed; 20 cases of ChRCC were included for comparison. FISH analysis of formalin-fixed, paraffin-embedded sections was performed using centromeric probes for chromosomes 1, 2, 7 and 17. FISH analysis revealed ROs had frequent loss of signal for chromosome 1 (56%) and 17 (44%). Tumors with more than one loss were common (41%) and 10% cases showed loss of all chromosomes examined. A total of 18% cases did not show any abnormality.Our study shows that chromosomal abnormalities in both ROs and ChRCCs are common with frequent loss of chromosomes 1 and 17. No association was found between overall patient survival and the extent of chromosomal abnormalities. FISH results, even those showing significant chromosomal abnormalities, should not alter the primarily morphology-based diagnosis of RO.


The digitization of organic synthesis.
Organic chemistry has largely been conducted in an ad hoc manner by academic laboratories that are funded by grants directed towards the investigation of specific goals or hypotheses. Although modern synthetic methods can provide access to molecules of considerable complexity, predicting the outcome of a single chemical reaction remains a major challenge. Improvements in the prediction of 'above-the-arrow' reaction conditions are needed to enable intelligent decision making to select an optimal synthetic sequence that is guided by metrics including efficiency, quality and yield. Methods for the communication and the sharing of data will need to evolve from traditional tools to machine-readable formats and open collaborative frameworks. This will accelerate innovation and require the creation of a chemistry commons with standardized data handling, curation and metrics.


Work evaluations: critique of the state of the art of functional assessment of work.
The area of work evaluation is fertile ground for future research and development by occupational therapists. Current evaluations of work range from standardized work evaluations associated with vocational rehabilitation to highly technical physical capacity and work capacity instrumentation and equipment often associated with sports medicine. In addition, methods used to identify pain and abnormal illness behavior add the psychosocial component of work evaluation. The limitations of most of the traditional approaches to work evaluations are their lack of focus on the actual work environments and on the meaning of work to persons. Occupational therapy can play an important and unique role in linking work evaluations to psychosocial and environmental variables and in formulating comprehensive theoretical models of work that should improve and refine present work evaluations.


Medical education and MS: getting the training right.
Medical education needs continuous improvements to meet the changing demands of medical practice in the 21st century. We need to review the teaching methods used and the curriculum taught during various stages of a doctors training. General practitioners need to recognize the symptoms indicative of MS and refer the patient to a specialist; neurologists should confirm the diagnosis, and effectively treat, manage and support the patient. Training should be adapted to reflect these different tasks and equip the physician accordingly. We suggest a training programme for undergraduate students comprising three lectures and two interactive sessions. These would provide the student with a basic knowledge of MS and its management. For those wishing to specialize in neurology, we recommend a series of eight lectures, interactive sessions discussing case reports with typical and atypical presentations, two magnetic resonance imaging reading sessions with a specialist neuroradiologist and active practice in an MS clinic.


Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort.
Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research. ClinicalTrials.gov identifier NCT01655706 . Registered July 27, 2012.


Impacts of atmospheric chlor-alkali factory emissions in surrounding populations.
Environmental exposures need to be assessed for the understanding of the health risks of general population. Organochlorine compounds (OCs) from chlor-alkali plants (CAPs) are significant for the exposomes of individuals living in locations receiving their emissions and have to be determined. The aims of the study are to identify the area of influence of past and present OC emissions from CAPs and to set quantitative body burden estimates. A CAP situated in a rural area was selected for study. The geographic distribution of the atmospheric emissions was monitored using olive tree leaves. Human biomonitoring was assessed by serum analysis from general population (n=1340). OC concentrations followed exponential decay functions with maxima in the immediate vicinity of the factory. The individuals living within 1km exhibited hexachlorobenzene (HCB), polychlorobiphenyls (PCBs) and DDT-DDE (dichlorodiphenyltrichloroethane-dichlorodiphenyldichloroethylene) concentrations that were 12, 1.3-1.9 and 3.9 times higher than in sites not influenced by the emissions from this factory. Individuals from municipalities situated 15-25km away from the CAP showed 1.5, 1.2-1.4 and 1.3 times higher serum HCB, PCB and DDT concentrations than in distant sites. The high serum concentrations of DDT and PCBs were observed even 23-31years and 9-17years after manufacture completion of these compounds, respectively. Our methodology provides a way for assessment of the influence of past and present atmospheric OCs emissions from CAPs into the exposome of individuals living in nearby areas.


