Absolute cardiovascular risk and GP decision making in TIA and minor stroke.
Transient ischaemic attacks (TIA) and minor strokes (TIAMS) have the same pathophysiological mechanism as stroke and carry a high risk of recurrent ischaemic events. Diagnosis of TIAMS can be challenging and often occurs in general practice. Absolute cardiovascular risk (ACVR) is recommended as the basis for vascular risk management. Consideration of cardiovascular risk in TIAMS diagnosis has been recommended but its utility is not established. Firstly, to document the ACVR of patients with incident TIAMS and with TIAMS-mimics. Secondly, to evaluate the utility of ACVR calculation in informing the initial diagnosis of TIAMS. The International comparison of Systems of care and patient outcomes in minor Stroke and TIA (InSiST) study is an inception cohort study of patients of 17 Australian general practices presenting as possible TIAMS. An expert panel determines whether participants have had TIAMS or TIAMS-mimics. ACVR was calculated at baseline for each participating patient. In this cross-sectional baseline analysis, ACVR of TIAMS and TIAMS-mimics were compared univariately and, also, when adjusted for age and sex. The diagnostic utility of ACVR was evaluated via receiver operating characteristic (ROC) curves. Of 179 participants, 87 were adjudicated as TIAMS. The presence of motor and speech symptoms and body mass index were associated with a diagnosis of TIAMS. ACVR was associated with TIAMS diagnosis on univariate analysis, but not when age- and sex-adjusted. ACVR did not significantly improve area under ROC curves beyond that of age and sex. In patients presenting with transient or minor neurological symptoms, calculation of ACVR did not improve diagnostic accuracy for TIAMS beyond that of age and sex.


A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease.
Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute Aβ application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and Aβ(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.


A role for endothelial NO synthase in LTP revealed by adenovirus-mediated inhibition and rescue.
Pharmacological studies support the idea that nitric oxide (NO) serves as a retrograde messenger during long-term potentiation (LTP) in area CA1 of the hippocampus. Mice with a defective form of the gene for neuronal NO synthase (nNOS), however, exhibit normal LTP. The myristoyl protein endothelial NOS (eNOS) is present in the dendrites of CA1 neurons. Recombinant adenovirus vectors containing either a truncated eNOS (a putative dominant negative) or an eNOS fused to a transmembrane protein were used to demonstrate that membrane-targeted eNOS is required for LTP. The membrane localization of eNOS may optimally position the enzyme both to respond to Ca2+ influx and to release NO into the extracellular space during LTP induction.


p53 Family Members Regulate Phenotypic Response to Aurora Kinase A Inhibition in Triple-Negative Breast Cancer.
Triple-negative breast cancer (TNBC) is an aggressive disease with a poor prognosis. Advances in the treatment of TNBC have been hampered by the lack of novel effective targeted therapies. The primary goal of this study was to evaluate the efficacy of targeting Aurora kinase A (AurA), a key regulator of mitosis, in TNBC models. A secondary objective was to determine the role of the p53 family of transcriptional regulators, commonly mutated in TNBC, in determining the phenotypic response to the AurA inhibitor alisertib (MLN8237). Alisertib exhibited potent antiproliferative and proapoptotic activity in a subset of TNBC models. The induction of apoptosis in response to alisertib exposure was dependent on p53 and p73 activity. In the absence of functional p53 or p73, there was a shift in the phenotypic response following alisertib exposure from apoptosis to cellular senescence. In addition, senescence was observed in patient-derived tumor xenografts with acquired resistance to alisertib treatment. AurA inhibitors are a promising class of novel therapeutics in TNBC. The role of p53 and p73 in mediating the phenotypic response to antimitotic agents in TNBC may be harnessed to develop an effective biomarker selection strategy in this difficult to target disease.


Stable transmission and expression of the hepatitis B virus total genome in hybrid transgenic mice until F10 generation.
The aim of the present study was the generation of transgenic mice carrying the complete Hepatitis B Virus (HBV) genome and investigation of the presence of Hepatitis B surface antigen (HBsAg) expression through successive generations. Transgenic mice were generated by microinjecting HBV genome into fertilized eggs. Integration and expression of HBsAg in transgenic mice were analyzed by genomic DNA PCR, Southern and slot blots and enzyme-linked immunosorbent assay (ELISA). Expression was also confirmed by Western blotting and RT-PCR. Histological changes in liver tissue of transgenic mice were examined by HE staining. The HBV genome was transmitted to the F10 generation and the presence of HBV X gene transcripts was confirmed by RT-PCR analysis using liver cDNAs from the F10 generation mice. During an observation period of 2.5 years, mice were sacrificed and their organs subjected to histopathological examination. In the liver, slight histopathologic alterations were observed but none of these lineages had any hepatocellular carcinoma (HCC). HBV DNA can be stably transmitted and expressed in the transgenic mice until F10 generation. However, although we showed the presence of X gene transcripts in liver tissues of F10 generation mice by RT-PCR in these animals, long-term expression of the HBV complete genome and expression of X protein in hepatocytes did not cause neoplasia during the life span and HCC. These transgenic mice should be useful for detailed studies of the replication and expression of HBV and for physiological studies of HBV genome.


One decade of glioblastoma multiforme surgery in 342 elderly patients: what have we learned?
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults with peak incidence in patients older than 65 years. These patients are mostly underrepresented in clinical trials and often undertreated due to concomitant diseases. Recently, different therapeutic approaches for elderly patients with GBM were discussed. To date, there is no defined standard treatment. The aim of the present study is to evaluate the functional and oncological outcome in surgical treatment of elderly patients. A total of 342 elderly patients aged ≥ 65 years were retrospectively analyzed in our neurosurgical center. Surgical therapy, adjuvant treatment, overall survival (OS) and functional outcome using Karnofsky performance scale (KPS) and Neurological assessment of neuro-oncology-score were analyzed. The median age at GBM diagnosis was 73.4 (IQR 9.28) years. Median overall survival was 7.5 (CI 95% 6.0-9.1) months and median preoperative or postoperative KPS was 80 (IQR 20). Surgical resection was performed in 216 (63.2%) patients, in 125 patients (36.5%) patients a stereotactic biopsy was performed. The median OS was significantly higher in patients with gross total resection (GTR) compared to partial resection and biopsy (10.8 months; CI 95% 9.5-12.3). Patients with combined radio- and chemo-therapy (RCT) showed significant longer OS, particularly MGMT-negative GBM. Higher preoperative KPS was found to be associated with improved overall survival. GTR and adjuvant combined RCT provides benefits for overall survival in elderly patients. Therapy decision should be made in regard to preoperative functional status instead of biological age.


PIMGAVir and Vir-MinION: Two Viral Metagenomic Pipelines for Complete Baseline Analysis of 2nd and 3rd Generation Data.
The taxonomic classification of viral sequences is frequently used for the rapid identification of pathogens, which is a key point for when a viral outbreak occurs. Both Oxford Nanopore Technologies (ONT) MinION and the Illumina (NGS) technology provide efficient methods to detect viral pathogens. Despite the availability of many strategies and software, matching them can be a very tedious and time-consuming task. As a result, we developed PIMGAVir and Vir-MinION, two metagenomics pipelines that automatically provide the user with a complete baseline analysis. The PIMGAVir and Vir-MinION pipelines work on 2nd and 3rd generation data, respectively, and provide the user with a taxonomic classification of the reads through three strategies: assembly-based, read-based, and clustering-based. The pipelines supply the scientist with comprehensive results in graphical and textual format for future analyses. Finally, the pipelines equip the user with a stand-alone platform with dedicated and various viral databases, which is a requirement for working in field conditions without internet connection.


In erosive hand osteoarthritis more inflammatory signs on ultrasound are found than in the rest of hand osteoarthritis.
To compare inflammation as assessed by ultrasound between patients with the subset erosive hand osteoarthritis (EOA) versus non-EOA. Consecutive hand osteoarthritis (HOA) patients (fulfilling ACR criteria) were included. Eighteen interphalangeal joints were scored on radiographs using the Verbruggen-Veys anatomical phase score; E and R phases were defined as erosive. Patients were assigned to EOA when at least one joint was erosive. Effusion, synovial thickening and power Doppler signal (PDS) were scored with ultrasound on a 4-point scale. Generalised estimated equation analyses were used to compare ultrasound features between EOA and HOA, and to associate ultrasound features with.anatomical phases; OR with 95% CI were calculated with adjustments for patient effects and confounders. Of 55 HOA patients (mean age 61 years, 86% women) 51% had EOA. In 94 erosive joints, synovial thickening, effusion and PDS were found in 13%, 50% and 15%, respectively; in 896 non-erosive joints in 10%, 26% and 8%, respectively. In summated scores of PDS, effusion was higher in EOA than in non-EOA. Effusion and synovial thickening were more frequent in S, J, E and R phases compared to N phase. PDS was only associated with E phase (OR 5.3, 95% CI 1.3 to 20.5) not with other phases. Non-erosive joints in EOA demonstrated more PDS (OR 3.2, 95% CI 1.6 to 6.4) and effusion (OR 2.2, 95% CI 1.2 to 3.8) in comparison to joints in non-EOA. Inflammatory signs are more frequent in EOA than in non-EOA, not only in erosive joints but also in non-erosive joints, suggesting an underlying systemic cause for erosive evolution.


