Use of intravenous lipid emulsion to reverse central nervous system toxicity of an iatrogenic local anesthetic overdose in a patient on peritoneal dialysis.
To describe a case of severe central nervous system toxicity after an overdose of lidocaine by local infiltration in a peritoneal dialysis patient and subsequent treatment of the toxicity with lipid emulsion. A 31-year-old male received an iatrogenic overdose of 1600 mg of lidocaine 2% by infiltration during an attempt to remove and replace a peritoneal dialysis catheter. Within 10 minutes after the last lidocaine injection, the patient exhibited features of local anesthetic toxicity, which included tachycardia, hypertension, shortness of breath, dizziness, and a choking sensation that progressed to hallucinations, dysarthria, and uncoordinated, weak limb movement. Within 10 minutes after administration of a single 1.5-mg/kg intravenous bolus of 1.5 mL/kg [corrected], the patient improved dramatically. After observation overnight in a monitored care setting, the patient was discharged home with no apparent neurologic sequelae. Systemic toxicity due to regional anesthesia with local anesthetic agents such as lidocaine has been well described in the medical literature. The use of lipid emulsion as an antidote to the toxicity of local anesthetics and other lipophilic drugs has been suggested as a valuable intervention in both early, rapidly progressive toxicity, as well as toxicity that is refractory to standard treatment. Patients with advanced chronic kidney disease may be more susceptible to systemic effects of lidocaine due to decreased drug elimination. Central nervous system toxicity due to an overdose of lidocaine was quickly reversed by intravenous lipid emulsion in our patient.


Tunable transition from hydration to monomer-supported lubrication in zwitterionic monolayers revealed by molecular dynamics simulation.
The tribology of 2-methacryloyloxyethyl phosphorylcholine monolayers in water is studied using molecular dynamics simulations. Our results show two distinct shear regimes where the first is dominated by hydration lubrication, exhibiting near zero friction coefficients, and the second by chain-chain interactions, resembling monomer-supported lubrication. These results provide insight into the hydration lubrication mechanism - a phenomena thought to underlie the extremely efficient lubrication provided by surfaces functionalized with polyzwitterionic polymer brushes and the mammalian synovial joint.


Control of Microthrix parvicella and sludge bulking by ozone in a full-scale WWTP.
Bulking and rising sludge are common problems in wastewater treatment plants (WWTPs) and are primarily caused by increased growth of filamentous bacteria such as Microthrix parvicella. It has a negative impact on sludge settling properties in activated sludge (AS) process, in addition to being responsible for foam formation. Different methods can be used to control sludge bulking. The aim of this study was to evaluate the dosage of on-site generated ozone in the recycled AS flow in a full-scale WWTP having problems caused by M. parvicella. The evaluation of the experiment was assessed by process data, microscopic analysis and microbial screening on the experimental and control line before, during and after the period of ozone dosage. The ozone treatment resulted in decreased abundance of M. parvicella and improved the settling properties, without impairing the overall process performance. Both chemical oxygen demand (COD)- and N-removal were unaffected and the dominant populations involved in nitrification, as analysed by fluorescent in situ hybridization, remained during the experimental period. When the ozone treatment was terminated, the problems with sludge bulking reappeared, indicating the importance of continuous evaluation of the process.


Linear optical pulse compression based on temporal zone plates.
We propose and demonstrate time-domain equivalents of spatial zone plates, namely temporal zone plates, as alternatives to conventional time lenses. Both temporal intensity zone plates, based on intensity-only temporal modulation, and temporal phase zone plates, based on phase-only temporal modulation, are introduced and studied. Temporal zone plates do not exhibit the limiting tradeoff between temporal aperture and frequency bandwidth (temporal resolution) of conventional linear time lenses. As a result, these zone plates can be ideally designed to offer a time-bandwidth product (TBP) as large as desired, practically limited by the achievable temporal modulation bandwidth (limiting the temporal resolution) and the amount of dispersion needed in the target processing systems (limiting the temporal aperture). We numerically and experimentally demonstrate linear optical pulse compression by using temporal zone plates based on linear electro-optic temporal modulation followed by fiber-optics dispersion. In the pulse-compression experiment based on temporal phase zone plates, we achieve a resolution of ~25.5 ps over a temporal aperture of ~5.77 ns, representing an experimental TBP larger than 226 using a phase-modulation amplitude of only ~0.8π rad. We also numerically study the potential of these devices to achieve temporal imaging of optical waveforms and present a comparative analysis on the performance of different temporal intensity and phase zone plates.


The natural history of early-onset dementia: the Artemis Project.
The natural history of early-onset Alzheimer's disease (AD) and fronto-temporal dementia (FTD) remains to be described in detail. We seek to describe the natural history of early onset AD and FTD in terms of changes in cognitive assessment and staging, medical history and survival. Longitudinal prospective cohort analysis. Neurodegenerative disorders research clinic. In total, 155 consecutive patients with clinically confirmed sporadic early-onset AD or FTD at a neurodegenerative disorders research clinic in Subiaco, Western Australia (The Artemis Project). A detailed history was recorded from the patients at baseline, including education, family history and medical history. Mini-mental state exam (MMSE), Global Deterioration Scale (GDS) and total functional capacity (TFC) were determined at each visit from 1994 until 2011. Kaplan-Meier survival analysis was performed. Patients with FTD were more likely to have a family history of dementia (p=0.026), to develop at least one cerebrovascular risk factor (p=0.003), manifest depression (Fisher's exact p=0.007) and to die during the follow-up period (Pearson χ(2) 8.97, p=0.003). Kaplan-Meier survival estimates revealed a highly significant difference in the proportion of patients surviving the follow-up period (log rank 7.25, p=0.007) with FTD patients experiencing poorer survival than those with AD. The mean MMSE and TFC were consistently lower in those with FTD compared with those with AD over a decade of follow-up; mean GDS was consistently higher in those with FTD over the follow-up period. We believe that the difference in survival in patients with AD and FTD in our cohort might relate to the development of one or more cerebrovascular risk factors in FTD patients and the severity of the underlying pathology.


Denaturing gradient gel electrophoresis of neonatal intestinal microbiota in relation to the development of asthma.
The extended 'hygiene hypothesis' suggests that the initial composition of the infant gut microbiota is a key determinant in the development of atopic disease. Several studies have demonstrated that the microbiota of allergic and non-allergic infants are different even before the development of symptoms, with a critical time window during the first 6 months of life. The aim of the study was to investigate the association between early intestinal colonisation and the development of asthma in the first 3 years of life using DGGE (denaturing gradient gel electrophoresis). In a prospective birth cohort, 110 children were classified according to the API (Asthma Predictive Index). A positive index included wheezing during the first three years of life combined with eczema in the child in the first years of life or with a parental history of asthma. A fecal sample was taken at the age of 3 weeks and analysed with DGGE using universal and genus specific primers. The Asthma Predictive Index was positive in 24/110 (22%) of the children. Using universal V3 primers a band corresponding to a Clostridum coccoides XIVa species was significantly associated with a positive API. A Bacteroides fragilis subgroup band was also significantly associated with a positive API. A final DGGE model, including both bands, allowed correct classification of 73% (80/110) of the cases. Fecal colonisation at age 3 weeks with either a Bacteroides fragilis subgroup or a Clostridium coccoides subcluster XIVa species is an early indicator of possible asthma later in life. These findings need to be confirmed in a new longitudinal follow-up study.


Me, Myself and My Brain Implant: Deep Brain Stimulation Raises Questions of Personal Authenticity and Alienation.
In this article, I explore select case studies of Parkinson patients treated with deep brain stimulation (DBS) in light of the notions of alienation and authenticity. While the literature on DBS has so far neglected the issues of authenticity and alienation, I argue that interpreting these cases in terms of these concepts raises new issues for not only the philosophical discussion of neuro-ethics of DBS, but also for the psychological and medical approach to patients under DBS. In particular, I suggest that the experience of alienation and authenticity varies from patient to patient with DBS. For some, alienation can be brought about by neurointerventions because patients no longer feel like themselves. But, on the other hand, it seems alienation can also be cured by DBS as other patients experience their state of mind as authentic under treatment and retrospectively regard their former lives without stimulation as alienated. I argue that we must do further research on the relevance of authenticity and alienation to patients treated with DBS in order to gain a deeper philosophical understanding, and to develop the best evaluative criterion for the behavior of DBS patients.


Lack of Sphenoid Pneumatization Does Not Affect Endoscopic Endonasal Pediatric Skull Base Surgery Outcomes.
Currently, due to the rarity of pathology, there are limited data surrounding outcomes of pediatric skull base surgery. Traditionally, surgeons have proceeded with caution when electing endonasal endoscopic transsellar/transplanum approaches to the skull base in pediatric patients due to poor sphenoid pneumatization. In this study, we review outcomes of endoscopic pediatric skull base surgery based on sphenoid pneumatization patterns. Retrospective chart review. A review of all cases of pediatric (age < 18 years) craniopharyngioma managed via an endoscopic endonasal approach at a tertiary academic medical center. A total of 27 patients were included in the analysis. The median age was 8 years. Nineteen (70%) patients were male. Presellar, sellar/postsellar, and conchal sphenoid pneumatizations were found in 6, 11, and 10 patients, respectively. There was no significant association between sphenoid pneumatization pattern and extent of resection (gross vs. subtotal, P = .414), postoperative cerebrospinal fluid (CSF) leak (P = .450), intraoperative estimated blood loss (P = .098), total operative time (P = .540), and length of stay (P = .336). On multivariate analysis, after accounting for age, sex, preoperative cranial nerve involvement, and cavernous sinus invasion, there remained no significant association between sphenoid pneumatization pattern and extent of resection (P = .999) and postoperative CSF leak (P = .959). Sphenoid pneumatization pattern does not appear to affect outcomes in endoscopic skull base surgery in the pediatric population. Importantly, lack of sphenoid pneumatization does not impede gross total resection or increase complications. Thorough knowledge of the anatomy during the endoscopic approach is critical to optimize outcomes. 4 Laryngoscope, 129:832-836, 2019.