Papillary Renal Neoplasm With Reverse Polarity: A Morphologic, Immunohistochemical, and Molecular Study.
We evaluated the clinicopathologic and chromosomal characteristics of a distinct subset of papillary renal tumors and compared them to a control series of papillary renal cell carcinoma types 1 and 2. Of the 18 patients, 9 were women and 9 were men, ranging in age from 46 to 80 years (mean, 64 y; median, 66 y). The tumors ranged in diameter from 0.6 to 3 cm (mean, 1.63 cm; median, 1.4 cm). Fourteen tumors were WHO/ISUP grade 2 and 4 were grade 1. All were stage category pT1. The tumors had branching papillae with thin fibrovascular cores, covered by cuboidal to columnar cells with granular eosinophilic cytoplasm, smooth luminal borders, and mostly regular and apically located nuclei with occasional nuclear clearing and inconspicuous nucleoli. Tubule formation and clear cytoplasmic vacuoles were observed in 5 and 9 tumors, respectively. Ten tumors had pseudocapsules. Psammoma bodies, necrosis, mitotic figures and intracellular hemosiderin are absent from all tumors. In contrast, papillary renal cell carcinoma type 1 consisted of delicate papillae covered by a single layer of cells with scanty pale cytoplasm with nuclei generally located in a single layer on the basement membrane of the papillary cores, while type 2 tumors had broad papillae covered by pseudostratified cells with eosinophilic cytoplasm and more randomly located nuclei. Both had occasional psammoma bodies, foamy macrophages and intracellular hemosiderin. Immunohistochemically, all were positive for pancytokeratin AE1/AE3, epithelial membrane antigen, MUC1, CD10, GATA3, and L1CAM. Cytokeratin 7 was positive in 16 tumors (1 had <5% positivity). CD117 and vimentin were always negative. α-methylacyl-CoA-racemase (AMACR/p504s) showed variable staining (range, 10% to 80%) in 5 tumors. However, all tumors in the control group were negative for GATA3 and positive for AMACR/p504s and vimentin immunostains. Fluorescence in situ hybridization analysis of the study group demonstrated chromosome 7 trisomy in 5 tumors (33%), trisomy 17 in 5 tumors (33%), and trisomy 7 and 17 in 3 tumors (20%). Chromosome Y deletion was found in 1 of 7 male patients and chromosome 3p was present in all tumors. No tumor recurrence or metastasis occurred. In summary, we propose the term papillary renal neoplasm with reverse polarity for this entity.


Abnormal retinal function associated with isotretinoin therapy for acne.
Three of 50 patients treated with isotretinoin (1 mg/kg/day) for cystic acne complained of poor night vision and/or excessive glare sensitivity. While still receiving the drug or shortly thereafter, two patients were found to have abnormal dark-adaptation curves, with elevations of either cone or rod thresholds, or both. Two patients had abnormal electroretinograms (ERGs). One had a mildly abnormal electro-oculogram. The dark-adaptation curves were normal for one patient several months after isotretinoin therapy was discontinued. Two patients had elevated cone thresholds at least one year later. Six months following cessation of therapy, the ERG was still abnormal for one patient, but continued improvement was evident at 25 months; for the second patient, the ERG was normal at one year. Analysis of Naka-Rushton parameters for the ERG scotopic b-wave stimulus-response curves indicated response compression for two patients, as evidenced by a reduction in the maximum response. For one patient, the half-saturation constant was elevated 0.7 log units, suggesting reduction of retinal sensitivity, perhaps from decrease in retinal photopigment concentration. We suspect that isotretinoin may complete for normal retinol binding sites on cell surfaces or transport molecules. A prospective study is currently underway to determine if a clinically measurable adverse effect on retinal function is seen with greater frequency.