Bone marrow cells in the 'pre-metastatic niche': within bone and beyond.
Metastasis, the spread of invasive carcinoma to sites distant from the primary tumor, is responsible for the majority of cancer-related deaths (Weigelt, B., Peterse, J. L., & van 't Veer, L. J. (2005). Breast cancer metastasis: Markers and models. Nature Reviews. Cancer, 5, 591-602). Despite progress in other areas of cancer therapeutics, the complexities of this process remain poorly understood. Consequently, there are few successful treatments that directly target this stage of carcinogenesis. Particularly enigmatic is the tissue-specificity of different tumor types observed in metastatic spread. One example is the predilection of colon cancer to spread to liver whereas breast, prostate, and lung carcinomas have a particular affinity to target and proliferate in bone. In 1889, Stephen Paget observed that circulating tumour cells would only "seed" where there was "congenial soil". Since then, attention has focused on explaining the dynamic adhesive and migratory capabilities intrinsic to tumor cells. Meanwhile, the earliest changes occurring within distant tissues that prime the "soil" to receive incoming cancer cells have largely been neglected. Recent work characterizing the importance of bone marrow-derived hematopoietic progenitor cells (HPC) in initiating these early changes has opened new avenues for cancer research and chemotherapeutic targeting (Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., et al. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438, 820-827). This review discusses the inextricable relationship between bone stromal components, metastasizing cells, and bone marrow-derived hematopoietic cells, and their roles in carcinogenesis and metastasis. Understanding these dynamics may help explain the tissue-specific tropism seen in metastasis. Moreover, exploring the earliest events promoting circulating cancer cells to engraft and establish at secondary sites may expose new targets for diagnostic and therapeutic strategies and reduce the morbidity and mortality from metastatic disease.


Initial experience of US Marine Corps forward resuscitative surgical system during Operation Iraqi Freedom.
Modern US Marine Corps (USMC) combat tactics are dynamic and nonlinear. While effective strategically, this can prolong the time it takes to transport the wounded to surgical capability, potentially worsening outcomes. To offset this, the USMC developed the Forward Resuscitative Surgical System (FRSS). By operating in close proximity to active combat units, these small, rapidly mobile trauma surgical teams can decrease the interval between wounding and arrival at surgical intervention with resultant improvement in outcomes. Case series. Echelon 2 surgical units during the invasion phase of Operation Iraqi Freedom. Ninety combat casualties, consisting of 30 USMC and 60 Iraqi patients, were treated in the FRSS between March 21 and April 22, 2003. Tactical surgical intervention consisting of selectively applied damage control or definitive trauma surgical procedures. Time to surgical intervention and outcome following treatment in the FRSS. Ninety combat casualties with 170 injuries required 149 procedures by 6 FRSS teams. The USMC patients were received within a median of 1 hour of wounding with the critically injured being received within a median of 30 minutes. Fifty-three USMC personnel were killed in action and 3 died of wounds for a killed in action rate of 13.5% and a died of wounds rate of 0.8% during the invasion phase of Operation Iraqi Freedom. All Marines treated in the FRSS survived. The use of the FRSS in close proximity to the point of engagement during the initial, dynamic combat phase of Operation Iraqi Freedom prevented delays in surgical intervention of USMC combat casualties with resultant beneficial effects on patient outcomes.


Racial difference in histologic subtype of renal cell carcinoma.
In the United States, renal cell carcinoma (RCC) has rapidly increased in incidence for over two decades. The most common histologic subtypes of RCC, clear cell, papillary, and chromophobe have distinct genetic and clinical characteristics; however, epidemiologic features of these subtypes have not been well characterized, particularly regarding any associations between race, disease subtypes, and recent incidence trends. Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, we examined differences in the age-adjusted incidence rates and trends of RCC subtypes, including analysis focusing on racial differences. Incidence rates increased over time (2001-2009) for all three subtypes. However, the proportion of white cases with clear cell histology was higher than among blacks (50% vs. 31%, respectively), whereas black cases were more likely than white cases to have papillary RCC (23% vs. 9%, respectively). Moreover, papillary RCC incidence increased more rapidly for blacks than whites (P < 0.01) over this period. We also observed that increased incidence of papillary histology among blacks is not limited to the smallest size strata. We observed racial differences in proportionate incidence of RCC subtypes, which appear to be increasing over time; this novel finding motivates further etiologic, clinical, molecular, and genetic studies.


Longer time spent in light physical activity is associated with reduced arterial stiffness in older adults.
Habitual moderate-to-vigorous-intensity physical activity attenuates arterial stiffening. However, it is unclear whether light physical activity also attenuates arterial stiffening. It is also unclear whether light physical activity has the same effects in fit and unfit individuals. This cross-sectional study was performed to determine the relationships between amount of light physical activity determined with a triaxial accelerometer and arterial stiffness. A total of 538 healthy men and women participated in this study. Subjects in each age category were divided into either high-light or low-light physical activity groups based on daily time spent in light physical activity. Arterial stiffness was measured by carotid-femoral pulse wave velocity. Two-way ANOVA indicated a significant interaction between age and time spent in light physical activity in determining carotid-femoral pulse wave velocity (P<0.05). In the older group, carotid femoral pulse wave velocity was higher in the low-light physical activity level group than in the high-light physical activity level group (945+/-19 versus 882+/-16 cm/s; P<0.01). The difference remained significant after normalizing carotid-femoral pulse wave velocity for amounts of moderate and vigorous physical activity. The carotid-femoral pulse wave velocity (r=-0.47; P<0.01) was correlated with daily time spent in light physical activity in older unfit subjects. No relationship was observed in older fit subjects. These results suggested that longer time spent in light physical activity is associated with attenuation of arterial stiffening, especially in unfit older people.


The effect of profound cooling on adrenergic neurotransmission in canine cutaneous veins.
1. Experiments were performed to investigate how profound cooling affects adrenergic neurotransmission and vascular smooth muscle reactivity in isolated saphenous veins of the dog. 2. Cooling from 37 to 5 degrees C caused progressive depression of the contractile responses to high K+ solutions, illustrating the direct inhibitory effect of cooling on depolarization-induced contraction of the venous smooth muscle cells. 3. During prolonged cooling to 20, 15 and 10 degrees C, the contractile response to exogenous norepinephrine (10(-8)-10(-6) M) was augmented compared to that at 37 degrees C. At 5 degrees C responses up to 10(-7) M were also augmented, but those at higher concentrations were depressed. When veins contracted with 2 x 10(-6) M-norepinephrine were cooled to 20, 15, 10 and 5 degrees C, there was a further increase in tension; this increase slowly subsided to control values at 5 degrees C but was sustained at the other temperatures. 4. Cooling to 20 and 15 degrees C augmented the contraction caused by low but not high frequencies of electrical stimulation of the adrenergic nerve endings. Further cooling to 10 degrees C depressed, and at 5 degrees C abolished the response, demonstrating that profound cooling interrupted adrenergic neurotransmission. 5. In rings stimulated electrically at a low frequency (0.5 Hz), warming from 7 to 9 degrees C or from 9 to 11 degrees C, caused marked increases in tension. This may be explained by the combination of resumption of adrenergic neurotransmission and the increased responsiveness of the cutaneous venous smooth muscle cells to adrenaline. 6. The combination of enhanced affinity for noradrenaline combined with inhibition of neurotransmitter disposition probably permits the cutaneous veins to remain constricted during exposure to severe cold.


Laboratory-based diagnosis of pneumococcal pneumonia: state of the art and unmet needs.
In view of the increasing use of pneumococcal vaccines, especially in the developing world, there is a need for appropriate diagnostics to understand the aetiology of pneumonia, to define the burden of pneumococcal disease, and to monitor vaccine efficacy and effectiveness. This article summarizes a meeting on the diagnosis, detection and serotyping of pneumococcal disease organized by PATH and Fondation Mérieux (18-20 October 2009, Fondation Mérieux Conference Centre, Les Pensières, France). Workers and experts met to discuss the gaps in the microbiology-based diagnosis of Streptococcus pneumoniae disease, with special emphasis on pneumonia. The meeting was designed to evaluate the state of the art of pneumococcal diagnostics and serotyping methodologies, identify research and development needs, and propose new guidelines to public health authorities to support the introduction of vaccines. Regarding detection, the main recommendations were to encourage chest X-rays and antigen detection in urine. Large-scale studies are needed to evaluate the diagnostic utility of test algorithms that associate chest X-rays, antigen detection in urine, S. pneumoniae quantitative PCR in nasopharyngeal aspirates and sputum, and C-reactive protein or procalcitonin measurement in blood. Efforts should be focused on proteomics to identify pneumococcus-specific antigens in urine or host markers in blood expressed during pneumonia. It was recommended to develop S. pneumoniae typing capacities, to understand the epidemiology of pneumococcal disease, and to evaluate vaccine effectiveness. Simple and effective approaches are encouraged, and new technologies based on beads, microarrays or deep sequencing should be developed to determine, in a single test capsular serotype, resistance profile and genotype.


