Noncalcified coronary plaque in systemic lupus erythematosus.
To study noncalcified coronary plaque (NCP) in systemic lupus erythematosus (SLE). Sixty-four-slice coronary multidetector computed tomography (MDCT) was performed in 39 consecutive patients with SLE. MDCT scans were evaluated semiquantitatively by a radiologist using dedicated software. The presence or absence of NCP in each coronary artery was assessed. Patients with mixed plaque (calcified and noncalcified portions) were included in the NCP group. The patient group was 90% women, 64% Caucasian, 31% African American, 5% other; mean age 50.5 +/- 9.6 years. Fifty-four percent (21/39) had NCP. Seventy-six percent (16/21) of those with NCP also had coronary calcium (range 0.7 to 1264.1 Agatston units). In univariate analysis, NCP was associated with age (p = 0.01), current nonsteroidal antiinflammatory drug (NSAID) use (p = 0.04), hormone replacement therapy (p = 0.02), current use of immunosuppressive drugs (p = 0.02), current low serum C3 level (p = 0.07), current physician's global assessment of activity (PGA; p = 0.05), and low-density lipoprotein cholesterol (p = 0.04). NCP was not associated with other risk factors for atherosclerosis, including total serum cholesterol, high sensitivity C-reactive protein, and lipoprotein(a). Unlike coronary calcium, which is not associated with SLE activity measures or with active serologies, NCP is more common in patients with SLE with current, 3-, and 6-month activity by PGA. NCP was also associated with the need for current NSAID or immunosuppressive therapy. NCP is an important part of the total atherosclerotic burden in SLE.


ZNF555 protein binds to transcriptional activator site of 4qA allele and ANT1: potential implication in Facioscapulohumeral dystrophy.
Facioscapulohumeral dystrophy (FSHD) is an epi/genetic satellite disease associated with at least two satellite sequences in 4q35: (i) D4Z4 macrosatellite and (ii) β-satellite repeats (BSR), a prevalent part of the 4qA allele. Most of the recent FSHD studies have been focused on a DUX4 transcript inside D4Z4 and its tandem contraction in FSHD patients. However, the D4Z4-contraction alone is not pathological, which would also require the 4qA allele. Since little is known about BSR, we investigated the 4qA BSR functional role in the transcriptional control of the FSHD region 4q35. We have shown that an individual BSR possesses enhancer activity leading to activation of the Adenine Nucleotide Translocator 1 gene (ANT1), a major FSHD candidate gene. We have identified ZNF555, a previously uncharacterized protein, as a putative transcriptional factor highly expressed in human primary myoblasts that interacts with the BSR enhancer site and impacts the ANT1 promoter activity in FSHD myoblasts. The discovery of the functional role of the 4qA allele and ZNF555 in the transcriptional control of ANT1 advances our understanding of FSHD pathogenesis and provides potential therapeutic targets.


Chronic L-arginine administration increases oxidative and nitrosative stress in rat hyperoxaluric kidneys and excessive crystal deposition.
Hyperoxaluric kidneys show an impaired diuretic response to acute infusion of L-arginine. In this study, we examined the chronic effect of l-arginine supplementation on CaOx crystal formation in hyperoxaluric rat kidneys. Eight groups were tested: control (received drinking water), L group (received L-arginine, 0.6%), LN group [received NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg)], L + LN group (received L-arginine + l-NAME), HP group [received hydroxyl-L-proline (HP, 5%) mixed with chow to induce hyperoxaluria], L + HP group (received HP + L-arginine), HP + LN group, and L + HP + LN group. The duration was 42 days, and each group had eight animals. Urinary biochemistry and renal CaOx amounts were measured, as well as renal expressions of nitric oxide synthase (NOS) isoforms and NAD(P)H oxidase. The distribution of inducible NOS (iNOS), NAD(P)H oxidase, ED1-positive cells, and nitrotyrosine was examined by immunohistochemical and immunofluorescence studies, whereas superoxide production from the kidneys was examined by fluorescence spectrometric assay. Compared with the HP group, the L + HP group had excessive CaOx crystal accumulation and enhanced endothelial NOS (eNOS), iNOS, and NAD(P)H oxidase protein expression in the kidney. Urinary excretion of nitrotyrosine was markedly increased. Increased superoxide formation in the L + HP kidney was derived from NAD(P)H oxidase and uncoupled eNOS, and increased nitrotyrosine formation might derive from iNOS and ED1-positive cells that gathered around the CaOx crystals. L-NAME cotreatment (L + HP + LN group) reduced renal oxidative nitrosative stress and tubular damage, which were induced by L + HP. The results showed that chronic l-arginine treatment to the hyperoxaluric kidney with massive CaOx crystal deposition may have a toxic effect by enhancing intrarenal oxidative and nitrosative stress.


"We lost all we had in a second": coping with grief and loss after a natural disaster.
Natural disasters cause immense suffering among affected communities. Most occur in developing countries, which have fewer resources to respond to the resulting traumas and difficulties. As a consequence, most survivors have to rely on their own coping resources and draw from what support remains within family, social networks and the wider community to manage and deal with their losses and consequent emotional distress. Taking the 2004 Asian tsunami as an example, this article reports findings from a qualitative study designed to investigate how survivors responded in Sri Lanka, and the range of coping strategies adopted and resources mobilized. In-depth interviews were conducted with 38 survivors purposively sampled from the Matara district of southern Sri Lanka. Survivors' accounts emphasized the importance of extended supportive networks, religious faith and practices, and cultural traditions in facilitating recovery and sustaining emotional well-being. Government and external aid responses that promoted these, through contributing to the re-establishment of social, cultural, and economic life, were particularly valued by participants. Recourse to professional mental health care and Western psychological interventions was limited and survivors preferred to seek help from traditional and religious healers. Our findings tentatively suggest that long-term mental health following disaster may, in the first instance, be promoted by supporting the re-establishment of those naturally occurring resources through which communities traditionally respond to suffering.


Validating predicted biological effects of Alzheimer's disease associated SNPs using CSF biomarker levels.
Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease.


Effects of scorpion venom on central and peripheral circulatory response in an open-chest dog model.
Scorpion venom can induce in dogs severe haemodynamic changes leading to rapid rise in systemic blood pressure and cardiac output, followed by reduction of cardiac output and blood pressure within 1 h. The decrease in cardiac output is not related to myocardial dysfunction (Tarasiuk et al. 1994). We hypothesized that scorpion venom affects cardiac output by reducing venous return to the heart. Venous return was studied by steady-state measurements of cardiac output, the pressure gradient and resistance to venous return, in 16 dogs following injection of 0.05 mg kg-1 venom obtained from the scorpion species Leiurus quinquestriatus. In eight of the 16 dogs, atropine (0.1 mg kg-1) was given 15 min prior to venom injection (n = 4) or 85 min (n = 4) after venom administration. In five additional dogs, the stability of the preparation over time was evaluated following the same protocol without the injection of the venom. At 15 min, the venom induced an increase in blood pressure (80%) and cardiac output (250%) (P < 0.001) with little effect on heart rate. At 90 min, cardiac output and heart rate declined considerably below baseline (P < 0.001). Atropine prevented the decrease in heart rate, but did not affect the reduction of cardiac output. Five minutes after venom injection, mean circulatory pressure increased by 300% (P < 0.001), which was accompanied by a rightward shift of the venous return curve with no effect on resistance to venous return. At 120 min, mean circulatory pressure recovered and resistance to venous return remained at 40% (P < 0.01) above baseline. This study indicates that, in dogs, scorpion venom affects cardiac output by modifying the determinants of venous return. The initial increase in cardiac output is related to increased mean circulatory pressure since resistance to venous return did not change. The later fall in cardiac output is related to the reduction of mean circulatory pressure and increased resistance to venous return.


Ocular Point-of-Care Ultrasonography to Diagnose Posterior Chamber Abnormalities: A Systematic Review and Meta-analysis.
Diagnosing posterior chamber ocular abnormalities typically requires specialist assessment. Point-of-care ultrasonography (POCUS) performed by nonspecialists, if accurate, could negate the need for urgent ophthalmologist evaluation. This meta-analysis sought to define the diagnostic test characteristics of emergency practitioner-performed ocular POCUS to diagnose multiple posterior chamber abnormalities in adults. PubMed (OVID), MEDLINE, EMBASE, Cochrane, CINAHL, and SCOPUS were searched from inception through June 2019 without restrictions. Conference abstracts and trial registries were also searched. Bibliographies of included studies and relevant reviews were manually searched, and experts in the field were queried. Included studies compared ocular POCUS performed by emergency practitioners with a reference standard of ophthalmologist evaluation. Pediatric studies were excluded. All 116 studies identified during abstract screening as potentially relevant underwent full-text review by multiple authors, and 9 studies were included. In accordance with PRISMA guidelines, multiple authors extracted data from included studies. Results were meta-analyzed for each diagnosis using a bivariate random-effects model. Data analysis was performed in July 2019. The outcomes of interest were diagnostic test characteristics of ocular POCUS for the following diagnoses: retinal detachment, vitreous hemorrhage, vitreous detachment, intraocular foreign body, globe rupture, and lens dislocation. Nine studies (1189 eyes) were included. All studies evaluated retinal detachment, but up to 5 studies assessed each of the other diagnoses of interest. For retinal detachment, sensitivity was 0.94 (95% CI, 0.88-0.97) and specificity was 0.94 (95% CI, 0.85-0.98). Sensitivity and specificity were 0.90 (95% CI, 0.65-0.98) and 0.92 (95% CI, 0.75-0.98), respectively, for vitreous hemorrhage and were 0.67 (95% CI, 0.51-0.81) and 0.89 (95% CI, 0.53-0.98), respectively, for vitreous detachment. Sensitivity and specificity were high for lens dislocation (0.97 [95% CI, 0.83-0.99] and 0.99 [95% CI, 0.97-1.00]), intraocular foreign body (1.00 [95% CI, 0.81-1.00] and 0.99 [95% CI, 0.99-1.00]), and globe rupture (1.00 [95% CI, 0.63-1.00] and 0.99 [95% CI, 0.99-1.00]). Results were generally unchanged in sensitivity analyses of studies with low risk of bias. This study suggests that emergency practitioner-performed ocular POCUS is an accurate test to assess for retinal detachment in adults. Its utility in diagnosing other posterior chamber abnormalities is promising but needs further study.


