Rheumatoid arthritis is associated with reduced adiposity but not with unfavorable major cardiovascular risk factor profiles and enhanced carotid atherosclerosis in black Africans from a developing population: a cross-sectional study.
Rheumatoid arthritis (RA) is characterized by inflamed joint-derived cytokine-mediated high-grade systemic inflammation that enhances cardiovascular metabolic risk and disease in developed populations. We investigated the potential impact of RA on cardiovascular risk factors including systemic inflammation and atherosclerosis, and their relationships in black Africans from a developing population. We evaluated demographic features, adiposity indices, major traditional cardiovascular risk factors, circulating C-reactive protein and interleukin-6 concentrations and ultrasound determined carotid intima-media thickness (cIMT) in 274 black Africans; 115 had established RA. Data were analyzed in confounder-adjusted mixed regression models. The body mass index and waist-height ratio were lower in RA compared to non-RA subjects (29.2 (6.6) versus 33.7 (8.0), P < 0.0001 and 0.58 (0.09) versus 0.62 (0.1), P = 0.0003, respectively). Dyslipidemia was less prevalent in patients with RA (odds ratio (OR) (95% confidence interval (CI) = 0.54 (0.30 to 1.00)); this disparity was no longer significant after further adjustment for reduced adiposity and chloroquine use. RA was also not associated with hypertension, current smoking and diabetes. The number of major traditional risk factors did not differ by RA status (1.1 (0.8) versus 1.2 (0.9), P = 0.7). Circulating C-reactive protein concentrations were similar and serum interleukin-6 concentrations reduced in RA (7.2 (3.1) versus 6.7 (3.1) mg/l, P = 0.7 and 3.9 (1.9) versus 6.3 (1.9) pg/ml, P < 0.0001, respectively). The cIMT was 0.700 (0.085) and 0.701 (0.111) mm in RA and non-RA subjects, respectively (P = 0.7). RA disease activity and severity parameters were consistently unrelated to systemic inflammation, despite the presence of clinically active disease in 82.6% of patients. In all participants, adiposity indices, smoking and converting angiotensin inhibitor non-use were associated with increased systemic inflammation, which related to more atherogenic lipid profiles, and circulating low density lipoprotein concentrations were associated with cIMT (partial R = 0.153, P = 0.032); RA did not impact on these relationships (interaction P ≥0.1). Among black Africans, patients with established RA experience reduced overall and abdominal adiposity but no enhanced major traditional risk factor and atherosclerosis burden. This study further suggests that an absent interleukin-6 release by inflamed RA joints into the circulation may account for this unaltered cardiovascular disease risk.


Beneficial effects of melittin on ovalbumin-induced atopic dermatitis in mouse.
Atopic dermatitis (AD) is an inflammatory skin disease characterized by intense pruritus and relapsable eczematous lesions. The hallmarks of AD are defects in the epidermal barrier and immunoglobulin E (IgE)-mediated sensitization to several environmental allergens, as well as an immune disorder mediated by an imbalance toward T-helper-2 response. Melittin, a major component of bee venom, has been studied in various inflammatory diseases. However, the beneficial effects of melittin on mouse with AD-like symptoms have not been explored. Therefore, we investigated the anti-allergic effects of melittin. AD was induced by ovalbumin (OVA) patch. After agent treatment, skin tissues and sera were extracted from the sacrificed mice were used to demonstrate the effects of melittin through various molecular biological methods. The results showed that OVA-induced skin thickening and inflammatory infiltration were decreased in the melittin-treated group. Melittin prevented OVA-induced filaggrin deficiency and imbalanced inflammatory mediators. Furthermore, melittin inhibited IL-4/IL-13-induced filaggrin downregulation through the blockade of STAT3 activation in human keratinocytes. In summary, this study has shown that melittin ameliorated OVA-induced AD-like symptoms from various perspectives. The findings of this study may be the first evidence of the anti-inflammatory effects of melittin on OVA-induced AD.


