New meanings of thin-skinned: The contrasting attentional profiles of typical 12-month-olds who show high, and low, stress reactivity.
Previous research is inconsistent as to whether a more labile (faster-changing) autonomic system confers performance advantages, or disadvantages, in infants and children. To examine this, we presented a stimulus battery consisting of mixed static and dynamic viewing materials to a cohort of 63 typical 12-month-old infants. While viewing the battery, infants' spontaneous visual attention (looks to and away from the screen) was measured. Concurrently, arousal was recorded via heart rate (HR), electrodermal activity, head velocity, and peripheral movement levels. In addition, stress reactivity was assessed using a mild behavioral stressor (watching a video of another infant crying). We found that infants who were generally more attentive showed smaller HR increases to the stressor. However, they also showed greater phasic autonomic changes to attractive, attention-getting stimulus events, a faster rate of change of both look duration and of arousal, and more general oscillatory activity in arousal. Finally, 4 sessions of attention training were applied to a subset of the infants (24 trained, 24 active controls), which had the effect of increasing visual sustained attention. No changes in HR responses to stressor were observed as a result of training, but concomitant increases in arousal lability were observed. Our results point to 2 contrasting autonomic profiles: infants with high autonomic reactivity to stressors show short attention durations, whereas infants with lower autonomic reactivity show longer attention durations and greater arousal lability. (PsycINFO Database Record


Vertical 1T-MoS2 nanosheets with expanded interlayer spacing edged on a graphene frame for high rate lithium-ion batteries.
Vertical 1T-MoS2 nanosheets with an expanded interlayer spacing of 9.8 Å were successfully grown on a graphene surface via a one-step solvothermal method. Such unique hybridized structures provided strong electrical and chemical coupling between the vertical nanosheets and graphene layers by means of C-O-Mo bonding. The merits are very beneficial for a high-efficiency electron/ion transport pathway and structural stability. As a proof of concept, the lithium ion battery with the as-obtained hybrid's electrode exhibited excellent rate performance with a 666 mA h g-1 capacity at a high current density of 3500 mA g-1. We can extend this method to produce various metallic 1T-MX2 (M = transition metal; X = chalcogen) vertically edged on a graphene frame as one of the promising hetero-structures for several specific applications in the fields of electronics, optics and catalysis.


A quantitative telomeric chromatin isolation protocol identifies different telomeric states.
Telomere composition changes during tumourigenesis, aging and in telomere syndromes in a poorly defined manner. Here we develop a quantitative telomeric chromatin isolation protocol (QTIP) for human cells, in which chromatin is cross-linked, immunopurified and analysed by mass spectrometry. QTIP involves stable isotope labelling by amino acids in cell culture (SILAC) to compare and identify quantitative differences in telomere protein composition of cells from various states. With QTIP, we specifically enrich telomeric DNA and all shelterin components. We validate the method characterizing changes at dysfunctional telomeres, and identify and validate known, as well as novel telomere-associated polypeptides including all THO subunits, SMCHD1 and LRIF1. We apply QTIP to long and short telomeres and detect increased density of SMCHD1 and LRIF1 and increased association of the shelterins TRF1, TIN2, TPP1 and POT1 with long telomeres. Our results validate QTIP to study telomeric states during normal development and in disease.


A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy.
Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.


Lysophosphatidic acid mediates myeloid differentiation within the human bone marrow microenvironment.
Lysophosphatidic acid (LPA) is a pleiotropic phospholipid present in the blood and certain tissues at high concentrations; its diverse effects are mediated through differential, tissue specific expression of LPA receptors. Our goal was to determine if LPA exerts lineage-specific effects during normal human hematopoiesis. In vitro stimulation of CD34+ human hematopoietic progenitors by LPA induced myeloid differentiation but had no effect on lymphoid differentiation. LPA receptors were expressed at significantly higher levels on Common Myeloid Progenitors (CMP) than either multipotent Hematopoietic Stem/Progenitor Cells (HSPC) or Common Lymphoid Progenitors (CLP) suggesting that LPA acts on committed myeloid progenitors. Functional studies demonstrated that LPA enhanced migration, induced cell proliferation and reduced apoptosis of isolated CMP, but had no effect on either HSPC or CLP. Analysis of adult and fetal human bone marrow sections showed that PPAP2A, (the enzyme which degrades LPA) was highly expressed in the osteoblastic niche but not in the perivascular regions, whereas Autotaxin (the enzyme that synthesizes LPA) was expressed in perivascular regions of the marrow. We propose that a gradient of LPA with the highest levels in peri-sinusoidal regions and lowest near the endosteal zone, regulates the localization, proliferation and differentiation of myeloid progenitors within the bone marrow marrow.


Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study.
To assess the impact on healthcare resource utilization, costs, and quality of life over 15 years from 5 years of statin use in men without a history of myocardial infarction in the West of Scotland Coronary Prevention Study (WOSCOPS). Six thousand five hundred and ninety-five participants aged 45-54 years were randomized to 5 years treatment with pravastatin (40 mg) or placebo. Linkage to routinely collected health records extended follow-up for secondary healthcare resource utilization to 15 years. The following new results are reported: cause-specific first and recurrent cardiovascular hospital admissions including myocardial infarction, heart failure, stroke, coronary revascularization and angiography; non-cardiovascular hospitalization; days in hospital; quality-adjusted life years (QALYs); costs of pravastatin treatment, treatment safety monitoring, and hospital admissions. Five years treatment of 1000 patients with pravastatin (40 mg/day) saved the NHS £710 000 (P < 0.001), including the cost of pravastatin and lipid and safety monitoring, and gained 136 QALYs (P = 0.017) over the 15-year period. Benefits per 1000 subjects, attributable to prevention of cardiovascular events, included 163 fewer admissions and a saving of 1836 days in hospital, with fewer admissions for myocardial infarction, stroke, heart failure and coronary revascularization. There was no excess in non-cardiovascular admissions or costs (or in admissions associated with diabetes or its complications) and no evidence of heterogeneity of effect over sub-groups defined by baseline cardiovascular risk. Five years' primary prevention treatment of middle-aged men with a statin significantly reduces healthcare resource utilization, is cost saving, and increases QALYs. Treatment of even younger, lower risk individuals is likely to be cost-effective.


The value of histopathological examination of surgically removed blood clot in determining the etiology of spontaneous intracerebral hemorrhage.
The surgical specimens from all evacuated spontaneous intracerebral and intracerebellar hemorrhages at the Toronto General Hospital from 1976 to 1981 were reviewed. Cases resulting from trauma or from pre-operatively diagnosed aneurysms or arteriovenous malformations were excluded, leaving 84 cases in which the etiology was unknown. Seventy-five of the cases were intracerebral hemorrhages, while 6 were intracerebellar and 3 were intraventricular. Brain tissue was received with the blood clot in 54 cases (64%). From this tissue, an anatomic diagnosis was made in 37 cases; and in 14, the specific etiology of the hemorrhage could be determined. The specific etiologic diagnoses were tumor (7), amyloid angiopathy (6) and abscess (1). In 4 other cases, vasculopathy associated with hypertension was suggested as a possible etiologic diagnosis. The high incidence of a specific etiologic diagnosis made from specimens in which tissue was included (25%) suggests that biopsy of adjacent brain tissue or preservation of tissue fragments identified at the time of surgery is of diagnostic value.


Egg parasitoids of the corn leafhopper, Dalbulus maidis, in the southernmost area of its distribution range.
Egg parasitoids of the corn leafhopper, Dalbulus maidis (DeLong and Wolcott) (Hemiptera: Cicadellidae), were surveyed exposing sentinel eggs of the leafhopper along a latitudinal transect of 600 km in Argentina, the southernmost area of its distribution range. Four parasitoid species were obtained: the mymarids Anagrus breviphragma Soyka (Hymenoptera: Mymaridae), Anagrus flaveolus Waterhouse, and Polynema sp., and the trichogrammatid Pseudoligosita longifrangiata (Viggiani) (Hymenoptera: Trichogrammatidae). The low parasitism rate, low species richness, and high proportion of generalist egg parasitoids were quite clear in the southern distribution limit of the vector, in contrast to regions where corn crops are available all year round and there are continuous and overlapping generations of the pest. Further studies need to be done in order to determine the native host of the above egg parasitoids, the seasonal abundance, and the possible occurrence of other species affecting D. maidis populations in the studied area.


Deciphering the complex leaf transcriptome of the allotetraploid species Nicotiana tabacum: a phylogenomic perspective.
Polyploidization is an important mechanism in plant evolution. By analyzing the leaf transcriptomes taken from the allotetraploid Nicotiana tabacum (tobacco) and parental genome donors, N. sylvesteris (S-Genome) and N. tomentosiformis (T-Genome), a phylogenomic approach was taken to map the fate of homeologous gene pairs in this plant. A comparison between the genes present in the leaf transcriptomes of N. tabacum and modern day representatives of its progenitor species demonstrated that only 33% of assembled transcripts could be distinguished based on their sequences. A large majority of the genes (83.6% of the non parent distinguishable and 87.2% of the phylogenetic topology analyzed clusters) expressed above background level (more than 5 reads) showed similar overall expression levels. Homeologous sequences could be identified for 968 gene clusters, and 90% (6% of all genes) of the set maintained expression of only one of the tobacco homeologs. When both homeologs were expressed, only 15% (0.5% of the total) showed evidence of differential expression, providing limited evidence of subfunctionalization. Comparing the rate of synonymous nucleotide substitution (Ks) and non-synonymous nucleotide substitution (Kn) provided limited evidence for positive selection during the evolution of tobacco since the polyploidization event took place. Polyploidization is a powerful mechanism for plant speciation that can occur during one generation; however millions of generations may be necessary for duplicate genes to acquire a new function. Analysis of the tobacco leaf transcriptome reveals that polyploidization, even in a young tetraploid such as tobacco, can lead to complex changes in gene expression. Gene loss and gene silencing, or subfunctionalization may explain why both homeologs are not expressed by the associated genes. With Whole Genome Duplication (WGD) events, polyploid genomes usually maintain a high percentage of gene duplicates. The data provided little evidence of preferential maintenance of gene expression from either the T- or S-genome. Additionally there was little evidence of neofunctionalization in Nicotiana tabacum suggesting it occurs at a low frequency in young polyploidy.


