Effect of drug law enforcement on drug market violence: a systematic review.
Violence is amongst the primary concerns of communities around the world and research has demonstrated links between violence and the illicit drug trade, particularly in urban settings. Given the growing emphasis on evidence-based policy-making, and the ongoing severe drug market violence in Mexico and other settings, we conducted a systematic review to examine the impacts of drug law enforcement on drug market violence. We conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Specifically, we undertook a search of English language electronic databases (Academic Search Complete, PubMed, PsycINFO, EMBASE, Web of Science, Sociological Abstracts, Social Service Abstracts, PAIS International and Lexis-Nexis), the Internet (Google, Google Scholar), and article reference lists, from database inception to January 24, 2011. Overall, 15 studies were identified that evaluated the impact of drug law enforcement on drug market violence, including 11 (73%) longitudinal analyses using linear regression, 2 (13%) mathematical drug market models, and 2 (13%) qualitative studies. Fourteen (93%) studies reported an adverse impact of drug law enforcement on levels of violence. Ten of the 11 (91%) studies employing longitudinal qualitative analyses found a significant association between drug law enforcement and drug market violence. Our findings suggest that increasing drug law enforcement is unlikely to reduce drug market violence. Instead, the existing evidence base suggests that gun violence and high homicide rates may be an inevitable consequence of drug prohibition and that disrupting drug markets can paradoxically increase violence. In this context, and since drug prohibition has not meaningfully reduced drug supply, alternative regulatory models will be required if drug supply and drug market violence are to be meaningfully reduced.


Supraventricular Tachycardia Classification in the 12-Lead ECG Using Atrial Waves Detection and a Clinically Based Tree Scheme.
Specific supraventricular tachycardia (SVT) classification using surface ECG is considered a challenging task, since the atrial electrical activity (AEA) waves, which are a crucial element for obtaining diagnosis, are frequently hidden. In this paper, we present a fully automated SVT classification method that embeds our recently developed hidden AEA detector in a clinically based tree scheme. The process begins with initial noise removal and QRS detection. Then, ventricular features are extracted. According to these features, an initial AEA-wave search window is defined and a single AEA-wave is detected. Using a synthetic Gaussian signal and a linear combination of 12-lead ECG signals, all AEA-waves are detected. In accord with the atrial and ventricular information found, classification to atrial fibrillation, atrial flutter, atrioventricular nodal reentry tachycardia, atrioventricular reentry tachycardia, or sinus rhythm is performed in the framework of a clinically oriented decision tree. A study was performed to evaluate the classification from 68 patients (26 were used for the classifier's design, 42 were used for its validation). Average sensitivity of 83.21% [95% confidence interval (CI): 79.33-86.49%], average specificity of 95.80% (95% CI: 94.73-96.67%), and average accuracy of 93.29% (95% CI: 92.13-94.28%) were achieved compared to the definite diagnosis. In conclusion, the presented method may serve as a valuable decision support tool, allowing accurate detection of SVTs using noninvasive means.


Can Alzheimer's disease be prevented?
Alzheimer's disease (AD) is the most common form of dementia. Survival time for an AD patient is generally 4 to 6 years after diagnosis, however, survival time can be as long as 20 years from the detection of initial symptoms, which can surface in the 30s, 40s, and beyond. This window of opportunity suggests that many people can prolong their life with life-changing choices related to diet, exercise, nutritional supplements, and nutraceuticals. This was emphasized in many recent studies and was described in detail in the book "Minimizing the Risk of Alzheimer's Disease" published in the USA in 2012.


Epithelial cell proliferation contributes to airway remodeling in severe asthma.
Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p=0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p=0.002) and Ki67 was increased (p<0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p<0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p=0.002), suggesting increased cell death. In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.


Pre-Columbian origins of Native American dog breeds, with only limited replacement by European dogs, confirmed by mtDNA analysis.
Dogs were present in pre-Columbian America, presumably brought by early human migrants from Asia. Studies of free-ranging village/street dogs have indicated almost total replacement of these original dogs by European dogs, but the extent to which Arctic, North and South American breeds are descendants of the original population remains to be assessed. Using a comprehensive phylogeographic analysis, we traced the origin of the mitochondrial DNA lineages for Inuit, Eskimo and Greenland dogs, Alaskan Malamute, Chihuahua, xoloitzcuintli and perro sín pelo del Peru, by comparing to extensive samples of East Asian (n = 984) and European dogs (n = 639), and previously published pre-Columbian sequences. Evidence for a pre-Columbian origin was found for all these breeds, except Alaskan Malamute for which results were ambigous. No European influence was indicated for the Arctic breeds Inuit, Eskimo and Greenland dog, and North/South American breeds had at most 30% European female lineages, suggesting marginal replacement by European dogs. Genetic continuity through time was shown by the sharing of a unique haplotype between the Mexican breed Chihuahua and ancient Mexican samples. We also analysed free-ranging dogs, confirming limited pre-Columbian ancestry overall, but also identifying pockets of remaining populations with high proportion of indigenous ancestry, and we provide the first DNA-based evidence that the Carolina dog, a free-ranging population in the USA, may have an ancient Asian origin.


EB1 regulates tubulin and actin cytoskeletal networks at the sertoli cell blood-testis barrier in male rats: an in vitro study.
During spermatogenesis, developing germ cells are transported across the seminiferous epithelium. Studies propose that because microtubules (MTs) serve as the tracks for transporting cell organelles, they may also serve a similar function in the transport of developing germ cells. Polarized MTs may provide the tracks along which polarized actin microfilaments, which act as vehicles to transport cargo, such as preleptotene spermatocytes through the blood-testis barrier (BTB) and spermatids across the epithelium. Yet the molecular mechanism(s) underlying these events remain unknown. Using an established in vitro Sertoli cell system to study BTB function, we demonstrated herein that a MT regulatory protein end-binding protein 1 (EB1) regulates the MT- and also the actin-based cytoskeleton of the Sertoli cell BTB in the rat. EB1 serves as a coordinator between the two cytoskeletons by regulating MT polymerization and actin filament bundling to modulate germ cell transport at the Sertoli cell BTB. A knockdown of EB1 by RNA interference was found to perturb the tight junction (TJ)-permeability barrier, as evidenced by mislocalization of junctional proteins critical for barrier function to facilitate spermatocyte transport, which was likely achieved by two coordinated events. First, EB1 knockdown resulted in changes in MT polymerization, thereby perturbing MT organization in Sertoli cells in which polarized MT no longer stretched properly across the cell cytosol to serve as the tracks. Second, EB1 knockdown perturbed actin organization via its effects on the branched actin polymerization-inducing protein called Arp3 (actin-related protein 3), perturbing microfilament bundling capability based on a biochemical assay, thereby causing microfilament truncation and misorganization, disrupting the function of the vehicle. This reduced actin microfilament bundling capability thus perturbed TJ-protein distribution and localization at the BTB, destabilizing the TJ barrier, leading to its remodeling to facilitate spermatocyte transport. In summary, EB1 provides a functional link between tubulin- and actin-based cytoskeletons to confer spermatocyte transport at the BTB.


Identification of glycoproteins targeted by Trypanosoma cruzi trans-sialidase, a virulence factor that disturbs lymphocyte glycosylation.
Trypanosoma cruzi, the agent of the American trypanosomiasis or Chagas disease, bypasses its lack of de novo synthesis of sialic acids by expressing a surface-anchored trans-sialidase. This enzyme transfers sialic acid residues from the host's sialylglycoconjugates to the parasite's galactosylglycoconjugates. In addition to carrying out a pivotal role in parasite persistence/replication within the infected mammal, the trans-sialidase is shed into the bloodstream and induces alterations in the host immune system by modifying the sialylation of the immune cells. A major obstacle to understand these events is the difficulty to identify the transferred sialic acid among all those naturally occurring on the cell surface. Here, we report the use of azido-modified unnatural sialic acid to identify those molecules that act as cell surface acceptors of the sialyl residue in the trans-sialidase-catalyzed reaction, which might then be involved in the immune alterations induced. In living parasites, we readily observed the transfer of azido-sialic acid to surface mucins. When evaluating mouse thymocytes and splenocytes as acceptors of the azido-sugar, a complex pattern of efficiently tagged glycoproteins was revealed. In both leukocyte populations, the main proteins labeled were identified as different CD45 isoforms. Disruption of the cell architecture increased the number and the molecular weight distribution of azido-sialic acid tagged proteins. Nevertheless, CD45 remained to be the main acceptor. Mass spectrometry assays allowed us to identify other acceptors, mainly integrins. The findings reported here provide a molecular basis to understand the abnormalities induced in the immune system by the trans-sialidase during T. cruzi infection.


The burden of common infectious disease syndromes at the clinic and household level from population-based surveillance in rural and urban Kenya.
Characterizing infectious disease burden in Africa is important for prioritizing and targeting limited resources for curative and preventive services and monitoring the impact of interventions. From June 1, 2006 to May 31, 2008, we estimated rates of acute lower respiratory tract illness (ALRI), diarrhea and acute febrile illness (AFI) among >50,000 persons participating in population-based surveillance in impoverished, rural western Kenya (Asembo) and an informal settlement in Nairobi, Kenya (Kibera). Field workers visited households every two weeks, collecting recent illness information and performing limited exams. Participants could access free high-quality care in a designated referral clinic in each site. Incidence and longitudinal prevalence were calculated and compared using Poisson regression. INCIDENCE RATES RESULTING IN CLINIC VISITATION WERE THE FOLLOWING: ALRI--0.36 and 0.51 episodes per year for children <5 years and 0.067 and 0.026 for persons ≥ 5 years in Asembo and Kibera, respectively; diarrhea--0.40 and 0.71 episodes per year for children <5 years and 0.09 and 0.062 for persons ≥ 5 years in Asembo and Kibera, respectively; AFI--0.17 and 0.09 episodes per year for children <5 years and 0.03 and 0.015 for persons ≥ 5 years in Asembo and Kibera, respectively. Annually, based on household visits, children <5 years in Asembo and Kibera had 60 and 27 cough days, 10 and 8 diarrhea days, and 37 and 11 fever days, respectively. Household-based rates were higher than clinic rates for diarrhea and AFI, this difference being several-fold greater in the rural than urban site. Individuals in poor Kenyan communities still suffer from a high burden of infectious diseases, which likely hampers their development. Urban slum and rural disease incidence and clinic utilization are sufficiently disparate in Africa to warrant data from both settings for estimating burden and focusing interventions.