Radiological pitfalls in patients with inducible dynamic proptosis.
We report two patients presenting with marked clinical unilateral enophthalmos who had positional variability and dynamic proptosis on valsalva. On orbital imaging, enophthalmos was not documented and in fact, globe proptosis of the same side was reported for one of the patients. During CT and MRI scanning patients are often instructed to hold their breath to eliminate motion artefact. This may inadvertently induce dynamic proptosis. The radiological pitfalls of imaging patients with inducible dynamic proptosis and how to identify such patients are discussed.


[Population structure of the forest Nentsi. V. F-statistics, genetic distances and the average heterozygosity (compared to the Nganasani)].
Aspects of population structure within two of the least disintegrated "anthropological isolates" in north-western (forest Nentsi) and north-central (Nganasani) Siberia were analysed on the basis of 14 polymorphic loci. The mean FIS values were found to be 0.008 in the forest Nentsi and -0.038 in the Nganasani. The negative FIS in the latter may be due to avoidance of close inbreeding. This is not the case with the Forest Nentsi who prefer matings of the uncle-niece and first cousin's type. The mean RST(FST) values of 0.026 for the forest Nentsi and 0.009 for less heterogeneous Nganasani fall within the range of values found in subdivided human groups with a similar pattern of material culture and economy. Analysis of covariance and variance matrices containing gene frequencies for seven forest Nentsi and three Nganasani subdivisions indicate that the population structure of both groups is the product of the counterbalancing action of genetic drift and migration. Pairwise genetic and geographic distance matrices between subpopulations within both groups are highly correlated, allowing us to ascribe more than 90 percent of variation among subdivisions of the Nganasani and almost 70 percent in the forest Nentsi to the effects of geographic barriers, namely distance. Mean locus heterozygosity was found to be higher in the forest Nentsi (0.332) than in the Nganasani (0.286) reflecting pronounced difference in their histories.


Radiation, work experience, and cause specific mortality among workers at an energy research laboratory.
A retrospective cohort mortality study was conducted among 8375 white male employees who had worked at the Oak Ridge National Laboratory for at least one month between 1943 and 1972. This plant has been the site of energy related research, including uranium and plutonium reactor technology and radioisotope production. Radiation doses, primarily from gamma rays, were generally low; the median cumulative exposure for workers was 0.16 rems. Historical follow up was conducted for the years 1943-77 and ascertainment of vital status was achieved for 92.3% of the cohort. Standardised mortality ratios (SMRs) were computed to contrast the subjects' cause specific mortality experience with that of the United States white male population. The observed number of 966 deaths from all causes was 73% of the number expected. Mortality deficits were also seen for arteriosclerotic heart disease (SMR = 0.75; 344 observed) and all cancers (SMR = 0.78; 194 observed). These results are indicative of the healthy worker effect and the favourable influence on health of the cohort's relatively high socioeconomic status. Non-statistically significant raised SMRs were seen for all leukaemias (SMR = 1.49, 16 observed), cancer of the prostate (SMR = 1.16, 14 observed), and Hodgkin's disease (SMR = 1.10, 5 observed). Internal comparisons of mortality (standardised rate ratios, SRRs) were made between subgroups of the cohort according to radiation dose level and duration of employment in various job categories. No consistent gradients of cause specific mortality were detected for radiation exposure. Leukaemia mortality was highest among workers with greater than or equal to 10 years employment in engineering (SRR = 2.40) and maintenance (SRR = 3.12) jobs. The association of leukaemia with employment in engineering was unexpected; maintenance jobs entail potential exposures to radiation and to a wide range of organic chemicals; metals, and other substances.


Non-aqueous bonding of leuprorelin to ochratoxin A for peptide-based solid-phase extraction.
The anticancer therapeutic leuprorelin was found to have excellent affinity to the carcinogen ochratoxin A (OTA), with an equilibrium constant of 2.2 × 108 M-1 at 273 K (dissociation constant Kd = 4.5 nM) when functionalized into a mesoporous polymer. Binding between the surface-bound leuprorelin and mycotoxin was corroborated with DFT calculations, and it was extended to the extraction of OTA from the heavily fatty matrices of coffee, achieving 95% recovery with improved cyclability as compared with immunoaffinity. This work presents the potential of peptide-mycotoxin interactions for durable non-aqueous extraction.


Size-dependent subnanometer Pd cluster (Pd4, Pd6, and Pd17) water oxidation electrocatalysis.
Water oxidation is a key catalytic step for electrical fuel generation. Recently, significant progress has been made in synthesizing electrocatalytic materials with reduced overpotentials and increased turnover rates, both key parameters enabling commercial use in electrolysis or solar to fuels applications. The complexity of both the catalytic materials and the water oxidation reaction makes understanding the catalytic site critical to improving the process. Here we study water oxidation in alkaline conditions using size-selected clusters of Pd to probe the relationship between cluster size and the water oxidation reaction. We find that Pd4 shows no reaction, while Pd6 and Pd17 deposited clusters are among the most active (in terms of turnover rate per Pd atom) catalysts known. Theoretical calculations suggest that this striking difference may be a demonstration that bridging Pd-Pd sites (which are only present in three-dimensional clusters) are active for the oxygen evolution reaction in Pd6O6. The ability to experimentally synthesize size-specific clusters allows direct comparison to this theory. The support electrode for these investigations is ultrananocrystalline diamond (UNCD). This material is thin enough to be electrically conducting and is chemically/electrochemically very stable. Even under the harsh experimental conditions (basic, high potential) typically employed for water oxidation catalysts, UNCD demonstrates a very wide potential electrochemical working window and shows only minor evidence of reaction. The system (soft-landed Pd4, Pd6, or Pd17 clusters on a UNCD Si-coated electrode) shows stable electrochemical potentials over several cycles, and synchrotron studies of the electrodes show no evidence for evolution or dissolution of either the electrode material or the clusters.


A randomized, controlled trial of alpha-rhythm EEG neurofeedback in posttraumatic stress disorder: A preliminary investigation showing evidence of decreased PTSD symptoms and restored default mode and salience network connectivity using fMRI.
The default-mode network (DMN) and salience network (SN) have been shown to display altered connectivity in posttraumatic stress disorder (PTSD). Restoring aberrant connectivity within these networks with electroencephalogram neurofeedback (EEG-NFB) has been shown previously to be associated with acute decreases in symptoms. Here, we conducted a double-blind, sham-controlled randomized trial of alpha-rhythm EEG-NFB in participants with PTSD (n = 36) over 20-weeks. Our aim was to provide mechanistic evidence underlying clinical improvements by examining changes in network connectivity via fMRI. We randomly assigned participants with a primary diagnosis of PTSD to either the experimental group (n = 18) or sham-control group (n = 18). We collected resting-state fMRI scans pre- and post-NFB intervention, for both the experimental and sham-control PTSD groups. We further compared baseline brain connectivity measures pre-NFB to age-matched healthy controls (n = 36). With regard to the primary outcome measure of PTSD severity, we found a significant main effect of time in the absence of a group × time interaction. Nevertheless, we found significantly decreased PTSD severity scores in the experimental NFB group only, when comparing post-NFB (dz = 0.71) and 3-month follow-up scores (dz = 0.77) to baseline measures. Interestingly, we found evidence to suggest a shift towards normalization of DMN and SN connectivity post-NFB in the experimental group only. Both decreases in PTSD severity and NFB performance were correlated to DMN and SN connectivity post-NFB in the experimental group. Critically, remission rates of PTSD were significant higher in the experimental group (61.1%) as compared to the sham-control group (33.3%). The current study shows mechanistic evidence for therapeutic changes in DMN and SN connectivity that are known to be associated with PTSD psychopathology with no patient dropouts. This preliminary investigation merits further research to demonstrate fully the clinical efficacy of EEG-NFB as an adjunctive therapy for PTSD.


Noncardiogenic pulmonary edema: an unusual and serious complication of anticancer therapy.
Noncardiogenic pulmonary edema (NCPE) is a rare and less well-recognizable pulmonotoxic syndrome of anticancer therapy than pneumonitis/fibrosis. NCPE is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension/congestive heart failure. The diagnosis of drug-related NCPE relies upon documented exclusion of any infectious, metabolic, or cancer-related causes. The time proximity to therapy with drugs that are known to precipitate NCPE, any preceding episodes of flu-like symptoms during previous chemotherapy courses and possible response to corticosteroids may further support such a diagnosis. Cancer therapeutic agents clearly associated with NCPE are cytarabine, gemcitabine, and interleukin-2, as well as all-trans retinoic acid in acute promyelocytic leukemia patients, while a few other compounds have rarely or occasionally been implicated. The pathophysiology of lung injury in drug-induced NCPE remains unclear. There are indications suggesting that both a direct cytotoxic insult to the lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved in its pathogenesis. By distinction to drug-induced pulmonary pneumonitis that may lead to permanent pulmonary fibrosis, NCPE if not fatal, can be reversed upon prompt recognition, following immediate discontinuation of the offensive drug and start of intensive supportive treatment and intravenous corticosteroids.


Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung.
To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors. We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (α/β=3Gy) isodose volume and that of the total lung volume (TLV). Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (ΔFEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse ΔFEV1/FEV1pre (median=-0.16, range=-0.230 to -0.20). Five had VR20BED3<1 (low regional ventilation) and improved ΔFEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing ΔFEV1/FEV1pre (R2=0.25, p=0.03). After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.