Miniaturized high throughput detection system for capillary array electrophoresis on chip with integrated light emitting diode array as addressed ring-shaped light source.
A novel miniaturized, portable fluorescence detection system for capillary array electrophoresis (CAE) on a microfluidic chip was developed, consisting of a scanning light-emitting diode (LED) light source and a single point photoelectric sensor. Without charge coupled detector (CCD), lens, fibers and moving parts, the system was extremely simplified. Pulsed driving of the LED significantly increased the sensitivity, and greatly reduced the power consumption and photobleaching effect. The highly integrated system was robust and easy to use. All the advantages realized the concept of a portable micro-total analysis system (micro-TAS), which could work on a single universal serial bus (USB) port. Compared with traditional CAE detecting systems, the current system could scan the radial capillary array with high scanning rate. An 8-channel CAE of fluorescein isothiocyanate (FITC) labeled arginine (Arg) on chip was demonstrated with this system, resulting in a limit of detection (LOD) of 640 amol.


Outbreak of Chikungunya in the Republic of Congo and the global picture.
Chikungunya fever is a crippling disease caused by an arthropod-borne virus (arbovirus) transmitted to humans through mosquitoes. Although Chikungunya virus is not often associated with mortality, the effects of virus outbreaks are often devastating, causing significant economic loss due to the strain on health care. Chikungunya is quickly spreading globally as a result of viral genetic mutations leading to the adaptation of new vector hosts and insecticide resistance. The recent outbreak of Chikungunya fever in the republic of Congo has reported thousands of people affected. Here we review the past Chikungunya fever epidemiology and new reports aimed at therapeutic intervention of this disease.


Antiparasitic bromotyrosine derivatives from the marine sponge Verongula rigida.
Nine bromotyrosine-derived compounds were isolated from the Caribbean marine sponge Verongula rigida. Two of them, aeroplysinin-1 (1) and dihydroxyaerothionin (2), are known compounds for this species, and the other seven are unknown compounds for this species, namely: 3,5-dibromo-N,N,N-trimethyltyraminium (3), 3,5-dibromo-N,N,N, O-tetramethyltyraminium (4), purealidin R (5), 19-deoxyfistularin 3 (6), purealidin B (7), 11-hydroxyaerothionin (8) and fistularin-3 (9). Structural determination of the isolated compounds was performed using one- and two-dimensional NMR, MS and other spectroscopy data. All isolated compounds were screened for their in vitro activity against three parasitic protozoa: Leishmania panamensis, Plasmodium falciparum and Trypanosoma cruzi. Compounds 7 and 8 showed selective antiparasitic activity at 10 and 5 μM against Leishmania and Plasmodium parasites, respectively. Cytotoxicity of these compounds on a human promonocytic cell line was also assessed.


The broad-spectrum tospovirus resistance gene Sw-5 of tomato is a homolog of the root-knot nematode resistance gene Mi.
We used a positional cloning approach to isolate the Sw-5 disease resistance locus of tomato. Complementation experiments with overlapping cosmid clones enabled us to demonstrate that Sw-5 is a single gene locus capable of recognizing several tospovirus isolates and species. Analysis of the predicted Sw-5 protein suggests that it is a cytoplasmic protein, with a potential nucleotide binding site (NBS) domain and a C-terminal end consisting of leucine-rich repeats (LRRs). Based on its structural features, Sw-5 belongs to the class of NBS-LRR resistance genes that includes the tomato Mi, 12, and Prf genes; the Arabidopsis RPM1 gene; and the plant potato virus X resistance gene Rx. The overall similarity between the Sw-5 and Mi proteins of tomato suggests that a shared or comparable signal transduction pathway leads to both virus and nematode resistance in tomato. The similarity also supports the hypothesis that Sw-5 provides resistance via a hypersensitive response. Sw-5 is a member of a loosely clustered gene family in the telomeric region of chromosome 9. Members of this family map to other regions of chromosome 9 and also to chromosome 12, where several fungal, virus, and nematode genes have been mapped, suggesting that paralogs of Sw-5 may have evolved to provide different resistance specificities.


The Unheard Partner in Adapted Physical Activity Community Service Learning.
Community service learning (CSL), built on collaborative, reciprocal, and diverse disability-community partnerships, is a taken-for-granted pedagogical practice in adapted physical activity. Thus far, the CSL experiences of community members as they support student learning are virtually unknown. The purpose of the study was to understand how community members experienced an undergraduate adapted physical activity CSL course. Using an interpretative phenomenological analysis research approach, 9 adults (2 female, 7 male, mean age 50 years) experiencing disability participated in individual and focus-group interviews. Field notes and artifacts were also gathered. Relational ethics provided a heuristic framework to facilitate the interpretation of the findings. Four themes were crafted: (a) yes, we are willing partners; (b) but . . . we're in the dark; (c) subjected to being the subject; and (d) engage through relationships. Although overlooked as valuable collaborative and reciprocal partners, relational engagement remained central to the participants' CSL experience.


Feasibility and efficacy of upper limb robotic rehabilitation in a subacute cervical spinal cord injury population.
Multi-center pilot study. To investigate the use of an upper limb robotic rehabilitation device (Armeo Spring, Hocoma AG, Switzerland) in a subacute cervical spinal cord injury (SCI) population. Two Canadian inpatient rehabilitation centers. Twelve subjects (motor level C4-C6, ASIA Impairment Scale A-D) completed the training, which consisted of 16.1±4.6 sessions over 5.2±1.4 weeks. Two types of outcomes were recorded: (1) feasibility of incorporating the device into an inpatient rehabilitation program (compliance with training schedule, reduction in therapist time required and subject questionnaires) and (2) efficacy of the robotic rehabilitation for improving functional outcomes (Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP), action research arm test, grip dynamometry and range of motion). By the end of the training period, the robot-assisted training was shown to require active therapist involvement for 25±11% (mean±s.d.) of the total session time. In the group of all subjects and in a subgroup composed of motor-incomplete subjects, no statistically significant differences were found between intervention and control limbs for any of the outcome measures. In a subgroup of subjects with partial hand function at baseline, the GRASSP-Sensibility component showed a statistically significant increase (6.0±1.6 (mean±s.e.m.) point increase between baseline and discharge for the intervention limbs versus 1.9±0.9 points for the control limbs). The pilot results suggest that individuals with some preserved hand function after SCI may be better candidates for rehabilitation training using the Armeo Spring device.


Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia.
To evaluate response and outcome with a front-line intensive multiagent chemotherapy regimen in adults with Burkitt's-type acute lymphoblastic leukemia (B-ALL). From September 1992 to June 1997, 26 consecutive adults with newly diagnosed untreated B-ALL received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD). Their median age was 58 years (range, 17 to 79 years), and 46% were > or = 60 years. Patients received Hyper-CVAD alternated with courses of high-dose methotrexate and cytarabine. Granulocyte colony-stimulating factor and prophylactic antibiotics were administered for all eight planned courses. CNS prophylaxis alternated intrathecal methotrexate and cytarabine on days 2 and 7 of each course. Complete remission (CR) was obtained in 21 patients (81%). There were five induction deaths (19%). The median time to CR was 22 days (range, 15 to 89 days); 70% achieved CR within 4 weeks. The 3-year survival rate was 49% (+/- 11%); the 3-year continuous CR rate was 61% (+/- 11%). Twelve CR patients (57%) were in continuous CR at a median follow-up of 3+ years (range, 13+ months to 6.5+ years). Characteristics predicting for worse survival were age > or = 60 years, poor performance status, anemia, thrombocytopenia, peripheral blasts, and increased lactate dehydrogenase level. The 3-year survival rate was 77% for 14 patients younger than 60 years and 17% for 12 patients > or = 60 years (P <.01). Regression analysis identified older age, anemia, and presence of peripheral blasts as independent factors associated with shorter survival. Patients could be stratified according to (1) no or one adverse feature, (2) two adverse features, and (3) all adverse features. The 3-year survival rates were 89%, 47%, and 0%, respectively (P <.01). Hyper-CVAD is effective in adult B-ALL. Identification of patients with high risk for relapse and improved methods to detect residual disease may result in risk-oriented approaches.