A strategy to assemble nanoparticles with polymers for mitigating cytotoxicity and enabling size tuning.
We aim to develop a facile strategy for assembling nanoparticles within cross-linked polymer micelles that enables tuning of their overall hydrodynamic size and surface charge and to mitigate toxicity. Hydrophobic nanoparticles and amphiphilic co-polymers self-assembled upon solvent-selective precipitation. Size-tunability of the assembled nanostructure was achieved by controlling both the nanoparticle and polymer ratio and the kinetics of the assembly process. We were successful in creating polymer shells on the surface of inorganic nanoparticles. The shell thickness could be tuned, and protect the nanoparticles from environmental degradation and minimize the cytotoxicity of inorganic nanoparticles. This strategy provides a method to engineer the interactions of nanoparticles with biological systems, including their targeted delivery to diseased tissues and their safety of use without significantly altering their original materials properties.


The fall and rise of Group A Streptococcus diseases.
Streptococcus pyogenes (or Group A Streptococcus, GAS) is a Gram-positive human pathogen responsible for a diverse array of superficial, invasive and immune-related diseases. GAS infections have historically been diseases of poverty and overcrowding, and remain a significant problem in the developing world and in disadvantaged populations within developed countries. With improved living conditions and access to antibiotics, the rates of GAS diseases in developed societies have gradually declined during the 20th century. However, genetic changes in circulating GAS strains and/or changes in host susceptibility to infection can lead to dramatic increases in the rates of specific diseases. No situations exemplify this more than the global upsurge of invasive GAS disease that originated in the 1980s and the regional increases in scarlet fever in north-east Asia and the UK. In each case, increased disease rates have been associated with the emergence of new GAS strains with increased disease-causing capability. Global surveillance for new GAS strains with increased virulence is important and determining why certain populations suddenly become susceptible to circulating strains remains a research priority. Here, we overview the changing epidemiology of GAS infections and the genetic alterations that accompany the emergence of GAS strains with increased capacity to cause disease.


Older lesbian and gay adults' perceptions of barriers and facilitators to accessing health and aged care services in Australia.
Older lesbian and gay people can face considerable marginalisation, which may affect their perceptions and experiences of accessing health and aged care services. To inform strategies promoting accessibility, this study aimed to investigate perceived barriers and facilitators to health and aged care service access among older lesbian and gay adults. A sample of 752 cisgender lesbian women and gay men aged 60 years and older living in Australia responded to questions on a broad range of potential barriers and facilitators to service access. Several barriers and facilitators were commonly reported, with some differences between the women and the men. LGBTI inclusiveness was among commonly reported concerns. A majority of participants reported a lack of LGBTI-inclusive service providers and professionals as a barrier. A majority also reported a perceived lack of professionals adequately trained and competent to work with LGBTI individuals, with significantly more women than men indicating this as a barrier. Almost all participants indicated LGBTI-inclusive mainstream services as a facilitator for access. In all, inclusiveness appears to be a key issue for service access among older lesbian and gay people, which may need to be further addressed by service providers and policy makers for improving service accessibility.


Physician self-referral and imaging use appropriateness: negative cervical spine MRI frequency as an assessment metric.
Imaging self-referral is increasingly cited as a contributor to diagnostic imaging overuse. The purpose of this study was to determine whether ownership of MR imaging equipment by ordering physicians influences the frequency of negative cervical spine MR imaging findings. A retrospective review was performed of 500 consecutive cervical spine MRIs ordered by 2 separate referring-physician groups serving the same geographic community. The first group owned the scanners used and received technical fees for their use, while the second group did not. Final reports were reviewed, and for each group, the percentage of negative study findings and the frequency of abnormalities were calculated. The number of concomitant shoulder MRIs was recorded. Five hundred MRIs meeting inclusion criteria were reviewed (250 with financial interest, 250 with no financial interest). Three hundred fifty-two had negative findings (190 with financial interest, 162 with no financial interest); there were 17.3% more scans with negative findings in the financial interest group (P = .006). Among scans with positive findings, there was no significant difference in the mean number of lesions per scan, controlled for age (1.90 with financial interest, 2.19 with no financial interest; P = .23). Patients in the financial interest group were more likely to undergo concomitant shoulder MR imaging (24 with financial interest, 11 with no financial interest; P = .02). Cervical spine MRIs referred by physicians with a financial interest in the imaging equipment used were significantly more likely to have negative findings. There was otherwise a highly similar distribution and severity of disease between the 2 patient samples. Patients in the financial interest group were more likely to undergo concomitant shoulder MR imaging.


Seroprevalence of Cysticercosis among Epileptic Patients Attending Neurological Units in the Urban Area of Abidjan.
Cysticercosis is one of the main causes of secondary epilepsy in sub-Saharan Africa. To estimate the seroprevalence of cysticercosis among epileptic patients, we conducted a cross-sectional study of patients attending neurology consultation in Abidjan, Côte d'Ivoire. Methods: Patients' socio-demographic and lifestyle data were collected as well as blood samples for serological testing using ELISA and Western blot based on IgG antibodies detection. For qualitative variables comparison, Chi2 or Fisher tests were used; a Student's t-test was used to compare quantitative variables. A multivariate logistic regression model was fit to identify risks factors. Results: Among 403 epileptic patients included in the study, 55.3% were male; the median age was 16.9 years; 77% lived in Abidjan; 26.5% were workers. Most patients included in the study had tonic-clonic seizures (80%), and 11.2% had focal deficit signs. The seroprevalence of cysticercosis was 6.0%. The risk was higher in patients over 30 years old (aOR = 5.1 (1.3-20.0)) than in patients under 16. The risk was also considerably high in patients who reported epileptics in the family (aOR = 5 (1.7-14.6)). The risk was three-fold less in females than in males. Conclusions: This study highlighted the exposure of epileptic patients to Taenia solium larvae in an urban area. The risk of positive serology was increased with age, male gender, and family history of epilepsy.


The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.
Serotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression. We typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype. There were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction. Regardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.


Effect of age on the pharmacokinetics and distribution of tulathromycin in interstitial and pulmonary epithelial lining fluid in healthy calves.
OBJECTIVE To compare the plasma pharmacokinetics of tulathromycin between 3-week-old (preweaned) and 6-month-old (weaned) calves and to characterize the distribution of tulathromcyin into pulmonary epithelial lining fluid (PELF) and interstitial fluid (ISF) of preweaned and weaned calves following SC administration of a single dose (2.5 mg/kg). ANIMALS 8 healthy 3-week-old and 8 healthy 6-month-old Holstein steers. PROCEDURES A jugular catheter and SC ultrafiltration probe were aseptically placed in the neck of each calf before tulathromycin administration. Blood, ISF, and bronchoalveolar lavage fluid samples were collected at predetermined times before and after tulathromycin administration for quantification of drug concentration. A urea dilution method was used to estimate tulathromycin concentration in PELF from that in bronchoalveolar lavage fluid. Tulathromycin-plasma protein binding was determined by in vitro methods. Plasma pharmacokinetics were determined by a 2-compartment model. Pharmacokinetic parameters and drug concentrations were compared between preweaned and weaned calves. RESULTS Clearance and volume of distribution per fraction of tulathromycin absorbed were significantly greater for weaned calves than preweaned calves. Tulathromycin-plasma protein binding was significantly greater for weaned calves than preweaned calves. Maximum PELF tulathromycin concentration was significantly greater than the maximum plasma and maximum ISF tulathromycin concentrations in both groups. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that age affected multiple pharmacokinetic parameters of tulathromycin, likely owing to physiologic changes as calves mature from preruminants to ruminants. Knowledge of those changes may be useful in the development of studies to evaluate potential dose adjustments during treatment of calves with respiratory tract disease.


Korean Red Ginseng Pretreatment Protects Against Long-Term Sensorimotor Deficits After Ischemic Stroke Likely Through Nrf2.
Endogenous neuroprotective mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research, ultimately facilitating functional recovery. Transcriptional factor Nrf2, enriched in astrocytes, is a master regulator of endogenous defense systems against oxidative stress and inflammation. Korean Red Ginseng (Ginseng), one most widely used herbal medicine, has exhibited promising potentials in neuroprotection. Our study aimed to determine whether the standardized Ginseng extract pretreatment could attenuate acute sensorimotor deficits and improve long-term functional recovery after ischemic stroke though Nrf2 pathway and whether reactive astrogliosis is associated with such effect. Adult Nrf2-/- and matched wildtype control (WT) mice were pretreated with Ginseng orally for 7 days prior to permanent distal middle cerebral artery occlusion (pdMCAO). Using an optimized method that can accurately assess either severe or mild pdMCAO-induced sensorimotor deficits, neurobehavioral tests were performed over 28 days. The progression of lesion volume and the evolution of astrocytic and microglial activation were determined in the acute stage of ischemic stroke after pdMCAO (0-3 days). Nrf2-downstream target antioxidant genes expression levels was assessed by Western blot. We found that Ginseng pretreatment ameliorated acute sensorimotor deficits and promoted long-term functional recovery, prevented the acute enlargement of lesion volume (36.37 ± 7.45% on day 3), attenuated reactive astroglial progression but not microglia activation, and enhanced the induction of Nrf2-downstream target proteins after ischemic insult in WT mice, an effect which was lost in Nrf2 knockouts. The spatiotemporal pattern of reactive astrogliosis evaluation correlated well with acute ischemic damage progression in an Nrf2-dependent fashion during the acute phase of ischemia. In contrast, Nrf2 deficiency mice exhibited exacerbated ischemic condition compared to WT controls. Together, Ginseng pretreatment protects against acute sensorimotor deficits and promotes its long-term recovery after pdMCAO, at least partly, through Nrf2 activation, highlighting the potential efficacy of oral consumption of Ginseng for stroke preventative intervention in patients who are at great risk of recurrent stroke or transient ischemic attack. The attenuated reactive astrogliosis contributes to the Nrf2 pathway related neuroprotection against acute ischemic outcome and substantially long-term sensorimotor deficits in the context of ischemic stroke under pdMCAO.


Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes.
Motor vehicle crashes (MVCs) are a major public health problem. Research has demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to experience MVCs, but the effect of ADHD medication treatment on the risk of MVCs remains unclear. To explore associations between ADHD medication use and risk of MVCs in a large cohort of patients with ADHD. For this study, a US national cohort of patients with ADHD (n = 2 319 450) was identified from commercial health insurance claims between January 1, 2005, and December 31, 2014, and followed up for emergency department visits for MVCs. The study used within-individual analyses to compare the risk of MVCs during months in which patients received ADHD medication with the risk of MVCs during months in which they did not receive ADHD medication. Dispensed prescription of ADHD medications. Emergency department visits for MVCs. Among 2 319 450 patients identified with ADHD, the mean (SD) age was 32.5 (12.8) years, and 51.7% were female. In the within-individual analyses, male patients with ADHD had a 38% (odds ratio, 0.62; 95% CI, 0.56-0.67) lower risk of MVCs in months when receiving ADHD medication compared with months when not receiving medication, and female patients had a 42% (odds ratio, 0.58; 95% CI, 0.53-0.62) lower risk of MVCs in months when receiving ADHD medication. Similar reductions were found across all age groups, across multiple sensitivity analyses, and when considering the long-term association between ADHD medication use and MVCs. Estimates of the population-attributable fraction suggested that up to 22.1% of the MVCs in patients with ADHD could have been avoided if they had received medication during the entire follow-up. Among patients with ADHD, rates of MVCs were lower during periods when they received ADHD medication. Considering the high prevalence of ADHD and its association with MVCs, these findings warrant attention to this prevalent and preventable cause of mortality and morbidity.


Predictive value of sperm deoxyribonucleic acid (DNA) fragmentation index in male infertility.
Recently, damage to the sperm DNA has been studied as it is associated with reduced fertilization rates, embryo quality, and pregnancy rates, also higher rates of spontaneous miscarriage. To develop a diagnostic method in predicting male infertility. The design of this study is cross-sectional. Data were retrieved from medical records of Yasmin IVF Clinic Dr. Cipto Mangunkusumo General Hospital and Daya Medika Infertility Clinic from January to December 2015. Subjects were selected by consecutive sampling and divided into two groups: infertile and fertile. Sperm deoxyribonucleic acid fragmentation index (DFI) was determined by sperm chromatin dispersion (SCD) method using Halosperm® Kit. There were 114 subjects (36 fertile and 78 infertile) selected into this study. We found no significant difference in the age between both of groups. The median value of sperm DFI in infertile group was significantly higher, 29.95 (26.6-34.3)%, compared to 19.90 (15.6-24.4)% of the fertile group, with p < 0.001. Area Under Curve (AUC) of sperm DFI, 0.862 (95% CI 0.783, 0.941), was higher than concentration (AUC 0.744; 95% CI 0.657, 0.831), motility (AUC 0.668; 95% CI 0.572, 0.765), and morphology (AUC 0.718; 95% CI 0.697, 0.864) of the semen analysis. At the cut-off point of 26.1%, the sperm DFI had sensitivity of 80.8% (95% CI; 70.0, 88.5), specificity of 86.1% (95% CI; 69.7, 94.8), positive predictive value (PPV) of 92.6% (95% CI; 83.0, 97.3), negative predictive value (NPV) of 67.4% (95% CI; 51.9, 80.0), positive likelihood ratio (PLR) of 12.6 (95% CI; 5.4, 29.4), and negative likelihood ratio (NLR) of 0.48 (95% CI 0.31, 0.75). Sperm DFI of ≥26.1% had prevalence ratio of 2.84 (95% CI 1.86, 4.33) for the occurrence of male infertility. There was significant difference between the median value of sperm DFI of infertile men and fertile men. Compared to semen analysis, sperm DFI at cut-off point of 26.1% has a higher diagnostic value (AUC).


The fine-scale genetic structure of the British population.
Fine-scale genetic variation between human populations is interesting as a signature of historical demographic events and because of its potential for confounding disease studies. We use haplotype-based statistical methods to analyse genome-wide single nucleotide polymorphism (SNP) data from a carefully chosen geographically diverse sample of 2,039 individuals from the United Kingdom. This reveals a rich and detailed pattern of genetic differentiation with remarkable concordance between genetic clusters and geography. The regional genetic differentiation and differing patterns of shared ancestry with 6,209 individuals from across Europe carry clear signals of historical demographic events. We estimate the genetic contribution to southeastern England from Anglo-Saxon migrations to be under half, and identify the regions not carrying genetic material from these migrations. We suggest significant pre-Roman but post-Mesolithic movement into southeastern England from continental Europe, and show that in non-Saxon parts of the United Kingdom, there exist genetically differentiated subgroups rather than a general 'Celtic' population.


Humoral and cell-mediated autoimmunity in allergy to Aspergillus fumigatus.
A cDNA encoding an allergenic protein was isolated from an Aspergillus fumigatus (A. fumigatus) cDNA library displayed on the surface of filamentous phage. Serum immunoglobulin E (IgE) from A. fumigatus-sensitized individuals was used to enrich phage-expressing gene products binding to IgE. One of the cDNAs encoded a 26.7-kD protein that was identified as a manganese superoxide dismutase (MnSOD) sharing 51.5% identity and 67.2% homology to the corresponding human enzyme. Both human and A. fumigatus MnSOD coding sequences were expressed in Escherichia coli as [His]6-tagged fusion proteins and purified by Ni(2+)-chelate affinity chromatography. The two recombinant MnSODs were both recognized by IgE antibodies from subjects allergic to the A. fumigatus MnSOD and elicited specific immediate type allergic skin reactions in these individuals. Moreover, both human and A. fumigatus MnSOD induced proliferation in peripheral blood mononuclear cells of A. fumigatus-allergic subjects who showed specific IgE responses and reacted in skin tests to MnSOD. These observations provide evidence for autoreactivity to the human MnSOD in allergic persons sensitized to an environmental allergen from A. fumigatus who share a high degree of sequence homology to the corresponding human enzyme.


Diffusion-tensor imaging of human articular cartilage specimens with early signs of cartilage damage.
To assess the use of diffusion-tensor (DT) imaging of articular cartilage to detect and grade early cartilage damage in human specimens with early signs of cartilage damage. This study was approved by the institutional review board. Forty-three cartilage-on-bone samples drilled from 21 human patellae were examined with 17.6-T magnetic resonance (MR) imaging and a diffusion-weighted spin-echo sequence (spatial resolution, 50 × 100 × 800 μm). Subsequently, samples underwent histologic analysis with safranin O staining. Cartilage damage on safranin O histologic slides was quantified with Osteoarthritis Research Society International (OARSI) grades; grades ranged from 0 (healthy) to 6 (bone remodeling). Maps of longitudinal diffusivity (λ(l)), transverse diffusivity (λ(t)), mean diffusivity (MD), and fractional anisotropy (FA) were calculated. Cartilage was segmented, and region of interest (ROI) analysis was performed and compared with histologic findings. Significant differences in MR parameters between the OARSI groups were assessed with the Tukey test. The value of DT imaging in the diagnosis and grading of cartilage damage was assessed with logistic regression analysis. Samples had OARSI grades of 0 (n = 14), 1 (n = 11), 2 (n = 12), 3 (n = 4), and 4 (n = 2). Samples with an OARSI grade greater than 0 had significantly increased λ(l), λ(t), and MD (7%-25% increase) in the superficial cartilage growing deeper into cartilage with increasing OARSI grade. Samples with an OARSI grade greater than 0 showed significantly decreased FA in the deep cartilage (-25% to -35% decrease), suggesting that changes in the collagen architecture may occur early in cartilage degradation. DTI showed excellent performance in the detection of cartilage damage (accuracy, 0.95; 41 of 43 samples) and good performance in the grading of cartilage damage (accuracy, 0.74; 32 of 43 samples). DT imaging of articular cartilage can enable physicians to detect and grade early cartilage damage.


Relationships between species feeding traits and environmental conditions in fish communities: a three-matrix approach.
Understanding the relationships between species biological traits and the environment is crucial to predicting the effect of habitat perturbations on fish communities. It is also an essential step in the assessment of the functional diversity. Using two complementary three-matrix approaches (fourth-corner and RLQ analyses), we tested the hypothesis that feeding-oriented traits determine the spatial distributions of littoral fish species by assessing the relationship between fish spatial distributions, fish species traits, and habitat characteristics in two Laurentian Shield lakes. Significant associations between the feeding-oriented traits and the environmental characteristics suggested that fish communities in small lakes (displaying low species richness) can be spatially structured. Three groups of traits, mainly categorized by the species spatial and temporal feeding activity, were identified. The water column may be divided in two sections, each of them corresponding to a group of traits related to the vertical distribution of the prey coupled with the position of the mouth. Lake areas of low structural complexity were inhabited by functional assemblages dominated by surface feeders while structurally more complex areas were occupied by mid-water and benthic feeders. A third group referring to the time of feeding activity was observed. Our work could serve as a guideline study to evaluate species traits x environment associations at multiple spatial scales. Our results indicate that three-matrix statistical approaches are powerful tools that can be used to study such relationships. These recent statistical approaches open up new research directions such as the study of spatially based biological functions in lakes. They also provide new analytical tools for determining, for example, the potential size of freshwater protected areas.