Fentanyl-associated fatalities among illicit drug users in Wayne County, Michigan (July 2005-May 2006).
During the summer of 2005, multiple cities in the United States began to report outbreaks of fentanyl-associated fatalities among illicit drug users. The objectives of this study were to (1) determine if an outbreak of fentanyl-associated fatalities occurred in mid-2005 to mid-2006 and (2) to examine trends and compare features of fentanyl-contaminated heroin-associated fatalities (FHFs) with non-fentanyl, heroin-associated fatalities (NFHFs) among illicit drug users. Baseline prevalence of fentanyl- and heroin-associated deaths was estimated from January to May 2005 based on recorded cause of death (determined by the medical examiner (ME)) using the Wayne County, MI, USA toxicology database. The database was then queried for both FHFs and NFHFs between July 1, 2005 and May 12, 2006. A FHF was defined as having fentanyl or norfentanyl (metabolite) detected in any postmortem biological sample and either (1) detection of heroin or its metabolite (6-acetylmorphine) and/or cocaine or its metabolite (benzoylecgonine) in a postmortem biological specimen or (2) confirmation of fentanyl abuse as the cause of death by the ME or a medical history available sufficient enough to exclude prescription fentanyl or other therapeutic opioid use. A NFHF was defined as detection of heroin, 6-acetylmorphine (heroin metabolite) or morphine in any postmortem biological specimen, heroin overdose listed as the cause of death by the ME, and absence of fentanyl detection on postmortem laboratory testing. Information was systematically collected, trended for each group and then compared between the two groups with regard to demographic, exposure, autopsy, and toxicology data. Logistic regression was performed using SAS v 9.1 examining the effects of age, gender, and marital status with fentanyl group status. Monthly prevalence of fentanyl-associated fatalities among illicit drug users increased from an average of two in early 2005 to a peak of 24 in May, 2006. In total, 101 FHFs and 90 NFHFs were analyzed. The median age of decedents was 46 and 45 years for the fentanyl and non-fentanyl groups, respectively. Fentanyl-contaminated heroin-associated fatalities (FHFs) were more likely to be female (p = 0.003). Women aged over 44 years (OR = 4.67;95 % CI = 1.29-16.96) and divorced/widowed women (OR = 14.18;95 % CI = 1.59-127.01) were more likely to be FHFs when compared to women aged less than 44 years and single, respectively. A significant interaction occurred between gender and age, and gender and marital status. Most FHFs had central (heart) blood samples available for fentanyl testing (n = 96; 95 %): fentanyl was detected in most (n = 91; 95 %). Of these, close to half had no detectable heroin (or 6-acetylmorphine) concentrations (n = 37; 40.7 %). About half of these samples had detectable cocaine concentrations (n = 20; 54 %). Median fentanyl concentration in central blood samples was 0.02 μg/ml (n = 91, range <0.002-0.051 μg/ml) and 0.02 μg/ml (n = 32, range <0.004-0.069 μg/ml) in peripheral blood samples. The geometric mean of the ratio of central to peripheral values was 2.10 (median C/P = 1.75). At autopsy, pulmonary edema was the most frequently encountered finding for both groups (77 %). Illicit drugs may contain undeclared ingredients that may increase the likelihood of fatality in users. Gender differences in fentanyl-related mortality may be modified by age and/or marital status. These findings may help inform public health and prevention activities if fatalities associated with fentanyl-contaminated illicit drugs reoccur.