Unspoken victims: A national study of male rape incidents and police investigations in South Africa.
The burden of sexual violence has been well described in children of both sexes and in women, but there is minimal literature on adult male rape victims. Studies of adult male rape victims have mainly been conducted among incarcerated males or military personnel, and in high-income countries. To describe the epidemiology, occurrence and reporting of rape cases involving male victims, both child (<18 years old) and adult, in South Africa (SA). The study consisted of a nationally representative sample of case dockets maintained by the SA Police Service of rape incidents reported in 2012. A retrospective review of the dockets provided sociodemographic information on the victim and suspect, the circumstances of the rape and the medicolegal services provided to the victim. Data on male victims were analysed using Stata 13 to test for significant differences between child and adult male victims. The study comprised 209 male victims, including 120 (57.4%) children and 89 (42.6%) adults. The findings showed that there were significant differences in the occurrence and reporting of rape of male victims by age. Adult males experienced more violent rapes, perpetrators were more likely to be armed and often humiliated the victim, and rapes were more likely to occur in institutional settings. Adult males reported incidents of rape earlier and therefore had visible non-genital injuries during the medical examination. In contrast, more child rapes involved known perpetrators, occurred in a home and perpetrators were more likely to act kindly to the victim after the incident. This parallels the patterns in rape circumstances seen in female adult and child victims. While there is political commitment to understanding sexual violence against women as a societal problem, work on such violence against men lags behind and is little understood. Rape of males needs to be acknowledged, and their vulnerabilities to sexual abuse and rape need to be addressed. Prevention efforts to end violence against women and girls, especially in relation to children, can be used to address violence against men and boys.


Conopeptides from Cape Verde Conus crotchii.
Marine Cone snails of the genus Conus contain complex peptide toxins in their venom. Living in tropical habitats, they usually use the powerful venom for self-defense and prey capture. Here, we study Conus crotchii venom duct using a peptide mass-matching approach. The C. crotchii was collected on the Cape Verde archipelago in the Boa Vista Island. The venom was analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). About 488 molecular masses between 700 Da and 3000 Da were searched bymatching with known peptide sequences from UniProtKB protein sequence database. Through this method we were able to identify 12 conopeptides. For validation we considered the error between the experimental molecular mass (monoisotopic) and the calculated mass of less than 0.5 Da. All conopeptides detected belong to the A-, O1-, O2-, O3-, T- and D-superfamilies, which can block Ca²⁺ channels, inhibit K⁺ channels and act on nicotinic acetylcholine receptors (nAChRs). Only a few of the detected peptides have a 100% UniProtKB database similarity, suggesting that several of them could be newly discovered marine drugs.


MtDNA variation in the Altai-Kizhi population of southern Siberia: a synthesis of genetic variation.
The native peoples of Gorno Altai in southern Siberia represent a genetically diverse population and have been of great interest to anthropological genetics. In particular, the southern Altaian population is argued to be the best candidate for the New World ancestral population. In this study we sampled Altai-Kizhi from the southern Altaian village of Mendur-Sokkon, analyzed mtDNA RFLP markers and HVS-I sequences, and compared the results to other published mtDNA data from Derenko et al. (2003) and Shields et al. (1993) encompassing the same region. Because each independent study uses different sampling techniques in characterizing gene pools, in this paper we explore the accuracy and reliability of evolutionary studies on human populations. All the major Native American haplogroups (A, B, C, and D) were identified in the Mendur-Sokkon sample, including a single individual belonging to haplogroup X. The most common mtDNA lineages are C (35.7%) and D (13.3%), which is consistent with the haplogroup profiles of neighboring Siberian groups. The Mendur-Sokkon sample exhibits depressed HVS-I diversity values and neutrality test scores, which starkly differs from the Derenko et al. (2003) data set and more closely resembles the results for neighboring south Siberian groups. Furthermore, the multidimensional scaling plot of DA genetic distances does not cluster the Altai samples, showing different genetic affinities with various Asian groups. The findings underscore the importance of sampling strategy in the reconstruction of evolutionary history at the population level.


Oral health problems in leukaemic paediatric patients in the United Arab Emirates: a retrospective study.
The aim of this study was to estimate the prevalence of oral health problems in leukaemic paediatric patients in the United Arab Emirates (UAE) and correlate it to the phase of chemotherapy. Medical records of 120 paediatric leukaemic patients (age below 15 years) in the UAE were reviewed for the occurrence of oral health problems. Records from the three main hospitals that provide cancer therapy were accessed after obtaining the required permissions. The overall prevalence of oral health problems in leukaemic patients in our study is 60%. The most common oral health problem recorded in the patients' records was oral mucositis and ulceration (52.4%) followed by dental caries and oral candidiasis accounting for 18.3% and 14.2% respectively. Other oral health problems recorded were gingivitis and gingival bleeding, herpetic gingivostomatitis, poor oral hygiene, and facial palsy. The peak occurrence of most oral problems was during phase IV (maintenance). Oral health problems were more common among patients who received treatment and follow-up locally rather than abroad. Collected data were analysed using statistical software International Business Machines (IBM) Statistical Package for Social Sciences (SPSS, version 20, Chicago, SPSS Inc). Descriptive statistics were performed to describe the characteristics of the study population. The association between oral health problems and other risk factors was analysed using the Chi-squared test. A P-value of <0.05 was considered statistically significant. This is the first study to describe oral health problems and its correlation to the phase of chemotherapy in leukaemic paediatric patients in the UAE. Oral health problems as a result of leukaemia and its management are both variable and unavoidable. Therefore, oral and dental care is of critical importance in maintaining the overall wellbeing of the patient before, during, and after treatment. This can be achieved by close liaison between the oncology and dental teams.


Measurement of de novo hepatic lipogenesis in humans using stable isotopes.
Direct measurement of de novo lipogenesis has not previously been possible in humans. We measured de novo hepatic lipogenesis in normal men by means of stable isotopes and by combining the acetylated-xenobiotic probe technique with mass isotopomer analysis of secreted very low density lipoprotein-fatty acids (VLDL-FA). Sulfamethoxazole (SMX) was administered with [13C]acetate during an overnight fast followed by refeeding with intravenous glucose (7-10 mg/kg of weight per min), oral Ensure (7-10 mg of carbohydrate/kg of weight per min), or a high-carbohydrate mixed-meal breakfast (3.5 g of carbohydrate/kg of weight). Respiratory quotients remained less than 1.0. High-performance liquid chromatography/mass spectrometry-determined enrichments in SMX-acetate attained stable plateau values, and hepatic acetyl-coenzyme A (CoA) dilution rate did not increase with refeeding (approximately 0.024 mmol/kg per min). The fraction of VLDL-palmitate derived from de novo lipogenesis was only 0.91 +/- 0.27% (fasted) and 1.64-1.97% (fed). For stearate, this was 0.37 +/- 0.08% and 0.47-0.64%. Precursor enrichments predicted from isotopomer ratios were close to measured SMX-acetate enrichments, indicating that SMX-acetate samples the true lipogenic acetyl-CoA pool. Stearate synthesis was less than palmitate and the two did not move in parallel. Estimated total VLDL-FA synthesis is less than 500 mg/day. Thus, de novo hepatic lipogenesis is a quantitatively minor pathway, consistent with gas exchange estimates; fatty acid futile cycling (oxidation/resynthesis) is not thermogenically significant; and synthesis rates of different nonessential fatty acids by human liver are not identical in nonoverfed normal men. The contribution and regulation of de novo lipogenesis in other settings can be studied using this technique.


Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial.
Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30-65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy. This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292. From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56·5%, 95% CI 47·8-64·9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54·2%, 95% CI 45·7-62·6) who received concurrent treatment (difference 2·3%, 95% CI -9·3 to 13·9). No treatment-related deaths occurred. The most common severe toxic effects were neutropenia (35 [25·3%] of 138 patients in the sequential group vs 45 [31·7%] of 142 patients in the concurrent group) and fatigue (six [4·3%] vs 12 [8·5%]). Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one (0·8%) of 130 patients who received sequential treatment and four (2·9%) of 137 patients who received concurrent treatment; by week 24, it had dropped below this limit in nine (7·1%) of 126 patients and in six (4·6%) of 130 patients, respectively. Concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted. US National Cancer Institute.


Inhibitory action of Epilobium hirsutum extract and its constituent ellagic acid on drug-metabolizing enzymes.
Epilobium hirsutum (EH) is a medicinal plant for treating various diseases. Despite its wide usage, there is no available information about its potential influences on drug metabolism. The present study was undertaken to determine the in vivo effects of EH on hepatic CYP2B, CYP2C, CYP2D, and CYP3A enzymes that are primarily involved in drug metabolism. Male Wistar rats were injected intraperitoneally with EH water extract (EHWE) and ellagic acid (EA) at a daily dose of 37.5 and 20 mg/kg, respectively, for 9 days and hepatic drug-metabolizing enzymes were assessed at activity, protein and mRNA levels. Erythromycin N-demethylase activity was inhibited by 53 and 21 % in EHWE- and EA-treated rats, respectively. Benzphetamine N-demethylase and 7-benzyloxyresorufin-O-debenzylase activities were decreased by 53 and 43 %, and 57 and 57 % in EHWE-and EA-treated rats, respectively. Moreover, protein levels of CYP2B1, CYP2C6, CYP2D2, and CYP3A1 also decreased by 55, 15, 33, and 82 % as a result of EHWE treatment of rats, respectively. Similarly, CYP2B1, CYP2C6, CYP2D2, and CYP3A1 protein levels decreased by 62, 63, 49, and 37 % with EA treatment, respectively. qRT-PCR analyses also showed that mRNA levels of these enzymes were significantly inhibited with bothEHWE and EA treatments. In conclusion, inhibition of drug clearances leading to drug toxicity because of the lowered activity and expression of drug-metabolizing enzymes might be observed in the people who used EH as complementary herbal remedy that might be contributed by its EA content.