Cued by What We See and Hear: Spatial Reference Frame Use in Language.
To what extent is the choice of what to say driven by seemingly irrelevant cues in the visual world being described? Among such cues, how does prior description affect how we process spatial scenes? When people describe where objects are located their use of spatial language is often associated with a choice of reference frame. Two experiments employing between-participants designs (N = 490) examined the effects of visual cueing and previous description on reference frame choice as reflected in spatial prepositions (in front of, to the left of, etc.) to describe pictures of object pairs. Experiment 1 examined the effects of visual and linguistic cues on spatial description choice through movement of object(s) in spatial scenes, showing sizeable effects of visual cueing on reference frame choice. Experiment 2 monitored eye movements of participants following a linguistic example description, revealing two findings: eye movement "signatures" associated with distinct reference frames as expressed in language, and transfer of these eye movement patterns just prior to spatial description for different (later) picture descriptions. Both verbal description and visual cueing similarly influence language production choice through manipulation of visual attention, suggesting a unified theory of constraints affecting spatial language choice.


The Oxford Ankle Foot Questionnaire for children: responsiveness and longitudinal validity.
To evaluate how scores from the Oxford Ankle Foot Questionnaire change over time and with treatment using both distribution-based and anchor-based approaches. Eighty children aged 5-16 and their parent or career completed questionnaires at orthopaedic or trauma outpatient clinics. They were asked to complete and return a second set of questionnaires again within 2 weeks (retest), and then mailed a third set of questionnaires to complete again after 2 months (follow-up). The follow-up questionnaires included a global rating of change 'transition' item. Child- and parent-reported mean domain scores (Physical, School & Play, and Emotional) were all stable at retest, whereas positive mean changes were observed at follow-up. As we hypothesised, trauma patients had poorer scores than elective patients at baseline, and showed greater improvement at follow-up. For trauma patients, mean changes in per cent scores were large (scores improved between 40 and 56 for the Physical and School & Play domains, and 17 and 21 for Emotional); all effect sizes (ES) were large (>0.8). For elective patients, the mean improvement in per cent scores were more moderate (Physical: child 10, ES = 0.4, parent 11, ES = 0.5; School & Play child 0, ES = 0, parent 9 ES = 0.4; Emotional: child 6, ES = 0.2; parents 8, ES > 0.3). Minimal detectable change (MDC(90)), an indication of measurement error, ranged from 6 to 8. Half the standard deviation of baseline scores ranged from 11 to 18. Minimal important difference could only be calculated for elective patients (9 child and 13 parent ratings), these ranged from 7 to 17. The findings support the responsiveness and longitudinal validity of the scales. Changes in domain scores of, or exceeding, the MDC(90) (6-8) are likely to be beyond measurement error; further work is required to refine the estimate of change that can be considered important.


On-tissue chemical derivatization in mass spectrometry imaging.
Mass spectrometry imaging (MSI) combines molecular and spatial information in a valuable tool for a wide range of applications. Matrix-assisted laser desorption/ionization (MALDI) is at the forefront of MSI ionization due to its wide availability and increasing improvement in spatial resolution and analysis speed. However, ionization suppression, low concentrations, and endogenous and methodological interferences cause visualization problems for certain molecules. Chemical derivatization (CD) has proven a viable solution to these issues when applied in mass spectrometry platforms. Chemical tagging of target analytes with larger, precharged moieties aids ionization efficiency and removes analytes from areas of potential isobaric interferences. Here, we address the application of CD on tissue samples for MSI analysis, termed on-tissue chemical derivatization (OTCD). MALDI MSI will remain the focus platform due to its popularity, however, alternative ionization techniques such as liquid extraction surface analysis and desorption electrospray ionization will also be recognized. OTCD reagent selection, application, and optimization methods will be discussed in detail. MSI with OTCD is a powerful tool to study the spatial distribution of poorly ionizable molecules within tissues. Most importantly, the use of OTCD-MSI facilitates the analysis of previously inaccessible biologically relevant molecules through the adaptation of existing CD methods. Though further experimental optimization steps are necessary, the benefits of this technique are extensive.