Cucurbitacin E reduces obesity and related metabolic dysfunction in mice by targeting JAK-STAT5 signaling pathway.
Several members of cucurbitaceae family have been reported to regulate growth of cancer by interfering with STAT3 signaling. In the present study, we investigated the unique role and molecular mechanism of cucurbitacins (Cucs) in reducing symptoms of metabolic syndrome in mice. Cucurbitacin E (CuE) was found to reduce adipogenesis in murine adipocytes. CuE treatment diminished hypertrophy of adipocytes, visceral obesity and lipogenesis gene expression in diet induced mice model of metabolic syndrome (MetS). CuE also ameliorated adipose tissue dysfunction by reducing hyperleptinemia and TNF-alpha levels and enhancing hypoadiponectinemia. Results show that CuE mediated these effects by attenuating Jenus kinase- Signal transducer and activator of transcription 5 (JAK- STAT5) signaling in visceral fat tissue. As a result, CuE treatment also reduced PPAR gamma expression. Glucose uptake enhanced in adipocytes after stimulation with CuE and insulin resistance diminished in mice treated with CuE, as reflected by reduced glucose intolerance and glucose stimulated insulin secretion. CuE restored insulin sensitivity indirectly by inhibiting JAK phosphorylation and improving AMPK activity. Consequently, insulin signaling was up-regulated in mice muscle. As CuE positively regulated adipose tissue function and suppressed visceral obesity, dyslipedemia, hyperglycemia and insulin resistance in mice model of MetS, we suggest that CuE can be used as novel approach to treat metabolic diseases.


Meristem aging is not responsible for age-related changes in growth and abscisic acid levels in the Mediterranean shrub, Cistus clusii.
To obtain new insights into the mechanisms underlying aging in perennials, we measured abscisic acid levels, growth and other stress indicators in leaves of Cistus clusii Dunal plants of different ages grown under Mediterranean field conditions. Recently emerged leaves from 9-year-old plants were compared to those of 1-year-old plants (obtained from cuttings from 9-year-old plants) to evaluate the effects of meristem aging on plant aging. Rooting and successful establishment of the cuttings allowed us to compare the physiology of plants with old meristems, but of different size. Plants obtained from cuttings were rejuvenated, with new leaves displaying a higher leaf area and chlorophyll content, but smaller leaf mass per unit area ratios and endogenous abscisic acid levels than those of 9-year-old plants. A comparative study in 1-, 4- and 9-year-old plants revealed that abscisic acid levels increase during the early stages of plant life (with increases of 90% between 1- and 4-year-old plants), but then remain constant at advanced developmental stages (between 4- and 9-year-old plants). Although leaf biomass was 53% smaller in 9-year-old compared to 4-year-old plants, the dry matter produced per shoot apical meristem was equivalent in both plant groups due to an increased number of leaves per shoot in the former. It is concluded that (i) C. clusii plants maintain the capacity to rejuvenate for several years; (ii) newly emerged leaves accumulate higher amounts of abscisic acid during early stages of plant life, but the levels of this phytohormone later remain constant; and (iii) although plant aging leads to the production of smaller leaves, the amount of biomass produced per shoot apical meristem remains constant at advanced developmental stages.


A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion.
Wnt proteins are lipid-modified glycoproteins that play a central role in development, adult tissue homeostasis and disease. Secretion of Wnt proteins is mediated by the Wnt-binding protein Wntless (Wls), which transports Wnt from the Golgi network to the cell surface for release. It has recently been shown that recycling of Wls through a retromer-dependent endosome-to-Golgi trafficking pathway is required for efficient Wnt secretion, but the mechanism of this retrograde transport pathway is poorly understood. Here, we report that Wls recycling is mediated through a retromer pathway that is independent of the retromer sorting nexins SNX1-SNX2 and SNX5-SNX6. We have found that the unrelated sorting nexin, SNX3, has an evolutionarily conserved function in Wls recycling and Wnt secretion and show that SNX3 interacts directly with the cargo-selective subcomplex of the retromer to sort Wls into a morphologically distinct retrieval pathway. These results demonstrate that SNX3 is part of an alternative retromer pathway that functionally separates the retrograde transport of Wls from other retromer cargo.


Discrimination in a Low-Wage Labor Market: A Field Experiment.
Decades of racial progress have led some researchers and policymakers to doubt that discrimination remains an important cause of economic inequality. To study contemporary discrimination, we conducted a field experiment in the low-wage labor market of New York City, recruiting white, black, and Latino job applicants who were matched on demographic characteristics and interpersonal skills. These applicants were given equivalent résumés and sent to apply in tandem for hundreds of entry-level jobs. Our results show that black applicants were half as likely as equally qualified whites to receive a callback or job offer. In fact, black and Latino applicants with clean backgrounds fared no better than white applicants just released from prison. Additional qualitative evidence from our applicants' experiences further illustrates the multiple points at which employment trajectories can be deflected by various forms of racial bias. These results point to the subtle yet systematic forms of discrimination that continue to shape employment opportunities for low-wage workers.


Image Super-Resolution as a Defense Against Adversarial Attacks.
Convolutional Neural Networks have achieved significant success across multiple computer vision tasks. However, they are vulnerable to carefully crafted, human-imperceptible adversarial noise patterns which constrain their deployment in critical security-sensitive systems. This paper proposes a computationally efficient image enhancement approach that provides a strong defense mechanism to effectively mitigate the effect of such adversarial perturbations. We show that deep image restoration networks learn mapping functions that can bring off-the-manifold adversarial samples onto the natural image manifold, thus restoring classification towards correct classes. A distinguishing feature of our approach is that, in addition to providing robustness against attacks, it simultaneously enhances image quality and retains models performance on clean images. Furthermore, the proposed method does not modify the classifier or requires a separate mechanism to detect adversarial images. The effectiveness of the scheme has been demonstrated through extensive experiments, where it has proven a strong defense in gray-box settings. The proposed scheme is simple and has the following advantages: (1) it does not require any model training or parameter optimization, (2) it complements other existing defense mechanisms, (3) it is agnostic to the attacked model and attack type and (4) it provides superior performance across all popular attack algorithms. Our codes are publicly available at https://github.com/aamir-mustafa/super-resolution-adversarial-defense.


Antiretroviral therapy during pregnancy and the risk of an adverse outcome.
Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation.


Extension of spine fusion to the sacrum following long fusions for deformity correction.
Retrospective review of prospective database. To investigate the long-term results after extension of previous long spine fusions to the sacrum. Long spine fusions not involving the sacrum may be complicated by distal degeneration and require subsequent extension to the sacrum. The clinical and radiographical outcomes after such revision remain unknown. Patients who had extension of a long fusion (≥5 levels with a thoracic level at the cranial end) to the sacrum between 2002 and 2007 at a single institution were analyzed. Oswestry Disability Index and Scoliosis Research Society scores and/or radiographical parameters were assessed at baseline, 6 weeks and 1 year, 2, 3, and/or 5 years postoperatively (PO) and complications were recorded. There were 74 patients with an average age of 49 years (range, 19-76 yr) and average clinical follow-up of 4.5 years (range, 3 mo-10 yr, 82% >2 yr PO). All had degeneration distal to prior fusions and 72% (n = 53) had fixed sagittal imbalance. Sagittal alignment improved at all PO time points from baseline (mean, 78 mm), but worsened between 1 year (mean, 21 mm) and 5 years PO (mean, 44 mm, P = 0.01). Major surgical complications occurred in 30% (n = 22) and there were 17 major reoperations in 15 patients (20%). Significant improvements (P < 0.05) in Oswestry Disability Index and all Scoliosis Research Society domain scores were found at each PO time point with no deterioration from 1 to 5 years PO. Mean outcome scores at 5 years PO were similar in groups with major surgical complications versus without and with major reoperation versus without. Extension of long fusions to the sacrum resulted in significant and sustained improvements in Oswestry Disability Index and Scoliosis Research Society scores and alignment during 5 years PO compared with baseline. Major surgical complications occurred in 30% and reoperations were performed in 20%, but outcome scores after treatment were similar to those without complications or reoperations.


Neural correlates of the dependence of compensatory eye movements during translation on target distance and eccentricity.
To stabilize objects of interest on the fovea during translation, vestibular-driven compensatory eye movements [translational vestibulo-ocular reflex (TVOR)] must scale with both target distance and eccentricity. To identify the neural correlates of these properties, we recorded from different groups of eye movement-sensitive neurons in the prepositus hypoglossi and vestibular nuclei of macaque monkeys during lateral and fore-aft displacements. All neuron types exhibited some increase in modulation amplitude as a function of target distance during high-frequency (4 Hz) lateral motion in darkness, with slopes that were correlated with the cell's pursuit gain, but not eye position sensitivity. Vergence angle dependence was largest for burst-tonic (BT) and contralateral eye-head (EH) neurons and smallest for ipsilateral EH and position-vestibular-pause (PVP) cells. On the other hand, the EH and PVP neurons with ipsilateral eye movement preferences exhibited the largest vergence-independent responses, which would be inappropriate to drive the TVOR. In addition to target distance, the TVOR also scales with target eccentricity, as evidenced during fore-aft motion, where eye velocity amplitude exhibits a "V-shaped " dependence and phase shifts 180 degrees for right versus left eye positions. Both the modulation amplitude and phase of BT and contralateral EH cells scaled with eye position, similar to the evoked eye movements during fore-aft motion. In contrast, the response modulation of ipsilateral EH and PVP cells during fore-aft motion was characterized by neither the V-shaped scaling nor the phase reversal. These results show that distinct premotor cell types carry neural signals that are appropriately scaled by vergence angle and eye position to generate the geometrically appropriate compensatory eye movements in the translational vestibulo-ocular reflex.