Design and validation of a clinical instrument for spectral diagnosis of cutaneous malignancy.
We report a probe-based portable and clinically compatible instrument for the spectral diagnosis of melanoma and nonmelanoma skin cancers. The instrument combines two modalities--diffuse reflectance and intrinsic fluorescence spectroscopy--to provide complementary information regarding tissue morphology, function, and biochemical composition. The instrument provides a good signal-to-noise ratio for the collected reflectance and laser-induced fluorescence spectra. Validation experiments on tissue phantoms over a physiologically relevant range of albedos (0.35-0.99) demonstrate an accuracy of close to 10% in determining scattering, absorption and fluorescence characteristics. We also demonstrate the ability of our instrument to collect in vivo diffuse reflectance and fluorescence measurements from clinically normal skin, dysplastic nevus, and malignant nonmelanoma skin cancer.


Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure.
Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH, such as Roundup, pose a particular health risk to liver and kidneys although low environmentally relevant doses have not been examined. To address this issue, a 2-year study in rats administering 0.1 ppb Roundup (50 ng/L glyphosate equivalent) via drinking water (giving a daily intake of 4 ng/kg bw/day of glyphosate) was conducted. A marked increased incidence of anatomorphological and blood/urine biochemical changes was indicative of liver and kidney structure and functional pathology. In order to confirm these findings we have conducted a transcriptome microarray analysis of the liver and kidneys from these same animals. The expression of 4224 and 4447 transcript clusters (a group of probes corresponding to a known or putative gene) were found to be altered respectively in liver and kidney (p < 0.01, q < 0.08). Changes in gene expression varied from -3.5 to 3.7 fold in liver and from -4.3 to 5.3 in kidneys. Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. Pathway analysis suggests a modulation of the mTOR and phosphatidylinositol signalling pathways. Gene disturbances associated with the chronic administration of ultra-low dose Roundup reflect a liver and kidney lipotoxic condition and increased cellular growth that may be linked with regeneration in response to toxic effects causing damage to tissues. Observed alterations in gene expression were consistent with fibrosis, necrosis, phospholipidosis, mitochondrial membrane dysfunction and ischemia, which correlate with and thus confirm observations of pathology made at an anatomical, histological and biochemical level. Our results suggest that chronic exposure to a GBH in an established laboratory animal toxicity model system at an ultra-low, environmental dose can result in liver and kidney damage with potential significant health implications for animal and human populations.


Cyclin D1 expression in ductal carcinoma of the breast and its correlation with other prognostic parameters.
Cyclin D1 is a cell cycle regulatory gene emerging as a potentially significant oncogene in invasive breast cancers. In this study, we attempted to see the expression of Cyclin D1 in invasive ductal carcinomas of the breast in our population and correlate its expression with other known prognostic parameters. A total of 39 cases were selected from our case files from January 2011. Immunohistochemistry for Cyclin D1 was performed and interpreted as positive when >10% of the tumor cells expressed the marker with a moderate to strong intensity of staining. Clinicopathological parameters such as laterality, focality, tumor size, grade, ductal carcinoma in situ (DCIS), axillary lymph node (ALN) metastasis, hormone receptor status and human epidermal growth factor receptor 2 status were analyzed and correlated with Cyclin D1 expression. The patients' age ranged from 30 to 76 years (mean = 53.18). The tumors were unilateral and unifocal in 38 cases; one patient had bilateral synchronous tumors. The majority were grade2 (67.5%) and tumor size T2 (57.5%). Nearly 35% were associated with DCIS and 57.5% had ALN metastasis. Estrogen receptors (ER) and progesterone receptor (PgR) positivity was seen in 65% of the cases and 25% was triple negative. Cyclin D1 expression was seen in 67.5% of the cases in our study. Among the ER, PgR positive and Her-2 negative tumors, Cyclin D1 expression was seen in the majority of cases (92%) cases, whereas none of the triple negative tumors showed Cyclin D1 expression. The other prognostic parameters such as tumor size, grade and lymph node status did not show any association with Cyclin D 1 positivity. Cyclin D1 expression was seen in 67.5% of ductal carcinoma and it showed a significant correlation with ER, PgR expression (92% in this study), which is in concordance with other similar studies in literature.


Composition, Predicted Functions and Co-occurrence Networks of Rhizobacterial Communities Impacting Flowering Desert Events in the Atacama Desert, Chile.
Flowering desert (FD) events consist of the rapid flowering of a wide variety of native plants in the Atacama Desert of Chile, which is categorized as the driest desert in the world. While ephemeral plants are an integral part of the desert ecosystem, there is little knowledge on plant-microbe interactions that occur during FD events. Consequently, the overall goals of this present study were to investigate changes in the composition and potential functions of rhizobacterial community of Cistanthe longiscapa (Montiaceae) during the 2014 and 2015 FD events and determine the composition, potential functions, and co-occurrence networks of rhizobacterial community associated with the root zone of C. longiscapa during pre- (PF) and full-flowering (FF) phenological stages. Results of this study showed that the Proteobacteria and Actinobacteria were the dominant taxa in rhizosphere soils during the three FD events (2014, 2015, and 2017) examined. In general, greater microbial richness and diversity were observed in rhizosphere soils during the 2015-, compared with the 2014-FD event. Similarly, predicted functional analyses indicated that a larger number of sequences were assigned to information processing (e.g., ion channel, transporters and ribosome) and metabolism (e.g., lipids, nitrogen, and sulfur) during 2015 compared with 2014. Despite the lack of significant differences in diversity among PF and FF stages, the combined analysis of rhizobacterial community data, along with data concerning rhizosphere soil properties, evidenced differences among both phenological stages and suggested that sodium is a relevant abiotic factor shaping the rhizosphere. In general, no significant differences in predicted functions (most of them assigned to chemoheterotrophy, magnesium metabolisms, and fermentation) were observed among PF and FF. Co-occurrence analysis revealed the complex rhizobacterial interactions that occur in C. longiscapa during FD, highlighting to Kouleothrixaceae family as keystone taxa. Taken together this study shows that the composition and function of rhizobacteria vary among and during FD events, where some bacterial groups and their activity may influence the growth and flowering of native plants, and therefore, the ecology and trophic webs in Atacama Desert.


Disease- and Treatment-related Morbidity in Adolescents With Perinatal HIV Infection in Asia.
Perinatally HIV-infected adolescents (PHIVA) are exposed to a chronic systemic infection and long-term antiretroviral therapy (ART), leaving them susceptible to morbidities associated with inflammation, immunodeficiency and drug toxicity. Data collected 2001 to 2016 from PHIVA 10-19 years of age within a regional Asian cohort were analyzed using competing risk time-to-event and Poisson regression analyses to describe the nature and incidence of morbidity events and hospitalizations and identify factors associated with disease-related, treatment-related and overall morbidity. Morbidity was defined according to World Health Organization clinical staging criteria and U.S. National Institutes of Health Division of AIDS criteria. A total 3,448 PHIVA contributed 17,778 person-years. Median age at HIV diagnosis was 5.5 years, and ART initiation was 6.9 years. There were 2,562 morbidity events and 307 hospitalizations. Cumulative incidence for any morbidity was 51.7%, and hospitalization was 10.0%. Early adolescence was dominated by disease-related infectious morbidity, with a trend toward noninfectious and treatment-related morbidity in later adolescence. Higher overall morbidity rates were associated with a CD4 count <350 cells/µL, HIV viral load ≥10,000 copies/mL and experiencing prior morbidity at age <10 years. Lower overall morbidity rates were found for those 15-19 years of age compared with 10-14 years and those who initiated ART at age 5-9 years compared with <5 or ≥10 years. Half of our PHIVA cohort experienced a morbidity event, with a trend from disease-related infectious events to treatment-related and noninfectious events as PHIVA age. ART initiation to prevent immune system damage, optimize virologic control and minimize childhood morbidity are key to limiting adolescent morbidity.


The polarity of the cauliflower mosaic virus genome.
We have demonstrated that the 5' termini of the DNAs of cauliflower mosaic virus (CaMV) isolates CM4-184 and Cabb B-JI have free hydroxyl groups accessible for phosphorylation using polynucleotide kinase. This has enabled us, using the Cabb B-JI isolate, to label and identify the 5' nucleotides. Digestion of 5' terminally labelled DNA with EcoRI restriction endonuclease revealed that only three of the eleven single-stranded EcoRI fragments were labelled, those situated adjacent to the three known gaps in the double-stranded genome. Identification of the labelled fragments indicated the polarity of the genome. Hybridization experiments using RNA transcripts from infected leaves gave results consistent with the polarity data and confirmed the direction of transcription. Transcription on the largest DNA strand (alpha strand) is initiated between map units 0.24 and 0.30 and terminates between map units 0.0 and 0.24.


The human lung: did evolution get it wrong?
Some 300 million yrs ago, the ancestors of modern reptiles emerged from water and were committed to air breathing. They were exothermic and incapable of sustained levels of high physical activity. But from them evolved the two great classes of vertebrates with high levels of maximal oxygen consumption: the mammals and birds. A remarkable feature of these two divergent evolutionary lines is that, although the physiology of many organ systems shows many similarities, the lungs are radically different. A major difference is that the ventilation of the gas-exchanging tissue has a flow-through pattern in the bird but is reciprocating in the mammal. The result is that mammals have a reduced alveolar and arterial oxygen tension, a potential for uneven ventilation, and relatively large terminal air spaces. This in turn means that the pulmonary capillaries are poorly supported compared with the bird. The result is that the pulmonary capillaries in the bird have much thinner and more uniform walls, with more efficient gas exchange. Other advantages of the bird lung are that it utilises a more efficient cross-current pattern of gas-exchange, and the bird has separated the ventilatory and gas exchange functions. From a structure-function standpoint, the bird lung is superior.