Expression of HPCA-1 and HLA-DR antigens on growth factor- and stroma-dependent colony forming cells.
The expression of HLA-DR and HPCA-1 antigens (recognized by the L243 and BI.3C5 antibodies respectively) on adult human bone marrow cells was examined by fluorescence activated cell sorting and colony assays. Nearly all the (day 14) lineage restricted and multipotential colony forming cells analysed in methylcellulose cultures in the presence of added growth factors express HLA-DR and HPCA-1 determinants. Two colour cell sorting reveals that the lineage restricted HLA-DR positive progenitors express variable levels of BI.3C5 positivity whereas most of the multipotential progenitors, the multi-CFC or CFU-GEMM, are highly BI.3C5 positive. The isolated HLA-DR and BI.3C5 positive populations also contain haemopoietic precursors which adhere to and form colonies on pre-formed stromal layers. Thus, haemopoietic progenitors assayed in both types of culture system can be analysed and enriched by simultaneous two-colour sorting using anti-HLA-DR and BI.3C5 monoclonal antibodies. Similarities in the antigenic phenotype of such cells, however, precludes the use of these reagents for segregating growth factor-dependent from stroma-dependent progenitors.


Running after cycling induces inter-limb differences in muscle activation but not in kinetics or kinematics.
Overuse injuries are a common problem to triathletes' population. Overuse injuries may arise from inter-limb biomechanical differences during running, but the literature lacks information regarding inter-limb differences in triathletes. In this study inter-limb differences were investigated in injury-free triathletes during the running portion of a simulated cycle-run transition. Thirteen triathletes performed a 5 km run preceded by a 20 min cycling trial at 70% of maximal power output. During the Start, Mid and End stages of running, kinetic, kinematic and muscle activation variables were compared between the preferred and non-preferred limbs across the stance phase. A statistical parametric mapping analysis showed no differences between limbs when considering kinetic and kinematic variables (p > 0.05, ES<0.60). A lower soleus activation was observed in the preferred limb (p < 0.05, ES>0.60) from 53.40-75.9% of the stance phase at the End stage of running. In conclusion, inter-limb differences in kinetic or kinematic variables may not represent a risk for overloading in triathletes. However, inter-limb differences in triceps surae activation during running after cycling may represent one potential factor leading to overuse injuries in triathletes and should be further investigated.


Seasonal patterns of leaf gas exchange and water relations in dry rain forest trees of contrasting leaf phenology.
Diurnal and seasonal patterns of leaf gas exchange and water relations were examined in tree species of contrasting leaf phenology growing in a seasonally dry tropical rain forest in north-eastern Australia. Two drought-deciduous species, Brachychiton australis (Schott and Endl.) A. Terracc. and Cochlospermum gillivraei Benth., and two evergreen species, Alphitonia excelsa (Fenzal) Benth. and Austromyrtus bidwillii (Benth.) Burret. were studied. The deciduous species had higher specific leaf areas and maximum photosynthetic rates per leaf dry mass in the wet season than the evergreens. During the transition from wet season to dry season, total canopy area was reduced by 70-90% in the deciduous species and stomatal conductance (g(s)) and assimilation rate (A) were markedly lower in the remaining leaves. Deciduous species maintained daytime leaf water potentials (Psi(L)) at close to or above wet season values by a combination of stomatal regulation and reduction in leaf area. Thus, the timing of leaf drop in deciduous species was not associated with large negative values of daytime Psi(L) (greater than -1.6 MPa) or predawn Psi(L) (greater than -1.0 MPa). The deciduous species appeared sensitive to small perturbations in soil and leaf water status that signalled the onset of drought. The evergreen species were less sensitive to the onset of drought and g(s) values were not significantly lower during the transitional period. In the dry season, the evergreen species maintained their canopies despite increasing water-stress; however, unlike Eucalyptus species from northern Australian savannas, A and g(s) were significantly lower than wet season values.