Exposure to Hyperbaric Oxygen Intensified Vancomycin-Induced Nephrotoxicity in Rats.
It has been suggested that oxidative stress is a potential mechanism for vancomycin-induced nephrotoxicity and hyperbaric oxygen therapy (HBO) has been shown to be effective in treating renal toxicity that has been pharmacologically induced in animal models. The aim of this study was to investigate the effect of HBO therapy on vancomycin-induced nephrotoxicity in rats. The study group comprised 36 Sprague Dawley male rats. We treated 30 with 500 mg/kg of intraperitoneal vancomycin once a day for 7 days. Half of these rats received a daily 1-hour treatment with HBO at 2 Atmospheres (ATM) on the same 7 days and formed the HBO+ group. The other 15 subjects received no HBO treatment (HBO- group). The remaining six rats served as the control group, three received HBO treatments alone and no treatment was administered to the other three rats. Laboratory results were obtained on day 8 and the intervention and control groups were compared. Rats in the HBO+ group gained less weight than the HBO- group (11.6 grams vs 22.6 grams; P = 0,008) and had significantly higher serum blood urea nitrogen (99.6 vs 52.6 mg/dL; P<0.001), serum creatinine (0.42 vs 0.16 mg/dL; P = 0.001) and magnesium (3.6 vs 3.1 mg/dL; P = 0.014). The vancomycin blood levels were also higher in the HBO+ group (27.8 vs 6.7 μg/mL; P = 0.078). There were no pathological kidney changes in the control group. All the kidneys from the treated groups (vancomycin +HBO and vancomycin HBO-) showed moderate to severe histopathological changes with no statistical significance between them. This study demonstrated that exposure to hyperbaric oxygen intensified vancomycin-induced nephrotoxicity in rats.


Regional Targeting of Bladder and Urethra Afferents in the Lumbosacral Spinal Cord of Male and Female Rats: A Multiscale Analysis.
Sensorimotor circuits of the lumbosacral spinal cord are required for lower urinary tract (LUT) regulation as well as being engaged in pelvic pain states. To date, no molecular markers have been identified to enable specific visualization of LUT afferents, which are embedded within spinal cord segments that also subserve somatic functions. Moreover, previous studies have not fully investigated the patterning within or across spinal segments, compared afferent innervation of the bladder and urethra, or explored possible structural sex differences in these pathways. We have addressed these questions in adult Sprague Dawley rats, using intramural microinjection of the tract tracer, B subunit of cholera toxin (CTB). Afferent distribution was analyzed within individual sections and 3D reconstructions from sections across four spinal cord segments (L5-S2), and in cleared intact spinal cord viewed with light sheet microscopy. Simultaneous mapping of preganglionic neurons showed their location throughout S1 but restricted to the caudal half of L6. Afferents from both LUT regions extended from L5 to S2, even where preganglionic motor pathways were absent. In L6 and S1, most afferents were associated with the sacral preganglionic nucleus (SPN) and sacral dorsal commissural nucleus (SDCom), with very few in the superficial laminae of the dorsal horn. Spinal innervation patterns by bladder and urethra afferents were remarkably similar, likewise the patterning in male and female rats. In conclusion, microscale to macroscale mapping has identified distinct features of LUT afferent projections to the lumbosacral cord and provided a new anatomic approach for future studies on plasticity, injury responses, and modeling of these pathways.


Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications.
For almost three decades following the discovery of the human Hepatitis B Virus (HBV) the early events of virus infection (attachment to hepatocytes, specific binding to a receptor on hepatocytes) remained enigmatic. The gradual improvement of tissue culture systems for HBV has enabled the identification of viral determinants for viral infectivity and facilitated the discovery of the human sodium taurocholate co-transporting polypeptide (hNTCP) as a liver specific receptor of HBV and its satellite, the human Hepatitis Delta Virus (HDV). These findings are currently leading basic and clinical research activities in new directions. (1) Stable hNTCP-expressing cell lines have become a valuable platform to study the full HBV replication cycle from its native template, the cccDNA. (2) The suitability of NTCP complemented cell culture systems for high throughput screening approaches will facilitate identification of novel host factors involved in HBV replication (including those that determine the peculiar host specificity of HBV infection) and will enable identification and development of novel drug candidates for improved therapeutics. (3) Since NTCP is a major host-specific restriction factor for HBV and HDV, hNTCP-expressing animals provide the basis for future susceptible in vivo models. (4) The concept obtained with the entry inhibitor Myrcludex B demonstrates that NTCP is a suitable target for clinical interference with viral entry. This will foster further clinical approaches aiming at curative combination therapies.


Pacemaker bigeminy: pseudomalfunction.
The first reported unique case of atrial synchronized pacemaker-induced bigeminy is described and related literature is briefly discussed. The arrhythmia reported in this case can be erroneously misinterpreted as a malfunctioning pacemaker unless the physician is fully familiar with the specific nature of the atrial synchronized pacemaker. By recognizing this type of pacemaker bigeminy as an arrhythmia simply related to a normally functioning pacemaker, unnecessary surgery can be avoided.


DDParcel: deep learning anatomical brain parcellation from diffusion MRI.
Parcellation of anatomically segregated cortical and subcortical brain regions is required in diffusion MRI (dMRI) analysis for region-specific quantification and better anatomical specificity of tractography. Most current dMRI parcellation approaches compute the parcellation from anatomical MRI (T1- or T2-weighted) data, using tools such as FreeSurfer or CAT12, and then register it to the diffusion space. However, the registration is challenging due to image distortions and low resolution of dMRI data, often resulting in mislabeling in the derived brain parcellation. Furthermore, these approaches are not applicable when anatomical MRI data is unavailable. As an alternative we developed the Deep Diffusion Parcellation (DDParcel), a deep learning method for fast and accurate parcellation of brain anatomical regions directly from dMRI data. The input to DDParcel are dMRI parameter maps and the output are labels for 101 anatomical regions corresponding to the FreeSurfer Desikan-Killiany (DK) parcellation. A multi-level fusion network leverages complementary information in the different input maps, at three network levels: input, intermediate layer, and output. DDParcel learns the registration of diffusion features to anatomical MRI from the high-quality Human Connectome Project data. Then, to predict brain parcellation for a new subject, the DDParcel network no longer requires anatomical MRI data but only the dMRI data. Comparing DDParcel's parcellation with T1w-based parcellation shows higher test-retest reproducibility and a higher regional homogeneity, while requiring much less computational time. Generalizability is demonstrated on a range of populations and dMRI acquisition protocols. Utility of DDParcel's parcellation is demonstrated on tractography analysis for fiber tract identification.


NMR structure and dynamics of Q4DY78, a conserved kinetoplasid-specific protein from Trypanosoma cruzi.
The 106-residue protein Q4DY78 (UniProt accession number) from Trypanosoma cruzi is highly conserved in the related kinetoplastid pathogens Trypanosoma brucei and Leishmania major. Given the essentiality of its orthologue in T. brucei, the high sequence conservation with other trypanosomatid proteins, and the low sequence similarity with mammalian proteins, Q4DY78 is an attractive protein for structural characterization. Here, we solved the structure of Q4DY78 by solution NMR and evaluated its backbone dynamics. Q4DY78 is composed of five α -helices and a small, two-stranded antiparallel β-sheet. The backbone RMSD is 0.22 ± 0.05 Å for the representative ensemble of the 20 lowest-energy structures. Q4DY78 is overall rigid, except for N-terminal residues (V8 to I10), residues at loop 4 (K57 to G65) and residues at the C-terminus (F89 to F112). Q4DY78 has a short motif FPCAP that could potentially mediate interactions with the host cytoskeleton via interaction with EVH1 (Drosophila Enabled (Ena)/Vasodilator-stimulated phosphoprotein (VASP) homology 1) domains. Albeit Q4DY78 lacks calcium-binding motifs, its fold resembles that of eukaryotic calcium-binding proteins such as calcitracin, calmodulin, and polcacin Bet V4. We characterized this novel protein with a calcium binding fold without the capacity to bind calcium.


Respiratory depression and analgesia by opioid drugs in freely behaving larval zebrafish.
An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by μ-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.


Self-assembly of the JC virus major capsid protein, VP1, expressed in insect cells.
The major capsid protein of human polyomavirus JC virus, VP1, has been cloned into a baculovirus genome and expressed in insect cells. The VP1 protein was expressed in the cytoplasm and transported into the nucleus. It was then purified by a sucrose cushion and CsCI density gradient centrifugation to near homogeneity. Electron microscopy showed that isolated recombinant VP1 protein self-assembled into a capsid-like structure similar to the natural empty capsid. Both chelator (EDTA) and reducing agent (DTT) are required to disrupt the capsid structure into the pentameric capsomeres, as demonstrated by haemagglutination assay and electron microscopy. These results suggest that JC virus VP1 can be transported into the nucleus and self-assembled to form capsid-like particles without the involvement of the viral minor capsid proteins, VP2 and VP3. In addition, metal ions and disulphide bonds appear to be important in maintaining the integrity of the viral capsid structure.


Prevalence of and risk factors for cranial neuropathy in diabetic and non-diabetic patients.
Diabetes mellitus (DM) is a major global health concern and is associated with high morbidity and mortality as well as poor quality of life. This health burden is mostly due to complications associated with DM. Cranial nerve neuropathy is not a well-studied complication of DM. In this study, we aimed to study the prevalence and risk factors for the development of cranial neuropathy in diabetic patients. This is a cross-sectional study among diabetics who are attending Almanhal Primary Healthcare Center, Abha, Aseer Province, Saudi Arabia. A total of 714 subjects were included, 238 of them were in the study group and 476 were controls chosen randomly from the same community. SPSS program was used to calculate demographic, clinical, and biochemical parameters as well as to measure the statistically significant differences. Analysis was conducted using the SPSS statistical package and p-value lower than or equal to 0.05 was considered statistically significant. The diabetic patients were significantly older than the control group; the mean standard deviation (SD) age was 59.78 (8.26), and 34.04 (9.45) for both study and control groups, respectively. The prevalence of cranial neuropathy was higher in diabetic patients. Among diabetic patients, hyperlipidemia, gestational DM, compliance with DM treatment, and the presence of microvascular complications of DM are significant risk factors for the development of cranial neuropathy. Our results indicate that the prevalence of cranial neuropathy is higher in the diabetic population than in the non-diabetic population. The oculomotor and trigeminal nerves were the most commonly affected nerves in diabetic patients compared to the abducent and facial nerves in non-diabetic patients.


Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons.
The retinitis pigmentosa GTPase regulator (RPGR) and nephrocystin-4 (NPHP4) comprise two key partners of the assembly complex of the RPGR-interacting protein 1 (RPGRIP1). Mutations in RPGR and NPHP4 are linked to severe multisystemic diseases with strong retinal involvement of photoreceptor neurons, whereas those in RPGRIP1 cause the fulminant photoreceptor dystrophy, Leber congenital amaurosis (LCA). Further, mutations in Rpgrip1 and Nphp4 suppress the elaboration of the outer segment compartment of photoreceptor neurons by elusive mechanisms, the understanding of which has critical implications in uncovering the pathogenesis of syndromic retinal dystrophies. Here we show RPGRIP1 localizes to the photoreceptor connecting cilium (CC) distally to the centriole/basal body marker, centrin-2 and the ciliary marker, acetylated-α-tubulin. NPHP4 abuts proximally RPGRIP1, RPGR and the serologically defined colon cancer antigen-8 (SDCCAG8), a protein thought to partake in the RPGRIP1 interactome and implicated also in retinal-renal ciliopathies. Ultrastructurally, RPGRIP1 localizes exclusively throughout the photoreceptor CC and Rpgrip1(nmf247) photoreceptors present shorter cilia with a ruffled membrane. Strikingly, Rpgrip1(nmf247) mice without RPGRIP1 expression lack NPHP4 and RPGR in photoreceptor cilia, whereas the SDCCAG8 and acetylated-α-tubulin ciliary localizations are strongly decreased, even though the NPHP4 and SDCCAG8 expression levels are unaffected and those of acetylated-α-tubulin and γ-tubulin are upregulated. Further, RPGRIP1 loss in photoreceptors shifts the subcellular partitioning of SDCCAG8 and NPHP4 to the membrane fraction associated to the endoplasmic reticulum. Conversely, the ciliary localization of these proteins is unaffected in glomeruli or tubular kidney cells of Rpgrip1(nmf247), but NPHP4 is downregulated developmentally and selectively in kidney cortex. Hence, RPGRIP1 presents cell type-dependent pathological effects crucial to the ciliary targeting and subcellular partitioning of NPHP4, RPGR and SDCCAG8, and acetylation of ciliary α-tubulin or its ciliary targeting, selectively in photoreceptors, but not kidney cells, and these pathological effects underlie photoreceptor degeneration and LCA.


Update on pediatric pheochromocytoma.
Pheochromocytomas are rare tumors in children arising from chromaffin cells of adrenal medullary or extra-adrenal paraganglionic tissue. The tumors are characterized by synthesis, metabolism, and secretion of catecholamines. The formerly used guidelines for pheochromocytoma have been changed by recent discoveries, implementation of new approaches, and understanding of biochemistry, genetics, imaging, pathophysiology, and nomenclature of these tumors. In children, pheochromocytomas are more frequently familial, extra-adrenal, bilateral, and multifocal than in adults. Because of a highly variable clinical presentation, pheochromocytoma is often referred to as the great mimic. Measurements of plasma or urinary fractionated metanephrines are recommended as first-line biochemical tests for diagnosis, with optimum diagnostic sensitivity to be preferred over specificity. In general, localization studies must be used secondary to clinical and biochemical evidence. Adequate preoperative treatment with alpha-blockade is mandatory, including for pheochromocytomas that do not secrete but only synthesize catecholamines. Because approximately 40% of pheochromocytomas in children have a hereditary basis, proper genetic testing should be performed, with appropriate implications for future follow-up and treatment options. The risk for development of malignant disease depends highly on the underlying mutation, which may also impact recommendations concerning screening and surgical or systemic treatment. This article reviews recent advances in biochemistry, genetics, and imaging and outlines recommendations for improved evaluation and treatment of children with benign or malignant pheochromocytomas.


Quasilinear singularly perturbed problem with boundary perturbation.
A class of quasilinear singularly perturbed problems with boundary perturbation is considered. Under suitable conditions, using theory of differential inequalities we studied the asymptotic behavior of the solution for the boundary value problem.


Body-Centered-Cubic-Kernelled Ag15Cu6 Nanocluster with Alkynyl Protection: Synthesis, Total Structure, and CO2 Electroreduction.
While atomically monodisperse nanostructured materials are highly desirable to unravel the size- and structure-catalysis relationships, their controlled synthesis and the atomic-level structure determination pose challenges. Particularly, copper-containing atomically precise alloy nanoclusters are potential catalyst candidates for the electrochemical CO2 reduction reaction (eCO2RR) due to high abundance and tunable catalytic activity of copper. Herein, we report the synthesis and total structure of an alkynyl-protected 21-atom AgCu alloy nanocluster [Ag15Cu6(C≡CR)18(DPPE)2]-, denoted as Ag15Cu6 (HC≡CR: 3,5-bis(trifluoromethyl)phenylacetylene; DPPE: 1,2-bis(diphenylphosphino)ethane). The single-crystal X-ray diffraction reveals that Ag15Cu6 consists of an Ag11Cu4 metal core exhibiting a body-centered cubic (bcc) structure, which is capped by 2 Cu atoms, 2 Ag2DPPE motifs, and 18 alkynyl ligands. Interestingly, the Ag15Cu6 cluster exhibits excellent catalytic activity for eCO2RR with a CO faradaic efficiency (FECO) of 91.3% at -0.81 V (vs the reversible hydrogen electrode, RHE), which is much higher than that (FECO: 48.5% at -0.89 V vs RHE) of Ag9Cu6 with bcc structure. Furthermore, Ag15Cu6 shows superior stability with no significant decay in the current density and FECO during a long-term operation of 145 h. Density functional theory calculations reveal that the de-ligated Ag15Cu6 cluster can expose more space at the pair of AgCu dual metals as the efficient active sites for CO formation.


Grasping movement plans.
Despite the great amount of research that has been done regarding the time it takes to move the hand to targets of varying distances and widths, it is unclear whether target distance and width are both represented in movement plans prior to movement initiation. We addressed this question by studying performance in an object manipulation task. Our participants reached out and took hold of a familiar object (a bathroom plunger) to move it to wide or narrow targets of varying heights. Grasp heights on the plunger were additively affected by target height and target width, suggesting that both factors were taken into account by participants prior to moving the plunger from its initial position. Another factor we manipulated was the width of the base from which the plunger was lifted on its way to its next position. This factor also affected grasp heights, but no more so than target widths. The latter result contradicts the view that movement starts are planned in moredetail than movement ends, as might be expected from the fact that movement starts come sooner. Together, our results suggest that forthcoming movements are planned in considerable detail. A surprising methodological implication of this study is that recording how people prepare to move can reveal as much--or in some cases more--about what they have planned than can recording their subsequent movements.


Functional definition of the N450 event-related brain potential marker of conflict processing: a numerical stroop study.
Several conflict processing studies aimed to dissociate neuroimaging phenomena related to stimulus and response conflict processing. However, previous studies typically did not include a paradigm-independent measure of either stimulus or response conflict. Here we have combined electro-myography (EMG) with event-related brain potentials (ERPs) in order to determine whether a particularly robust marker of conflict processing, the N450 ERP effect usually related to the activity of the Anterior Cingulate Cortex (ACC), is related to stimulus- or to response-conflict processing. EMG provided paradigm-independent measure of response conflict. In a numerical Stroop paradigm participants compared pairs of digits and pressed a button on the side where they saw the larger digit. 50% of digit-pairs were preceded by an effective cue which provided accurate information about the required response. 50% of trials were preceded by a neutral cue which did not communicate the side of response. EMG showed that response conflict was significantly larger in neutrally than in effectively cued trials. The N450 was similar when response conflict was high and when it was low. We conclude that the N450 is related to stimulus or abstract, rather than to response conflict detection/resolution. Findings may enable timing ACC conflict effects.


Autosomal recessive cutis laxa: a novel mutation in the FBLN5 gene in a family.
FBLN5-related cutis laxa (CL) is a rare syndrome that can be inherited in an autosomal dominant or recessive manner. Autosomal recessive cutis laxa (ARCL), type IA, has been reported to be more severe. The disease is characterized by microcephaly, sagging cheeks, loose, wrinkled and redundant skin, emphysema, aorta or pulmonary artery abnormalities, inguinal hernia, and anomalies of internal organs. Homozygous mutations in the FBLN5 gene are responsible for the clinical manifestations. We report a family study of a child with ARCL. FBLN5 genes of the patient and parents were sequenced using next-generation sequencing technologies. Analyses showed that the patient was homozygous for the novel c.518A>G, p.R173H mutation in exon 6 of the FBLN5 gene, whereas the parents were heterozygous. The mutation was found to be 'possibly pathogenic' in bioinformatic analysis. We identified a novel FBLN5 mutation in a CL patient; pedigree and parental genetic analyses suggested ARCL. Our results also suggest that the mutation analysis provides useful evidence to support the clinical diagnosis and define the inheritance mode of CL in an apparently sporadic case.


Implementation and dissemination of an African American popular opinion model to improve lupus awareness: an academic-community partnership.
Lupus is a chronic, autoimmune disease that disproportionately affects African Americans. We adapted the Centers for Disease Control and Prevention's Popular Opinion Leader model to implement an intervention tailored for African American individuals that leverages an academic-community partnership and community-based social networks to disseminate culturally appropriate lupus education. Academic rheumatologists, social scientists, and researchers in Boston, MA and Chicago, IL partnered with local lupus support groups, community organizations, and churches in neighborhoods with higher proportions of African Americans to develop curriculum and recruit community leaders with and without lupus (Popular Opinion Leaders; POLs). POLs attended four training sessions focused on lupus education, strategies to educate others, and a review of research methods. POLs disseminated information through their social networks and recorded their impact, which was mapped using a geographic information system framework. We trained 18 POLs in greater Boston and 19 in greater Chicago: 97% were African American, 97% were female; and the mean age was 57 years. Fifty-nine percent of Boston POLs and 68% of Chicago POLs had lupus. POLs at both sites engaged members of their social networks and communities in conversations about lupus, health disparities, and the importance of care. Boston POLs documented 97 encounters with 547 community members reached. Chicago POLs documented 124 encounters with 4083 community members reached. An adapted, community-based POL model can be used to disseminate lupus education and increase awareness in African American communities. Further research is needed to determine the degree to which this may begin to reduce disparities in access to care and outcomes.