The role of PhD-prepared, hospital-based nurses: an inter-Nordic study.
Little is known about PhD-prepared nurses employed at Nordic university hospitals, how they are organised, what their practices look like or what career pathway they have chosen. The purpose was to investigate and compare the prevalence of PhD-prepared nurses employed at university hospitals in the Nordic countries, to investigate what functions they fulfil and what research activities they undertake and to document how they describe their ideal work life. A descriptive cross-sectional study. An electronic questionnaire was sent to 245 PhD-prepared nurses working at a university hospital in one of six Nordic countries and 166 responses were achieved (response rate 67%). Descriptive analyses were performed using SPSS Statistics. The study found notable differences among PhD-prepared nurses employed at university hospitals with respect to work function; organisational structure; satisfaction about time split between research and practice; and the mean scores of time spend on research, clinical practice and teaching, supervision and administration. In order to succeed with capacity building among the nursing workforce, collaboration and networking with other researchers and close contact to clinical practice is important. The role of the hospital-based, PhD-prepared nurse needs to be better described and defined to ensure that evidence-based care is provided.


Using targeted spirometry to reduce non-diagnosed chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is increasing worldwide and thus its associated morbidity and mortality. However, COPD often goes undiagnosed. We evaluated the rate of non-diagnosed irreversible airway obstruction (AO) and characterized this patient group. We further assessed the possible effects of conducting targeted spirometry in a population sample in Salzburg, Austria, as part of the Burden of Obstructive Lung Disease (BOLD) study. 1,258 adults ≥40 years of age completed a questionnaire and performed spirometry before and after bronchodilator therapy (post-BD). Irreversible AO was defined as post-BD FEV(1)/FVC below the lower limit of normal; we used the FEV(1)% predicted (pred.) to further grade the disease. Participants without a physician diagnosis of COPD who reported respiratory symptoms and a history of risk factors (ever smoking or occupational risk) were defined as eligible for targeted spirometry. 85.9% (171/199) of the participants with irreversible AO did not report a prior diagnosis of COPD. Non-diagnosed AO was inversely related to severity, age, self-reported prior respiratory diseases and cough as a respiratory symptom. 343 participants were eligible for targeted spirometry and irreversible AO was present in 86 (25.1%) participants. Therefore, targeted spirometry could reduce the underdiagnosis of irreversible AO of any severity by 50.3% (86 of 171). The diagnosis of 1 person with FEV(1) <80% pred. would require spirometry in 8.4 subjects (95% confidence interval 6.2-11.1). Although several factors are associated with non-diagnosed AO, spirometry in individuals with respiratory symptoms and exposure to risk factors could reduce undiagnosed irreversible AO by half.


Covalent modification of proteins by green tea polyphenol (-)-epigallocatechin-3-gallate through autoxidation.
Green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has various beneficial properties including chemopreventive, anticarcinogenic, and antioxidant actions. The interaction with proteins known as EGCG-binding targets may be related to the anticancer effects. However, the binding mechanisms for this activity remain poorly understood. Using mass spectrometry and chemical detection methods, we found that EGCG forms covalent adducts with cysteinyl thiol residues in proteins through autoxidation. To investigate the functional modulation caused by binding of EGCG, we examined the interaction between EGCG and a thiol enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Concentration-dependent covalent binding of EGCG to GAPDH was found to be coupled to the irreversible inhibition of GAPDH activity. Mutation experiments revealed that EGCG is primarily bound to the cysteinyl thiol group of the active center, indicating that the irreversible inhibition of GAPDH is due to the covalent attachment of EGCG to the active-center cysteine. Moreover, using EGCG-treated cancer cells, we identified GAPDH as a target of EGCG covalent binding through specific interactions between catechols and aminophenyl boronate agarose resin. Based on these findings, we propose that the covalent modification of proteins by EGCG may be a novel pathway related to the biological activity of EGCG.


A psychometric evaluation of a negative mood scale in the MDS-HC using a large sample of community-dwelling Hong Kong Chinese older adults.
negative mood is an important construct when assessing the health of older persons. The profile of mood states questionnaire is commonly used to measure mood; however, it might not be suitable for older adults with low education level and those who are not originated North American. to examine a negative mood scale formed by nine items in the Mood Section of the Minimum Data Set-Home Care of the Resident Assessment Instrument. a secondary analysis of data from 3,523 older persons aged 60 or over who had first applied for the long-term care services in Hong Kong and completed the screening tool in 2006. Exploratory and confirmatory factor analyses were used to test the factor structure and multiple-group confirmatory factor analysis to test the gender invariance of the Negative Mood Scale in the Minimum Data Set-Home Care. Its reliability using Cronbach's alpha was examined. both a three-factor model at the first level and a one-factor model at the second level provided excellent fits to the overall data, and held equally well for both males and females, and two randomly split samples. Multiple-group confirmatory factor analyses revealed both genders demonstrating an equivalent pattern of factor loadings. Cronbach's alpha value was acceptable for the overall data (0.66). the Negative Mood Scale is a reliable and valid scale and both genders responded to it using the same framework and metric, suggesting it could be used to measure negative mood in Chinese community-dwelling older adults. Further testing of the instrument is needed.


Pseudotyped retroviruses for infecting axolotl in vivo and in vitro.
Axolotls are poised to become the premiere model system for studying vertebrate appendage regeneration. However, very few molecular tools exist for studying crucial cell lineage relationships over regeneration or for robust and sustained misexpression of genetic elements to test their function. Furthermore, targeting specific cell types will be necessary to understand how regeneration of the diverse tissues within the limb is accomplished. We report that pseudotyped, replication-incompetent retroviruses can be used in axolotls to permanently express markers or genetic elements for functional study. These viruses, when modified by changing their coat protein, can infect axolotl cells only when they have been experimentally manipulated to express the receptor for that coat protein, thus allowing for the possibility of targeting specific cell types. Using viral vectors, we have found that progenitor populations for many different cell types within the blastema are present at all stages of limb regeneration, although their relative proportions change with time.


Snake venom ophthalmia and blindness caused by the spitting cobra (Naja nigricollis) in Nigeria.
Venom entered the eyes of 9 patients spat at by the spitting cobra, Naja nigricollis. In 5 the only effect was a simple conjunctivitis but 4 had corneal ulceration, 1 developed anterior uveitis indicating absorption of venom in the anterior chamber, and 2 were permanently blinded. Treatment of this rare emergency is discussed: immediate irrigation of the eye with water, careful examination for corneal abrasion, and prevention of secondary infection are recommended. The value of local specific antivenom is unproven.


Bartonella henselae Bloodstream Infection in a Boy With Pediatric Acute-Onset Neuropsychiatric Syndrome.
With the advent of more sensitive culture and molecular diagnostic testing modalities, Bartonella spp. infections have been documented in blood and/or cerebrospinal fluid specimens from patients with diverse neurological symptoms. Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by an unusually abrupt onset of cognitive, behavioral, or neurological symptoms. Between October 2015 and January 2017, a 14-year-old boy underwent evaluation by multiple specialists for sudden-onset psychotic behavior (hallucinations, delusions, suicidal and homicidal ideation). In March 2017, Bartonella spp. serology (indirect fluorescent antibody assays) and polymerase chain reaction (PCR) amplification, DNA sequencing, and Bartonella enrichment blood culture were used on a research basis to assess Bartonella spp. exposure and bloodstream infection, respectively. PCR assays targeting other vector-borne infections were performed to assess potential co-infections. For 18 months, the boy remained psychotic despite 4 hospitalizations, therapeutic trials involving multiple psychiatric medication combinations, and immunosuppressive treatment for autoimmune encephalitis. Neurobartonellosis was diagnosed after cutaneous lesions developed. Subsequently, despite nearly 2 consecutive months of doxycycline administration, Bartonella henselae DNA was PCR amplified and sequenced from the patient's blood, and from Bartonella alphaproteobacteria growth medium enrichment blood cultures. B henselae serology was negative. During treatment with combination antimicrobial chemotherapy, he experienced a gradual progressive decrease in neuropsychiatric symptoms, cessation of psychiatric drugs, resolution of Bartonella-associated cutaneous lesions, and a return to all pre-illness activities. This case report suggests that B henselae bloodstream infection may contribute to progressive, recalcitrant neuropsychiatric symptoms consistent with PANS in a subset of patients.


A systems-level approach to parental genomic imprinting: the imprinted gene network includes extracellular matrix genes and regulates cell cycle exit and differentiation.
Genomic imprinting is an epigenetic mechanism that restrains the expression of ∼ 100 eutherian genes in a parent-of-origin-specific manner. The reason for this selective targeting of genes with seemingly disparate molecular functions is unclear. In the present work, we show that imprinted genes are coexpressed in a network that is regulated at the transition from proliferation to quiescence and differentiation during fibroblast cell cycle withdrawal, adipogenesis in vitro, and muscle regeneration in vivo. Imprinted gene regulation is not linked to alteration of DNA methylation or to perturbation of monoallelic, parent-of-origin-dependent expression. Overexpression and knockdown of imprinted gene expression alters the sensitivity of preadipocytes to contact inhibition and adipogenic differentiation. In silico and in cellulo experiments showed that the imprinted gene network includes biallelically expressed, nonimprinted genes. These control the extracellular matrix composition, cell adhesion, cell junction, and extracellular matrix-activated and growth factor-activated signaling. These observations show that imprinted genes share a common biological process that may account for their seemingly diverse roles in embryonic development, obesity, diabetes, muscle physiology, and neoplasm.