Nonbridging phosphate oxygens in 16S rRNA important for 30S subunit assembly and association with the 50S ribosomal subunit.
Ribosomes are composed of RNA and protein molecules that associate together to form a supramolecular machine responsible for protein biosynthesis. Detailed information about the structure of the ribosome has come from the recent X-ray crystal structures of the ribosome and the ribosomal subunits. However, the molecular interactions between the rRNAs and the r-proteins that occur during the intermediate steps of ribosome assembly are poorly understood. Here we describe a modification-interference approach to identify nonbridging phosphate oxygens within 16S rRNA that are important for the in vitro assembly of the Escherichia coli 30S small ribosomal subunit and for its association with the 50S large ribosomal subunit. The 30S small subunit was reconstituted from phosphorothioate-substituted 16S rRNA and small subunit proteins. Active 30S subunits were selected by their ability to bind to the 50S large subunit and form 70S ribosomes. Analysis of the selected population shows that phosphate oxygens at specific positions in the 16S rRNA are important for either subunit assembly or for binding to the 50S subunit. The X-ray crystallographic structures of the 30S subunit suggest that some of these phosphate oxygens participate in r-protein binding, coordination of metal ions, or for the formation of intersubunit bridges in the mature 30S subunit. Interestingly, however, several of the phosphate oxygens identified in this study do not participate in any interaction in the mature 30S subunit, suggesting that they play a role in the early steps of the 30S subunit assembly.


Sporozoite vaccine induces genetically restricted T cell elimination of malaria from hepatocytes.
The target of the CD8+ T cell-dependent immunity that protects mice immunized with irradiation-attenuated malaria sporozoites has not been established. Immune BALB/c mice were shown to develop malaria-specific, CD8+ T cell-dependent inflammatory infiltrates in their livers after challenge with Plasmodium berghei sporozoites. Spleen cells from immune BALB/c and C57BL/6 mice eliminated hepatocytes infected with the liver stage of P. berghei in vitro. The activity against infected hepatocytes is not inhibited by antibodies to interferon-gamma and is not present in culture supernatants. It is genetically restricted, an indication that malaria antigens on the hepatocyte surface are recognized by immune T effector cells. Subunit vaccine development will require identification of the antigens recognized by these T cells and a method of immunization that induces such immunity.


Large-scale expansion and exploitation of pluripotent stem cells for regenerative medicine purposes: beyond the T flask.
Human pluripotent stem cells will likely be a significant part of the regenerative medicine-driven healthcare revolution. In order to realize this potential, culture processes must be standardized, scalable and able to produce clinically relevant cell numbers, whilst maintaining critical biological functionality. This review comprises a broad overview of important bioprocess considerations, referencing the development of biopharmaceutical processes in an effort to learn from current best practice in the field. Particular focus is given to the recent efforts to grow human pluripotent stem cells in microcarrier or aggregate suspension culture, which would allow geometric expansion of productive capacity were it to be fully realized. The potential of these approaches is compared with automation of traditional T-flask culture, which may provide a cost-effective platform for low-dose, low-incidence conditions or autologous therapies. This represents the first step in defining the full extent of the challenges facing bioprocess engineers in the exploitation of large-scale human pluripotent stem cell manufacture.