Asymmetric crying facies associated with congenital hypoparathyroidism and 22q11 deletion.
Asymmetric crying facies is caused by congenital hypoplasia or agenesis of the depressor anguli oris muscle. Associations of this facial defect with major congenital anomalies have been reported, most commonly in the cardiovascular system and less frequently involving the genitourinary, musculoskeletal, cervicofacial, respiratory, and rarely, the endocrine system. CATCH 22 is a medical acronym for cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia and a variable deletion on chromosome 22q11. The deletion within chromosme region of 22q11 may occur in patients with dysmorphologic and cardiological syndromes: DiGeorge syndrome, velo-cardiofacial syndrome and conotruncal anomaly face syndrome. We report a newborn infant who had asymmetric crying facies associated with congenital hypoparathyroidism, severe neonatal hypocalcemia and tetralogy of Fallot. Genetic confirmation of chromosome 22q11 deletion was made.


Association of Suicidality and Depression With 5α-Reductase Inhibitors.
There have been concerns raised by patients and regulatory agencies regarding serious psychiatric adverse effects associated with 5α-reductase inhibitors. To determine if there is an increased risk of suicide, self-harm, or depression among older men starting a 5α-reductase inhibitor for prostatic enlargement. A population-based, retrospective, matched cohort study using linked administrative data for 93 197 men ages 66 years or older (median [IQR] age, 75 [70-80] years) in Ontario, Canada, who initiated a new prescription for a 5α-reductase inhibitor during the study period (2003 through 2013). Participants were matched (using a propensity score that included 44 of our 96 covariates that included medical comorbidities, medication usage, and health care system utilization) to an equal number of men not prescribed a 5α-reductase inhibitor. Duration of finasteride or dutasteride usage. Suicide. Secondary outcomes were self-harm and depression. Men who used 5α-reductase inhibitors were not at a significantly increased risk of suicide (HR, 0.88; 95% CI, 0.53-1.45). Risk of self-harm was significantly increased during the initial 18 months after 5α-reductase inhibitor initiation (HR, 1.88; 95% CI, 1.34-2.64), but not thereafter. Incident depression risk was elevated during the initial 18 months after 5α-reductase inhibitor initiation (HR, 1.94; 95% CI, 1.73-2.16), and continued to be elevated, but to a lesser degree, for the remainder of the follow-up period (HR, 1.22; 95% CI, 1.08-1.37). The absolute increases in the event rates for these 2 outcomes were 17 per 100 000 patient-years and 237 per 100 000 patient-years, respectively. The type of 5α-reductase inhibitor (finasteride or dutasteride) did not significantly modify the observed associations with suicide, self-harm, and depression. In a large cohort of men ages 66 years or older, we did not demonstrate an increased risk of suicide associated with 5α-reductase inhibitor use. However, the risk of self-harm and depression were increased compared with unexposed men. This is in keeping with postmarketing experience and patient concerns, and discontinuation of the medication in these circ umstances may be appropriate.


A Monte Carlo simulation of monoenergetic neutrons traversing rectangular and spherical polyethylene moderators.
A Monte Carlo-based simulation of the transport of a series of monoenergetic neutron sources through first a rectangular block of 0.93 g cm(-3) density polyethylene and secondly through a sphere made of the same substance is presented here. In both instances, the neutron fields are monitored at closely spread intervals through the moderator mass, producing a lot of data in the process. To reduce the amount of data presented, a figure of merit is created by estimating the cross section for each discrete neutron energy and by applying this to the number of neutrons present of each energy giving an arbitrary response figure. This work was undertaken in order to aid the design and development of a novel neutron spectrometer.


First Report of Potato spindle tuber viroid Naturally Infecting Greenhouse Tomatoes in North Carolina.
In spring 2012, a severe disease was observed on a limited number of tomato plants (Solanum lycopersicum L.) in a research greenhouse facility in western North Carolina. The first symptoms noted were downward curling of the terminal leaves accompanied by a rough puckered darker green texture. This was followed in time by greater distortion of the leaves with pale green on leaf margins. Older leaves with symptoms developed necrosis, with necrotic spots and streaks appearing on a few fruits. On some of these affected fruits, stems, peduncles, pedicels, and sepals also showed symptoms. Infected plants were badly stunted, and fruits in the upper parts of plants displaying severe symptoms remained very small. In just a few months, the disease spread to other tomato plants inside the greenhouse. A survey in May 2012 showed a disease incidence of 18% (156 symptomatic plants out of a total of 864) in this greenhouse. Initial screenings for possible viruses using ELISA (Agdia, Elkhart, IN), as well as a reverse transcription (RT)-PCR panel of 15 common tomato viruses in our laboratory were negative. Because of the symptoms and negative results for viruses, a viroid infection was suspected. Total plant RNA was prepared using TRIzol reagent (Invitrogen, Carlsbad, CA) from leaf tissues of eight diseased plants and one seed sample. Using real-time RT-PCR developed against Potato spindle tuber viroid (PSTVd) and some related pospiviroids (1), positive signals were observed with a mean Ct = 13.24 for leaf tissues and Ct = 19.91 for the seed sample. To obtain a full viroid genome, RT-PCR using two different sets of primers, one specific for PSTVd (PSTVd-F and PSTVd-R) (2), and a universal primer set for pospiviroids (MTTVd-F and MTTVd-R) (3) was performed. RT-PCR generated amplicons with expected size of ~360 bp from all eight leaf and one seed samples, but not from a healthy control. PCR products were cloned using the TOPO TA cloning kit (Invitrogen, Carlsbad, CA). A total of 22 full genomic sequences were obtained. A multi-sequence alignment generated a consensus sequence of 360 nt, designated as NC12-01 (GenBank Accession No. JX280944). BLASTn search in the NCBI database revealed the highest sequence identity of 96.9% to Australian (AY962324) and UK (AJ583449) isolates of PSTVd and 95.9% identity to the tomato isolate of PSTVd-CA1 (HM753555). Similar disease symptoms were observed on two 'Rutgers' tomato plants 2 weeks post mechanical inoculation and the presence of PSTVd was confirmed by real-time RT-PCR (1). A mock-inoculated plant did not show any symptoms. In the U.S., natural infection of PSTVd on tomato was first identified in California in 2010 (3). To our knowledge, this is the first report of a natural occurrence of PSTVd on tomato in the eastern U.S. The diseased plants were contained, properly disposed of, and eradicated in this location. The broader geographic distribution of PSTVd on tomato in the U.S., and the potential latent infection in potato and a number of ornamentals (4), emphasizes the need for better plant and seed health tests for viroids on these plants. References: (1) N. Boonham et al. J. Virol. Methods 116:139, 2004. (2) H. Bostan et al. J. Virol. Methods 116:189, 2004. (3) K.-S. Ling and D. Sfetcu. Plant Dis. 94:1376, 2010. (4) R. A. Owens and J. Th. J. Verhoeven. The Plant Health Instructor. DOI: 10.1094/PHI-I-2009-0804-01, 2009.


Selenium supplementation suppresses immunological and serological features of lupus in B6.Sle1b mice.
Systemic lupus erythematosus (SLE) is a debilitating multi-factorial immunological disorder characterized by increased inflammation and development of anti-nuclear autoantibodies. Selenium (Se) is an essential trace element with beneficial anti-cancer and anti-inflammatory immunological functions. In our previous proteomics study, analysis of Se-responsive markers in the circulation of Se-supplemented healthy men showed a significant increase in complement proteins. Additionally, Se supplementation prolonged the life span of lupus prone NZB/NZW-F1 mice. To better understand the protective immunological role of Se in SLE pathogenesis, we have investigated the impact of Se on B cells and macrophages using in vitro Se supplementation assays and the B6.Sle1b mouse model of lupus with an oral Se or placebo supplementation regimen. Analysis of Se-treated B6.Sle1b mice showed reduced splenomegaly and splenic cellularity compared to untreated B6. Sle1b mice. A significant reduction in total B cells and notably germinal center (GC) B cell numbers was observed. However, other cell types including T cells, Tregs, DCs and pDCs were unaffected. Consistent with reduced GC B cells there was a significant reduction in autoantibodies to dsDNA and SmRNP of the IgG2b and IgG2c subclass upon Se supplementation. We found that increased Se availability leads to impaired differentiation and maturation of macrophages from mouse bone marrow derived progenitors in vitro. Additionally, Se treatment during in vitro activation of B cells with anti-CD40L and LPS inhibited optimal B cell activation. Overall our data indicate that Se supplementation inhibits activation, differentiation and maturation of B cells and macrophages. Its specific inhibitory effect on B cell activation and GC B cell differentiation could be explored as a potential therapeutic supplement for SLE patients.