Stromal cell-derived factor-1 as a potential therapeutic target for osteoarthritis and rheumatoid arthritis.
With age, joints become subject to chronic inflammatory processes that lead to degeneration of articular cartilage. Although multifactorial, cytokines have been shown to play a role in the pathogenesis of these chronic disease states. Stromal cell-derived factor 1 (SDF-1) is a chemokine that has been shown to be active in homeostatic mechanisms and developmental processes throughout the body, such as endochondral bone formation. SDF-1 plays a role in the transition from cartilage to bone. Although it has been shown to be a factor in normal development, it has also been shown to involve in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). In RA, SDF-1 has been shown to stimulate the recruitment of proinflammatory cells, as well as osteoclasts to the synovium, aiding in the facilitation of synovial degradation. Similarly, in OA, SDF-1 has been shown to regulate key proteins involved in the degradation of the cartilage of the joint. Because of its role in degenerative joint disease, SDF-1 has been investigated as a potential therapeutic target. Animal studies have been employing SDF-1 inhibitors, such as AMD3100 and T140, to study their effects on attenuating degenerative joint disease. These studies have shown promising results in slowing the progression of cartilage degradation and could potentially be used as therapeutic target for humans OA and RA.


Opposing actions of angiotensin-(1-7) and angiotensin II in the brain of transgenic hypertensive rats.
Lack of specific antagonists to the amino-terminal heptapeptide angiotensin-(1-7) [Ang-(1-7)] prompted us to evaluate the central effects of delivering a specific affinity-purified Ang-(1-7) antibody on the blood pressure and heart rate of 12-week-old conscious homozygous female rats (n = 12) expressing the mouse submandibular Ren-2d gene [(mRen-2d)27] in their genome. Another group of transgenic hypertensive and strain-matched Sprague-Dawley controls were injected with a specific Ang II monoclonal antibody (KAA8). Cerebroventricular administration of the affinity-purified Ang-(1-7) antibody in conscious transgenic hypertensive rats caused significant dose-related elevations in blood pressure associated with tachycardia. The hypertensive response was augmented in transgenic rats studied 7 to 10 days after cessation of lisinopril therapy. Neutralization of Ang II with the Ang II antibody caused a hemodynamic response opposite to that obtained with the Ang-(1-7) antibody. All doses of the Ang II antibody produced hypotension and bradycardia. The magnitude of the depressor response was significantly augmented in transgenic rats weaned off lisinopril therapy. In contrast, central administration of either the Ang-(1-7) or Ang II antibodies had no effect on normotensive rats. Central injections of an affinity-purified IgG fraction were ineffective in both control and transgene-positive rats. These data suggest that in the brain of transgenic hypertensive rats, Ang-(1-7) opposes the action of Ang II on the central mechanism or mechanisms that contribute to the maintenance of this model of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)


Prognostic significance of p53 immunoreactivity in patients with glioma.
Abnormal p53 as revealed by immunostaining has been shown to be a predictor of poor outcome in a variety of malignant tumors. This study examines the relationship of p53 immunostaining and survival in 182 adult patients with gliomas. Tumor tissues obtained from patients with glioma within 4 months of initial diagnosis were investigated by immunohistochemical analysis for detection of p53 protein abnormalities using the monoclonal antibody PAb 1801. There were 122 patients with glioblastoma multiforme, 48 patients with anaplastic glioma, and 12 patients with low-grade glioma. Among these patients, 73 of those with glioblastoma multiforme, 35 with anaplastic glioma, and 6 with low-grade glioma had positive p53 immunoreactivity. Kaplan-Meier survival plots (log rank test) showed that the patients with anaplastic astrocytoma or low-grade glioma and p53-positive tumors had longer survival times compared to the patients with p53-negative tumors. No differences in survival were detected among the glioblastoma patients. Cox proportional hazards regression analysis, adjusted for age at diagnosis, showed that the p53 positivity was a significant predictor of longer survival (relative risk = 0.56; 95% confidence intervals = 0.35, 0.90; P = 0. 015) in anaplastic astrocytoma patients, but not in glioblastoma patients (relative risk = 1.03; 95% confidence intervals = 0.82, 1. 29; P = 0.80). These results suggest that anaplastic glioma patients with p53 protein alterations may have a better response to chemoradiation, possibly because the malignant cells cannot arrest in G1 to correct lethal damage induced by chemotherapy or radiotherapy.


Evaluation of testicular biopsies for carcinoma in situ: immunohistochemistry is mandatory.
Carcinoma in situ (CIS) is the common precursor of all type II testicular germ cell tumors (TGCTs), i.e. seminomas and non-seminomas, which can be diagnosed using a surgical biopsy. The objective of this study was to investigate the additional value of immunohistochemistry for the diagnosis of CIS in assessing testicular biopsies taken in the context of infertility. A series of 21 infertile patients were retrieved from the Dutch pathological database (PALGA), being diagnosed with an invasive TGCT, while a matched previously obtained testicular biopsy was diagnosed as non-malignant. From 20 patients, both the invasive tumors as well as the biopsies were revised using morphology and immunohistochemistry for OCT3/4, placental-like alkaline phosphatase and c-KIT, all known established markers for CIS. The presence of CIS or invasive malignancies was scored. There are no interventions. Morphological criteria alone allowed an experienced pathologist in TGCTs to diagnose CIS in five and an invasive tumor in two cases (total n = 7, 35%). Application of immunohistochemistry resulted in the identification of an additional four cases of CIS (total n = 11, 55%, additional value of 20%). The initial correct diagnosis of CIS could have prevented a second gonadectomy in four patients (20%). This study, for the first time, really shows that time of progression from CIS to seminoma is longer than to non-seminoma. Our study demonstrates that immunohistochemistry should be performed for the diagnosis of CIS of the testis on single biopsies obtained because of infertility, resulting in an extra diagnostic yield of at least 20%. Application of this protocol will allow early diagnosis, and therefore prevent any adverse anti-cancer treatment sequelae including gonadectomy, and requiring life long androgen supplementation in some patients.


Genomic studies in fragile X premutation carriers.
The FMR1 premutation is defined as having 55 to 200 CGG repeats in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1). The clinical involvement has been well characterized for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The behavior/psychiatric and other neurological manifestations remain to be specified as well as the molecular mechanisms that will explain the phenotypic variability observed in individuals with the FMR1 premutation. Here we describe a small pilot study of copy number variants (CNVs) in 56 participants with a premutation ranging from 55 to 192 repeats. The participants were divided into four different clinical groups for the analysis: those with behavioral problems but no autism spectrum disorder (ASD); those with ASD but without neurological problems; those with ASD and neurological problems including seizures; and those with neurological problems without ASD. We found 12 rare CNVs (eight duplications and four deletions) in 11 cases (19.6%) that were not found in approximately 8,000 controls. Three of them were at 10q26 and two at Xp22.3, with small areas of overlap. The CNVs were more commonly identified in individuals with neurological involvement and ASD. The frequencies were not statistically significant across the groups. There were no significant differences in the psychometric and behavior scores among all groups. Further studies are necessary to determine the frequency of second genetic hits in individuals with the FMR1 premutation; however, these preliminary results suggest that genomic studies can be useful in understanding the molecular etiology of clinical involvement in premutation carriers with ASD and neurological involvement.


Complications of orbital implants: a review of 542 patients who have undergone orbital implantation and 275 subsequent PEG placements.
To inform patients and physicians of the complications associated with three commonly used orbital implants, as well as associated anophthalmic socket issues. A retrospective chart review of 542 patients who underwent eviscerations, enucleations and secondary procedures by one surgeon (Dr. James Oestreicher) was completed, paying special attention to complications in the follow-up period prior to pegging, as well as those that occurred post-pegging. Approximately 60% of patients experienced complications prior to implant drilling, with discharge being the most prevalent (15.9%). Secondary procedures were associated with significantly greater complication rates prior to implant drilling. Silicone implants had significantly less pre-pegging pyogenic granuloma (P = 0.011) and hypo-ophthalmos (P = 0.042) than the other implant types. Seven implants had to be removed due to exposure. Implant drilling and peg placement were performed in 275 patients. Implant drilling complications were experienced by 67.4% of pegged patients, with a change in discharge from prior to pegging (27.2%) being the most prevalent. Plastic peg systems had a significantly higher incidence of complications than titanium systems. The majority of orbital implantations involve complications, these being largely minor ones which resolve spontaneously or are easily treated. Secondary implant procedures involve a higher likelihood of complications. Silicone implants have the smallest amount of complications. Should patients decide to undergo pegging, evidence sides strongly for the use of a titanium peg and sleeve system over the other peg types. Implant removal is a rare event; occurring in 1.3% (n = 7) of the study population.


Association between age and repair of oxidatively damaged DNA in human peripheral blood mononuclear cells.
It has been hypothesised that positive associations between age and levels of oxidative stress-generated damage to DNA may be related to an age-dependent decline in DNA repair activity. The objective of this study was to investigate the association between age and repair activity of oxidatively damaged DNA in peripheral blood mononuclear cells (PBMCs). We isolated PBMCs from subjects aged 18-83 years, as part of a health survey of the Danish population that focussed on lifestyle factors. The level of DNA repair activity was measured as incisions on potassium bromate-damaged DNA by the comet assay. There was an inverse association between age and DNA repair activity with a 0.65% decline in activity per year from age 18 to 83 (95% confidence interval: 0.16-1.14% per year). Univariate regression analysis also indicated inverse associations between DNA repair activity and waist-hip ratio (P < 0.05) and plasma concentrations of glycosylated hemoglobin (P = 0.07). However, multivariate regression analysis only showed an inverse association between age and DNA repair activity (P < 0.05), indicating that the decline in repair activity was not mediated by metabolic risk factors. In summary, the results show an inverse association between age and DNA repair activity of oxidatively damaged DNA.