Coffee or Tea? A prospective cohort study on the associations of coffee and tea intake with overall and cause-specific mortality in men versus women.
Coffee and tea intake have been associated with reduced mortality, but no studies have investigated possible substitution effects. The relationship of mortality with coffee, tea, and substituting coffee with tea was investigated in the Netherlands Cohort Study. In 1986, 120,852 men and women aged 55-69 years provided information on dietary and lifestyle habits. Mortality follow-up until 1996 consisted of linkage to Statistics Netherlands. Multivariate case-cohort analyses were based on 8665 deaths and 3166 subcohort members with complete data on coffee, tea and confounders. Higher coffee intake was significantly, nonlinearly related to lower overall and cause-specific mortality in women. In men, coffee was significantly positively related to cancer and cardiovascular mortality, and inversely to respiratory and other causes of death. Tea intake was significantly, nonlinearly related to lower overall, cancer and cardiovascular mortality in men, but showed no association with mortality in women. In substitution analyses, increasing the proportion tea (replacing coffee with tea) was significantly and nonlinearly related to lower overall, cancer and cardiovascular mortality in men, but in women higher tea proportions were positively associated with overall mortality (and most causes of death). This study suggests that for men, compared to exclusive coffee drinkers, those drinking 30-50% tea showed the lowest mortality; any tea drinking seemed better than only coffee. For women, those who drank exclusively coffee or drinking up to 40% tea had the lowest mortality, but those drinking higher percentages of tea were at increased mortality risk [HR = 1.41 (95% CI 1.01-1.99) for 80-100% tea compared to exclusive coffee drinkers].


Co.Vi.Wo.: Color Visual Words Based on Non-Predefined Size Codebooks.
Due to the rapid development of information technology and the continuously increasing number of available multimedia data, the task of retrieving information based on visual content has become a popular subject of scientific interest. Recent approaches adopt the bag-of-visual-words (BOVW) model to retrieve images in a semantic way. BOVW has shown remarkable performance in content-based image retrieval tasks, exhibiting better retrieval effectiveness over global and local feature (LF) representations. The performance of the BOVW approach depends strongly, however, on predicting the ideal codebook size, a difficult and database-dependent task. The contribution of this paper is threefold. First, it presents a new technique that uses a self-growing and self-organized neural gas network to calculate the most appropriate size of a codebook for a given database. Second, it proposes a new soft-weighting technique, whereby each LF is classified into only one visual word (VW) with a degree of participation. Third, by combining the information derived from the method that automatically detects the number of VWs, the soft-weighting method, and a color information extraction method from the literature, it shapes a new descriptor, called color VWs. Experimental results on two well-known benchmarking databases demonstrate that the proposed descriptor outperforms 15 contemporary descriptors and methods from the literature, in terms of both precision at K and its ability to retrieve the entire ground truth.


Day-care management of sickle cell painful crisis in Jamaica: a model applicable elsewhere?
In the U.K. and the U.S.A., painful crises account for 80-90% of sickle-related hospital admissions, with average durations of 5-11 d. In Jamaica, many severe painful crises are managed in a day-care centre. Patients (n=1160) with homozygous sickle cell (SS) disease aged 18 years and over were registered with the clinic during a 1-year study period. Of these, 216 patients with 476 painful crises attended the day-care facility for a total of 686 d. Most patients (119 or 55.1%) had single crises and for most crises (338 or 71%), patients attended for only 1 d, when they were given bed rest, assurance, rehydration and analgesia. Patients with complicated painful crises were usually referred for admission after initial pain relief and the rest were monitored during the day. In the evening they were given the option of hospital admission or allowed home with oral analgesia. Hospital admission for complicated painful crises or inadequate pain relief occurred in 42 (8.8%) crises and home management in 434 (91.2%) crises. Of 186 patients initially selecting home management, 20% returned for further day-care and five (2.7%) died during subsequent admission for that painful crisis, one without other known complications, two with acute chest syndrome (one associated with Salmonella septicaemia), another with Salmonella septicaemia, and one with dengue haemorrhagic fever. With suitable oral analgesia, adequate education and support, the majority of severe painful crises in SS disease in Jamaica have been managed on an outpatient basis. This model of patient care may merit assessment in other communities where painful crises are a common clinical problem.