Debrief in Emergency Departments to Improve Compassion Fatigue and Promote Resiliency.
The purpose of this case study was to describe compassion fatigue using one nurse's experience as an example and to present the process of Personal Reflective Debrief as an intervention to prevent compassion fatigue in emergency department (ED) nurses. Debriefing after adverse outcomes using a structured model has been used in health care as a nonthreatening and relatively low-cost way to discuss unanticipated outcomes, identify opportunities for improvement, and heal as a group. There are many methods of debrief tailored to specific timing around events, specific populations of health care workers, and amount of time for debriefing. Debrief with personal and group reflection will help develop insights that nurses may need to understand their own emotions and experiences, as well as to develop knowledge that can be used in subsequent situations. Regular engagement in a proactive scheduled Personal Reflective Debrief has been identified as a method of promoting resiliency in an environment where the realities of emergency nursing make compassion fatigue an imminent concern. Nurses working in the ED normally experience some level of stress because of high acuity patients and high patient volume; yet, repeated exposure puts them at risk for developing compassion fatigue. The Personal Reflective Debrief is one way emergency nurses can alleviate some of this caring-related stress and thereby become more resilient. Increasing nurses' resilience to workplace stress can counter compassion fatigue. The key is to provide planned, proactive resources to positively improve resiliency.


Cardiac sympathectomy and spinal cord stimulation attenuate reflex-mediated norepinephrine release during ischemia preventing ventricular fibrillation.
The purpose of this study was to define the mechanism by which cardiac neuraxial decentralization or spinal cord stimulation (SCS) reduces ischemia-induced ventricular fibrillation (VF). Direct measurements of norepinephrine (NE) levels in the left ventricular interstitial fluid (ISF) by microdialysis, in response to transient (15-minute) coronary artery occlusion (CAO), were performed in anesthetized canines. Responses were studied in animals with intact neuraxes and were compared with those in which the intrathoracic component of the cardiac neuraxes (stellate ganglia) or the intrinsic cardiac neuronal (ICN) system was surgically delinked from the central nervous system and those with intact neuraxes with preemptive SCS (T1-T3). With intact neuraxes, animals with exaggerated NE release due to CAO were at increased risk for VF. During CAO, there was a 152% increase in NE when the neuraxes were intact compared with 114% following stellate decentralization and 16% following ICN decentralization. During SCS, CAO NE levels increased by 59%. Risk for CAO-induced VF was 38% in controls, 8% following decentralization, and 11% following SCS. These data indicate that ischemia-related afferent neuronal transmission differentially engages central and intrathoracic sympathetic reflexes and amplifies sympathoexcitation. Differences in regional ventricular NE release are associated with increased risk for VF. Surgical decentralization or SCS reduced NE release and VF.


Impacts of climate, host and landscape factors on Culicoides species in Scotland.
Culicoides biting midges (Diptera: Ceratopogonidae) vector a wide variety of internationally important arboviral pathogens of livestock and represent a widespread biting nuisance. This study investigated the influence of landscape, host and remotely-sensed climate factors on local abundance of livestock-associated species in Scotland, within a hierarchical generalized linear model framework. The Culicoides obsoletus group and the Culicoides pulicaris group accounted for 56% and 41%, respectively, of adult females trapped. Culicoides impunctatus Goetghebuer and C. pulicaris s.s. Linnaeus were the most abundant and widespread species in the C. pulicaris group (accounting for 29% and 10%, respectively, of females trapped). Abundance models performed well for C. impunctatus, Culicoides deltus Edwards and Culicoides punctatus Meigen (adjusted R(2) : 0.59-0.70), but not for C. pulicaris s.s. (adjusted R(2) : 0.36) and the C. obsoletus group (adjusted R(2) : 0.08). Local-scale abundance patterns were best explained by models combining host, landscape and climate factors. The abundance of C. impunctatus was negatively associated with cattle density, but positively associated with pasture cover, consistent with this species' preference in the larval stage for lightly grazed, wet rush pasture. Predicted abundances of this species varied widely among farms even over short distances (less than a few km). Modelling approaches that may facilitate the more accurate prediction of local abundance patterns for a wider range of Culicoides species are discussed.


Distinct regions of RPB11 are required for heterodimerization with RPB3 in human and yeast RNA polymerase II.
In Saccharomyces cerevisiae, RNA polymerase II assembly is probably initiated by the formation of the RPB3-RPB11 heterodimer. RPB3 is encoded by a single copy gene in the yeast, mouse and human genomes. The RPB11 gene is also unique in yeast and mouse, but in humans a gene family has been identified that potentially encodes several RPB11 proteins differing mainly in their C-terminal regions. We compared the abilities of both yeast and human proteins to heterodimerize. We show that the yeast RPB3/RPB11 heterodimer critically depends on the presence of the C-terminal region of RPB11. In contrast, the human heterodimer tolerates significant changes in RPB11 C-terminus, allowing two human RPB11 variants to heterodimerize with the same efficiency with RPB3. In keeping with this observation, the interactions between the conserved N-terminal 'alpha-motifs' is much more important for heterodimerization of the human subunits than for those in yeast. These data indicate that the heterodimerization interfaces have been modified during the course of evolution to allow a recent diversification of the human RPB11 subunits that remains compatible with heterodimerization with RPB3.


On phylogenetic relationships among major lineages of the Gammaherpesvirinae.
Phylogenetic relationships within the subfamily Gammaherpesvirinae of the family Herpesviridae were investigated for three species in the genus Lymphocryptovirus (or gamma1 group) and nine in the genus Rhadinovirus (or gamma2 group). Alignments of amino acid sequences from up to 28 genes were used to derive trees by maximum-likelihood and Bayesian Monte Carlo Markov chain methods. Two problem areas were identified involving an unresolvable multifurcation for a clade within the gamma2 group, and a high divergence for Murid herpesvirus 4 (MHV4). A robust final tree was obtained, which was valid for genes from across the virus genomes and was rooted by reference to previous analyses of the whole family Herpesviridae. This tree comprised four major lineages: the gamma1 group of primate viruses; a clade of artiodactyl gamma2 viruses; a clade of perissodactyl gamma2 viruses; and a clade of gamma2 viruses with a multifurcation at its base and containing Old World and New World primate viruses, Bovine herpesvirus 4 and MHV4. Developing previous work it was proposed, on the basis of similarities between the gammaherpesvirus tree and the tree of corresponding mammalian hosts, that the first three of these major viral lineages arose in a coevolutionary manner with host lineages, while the fourth had its origin in an ancient interspecies transfer. Transfer of dates from mammalian palaeontology then allowed estimation of dates for nodes in the gammaherpesvirus tree.


Equivalence of self- and staff-collected nasal swabs for the detection of viral respiratory pathogens.
The need for the timely collection of diagnostic biosamples during symptomatic episodes represents a major obstacle to large-scale studies on acute respiratory infection (ARI) epidemiology. This may be circumvented by having the participants collect their own nasal swabs. We compared self- and staff-collected swabs in terms of swabbing quality and detection of viral respiratory pathogens. We conducted a prospective study among employees of our institution during the ARI season 2010/2011 (December-March). Weekly emails were sent to the participants (n = 84), reminding them to come to the study center in case of new symptoms. The participants self-collected an anterior nasal swab from one nostril, and trained study personnel collected one from the other nostril. The participants self-collected another two swabs (one from each nostril) on a subsequent day. Human β-actin DNA concentration was determined in the swabs as a quality control. Viral respiratory pathogens were detected by multiplex RT-PCR (Seeplex RV15 kit, Seegene, Eschborn, Germany). Of 84 participants, 56 (67%) reported at least one ARI episode, 18 participants two, and one participant three. Self-swabbing was highly accepted by the participants. The amount of β-actin DNA per swab was higher in the self- than in the staff-collected swabs (p = 0.008). β-actin concentration was lower in the self-swabs collected on day 1 than in those collected on a subsequent day (p<0.0001). A respiratory viral pathogen was detected in 31% (23/75) of staff- and in 35% (26/75) of self-collected swabs (p = 0.36). With both approaches, the most frequently identified pathogens were human rhinoviruses A/B/C (12/75 swabs, 16%) and human coronavirus OC43 (4/75 swabs, 5%). There was almost perfect agreement between self- and staff-collected swabs in terms of pathogen detection (agreement = 93%, kappa = 0.85, p<0.0001). Nasal self-swabbing for identification of viral ARI pathogens proved to be equivalent to staff-swabbing in this population in terms of acceptance and pathogen detection.


Lack of Control of Citrus Canker by Induced Systemic Resistance Compounds.
Induced systemic resistance compounds (ISRs), acibenzolar-S-methyl (Actigard), and harpin protein (Messenger) were assayed in the greenhouse against Xanthomonas axonopodis pv. citrumelo, the cause of citrus bacterial spot (CBS), and X. axonopodis pv. citri, the cause of Asiatic citrus canker. Actigard and Messenger applied as foliar sprays 3 to 7 days before inoculation reduced numbers of lesions when either bacterium at 103 or 104 CFU/ml was injection-infiltrated into Swingle citrumelo leaves. Based on this activity, the ISRs were evaluated in southern Brazil in orchards of sweet oranges with low to moderate canker disease incidence in spray programs with and without copper oxychloride (COC) and copper hydroxide (CuOH). Actigard and Messenger were applied full season or in the first two or three sprays of a six-spray program in an attempt to reduce early canker disease on foliage and thereby reduce subsequent fruit infection and premature drop. Sprays of COC and CuOH were moderately to highly effective in reducing canker disease incidence and preventing premature fruit drop. Actigard or Messenger in combination with COC and CuOH, respectively, did not significantly reduce citrus canker incidence on foliage or fruit drop compared with Cu alone. The lack of additional control with ISRs means they cannot be recommended at this time to augment Cu programs for management of citrus canker.