An automated microfluidic chip system for detection of piscine nodavirus and characterization of its potential carrier in grouper farms.
Groupers of the Epinephelus spp. are an important aquaculture species of high economic value in the Asia Pacific region. They are susceptible to piscine nodavirus infection, which results in viral nervous necrosis disease. In this study, a rapid and sensitive automated microfluidic chip system was implemented for the detection of piscine nodavirus; this technology has the advantage of requiring small amounts of sample and has been developed and applied for managing grouper fish farms. Epidemiological investigations revealed an extremely high detection rate of piscine nodavirus (89% of fish samples) from 5 different locations in southern Taiwan. In addition, positive samples from the feces of fish-feeding birds indicated that the birds could be carrying the virus between fish farms. In the present study, we successfully introduced this advanced technology that combines engineering and biological approaches to aquaculture. In the future, we believe that this approach will improve fish farm management and aid in reducing the economic loss experienced by fish farmers due to widespread disease outbreaks.


A methodology of phenotyping ICU patients from EHR data: High-fidelity, personalized, and interpretable phenotypes estimation.
Computing phenotypes that provide high-fidelity, time-dependent characterizations and yield personalized interpretations is challenging, especially given the complexity of physiological and healthcare systems and clinical data quality. This paper develops a methodological pipeline to estimate unmeasured physiological parameters and produce high-fidelity, personalized phenotypes anchored to physiological mechanics from electronic health record (EHR). A methodological phenotyping pipeline is developed that computes new phenotypes defined with unmeasurable computational biomarkers quantifying specific physiological properties in real time. Working within the inverse problem framework, this pipeline is applied to the glucose-insulin system for ICU patients using data assimilation to estimate an established mathematical physiological model with stochastic optimization. This produces physiological model parameter vectors of clinically unmeasured endocrine properties, here insulin secretion, clearance, and resistance, estimated for individual patient. These physiological parameter vectors are used as inputs to unsupervised machine learning methods to produce phenotypic labels and discrete physiological phenotypes. These phenotypes are inherently interpretable because they are based on parametric physiological descriptors. To establish potential clinical utility, the computed phenotypes are evaluated with external EHR data for consistency and reliability and with clinician face validation. The phenotype computation was performed on a cohort of 109 ICU patients who received no or short-acting insulin therapy, rendering continuous and discrete physiological phenotypes as specific computational biomarkers of unmeasured insulin secretion, clearance, and resistance on time windows of three days. Six, six, and five discrete phenotypes were found in the first, middle, and last three-day periods of ICU stays, respectively. Computed phenotypic labels were predictive with an average accuracy of 89%. External validation of discrete phenotypes showed coherence and consistency in clinically observable differences based on laboratory measurements and ICD 9/10 codes and clinical concordance from face validity. A particularly clinically impactful parameter, insulin secretion, had a concordance accuracy of 83%±27%. The new physiological phenotypes computed with individual patient ICU data and defined by estimates of mechanistic model parameters have high physiological fidelity, are continuous, time-specific, personalized, interpretable, and predictive. This methodology is generalizable to other clinical and physiological settings and opens the door for discovering deeper physiological information to personalize medical care.


Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery.
The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment of pharmacokinetic principles for optimizing regional drug exposure along the neuraxis. Here, we have utilized high-resolution single-photon emission tomography with X-ray computed tomography to study the behavior of multiple molecular imaging tracers following an IT bolus injection, with supporting histology, autoradiography, block-face tomography, and MRI. Using simultaneous dual-isotope imaging, we demonstrate that the regional CNS tissue exposure of molecules with varying chemical properties is affected by IT space anatomy, cerebrospinal fluid (CSF) dynamics, CSF clearance routes, and the location and volume of the injected bolus. These imaging approaches can be used across species to optimize the safety and efficacy of IT drug therapy for neurological disorders.


The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification.
The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J Mir34a-/- mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.


The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia.
Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria. Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes. The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocyte-specific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cis-regulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposase-accessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis-regulatory elements containing ETV1-binding sites. Various genes involved in Ca2+ handling or gap junction formation ( Ryr2, Jph2, Gja5), potassium channels ( Kcnh2, Kcnk3), and genes implicated in atrial fibrillation ( Tbx5) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation. This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.