Pituitary carcinoma diagnosed on fine needle aspiration: Report of a case and review of pathogenesis.
Pituitary carcinoma (PC) is a very rare entity (0.2% of all pituitary tumors), with only about 140 cases reported in English literature. There are no reliable histological, immunohistochemical or ultrastructural features distinguishing pituitary adenoma (PA) from PC. By definition, a diagnosis of PC is made after a patient with PA develops non-contiguous central nervous system (CNS) or systemic metastases. To date, only three cases of PC have been reportedly diagnosed on fine needle aspiration (FNA). Two of the reported cases were diagnosed on FNA of the cervical lymph nodes and one on FNA of the vertebral bone lesion. Herein, we present a case of PC, diagnosed on FNA of the liver lesion. In this case, we describe cytologic features of PC and compare them to histologic features of the tumor in the pituitary. Clinical behavior of tumor, pathogenesis of metastasis and immunochemical and prognostic markers will also be described.


Statistical image-domain multimaterial decomposition for dual-energy CT.
Dual-energy CT (DECT) enhances tissue characterization because of its basis material decomposition capability. In addition to conventional two-material decomposition from DECT measurements, multimaterial decomposition (MMD) is required in many clinical applications. To solve the ill-posed problem of reconstructing multi-material images from dual-energy measurements, additional constraints are incorporated into the formulation, including volume and mass conservation and the assumptions that there are at most three materials in each pixel and various material types among pixels. The recently proposed flexible image-domain MMD method decomposes pixels sequentially into multiple basis materials using a direct inversion scheme which leads to magnified noise in the material images. In this paper, we propose a statistical image-domain MMD method for DECT to suppress the noise. The proposed method applies penalized weighted least-square (PWLS) reconstruction with a negative log-likelihood term and edge-preserving regularization for each material. The statistical weight is determined by a data-based method accounting for the noise variance of high- and low-energy CT images. We apply the optimization transfer principles to design a serial of pixel-wise separable quadratic surrogates (PWSQS) functions which monotonically decrease the cost function. The separability in each pixel enables the simultaneous update of all pixels. The proposed method is evaluated on a digital phantom, Catphan©600 phantom and three patients (pelvis, head, and thigh). We also implement the direct inversion and low-pass filtration methods for a comparison purpose. Compared with the direct inversion method, the proposed method reduces noise standard deviation (STD) in soft tissue by 95.35% in the digital phantom study, by 88.01% in the Catphan©600 phantom study, by 92.45% in the pelvis patient study, by 60.21% in the head patient study, and by 81.22% in the thigh patient study, respectively. The overall volume fraction accuracy is improved by around 6.85%. Compared with the low-pass filtration method, the root-mean-square percentage error (RMSE(%)) of electron densities in the Catphan©600 phantom is decreased by 20.89%. As modulation transfer function (MTF) magnitude decreased to 50%, the proposed method increases the spatial resolution by an overall factor of 1.64 on the digital phantom, and 2.16 on the Catphan©600 phantom. The overall volume fraction accuracy is increased by 6.15%. We proposed a statistical image-domain MMD method using DECT measurements. The method successfully suppresses the magnified noise while faithfully retaining the quantification accuracy and anatomical structure in the decomposed material images. The proposed method is practical and promising for advanced clinical applications using DECT imaging.


New Sources of Resistance in Sorghum (Sorghum bicolor) Germplasm Are Effective Against a Diverse Array of Potyvirus spp.
Sorghum is a host to numerous Potyvirus spp. and its germplasm encompasses a wide range of infection responses to these viruses. We determined how 183 mini-core-collection sorghum germplasm accessions responded to mechanical inoculation with Maize dwarf mosaic virus (MDMV) in growth regimes in which they were maintained at 30°C followed by 16°C for 5 days. Accessions that appeared immune to MDMV in this initial screening were evaluated for their response in a similar temperature maintenance regime to mechanical inoculation with MDMV, Sugarcane mosaic virus strain MDB (SCMV-MDB), Sorghum mosaic virus (SrMV), Zea mosaic virus (ZeMV), and Kansas, Nigerian, and Australian isolates of Johnsongrass mosaic virus (JGMV-KS, -N, and -Aus, respectively). In both experiments, MDMV systemically infected all accessions except international sorghum accession number (IS) 7679 and IS 20740. These accessions also proved resistant to MDMV, SCMV-MDB, SrMV, and JGMV-N but both were susceptible to the JGMV-KS and JGMV-Aus isolates. IS 7679 but not IS 20740 was resistant to infection with ZeMV. These observations suggest that IS 7679 and IS 20740 might serve as new sources of resistance to several Potyvirus spp. that systemically infect sorghum.


Determination of ibogaine in plasma by gas chromatography--chemical ionization mass spectrometry.
Ibogaine is naturally occurring indole alkaloid that is currently being considered as a treatment medication for drug dependence. Although there have been a variety of investigations regarding the mechanisms of action and pharmacology of ibogaine, relatively little has been reported regarding quantitative methods. Because of the paucity of analytical methodologies, studies involving the pharmacokinetics and metabolism of ibogaine have also been limited. A method is described for the determination of ibogaine levels in plasma by gas chromatography -- methane chemical ionization mass spectrometry. [13C2H3]Ibogaine was synthesized and used as an internal standard to control for recovery during sample preparation. The assay requires one ml of plasma and is shown to be a selective and sensitive means of ibogaine quantitation.


Relationship between history of coronary heart disease at dialysis initiation and onset of events associated with heart disease: a propensity-matched analysis of a prospective cohort study.
Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD) events, and a number of reports have shown a relationship between CKD and CVD in pre-dialysis or maintenance dialysis patients. However, few studies have reported serial observations during dialysis initiation and maintenance. Therefore, we examined whether the incidence of heart disease events differed between CKD patients with and without a history of coronary heart disease (CHD) at dialysis initiation. The subjects were patients in the 17 centers participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) from October 2011 to September 2013. We excluded nine patients whose outcomes were unknown, as determined by a survey conducted at the end of March 2015. Thus, we enrolled 1,515 subjects into the study. We classified patients into 2 groups according to the history of CHD (i.e., a CHD group and a non-CHD group). Propensity scores (PS) represented the probability of being assigned to a group with or without a history of CHD. Onset of heart disease events and associated mortality and all-cause mortality were compared in PS-matched patients by using the log-rank test for Kaplan-Meier curves. Factors contributing to heart disease events were examined using stepwise multivariate Cox proportional hazards analysis. There were 254 patients in each group after PS-matching. During observation, heart disease events occurred in 85 patients (33.5%) in the CHD group and 48 (18.9%) patients in the non-CHD group. The incidence was significantly higher in the CHD group (p < 0.0001). The CHD group was associated with higher incidence of heart disease events (vs. the non-CHD group, hazard ratio = 1.750, 95% confidence interval = 1.160-2.639). In addition, comorbidities such as diabetes mellitus, low body mass index, and low serum high-density lipoprotein cholesterol were associated with higher incidence of events. History of CHD at dialysis initiation was associated with a higher incidence of heart disease events and mortality and all-cause mortality. UMIN 000007096 . Registered 18 January 2012.


Effects of 6 months of resveratrol versus placebo on pentraxin 3 in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial.
The anti-inflammatory effects of the polyphenol resveratrol in patients with type 2 diabetes mellitus (T2DM) are controversial. Its role on pentraxin 3 (PTX3) concentrations, a human acute phase protein, has never been evaluated. Our aim was to determine whether a two-dosage resveratrol supplementation (500 and 40 mg/day) has an impact on PTX3 values in T2DM patients from a double-blind randomized placebo-controlled trial. Variations in total antioxidant status (TAS) were evaluated too. A total of 192 T2DM patients were randomized to receive resveratrol 500 mg/day (Resv 500 arm), resveratrol 40 mg/day (Resv 40 arm) or placebo for 6 months. At baseline and at the trial end, PTX3 and TAS values were determined. A dose-dependent increase in PTX3 concentrations of 4.7% (Resv 40 arm) and 26.3% (Resv 500 arm), and 8.0% reduction after placebo were found. Adjusted mean differences of change versus placebo were 0.16 (95% CI 0.01-0.32) and 0.25 (0.09-0.42) in the Resv 40 and Resv 500 arms, respectively. At subgroup analyses, lower diabetes duration, aspirin, alcohol use, younger age, female gender, smoking (Resv 500 arm) and female gender and aspirin use (Resv 40 arm) were associated with higher PTX3 increments. A dose-dependent increment in TAS values in the resveratrol arms (1.4 and 6.4% for Resv 40 and Resv 500, respectively), and a reduction in placebo arm (-8.9%) were observed. Adjusted mean differences of change were 28.5 (95% CI 10.1-46.8) and 44.8 (25.4-64.1) in the Resv 40 and Resv 500 arms, respectively. Resveratrol supplementation increased PTX3 and TAS levels in a dose-dependent manner in T2DM patients. At present, potential clinical implications of these results remain unclear. CLINICALTRIALS. NCT02244879.