Endogenous spontaneous ultraweak photon emission in the formation of eye-specific retinogeniculate projections before birth.
In 1963, it was suggested [Sperry, R.W. (1963). Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc. Natl. Acad. Sci. USA 50, 703-710.] that molecular cues can direct the development of orderly connections between the eye and the brain (the "chemoaffinity hypothesis"). In the same year, the amazing degree of functional accuracy of the visual pathway in the absence of any external light/photon perception prior to birth [Wiesel, T.N and Hubel, D.H. (1963). Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26, 1003-1017.] was discovered. These recognitions revealed that the wiring of the visual system relies on innate cues. However, how the eye-specific retinogeniculate pathway can be developed before birth without any visual experience is still an unresolved issue. In the present paper, we suggest that Müller cells (functioning as optical fibers), Müller cell cone (i.e. the inner half of the foveola that is created of an inverted cone-shaped zone of Müller cells), discrete retinal noise of rods, and intrinsically photosensitive retinal ganglion cells might have key functions by means of retinal spontaneous ultraweak photon emission in the development of eye-specific retinogeniculate pathways prior to birth.


A systematic review of randomized controlled trials examining psychological interventions for needle-related procedural pain and distress in children and adolescents: an abbreviated cochrane review.
To report the results of a systematic review of randomized controlled trials (RCTs) of psychological interventions for children and adolescents undergoing needle-related procedures. A variety of cognitive-behavioral psychological interventions for managing procedural pain and distress in children and adolescents between 2 and 19 years of age were examined. Outcome measures included pain and distress as assessed by self-report, observer report, behavioral/observational measures, and physiological correlates. Twenty-eight trials met the criteria for inclusion in the review and provided the data necessary for pooling the results. Together, the trials included 1,039 participants in treatment conditions and 951 in control conditions. The largest effect sizes for treatment improvement over control conditions were found for distraction, combined cognitive-behavioral interventions, and hypnosis, with promising but limited evidence for several other psychological interventions. Recommendations for conducting future RCTs are provided, and particular attention to the quality of trial design and reporting is highlighted.


The Quality Sequencing Minimum (QSM): providing comprehensive, consistent, transparent next generation sequencing data quality assurance.
Next generation sequencing (NGS) is routinely used in clinical genetic testing. Quality management of NGS testing is essential to ensure performance is consistently and rigorously evaluated. Three primary metrics are used in NGS quality evaluation: depth of coverage, base quality and mapping quality. To provide consistency and transparency in the utilisation of these metrics we present the Quality Sequencing Minimum (QSM). The QSM defines the minimum quality requirement a laboratory has selected for depth of coverage (C), base quality (B) and mapping quality (M) and can be applied per base, exon, gene or other genomic region, as appropriate. The QSM format is CX_BY(P Y)_MZ(P Z). X is the parameter threshold for C, Y the parameter threshold for B, P Y the percentage of reads that must reach Y, Z the parameter threshold for M, P Z the percentage of reads that must reach Z. The data underlying the QSM is in the BAM file, so a QSM can be easily and automatically calculated in any NGS pipeline. We used the QSM to optimise cancer predisposition gene testing using the TruSight Cancer Panel (TSCP). We set the QSM as C50_B10(85)_M20(95). Test regions falling below the QSM were automatically flagged for review, with 100/1471 test regions QSM-flagged in multiple individuals. Supplementing these regions with 132 additional probes improved performance in 85/100. We also used the QSM to optimise testing of genes with pseudogenes such as PTEN and PMS2. In TSCP data from 960 individuals the median number of regions that passed QSM per sample was 1429 (97%). Importantly, the QSM can be used at an individual report level to provide succinct, comprehensive quality assurance information about individual test performance. We believe many laboratories would find the QSM useful. Furthermore, widespread adoption of the QSM would facilitate consistent, transparent reporting of genetic test performance by different laboratories.


Resident versus no resident: a single institutional study on operative complications, mortality, and cost.
Previous studies have demonstrated an increase in surgical morbidity, mortality, duration of stay, and costs in teaching hospitals. These studies are confounded by many variables. Controlling for these variables, we studied the effect of surgical residents on these outcomes during rotations with non-academic-based teaching faculty at a teaching hospital. Patients received care at a single teaching hospital from a group of 8 surgeons. Four surgeons did not have resident coverage (group 1) and the other 4 had coverage (group 2). Continuous severity adjusted complications, mortality, length of stay, cost, and hospital margin data were collected and compared. Five common procedures were examined: bowel resection, laparoscopic cholecystectomy, hernia, mastectomy, and appendectomy. Comparing all procedures together, there were no differences in complications between the groups, although there was greater mortality, a greater duration of stay, and higher costs in group 2. When comparing the 5 most common procedures individually, there was no difference in complications or mortality, although a greater length of stay and higher costs in group 2. Comparing the most common procedures performed individually, patients cared for by surgeons with surgical residents at a teaching hospital have an increase in duration of stay and cost, although no difference in complications or mortality compared to surgeons without residents.


Depression and mental health among older Mexican American spouses.
Although the association between marriage and well-being is well established, few studies have focused on learning more about the context of marriage and mental health. Recent research studying the mechanisms of marriage and health has focused on contagion of well-being among spouses. This study examined the association of depression with self-esteem, social support, life satisfaction, concern for independence, and cognitive function using baseline data for 553 older, Mexican American couples. Overall, we found evidence to suggest an interdependent relationship between husbands' and wives' emotional states, but the association was not equal for couples. Husbands' depression was significantly associated with the well-being of their wife, but the wife's depression was rarely associated with the husband's well-being. The findings from this study add to the increasing literature on spousal contagion by focusing on an under studied minority group, examining how depression affects well-being, and highlighting unequal effects of marriage on spousal well-being.


Cancer in General Responders Participating in World Trade Center Health Programs, 2003-2013.
Following the September 11, 2001, attacks on the World Trade Center (WTC), thousands of workers were exposed to an array of toxins known to cause adverse health effects, including cancer. This study evaluates cancer incidence in the WTC Health Program General Responder Cohort occurring within 12 years post exposure. The study population consisted of 28 729 members of the General Responder Cohort enrolled from cohort inception, July 2002 to December 31, 2013. Standardized incidence ratios (SIRs) were calculated with cancer case inclusion and follow-up starting post September 11, 2001 (unrestricted) and, alternatively, to account for selection bias, with case inclusion and follow-up starting 6 months after enrollment in the WTC Health Program (restricted). Case ascertainment was based on linkage with six state cancer registries. Under the restricted criterion, hazard ratios were estimated using multivariable Cox proportional hazards models for all cancer sites combined and for prostate cancer. Restricted analyses identified 1072 cancers in 999 responders, with elevations in cancer incidence for all cancer sites combined (SIR = 1.09, 95% confidence interval [CI] = 1.02 to 1.16), prostate cancer (SIR = 1.25, 95% CI = 1.11 to 1.40), thyroid cancer (SIR = 2.19, 95% CI = 1.71 to 2.75), and leukemia (SIR = 1.41, 95% CI = 1.01 to 1.92). Cancer incidence was not associated with any WTC exposure index (composite or individual) for all cancer sites combined or for prostate cancer. Our analyses show statistically significant elevations in cancer incidence for all cancer sites combined and for prostate and thyroid cancers and leukemia. Multivariable analyses show no association with magnitude or type of exposure.


The effect of post-translational modifications on the hemorrhagic activity of snake venom metalloproteinases.
Metalloproteinases (MPs) are Zn(+)-dependent endoproteolytic enzymes, abundant in crotalid and viperid snake venoms. Most snake venom metalloproteinases (svMPs) are active on extracellular matrix components and this effect is thought to result in bleeding as a consequence of the basement membrane disruption in capillaries. Jararhagin and ACLH are hemorrhagic svMPs from Bothrops jararaca and Agkistrodon contortrix laticinctus venom, respectively. Both enzymes demonstrate proteolytic activity on fibrinogen and fibronectin and jararhagin inhibits collagen-induced platelet aggregation in vitro. This work describes the expression, purification and successful refolding of the recombinant ACLH zymogen (rPRO-ACLH) as well as the catalytic domain of jararhagin (rCDJARA). The heterologous proteins were produced in E. coli, an in vivo expression system that does not make post-translational modifications. The recombinant refolded proteins did not show any hemorrhagic activity in mice skin, as well as the native deglycosylated jararhagin and ACLH. However, they preserved their proteolytic activity on fibrinogen and fibronectin. It seems that the hemorrhagic properties of these hemorrhagins are dependent on post-translational modifications, whereas their proteolytic activity is not dependent on such modifications.