Development and implementation of a highly-multiplexed SNP array for genetic mapping in maritime pine and comparative mapping with loblolly pine.
Single nucleotide polymorphisms (SNPs) are the most abundant source of genetic variation among individuals of a species. New genotyping technologies allow examining hundreds to thousands of SNPs in a single reaction for a wide range of applications such as genetic diversity analysis, linkage mapping, fine QTL mapping, association studies, marker-assisted or genome-wide selection. In this paper, we evaluated the potential of highly-multiplexed SNP genotyping for genetic mapping in maritime pine (Pinus pinaster Ait.), the main conifer used for commercial plantation in southwestern Europe. We designed a custom GoldenGate assay for 1,536 SNPs detected through the resequencing of gene fragments (707 in vitro SNPs/Indels) and from Sanger-derived Expressed Sequenced Tags assembled into a unigene set (829 in silico SNPs/Indels). Offspring from three-generation outbred (G2) and inbred (F2) pedigrees were genotyped. The success rate of the assay was 63.6% and 74.8% for in silico and in vitro SNPs, respectively. A genotyping error rate of 0.4% was further estimated from segregating data of SNPs belonging to the same gene. Overall, 394 SNPs were available for mapping. A total of 287 SNPs were integrated with previously mapped markers in the G2 parental maps, while 179 SNPs were localized on the map generated from the analysis of the F2 progeny. Based on 98 markers segregating in both pedigrees, we were able to generate a consensus map comprising 357 SNPs from 292 different loci. Finally, the analysis of sequence homology between mapped markers and their orthologs in a Pinus taeda linkage map, made it possible to align the 12 linkage groups of both species. Our results show that the GoldenGate assay can be used successfully for high-throughput SNP genotyping in maritime pine, a conifer species that has a genome seven times the size of the human genome. This SNP-array will be extended thanks to recent sequencing effort using new generation sequencing technologies and will include SNPs from comparative orthologous sequences that were identified in the present study, providing a wider collection of anchor points for comparative genomics among the conifers.


A mutator phenotype characterizes one of two complementation groups in human cells tolerant to methylation damage.
Sixty % of clones isolated from HeLa cells treated with toxic concentrations of a methylating carcinogen showed increased resistance to the cytotoxicity of N-methyl-N-nitrosourea. D37 values were 6- to 100-fold higher than in the parental cell population. The absence of detectable levels of the repair enzyme O6-methylguanine-DNA methyltransferase indicated that the resistant clones were able to tolerate the presence of O6-methylguanine in their DNA. Analysis of N-methyl-N-nitrosourea survival in the hybrids between tolerant clones and HeLa cells showed that tolerance can be either recessive or codominant. Fusion between tolerant clones indicated two complementation groups. We measured spontaneous mutation rates at microsatellites and at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in several tolerant clones. All the clones of Complementation Group I showed unstable microsatellites and 4-8-fold increases in mutation rates at hprt. No significant alterations in spontaneous mutation rates were found in clones of Complementation Group II. The data indicate that tolerance to methylation damage can be conferred by alterations in at least two different gene products and that one of the two groups has the mutator phenotype typical of mismatch correction defective cells.


Responsible Conduct of Research Measure: initial development and pilot study.
Although much discussion has been focused on research misconduct (RM) and questionable research practices, to date no self-report measures exist to examine this phenomenon. To help fill this void, the authors developed the Responsible Conduct of Research Measure (RCRM) through multiple pilot study waves involving researchers in the social and behavioral sciences. Preliminary results reveal adequate validity and reliability. The authors discuss limitations of the study as well as some possible directions for future research on this topic.


Specific T helper cells that activate B cells polyclonally. In vitro enrichment and cooperative function.
C3H/HeJ T cells which specifically recognize B cell-surface antigens of the related, major histocompatibility complex-compatible C3H/Tif strain, can be substantially enriched in vitro by long-term exposure (2--6 wk) of primed lymph node cells to the relevant cellular antigens. These enriched T cells contain functional helper cells as demonstrated by their capacity to induce large numbers of Ig-secreting plaque-forming cells (PFC) in cultures of antigenic B cells. The cooperative interaction results in activation of a large fraction of all splenic B cells, with consequent exponential growth and maturation to high rate secretion of IgM, IgG1, and IgG2, but not IgG3. The IgM PFC response includes antibody specificities to a number of different antigens and can be considered, therefore, as polyclonal. The T helper cell-dependent B-cell response is insensitive to inhibition by anti-delta antibodies, and in contrast with lipopolysaccharide-induced PFC responses, is only partially sensitive to the inhibitory effects of anti-mu antibodies. Finally, B-cell activation to growth and maturation by helper T cells strictly required direct T-cell recognition of antigens on the surface of responding B cells, leading us to the conclusions that if any soluble factors are generated in the collaborative process, they are either antigen specific or incompetent to initiate B-cell growth.