Sociodemographic inequities and active transportation in adults from Latin America: an eight-country observational study.
Active transportation is a crucial sort of physical activity for developing sustainable environments and provides essential health benefits. This is particularly important in Latin American countries because they present the highest burden of non-communicable diseases relative to other worldwide regions. This study aimed to examine the patterns of active transportation and its association with sociodemographic inequities in Latin American countries. This cross-sectional study was conducted in eight countries. Participants (n = 8547, 18-65 years) self-reported their active transportation (walking, cycling, and total) using the International Physical Activity Questionnaire. Sex, age, ethnicity, socioeconomic level, education level, public and private transport use, and transport mode were used as sociodemographic inequities. Participants spent a total of 19.9, 3.1, and 23.3 min/day with walking, cycling, and total active transportation, respectively. Mixed and other ethnicity (Asian, Indigenous, Gypsy, and other), high socioeconomic level as well as middle and high education level presented higher walking than Caucasian, low socioeconomic and education level. Private transport mode and use of ≥ 6 days/week of private transport showed lower walking than public transport mode and ≤ 2 days/week of private transport. Use of ≥ 3 days/week of public transport use presented higher walking than ≤ 2 days/week of public transport. Men had higher cycling for active transportation than women. Use of ≥ 3 days/week of public transport use presented higher cycling than ≤ 2 days/week of public transport. ≥6 days/week showed lower cycling than ≤ 2 days/week of private transport use. Men (b: 5.57: 95 %CI: 3.89;7.26), black (3.77: 0.23;7.31), mixed (3.20: 1.39;5.00) and other ethnicity (7.30: 2.55;12.04), had higher total active transportation than women and Caucasian. Private transport mode (-7.03: -11.65;-2.41) and ≥ 6 days/week of private transport use (-4.80: -6.91;-0.31) showed lower total active transportation than public transport mode and ≤ 2 days/week of private transport use. Use of 3-5 (5.10: 1.35;8.85) and ≥ 6 days/week (8.90: 3.07;14.73) of public transport use presented higher total active transportation than ≤ 2 days/week of public transport use. Differences among countries were observed. Sociodemographic inequities are associated differently with active transportation across Latin American countries. Interventions and policies that target the promotion of active policies transportation essential to consider sociodemographic inequities. ClinicalTrials.Gov NCT02226627. Retrospectively registered on August 27, 2014.


Cytotoxicity of dental glass ionomers evaluated using dimethylthiazol diphenyltetrazolium and neutral red tests.
The purpose of this study was to assess the cytotoxicity of some commonly used glass ionomers. Three chemically cured glass ionomers (Fuji II, Lining cement, and Ketac Silver) and one light-cured (Fuji II LC) were tested. Extracts of mixed non-polymerized materials and polymerized specimens were prepared in accordance with ISO standard 10993-12. The polymerized specimens were cured and placed either directly in the medium (freshly cured), left for 24 h (aged), or aged plus ground before being placed in the medium. The cytotoxicity of extracts was evaluated on mouse fibroblasts (L, 929), using dimethylthiazol diphenyltetrazolium (MTT) and neutral red (NR) assays. Further, the concentrations of aluminum, arsenic and lead were analyzed in aqueous extracts from freshly cured and aged samples, and the fluoride levels analyzed in aqueous extracts from freshly cured samples. All extracts except that of non-polymerized Ketac Silver were rated as severely cytotoxic in both assays. Extracts of polymerized material were significantly more cytotoxic than extracts of non-polymerized material. All freshly cured glass ionomers released aluminum and fluoride concentrations far above what is considered cytotoxic (aluminum >0.2 ppm and fluoride >20 ppm). Extracts from freshly cured Lining Cement contained the highest concentrations of aluminum and fluoride (215 ppm and 112 ppm). Extracts from freshly cured Ketac Silver had the lowest concentrations of aluminum and fluoride but the highest of lead (100 ppm). It can be concluded that all extracts from non-cured, freshly cured, and aged glass ionomers contained cytotoxic levels of substances. Curing did not reduce the toxicity significantly.


Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.
Voltage-gated sodium channels (Nav channels) are critical for electrical signaling in the nervous system and are the primary targets of the insecticides DDT and pyrethroids. In Drosophila melanogaster, besides the canonical Nav channel, Para (also called DmNav), there is a sodium channel-like cation channel called DSC1 (Drosophila sodium channel 1). Temperature-sensitive paralytic mutations in DmNav (para(ts)) confer resistance to DDT and pyrethroids, whereas DSC1 knockout flies exhibit enhanced sensitivity to pyrethroids. To further define the roles and interaction of DmNav and DSC1 channels in DDT and pyrethroid neurotoxicology, we generated a DmNav/DSC1 double mutant line by introducing a para(ts1) allele (carrying the I265N mutation) into a DSC1 knockout line. We confirmed that the I265N mutation reduced the sensitivity to two pyrethroids, permethrin and deltamethrin of a DmNav variant expressed in Xenopus oocytes. Computer modeling predicts that the I265N mutation confers pyrethroid resistance by allosterically altering the second pyrethroid receptor site on the DmNav channel. Furthermore, we found that I265N-mediated pyrethroid resistance in para(ts1) mutant flies was almost completely abolished in para(ts1);DSC1(-/-) double mutant flies. Unexpectedly, however, the DSC1 knockout flies were less sensitive to DDT, compared to the control flies (w(1118A)), and the para(ts1);DSC1(-/-) double mutant flies were even more resistant to DDT compared to the DSC1 knockout or para(ts1) mutant. Our findings revealed distinct roles of the DmNav and DSC1 channels in the neurotoxicology of DDT vs. pyrethroids and implicate the exciting possibility of using DSC1 channel blockers or modifiers in the management of pyrethroid resistance.


Isolation of Human Colon Stem Cells Using Surface Expression of PTK7.
Insertion of reporter cassettes into the Lgr5 locus has enabled the characterization of mouse intestinal stem cells (ISCs). However, low cell surface abundance of LGR5 protein and lack of high-affinity anti-LGR5 antibodies represent a roadblock to efficiently isolate human colonic stem cells (hCoSCs). We set out to identify stem cell markers that would allow for purification of hCoSCs. In an unbiased approach, membrane-enriched protein fractions derived from in vitro human colonic organoids were analyzed by quantitative mass spectrometry. Protein tyrosine pseudokinase PTK7 specified a cell population within human colonic organoids characterized by highest self-renewal and re-seeding capacity. Antibodies recognizing the extracellular domain of PTK7 allowed us to isolate and expand hCoSCs directly from patient-derived mucosa samples. Human PTK7+ cells display features of canonical Lgr5+ ISCs and include a fraction of cells that undergo differentiation toward enteroendocrine lineage that resemble crypt label retaining cells (LRCs).


Risk factors associated with physician trainee concern over missed educational opportunities during the COVID-19 pandemic.
The COVID-19 pandemic resulted in a transformation of clinical care practices to protect both patients and providers. These changes led to a decrease in patient volume, impacting physician trainee education due to lost clinical and didactic opportunities. We measured the prevalence of trainee concern over missed educational opportunities and investigated the risk factors leading to such concerns. All residents and fellows at a large academic medical center were invited to participate in a web-based survey in May of 2020. Participants responded to questions regarding demographic characteristics, specialty, primary assigned responsibility during the previous 2 weeks (clinical, education, or research), perceived concern over missed educational opportunities, and burnout. Multivariable logistic regression was used to assess the relationship between missed educational opportunities and the measured variables. 22% (301 of 1375) of the trainees completed the survey. 47% of the participants were concerned about missed educational opportunities. Trainees assigned to education at home had 2.85 [95%CI 1.33-6.45] greater odds of being concerned over missed educational opportunities as compared with trainees performing clinical work. Trainees performing research were not similarly affected [aOR = 0.96, 95%CI (0.47-1.93)]. Trainees in pathology or radiology had 2.51 [95%CI 1.16-5.68] greater odds of concern for missed educational opportunities as compared with medicine. Trainees with greater concern over missed opportunities were more likely to be experiencing burnout (p = 0.038). Trainees in radiology or pathology and those assigned to education at home were more likely to be concerned about their missed educational opportunities. Residency programs should consider providing trainees with research or at home clinical opportunities as an alternative to self-study should future need for reduced clinical hours arise.


Prevalence rates of male and female sexual violence perpetrators in a national sample of adolescents.
IMPORTANCE Sexual violence can emerge in adolescence, yet little is known about youth perpetrators-especially those not involved with the criminal justice system. OBJECTIVE To report national estimates of adolescent sexual violence perpetration and details of the perpetrator experience. DESIGN, SETTING, AND PARTICIPANTS Data were collected online in 2010 (wave 4) and 2011 (wave 5) in the national Growing Up With Media study. Participants included 1058 youths aged 14 to 21 years who at baseline read English, lived in the household at least 50% of the time, and had used the Internet in the last 6 months. Recruitment was balanced on youths' biological sex and age. MAIN OUTCOMES AND MEASURES Forced sexual contact, coercive sex, attempted rape, and completed rape. RESULTS Nearly 1 in 10 youths (9%) reported some type of sexual violence perpetration in their lifetime; 4% (10 females and 39 males) reported attempted or completed rape. Sixteen years old was the mode age of first sexual perpetration (n = 18 [40%]). Perpetrators reported greater exposure to violent X-rated content. Almost all perpetrators (98%) who reported age at first perpetration to be 15 years or younger were male, with similar but attenuated results among those who began at ages 16 or 17 years (90%). It is not until ages 18 or 19 years that males (52%) and females (48%) are relatively equally represented as perpetrators. Perhaps related to age at first perpetration, females were more likely to perpetrate against older victims, and males were more likely to perpetrate against younger victims. Youths who started perpetrating earlier were more likely than older youths to get in trouble with caregivers; youths starting older were more likely to indicate that no one found out about the perpetration. CONCLUSIONS AND RELEVANCE Sexual violence perpetration appears to emerge earlier for males than females, perhaps suggesting different developmental trajectories. Links between perpetration and violent sexual media are apparent, suggesting a need to monitor adolescents' consumption of this material. Victim blaming appears to be common, whereas experiencing consequences does not. There is therefore urgent need for school programs that encourage bystander intervention as well as implementation of policies that could enhance the likelihood that perpetrators are identified.


X-ray structure of the high-salt form of the peridinin-chlorophyll a-protein from the dinoflagellate Amphidinium carterae: modulation of the spectral properties of pigments by the protein environment.
Light-harvesting complexes have evolved into very different structures but fulfill the same function, efficient harvesting of solar energy. In these complexes, pigments are fine-tuned and properly arranged to gather incoming photons. In the photosynthetic dinoflagellate Amphidinium carterae, two variants of the soluble light-harvesting complex PCP have been found [main form PCP (MFPCP) and high-salt PCP (HSPCP)], which show small variations in their pigment arrangement and tuning mechanisms. This feature makes them ideal models for studying pigment-protein interactions. Here we present the X-ray structure of the monomeric HSPCP determined at 2.1 A resolution and compare it to the structure of trimeric MFPCP. Despite the high degree of structural similarity (rmsd C(alpha)-C(alpha) of 1.89 A), the sequence variations lead to a changed overall pigment composition which includes the loss of two carotenoid molecules and a dramatic rearrangement of the chlorophyll phytol chains and of internal lipid molecules. On the basis of a detailed structural comparison, we favor a macrocycle geometry distortion of the chlorophylls rather than an electrostatic effect to explain energetic splitting of the chlorophyll a Q(y) bands [Ilagan, R. P. (2006) Biochemistry 45, 14052-14063]. Our analysis supports their assignment of peridinin 611* as the single blue-shifted peridinin in HSPCP but also highlights another electrostatic feature due to glutamate 202 which could add to the observed binding site asymmetry of the 611*/621* peridinin pair.