Pressure effects on the growth of human scar fibroblasts.
Although pressure therapy is the mainstay of treatment for hypertrophic scars, its actual mechanism remains unknown. An in vitro study was designed to investigate the effects of positive pressure on the growth of human scar-derived fibroblasts through its transforming growth factor beta1 (TGF-beta1) secretion. A pneumatic pressure system connecting to a cell culture chamber was designed. Six-well cultured plates with fibroblasts implanted were treated with different pressure settings. Cells were treated with constant pressure 20 mm Hg above atmosphere pressure (group A n = 18) or with 40 mm Hg above atmosphere pressure (group B n = 18) daily for nine successive days. Cells without pressure were treated as the control study (group C n = 6). Each experimental group was divided into daily pressure applied at 24 hours (n = 6), 18 hours (n = 6), and 12 hours (n = 6). Cell counting was performed on the 2nd, 4th, 7th, 9th, 11th, and 14th day after implantation. On day 4, the concentration of transforming growth factor beta1 was measured, and cell doubling time was calculated. Compared with the control group, there was a significant decrease in cell count and the concentration in the 18-hour and 24-hour 20 mm Hg or 40 mm Hg pressure treated group. The cell doubling time was significantly increased in the 24-hour 20 mm Hg or 40 mm Hg pressure treated groups, and the 18-hour 40 mm Hg pressure treated group. (P < .05) Pressure inhibits the growth and activity of human scar fibroblasts, and a higher pressure application can shorten the daily application period. There should be an optimal pressure level corresponding to a daily application period to achieve the most effective results on pressure therapy for scars.


[Review of the utilization of the RAND appropriateness method in the biomedical literature (1999-2004)].
To identify and describe studies using the RAND/UCLA method to evaluate the appropriateness of health procedures. This method is a consensus technique that involves several phases to develop appropriateness criteria. We performed a literature search in 2005. OVIDMedline, ISI Web of Knowledge, IME and Highwire were consulted. Articles published between 1999 and 2004 and using the key words "appropriateness", "utilization review" and "physician practice patterns" were selected. Studies using the RAND method were included and those that did not explain the methodology in sufficient detail were excluded. Information on the procedure studied, the place and year of publication, and the characteristics of the journal were extracted from each article. A total of 5092 articles were identified and 205 were selected. Slightly more than half analyzed surgical or medical procedures, while 16.5% evaluated healthcare quality. More than 50% were published in journals of public health, general medicine, and gastroenterology and hepatology. The mean impact factor was 4.07. A quarter (25.4%) of the articles was published in 1999. CONCLUSIONS AND PERSPECTIVE: The RAND method is still widely used. Appropriateness criteria can be used to review utilization of procedures, to design guidelines, or to support for decision making. These tools should be reviewed to obtain evermore valid and reliable results.


Protective Effects of Intratracheally-Administered Bee Venom Phospholipase A2 on Ovalbumin-Induced Allergic Asthma in Mice.
Asthma is a common chronic disease characterized by bronchial inflammation, reversible airway obstruction, and airway hyperresponsiveness (AHR). Current therapeutic options for the management of asthma include inhaled corticosteroids and β2 agonists, which elicit harmful side effects. In the present study, we examined the capacity of phospholipase A2 (PLA2), one of the major components of bee venom (BV), to reduce airway inflammation and improve lung function in an experimental model of asthma. Allergic asthma was induced in female BALB/c mice by intraperitoneal administration of ovalbumin (OVA) on days 0 and 14, followed by intratracheal challenge with 1% OVA six times between days 22 and 30. The infiltration of immune cells, such as Th2 cytokines in the lungs, and the lung histology, were assessed in the OVA-challenged mice in the presence and absence of an intratracheal administration of bvPLA2. We showed that the intratracheal administration of bvPLA2 markedly suppressed the OVA-induced allergic airway inflammation by reducing AHR, overall area of inflammation, and goblet cell hyperplasia. Furthermore, the suppression was associated with a significant decrease in the production of Th2 cytokines, such as IL-4, IL-5, and IL-13, and a reduction in the number of total cells, including eosinophils, macrophages, and neutrophils in the airway.


The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement.
We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single-case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts. Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008) provides suitable guidance for reporting between-groups intervention studies in the behavioral sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015; Vohra et al., 2015), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioral sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated.


Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar.
Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating.


Painted supported lipid membranes.
We report herein measurements on a novel type of supported lipid films, which we call painted supported membranes (PSM). These membranes are formed in a self-assembly process on alkylated gold films from an organic solution. The formation process was investigated with surface plasmon resonance microscopy. The optical and electrical properties of the films were determined for various types of lipids and as a function of temperature by means of cyclic voltammetry and potential relaxation after charge injection. We could show that these films exhibit an extraordinarily high specific resistivity which, depending on the lipid, may be as high as 10(9) ohm/cm(2). We could also show that due to this low conductivity, an electrical polarization across the PSM relaxes with characteristic time constants of up to 20 min. The electrical properties together with their high mechanical stability and accessibility to surface sensitive techniques make these films well suitable model membranes for optical and electrical investigations. Examples for such applications are given in the subsequent article by Seifert et al.


On-line microcolumn-based dynamic leaching method for investigation of lead bioaccessibility in shooting range soils.
In this work, a miniaturized flow-through leaching test is presented for rapid screening of potential chemical extractants to explore the bioaccessibility of lead (Pb) in contaminated shooting range soils in Valkeala, Finland. The method combines the versatility of microcolumn-based extraction methods with on-line inductively coupled plasma optical emission spectrometry (ICP OES) analysis for expedient assessment of the magnitude of the bioaccessible pools and the leaching kinetics of lead from polluted soils under variable physicochemical scenarios. Acids and salt solutions were studied as potential extractants. The efficiency of the extractants relative to the initial total amount of lead in the soil sample (509 ± 21 mg/kg) were found to increase in the following order: 0.11 M acetic acid (55%) < 1 M MgCl2 (58%) < 0.1 M NH2OH·HCl (61%) < 0.1 M citric acid (93%) < 0.1 M HCl (96%). The proposed on-line microcolumn-based method was further explored for implementation of the modified BCR (now termed Standards, Measurements and Testing Programme, SM&T) sequential extraction procedure to avail the information about different fractions available in the solid sample, and validated by mass balance calculations. The equivalent sequential procedure in a batch format was then studied and compared against the on-line microcolumn extraction method. The on-line dynamic extraction system presented in this work accepts a substantial amount of sample (2.5 g) as compared to previous flow-through mini-column setups (generally accommodating < 0.25 g of sample), thus maintaining sample representativeness and fostering comprehension of the extraction patterns for non-homogenous soil materials. The use of cotton buds and Teflon membranes and holders in the microcolumn setup facilitates the repeatable flow-through leaching of trace elements and restrict formation of preferential channels. Monitoring of the leachable trace elements in real time delivers detailed insight into the ongoing extraction process and provides a time-saving assessment of potential chemical extractants.


An O(N(2)) square root unscented Kalman Filter for visual simultaneous localization and mapping.
This paper develops a Square Root Unscented Kalman Filter (SRUKF) for performing video-rate visual simultaneous localization and mapping (SLAM) using a single camera. The conventional UKF has been proposed previously for SLAM, improving the handling of nonlinearities compared with the more widely used Extended Kalman Filter (EKF). However, no account was taken of the comparative complexity of the algorithms: In SLAM, the UKF scales as O(N;{3}) in the state length, compared to the EKF's O(N;{2}), making it unsuitable for video-rate applications with other than unrealistically few scene points. Here, it is shown that the SRUKF provides the same results as the UKF to within machine accuracy and that it can be reposed with complexity O(N;{2}) for state estimation in visual SLAM. This paper presents results from video-rate experiments on live imagery. Trials using synthesized data show that the consistency of the SRUKF is routinely better than that of the EKF, but that its overall cost settles at an order of magnitude greater than the EKF for large scenes.


ARL13B regulates Sonic hedgehog signaling from outside primary cilia.
ARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of Arl13b disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To determine whether ARL13B is required within cilia, we knocked in a cilia-excluded variant of ARL13B (V358A) and showed it retains all known biochemical function. We found that ARL13BV358A protein was expressed but could not be detected in cilia, even when retrograde ciliary transport was blocked. We showed Arl13bV358A/V358A mice are viable and fertile with normal Shh signal transduction. However, in contrast to wild type cilia, Arl13bV358A/V358A cells displayed short cilia and lacked ciliary ARL3 and INPP5E. These data indicate that ARL13B's role within cilia can be uncoupled from its function outside of cilia. Furthermore, these data imply that the cilia defects upon complete absence of ARL13B do not underlie the alterations in Shh transduction, which is unexpected given the requirement of cilia for Shh transduction.


Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study.
Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [(11)C](R)-PK11195 PET of the brain. Volumes of interest were defined to obtain [(11)C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clinically (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathology is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.


Psychosocial correlates in treatment seeking gamblers: Differences in early age onset gamblers vs later age onset gamblers.
Age of onset is an important factor in the development and trajectory of psychiatric disorders; however, little is known regarding the age of onset in relation to disordered gambling in treatment seeking samples in the UK. Utilising a large residential treatment seeking gambler cohort, the current study examined the relationship between age of gambling onset and a range of variables thought to be associated with disordered gambling. Data were collected from 768 gamblers attending residential treatment for disordered gambling. Individuals were grouped per the age they started gambling as either a child (≤12), adolescent (13-15), or young adult/adult (≤16). Data were analysed using linear, backward stepwise, and multinomial logistic regressions to identify significant relationships between age of onset and variables of theoretical significance. Results indicate the younger age of gambling onset was associated with increased gambling severity. Those who began gambling at an earlier age were more likely to have abused drugs or solvents, committed an unreported crime, been verbally aggressive and experienced violent outbursts. They are less likely to report a positive childhood family environment and are more likely to have had a parent with gambling and/or alcohol problems. Gamblers who began gambling at an earlier age experience negative life events and exhibit some antisocial behaviors more than later onset gamblers, indicating that when addressing gambling behavior, it is important to consider the developmental trajectory of the disorder, rather than merely addressing current gambling behavior. However, the direction of the relationship between gambling and significant variables is in some instance unclear, indicating a need for further research to define causality.


Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo.
Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG). However, (18)F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-(18)F-(2S,4R)-fluoroglutamine ((18)F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced (18)F-FGln tumor avidity, corresponding with decreased tumor burden. (18)F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where (18)F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that (18)F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.


The Mathematics (and Metaphysics) of Identical Twins.
The metaphysics of early embryos is a hotly debated topic in contemporary bioethics and metaphysics. Many contemporary Aristotelians believe that a human being is present from the moment of conception. At the same time, certain findings in modern embryology about the formation of identical twins challenge this belief. It becomes much harder when these theories are taken into account to understand the continued identity over time of the embryo(s) given the twinning process. In this article, I will consider the philosophical implications of two models of monozygotic twinning within an Aristotelian metaphysical schema one of which is the standard, or traditional, model. The other of which is a new model recently put forward by Herranz. For the sake of completeness, I will also consider the philosophical implications of chimeras for the Aristotelian position. I will explain how Aristotelians can understand the process of twinning while holding on to their belief that a human being is present from the moment of conception. I will argue that a human being is present from the moment of conception. I will argue for this on Aristotelian grounds, and I will then defend this claim from criticisms based on a number of findings in modern embryology.


Targeting trachoma control through risk mapping: the example of Southern Sudan.
Trachoma is a major cause of blindness in Southern Sudan. Its distribution has only been partially established and many communities in need of intervention have therefore not been identified or targeted. The present study aimed to develop a tool to improve targeting of survey and control activities. A national trachoma risk map was developed using Bayesian geostatistics models, incorporating trachoma prevalence data from 112 geo-referenced communities surveyed between 2001 and 2009. Logistic regression models were developed using active trachoma (trachomatous inflammation follicular and/or trachomatous inflammation intense) in 6345 children aged 1-9 years as the outcome, and incorporating fixed effects for age, long-term average rainfall (interpolated from weather station data) and land cover (i.e. vegetation type, derived from satellite remote sensing), as well as geostatistical random effects describing spatial clustering of trachoma. The model predicted the west of the country to be at no or low trachoma risk. Trachoma clusters in the central, northern and eastern areas had a radius of 8 km after accounting for the fixed effects. In Southern Sudan, large-scale spatial variation in the risk of active trachoma infection is associated with aridity. Spatial prediction has identified likely high-risk areas to be prioritized for more data collection, potentially to be followed by intervention.


The assessment of plasma ascorbic acid, alpha tocopherol and albumin creatinine ratio in patients with chronic renal failure.
Albumin: creatinine ratio is used to assess chronic renal damage while the status of Antioxidant vitamins could be compromised in chronic renal failure patients. To assess the levels of Antioxidant vitamins and Albumin creatinine ratio, in patients with chronic renal failure. (CRF) METHODS. Thirty patients (15 males, 15 females), aged 17-80 years old diagnosed as having chronic renal failure but clinically stable were recruited from the University of Benin Teaching Hospital. The control subjects were apparently healthy individuals. Blood and urine samples were collected for antioxidant Vitamin C and E, albumin and creatinine assays respectively. Plasma vitamin E level significantly decreased ( p < 0.05) while Plasma vitamin C showed no significant difference (p > 0.05), in chronic renal failure patients when compared to the control subjects. Albumin creatinine ratio was significantly increased ( p < 0.05) compared to the control groups There are reduced levels of plasma antioxidant vitamins C and E in patients with chronic renal failure. These findings suggest that supplementation with antioxidant vitamins C and E could be beneficial to slow down the process of progressive renal damage in CRF. However we advice that more interventional studies be carried out on a larger scale to truly establish the beneficial effects of antioxidant supplementation in CRF patients.


Efficient in vivo manipulation of mouse genomic sequences at the zygote stage.
We describe a transgenic mouse line carrying the cre transgene under the control of the adenovirus EIIa promoter that targets expression of the Cre recombinase to the early mouse embryo. To assess the ability of this recombinase to excise loxP-flanked DNA sequences at early stages of development, we bred EIIa-cre transgenic mice to two different mouse lines carrying loxP-flanked target sequences: (i) a strain with a single gene-targeted neomycin resistance gene flanked by 1oxP sites and (ii) a transgenic line carrying multiple transgene copies with internal loxP sites. Mating either of these loxP-carrying mouse lines to EIIa-cre mice resulted in first generation progeny in which the loxP-flanked sequences had been efficiently deleted from all tissues tested, including the germ cells. Interbreeding of these first generation progeny resulted in efficient germ-line transmission of the deletion to subsequent generations. These results demonstrate a method by which loxP-flanked DNA sequences can be efficiently deleted in the early mouse embryo. Potential applications of this approach are discussed, including reduction of multicopy transgene loci to produce single-copy transgenic lines and introduction of a variety of subtle mutations into the line.


Gitelman syndrome and glomerular proteinuria: a link between loss of sodium-chloride cotransporter and podocyte dysfunction?
We report on a 27-year-old patient presenting with chronic hypokalaemia, inappropriate kaliuresis, hypomagnesaemia and alkalosis, associated with moderate proteinuria. Genetic analysis evidenced a homozygous mutation (p.Arg399Cys) in the SLC12A3 gene coding for the sodium-chloride cotransporter (NCC), confirming the diagnosis of Gitelman syndrome. Further genetic testing did not show any mutation in NPHS2. A renal biopsy was performed in view of the unusual association with proteinuria. Light microscopy showed hypertrophy of the juxtaglomerular apparatus and discrete mesangial thickening. In addition to possible focal segmental glomerular sclerosis lesions, electron microscopy showed extensive segments of variably thickened glomerular basement membrane (GBM), contrasting with segments of regular GBM of low range thickness, and effacement of podocyte foot processes. Of interest, alterations of the GBM were also observed in a Slc12a3 knock-out mouse model for Gitelman syndrome. These data suggest that the association between Gitelman syndrome and secondary changes of the GBM is probably not coincidental. Possible mechanisms include angiotensin II- or renin-induced podocyte lesions, as well as chronic hypokalaemia.


Volume assessment accuracy in computed tomography: a phantom study.
There is a broad push in the cancer imaging community to eventually replace linear tumor measurements with three-dimensional evaluation of tumor volume. To evaluate the potential accuracy of volume measurement in tumors by CT, a gelatin phantom consisting of 55 polymethylmethacrylate (PMMA) spheres spanning diameters from 1.6 mm to 25.4 mm was fabricated and scanned using thin slice (0.625 mm) CT (GE LightSpeed 16). Nine different reconstruction combinations of field of view dimension (FOV = 20, 30, 40 cm) and CT kernel (standard, lung, bone) were analyzed. Contiguous thin-slice images were averaged to produce CT images with greater thicknesses (1.25, 2.50, 5.0 mm). Simple grayscale thresholding techniques were used to segment the PMMA spheres from the gelatin background, where a total of 1800 spherical volumes were evaluated across the permutations studied. The geometric simplicity of the phantom established upper limits on measurement accuracy. In general, smaller slice thickness and larger sphere diameters produced more accurate volume assessment than larger slice thickness and smaller sphere diameter. The measured volumes were smaller than the actual volumes by a common factor depending on slice thickness; overall, 0.625 mm slices produced on average 18%, 1.25 mm slices produced 22%, 2.5 mm CT slices produced 29%, and 5.0 mm slices produced 39% underestimates of volume (mm3). Field of view did not have a significant effect on volume accuracy. Reconstruction algorithm significantly affected volume accuracy (p < 0.0001), with the lung kernel having the smallest error, followed by the bone and standard kernels. The results of this investigation provide guidance for CT protocol development and may guide the development of more advanced techniques to promote quantitatively accurate CT volumetric analysis of tumors.


Live Imaging of Microtubule Dynamics in Glioblastoma Cells Invading the Zebrafish Brain.
With a dismal median survival time in real populations-between 6 to 15 months-glioblastoma (GBM) is the most devastating malignant brain tumor. Treatment failure is mainly due to the invasiveness of GBM cells, which speaks for the need for a better understanding of GBM motile properties. To investigate the molecular mechanism supporting GBM invasion, new physiological models enabling in-depth characterization of protein dynamics during invasion are required. These observations would pave the way to the discovery of novel targets to block tumor infiltration and improve patient outcomes. This paper reports how an orthotopic xenograft of GBM cells in the zebrafish brain permits subcellular intravital live imaging. Focusing on microtubules (MTs), we describe a procedure for MT labeling in GBM cells, microinjecting GBM cells in the transparent brain of 3 days post fertilization (dpf) zebrafish larvae, intravital imaging of MTs in the disseminating xenografts, altering MT dynamics to assess their role during GBM invasion, and analyzing the acquired data.