Detection of Y Chromosome Microdeletions and Hormonal Profile Analysis of Infertile Men undergoing Assisted Reproductive Technologies.
Y chromosome deletions (YCDs) in azoospermia factor (AZF) region are associated with abnormal spermatogenesis and may lead to azoospermia or severe oligozoospermia. Assisted reproductive technologies (ART) by intracytoplasmic sperm injection (ICSI) and testicular sperm extraction (TESE) are commonly required for infertility management of patients carrying YCDs. The aim of this study was to estimate the frequency of YCDs, to find the most frequent variant in infertile men candidate for ART and to compare YCD distribution with a control fertile group. The semen parameters, hormonal profiles and ART outcomes of the infertile group were studied. This case-control study consisted of 97 oligozoospermic or non-obstructive azoospermic (NOA) infertile men, who had undergone ART, as the case group and 100 fertile men as the control group. DNA samples were extracted from blood samples taken from all 197 participants and YCDs were identified by multiplex polymerase chain reaction (PCR) of eight known sequence-tagged sites. The chi-square test was used to compare the mean values of hormone and sperm parameters between the two groups. P<0.05 was considered statistically significant. No YCD was detected in the control group. However, 20 out of 97 (20.6%) infertile men had a YCD. AZFc, AZFbc and AZFabc deletions were detected in 15 (75%), four (20%) and one (5%) YCD-positive patients. No fertilization or clinical pregnancy was seen following ICSI in this sub-group with YCD. The mean level of FSH was significantly higher in the group with YCD (28.45 ± 22.2 vs. 4.8 ± 3.17 and 10.83 ± 7.23 in YCD-negative patients with and without clinical pregnancy respectively). YCD is frequent among NOA men and YCD screening before ART and patient counseling is thus strongly recommended.


Proso Millet (Panicum miliaceum L.) and Its Potential for Cultivation in the Pacific Northwest, U.S.: A Review.
Proso millet (Panicum miliaceum L.) is a warm season grass with a growing season of 60-100 days. It is a highly nutritious cereal grain used for human consumption, bird seed, and/or ethanol production. Unique characteristics, such as drought and heat tolerance, make proso millet a promising alternative cash crop for the Pacific Northwest (PNW) region of the United States. Development of proso millet varieties adapted to dryland farming regions of the PNW could give growers a much-needed option for diversifying their predominantly wheat-based cropping systems. In this review, the agronomic characteristics of proso millet are discussed, with emphasis on growth habits and environmental requirements, place in prevailing crop rotations in the PNW, and nutritional and health benefits. The genetics of proso millet and the genomic resources available for breeding adapted varieties are also discussed. Last, challenges and opportunities of proso millet cultivation in the PNW are explored, including the potential for entering novel and regional markets.