Voice Therapy in the Context of the COVID-19 Pandemic: Guidelines for Clinical Practice.
Since the beginning of the new pandemic, COVID-19 health services have had to face a new scenario. Voice therapy faces a double challenge, interventions using telepractice, and delivering rehabilitation services to a growing population of patients at risk of functional impairment related to the COVID-19 disease. Moreover, as COVID-19 is transmitted through droplets, it is critical to understand how to mitigate these risks during assessment and treatment. To promote safety, and effective clinical practice to voice assessment and rehabilitation in the pandemic COVID-19 context for speech-language pathologists. A group of 11 experts in voice and swallowing disorders from five different countries conducted a consensus recommendation following the American Academy of Otolaryngology-Head and Neck Surgery rules building a clinical guide for speech-language pathologists during this pandemic context. The clinical guide provides 65 recommendations for clinicians in the management of voice disorders during the pandemic and includes advice from assessment, direct treatment, telepractice, and teamwork. The consensus was reached 95% for all topics. This guideline should be taken only as recommendation; each clinician must attempt to mitigate the risk of infection and achieve the best therapeutic results taking into account the patient's particular reality.


Leukotriene D4 relaxes canine renal and superior mesenteric arteries.
To characterize the influences of leukotriene D4 on regional vascular smooth muscle, effects of leukotriene D4 on vasomotor tone of canine renal and superior mesenteric arterial rings were determined. Vascular smooth muscle tone was measured with isometric force transducers. After tone had been induced with norepinephrine, leukotriene D4, in concentrations of 10(-8) M to 10(-7) M, produced dose-dependent relaxation of renal and superior mesenteric arterial rings. Leukotriene D4-induced relaxation was observed only in those ring preparations in which care had been taken to avoid damaging the luminal surface. Acetylcholine (10(-7) M) also decreased tone in these same ring segments. Neither acetylcholine nor leukotriene D4 altered tone of arterial rings after the endothelium had been intentionally disrupted by rubbing with a cotton-tipped applicator. Nitroglycerin (10(-6) M) relaxed rings both before and after rubbing the intimal surface. These results demonstrate that leukotriene D4 possesses the capacity to relax canine superior mesenteric and renal arterial rings in an endothelial-dependent manner. Because relaxation of renal and superior mesenteric arterial rings in response to leukotriene D4 was not altered after incubation with indomethacin (10(-5) M), the observed endothelial-dependent relaxation induced by leukotriene D4 did not appear to be related to release of a cyclooxygenase metabolite(s). In contrast, FPL 55712 (10(-5) M) attenuated the relaxation produced by leukotriene D4, suggesting that this response was a receptor-linked consequence.


Updating working memory in aircraft noise and speech noise causes different fMRI activations.
The present study used fMRI/BOLD neuroimaging to investigate how visual-verbal working memory is updated when exposed to three different background-noise conditions: speech noise, aircraft noise and silence. The number-updating task that was used can distinguish between "substitution processes," which involve adding new items to the working memory representation and suppressing old items, and "exclusion processes," which involve rejecting new items and maintaining an intact memory set. The current findings supported the findings of a previous study by showing that substitution activated the dorsolateral prefrontal cortex, the posterior medial frontal cortex and the parietal lobes, whereas exclusion activated the anterior medial frontal cortex. Moreover, the prefrontal cortex was activated more by substitution processes when exposed to background speech than when exposed to aircraft noise. These results indicate that (a) the prefrontal cortex plays a special role when task-irrelevant materials should be denied access to working memory and (b) that, when compensating for different types of noise, either different cognitive mechanisms are involved or those cognitive mechanisms that are involved are involved to different degrees.


Do we need genomic research for the prevention of common diseases with environmental causes?
Concerns have been raised about the value of genomic research for prevention and public health, especially for complex diseases with risk factors that are amenable to environmental modification. Given that gene-environment interactions underlie almost all human diseases, the public health significance of genomic research on common diseases with modifiable environmental risks is based not necessarily on finding new genetic "causes" but on improving existing approaches to identifying and modifying environmental risk factors to better prevent and treat disease. Such applied genomic research for environmentally caused diseases is important, because 1) it could help stratify disease risks and differentiate interventions for achieving population health benefits; 2) it could help identify new environmental risk factors for disease or help confirm suspected environmental risk factors; and 3) it could aid our understanding of disease occurrence in terms of transmission, natural history, severity, etiologic heterogeneity, and targets for intervention at the population level. While genomics is still in its infancy, opportunities exist for developing, testing, and applying the tools of genomics to clinical and public health research, especially for conditions with known or suspected environmental causes. This research is likely to lead to population-wide health promotion and disease prevention efforts, not only to interventions targeted according to genetic susceptibility.


Meta-analysis of heterogeneous data sources for genome-scale identification of risk genes in complex phenotypes.
Meta-analyses of large-scale association studies typically proceed solely within one data type and do not exploit the potential complementarities in other sources of molecular evidence. Here, we present an approach to combine heterogeneous data from genome-wide association (GWA) studies, protein-protein interaction screens, disease similarity, linkage studies, and gene expression experiments into a multi-layered evidence network which is used to prioritize the entire protein-coding part of the genome identifying a shortlist of candidate genes. We report specifically results on bipolar disorder, a genetically complex disease where GWA studies have only been moderately successful. We validate one such candidate experimentally, YWHAH, by genotyping five variations in 640 patients and 1,377 controls. We found a significant allelic association for the rs1049583 polymorphism in YWHAH (adjusted P = 5.6e-3) with an odds ratio of 1.28 [1.12-1.48], which replicates a previous case-control study. In addition, we demonstrate our approach's general applicability by use of type 2 diabetes data sets. The method presented augments moderately powered GWA data, and represents a validated, flexible, and publicly available framework for identifying risk genes in highly polygenic diseases. The method is made available as a web service at www.cbs.dtu.dk/services/metaranker.


Changing Trends for Suicidal Death in Patients With Bladder Cancer: A 40+ Year Population-level Analysis.
Previous studies suggest that patients with bladder cancer (BCa) are at increased risk of suicide compared with the general population. The objective of this study is to improve our understanding of patients at high risk for suicidal death and to better characterize patients at risk of delayed suicide years after diagnosis. Patients with bladder urothelial carcinoma were identified between 1973 and 2013 using the Surveillance, Epidemiology, and End Results (SEER) database (n = 333,679). Competing risks models were performed to generate hazard ratios (HRs) to identify variables associated with suicidal death. Among patients dying of suicide, logistic regression modelling was used to generate odds ratios (ORs) for factors associated with suicide > 36 months after diagnosis. There were 794 patients (0.24%) that died of suicide, 190,734 patients (57.2%) that died from other causes, and 142,151 patients (42.6%) that were alive. Significant factors associated with suicide included diagnosis between 1973 and 1983 (HR, 2.22), unmarried (HR, 1.74), white race (HR, 2.22), male (HR, 6.91), regional disease (HR, 2.49), living in the Southeast United States (HR, 2.43), and not undergoing a radical cystectomy (HR, 1.42). Older age was associated with suicide, whereas younger age was protective. No radical cystectomy (OR, 0.45), older age (OR, 0.32), unmarried status (OR, 0.65), and regional disease (OR, 0.19) were significantly associated with decreased odds of suicidal death > 36 months after diagnosis. Those at highest risk for suicidal death include male gender, the elderly, white, unmarried, and patients with nonlocalized disease. These patients may benefit from targeted survivorship care plans.


Oral Microbiota in Infants Fed a Formula Supplemented with Bovine Milk Fat Globule Membranes - A Randomized Controlled Trial.
In a recent study, supplementation of infant formula with milk fat globule membranes (MFGM) decreased the incidence of otitis media in infants <6 months of age. The aim of the present study was to characterize the oral microbiota in infants fed MFGM-supplemented formula and compare it to that of infants fed standard formula or breast milk. In a prospective double-blinded randomized controlled trial, exclusively formula-fed infants <2 months of age were randomized to be fed experimental formula (EF, n = 80) with reduced energy and protein and supplemented with a bovine MFGM concentrate, or standard formula (SF, n = 80) until 6 months of age. A breast-fed reference (BFR, n = 80) group was also recruited. The oral microbiota was analyzed at 4 (n = 124) and 12 (n = 166) months of age using Illumina MiSeq multiplex sequencing and taxonomic resolution against the HOMD 16S rDNA database of oral bacteria. Species richness in the oral samples did not differ between the EF and SF groups, but partial least square modeling identified a few taxa that were significantly associated with being in either group, e.g. lower level of Moraxella catarrhalis in the EF group. Infants in the BFR group had significantly lower species richness at 4 months of age and their microbiota pattern differed markedly from the formula-fed groups. Supplementation of infant formula with MFGM yielded moderate effects on the oral microbiome. Moraxella catarrhalis was less prevalent in infants fed EF than in those fed SF and may be associated with the decrease in otitis media seen in the same group.


Does mirror imaging a radiograph affect reliability of age assessment using the Greulich and Pyle atlas?
Age estimation is routinely undertaken by comparing radiographs of the individual in question to published reference samples of individuals of known age. This study examines the reliability of age estimation utilizing the Greulich and Pyle atlas in relation to both left- and right-hand/wrist radiographs and explores whether reversing right-hand/wrist radiographs, so that they are in the same anatomical orientation as those images used in the atlas affects reliability. A total of 403 left-hand/wrist radiographs and 415 right-hand/wrist radiographs were age assessed using the Greulich and Pyle atlas. Analysis showed that there is no significant loss in reliability when radiographs of the right hand (women R(2) = 0.887 and men R(2) = 0.907) are utilized instead of the left (women R(2) = 0.939 and men R(2) = 0.940) or when they are assessed as mirror images to those printed in the reference atlas (reversed female left hand R(2) = 0.929 and reversed male left hand R(2) = 0.931).