The Affordable Care Act may increase the number of people getting tested for HIV by nearly 500,000 by 2017.
People are much less likely to engage in risky sexual behavior if they know that they are HIV-positive. Unfortunately, more than 18 percent of people living with HIV/AIDS in the United States are unaware of their HIV status, and about half of new HIV infections are transmitted from that "HIV unaware" population. For these reasons, HIV testing is at the forefront of HIV prevention strategies in the United States. The Affordable Care Act (ACA) may support these strategies, since gaining coverage increases the likelihood of being tested for HIV. We modeled the impact of the ACA on HIV testing, diagnoses, and awareness of being HIV-positive, assuming that only the eighteen states (and the District of Columbia) that had committed to expand Medicaid as of July 2013 did expand the program. We found that the ACA will result in an additional 466,153 people's being tested for HIV and 2,598 new diagnoses of HIV by 2017. Among people living with HIV/AIDS who gain insurance through the ACA, the share of the HIV unaware will decline by 22 percent. The impact on both HIV testing and new diagnoses would be nearly 30 percent larger if all fifty states expanded Medicaid. Policy makers should consider such epidemiological benefits when analyzing insurance expansion policies.


Ecotoxicological assessment of persistent organic and heavy metal contamination in Hong Kong coastal sediment.
The aim of the present project is to determine the feasibility of measuring hepatic cytochrome P4501A1 (CYP1A1) and metallothionein (MT) mRNA in fish as an integrative measurement of persistent organic pollutants (POPs) and heavy metal contamination in sediment arising in Hong Kong. Sediment samples were collected from different sites, including Victoria Harbour (VS6), Yim Tin Tsai (YTT) at Tolo Harbour, Mai Po marshes (MPM) at Deep Bay, and Southern Waters (SS6) of coastal waters. The samples were analyzed for total and extractable concentrations of Cd, Cu, Ni, Zn, and Pb, as well as PCBs and PAHs. In addition, biomarker responses were studied in tilapia exposed experimentally to coastal sediment for 7 days. Using RT-PCR technique, hepatic CYP1A1 and MT mRNA were measured. Three control groups were used, including one negative control group maintained in sea water only; the second and third positive control groups were in sea water but were intraperitoneally injected with either beta-naphthoflavone (40 microg/g body weight) or cadmium chloride (10 microg/g body weight), respectively. The chemical data showed that VS6, YTT, and MPM were classified as Class C sediment according to the sediment quality criteria defined by the Hong Kong Environmental Protection Department, indicating the sites were heavily polluted. The exposure of tilapia to the sediment induced hepatic CYP1A1 (VS6 > YTT > MPM > SS6) and MT (VS6 > MPM > YTT > SS6) levels. The induction patterns were comparable to the levels of POPs and metal contamination in the sediment, indicating that the biomarker responses could be used to differentiate low to high levels of contamination among sediment.


A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker.
Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface "membrane clock" (M clock). Localized subsarcolemmal Ca(2+) releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular "Ca(2+) clock," because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca(2+) clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca(2+), and protein kinase A and CaMKII-dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein-coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs.


Emollient therapy for preterm newborn infants--evidence from the developing world.
Application of emollients is a widespread traditional newborn care practice in many low and middle-income countries (LMICs) and may have the potential to decrease infection and consequent mortality in preterm neonates. We systematically reviewed literature published up to December 2012 to identify studies describing the effectiveness of emollient therapy. We used a standardized abstraction and grading format to estimate the effect of emollient therapy by applying the standard Child Health Epidemiology Reference Group (CHERG) rules. We included seven studies and one unpublished trial in this review. Topical emollient therapy significantly reduced neonatal mortality by 27% (RR: 0.73, 95% CI: 0.56, 0.94) and hospital acquired infection by 50% (RR: 0.50, 95% CI: 0.36, 0.71). There were significant increases in weight (g) (MD: 98.04, 95% CI: 42.64, 153.45) and weight gain (g/kg/day) (MD: 1.57, 95% CI: 0.79, 2.36), whereas the impacts were non-significant for length and head circumference. Emollient therapy is associated with improved weight gain, reduced risk of infection and associated newborn mortality in preterm neonates and is a potentially promising intervention for use in low resource settings. Large scale effectiveness trials are required to further assess the impact of this intervention.