Quantitative comparison of different fluorescent protein couples for fast FRET-FLIM acquisition.
The fluorescent-protein based fluorescence resonance energy transfer (FRET) approach is a powerful method for quantifying protein-protein interactions in living cells, especially when combined with fluorescence lifetime imaging microscopy (FLIM). To compare the performance of different FRET couples for FRET-FLIM experiments, we first tested enhanced green fluorescent protein (EGFP) linked to different red acceptors (mRFP1-EGFP, mStrawberry-EGFP, HaloTag (TMR)-EGFP, and mCherry-EGFP). We obtained a fraction of donor engaged in FRET (f(D)) that was far from the ideal case of one, using different mathematical models assuming a double species model (i.e., discrete double exponential fixing the donor lifetime and double exponential stretched for the FRET lifetime). We show that the relatively low f(D) percentages obtained with these models may be due to spectroscopic heterogeneity of the acceptor population, which is partially caused by different maturation rates for the donor and the acceptor. In an attempt to improve the amount of donor protein engaged in FRET, we tested mTFP1 as a donor coupled to mOrange and EYFP, respectively. mTFP1 turned out to be at least as good as EGFP for donor FRET-FLIM experiments because 1), its lifetime remained constant during light-induced fluorescent changes; 2), its fluorescence decay profile was best fitted with a single exponential model; and 3), no photoconversion was detected. The f(D) value when combined with EYFP as an acceptor was the highest of all tandems tested (0.7). Moreover, in the context of fast acquisitions, we obtained a minimal f(D) (mf(D)) for mTFP1-EYFP that was almost two times greater than that for mCherry-EGFP (0.65 vs. 0.35). Finally, we compared EGFP and mTFP1 in a biological situation in which the fusion proteins were highly immobile, and EGFP and mTFP1 were linked to the histone H4 (EGFP-H4 and mTFP1-H4) in fast FLIM acquisitions. In this particular case, the fluorescence intensity was more stable for EGFP-H4 than for mTFP1-H4. Nevertheless, we show that mTFP1/EYFP stands alone as the best FRET-FLIM couple in terms of f(D) analysis.


Applying conventional and saturated generalized gamma distributions in parametric survival analysis of breast cancer.
The generalized gamma distribution statistics constitute an extensive family that contains nearly all of the most commonly used distributions including the exponential, Weibull and log normal. A saturated version of the model allows covariates having effects through all the parameters of survival time distribution. Accelerated failure-time models assume that only one parameter of the distribution depends on the covariates. We fitted both the conventional GG model and the saturated form for each of its members including the Weibull and lognormal distribution; and compared them using likelihood ratios. To compare the selected parameter distribution with log logistic distribution which is a famous distribution in survival analysis that is not included in generalized gamma family, we used the Akaike information criterion (AIC; r=l(b)-2p). All models were fitted using data for 369 women age 50 years or more, diagnosed with stage IV breast cancer in BC during 1990-1999 and followed to 2010. In both conventional and saturated parametric models, the lognormal was the best candidate among the GG family members; also, the lognormal fitted better than log-logistic distribution. By the conventional GG model, the variables "surgery", "radiotherapy", "hormone therapy", "erposneg" and interaction between "hormone therapy" and "erposneg"are significant. In the AFT model, we estimated the relative time for these variables. By the saturated GG model, similar significant variables are selected. Estimating the relative times in different percentiles of extended model illustrate the pattern in which the relative survival time change during the time. The advantage of using the generalized gamma distribution is that it facilitates estimating a model with improved fit over the standard Weibull or log- normal distributions. Alternatively, the generalized F family of distributions might be considered, of which the generalized gamma distribution is a member and also includes the commonly used log-logistic distribution.


Physical activity in Ontario preschoolers: prevalence and measurement issues.
Early childhood is a critical period for the development of active living behaviours; however, very little is known about the physical activity levels of preschoolers from Canada. The objectives of this study were to (i) examine physical activity in a sample of Ontario preschoolers by using high-frequency accelerometry to determine activity and step counts; (ii) assess the relationship between step counts and physical activity; (iii) examine the influence of epoch length or sampling interval on physical activity; and (iv) compare measured physical activity to existing recommendations. Thirty 3- to 5-year-old children wore accelerometers to monitor habitual physical activity in 3-s epochs over a 7-day period. Preschoolers engaged in an average of 220 min of daily physical activity, 75 min of which were spent in moderate-to-vigorous physical activity (MVPA), and they accumulated 7529 ± 1539 steps·day(-1). Preschoolers who engaged in more MVPA also took more steps on a daily basis (r = 0.81, p < 0.001). Compared with a 3-s epoch, sampling intervals of 15, 30, and 60 s resulted in an average of 2.9, 9.0, and 16.7 missed minutes of MVPA per day, respectively. All 30 preschoolers met the National Association for Sport and Physical Education recommendation of at least 120 min of total physical activity per day for preschool-age children. Our data highlight important methodological considerations when measuring physical activity in preschoolers and the need for preschool-specific physical activity guidelines for Canadian children.


Psychological intervention with couples coping with breast cancer: a systematic review.
Information about psychological intervention with couples coping with breast cancer is not well-disseminated. This can be explained, at least in part, by the absence of knowledge about the efficacy of this kind of intervention. The aim of the present systematic review is to identify and describe psychological interventions for couples coping with breast cancer and evaluate their efficacy. Studies identified by a searching multiple literature databases related to health and psychology between 1975 and 2013. Rigorous inclusion and exclusion criteria were utilised. Of 129 abstracts, 13 were extracted for further analysis and a final ten studies were deemed eligible for inclusion. Data were extracted from each study regarding study sample characteristics, design, results and methodological limitations. The results obtained were mixed in regard to efficacy, although the overwhelming majority of studies (eight studies) found benefits for both women and their partners in some dimensions, such as quality of life, psychological distress, relationship functioning and physical symptoms associated with cancer. Psychological interventions for couples coping with breast cancer appear to be effective for both women and their partners. However, further studies are needed to evaluate the efficacy of couple-based interventions and, to identify for whom and how they are more effective.


Negative T wave in chest lead V1: relation to sex and future cardiovascular risk factors.
The significance of T-wave negativity in lead V1 in adults and its relationship with cardiovascular risk factors have not been clarified. This study was designed to determine the prevalence of negative T waves in chest lead V1 in an adult cohort. The study included 508 adults (278 males, mean age 51.5+/-9.7 years; 230 females, mean age 51.2+/-10.0 years) enrolled in the longitudinal Turkish Adult Risk Factor survey from all geographical regions of Turkey, whose prospective data on the prevalence of coronary heart disease and its risk factors were available for comparative assessment of T-wave groups. Associations of negative T waves were sought in relation to age, sex, cardiovascular risk factors, and coronary heart disease. The prevalence of T-wave negativity in women was significantly higher than that of men (38.3% vs 7.2%; p<0.001). No age-related differences were found between the two sexes with respect to the presence or absence of negative T waves (p>0.05). Cardiovascular risk factors and cardiometabolic conditions did not differ among men with respect to the T-wave pattern. However, women presenting negative T waves in lead V1 had significantly lower systolic blood pressure (p=0.007) and HDL-cholesterol (p=0.034) values, and a higher incidence of type 2 diabetes (p=0.048) than women with positive T waves. No convincing explanation could be offered for the significantly higher female predilection for the presence of negative T-waves in lead V1. Negative T waves in lead V1 were not associated with adverse cardiometabolic risks.


IL-17 boosts proinflammatory outcome of antiviral response in human cells.
Excessive inflammation during bacterial and viral infections is destructive to the host and involves elevated production of proinflammatory cytokines. It is especially deleterious in organs with space constraints such as lung and the CNS. Indeed, a number of viruses that infect lungs, such as avian influenza virus, SARS-associated coronavirus, and respiratory syncytial virus, elicit a very high level of proinflammatory cytokines; however, it is unclear what triggers their production. In this study, we show that IL-17 commonly produced during viral infection specifically augments a proinflammatory response by directly synergizing with antiviral signaling. Costimulation of primary human fibroblasts with IL-17 greatly enhanced respiratory syncytial virus-induced or synthetic dsRNA-based viral mimic polyinosinic:polycytidylic acid-induced expression of proinflammatory genes without affecting expression of IFN-β-stimulated or IFN-stimulated genes. Knockdown of expression of known mediators of the antiviral signaling pathway revealed that the IL-17-poly(I:C) synergy depends on the presence of the transcriptional factors RelA and IFN regulatory factor 3 and IκB kinases. Moreover, this synergy was blocked by an IκB kinase inhibitor, BAY 11-7082. These findings shed light on the molecular mechanisms behind IL-17-dependent immunopathology observed in viral infections.


An electric-field induced dynamical state in dispersions of charged colloidal rods.
The response of concentrated dispersions of charged colloids to low-frequency electric fields is governed by field-induced inter-colloidal interactions resulting from the polarization of electric double layers and the layer of condensed ions, association and dissociation of condensed ions, as well as hydrodynamic interactions through field-induced electro-osmotic flow. The phases and states that can be formed by such field-induced interactions are an essentially unexplored field of research. Experiments on concentrated suspensions of rod-like colloids (fd-virus particles), within the isotropic-nematic phase coexistence region, showed that a number of phases/states are induced, depending on the field amplitude and frequency [Soft Matter, 2010, 6, 273]. In particular, a dynamical state is found where nematic domains form and melt on a time scale of the order of seconds. We discuss the microscopic origin of this dynamical state, which is attributed to the cyclic, electric-field induced dissociation and association of condensed ions. A semi-quantitative theory is presented for the dynamics of melting and formation of nematic domains, including a model for the field-induced dissociation/association of condensed ions. The resulting equation of motion for the orientational order parameter is solved numerically for parameters complying with the fd-virus system. A limit-cycle is found, with a cycling-time that diverges at the transition line in the field-amplitude versus frequency plane where the dynamical state first appears, in accord with experimental findings.