The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium.
We have recently shown that the neuronal exchange factor p140 Ras-GRF becomes activated in vivo in response to elevated calcium levels [C. L. Farnsworth, N. W. Freshney, L. B. Rosen, A. Ghosh, M. E. Greenberg, and L. A. Feig, Nature (London) 376:524-527, 1995]. Activation is mediated by calcium-induced calmodulin binding to an IQ domain near the N terminus of Ras-GRF. Here we show that the adjacent N-terminal pleckstrin homology (PH), coiled-coil, and IQ domains function cooperatively to allow Ras-GRF activation. Deletion of the N-terminal PH domain redistributes a large percentage of Ras-GRF from the particulate to the cytosolic fraction of cells and renders the protein insensitive to calcium stimulation. A similar cellular distribution and biological activity are observed when only the core catalytic domain is expressed. Although the PH domain is necessary for particulate association of Ras-GRF, it is not sufficient for targeting the core catalytic domain to this cellular location. This requires the PH domain and the adjacent coiled-coil and IQ sequences. Remarkably, this form of Ras-GRF is constitutively activated. The PH and coiled-coil domains must also perform an additional function, since targeting to the particulate fraction of cells is not sufficient to allow Ras-GRF activation by calcium. A Ras-GRF mutant containing the PH domain from Ras-GTPase-activating protein in place of its own N-terminal PH domain localizes to the particulate fraction of cells but does not respond to calcium. Similar phenotypes are seen with mutant Ras-GRFs containing point mutations in either the PH or coiled-coil domain. These findings argue that the N-terminal PH, coiled-coil, and IQ domains of Ras-GRF function together to connect Ras-GRF to multiple components in the particulate fractions of cells that are required for responsiveness of the protein to calcium signaling.


Phosphatidylinositol 3-kinase: the oncoprotein.
The catalytic and regulatory subunits of class I phosphoinositide 3-kinase (PI3K) have oncogenic potential. The catalytic subunit p110α and the regulatory subunit p85 undergo cancer-specific gain-of-function mutations that lead to enhanced enzymatic activity, ability to signal constitutively, and oncogenicity. The β, γ, and δ isoforms of p110 are cell-transforming as overexpressed wild-type proteins. Class I PI3Ks have the unique ability to generate phosphoinositide 3,4,5 trisphosphate (PIP(3)). Class II and class III PI3Ks lack this ability. Genetic and cell biological evidence suggests that PIP(3) is essential for PI3K-mediated oncogenicity, explaining why class II and class III enzymes have not been linked to cancer. Mutational analysis reveals the existence of at least two distinct molecular mechanisms for the gain of function seen with cancer-specific mutations in p110α; one causing independence from upstream receptor tyrosine kinases, the other inducing independence from Ras. An essential component of the oncogenic signal that is initiated by PI3K is the TOR (target of rapamycin) kinase. TOR is an integrator of growth and of metabolic inputs. In complex with the raptor protein (TORC1), it controls cap-dependent translation, and this function is essential for PI3K-initiated oncogenesis.


Clinical Nursing Leadership Education in Long-Term Care: Intervention Design and Evaluation.
The main objective of the current case study was to investigate the perceived leadership learning needs and feasibility of delivering leadership education to registered staff involved in direct care in long-term care (LTC) homes. The study was conducted in Ontario, Canada, and participants included RNs, registered practical nurses, and nursing administrators. Phase 1 bilingual web-based survey and bilingual focus group needs assessment data supported a preference for external training along with in-house mentoring to support sustainability. An intervention designed using insights gained from Phase 1 data was delivered via a 2-day, in-person workshop. Phases 2 and 3 evaluation survey data identified aspects of leadership training for LTC that require ongoing refinement. Findings suggest that communication skills and managing day-to-day nursing demands in the context of regulatory frameworks were areas of particular interest for leadership training in the LTC setting. [Journal of Gerontological Nursing, 43(4), 49-56.].


Change in gut microbiota is correlated with alterations in the surface molecule expression of monocytes after Roux-en-Y gastric bypass surgery in obese type 2 diabetic patients.
Objectives: Persistent low-grade chronic inflammation is common in type 2 diabetes (T2D) and obesity. To date, the underlying molecular mechanism is not well understood. In this study, we aimed to investigate gut microbiota and the expression of monocyte surface molecules in obese T2D subjects who underwent Roux-en-Y gastric bypass (RYGB) surgery. Methods: Twenty-four T2D patients were enrolled. Gut microbiota was assessed by measuring bacterial DNA. The phenotypes and biological functions of monocytes, and the expression of monocyte surface molecules were examined by flow cytometry. Results: RYGB led to significant alterations in the phenotypes of monocytes. Moreover, the ability of monocyte migration was significantly decreased after RYGB (P<0.05), which was consistent with reduced Chemokine-receptors CCR2 expression of CD14+CD16+ monocytes (P<0.05) and CX3CR1 expression of the three monocytes subsets (P<0.05). RYGB also resulted in a shift of gut microbiota in the obese T2D patients. Spearman's rank correlation coefficient showed a link between gut microbiota and monocyte subsets where the increased Bacteroidetes was negatively correlated with the variation of CD14dimCD16+ monocyte percentage (r=-0.477, P<0.05). Furthermore, the decreased counts of Escherichia were positively correlated with the variation of TNF-α secretion (r=0.442, P<0.05) and TLR4 (r=0.425, P<0.05) expression onCD14+CD16+ monocytes. Conclusions: This study, for the first time, demonstrated a link between the changes in gut microbiota and alterations in both phenotypes and functions of monocytes after RYGB, which may contribute significantly to the low-grade chronic inflammation in obese T2D patients.


Classification of Discrete Dynamical Systems Based on Transients.
In order to develop systems capable of artificial evolution, we need to identify which systems can produce complex behavior. We present a novel classification method applicable to any class of deterministic discrete space and time dynamical systems. The method is based on classifying the asymptotic behavior of the average computation time in a given system before entering a loop. We were able to identify a critical region of behavior that corresponds to a phase transition from ordered behavior to chaos across various classes of dynamical systems. To show that our approach can be applied to many different computational systems, we demonstrate the results of classifying cellular automata, Turing machines, and random Boolean networks. Further, we use this method to classify 2D cellular automata to automatically find those with interesting, complex dynamics. We believe that our work can be used to design systems in which complex structures emerge. Also, it can be used to compare various versions of existing attempts to model open-ended evolution (Channon, 2006; Ofria & Wilke, 2004; Ray, 1991).


Magnetic bubble materials.
Physicists, materials scientists, and engineers combined to bring solid-state bubble devices into the computer memory and recording marketplace. Devices with smaller bubbles are being developed for increased data capacity and lower cost. Epitaxial garnet films made by isothermal dipping in molten solutions helped put the technology in place and will probably satisfy the material needs of future devices with bubbles scaled down from 2 to 0.5 micrometer in size.


Interdigestive gastric motility patterns: the role of vagal and nonvagal extrinsic innervation.
Our study was designed to determine separately the roles of vagal and nonvagal extrinsic innervation in the initiation and coordination of patterns of gastric contractile activity and in the organization of the gastric slow wave. Four dogs first underwent transection of all extrinsic and intrinsic neural continuity to the stomach, except for careful preservation of vagal innervation to the stomach (stage 1). Manometry catheters and serosal electrodes were placed in the antrum, and electrodes were fixed to the small intestine. After recovery, motility was recorded during fasting and after feeding. A cyclic motor pattern occurred in the stomach with a period that was not different from that of the migrating motor complex in the small intestine (113 +/- 11 minutes vs 112 +/- 11 minutes; p greater than 0.05). Gastric and intestinal motility remained coordinated in time. Feeding inhibited this cyclic motor pattern in stomach and intestine. Antral tachygastria (slow wave frequency greater than 8 cycles/min) was infrequent (less than 1% of time). Each animal was restudied after completing extrinsic gastric denervation by a transthoracic vagotomy (stage 2). Vagotomy did not alter the presence, appearance, or period of cyclic gastric activity, nor did it disrupt temporal coordination with the duodenal migrating motor complex or increase the prevalence of tachygastria. In conclusion, neither vagal nor nonvagal extrinsic innervation to the stomach was required for initiation or coordination of the characteristic cyclic gastric motility pattern during fasting; although vagal innervation may modulate gastric myoelectric activity, its precise role is not evident in this study.


The regulation of cysteine cathepsins and cystatins in human gliomas.
Cysteine cathepsins play an important role in shaping the highly infiltrative growth pattern of human gliomas. We have previously demonstrated that the activity of cysteine cathepsins is elevated in invasive glioblastoma (GBM) cells in vitro, in part due to attenuation of their endogenous inhibitors, the cystatins. To investigate this relationship in vivo, we established U87-MG xenografts in non-obese diabetic (NOD)/severe combined immunodeficiency (SCID)-enhanced green fluorescent protein (eGFP) mice. Here, tumor growth correlated with an elevated enzymatic activity of CatB both in the tumor core and at the periphery, whereas CatS and CatL levels were higher at the xenograft edge compared to the core. Reversely, StefB expression was detected in the tumor core, but it was generally absent in the tumor periphery, suggesting that down-regulation of this inhibitor correlates with in vivo invasion. In human GBM samples, all cathepsins were elevated at the tumor periphery compared to brain parenchyma. CatB was also typically associated with angiogenic endothelia and necrotic areas. StefB was mainly detected in the tumor core, whereas CysC and StefA were evenly distributed, reflecting the observations in the xenografts. However, at the mRNA level, no differences in cathepsins and cystatins were observed between the tumor center and the periphery in both human biopsies and xenografts. Interestingly, in human tumors, cathepsin and stefin transcript levels correlated with CD68 and CXCR4 levels, but not with epidermal growth factor receptor (EGFR). Moreover, we reveal for the first time that an elevated StefA mRNA level is a highly significant prognostic factor for patient survival.