Synergistic Inhibition of SARS-CoV-2 Replication Using Disulfiram/Ebselen and Remdesivir.
The SARS-CoV-2 replication and transcription complex (RTC) comprising nonstructural protein (nsp) 2-16 plays crucial roles in viral replication, reducing the efficacy of broad-spectrum nucleoside analog drugs such as remdesivir and evading innate immune responses. Most studies target a specific viral component of the RTC such as the main protease or the RNA-dependent RNA polymerase. In contrast, our strategy is to target multiple conserved domains of the RTC to prevent SARS-CoV-2 genome replication and to create a high barrier to viral resistance and/or evasion of antiviral drugs. We show that the clinically safe Zn-ejector drugs disulfiram and ebselen can target conserved Zn2+ sites in SARS-CoV-2 nsp13 and nsp14 and inhibit nsp13 ATPase and nsp14 exoribonuclease activities. As the SARS-CoV-2 nsp14 domain targeted by disulfiram/ebselen is involved in RNA fidelity control, our strategy allows coupling of the Zn-ejector drug with a broad-spectrum nucleoside analog that would otherwise be excised by the nsp14 proofreading domain. As proof-of-concept, we show that disulfiram/ebselen, when combined with remdesivir, can synergistically inhibit SARS-CoV-2 replication in Vero E6 cells. We present a mechanism of action and the advantages of our multitargeting strategy, which can be applied to any type of coronavirus with conserved Zn2+ sites.


Workplace health in dental care - a salutogenic approach.
The purpose was to explore self-reported psychosocial health and work environments among different dental occupations and workplaces from a salutogenic perspective. A further purpose was to analyse possible associations between three salutogenic measurements: The Sense of Coherence questionnaire (SOC), the Salutogenic Health Indicator Scale (SHIS) and the Work Experience Measurement Scale (WEMS). Employees in the Public Dental Service in a Swedish county council (n = 486) were invited to respond to a self-reported web survey including demographics, work-related factors, the SOC, the SHIS and the WEMS. This study showed positive associations between employee characteristics and self-reported overall psychosocial health as well as experienced work environment. Autonomy was reported more among men than women (P < 0.000) and to a higher degree by dentists and dental hygienists than dental nurses (P < 0.000). Meaningfulness, happiness, job satisfaction, autonomy and positive to reorganization were reported by personnels aged less than 40 years (P ≤ 0.047). Clinical coordinators reported significant better health (SOC, SHIS) and experienced more autonomy, better management and more positive to reorganization than other dental professions. Dental hygienists and nurses experienced less time pressure than dentists (P ≤ 0.007). Better health and positive work experiences were also seen in smaller clinics (P ≤ 0.29). Dental professionals reported a high degree of overall psychosocial health as well as a positive work experience. Some variations could be seen between employee characteristics such as gender, years in dental care, professionals, managing position and workplace size. Identify resources and processes at each workplace are important and should be included in the employee's/employers dialogue.


Neural correlates of subsecond time distortion in the middle temporal area of visual cortex.
How does the brain represent the passage of time at the subsecond scale? Although different conceptual models for time perception have been proposed, its neurophysiological basis remains unknown. We took advantage of a visual duration illusion produced by stimulus novelty to link changes in cortical activity in monkeys with distortions of duration perception in humans. We found that human subjects perceived the duration of a subsecond motion pulse with a novel direction longer than a motion pulse with a repeated direction. Recording from monkeys viewing identical motion stimuli but performing a different behavioral task, we found that both the duration and amplitude of the neural response in the middle temporal area of visual cortex were positively correlated with the degree of novelty of the motion direction. In contrast to previous accounts that attribute distortions in duration perception to changes in the speed of a putative internal clock, our results suggest that the known adaptive properties of neural activity in visual cortex contributes to subsecond temporal distortions.


ATP-evoked sustained vasoconstrictions mediated by heteromeric P2X1/4 receptors in cerebral arteries.
Current knowledge states that vasoconstrictor responses to ATP are mediated by rapidly desensitizing ligand-gated P2X1 receptors in vascular smooth muscle cells (VSMCs). However, ATP is implicated in contributing to pathological conditions involving sustained vasoconstrictor response such as cerebral vasospasm. The purpose of this study is to test the hypothesis that the stimulation of VSMC P2XR receptors (P2XRs) contributes to ATP-evoked sustained vasoconstrictions in rat middle cerebral arteries (RMCAs). Reverse transcription- polymerase chain reaction, Western blot, and immunocytochemistry were used to analyze expression of mRNA and proteins in RMCAs VSMCs. Ionic currents and calcium responses were investigated using patch-clamp and confocal imaging techniques, respectively. Functional responses were confirmed using wire myography. Expression of mRNA and protein for P2X1R and P2X4R subunits was identified in RMCA VSMCs. Confocal imaging in fluo-3-loaded VSMCs showed that ATP and a selective P2XR agonist, αβmeATP, evoked similar dose-dependent increases in [Ca(2+)]i. Patch-clamp experiments identified 2 components of P2XR-mediated currents: consisting of a fast desensitizing phase mediated by homomeric P2X1Rs and a slowly desensitizing phase involving heteromeric P2X1/4Rs. Isometric tension measurements showed that ≈80%:20% of initial ATP-evoked vasoconstriction in RMCA is mediated by homomeric P2X1Rs and heteromeric P2X1/4Rs, respectively. The sustained slowly desensitizing and rapidly recovering from desensitization responses are mediated by heteromeric P2X1/4Rs. This study reveals for the first time that apart from rapidly desensitizing homomeric P2X1Rs, heteromeric P2X1/4Rs contribute to the sustained component of the purinergic-mediated vasoconstriction in RMCA. Our study, therefore, identifies possible novel targets for therapeutical intervention in cerebral circulation.


Risk factors for 48-hours mortality after prehospital treatment of opioid overdose.
Opioid overdose is commonly treated by prehospital emergency services and the majority of the patients are discharged immediately after treatment and a short observation period. There is a minor risk for rebound opioid toxicity and other life-threatening conditions might occur after such episodes. The authors describe the short-term outcome and identify risk factors for death within 48 h after prehospital treatment of opioid overdose in Copenhagen, the capital of Denmark. Data on all cases of opioid overdose treated by the medical emergency care unit between 1994 and 2003 were recorded prospectively. Risk factors for death within 48 h after initial medical emergency care unit contact were analysed in a multivariable logistic regression analysis. The authors recorded 4762 episodes of opioid overdose, covering 1967 unique identified patients. A total of 78 patients (8.4%, 95% CI 7.0 to 10.4) died within 48 h in the period 1999-2003, and 85% (66/78) of these had cardiac arrest and died. The authors found age >50 years and overdose during the weekend significantly associated with 48-h mortality. Gender, former episodes of opioid overdose, time of the day, month or year were not significantly associated with increased mortality. The author found a 48-hours mortality of 8.4%. Advanced age and opioid overdose in the weekends were significant risk factors. Release on scene after treatment was associated with a very small risk.


2,4,5-Tribromo-1H-imidazole in the egg masses of three muricid molluscs.
From analysis by gas chromatography/mass spectrometry (GC/MS), the presence of either 2,4,5-tribromo-1H-imidazole (1) or 3,4,5-tribromo-1H-pyrazole (2) was tentatively identified in lipophilic extracts from the egg masses of three muricid molluscs. Synthesis of these compounds, followed by comparison of the GC retention times and fragmentation patterns from electron impact MS, with those of the natural products, indicated that it was 2,4,5-tribromo-1H-imidazole rather than the pyrazole. This imidazole is likely to be responsible for some of the antimicrobial activity observed in the egg extracts. This is the first report of this compound from a natural source.


Holographic recording in acrylamide photopolymers: thickness limitations.
Holographic recording in thick photopolymer layers is important for application in holographic data storage, volume holographic filters, and correlators. Here, we studied the characteristics of acrylamide-based photopolymer layers ranging in thickness from 250 microm to 1 mm. For each thickness, samples with three different values of absorbance were studied. By measuring the diffraction efficiency growth of holographically recorded gratings and studying the diffraction patterns obtained, the influence of scattering on the diffraction efficiency of thick volume holographic gratings was analyzed. It was found that, above a particular thickness and absorbance, the diffraction efficiency significantly decreased because of increased holographic scattering. From the diffraction efficiency dependence on absorbance and thickness it is possible to choose photopolymer layer properties that are suitable for a particular holographic application. This study was carried out to determine the highest layer thickness that could be used for phase code multiplexed holographic data storage utilizing thick photopolymer layers as a recording medium. Based on our studies to date we believe that the layer to be used for phase coded reference beam recording with 0.1 absorbance at 532 nm can have a thickness up to 450 microm. The potential use of thicker layers characterized by low scattering losses is part of our continuing research.


Toward Precision Medicine Using a "Digital Twin" Approach: Modeling the Onset of Disease-Specific Brain Atrophy in Individuals with Multiple Sclerosis.
Digital Twin (DT) is a novel concept that may bring a paradigm shift for precision medicine. In this study we demonstrate a DT application for estimating the age of onset of disease-specific brain atrophy in individuals with multiple sclerosis (MS) using brain MRI. We first augmented longitudinal data from a well-fitted spline model derived from a large cross-sectional normal aging data. Then we compared different mixed spline models through both simulated and real-life data and identified the mixed spline model with the best fit. Using the appropriate covariate structure selected from 52 different candidate structures, we augmented the thalamic atrophy trajectory over the lifespan for each individual MS patient and a corresponding hypothetical twin with normal aging. Theoretically, the age at which the brain atrophy trajectory of an MS patient deviates from the trajectory of their hypothetical healthy twin can be considered as the onset of progressive brain tissue loss. With a 10-fold cross validation procedure through 1000 bootstrapping samples, we found the onset age of progressive brain tissue loss was, on average, 5-6 years prior to clinical symptom onset. Our novel approach also discovered two clear patterns of patient clusters: earlier onset vs. simultaneous onset of brain atrophy.