Evaluation of hyaluronic acid-P40 conjugated cream in a mouse model of dermatitis induced by oxazolone.
P40 is a particulate fraction or fragment isolated from Corynebacterium granulosum, which exhibits a wide spectrum of pharmacological functions including antitumor, antibacterial, phagocytic, antiviral and cytokine induction effects. In the present study, the immunomodulatory potential of P40-conjugated with hyaluronic acid was assessed in a mouse model of dermatitis induced by oxazolone. Oxazolone-induced allergic contact dermatitis is a T cell-mediated Th2-like hypersensitivity reaction, which mimics the corresponding reaction in humans. Female cluster of differentiation-1 mice were sensitized on days 0 and 1 by the application of 2% oxazolone onto a shaved back. The disease was induced by re-challenge on day 7 using 15% oxazolone in the inner and outer of the left ears of the mice. Mice were topically treated with hyaluronic acid-P40 conjugate cream or with placebo to the inner and outer surface of the left ear for 7 consecutive days starting from 1 h after the sensitization. A significant reduction in ear thickness and weight and in edema and leukocyte recruitment were observed in the mice treated with hyaluronic-P40 conjugate cream compared with mice treated with the cream base alone (P<0.05). Thus, P40-conjugated with hyaluronic acid may constitute an innovative dermatitis treatment.


The effects of aging on the neural basis of implicit associative learning in a probabilistic triplets learning task.
Few studies have investigated how aging influences the neural basis of implicit associative learning, and available evidence is inconclusive. One emerging behavioral pattern is that age differences increase with practice, perhaps reflecting the involvement of different brain regions with training. Many studies report hippocampal involvement early on with learning becoming increasingly dependent on the caudate with practice. We tested the hypothesis that the contribution of these regions to learning changes with age because of differential age-related declines in the striatum and hippocampi. We assessed age-related differences in brain activation during implicit associative learning using the Triplets Learning Task. Over three event-related fMRI runs, 11 younger and 12 healthy older adults responded to only the third (target) stimulus in sequences of three stimuli ("triplets") by corresponding key press. Unbeknown to participants, the first stimulus' location predicted one target location for 80% of trials and another target location for 20% of trials. Both age groups learned associative regularities but differences in favor of the younger adults emerged with practice. The neural basis of learning (response to predictability) was examined by identifying regions that showed a greater response to triplets that occurred more frequently. Both age groups recruited the hippocampus early, but with training, the younger adults recruited their caudate whereas the older adults continued to rely on their hippocampus. This pattern enables older adults to maintain near-young levels of performance early in training, but not later, and adds to evidence that implicit associative learning is supported by different brain networks in younger and older adults.


Different effects of atrial and C-type natriuretic peptide on the urinary excretion of endothelin-1 in man.
1. Following the observation that brain natriuretic peptide enhances the urinary excretion rate of endothelin-1, the relationship between natriuretic peptides and urinary endothelin-1 was further investigated. Six healthy volunteers received, on three different occasions, increasing doses of atrial or C-type natriuretic peptide (0, 2 and 4 pmol.min-1.kg-1 for 1 h each), or placebo.2. Atrial natriuretic peptide caused significant increases in the urinary excretion of cGMP, sodium and endothelin-1, without affecting plasma endothelin-1, renal plasma flow, glomerular filtration rate and urine flow rate. C-type natriuretic peptide did not modify any of these parameters. During atrial natriuretic peptide infusion, urinary endothelin-1 directly correlated with plasma atrial natriuretic peptide, urinary cGMP and sodium excretion.3. These results indicate that enhancement of the urinary excretion of endothelin-1 by natriuretic peptides is dose-dependent and somewhat related to their ability to bind to natriuretic peptide receptors A, activate guanylate cyclase and induce a natriuretic response.