The pediatric liver transplant program at the Université Catholique de Louvain, Cliniques Saint-Luc, Brussels: overall results in 444 children (1984-1997).
Between 1984 and 1997, a total of 444 children (< 15 years) received an orthotopic liver transplant (OLT) at Saint-Luc University Clinics. Biliary atresia constituted the indication for OLT in 304 cases (68%). Median age (range) at OLT was 2.1 years (0.3-14.5). 177 children (40%) received a whole liver graft, 184 (41%) a reduced-size graft, 26 (6%) a split liver graft, whereas a living-related donor graft was used in 57 children (13%). Most grafts were ABO-identical or -compatible, in 395 cases (89%) and 40 (9%), respectively. Overall actuarial patient survivals at one and five years were 85% and 81%. The overall retransplantation rate was 19%. The results of uni- and multivariate statistical analyses showed a significant impact of year of transplantation (learning curve effect), with a 15% improvement of patient survival between the 1984-7 and the 1995-7 periods (p < 0.002). Results differed according to the indications for OLT, the best survivals being recorded for familial cholestasis, the worst for liver tumor (p = 0.004). Five year patient survival was significantly better after elective OLT (82%), when compared to highly urgent OLT (63%) (p < 0.001). Patient survivals were comparable in the children receiving primary cyclosporin-A microemulsion or tacrolimus immunosuppression, which were significantly higher than in the historical group treated with cyclosporin-A. No impact of the age at OLT, type of graft and ischemic time could be reported. In conclusion, this series illustrates the progressive improvements introduced in our pediatric liver transplant program between 1984 and 1997, including the technical variants allowing pediatric OLT using adult donors as well as the introduction of new immunosuppressive strategies.


Powerful and Adaptive Testing for Multi-trait and Multi-SNP Associations with GWAS and Sequencing Data.
Testing for genetic association with multiple traits has become increasingly important, not only because of its potential to boost statistical power, but also for its direct relevance to applications. For example, there is accumulating evidence showing that some complex neurodegenerative and psychiatric diseases like Alzheimer's disease are due to disrupted brain networks, for which it would be natural to identify genetic variants associated with a disrupted brain network, represented as a set of multiple traits, one for each of multiple brain regions of interest. In spite of its promise, testing for multivariate trait associations is challenging: if not appropriately used, its power can be much lower than testing on each univariate trait separately (with a proper control for multiple testing). Furthermore, differing from most existing methods for single-SNP-multiple-trait associations, we consider SNP set-based association testing to decipher complicated joint effects of multiple SNPs on multiple traits. Because the power of a test critically depends on several unknown factors such as the proportions of associated SNPs and of traits, we propose a highly adaptive test at both the SNP and trait levels, giving higher weights to those likely associated SNPs and traits, to yield high power across a wide spectrum of situations. We illuminate relationships among the proposed and some existing tests, showing that the proposed test covers several existing tests as special cases. We compare the performance of the new test with that of several existing tests, using both simulated and real data. The methods were applied to structural magnetic resonance imaging data drawn from the Alzheimer's Disease Neuroimaging Initiative to identify genes associated with gray matter atrophy in the human brain default mode network (DMN). For genome-wide association studies (GWAS), genes AMOTL1 on chromosome 11 and APOE on chromosome 19 were discovered by the new test to be significantly associated with the DMN. Notably, gene AMOTL1 was not detected by single SNP-based analyses. To our knowledge, AMOTL1 has not been highlighted in other Alzheimer's disease studies before, although it was indicated to be related to cognitive impairment. The proposed method is also applicable to rare variants in sequencing data and can be extended to pathway analysis.


Acoustic actuated fluorescence activated sorting of microparticles.
In this paper, we present a fluorescence activated sorter realized in a continuous flow microfluidic chip. Sorting is achieved by deflecting a focused particle stream with short acoustic bursts (2.5 ms), in a fluorescence activated configuration. The system utilizes two-dimensional acoustic pre-focusing, using a single actuation frequency, to position all particles in the same fluid velocity regime at flow rates up to 1.7 mL min(-1). Particles were sorted based on their fluorescence intensities at throughputs up to 150 particles s(-1). The highest purity reached was 80% when sorting at an average rate of 50 particles s(-1). The average recovery of a sort was 93.2 ± 2.6%. The presented system enables fluorescence activated cell sorting in a continuous flow microfluidic format that allows aseptic integration of downstream microfluidic functionalities, opening for medical and clinical applications.


[Work site health promotion in Germany--1: Program availability and effect on occupational characteristics].
Worksite health promotion and disease prevention is becoming more and more established in Germany. This study investigates the state of the health programmes utilising a representative sample of 116 companies with company health insurance. 105 companies answered the detailed questions during phone interviews or using written questionnaires. 60% of the companies offer worksite health promotion and disease prevention programmes. The focus is mainly on behavioural aspects, while structural aspects play a minor role within the programmes. To a great extent the health promotion and disease prevention programmes are independent of structural characteristics of the company and the company location. At present, an evaluation of the health benefits and cost-effectiveness of the health programmes is only of secondary interest.


Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis.
Spinocerebellar ataxias (SCAs) are rare dominantly inherited neurodegenerative disorders that lead to severe disability and premature death. To better characterize the natural history of the most common SCAs, SCA1, SCA2, SCA3 and SCA6, we performed a meta-analysis of literature to determine disease progression, provide data for sample-sizes calculations for interventional trials and study the impact of geographical locations and study follow-up on disease progression. A systematic literature search from MEDLINE and EMBASE databases for longitudinal natural history studies of SCA patients was conducted. Studies using the Scale for the Assessment and Rating Ataxia (SARA) as outcome measure were considered. Random-effect (RE) meta-analysis was applied to estimate pooled disease progression. Six studies with 1215 SCA patients enrolled between 2005 and 2016 were finally selected. Annual pooled SARA score increase was 1.83 (1.46-2.20) in patients with SCA1, 1.40 (1.19-1.61) in patients with SCA2, 1.41 (0.97-1.84) in patients with SCA3, and 0.81 (0.66-0.97) in patients with SCA6. For patients with SCA3, disease progression was faster in studies located in Asia and Europe than in the US. Two-arm interventional trials of 1-year duration to achieve 80% power and α level of 5% would require 92 patients per group with SCA1, 97 with SCA2, 115 with SCA3, and 430 with SCA6 to detect a 50% reduction in disease progression. This meta-analysis provides quantitative data on the progression of the most common spinocerebellar ataxias based on patient numbers that exceed those of previous studies and confirms that disease progression is faster in SCA1, intermediate in SCA2 and SCA3 and slower in SCA6, with similar rates of disease progression in SCA2 and SCA3 between different populations, suggesting a possibility of international collaborative studies. Nevertheless, individual-patient data meta-analysis is needed to better understand the risk factors that influence disease progression and improve patient stratification in interventional trials.


Additive effects of the herbicide glyphosate and elevated temperature on the branched coral Acropora formosa in Nha Trang, Vietnam.
The combined effects of the herbicide glyphosate and elevated temperature were studied on the tropical staghorn coral Acropora formosa, in Nha Trang bay, Vietnam. The corals were collected from two different reefs, one close to a polluted fish farm and one in a marine-protected area (MPA). In the laboratory, branches of the corals were exposed to the herbicide glyphosate at ambient (28 °C) and at 3 °C elevated water temperatures (31 °C). Effects of herbicide and elevated temperature were studied on coral bleaching using photography and digital image analysis (new colorimetric method developed here based on grayscale), chlorophyll a analysis, and symbiotic dinoflagellate (Symbiodinium, referred to as zooxanthellae) counts. All corals from the MPA started to bleach in the laboratory before they were exposed to the treatments, indicating that they were very sensitive, as opposed to the corals collected from the more polluted site, which were more tolerant and showed no bleaching response to temperature increase or herbicide alone. However, the combined exposure to the stressors resulted in significant loss of color, proportional to loss in chlorophyll a and zooxanthellae. The difference in sensitivity of the corals collected from the polluted site versus the MPA site could be explained by different symbiont types: the resilient type C3u and the stress-sensitive types C21 and C23, respectively. The additive effect of elevated temperatures and herbicides adds further weight to the notion that the bleaching of coral reefs is accelerated in the presence of multiple stressors. These results suggest that the corals in Nha Trang bay have adapted to the ongoing pollution to become more tolerant to anthropogenic stressors, and that multiple stressors hamper this resilience. The loss of color and decrease of chlorophyll a suggest that bleaching is related to concentration of chloro-pigments. The colorimetric method could be further fine-tuned and used as a precise, non-intrusive tool for monitoring coral bleaching in situ.


Abomasal emptying in sheep as related to the amount of protein entering the abomasum.
In sheep, provided with re-entrant cannulas in the caudal duodenum and with an infusion tube into the abomasal fundus, emptying of the liquid phase of the abomasal contents was studied with [57Co]EDTA. Radioactivity was measured continuously with Geiger-Müller counters placed along the re-entrant cannulas. It appeared that first-order kinetics could be applied to the elimination of [57Co]EDTA from the abomasum. Mean retention time of this label in the abomasum was 40-50 min. Infusion of a suspension of soya-bean protein in saline (9 g sodium chloride/l) caused an initially decreased rate of abomasal emptying, but after 48 h an adaptation had occurred to the original rate of emptying producing an increased volume of abomasal contents and increased flow-rate of digesta into the duodenum.