[Hydrogen can alleviate post-cardiac arrest myocardium injury in rabbits].
To investigate the effects of hydrogen (H2) on myocardium injury post-cardiac arrest (CA) in rabbits. Sixty New Zealand rabbits were randomly divided into H2 treatment group (n = 30) and control group (n = 30) by random number table. The rabbit CA model was established by means of electrical stimulation of external membrane, both groups were mechanically ventilated. Cardiopulmonary resuscitation (CPR) was performed after 6 minutes of nonintervention, and stopped after restoration of spontaneous circulation (ROSC). Inhalation of 2% H2 gas was conferred to rabbits immediately at the end of CA modeling for 72 hours in H2 treatment group. Air was given to rabbits in control group instead. The survival rate of rabbits was analyzed. Heart rate, ventricular premature beat frequency, and the levels of blood samples cardiac troponin I (cTnI), left ventricular ejection fraction (LVEF), B-type natriuretic peptide (BNP), and blood lactic acid (Lac) were collected before CA and after ROSC in all rabbits. Rabbits were sacrificed and microstructure injury was observed by electric microscope after ROSC 72 hours. There were 28 animals ROSC in both groups; the survival number in H2 treatment group was higher than that in control group at 72 hours after ROSC (number: 15 vs. 7, χ2 = 4.791, P = 0.029). In the early stage of ROSC, the heart rate of two groups slowed down, the number of premature ventricular increased, and then gradually recovered; the heart rate in H2 treatment group was returning to normal more quickly than that in control group at 48 hours after ROSC (bpm: 319±63 vs. 362±40, P < 0.05); the ventricular premature beat frequency was lower than that in control group at 72 hours after ROSC (times per minutes: 9.1±4.3 vs. 15.0±8.0, P < 0.05). The animals of two groups had different degrees of myocardial damage and cardiac insufficiency after ROSC, and restored with the extension of time. Compared with control group, the level of BNP in H2 treatment group was significant decreased at 24 hours after ROSC (ng/L: 385±98 vs. 488±174, P < 0.05), the levels of cTnI and Lac were significant decreased at 48 hours after ROSC [cTnI (μg/L: 1.83±0.68 vs. 2.83±0.98, Lac (mmol/L): 5.5±1.6 vs. 7.9±2.6, both P < 0.01], the LVEF was slightly higher than that at 72 hours after ROSC (0.690±0.040 vs. 0.650±0.041, P = 0.051). Compared with control group, less damage to myocardial ultra structure was found in H2 treatment group at 72 hours after ROSC. Inhalation of H2 alleviates cardiac dysfunction and myocardial injury after CPR.


Mode calculations in unstable resonators with flowing saturable gain. 1:hermite-gaussian expansion.
We present a procedure for calculating the three-dimensional mode pattern, the output beam characteristics, and the power output of an oscillating high-power laser taking into account a nonuniform, transversely flowing, saturable gain medium; index inhomogeneities inside the laser resonator; and arbitrary mirror distortion and misalignment. The laser is divided into a number of axial segments. The saturated gain-and-index variation. across each short segment is lumped into a complex gain profile across the midplane of that segment. The circulating optical wave within the resonator is propagated from midplane to midplane in free-space fashion and is multiplied by the lumped complex gain profile upon passing through each midplane. After each complete round trip of the optical wave inside the resonator, the saturated gain profiles are recalculated based upon the circulating fields in the cavity. The procedure when applied to typical unstable-resonator flowing-gain lasers shows convergence to a single distorted steady-state mode of oscillation. Typical near-field and far-field results are presented. Several empirical rules of thumb for finite truncated Hermite-Gaussian expansions, including an approximate sampling theorem, have been developed as part of the calculations.


Effects of mutations in the helix G region of horseradish peroxidase.
Horseradish peroxidase (HRP) has long attracted intense research interest and is used in many biotechnological fields, including diagnostics, biosensors and biocatalysis. Enhancement of HRP catalytic activity and/or stability would further increase its usefulness. Based on prior art, we substituted solvent-exposed lysine and glutamic acid residues near the proximal helix G (Lys 232, 241; Glu 238, 239) and between helices F and F' (Lys 174). Three single mutants (K232N, K232F, K241N) demonstrated increased stabilities against heat (up to 2-fold) and solvents (up to 4-fold). Stability gains are likely due to improved hydrogen bonding and space-fill characteristics introduced by the relevant substitution. Two double mutants showed stability gains but most double mutations were non-additive and non-synergistic. Substitutions of Lys 174 or Glu 238 were destabilising. Unexpectedly, notable alterations in steady-state Vm/E values occurred with reducing substrate ABTS (2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)), despite the distance of the mutated positions from the active site.