Repeated ECS differentially affects rat brain 5-HT1A and 5-HT2A receptor expression.
We investigated the effect of electroconvulsive shock (ECS), administered five times over 10 days, on 5-HT1A and 5-HT2A receptor mRNA and binding site densities in the rat brain using in situ hybridization histochemistry and quantitative autoradiography. ECS treatment increased 5-HT1A receptor mRNA abundance and binding site densities in the dentate gyrus, but decreased these parameters in the CA3c layer of the hippocampus. No changes in 5-HT1A receptor mRNA and binding sites occurred in other hippocampal subfields, neocortex or raphe nuclei. Repeated ECS was also found to increase 5-HT2A receptor binding site densities in the neocortex and this was accompanied by a non-significant increase in cortical 5-HT2A receptor mRNA abundance. Our study demonstrates that in the rat, repeated ECS produces anatomically and molecularly discrete effects on 5-HT1A and 5-HT2A receptor gene expression. These changes may be relevant to the therapeutic effect of repeated ECS in depression.


Is low-dose hydrochlorothiazide effective?
In a double-blind crossover study, 13 patients with pretreatment diastolic blood pressure between 95 and 109 mm Hg received nadolol, 80 mg/day, plus placebo of hydrochlorothiazide and nadolol, plus three different doses of active hydrochlorothiazide. Patients remained on each active regimen for 3 weeks, with an intervening placebo period of 2 to 4 weeks. With 12.5 mg of hydrochlorothiazide daily plus nadolol, there was no greater reduction of blood pressure than with nadolol alone. A dose of 25 mg of hydrochlorothiazide was associated with a significantly greater decrease in systolic but not diastolic pressure, as compared with nadolol alone. A significantly greater reduction in both systolic and diastolic blood pressure was obtained only with the 50 mg/day dose of hydrochlorothiazide. Extension to 6 weeks of treatment with 12.5 mg/day failed to lower the blood pressure more than the level seen at 3 weeks. These results suggest that in combination with nadolol, 12.5 mg of hydrochlorothiazide per day has no significant antihypertensive effect. There was no evidence of a flat dose-response curve in the daily dose range of 12.5 to 50 mg. For most patients, a dose of 50 mg of hydrochlorothiazide was required to lower both systolic and diastolic blood pressure significantly below the level obtained with nadolol alone.


Illnesses at high altitude.
High-altitude illnesses have profound consequences on the health of many unsuspecting and otherwise healthy individuals who sojourn to high altitude for recreation and work. The clinical manifestations of high-altitude illnesses are secondary to the extravasation of fluid from the intravascular to extravascular space, especially in the brain and lungs. The most common of these illnesses, which can present as low as 2,000 m, is acute mountain sickness, which is usually self-limited but can progress to the more severe and potentially fatal entities of high-altitude cerebral edema and high-altitude pulmonary edema. This article will briefly review normal adaptation to high altitude and then more extensive reviews of the clinical presentations, prevention, and treatments of these potentially fatal conditions. Research on the mechanisms of these conditions will also be reviewed. A better understanding of these disorders by practitioners will lead to improved prevention and rational treatment for the increasing number of people visiting high-altitude areas around the globe. There will not be space for writing about high-altitude residents, medical conditions in low-altitude residents going to high altitude, or training for athletes at high altitude. These topics deserve another article.


A characterization of local LOINC mapping for laboratory tests in three large institutions.
We characterized the use of laboratory LOINC® codes in three large institutions, focused on the following questions: 1) How many local codes had been voluntarily mapped to LOINC codes by each institution? 2) Could additional mappings be found by expert manual review for any local codes that were not initially mapped to LOINC codes by the local institution? and 3) Are there any common characteristics of unmapped local codes that might explain why some local codes were not mapped to LOINC codes by the local institution? With Institutional Review Board (IRB) approval, we obtained deidentified data from three large institutions. We calculated the percentage of local codes that have been mapped to LOINC by personnel at each of the institutions. We also analyzed a sample of unmapped local codes to determine whether any additional LOINC mappings could be made and identify common characteristics that might explain why some local codes did not have mappings. Concept type coverage and concept token coverage (volume of instance data covered) of local codes mapped to LOINC codes were 0.44/0.59, 0.78/0.78 and 0.79/0.88 for ARUP, Intermountain, and Regenstrief, respectively. After additional expert manual mapping, the results showed mapping rates of 0.63/0.72, 0.83/0.80 and 0.88/0.90, respectively. After excluding local codes which were not useful for inter-institutional data exchange, the mapping rates became 0.73/0.79, 0.90/0.99 and 0.93/0.997, respectively. Local codes for two institutions could be mapped to LOINC codes with 99% or better concept token coverage, but mapping for a third institution (a reference laboratory) only achieved 79% concept token coverage. Our research supports the conclusions of others that not all local codes should be assigned LOINC codes. There should also be public discussions to develop more precise rules for when LOINC codes should be assigned.


Reproductive history and cigarette smoking as risk factors for thyroid cancer in women: a population-based case-control study.
A population-based case-control study was conducted in Northern Norway and Central Sweden to investigate hormonal and reproductive factors and cigarette smoking as determinants of papillary and follicular thyroid carcinoma in women. Information on 191 histologically confirmed cases and 341 age-matched controls was included. No clear association was found with regard to the number of live births, number of pregnancies, a history of incomplete pregnancies, or the use of oral contraceptives or hormonal replacement therapy. However, an early first childbirth (before 20 years of age, or less than 5 years after menarche) was associated with an increased risk of thyroid cancer. There was an increased risk of thyroid cancer among women with a history of artificial menopause compared to those with a spontaneous menopause [odds ratio (OR), 2.52; 95% confidence interval (CI), 0.96-6.62], which was more pronounced for the papillary carcinoma and after adjustment for age at menopause and use of replacement therapy. Cigarette smokers had a decreased risk of borderline statistical significance compared to nonsmokers (OR, 0.69; 95% CI, 0.47-1.01), particularly among premenopausal women (OR, 0.60; 95% CI, 0.38-0.96). This negative association persisted after adjustment for parity, hormonal treatments, and education. Women who started smoking before the age of 15 experienced a marked reduction in risk (OR, 0.38%; 95% CI, 0.18-0.80¿). Moreover, there was a suggestion of a dose-response effect with the amount of cigarettes smoked daily and with duration of the habit. Both the increased risk of artificial menopause and the negative association with smoking are compatible with a relation between levels of estrogens and thyroid cancer among women.


Transgenic farm animals: present and future.
Until recently, pronuclear microinjection of deoxyribonucleic acid (DNA) was the standard method for producing transgenic animals. This technique is now being replaced by more efficient protocols based on somatic nucleartransferthat also permit targeted genetic modifications. Lentiviral vectors and small interfering ribonucleic acid technology are also becoming important tools for transgenesis. Transgenic farm animals are important in human medicine as sources of biologically active proteins, as donors in xenotransplantation, and for research in cell and gene therapy. Typical agricultural applications include improved carcass composition, lactational performance and wool production, as well as enhanced disease resistance and reduced environmental impact. Product safety can be ensured by standardisation of procedures and monitored by polymerase chain reaction and array technology. As sequence information and genomic maps of farm animals are refined, it becomes increasingly practical to remove or modify individual genes. This approach to animal breeding will be instrumental in meeting global challenges in agricultural production in the future.


A mathematical model of skeletal muscle disease and immune response in the mdx mouse.
Duchenne muscular dystrophy (DMD) is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.


Real-time genomic epidemiological evaluation of human Campylobacter isolates by use of whole-genome multilocus sequence typing.
Sequence-based typing is essential for understanding the epidemiology of Campylobacter infections, a major worldwide cause of bacterial gastroenteritis. We demonstrate the practical and rapid exploitation of whole-genome sequencing to provide routine definitive characterization of Campylobacter jejuni and Campylobacter coli for clinical and public health purposes. Short-read data from 384 Campylobacter clinical isolates collected over 4 months in Oxford, United Kingdom, were assembled de novo. Contigs were deposited at the pubMLST.org/campylobacter website and automatically annotated for 1,667 loci. Typing and phylogenetic information was extracted and comparative analyses were performed for various subsets of loci, up to the level of the whole genome, using the Genome Comparator and Neighbor-net algorithms. The assembled sequences (for 379 isolates) were diverse and resembled collections from previous studies of human campylobacteriosis. Small subsets of very closely related isolates originated mainly from repeated sampling from the same patients and, in one case, likely laboratory contamination. Much of the within-patient variation occurred in phase-variable genes. Clinically and epidemiologically informative data can be extracted from whole-genome sequence data in real time with straightforward, publicly available tools. These analyses are highly scalable, are transparent, do not require closely related genome reference sequences, and provide improved resolution (i) among Campylobacter clonal complexes and (ii) between very closely related isolates. Additionally, these analyses rapidly differentiated unrelated isolates, allowing the detection of single-strain clusters. The approach is widely applicable to analyses of human bacterial pathogens in real time in clinical laboratories, with little specialist training required.