Seasonal Shifts in Diet and Gut Microbiota of the American Bison (Bison bison).
North American bison (Bison bison) are becoming increasingly important to both grassland management and commercial ranching. However, a lack of quantitative data on their diet constrains conservation efforts and the ability to predict bison effects on grasslands. In particular, we know little about the seasonality of the bison diet, the degree to which bison supplement their diet with eudicots, and how changes in diet influence gut microbial communities, all of which play important roles in ungulate performance. To address these knowledge gaps, we quantified seasonal patterns in bison diet and gut microbial community composition for a bison herd in Kansas using DNA sequencing-based analyses of both chloroplast and microbial DNA contained in fecal matter. Across the 11 sampling dates that spanned 166 days, we found that diet shifted continuously over the growing season, allowing bison to take advantage of the seasonal availability of high-protein plant species. Bison consumed more woody shrubs in spring and fall than in summer, when forb and grass intake predominated. In examining gut microbiota, the bacterial phylum Tenericutes shifted significantly in relative abundance over the growing season. This work suggests that North American bison can continuously adjust their diet with a high reliance on non-grasses throughout the year. In addition, we find evidence for seasonal patterns in gut community composition that are likely driven by the observed dietary changes.


How important are human immunodeficiency virus (HIV) clinical markers to the long-term formal employment among people living with HIV in developing countries? A study in South Africa.
To examine the relationship of Human Immunodeficiency Virus (HIV) clinical markers and socio-demographic characteristics with long-term formal employment among people living with HIV (PLHIV). 554 adults, 55% females, on HIV treatment for at least two years at two public hospitals in Johannesburg, South Africa. A retrospective cohort design, tracing changes in study participants' formal employment status since the first HIV-positive diagnosis. Data collection included historical medical records review and interviewer-administered questionnaires. 44% of all study participants (39% and 49% among males and females, respectively) were formally employed at the time of the study, primarily in low-skilled jobs in the private sector. The majority (83%) of males and 60% of females remained in formal employment since being diagnosed as HIV-positive. Female gender, education to grade 12 or higher, a smaller household size and being married were significantly associated with current formal employment. Formal employment was unrelated to HIV treatment indicators (CD4 count, viral load and duration since diagnosis). Of those in formal employment, 68 (28%) were aware of HIV policies at their workplaces, which was also positively associated with the duration in their current employment. PLHIV in developing country contexts can enter into and maintain formal employment, especially when treatment and workplace support are available. Thus, employer organisations should implement effective workplace HIV policies to enhance employment experiences of their workforce living with HIV. Care and support services for people on HIV treatment should also address their career development needs.


Blue and red light modulates SigB-dependent gene transcription, swimming motility and invasiveness in Listeria monocytogenes.
In a number of gram-positive bacteria, including Listeria, the general stress response is regulated by the alternative sigma factor B (SigB). Common stressors which lead to the activation of SigB and the SigB-dependent regulon are high osmolarity, acid and several more. Recently is has been shown that also blue and red light activates SigB in Bacillus subtilis. By qRT-PCR we analyzed the transcriptional response of the pathogen L. monocytogenes to blue and red light in wild type bacteria and in isogenic deletion mutants for the putative blue-light receptor Lmo0799 and the stress sigma factor SigB. It was found that both blue (455 nm) and red (625 nm) light induced the transcription of sigB and SigB-dependent genes, this induction was completely abolished in the SigB mutant. The blue-light effect was largely dependent on Lmo0799, proving that this protein is a genuine blue-light receptor. The deletion of lmo0799 enhanced the red-light effect, the underlying mechanism as well as that of SigB activation by red light remains unknown. Blue light led to an increased transcription of the internalin A/B genes and of bacterial invasiveness for Caco-2 enterocytes. Exposure to blue light also strongly inhibited swimming motility of the bacteria in a Lmo0799- and SigB-dependent manner, red light had no effect there. Our data established that visible, in particular blue light is an important environmental signal with an impact on gene expression and physiology of the non-phototrophic bacterium L. monocytogenes. In natural environments these effects will result in sometimes random but potentially also cyclic fluctuations of gene activity, depending on the light conditions prevailing in the respective habitat.


Prevalence of Trypanosoma congolense and Trypanosoma vivax in Lira District, Uganda.
Trypanosomes are the causative agents of animal African trypanosomiasis (AAT) and human African trypanosomiasis (HAT), the former affecting domestic animals prevalent in Sub-Saharan Africa. The main species causing AAT in cattle are T. congolense, T. vivax, and T. b. brucei. Northern Uganda has been politically unstable with no form of vector control in place. The return of displaced inhabitants led to the restocking of cattle from AAT endemic areas. It was thus important to estimate the burden of trypanosomiasis in the region. This study was designed to compare the prevalence of animal African trypanosomes in cattle in Lira District using microscopy and polymerase chain reaction amplification (PCR) methods. In this cross-sectional study, a total of 254 cattle from the three villages of Acanakwo A, Barropok, and Acungkena in Lira District, Uganda, were selected by simple random sampling technique and screened for trypanosomiasis using microscopy and PCR methods. The prevalence of trypanosomiasis according to microscopic results was 5/254 (2.0%) as compared to 11/254 (4.3%) trypanosomiasis prevalence according to PCR analysis. The prevalence of trypanosomiasis infection in the animal studied is 11/254 (4.3%). Trypanosoma congolense was the most dominant trypanosome species with a proportion of 9/11 (81.8%), followed by T. vivax 1/11 (9.1%) and mixed infection of T. congolense/T. vivax1/11 (9.1%). Barropok village had the highest prevalence of trypanosomiasis with 6/11 (54.5%). There is a statistically significant relationship (OR = 6.041; 95% CI: 1.634-22.331; p < 0.05) between abnormal PCV and trypanosome infection. Polymerase reaction amplification was the most reliable diagnostic method due to its high sensitivity and specificity as compared to the conventional microscopic method. Polymerase reaction amplification appears to have adequate accuracy to substitute the use of a microscope where facilities allow. This study, therefore, underscores the urgent need for local surveillance schemes more especially at the grassroots in Uganda to provide data for reference guideline development needed for the control of trypanosomiasis in Uganda.


Prophylactic effects of the histamine H1 receptor antagonist epinastine and the dual thromboxane A2 receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells antagonist ramatroban on allergic rhinitis model in mice.
The prophylactic use of anti-allergic drugs has been proposed to be effective in the treatment of seasonal allergic rhinitis in humans. However, there is little information regarding the prophylactic effect of thromboxane A(2) (TXA(2)) receptor antagonist on allergic rhinitis. Recent studies revealed that a TXA(2) receptor antagonist ramatroban could block the prostaglandin D(2) (PGD(2)) receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). In the present study, we investigated the prophylactic effects of the histamine H(1) receptor antagonist epinastine and the TXA(2) receptor antagonist ramatroban and seratrodast on mouse models of allergic rhinitis. Female BALB/c mice were sensitized by an intraperitoneal injection of ovalbumin and alum on days 0, 5, 14 and 21. Seven days later, mice were sensitized by intranasal application of ovalbumin thrice a week. Drugs were administered once a day from day 22. The severity of allergic rhinitis was assessed by determining the extent of 2 nasal allergic symptoms (sneezing and nasal rubbing). Histamine sensitivity and eosinophil infiltration into the nasal mucosa were also determined. Epinastine and ramatroban significantly reduced nasal symptoms and the number of eosinophils in the nasal mucosa. Seratrodast showed no effect on nasal symptoms and eosinophil infiltration into the nasal mucosa. In addition, histamine sensitivity was reduced by epinastine and ramatroban. These results indicate that epinastine and ramatroban induce the prophylactic effect on allergic rhinitis.


Impact of clinical, psychological, and social factors on decreased Tinetti test score in community-living elderly subjects: a prospective study with two-year follow-up.
Balance and gait are essential to maintain physical autonomy, particularly in elderly people. Thus the detection of risk factors of balance and gait impairment appears necessary in order to prevent falls and dependency. The objective of this study was to analyze the impact of demographic, social, clinical, psychological, and biological parameters on the decline in balance and gait assessed by the Tinetti test (TT) after a two-year follow-up. This prospective study was conducted among community-living, young elderly volunteers in the centre "Investigations Preventives et Cliniques" and "Observatoire De l'Age" (Paris, France). Three hundred and forty-four participants aged 63.5 on average were enrolled and performed the TT twice, once at inclusion and again two years later. After the two-year follow-up, two groups were constituted according to whether or not there was a decrease in the TT score: the "TT no-deterioration" group comprised subjects with a decrease of less than two points and the "TT deterioration" group comprised those with a decrease of two points or more. Selected demographic, social, clinical, psychological, and biological parameters for the two groups were then compared. Statistical analysis showed that female sex, advanced age, high body mass index, osteoarticular pain, and a high level of anxiety all have a negative impact on TT score. Knowledge of predictive factors of the onset or worsening of balance and gait disorders could allow clinicians to detect young elderly people who should benefit from a specific prevention program.


Enhanced efficacy of photodynamic therapy after fractional resurfacing: fractional photodynamic rejuvenation.
Conventional ablative resurfacing is the gold standard for removing signs of cutaneous photodamage. Despite the excellent results one can achieve with this technique, it is accompanied with significant downtime and risks. Fractional resurfacing and photodynamic therapy (PDT) with aminolevulinic acid (ALA) have been used to improve the signs of photodamage with less downtime. However, independently they do not yield results as good as ablative resurfacing. This pilot study will examine the potential for synergistic effects of combining fractional resurfacing and ALA-PDT. Four women with Fitzpatrick skin types II or III, mild to moderate rhytides and no actinic keratosis in the perioral area were treated. The perioral area was treated with 2 sessions of fractional resurfacing with the Fraxel SR (formerly Fraxel SR750, Reliant Technologies Inc, Palo Alto, CA) 3 weeks apart. Immediately after each fractional treatment we applied methyl 5-aminolevulinate (MAL or Metvix) on one half of the perioral area and 3 hours later we illuminated that area with a red light (Aktilite lamp, PhotoCure ASA, Oslo, Norway) in a dose of 37 J/cm2. Prior to treatment and at 4 and 12 weeks after the final treatment, a blinded investigator evaluated each side of the perioral area and rated the improvement from baseline as excellent, good, fair, or poor improvement of superficial wrinkles by comparing the results with pretreatment photographs. Patients also completed an evaluation form assessing their satisfaction with the treatment on each side of the perioral area while comparing the results with pretreatment photographs. The study showed increased improvement in superficial wrinkles in 3 out of 4 patients on the combined treatment side. In one patient, the investigator found no significant difference when comparing both sides. All the patients noted greater improvement in the combined fractional and PDT-treated side compared to the side only treated with fractional surfacing. This pilot study shows a potential for enhanced clinical results when using combined fractional resurfacing and ALA-PDT compared to fractional resurfacing alone.