Potential inconsistencies in Zika surveillance data and our understanding of risk during pregnancy.
A significant increase in microcephaly incidence was reported in Northeast Brazil at the end of 2015, which has since been attributed to an epidemic of Zika virus (ZIKV) infections earlier that year. Further incidence of congenital Zika syndrome (CZS) was expected following waves of ZIKV infection throughout Latin America; however, only modest increases in microcephaly and CZS incidence have since been observed. The quantitative relationship between ZIKV infection, gestational age and congenital outcome remains poorly understood. We characterised the gestational-age-varying risk of microcephaly given ZIKV infection using publicly available incidence data from multiple locations in Brazil and Colombia. We found that the relative timings and shapes of ZIKV infection and microcephaly incidence curves suggested different gestational risk profiles for different locations, varying in both the duration and magnitude of gestational risk. Data from Northeast Brazil suggested a narrow window of risk during the first trimester, whereas data from Colombia suggested persistent risk throughout pregnancy. We then used the model to estimate which combination of behavioural and reporting changes would have been sufficient to explain the absence of a second microcephaly incidence wave in Bahia, Brazil; a population for which we had two years of data. We found that a 18.9-fold increase in ZIKV infection reporting rate was consistent with observed patterns. Our study illustrates how surveillance data may be used in principle to answer key questions in the absence of directed epidemiological studies. However, in this case, we suggest that currently available surveillance data are insufficient to accurately estimate the gestational-age-varying risk of microcephaly from ZIKV infection. The methods used here may be of use in future outbreaks and may help to inform improved surveillance and interpretation in countries yet to experience an outbreak of ZIKV infection.


Intergenic transcription in the human beta-globin gene cluster.
Our previous studies on nascent transcription across the human beta-globin gene cluster revealed the presence of intergenic transcripts in addition to the expected genic transcripts. We now show that transcription into the beta-globin locus control region (LCR) begins within an ERV9 endogenous retroviral long terminal repeat upstream of DNase I hypersensitive site 5. However, in a transgenic mouse, which has the human beta-globin LCR but lacks the ERV9 LTR, transcription begins upstream of the transgenic locus. We postulate that in this transgenic mouse nearby endogenous mouse promoters are activated by the LCR. Intergenic transcription is also detected across the whole transgenic globin gene locus independently of the stage of erythroid development. Intergenic transcription in the beta-globin cluster is erythroid specific; however, it can be induced in nonerythroid cells by several means: by transinduction with a plasmid transcribing part of the cluster, by exogenous addition of transcription factors, and by treatment with the histone deacetylase inhibitor trichostatin A.


Dynamic Neural Fields with Intrinsic Plasticity.
Dynamic neural fields (DNFs) are dynamical systems models that approximate the activity of large, homogeneous, and recurrently connected neural networks based on a mean field approach. Within dynamic field theory, the DNFs have been used as building blocks in architectures to model sensorimotor embedding of cognitive processes. Typically, the parameters of a DNF in an architecture are manually tuned in order to achieve a specific dynamic behavior (e.g., decision making, selection, or working memory) for a given input pattern. This manual parameters search requires expert knowledge and time to find and verify a suited set of parameters. The DNF parametrization may be particular challenging if the input distribution is not known in advance, e.g., when processing sensory information. In this paper, we propose the autonomous adaptation of the DNF resting level and gain by a learning mechanism of intrinsic plasticity (IP). To enable this adaptation, an input and output measure for the DNF are introduced, together with a hyper parameter to define the desired output distribution. The online adaptation by IP gives the possibility to pre-define the DNF output statistics without knowledge of the input distribution and thus, also to compensate for changes in it. The capabilities and limitations of this approach are evaluated in a number of experiments.


Patient-reported outcomes in polymyalgia rheumatica.
To prospectively evaluate the disease course and the performance of clinical, patient-reported outcome (PRO) and musculoskeletal ultrasound measures in patients with polymyalgia rheumatica (PMR). The study population included 85 patients with new-onset PMR who were initially treated with prednisone equivalent dose of 15 mg daily tapered gradually, and followed for 26 weeks. Data collection included physical examination findings, laboratory measures of acute-phase reactants, and PRO measures. Ultrasound evaluation was performed at baseline and Week 26 to assess for features previously reported to be associated with PMR. Response to corticosteroid treatment was defined as 70% improvement in PMR on visual analog scale (VAS). At baseline, 77% had hip pain in addition to shoulder pain and 100% had abnormal C-reactive protein or erythrocyte sedimentation rate. On ultrasound, 84% had shoulder findings and 32% had both shoulder and hip findings. Response to corticosteroid treatment occurred in 73% of patients by Week 4 and was highly correlated with percentage improvement in other VAS measures. Presence of ultrasound findings at baseline predicted response to corticosteroids at 4 weeks. Factor analysis revealed 6 domains that sufficiently represented all the outcome measures: PMR-related pain and physical function, an elevated inflammatory marker, hip pain, global pain, mental function, and morning stiffness. PRO measures and inflammatory markers performed well in assessing disease activity in patients with PMR. A minimum set of outcome measures consisting of PRO measures of pain and function and an inflammatory marker should be used in practice and in clinical trials in PMR.


Enhanced methanol oxidation and oxygen reduction reactions on palladium-decorated FeCo@Fe/C core-shell nanocatalysts in alkaline medium.
Palladium based nano-alloys are well known for their unique electrocatalytic properties. In this work, a palladium-decorated FeCo@Fe/C core-shell nanocatalyst has been prepared by a new method called microwave-induced top-down nanostructuring and decoration (MITNAD). This simple, yet efficient technique, resulted in the generation of sub-10 nm sized FeCo@Fe@Pd nanocatalysts (mainly 3-5 nm) from a micron-sized (0.21-1.5 μm) FeCo@Fe/C. The electrocatalytic activities of the core-shell nanocatalysts were explored for methanol oxidation reaction (MOR) and oxygen reduction reaction (ORR) in alkaline medium. A negative shift of 300 mV in the onset potential for MOR was observed, with a current thrice that of the Pd/C catalysts. A very low resistance to electron transfer (Rct) was observed while the ratio of forward-to-backward oxidation current (If/Ib) was doubled. The overpotential of ORR was significantly reduced with a positive shift of about 250 mV and twice the reduction current density was observed in comparison with Pd/C nanocatalysts with the same mass loading. The kinetic parameters (in terms of the Tafel slope (b) = -59.7 mV dec(-1) (Temkin isotherm) and high exchange current density (jo) = 1.26 × 10(-2) mA cm(-2)) provide insights into the favorable electrocatalytic performance of the catalysts in ORR in alkaline media. Importantly, the core-shell nanocatalyst exhibited excellent resistance to possible methanol cross-over during ORR, which shows excellent promise for application in direct alkaline alcohol fuel cells (DAAFCs).


Effects of cerebellar transcranial direct current stimulation (tDCS) on motor skill learning in swallowing.
This study evaluated the effects of cerebellar tDCS on motor learning for swallowing. In a double-blind RCT, 39 healthy adults received either sham, anodal tDCS, or cathodal tDCS in two sessions on two consecutive days. Following 20 min cerebellar tDCS (2 mA) or sham, they underwent swallowing skill training that targeted control of timing and magnitude of submental muscle activation during swallowing. Linear mixed models were used to identify the effects of stimulation on timing and magnitude accuracy as measured by the change in task performance for each training session, and for skill retention on days 3 and 10 post-intervention. Only the sham group had a reduced temporal error from baseline to all following timepoints. When compared to error changes in the sham group, changes from baseline in temporal errors were higher at all timepoints post-intervention for the anodal group, and higher at both retention assessments for the cathodal group. Amplitude errors were smaller for all conditions at all timepoints post-intervention compared to baseline. Cerebellar tDCS was found to inhibit temporal aspects of motor skill learning in swallowing. For the tDCS parameters used in this study, there is no support for use of tDCS to facilitate swallowing rehabilitation. Trial Registry Number (https://www.anzctr.org.au/): ACTRN12615000451505.IMPLICATIONS FOR REHABILITATIONCerebellar tDCS, in combination with motor skill training, has been demonstrated to increase motor skill learning in healthy individuals and neurologically impaired patients.In this study, cerebellar tDCS applied prior to swallowing skill training adversely affected timing measures of submental muscle activation during swallowing.In contrast to published outcomes in the corticospinal literature, both anodal and cathodal tDCS resulted in a relative inhibitory effect on motor skill learning in swallowing when compared to the sham condition.Swallowing skill training without tDCS produced increased accuracy in outcomes.


Curvature-controlled defect dynamics in active systems.
We have studied the collective motion of polar active particles confined to ellipsoidal surfaces. The geometric constraints lead to the formation of vortices that encircle surface points of constant curvature (umbilics). We have found that collective motion patterns are particularly rich on ellipsoids with four umbilics where vortices tend to be located near pairs of umbilical points to minimize their interaction energy. Our results provide a perspective on the migration of living cells, which most likely use the information provided from the curved substrate geometry to guide their collective motion.