Optogenetic stimulation of the cochlear nucleus using channelrhodopsin-2 evokes activity in the central auditory pathways.
Optogenetics has become an important research tool and is being considered as the basis for several neural prostheses. However, few studies have applied optogenetics to the auditory brainstem. This study explored whether optical activation of the cochlear nucleus (CN) elicited responses in neurons in higher centers of the auditory pathway and whether it elicited an evoked response. Viral-mediated gene transfer was used to express channelrhodopsin-2 (ChR2) in the mouse CN. Blue light was delivered via an optical fiber placed near the surface of the infected CN and recordings were made in higher-level centers. Optical stimulation evoked excitatory multiunit spiking activity throughout the tonotopic axis of the central nucleus of the inferior colliculus (IC) and the auditory cortex (Actx). The pattern and magnitude of IC activity elicited by optical stimulation was comparable to that obtained with a 50dB SPL acoustic click. This broad pattern of activity was consistent with histological confirmation of green fluorescent protein (GFP) label of cell bodies and axons throughout the CN. Increasing pulse rates up to 320Hz did not significantly affect threshold or bandwidth of the IC responses, but rates higher than 50Hz resulted in desynchronized activity. Optical stimulation also evoked an auditory brainstem response, which had a simpler waveform than the response to acoustic stimulation. Control cases showed no responses to optical stimulation. These data suggest that optogenetic control of central auditory neurons is feasible, but opsins with faster channel kinetics may be necessary to convey information at rates typical of many auditory signals.


Qualitative evaluation of a management course project: creating new job possibilities for occupational therapy.
SUMMARY A qualitative analysis of a ten-step management course project in occupational therapy education demonstrates the students changed perception of future job possibilities. The assignment, designed using a student-centered approach, bridges individual skills and interests with the creation of an occupational therapy position in an emerging market. The thematic analysis indicated the outcomes of the assignment were: a changed perception in the importance of a good fit between practitioner skills and the agency or program needs, added confidence in the students' skills based on a review of the two years of academic education, and a positive, anticipated transition of the academic knowledge base into real world experience. Student presentations served to measure the ability to articulate the services of occupational therapy within arenas unfamiliar to the profession.


Efficacy of bioresorbable plates in the osteosynthesis of linear mandibular fractures.
There are limited evidences available about the performance of biodegradable system in the treatment of linear mandibular fractures without the aid of postoperative maxillomandibular fixation (MMF). Hence, the present study was planned to evaluate the treatment outcomes in mandibular fractures, using 2.5 mm bioresorbable plates and screws without postoperative MMF. This cohort study compares both prospective and retrospective data. The prospective study treated 20 adult patients with linear mandibular fracture using bioresorbable plates and screws, without using postoperative MMF (Group 1). Retrospective data were collected from a previous published study in which patients were treated with bioresorbable plates and screws with 2 weeks postoperative MMF (Group 2) and those treated with metal plates and screws without postoperative MMF (Group 3). Group 1 patients were followed up at 2 and 4 months to evaluate the functional outcomes in terms of fracture mobility, malocclusion, pain, and soft-tissue deformity and compared with its preoperative findings. Further, the treatment outcomes of Group 1, Group 2, and Group 3 were compared among themselves at 2-month follow-up. Group 1 patients showed a significant improvement in the treatment outcomes at 2 and 4-month follow-up. In addition, when 2 months postoperative outcomes were compared among the three groups, no statistically significant difference was observed in the treatment outcomes. Endpoint osteosynthesis can be achieved with the bioresorbable fixation system when used in the treatment of un-displaced linear mandibular fractures, without postoperative MMF. A minor modification of using a lower size osteotomy drill can prevent screw loosening.


Math Anxiety Mediates the Link Between Number Sense and Math Achievements in High Math Anxiety Young Adults.
In the past few years, many studies have suggested that subjects with high sensory precision in the processing of non-symbolic numerical quantities (approximate number system; ANS) also have higher math abilities. At the same time, there has been interest in another non-cognitive factor affecting mathematical learning: mathematical anxiety (MA). MA is defined as a debilitating emotional reaction to mathematics that interferes with the manipulation of numbers and the solving of mathematical problems. Few studies have been dedicated to uncovering the interplay between ANS and MA and those have provided conflicting evidence. Here we measured ANS precision (numerosity discrimination thresholds) in a cohort of university students with either a high (>75th percentile; n = 49) or low (<25th percentile; n = 39) score on the Abbreviate Math Anxiety Scale (AMAS). We also assessed math proficiency using a standardized test (MPP: Mathematics Prerequisites for Psychometrics), visuo-spatial attention capacity by means of a Multiple Objects Tracking task (MOT) and sensory precision for non-numerical quantities (disk size). Our results confirmed previous studies showing that math abilities and ANS precision correlate in subjects with high math anxiety. Neither precision in size-discrimination nor visuo-spatial attentional capacity were found to correlate with math capacities. Interestingly, within the group with high MA, our data also revealed a relationship between ANS precision and MA, with MA playing a key role in mediating the correlation between ANS and math achievement. Taken together, our results suggest an interplay between extreme levels of MA and the sensory precision in the processing of non-symbolic numerosity.


Role of the postnatal radial glial scaffold for the development of the dentate gyrus as revealed by Reelin signaling mutant mice.
During dentate gyrus development, the early embryonic radial glial scaffold is replaced by a secondary glial scaffold around birth. In contrast to neocortical and early dentate gyrus radial glial cells, these postnatal glial cells are severely altered with regard to position and morphology in reeler mice lacking the secreted protein Reelin. In this study, we focus on the functional impact of these defects. Most radial glial cells throughout the nervous system serve as scaffolds for migrating neurons and precursor cells for both neurogenesis and gliogenesis. Precursor cell function has been demonstrated for secondary radial glial cells but the exact function of these late glial cells in granule cell migration and positioning is not clear. No data exist concerning the interplay between granule neurons and late radial glial cells during dentate gyrus development. Herein, we show that despite the severe morphological defects in the reeler dentate gyrus, the precursor function of secondary radial glial cells is not impaired during development in reeler mice. In addition, selective ablation of Disabled-1, an intracellular adaptor protein essential for Reelin signaling, in neurons but not in glial cells allowed us to distinguish effects of Reelin signaling on radial glial cells from possible secondary effects based on defective granule cells positioning.


Rescue and regulation of proboscipedia: a homeotic gene of the Antennapedia Complex.
The extraordinary positional conservation of the homeotic genes within the Antennapedia and the Bithorax Complexes (ANT-C and BX-C) in Drosophila melanogaster and the murine Hox and human HOX clusters of genes can be interpreted as a reflection of functional necessity. The homeotic gene proboscipedia (pb) resides within the ANT-C, and its sequence is related to that of Hox-1.5. We show that two independent pb minigene P-element insertion lines completely rescue the labial palp-to-first leg homeotic transformation caused by pb null mutations; thus, a homeotic gene of the ANT-C can properly carry out its homeotic function outside of the complex. Despite the complete rescue of the null, the minigene expresses pb protein in only a subset of pb's normal domains of expression. Therefore, the biological significance of the excluded expression pattern elements remains unclear except to note they appear unnecessary for specifying normal labial identity. Additionally, by using reporter gene constructs inserted into the Drosophila genome and by comparing pb-associated genomic sequences from two divergent species, we have located cis-acting regulatory elements required for pb expression in embryos and larvae.


Improvements in pain outcomes in a Canadian pediatric teaching hospital following implementation of a multifaceted knowledge translation initiative.
A previous audit performed at a tertiary ⁄ quaternary pediatric hospital in Toronto, Ontario, demonstrated suboptimal assessment and treatment of children's pain. Knowledge translation (KT) initiatives (education, reminders, audit and feedback) were implemented to address identified care gaps; however, the impact is unknown. To determine the impact of KT initiatives on pain outcomes including process outcomes (eg, pain assessment and management practices) and clinical outcomes (eg, pain prevalence and intensity); and to benchmark additional pain practices, particularly opioid administration and painful procedures. Medical records at The Hospital for Sick Children (Toronto, Ontario) were reviewed on a single day in September 2007. Pain assessment and management practices, and pain prevalence and intensity in the preceding 24 h were recorded on a standardized data collection form. Where possible, pain outcomes were compared with previous audit results. Records of 265 inpatients were audited. Sixty-three per cent of children underwent a documented pain assessment compared with 27% in an audit conducted previously (P<0.01). Eighty-three per cent of children with documented pain received at least one pain management intervention. Overall, 51% of children received pharmacological therapy, and 15% received either a psychological or physical pain-relieving intervention. Of those assessed, 44% experienced pain in the previous 24 h versus 66% in the previous audit (P<0.01). Fewer children experienced severe pain compared with the first audit (8.7% versus 26.1%; P<0.01). One-third of children received opioids; 19% of these had no recorded pain assessment. Among 131 children who underwent a painful procedure, 21% had a concurrent pain assessment. Painful procedures were accompanied by a pain-relieving intervention in 12.5% of cases. Following KT initiatives, significant improvements in pain processes (pain assessment documentation and pain management interventions) and clinical outcomes (pain prevalence, pain intensity) were observed. Further improvements are recommended, specifically with respect to procedural pain practices and opioid utilization patterns.


DPP6 establishes the A-type K(+) current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons.
Subthreshold-activating A-type K(+) currents are essential for the proper functioning of the brain, where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K(+) current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability.