Inhibition of the activity of a neuronal kappaB-binding factor by glutamate.
Activation of transcription factors with affinity for kappaB enhancers is generally correlated with enhanced survival of neurons. In an apparent exception, excitotoxic concentrations of glutamate have been reported to elevate the activity of one such factor, nuclear factor-kappaB (NF-kappaB). Our data indicate that the constitutive neuronal kappaB-binding factor (NKBF) is distinct from bona fide NF-kappaB (RelA/p50 heterodimer). Therefore, we analyzed glutamate's effects on KB-binding activity in highly enriched primary neuronal cultures and in mixed neuron/glia cocultures. Electrophoretic mobility shift assays indicated that a 30-60-min exposure to 50-500 microM glutamate reduced NKBF activity by as much as 70%. Subtoxic doses of glutamate had little or no effect on this DNA-binding activity. Selective antagonists of either NMDA or AMPA [(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate]/kai nat e receptors inhibited the influence of glutamate on NKBF activity. The effect of glutamate was mimicked by calcium ionophore, and it was blocked by lowering extracellular calcium concentrations or by cyclosporin A. Bona fide NF-kappaB was found only in cocultures containing significant numbers of glia, where it could be activated by glutamate. These data suggest that the primary influence of excitatory amino acids on neuronal KB-binding activity is an inhibitory one, strengthening the correlation between this transcriptional parameter and neuronal survival.


Is There an Association Between Cortisol and Hypertension in Overweight or Obese Children?
The precise mechanisms behind the development of hypertension in overweight or obese children are not yet completely understood. Alterations in hypothalamic-pituitary-adrenal axis activity may play a role. We aimed to investigate the association between cortisol parameters and hypertension in overweight or obese children. Random urine (n=180) and early-morning saliva samples (n=126) for assessment of cortisol and cortisone were collected from 1) hypertensive overweight children (n=50), 2) normotensive overweight children (n=145), and 3) normotensive non-overweight children (n=75). The age of participants was 10.4±3.3 years and 53% were boys. The urinary cortisol-to-cortisone ratio [β 1.11, 95% confidence interval (CI) 1.05-1.19] as well as urinary cortisol/creatinine (β 1.38, 95% CI 1.09-1.54), and cortisone/creatinine ratios (β 1.26, 95% CI 1.17-1.36) were significantly higher in overweight or obese than in non-overweight children. After adjusting for body mass index-standard deviation score and urinary cortisone/creatinine ratio, but not cortisol/creatinine ratio, was significantly associated with presence of hypertension (β 1.12, 95% CI 1.02-1.23). Salivary cortisol and cortisone levels were significantly lower in overweight or obese than in non-overweight children (β -4.67, 95% CI -8.19- -1.15, and β 0.89, 95% CI 0.80-0.97 respectively). There were no significant differences in cortisol parameters between hypertensive and normotensive overweight or obese children. This study provided further evidence for an increased cortisol production rate with decreased renal 11β-hydroxysteroid dehydrogenase 2 activity and flattening of early-morning peak cortisol and cortisone in overweight or obese children. However, there were no significant differences in cortisol parameters between hypertensive and normotensive overweight and obese children.


cis-Regulatory sequences driving the expression of the Hbox12 homeobox-containing gene in the presumptive aboral ectoderm territory of the Paracentrotus lividus sea urchin embryo.
Embryonic development is coordinated by networks of evolutionary conserved regulatory genes encoding transcription factors and components of cell signalling pathways. In the sea urchin embryo, a number of genes encoding transcription factors display territorial restricted expression. Among these, the zygotic Hbox12 homeobox gene is transiently transcribed in a limited number of cells of the animal-lateral half of the early Paracentrotus lividus embryo, whose descendants will constitute part of the ectoderm territory. To obtain insights on the regulation of Hbox12 expression, we have explored the cis-regulatory apparatus of the gene. In this paper, we show that the intergenic region of the tandem Hbox12 repeats drives GFP expression in the presumptive aboral ectoderm and that a 234 bp fragment, defined aboral ectoderm (AE) module, accounts for the restricted expression of the transgene. Within this module, a consensus sequence for a Sox factor and the binding of the Otx activator are both required for correct Hbox12 gene expression. Spatial restriction to the aboral ectoderm is achieved by a combination of different repressive sequence elements. Negative sequence elements necessary for repression in the endomesoderm map within the most upstream 60 bp region and nearby the Sox binding site. Strikingly, a Myb-like consensus is necessary for repression in the oral ectoderm, while down-regulation at the gastrula stage depends on a GA-rich region. These results suggest a role for Hbox12 in aboral ectoderm specification and represent our first attempt in the identification of the gene regulatory circuits involved in this process.


Development of Indirect Competitive Immuno-Assay Method Using SPR Detection for Rapid and Highly Sensitive Measurement of Salivary Cortisol Levels.
The monitoring of salivary cortisol as a key biomarker of an individual's stress response has been increasingly focused on. This paper describes the development of a novel cortisol immuno-assay method based on an indirect competitive method using a commercially available surface plasmon resonance instrument. The surface of an Au chip was modified with PEG6-COOH aromatic dialkanethiol self-assembled monolayers and hydrocortisone 3-(O-carboxymethyl) oxime (hydrocortisone 3-CMO) as a cortisol analog. A detection limit of 38 ppt range with a measurement range of 10 ppt-100 ppb was accomplished without the incubation of a mixing solution consisting of standard cortisol and an anti-cortisol antibody, and the time for quantification of cortisol concentration was 8 min from the sample injection. We experimentally compared our immuno-assay with a commercialized salivary cortisol enzyme-linked immunosorbent assay (ELISA) kit using human saliva samples. It was found that the results obtained by the cortisol immuno-assay had a good correlation with those obtained by ELISA assay (R = 0.96). Our findings indicate the potential utility of the cortisol immuno-assay for measurements of human salivary cortisol levels.


Microsatellite markers for the notothenioid fish Lepidonotothen nudifrons and two congeneric species.
Loss of genetic variability due to environmental changes, limitation of gene flow between pools of individuals or putative selective pressure at specific markers, were previously documented for Antarctic notothenioid fish species. However, so far no studies were performed for the Gaudy notothen Lepidonotothen nudifrons. Starting from a species-specific spleen transcriptome library, we aimed at isolating polymorphic microsatellites (Type I; i.e. derived from coding sequences) suitable to quantify the genetic variability in this species, and additionally to assess the population genetic structure and demography in nototheniids. We selected 43,269 transcripts resulting from a MiSeq sequencer run, out of which we developed 19 primer pairs for sequences containing microsatellite repeats. Sixteen loci were successfully amplified in L. nudifrons. Eleven microsatellites were polymorphic and allele numbers per locus ranged from 2 to 17. In addition, we amplified loci identified from L. nudifrons in two other congeneric species (L. squamifrons and L. larseni). Thirteen loci were highly transferable to the two congeneric species. Differences in polymorphism among species were detected. Starting from a transcriptome of a non-model organism, we were able to identify promising polymorphic nuclear markers that are easily transferable to other closely related species. These markers can be a key instrument to monitor the genetic structure of the three Lepidonotothen species if genotyped in larger population samples. When compared with anonymous loci isolated in other notothenioids, i.e. Type II (isolated from genomic libraries), they offer the possibility to test how the effects of occurring environmental change influence the population genetic structure in each species and subsequently the composition of the entire ecosystem.


[The impact of tap water fluoridation on human health].
The purpose of this review is to describe the osteological, neurological, endocrine and dermatological effects of fluoride ingestion. Additional aims are to evaluate whether the Chilean tap water fluoridation program has had any impact on dental health, and analyze the basis for the Chilean elementary school milk fluoridation program, which is targeted at children living in places where tap water has a fluoride concentration less than 0.3 mg/L, without any artificial fluoridation process. We discuss the finding that both public measures have no direct or remarkable effect on dental health, since topical dental hygiene products are the main and most effective contributors to the prevention of dental decay. We also suggest that the permanent and systematic ingestion of fluorides imposes health risks on the population. Therefore, we recommend reevaluating the national fluoridation program for public tap water and the elementary school milk program.


Expression and identification of HERV-W family in Japanese monkeys (Macaca fuscata).
We investigated structural genes (gag, pol, env) of HERV-W family in the Macaca fuscata (Japanese monkey). Those genes are expressed in various tissues (testis, prostate, kidney, cerebellum, thymus, pancreas, intestine, stomach, ovary) of the Japanese monkey in RT-PCR and sequencing analyses. Nine clones for gag, thirty-one clones for pol and thirty-four clones for env fragments of the HERV-W family in monkey tissues were identified and analyzed. These clones showed a high degree of sequence similarity, 82.2-84.7% for gag, 88.4-91.7% for pol, and 90.8-95.4% for env, to those of HERV-W family. Translation to amino acids in all clones derived from the monkey indicated that they showed multiple interruptions of frameshifts and termination codons by deletion/insertion or point mutation. Identical sequences from different tissues of the monkey were found in env and pol clones of the HERV-W family.


Helper NLRs Nrc2 and Nrc3 act codependently with Prf/Pto and activate MAPK signaling to induce immunity in tomato.
Plant intracellular immune receptors, primarily nucleotide-binding, leucine-rich repeat proteins (NLRs), detect pathogen effector proteins and activate NLR-triggered immunity (NTI). Recently, 'sensor' NLRs have been reported to function with 'helper' NLRs to activate immunity. We investigated the role of two helper NLRs, Nrc2 and Nrc3, on immunity in tomato to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) mediated by the sensor NLR Prf and the Pto kinase. An nrc2/nrc3 mutant no longer activated Prf/Pto-mediated NTI to Pst containing the effectors AvrPto and AvrPtoB. An nrc3 mutant showed intermediate susceptibility between wild-type plants and a Prf mutant, while an nrc2 mutant developed only mild disease. These observations indicate that Nrc2 and Nrc3 act additively in Prf-/Pto-mediated immunity. We examined at what point Nrc2 and Nrc3 act in the Prf/Pto-mediated immune response. In the nrc2/3 mutant, programmed cell death (PCD) normally induced by constitutively active variants of AvrPtoB, Pto, or Prf was abolished, but that induced by M3Kα or Mkk2 was not. PCD induced by a constitutively active Nrc3 was also abolished in a Nicotiana benthamiana line with reduced expression of Prf. MAPK activation triggered by expression of AvrPto in the wild-type tomato plants was completely abolished in the nrc2/3 mutant. These results indicate that Nrc2 and Nrc3 act with Prf/Pto and upstream of MAPK signaling. Nrc2 and Nrc3 were not required for PCD triggered by Ptr1, another sensor NLR-mediating Pst resistance, although these helper NLRs do appear to be involved in resistance to certain Pst race 1 strains.