Effects of Noninhibitory Serpin Maspin on the Actin Cytoskeleton: A Quantitative Image Modeling Approach.
Recent developments in quantitative image analysis allow us to interrogate confocal microscopy images to answer biological questions. Clumped and layered cell nuclei and cytoplasm in confocal images challenges the ability to identify subcellular compartments. To date, there is no perfect image analysis method to identify cytoskeletal changes in confocal images. Here, we present a multidisciplinary study where an image analysis model was developed to allow quantitative measurements of changes in the cytoskeleton of cells with different maspin exposure. Maspin, a noninhibitory serpin influences cell migration, adhesion, invasion, proliferation, and apoptosis in ways that are consistent with its identification as a tumor metastasis suppressor. Using different cell types, we tested the hypothesis that reduction in cell migration by maspin would be reflected in the architecture of the actin cytoskeleton. A hybrid marker-controlled watershed segmentation technique was used to segment the nuclei, cytoplasm, and ruffling regions before measuring cytoskeletal changes. This was informed by immunohistochemical staining of cells transfected stably or transiently with maspin proteins, or with added bioactive peptides or protein. Image analysis results showed that the effects of maspin were mirrored by effects on cell architecture, in a way that could be described quantitatively.


Polymorphisms of four bone mineral density candidate genes in Chinese populations and comparison with other populations of different ethnicity.
Studies on polymorphisms of candidate genes and their association with bone mineral density (BMD) have been reported in many populations, but few have been reported in Chinese populations. We investigated polymorphisms of the following five commonly used markers of four prominent BMD candidate genes with the purpose of identifying useful genetic markers for osteoporosis genetic research in Chinese: the Sp1 and RsaI polymorphisms of the collagen type 1 alpha l (Col1a1) gene, the -174G/C promoter polymorphism of the interleukin 6 (IL-6) gene, the Asn363Ser polymorphism of the glucocorticoid receptor (GR) gene, and the T --> C polymorphism in intron 5 of the transforming growth factor beta(1) (TGF-beta(1)) gene. We evaluated these polymorphisms using PCR-RFLP in samples of at least 124 random individuals. We compared the polymorphisms of these five markers with other populations using the chi(2) test and Fisher's exact two-tailed test. For the RsaI polymorphism, only three heterozygotes but no variant homozygote were identified. For the -174G/C polymorphic site, only one GC heterozygote and no CC homozygote were found. Alleles s, Ser, and A(1) at the Sp1, Asn363Ser, and T --> C marker sites that have been found to be polymorphic in other populations were not found in Chinese. Significant differences of allele and genotype frequency distributions were observed at these polymorphisms ( P < 0.001) after comparing with other populations. Our results suggest that variant alleles of the five markers are absent or too rare to be useful genetic makers in Chinese, despite the fact that they have been commonly used as polymorphic markers in osteoporosis genetic research in other populations.


Evolutionary Growth of Genome Representations on Artificial Cellular Organisms with Indirect Encodings.
Evolutionary design targets systems of continuously increasing complexity. Thus, indirect developmental mappings are often a necessity. Varying the amount of genotype information changes the cardinality of the mapping, which in turn affects the developmental process. An open question is how to find the genotype size and representation in which a developmental solution would fit. A restricted pool of genes may not be large enough to encode a solution or may need complex heuristics to find a realistic size. On the other hand, using the whole set of possible regulatory combinations may be intractable. In nature, the genomes of biological organisms are not fixed in size; they slowly evolve and acquire new genes by random gene duplications. Such incremental growth of genome information can be beneficial also in the artificial domain. For an evolutionary and developmental (evo-devo) system based on cellular automata, we investigate an incremental evolutionary growth of genomes without any a priori knowledge on the necessary genotype size. Evolution starts with simple solutions in a low-dimensional space and incrementally increases the genotype complexity by means of gene duplication, allowing the evolution of scalable genomes that are able to adapt genetic information content while compactness and efficiency are retained. The results are consistent when the target phenotypic complexity, the geometry size, and the number of cell states are scaled up.


The effect of corneal irregularity on astigmatism measurement by automated versus ray tracing keratometry.
The aim of this study was to compare the effect of corneal irregularity on astigmatism assessment using automated keratometry (AK) (IOLMaster) versus ray tracing keratometry (Pentacam). This is an observational case series approved by the institutional review board of Dongguk University Hospital, Goyang, South Korea. A total of 207 eyes of 207 cataract patients were included. Preoperative corneal astigmatism was measured by both IOLMaster and Pentacam. Corneal irregularity index (IR) was calculated in Fourier analysis map of Pentacam. AK by IOLMaster and total corneal refractive power (TCRP, 3 mm and 4 mm zone analysis with pupil centered) by Pentacam were selected and the difference between the 2 measurements (delta Δ) was calculated using vector analysis. Ocular residual astigmatism (ORA) after cataract surgery was calculated by subtracting 6-month postoperative refractive astigmatism (RA) measurements from corresponding preoperative values (AK, TCRP3, and TCRP4). The mean irregularity index measured was 0.042 ± 0.019 mm (mean ± standard deviation) and was positively correlated with age and magnitude of corneal astigmatism (P < 0.001 and P < 0.05). The difference (Δ) between TCRPs and AK (ΔTCRPs-AK) was 0.43 ± 0.37 (TCRP3) and 0.39 ± 0.35 (TCRP4) diopters. Linear regression analysis revealed that age (P < 0.001), IR (P < 0.001), and AK (P < 0.001) were positively correlated with ΔTCRPs-AK. In highly irregular corneas (IR over 0.77 diopters: mean + 2 standard deviation), postoperative ORAs calculated using TCRPs were significantly lower than ORAs calculated using AK. Corneal irregularities significantly impact astigmatism assessment by IOLMaster (AK) and Pentacam (TCRPs). Compared with AK, TCRPs were more accurate in predicting postoperative residual astigmatism in highly irregular corneas.


Metabolomics of aging assessed in individual parasitoid wasps.
Metabolomics studies of low-biomass organisms, such as small insects, have previously relied on the pooling of biological samples to overcome detection limits, particularly using NMR. We show that the differentiation of metabolite profiles of individual 1 mg parasitoid wasps of different ages is possible when using a modified sample preparation and a combination of untargeted NMR and LC-MS based metabolomics. Changes were observed between newly emerged and older wasps in glycerolipids, amino acids and circulatory sugars. This advance in chemical profiling has important implications for the study of the behaviour and ecology of parasitoids and many other species of small organisms because predictions and observations are typically made at the level of the individual. Thus, the metabolomic state of low-biomass individuals can now be related to their behaviour and ecological performance. We discuss specifically the utility of age-related metabolomic profiling but our new approach can be applied to a wide range of biological research.


Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole.
The interim (12-month) results of two similarly designed, ongoing studies (the Zometa-Femara Adjuvant Synergy Trials [Z-FAST and ZO-FAST]) suggest that zoledronic acid (4 mg intravenously every 6 months) when initiated with adjuvant letrozole increases bone mineral density (BMD) of the lumbar spine (LS) in postmenopausal women with early-stage breast cancer compared with patients who receive zoledronic acid only when bone loss became clinically significant or a fragility fracture occurred. An integrated analysis was performed to maximize the value of the large pool of data from the two studies in answering clinically relevant questions. The primary objective was to compare the change in LS BMD at month 12. Secondary objectives included comparing (a) the change in total hip (TH) BMD, (b) changes in bone turnover marker concentrations, (c) time to disease recurrence, and (d) safety at month 12. The integrated analysis included 1,667 patients. At month 12, LS BMD was 5.2% higher in the upfront group than in the delayed group; TH BMD was 3.5% higher. N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 21.3% and 12.8% in the upfront group and increased by 21.7% and 24.9% in the delayed group, respectively (p < .0001 for intergroup comparisons). Fewer patients receiving upfront zoledronic acid experienced disease recurrence than patients in the delayed group-seven patients (0.84%) versus 17 patients (1.9%) (p = .0401). Fracture rates were similar. No confirmed osteonecrosis of the jaw was reported. The results of this analysis strengthen the statistical validity of the preliminary results of the Z-FAST and ZO-FAST studies, showing that upfront zoledronic acid prevents aromatase inhibitor-associated bone loss more effectively than delayed-start zoledronic acid in postmenopausal women with early-stage breast cancer receiving letrozole. Additionally, disease recurrence appears to be lower with upfront zoledronic acid, but further follow-up is needed to confirm these interim results.


First-passage fingerprints of water diffusion near glutamine surfaces.
The extent to which biological interfaces affect the dynamics of water plays a key role in the exchange of matter and chemical interactions that are essential for life. The density and the mobility of water molecules depend on their proximity to biological interfaces and can play an important role in processes such as protein folding and aggregation. In this work, we study the dynamics of water near glutamine surfaces-a system of interest in studies of neurodegenerative diseases. Combining molecular-dynamics simulations and stochastic modelling, we study how the mean first-passage time and related statistics of water molecules escaping subnanometer-sized regions vary from the interface to the bulk. Our analysis reveals a dynamical complexity that reflects underlying chemical and geometrical properties of the glutamine surfaces. From the first-passage time statistics of water molecules, we infer their space-dependent diffusion coefficient in directions normal to the surfaces. Interestingly, our results suggest that the mobility of water varies over a longer length scale than the chemical potential associated with the water-protein interactions. The synergy of molecular dynamics and first-passage techniques opens the possibility for extracting space-dependent diffusion coefficients in more complex, inhomogeneous environments that are commonplace in living matter.


Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking.
Hepatitis C virus (HCV) is a global health concern infecting 170 million people worldwide. Previous studies indicate that the extract from milk thistle known as silymarin and its main component silibinin inhibit HCV infection. Here we investigated the mechanism of anti-HCV action of silymarin-derived compounds at the molecular level. By using live-cell confocal imaging, single particle tracking, transmission electron microscopy and biochemical approaches on HCV-infected human hepatoma cells and primary hepatocytes, we show that silibinin potently inhibits HCV infection and hinders HCV entry by slowing down trafficking through clathrin-coated pits and vesicles. Detailed analyses revealed that silibinin altered the formation of both clathrin-coated pits and vesicles in cells and caused abnormal uptake and trafficking of transferrin, a well-known cargo of the clathrin endocytic pathway. Silibinin also inhibited infection by other viruses that enter cells by clathrin-mediated endocytosis including reovirus, vesicular stomatitis and influenza viruses. Our study demonstrates that silibinin inhibits HCV early steps of infection by affecting endosomal trafficking of virions. It provides new insights into the molecular mechanisms of action of silibinin against HCV entry and also suggests that silibinin is a potential broad-spectrum antiviral therapy.


An International, Multicenter, Observational Study of Cerebral Oxygenation during Infant and Neonatal Anesthesia.
General anesthesia during infancy is associated with neurocognitive abnormalities. Potential mechanisms include anesthetic neurotoxicity, surgical disease, and cerebral hypoxia-ischemia. This study aimed to determine the incidence of low cerebral oxygenation and associated factors during general anesthesia in infants. This multicenter study enrolled 453 infants aged less than 6 months having general anesthesia for 30 min or more. Regional cerebral oxygenation was measured by near-infrared spectroscopy. We defined events (more than 3 min) for low cerebral oxygenation as mild (60 to 69% or 11 to 20% below baseline), moderate (50 to 59% or 21 to 30% below baseline), or severe (less than 50% or more than 30% below baseline); for low mean arterial pressure as mild (36 to 45 mmHg), moderate (26 to 35 mmHg), or severe (less than 25 mmHg); and low pulse oximetry saturation as mild (80 to 89%), moderate (70 to 79%), or severe (less than 70%). The incidences of mild, moderate, and severe low cerebral oxygenation were 43%, 11%, and 2%, respectively; mild, moderate, and severe low mean arterial pressure were 62%, 36%, and 13%, respectively; and mild, moderate, and severe low arterial saturation were 15%, 4%, and 2%, respectively. Severe low oxygen saturation measured by pulse oximetry was associated with mild and moderate cerebral desaturation; American Society of Anesthesiology Physical Status III or IV versus I was associated with moderate cerebral desaturation. Severe low cerebral saturation events were too infrequent to analyze. Mild and moderate low cerebral saturation occurred frequently, whereas severe low cerebral saturation was uncommon. Low mean arterial pressure was common and not well associated with low cerebral saturation. Unrecognized severe desaturation lasting 3 min or longer in infants seems unlikely to explain the subsequent development of neurocognitive abnormalities.


An expanded cell wall damage signaling network is comprised of the transcription factors Rlm1 and Sko1 in Candida albicans.
The human fungal pathogen Candida albicans is constantly exposed to environmental challenges impacting the cell wall. Signaling pathways coordinate stress adaptation and are essential for commensalism and virulence. The transcription factors Sko1, Cas5, and Rlm1 control the response to cell wall stress caused by the antifungal drug caspofungin. Here, we expand the Sko1 and Rlm1 transcriptional circuit and demonstrate that Rlm1 activates Sko1 cell wall stress signaling. Caspofungin-induced transcription of SKO1 and several Sko1-dependent cell wall integrity genes are attenuated in an rlm1Δ/Δ mutant strain when compared to the treated wild-type strain but not in a cas5Δ/Δ mutant strain. Genome-wide chromatin immunoprecipitation (ChIP-seq) results revealed numerous Sko1 and Rlm1 directly bound target genes in the presence of caspofungin that were undetected in previous gene expression studies. Notable targets include genes involved in cell wall integrity, osmolarity, and cellular aggregation, as well as several uncharacterized genes. Interestingly, we found that Rlm1 does not bind to the upstream intergenic region of SKO1 in the presence of caspofungin, indicating that Rlm1 indirectly controls caspofungin-induced SKO1 transcription. In addition, we discovered that caspofungin-induced SKO1 transcription occurs through self-activation. Based on our ChIP-seq data, we also discovered an Rlm1 consensus motif unique to C. albicans. For Sko1, we found a consensus motif similar to the known Sko1 motif for Saccharomyces cerevisiae. Growth assays showed that SKO1 overexpression suppressed caspofungin hypersensitivity in an rlm1Δ/Δ mutant strain. In addition, overexpression of the glycerol phosphatase, RHR2, suppressed caspofungin hypersensitivity specifically in a sko1Δ/Δ mutant strain. Our findings link the Sko1 and Rlm1 signaling pathways, identify new biological roles for Sko1 and Rlm1, and highlight the complex dynamics underlying cell wall signaling.


Large scale purification of rapeseed proteins (Brassica napus L.).
Rapeseed (Brassica napus L.) cruciferin (12S globulin), napin (2S albumin) and lipid transfer proteins (LTP) were purified at a multi-g scale. The procedure developed was simple, rather fast and resolutive; it permitted the recovery of these proteins with a good yield, such as 40% for cruciferin and 18% for napin. Nanofiltration eliminated the major phenolic compounds. The remaining protein fraction was fractionated by cation exchange chromatography (CEC) on a streamline SP-XL column in alkaline conditions. The unbound neutral cruciferin was polished by size exclusion chromatography. The alkaline napin isoforms and LTP, adsorbed on the beads, were eluted as a whole fraction and further separated by an other CEC step at acidic pH. Napins were polished by hydrophobic interaction chromatography (HIC). The fractions were characterized by reverse phase HPLC, electrophoresis, N-terminal sequencing and mass spectrometry. All the fractions contained less than 5% of impurities.


3-Nitropropionic acid-induced ischemia tolerance in the rat brain is mediated by reduced metabolic activity and cerebral blood flow.
Tissue tolerance to ischemia can be achieved by noxious stimuli that are below a threshold to cause irreversible damage ('preconditioning'). Understanding the mechanisms underlying preconditioning may lead to the identification of novel therapeutic targets for diseases such as stroke. We here used the oxidative chain inhibitor 3-nitropropionic acid (NPA) to induce ischemia tolerance in a rat middle cerebral artery occlusion (MCAO) stroke model. Cerebral blood flow (CBF) and structural integrity were characterized by longitudinal magnetic resonance imaging (MRI) in combination with behavioral, histologic, and biochemical assessment of NPA-preconditioned animals and controls. Using this approach we show that the ischemia-tolerant state is characterized by a lower energy charge potential and lower CBF, indicating a reduced baseline metabolic demand, and therefore a cellular mechanism of neural protection. Blood vessel density and structural integrity were not altered by NPA treatment. When subjected to MCAO, preconditioned animals had a characteristic MRI signature consisting of enhanced CBF maintenance within the ischemic territory and intraischemic reversal of the initial cytotoxic edema, resulting in reduced infarct volumes. Thus, our data show that tissue protection through preconditioning occurs early during ischemia and indicate that a reduced cellular metabolism is associated with tissue tolerance to ischemia.


Diabetes and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: a pre-specified analysis from the randomised TROPICAL-ACS trial.
A guided de-escalation of P2Y12 inhibitor treatment is considered an alternative treatment strategy in ACS patients undergoing PCI. However, the safety and efficacy of this strategy may differ in diabetic vs non-diabetic patients. The aim of this study was to compare the outcomes of platelet function testing (PFT)-guided de-escalation of dual antiplatelet therapy (DAPT) in ACS patients with and without diabetes mellitus. The TROPICAL-ACS trial randomised 2,610 biomarker-positive ACS patients 1:1 to either standard treatment with prasugrel for 12 months (control group) or PFT-guided DAPT de-escalation. The association and interaction of diabetes on clinical endpoints across treatment groups and on platelet reactivity was investigated. In diabetic patients (n=527, 20.2%), the overall event rates were high and the one-year incidence of the primary endpoint (cardiovascular death, myocardial infarction, stroke or bleeding ≥grade 2) did not differ between guided de-escalation and control group patients (12.5% vs 10.8%; HR 1.17, 95% CI: 0.71-1.93, p=0.55). In non-diabetic patients (n=2,083, 79.8%), the one-year incidence of the primary endpoint was lower in the guided de-escalation vs control group (6.1% vs 8.5%; HR 0.71, 95% CI: 0.52-0.99, p=0.04, pint=0.10). Diabetic patients showed higher platelet reactivity levels in both control (=on prasugrel, p=0.01) and guided de-escalation group (=on clopidogrel, p=0.005) patients. Although diabetic status did not significantly interfere with the treatment effects of guided DAPT de-escalation, our results suggest that this approach might be safe and effective in non-diabetic patients. Further investigation is definitely warranted in diabetic patients.


Microstructure and optical properties of Al2O3 prepared by oblique deposition using microsphere shell templates.
We fabricated an orderly inclined Al2O3 column array using a hollow microsphere template. The microstructure and optical properties were investigated with scanning electron micrography and a UV/VIS spectrometer, respectively. Microsphere shell templates were formed using atomic layer deposition to prevent the melting of polystyrene microspheres during the following high-temperature deposition process. An inclined Al2O3 column array with a 30° tilt angle was grown by oblique deposition on a substrate with a 75.5° tilt angle with respect to the substrate normal. Birefringence and photonic crystalline behavior can be observed in the orderly inclined column array. The difference in the refractive indices between the p and s polarizations of the orderly inclined Al2O3 column array was about 0.1. The photonic properties of the crystal were enhanced compared to those of substrates without patterns.


Social contact behaviors are associated with infection status for Trichuris sp. in wild vervet monkeys (Chlorocebus pygerythrus).
Social grooming in the animal kingdom is common and serves several functions, from removing ectoparasites to maintaining social bonds between conspecifics. We examined whether time spent grooming with others in a highly social mammal species was associated with infection status for gastrointestinal parasites. Of six parasites detected, one (Trichuris sp.) was associated with social grooming behaviors, but more specifically with direct physical contact with others. Individuals infected with Trichuris sp. spent significantly less time grooming conspecifics than those not infected, and time in direct contact with others was the major predictor of infection status. One model correctly predicted infection status for Trichuris sp. with a reliability of 95.17% overall when the variables used were time spent in direct contact and time spent grooming others. This decrease in time spent grooming and interacting with others is likely a sickness behavior displayed by individuals with less energy or motivation for non-essential behaviors. This study emphasizes the possible links between host behavior and parasitic infections and highlights the need for an understanding of a study population's parasitic infections when attempting to interpret animal behavior.