Conformational changes in a photosensory LOV domain monitored by time-resolved NMR spectroscopy.
Phototropins are light-activated kinases from plants that utilize light-oxygen-voltage (LOV) domains as blue light photosensors. Illumination of these domains leads to the formation of a covalent linkage between the protein and an internally bound flavin chromophore, destabilizing the surrounding protein and displacing an alpha-helix from its surface. Here we use a combination of spectroscopic tools to monitor the kinetic processes that spontaneously occur in the dark as the protein returns to the noncovalent ground state. Using time-resolved two-dimensional (2D) NMR methods, we measured the rate of this process at over 100 independent sites throughout the protein, establishing that regeneration of the dark state occurs cooperatively within a 1.6-fold range of observed rates. These data agree with other spectroscopic measurements of the kinetics of protein/FMN bond cleavage and global conformational changes, consistent with these processes experiencing a common rate-limiting step. Arrhenius analyses of the temperature dependence of these rates suggest that the transition state visited during this regeneration has higher energy than the denatured form of this protein domain despite the fact that there is no global unfolding of the domain during this process.


HTLV-1 infection in solid organ transplant donors and recipients in Spain.
HTLV-1 infection is a neglected disease, despite infecting 10-15 million people worldwide and severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1 associated illnesses due to immunosuppression, screening is being widely considered in the transplantation setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ transplants in a survey conducted in Spain. All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients attended since the year 2008. A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312 (42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards represented nearly 80%. Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients. Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in dialysis but otherwise asymptomatic. The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along with the rapid development of subacute myelopathy.


Runs of rapid spikes in sleep: a characteristic EEG expression of generalized malignant epileptic encephalopathies. A conceptual review with new pharmacological data.
The generalized repetitive fast discharge (GRFD) is an ictal pattern representing the EEG counterpart of tonic seizures occurring mainly in Lennox-Gastaut syndrome (LGS) during slow-wave sleep. The history of terminology, electromorphology, correlations with sleep, ictal clinical correlations and associations with different epileptic syndromes as well as the clinical significance of the pattern is described reviewing the pertinent literature and our own experiences. The physiopathogenesis from both the electrophysiological and pharmacological aspects is discussed in the framework of a concept according to which GRFD is considered as a malignant derivative of an existing slow spike-wave mechanism, due to the permanent or momentary breakdown of the GABA-ergic inhibitory process. In observations performed on some patients we found a paradoxical GRFD-eliciting effect of BDZ drugs and hexobarbiturate after chronic treatment with BDZ agents and/or barbiturate, and a GRFD-blocking effect of Anexate (Flumazenil), a BDZ antagonist on the pattern, appearing either spontaneously in slow-wave sleep or elicited by diazepam or barbiturate. Our findings support the assumption that BDZ (Barbiturate) GABA-Chloride Ionophore Complex plays an important role, both in the development of and possibly in the therapeutic approach to, the GRFD phenomena. Some hypotheses about the role played by the complex based on these observations are put forward.


Racial differences in opiate administration for pain relief at an academic emergency department.
The decision to treat pain in the emergency department (ED) is a complex, idiosyncratic process. Prior studies have shown that EDs undertreat pain. Several studies demonstrate an association between analgesia administration and race. This is the first Midwest single institution study to address the question of race and analgesia, in addition to examining the effects of both patient and physician characteristics on race-based disparities in analgesia administration. This was a retrospective chart review of patients presenting to an urban academic ED with an isolated diagnosis of back pain, migraine, or long bone fracture (LBF) from January 1, 2007 to December 31, 2011. Demographic and medication administration information was collected from patient charts by trained data collectors blinded to the hypothesis of the study. The primary outcome was the proportion of African-Americans who received analgesia and opiates, as compared to Caucasians, using Pearson's chi-squared test. We developed a multiple logistic regression model to identify which physician and patient characteristics correlated with increased opiate administration. Of the 2,461 patients meeting inclusion criteria, 57% were African-American and 30% Caucasian (n=2136). There was no statistically significant racial difference in the administration of any analgesia (back pain: 86% vs. 86%, p=0.81; migraine: 83% vs. 73%, p=0.09; LBF: 94% vs. 90%, p=0.17), or in opiate administration for migraine or LBF. African-Americans who presented with back pain were less likely to receive an opiate than Caucasians (50% vs. 72%, p<0.001). Secondary outcomes showed that higher acuity, older age, physician training in emergency medicine, and male physicians were positively associated with opiate administration. Neither race nor gender patient-physician congruency correlated with opiate administration. No race-based disparity in overall analgesia administration was noted for all three conditions: LBF, migraine, and back pain at this institution. A race-based disparity in the likelihood of receiving opiate analgesia for back pain was observed in this ED. The etiology of this is likely multifactorial, but understanding physician and patient characteristics of institutions may help to decrease the disparity by raising awareness of practice patterns and can provide the basis for quality improvement projects.


Fetal cortisol response to intrauterine microbial colonisation identified by the polymerase chain reaction and fetal inflammation.
To determine the fetal cortisol response to intrauterine infection. 16s ribosomal RNA genes or the urease genes of Ureaplasma spp were identified by the polymerase chain reaction in intrauterine samples. Cord blood cortisol, interleukin 6 (IL6) and IL8 were measured in samples from 31 infants born at <32 weeks gestation. 13 infants (median gestation 30 weeks, birth weight 1350 g) had at least one positive intrauterine sample for microbial genes and 18 infants (31 weeks, 1320 g) did not. The cord blood cortisol concentration was significantly higher in fetuses exposed to intrauterine infection and significantly increased in fetuses/mothers presenting in preterm labour with intact membranes compared with infants delivered by elective prelabour caesarean section (p<0.05). The cord blood cortisol concentration was increased in the mothers with prelabour premature rupture of membranes but this was not significant compared with the caesarean section group. The cord blood cortisol concentration was significantly increased in the presence of chorioamnionitis or funisitis and was moderately correlated with cord blood IL6 (r = 0.64, p<0.01) and IL8 (r = 0.52, p<0.01). In this study, cord blood cortisol was increased in the colonised group compared with non-colonised infants. It is unclear if infants born following prelabour premature rupture of the membranes mount an adequate anti-inflammatory response.


Primary care providers' knowledge, attitudes and practices of medical abortion: a systematic review.
Despite the availability of medical abortifacients, and their potential use in primary care, only a small proportion of primary healthcare professionals provide medical abortion services. Understanding the perspectives of primary care providers on delivering medical abortion is pertinent to identifying barriers to medical abortion service provision and increasing access for women globally. To understand the knowledge, attitudes and practices of primary healthcare providers regarding medical abortion services. Four databases (Medline, EMBASE, Web of Science (WOS) and Scopus) were searched using search terms related to medical abortion and primary care. The Joanna Briggs Institute Critical Appraisal tools were used to appraise the methodological quality of studies included. Some 22 studies were identified, conducted across 15 countries, comprising 6072 participants. Study participants comprised doctors and residents (n=8), nurses and nursing students (n=5), and pharmacists (n=3) and six studies were conducted with mixed samples of providers. Medical abortion was deemed acceptable by some doctors, but fear of criminal prosecution, in countries where abortion is still restrictive, left doctors and nurses circumspect about providing medical abortion. Pharmacists referred women to other providers with only a small proportion dispensing medical abortifacients. General practitioners, nurses and trainees had mixed knowledge of medical abortion and emphasised the need for training on delivery of medical abortion and dissemination of guidelines. Conversely, pharmacists reported poor knowledge regarding medical abortion regimens and complications. Increased dissemination of training and resources is pertinent to supporting primary care providers delivering medical abortion services and to increasing access for women on a global scale.


Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control.
Theories of the regulation of cognition suggest a system with two necessary components: one to implement control and another to monitor performance and signal when adjustments in control are needed. Event-related functional magnetic resonance imaging and a task-switching version of the Stroop task were used to examine whether these components of cognitive control have distinct neural bases in the human brain. A double dissociation was found. During task preparation, the left dorsolateral prefrontal cortex (Brodmann's area 9) was more active for color naming than for word reading, consistent with a role in the implementation of control. In contrast, the anterior cingulate cortex (Brodmann's areas 24 and 32) was more active when responding to incongruent stimuli, consistent with a role in performance monitoring.


A multiwell cell settling and adherence chamber for morphology and differential counting.
A simple multiwell chamber is described that can be used to prepare randomly distributed cells on a microscope slide, suitable for morphological identification and differential counting. To the eight wells of the chamber are added 50-microliter volumes of cell suspension at concentrations of 10(3)-10(6) cells/ml. As the cells settle, fluid is slowly wicked away by a damp filter paper sandwiched between the microscope slide and the acrylic top plate of the multiwell chamber. Within 20-40 minutes, the cell monolayers on the slide are completely dry. The combined settling and bulk fluid removal results in a distribution of adherent cells that are sufficiently spread to exhibit excellent morphology after staining. If the chamber is centrifuged for 30 seconds at 50x g immediately after addition of cells, recovery of cells in the monolayer is virtually 100%, and as few as 50 input cells per 50 microliters can be detected. Agreement between predicted and observed differential counts of cell mixtures indicates that cells in the monolayer were distributed randomly.


The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells.
Defining the transcriptional dynamics of a temporal process such as cell differentiation is challenging owing to the high variability in gene expression between individual cells. Time-series gene expression analyses of bulk cells have difficulty distinguishing early and late phases of a transcriptional cascade or identifying rare subpopulations of cells, and single-cell proteomic methods rely on a priori knowledge of key distinguishing markers. Here we describe Monocle, an unsupervised algorithm that increases the temporal resolution of transcriptome dynamics using single-cell RNA-Seq data collected at multiple time points. Applied to the differentiation of primary human myoblasts, Monocle revealed switch-like changes in expression of key regulatory factors, sequential waves of gene regulation, and expression of regulators that were not known to act in differentiation. We validated some of these predicted regulators in a loss-of function screen. Monocle can in principle be used to recover single-cell gene expression kinetics from a wide array of cellular processes, including differentiation, proliferation and oncogenic transformation.