Surface Chemistry of Gold Nanoparticles Produced by Laser Ablation in Pure and Saline Water.
Pulsed laser ablation in liquid (PLAL) is a powerful method for producing nanoparticle colloids with a long-term stability despite the absence of stabilizing organic agents. The colloid stability involves different reactivities and chemical equilibria with complex ionic-specific effects at the nanoparticle/solvent interface which must be strongly influenced by their chemical composition. In this work, the surface composition of PLAL-produced gold nanoparticles in alkaline and saline (NaBr) water is investigated by X-ray photoelectron spectroscopy on free-flying nanoparticles, exempt from any substrate or radiation damage artifact. The Au 4f photoelectron spectra with a depth profiling investigation are used to evaluate the degree of nanoparticle surface oxidation. In alkaline water, the results preclude any surface oxidation contrary to the case of nanoparticles produced in NaBr solution. In addition, the analysis of Br 3d core-level photoelectron spectra agrees with a clear signature of Br on the nanoparticle surface, which is confirmed by a specific valence band feature. This experimental study is supported by DFT calculations, evaluating the energy balance of halide adsorption on different configurations of gold surfaces including oxidation or adsorbed salts.


Motivational Enhancement for Increasing Adherence to CPAP: A Randomized Controlled Trial.
Motivational enhancement (ME) shows promise as a means of increasing adherence to CPAP for OSA. We performed an open-label, parallel-arm, randomized controlled trial of CPAP only or CPAP + ME, recruiting individuals 45 to 75 years with moderate or severe OSA without marked sleepiness and with either established cardiovascular disease (CVD) or at risk for CVD. All participants received standardized CPAP support from a sleep technologist; those randomly assigned to CPAP + ME also received standardized ME delivered by a psychologist during two appointments and six phone calls over 32 weeks. Mixed-effect models with subject-specific intercepts and slopes were fitted to compare objective CPAP adherence between arms, adjusting for follow-up duration, randomization factors, and device manufacturer. All analyses were intention-to-treat. Overall, 83 participants (n = 42 CPAP only; n = 41 CPAP + ME) contributed 14,273 nights of data for 6 months. Participants were predominantly male (67%) and had a mean ± SD age of 63.9 ± 7.4 years, a BMI of 31.1 ± 5.2 kg/m(2), and an apnea-hypopnea index of 26.2 ± 12.9 events/h. In our fully adjusted model, average nightly adherence for 6 months was 99.0 min/night higher with CPAP + ME compared with CPAP only (P = .003; primary analysis). A subset of 52 participants remained in the study for 12 months; modeling these data yielded a consistent difference in adherence between arms of 97 min/night (P = .006) favoring CPAP + ME. ME delivered during brief appointments and phone calls resulted in a clinically significant increase in CPAP adherence. This strategy may represent a feasible approach for optimizing management of OSA. ClinicalTrials.gov; No.: NCT01261390; URL: www.clinicaltrials.gov.


Monoclonal antibody to human thyrotropin.
Using the technique of somatic cell fusion, a monoclonal antibody to human TSH (hTSH) has been produced. The monoclonal antibody (anti-hTSH 1/1) has an affinity (Kd = 4.04 x 10(-9) M/liter) for hTSH which is slightly less than that of the polyclonal antisera (Kd = 9.8 x 10(-10) M/liter) derived from the same mouse used for the fusion experiment. The beta-subunit of hTSH displays nearly complete cross-reaction, but has a lower affinity (Kd = 2.6 x 10(-8) M/liter) for the monoclonal antibody. hCG and its alpha- and beta-subunits as well as human LH do not cross-react with this antibody. The high specificity of this antibody will make it useful as an immunofluorescent probe of hTSH-secreting cells as well as in the immunoabsorption and purification of hTSH.


Topiramate-induced psychosis: the picture at 12 months.
A 19-year-old white British man, not previously known to psychiatric services, presented with acute onset of florid psychotic symptoms. His symptoms included auditory hallucinations, misidentification of family members, thought interference and delusions of control. His level of distress was high and did not respond to verbal or medical de-escalation; therefore, he required nursing in seclusion. It was noted that he recently had an increase of his anti-epileptic medication to 100 mg topiramate twice per day. Topiramate was thought to be the cause of his psychosis and, consequently, was changed to phenytoin. Since discontinuation of the topiramate, his psychotic symptoms settled within 4 days and he was discharged shortly afterwards. He was monitored by the Early Intervention services. At 15-months post-discharge, there was no recurrence of any symptoms despite not receiving antipsychotic medication. To our knowledge, this is the first report that describes the progress of a patient past the initial psychotic episode. Therefore, we believe this is an important finding to report.


A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro.
Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states. The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships. The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively. The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.


Extraction and analysis by liquid chromatography - tandem mass spectrometry of intra- and extracellular microcystins and nodularin to study the fate of cyanobacteria and cyanotoxins across the freshwater-marine continuum.
The presence of microcystins (MCs) is increasingly being reported in coastal areas worldwide. To provide reliable data regarding this emerging concern, reproducible and accurate methods are required to quantify MCs in salt-containing samples. Herein, we characterized methods of extraction and analysis by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for nine MCs and one nodularin (NOD) variants in both cyanobacteria (intracellular) and dissolved forms (extracellular). Different approaches have been used to cope with salinity for the extraction of dissolved MCs but none assessed solid phase extraction (SPE) so far. It was found that salt had negligible effect on the SPE recovery of dissolved MCs using the C18 cartridge while an overestimation up to 67% was noted for some variants with a polymeric sorbent. The limits of detection (LOD) and quantification (LOQ) were 1.0-22 and 5.5-124 pg on column for the intracellular toxins, while 0.05-0.81 and 0.13-2.4 ng/mL were obtained for dissolved toxins. Extraction recoveries were excellent for intracellular (89-121%) and good to excellent for extracellular cyanotoxins (73-102%) while matrix effects were considered neglectable (<12% for 16/20 toxin-matrix combinations), except for the two MC-RR variants. The strategy based on the application of a corrective factor to compensate for losses proved useful as the accuracy was satisfactory (73-117% for intra- and 81-139% for extracellular cyanotoxins, bias <10% for 46/60 conditions, with a few exceptions), with acceptable precisions (intra- and inter-days variabilities <11%). We then applied this method on natural colonies of Microcystis spp. subjected to a salt shock, mimicking their estuarine transfer, in order to assess their survival and to quantify their toxins. The colonies of Microcystis spp. had both their growth and photosynthetic activity impaired at salinities from 10, while toxins remained mainly intracellular (>76%) even at salinity 20, suggesting a potential health risk and contamination of estuarine organisms.


Frequency chirp linearization for ultraflat optical frequency comb generation based on group velocity dispersion.
We propose to insert group velocity dispersion between cascaded phase and amplitude modulation for ultraflat optical frequency comb (OFC) generation. With the dispersion, the sinusoidally varied chirp of the continuous wave light induced by phase modulation becomes linear within a relatively wide time interval. This is useful to improve the flatness of the generated OFC by directly cascaded phase and amplitude modulation. Simulation shows a flat comb of 37 tones within 0.88 dB power variation when the modulation index of the phase modulation reaches 20. An ultraflat comb generator with 10 GHz frequency spacing is also demonstrated. The flatness of the 15 tones around the center wavelength has been improved to 0.98 dB.


Normobaric and hyperbaric oxygen therapy for the treatment and prevention of migraine and cluster headache.
Migraine and cluster headaches are severe and disabling. Migraine affects up to 18% of women, while cluster headaches are much less common (0.2% of the population). A number of acute and prophylactic therapies are available. Hyperbaric oxygen therapy (HBOT) is the therapeutic administration of 100% oxygen at environmental pressures greater than one atmosphere, while normobaric oxygen therapy (NBOT) is oxygen administered at one atmosphere. This is an updated version of the original Cochrane review published in Issue 3, 2008 under the title 'Normobaric and hyperbaric oxygen for migraine and cluster headache'. To examine the efficacy and safety of normobaric oxygen therapy (NBOT) and hyperbaric oxygen therapy (HBOT) in the treatment and prevention of migraine and cluster headache. We updated searches of the following databases up to 15 June 2015: CENTRAL (the Cochrane Library), MEDLINE, EMBASE, and CINAHL. For the original review we searched the following databases up to May 2008: CENTRAL, MEDLINE, EMBASE, CINAHL, DORCTIHM, and reference lists from relevant articles. We handsearched relevant journals and contacted researchers to identify trials. Randomised controlled trials comparing HBOT or NBOT with one another, other active therapies, placebo (sham) interventions, or no treatment in participants with migraine or cluster headache. Three review authors independently extracted data and assessed the quality of the evidence using the GRADE approach. In this update, we included 11 trials with 209 participants. Five trials (103 participants) compared HBOT versus sham therapy for acute migraine, three trials compared NBOT to sham therapy or ergotamine tartrate for cluster headache (145 participants), two trials evaluated HBOT for cluster headache (29 participants), and one trial (56 participants) compared NBOT to sham for a mixed group of headache. The risk of bias varied considerably across these trials but in general trial quality was poor to moderate. One trial may not have been truly randomised and two included studies were reported as abstracts only. Seven trials did not indicate allocation concealment or randomisation method. Notably, 10 of the 11 trials used a sham comparator therapy and masked the outcome assessor to allocation.We pooled data from three trials, which suggested that HBOT was effective in relieving migraine headaches compared to sham therapy (risk ratio (RR) 6.21, 95% CI 2.41 to 16.00; 58 participants, three trials). The quality of evidence was low, having been downgraded for small crossover studies with incomplete reporting. There was no evidence that HBOT could prevent migraine episodes, reduce the incidence of nausea and vomiting, or reduce the requirement for rescue medication. There was no evidence that HBOT was effective for the termination of cluster headache (RR 11.38, 95% CI 0.77 to 167.85; P = 0.08) (one trial), but this trial had low power.NBOT was effective in terminating cluster headache compared to sham in a single small study (RR 7.88, 95% CI 1.13 to 54.66), but not superior to ergotamine administration in another small trial (RR 1.17, 95% CI 0.94 to 1.46; P = 0.16). A third trial reported a statistically significant difference in the proportion of attacks successfully treated with oxygen (117 of 150 attacks were successfully treated with NBOT (78%) versus 30 of 148 attacks treated with NBOT (20%)). The proportion of responders was consistent across these three trials, and suggested more than 75% of headaches were likely to respond to NBOT.No serious adverse events during HBOT or NBOT were reported. Since the last version of this review, two new included studies have provided additional information to change the conclusions. There was some evidence that HBOT was effective for the termination of acute migraine in an unselected population, and some evidence that NBOT was similarly effective in cluster headache. Given the cost and poor availability of HBOT, more research should be done on patients unresponsive to standard therapy. NBOT is cheap, safe, and easy to apply, so will probably continue to be used despite the limited evidence in this review.