The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease.
Cardiovascular disease (CVD) remains a leading cause of mortality and morbidity worldwide. Numerous therapies are currently under investigation to improve pathological cardiovascular complications, but yet, there have been very few new medications approved for intervention/treatment. Therefore, new approaches to treat CVD are urgently required. Attempts to prevent vascular complications usually involve amelioration of contributing risk factors and underlying processes such as inflammation, obesity, hyperglycaemia, or hypercholesterolemia. Historically, the development of peptides as therapeutic agents has been avoided by the Pharmaceutical industry due to their low stability, size, rate of degradation, and poor delivery. However, more recently, resurgence has taken place in developing peptides and their mimetics for therapeutic intervention. As a result, increased attention has been placed upon using peptides that mimic the function of mediators involved in pathologic processes during vascular damage. This review will provide an overview on novel targets and experimental therapeutic approaches based on peptidomimetics for modulation in CVD. We aim to specifically examine apolipoprotein A-I (apoA-I) and apoE mimetic peptides and their role in cholesterol transport during atherosclerosis, suppressors of cytokine signaling (SOCS)1-derived peptides and annexin-A1 as potent inhibitors of inflammation, incretin mimetics and their function in glucose-insulin tolerance, among others. With improvements in technology and synthesis platforms the future looks promising for the development of novel peptides and mimetics for therapeutic use. However, within the area of CVD much more work is required to identify and improve our understanding of peptide structure, interaction, and function in order to select the best targets to take forward for treatment.


The Clinical Significance of Unknown Sequence Variants in BRCA Genes.
Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10-20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance.


Evaluation of an Internet-Based Behavioral Intervention to Improve Psychosocial Health Outcomes in Children With Insomnia (Better Nights, Better Days): Protocol for a Randomized Controlled Trial.
Up to 25% of 1- to 10-year-old children experience insomnia (ie, resisting bedtime, trouble falling asleep, night awakenings, and waking too early in the morning). Insomnia can be associated with excessive daytime sleepiness and negative effects on daytime functioning across multiple domains (eg, behavior, mood, attention, and learning). Despite robust evidence supporting the effectiveness of behavioral treatments for insomnia in children, very few children with insomnia receive these treatments, primarily due to a shortage of available treatment resources. The Better Nights, Better Days (BNBD) internet-based program provides a readily accessible electronic health (eHealth) intervention to support parents in providing evidence-based care for insomnia in typically developing children. The purpose of the randomized controlled trial (RCT) is to evaluate the effectiveness of BNBD in treating insomnia in children aged between 1 and 10 years. BNBD is a fully automated program, developed based on evidence-based interventions previously tested by the investigators, as well as on the extant literature on this topic. We describe the 2-arm RCT in which participants (500 primary caregivers of children with insomnia residing in Canada) are assigned to intervention or usual care. The effects of this behavioral sleep eHealth intervention will be assessed at 4 and 8 months postrandomization. Assessment includes both sleep (actigraphy, sleep diary) and daytime functioning of the children and daytime functioning of their parents. Results will be reported using the standards set out in the Consolidated Standards of Reporting Trials statement. If the intervention is supported by the results of the RCT, we plan to commercialize this program so that it is sustainable and available at a low cost to all families with internet access. ClinicalTrials.gov NCT02243501; https://clinicaltrials.gov/show/NCT02243501 (Archived by WebCite at http://www.webcitation.org/6x8Z5pBui).


Mechanical Versus Bioprosthetic Aortic Valve Replacement in Middle-Aged Adults: A Systematic Review and Meta-Analysis.
The choice of a bioprosthetic valve (BV) or mechanical valve (MV) in middle-aged adults undergoing aortic valve replacement is a complex decision that must account for numerous prosthesis and patient factors. A systematic review and meta-analysis was performed to compare long-term survival, major adverse prosthesis-related events, anticoagulant-related events, major bleeding, reoperation, and structural valve degeneration in middle-aged patients receiving a BV or MV. A comprehensive search from six electronic databases was performed from their inception to February 2016. Results from patients aged less than 70 years undergoing aortic valve replacement with a BV or MV were included. There were 12 studies involving 8,661 patients. Baseline characteristics were similar. There was no significant difference in long-term survival among patients aged 50 to 70 or 60 to 70 years. Compared with MVs, BVs had significantly fewer long-term anticoagulant-related events (hazard ratio [HR] 0.54, p = 0.006) and bleeding (HR 0.48, p < 0.00001) but significantly greater major adverse prosthesis-related events (HR 1.82, p = 0.02), including reoperation (HR 2.19, p < 0.00001). The present meta-analysis found no significant difference in survival between BVs and MVs in patients aged 50 to 70 or 60 to 70 years. Compared with MVs, BVs have reduced risk of major bleeding and anticoagulant-related events but increased risk of structural valve degeneration and reoperation. However, the mortality consequences of reoperation appear lower than that of major bleeding, and recent advances may further lower the reoperation rate for BV. Therefore, this review supports the current trend of using BVs in patients more than 60 years of age.


Clinical epidemiology, diagnosis and treatment of visceral leishmaniasis in the Pokot endemic area of Uganda and Kenya.
Between 2000 and 2010, Médecins Sans Frontières diagnosed and treated 4,831 patients with visceral leishmaniasis (VL) in the Pokot region straddling the border between Uganda and Kenya. A retrospective analysis of routinely collected clinical data showed no marked seasonal or annual fluctuations. Males between 5 and 14 years of age were the most affected group. Marked splenomegaly and anemia were striking features. An rK39 antigen-based rapid diagnostic test was evaluated and found sufficiently accurate to replace the direct agglutination test and spleen aspiration as the first-line diagnostic procedure. The case-fatality rate with sodium stibogluconate as first-line treatment was low. The VL relapses were rare and often diagnosed more than 6 months post-treatment. Post-kala-azar dermal leishmaniasis was rare but likely to be underdiagnosed. The epidemiological and clinical features of VL in the Pokot area differed markedly from VL in Sudan, the main endemic focus in Africa.


The more, the better: the use of multiple landmark configurations to solve the phylogenetic relationships in musteloids.
Although the use of landmark data to study shape changes along a phylogenetic tree has become a common practice in evolutionary studies, the role of this sort of data for the inference of phylogenetic relationships remains under debate. Theoretical issues aside, the very existence of historical information in landmark data has been challenged, since phylogenetic analyses have often shown little congruence with alternative sources of evidence. However, most analyses conducted in the past were based upon a single landmark configuration, leaving it unsettled whether the incorporation of multiple configurations may improve the rather poor performance of this data source in most previous phylogenetic analyses. In the present study, we present a phylogenetic analysis of landmark data that combines information derived from several skeletal structures to derive a phylogenetic tree for musteloids. The analysis includes nine configurations representing different skeletal structures for 24 species. The resulting tree presents several notable concordances with phylogenetic hypotheses derived from molecular data. In particular, Mephitidae, Procyonidae, and Lutrinae plus the genera Martes, Mustela, Galictis, and Procyon were retrieved as monophyletic. In addition, other groupings were in agreement with molecular phylogenies or presented only minor discordances. Complementary analyses have also indicated that the results improve substantially when an increasing number of landmark configurations are included in the analysis. The results presented here thus highlight the importance of combining information from multiple structures to derive phylogenetic hypotheses from landmark data.


Personal interaction with a Reiki practitioner decreases noise-induced microvascular damage in an animal model.
To determine whether Reiki, a process of transmission of healing energy, can significantly reduce microvascular leakage caused by exposure to excessive noise using an animal model. Reiki is beginning to be used in hospitals to accelerate recovery. Despite many anecdotes describing Reiki's success, few scientific studies are reported and none of those use animals. Animal models have the advantage over human subjects in that they provide well-controlled, easily interpretable experiments. The use of noise is relevant to hospital patients because of the excessive ambient noise in hospitals in the United Kingdom and United States. Loud noise can lead to several nonauditory disorders in humans and animals that impair recovery. In the rat, stress from noise damages the mesenteric microvasculature, leading to leakage of plasma into the surrounding tissue. One group of four rats simultaneously received daily noise and Reiki, while two other groups received "sham" Reiki or noise alone. A fourth group did not receive noise or additional treatment. The experiment was performed three times to test for reproducibility. Average number and area of microvascular leaks to fluorescent albumin per unit length of venule. In all three experiments, Reiki significantly reduced the outcome measures compared to the other noise groups (sham Reiki and noise alone) (p < 0.01). Application of Reiki significantly reduces noise-induced microvascular leakage in an animal model. Whether or not these effects are caused by Reiki itself, or the relaxing effect of the Reiki practitioner, this procedure could be useful for minimizing effects of environmental stress on research animals and hospital patients.


Emergence of porcine reproductive and respiratory syndrome virus deletion mutants: correlation with the porcine antibody response to a hypervariable site in the ORF 3 structural glycoprotein.
By using porcine immune sera to select a library of phage-displayed random peptides, we identified an antigenic sequence (RKASLSTS) in the C-terminus of the ORF 3 structural glycoprotein of European-type porcine reproductive and respiratory syndrome virus (PRRSV). Through the use of overlapping reading frames, the same PRRSV genetic locus codes for the ORF 3 "RKASLSTS" sequence, and a previously described ORF 4 epitope (Meulenberg, J. J. M., Van Nieuwstadt, A. P., Van Essen-Zandbergen, A., and Langeveld, J. P. M., 1997, J. Virol. 71, 6061-6067). Sequence analysis identified naturally occurring deletion mutants at this ORF 34 site. Phylogenetic analysis showed the presence of a highly accurate ORF 3 molecular clock, according to which deletion mutants and nondeleted viruses evolved at differing speeds. Furthermore, deletion mutants and nondeleted viruses evolved as separate lineages. These distinctions suggested that deletion mutants were a hitherto unrecognized subtype of European-type PRRSV. Currently, deletion mutants appear to be outcompeting nondeleted viruses in the field, highlighting the importance of the porcine antibody response against the minor structural glycoproteins of European-type PRRSV for viral evolution.