Predictors of Occurrence and Timing of Post-Tonsillectomy Hemorrhage: A Case-Control Study.
To describe cases and timing of pediatric post-tonsillectomy hemorrhage (PTH), to evaluate predictors of PTH, and to determine the optimal amount of postoperative care unit (PACU) monitoring time. Using the Pediatric Health Information System (PHIS) database and electronic medical records, a matched case-control study from 2005 to 2015 was performed. A single, tertiary-care institution. Each case of PTH was matched with 1 to 4 controls for the following factors: age, sex, surgeon, and time of year. A total of 124 cases of PTH and 479 tonsillectomy controls were included. The rate and timing of postoperative bleeding were assessed, and matched pair analysis was performed using conditional logistic regression. Our institutional PTH rate of 1.9% (130 of 6949) included 124 patients; 15% (19) were primary (≤24 hours), with 50% (9) occurring within 5 hours. Twenty-one percent (4 of 19) of primary PTH patients received operative intervention. Eighty-five percent (105 of 124) of all cases were secondary PTH, and 47% (49) of those patients received operative intervention. Cold steel (OR 1.9, 95% CI 1.1-3.3) and Coblation (OR 1.9, 95% CI 1.2-3.1) techniques and tonsillectomy alone (OR 3.7, 95% CI 1.9-7.2) increased odds of PTH. Patients who developed PTH had 4 times the odds of having a preceding postoperative respiratory event than controls (OR 4.0, 95% CI 1.6-10.0). We conducted a rigorous case-control study for PTH, finding that PTH was associated with use of cold steel and Coblation techniques and with tonsillectomy alone. Patients with a postoperative respiratory event may be more likely to develop a PTH and should be counseled accordingly. A PACU monitoring time of 4 hours is sufficient for outpatient tonsillectomy.


Single-row versus double-row rotator cuff repair: techniques and outcomes.
Double-row rotator cuff repair techniques incorporate a medial and lateral row of suture anchors in the repair configuration. Biomechanical studies of double-row repair have shown increased load to failure, improved contact areas and pressures, and decreased gap formation at the healing enthesis, findings that have provided impetus for clinical studies comparing single-row with double-row repair. Clinical studies, however, have not yet demonstrated a substantial improvement over single-row repair with regard to either the degree of structural healing or functional outcomes. Although double-row repair may provide an improved mechanical environment for the healing enthesis, several confounding variables have complicated attempts to establish a definitive relationship with improved rates of healing. Appropriately powered rigorous level I studies that directly compare single-row with double-row techniques in matched tear patterns are necessary to further address these questions. These studies are needed to justify the potentially increased implant costs and surgical times associated with double-row rotator cuff repair.


IL-22 mRNA in peripheral blood mononuclear cells from allergic rhinitic and asthmatic pediatric patients.
T helper (T(H) )-17 lymphocytes are characterized by the expression of many regulatory cytokines, including IL-17A and IL-22, but at present no clinical data are available on the expression of these cytokines in peripheral blood mononuclear cells (PBMC) from allergic asthmatic and rhinitic (AR) children. The aim of this study was to investigate a possible relationship between IL-22 and IL-17A mRNAs and clinical parameters in seroatopic, AR, and asthmatic children. The study, conducted during the pollen season, included 18 healthy and 18 allergic (n=9 asthmatic and n=9 rhinitic) children. Serum total and specific IgE, eosinophil count, and skin prick test were performed; in addition, IL-22 and IL-17A mRNA levels were detected in PBMC from healthy and allergic subjects by quantitative real-time PCR. Despite the absence of the mRNA for the IL-17A cytokine, IL-22 expression was found in PBMC from asthmatic patients, with increased IL-22 mRNA levels in patients with chronic severe respect to those with moderate asthma. A positive correlation between IL-22 mRNA and serum total IgE levels was found in asthmatic children. In addition, higher IL-22 and IL-17A mRNA levels were detected in both AR and asymptomatic seroatopic children, compared to healthy individuals, and a correlation between IL-22 and IL17A mRNA and serum total IgE levels was demonstrated. Moreover, the mRNA level of retinoic acid-related orphan receptor C, the T(H) 17 transcription factor, was found to be increased in AR but not in asthmatic patients. This study provides the first evidence that IL-22 mRNA might be expressed in chronic severe asthmatic and AR children. The expression of IL-22 and IL-17A mRNAs in asymptomatic monosensitized seroatopic children suggests a role of these cytokines in the early events involved in the development of these allergic diseases.


Laboratory rotational spectrum and astronomical search for methoxyacetaldehyde.
Methoxyacetaldehyde belongs to a group of structural isomers with the general formula C3H6O2, of which methyl acetate and ethyl formate are known interstellar molecules. Rotational data available for methoxyacetaldehyde are limited to 40 GHz, which makes predictions at higher frequencies rather uncertain. The aim of this work is to provide accurate experimental frequencies of methoxyacetaldehyde in the millimeter-wave region to support its detection in the interstellar medium. The rotational spectrum of methoxyacetaldehyde was recorded at room-temperature from 75 to 120 GHz and from 170 to 310 GHz using the millimeter-wave spectrometer in Valladolid. Additional measurements were also performed at conditions of supersonic expansion from 6 to 18 GHz. The assigned rotational transitions were analyzed using the S -reduced semirigid-rotor Hamiltonian. We newly assigned over 1000 lines for the most stable conformer of methoxyacetaldehyde in its ground state and five lowest excited vibrational states, and precise sets of spectroscopic constants were obtained. We searched for spectral features of methoxyacetaldehyde in the high-mass star-forming regions Orion KL and Sagittarius B2, as well as in the cold dark cloud Barnard 1 (B1-b). No lines belonging to methoxyacetaldehyde were detected above the detection limit of our data. We provide upper limits to the methoxyacetaldehyde colum density in these sources.


[The ultrastructure of psoriatic nail changes].
The various and subsequent psoriatic nail changes can only be understood on the basis of parakeratotic changes. If parakeratosis is localized in the nail matrix specific changes in the nail will result depending on localization and spreading in the matrix. Punctate indentations (pits) may develop; if there is a ribbon-like, square-dimensioned localization we see streaks and ridges (psoriasis unguis striata). If parakeratotic cells invade the whole of the matrix the so-called psoriasis unguis crateriformis will develop. Well-known to the dermatologist is the irregular salmon-colored patch--a type of psoriasis involving the nail-bed. This salmon-colored patch may finally cause onycholysis semilunaris as the nail plate is not fixed to the nail-bed any longer. There may be onycholysis, too, if the cuticle is involved in the course of the psoriatic change. A long-standing psoriasis of the nails is characterized by para- or hyperkeratotic masses ("Krümelnagel").


Regional differences in trabecular BMD and micro-architecture of weight-bearing bone under habitual gait loading--a pQCT and microCT study in human cadavers.
This study used both multi-slice pQCT and microCT to investigate regional changes in bone mineral density and structural parameters in the ultradistal tibia and in the mid-femoral neck under habitual gait loading. Twenty cadavers with 2 females and 18 males aged 70.8 +/- 8.5 were used in this study. Seventy-two cylindrical bone cores with 5 mm in diameter and 10 mm in length from the anterior/posterior and superior/inferior regions were obtained from ultradistal tibia and mid-femur neck, respectively, so that their differences in terms of volumetric trabecular bone mineral density (tBMD) as well as micro-architectural parameters could be studied. The results showed that the mean volumetric tBMD at both the organ (including the bone marrow spaces) and tissue levels (excluding the bone marrow spaces) were a 49.2% and 28.3%, respectively, lower in the anterior bone cores than in the posterior bone cores from the ultradistal tibia (P < 0.01). MicroCT measurements on BV/TV, BS/TV, Tb.N, Tb.Th, and DA were found to be on average of 33.5%, 23.6%, 9.1%, 18.0%, and 14.6%, respectively, lower in the anterior trabecular bone cores (P < 0.001), while Tb.Sp and SMI were 12.5% and 29.3%, respectively, higher in the anterior trabecular bone cores (P < 0.01). No significant difference in micro-architectural parameters was found in the trabecular bone cores obtained from mid-femoral neck, except that the mean DA of the inferior bone cores was significantly higher by 30.1% than that of the superior bone cores (P = 0.01). A statistically significant linear relationship with the correlation coefficient, ranging from 0.37 to 0.94 and -0.62 to -0.85, respectively, was shown between the tBMD at the organ level and all of the micro-architectural parameters (P < 0.05). We suggest that dynamic loading changes during the striking of the heel in normal gait, as well as the peaks of the hip joint reaction force occur during the heel strike and before toe off positions in the lifetime of the subject may account for such regional differences in BMD and micro-architecture. The findings from the correlation study also suggest that, apart from BMD, the micro-architecture may exhibit adaptation in response to such excessive loading.