Developmental changes in the cardiac effects of amrinone in the dog.
Amrinone, a bipyridine compound, has been shown to exert a positive inotropic effect on the heart, without producing cardiac arrhythmias. Because of preliminary observations suggesting that the actions of amrinone might change significantly with growth and development, we studied its effects on the contractility and electrophysiology of isolated cardiac muscle of 0- to 96-day-old beagles and Purkinje fibers of 5-year-old beagles. Amrinone's effects on ventricular muscle contractility were age-related. A significant decrease in contractility of right ventricular trabeculae and papillary muscles (not associated with changes in action potential characteristics) was observed in the 0- to 3-day newborn, whereas, by day 4-10, amrinone increased contractility. The magnitude of the increase became greater through day 96 of life. The negative inotropic effect of amrinone is unassociated with changes in the action potential plateau, suggesting that the slow inward current is not involved in this mechanism.


The impact of socioeconomic status on cardiovascular risk factors in African-Americans at high risk for type II diabetes. Implications for syndrome X.
The rate of type II diabetes in African-Americans is reaching epidemic proportions. African-Americans with type II diabetes suffer from more cardiovascular diseases (CVDs) associated with diabetes than the general population. Lower socioeconomic status (SES) and family history are often cited as contributory factors to the premature development of diabetes and CVDs in the general population. However, we are not aware of any study that has examined the relationships between SES and CVD risk factors (i.e., syndrome X) in a genetically enriched African-American population at high risk for type II diabetes. We studied 200 healthy first-degree relatives of African-American patients with type II diabetes (age 25-65 years, mean 42.5 +/- 8.4 years; 42 men, 158 women). Standard oral glucose tolerance test, metabolic, and anthropometric parameters, as well as questionnaires on SES, demographic characteristics, and physical activity, were obtained for each subject. SES was divided into quartiles based on annual income. To assess the impact of insulin on CVD risk, we examined clinical characteristics and metabolic parameters according to quartiles of fasting insulin concentrations. Clinical characteristics, including mean age, BMI, waist-to-hip ratio (WHR), percentage body fat and lean body mass, and blood pressure were not statistically different among SES quartiles. There were no significant differences in any of the metabolic, blood pressure, lipid and lipoprotein, or anthropometric parameters among SES quartiles. When examined by insulin quartile, BMI, WHR, and body fat content tended to be greatest in the fourth quartile. Similarly, fasting and postprandial serum C-peptide and glucose levels were significantly higher in the fourth quartile. We observed greater levels of very low density lipoprotein (VLDL) cholesterol and triglycerides and lower levels of HDL cholesterol in the fourth compared with the first through third insulin quartiles. Serum cholesterol and LDL cholesterol were not associated with increasing insulin concentration assessed by quartiles. We found similar systolic and diastolic blood pressure, irrespective of insulin quartiles. We found relationships between fasting insulin and systolic blood pressure (r = 0.181, P < 0.05) and triglycerides (r = 0.247, P < 0.01), VLDL cholesterol (r = 0.237, P < 0.01), WHR (r = 0.268, P < 0.005), BMI (r = 0.308, P < 0.001), and percentage of body fat (r = 0.237, P < 0.01). The present study demonstrates no SES/income effect on CVD risk factors or syndrome X in African-Americans at high risk for type II diabetes. Clustering of several components of syndrome X was seen in individuals in the highest quartiles compared with the lowest quartiles of insulin in our high-risk African-American population. We conclude that the well-established conventional risk factors for CVD in genetically enriched African-Americans are found only in individuals with the highest insulin levels, independent of SES.


Protein polarization driven by nucleoid exclusion of DnaK(HSP70)-substrate complexes.
Many bacterial proteins require specific subcellular localization for function. How Escherichia coli proteins localize at one pole, however, is still not understood. Here, we show that the DnaK (HSP70) chaperone controls unipolar localization of the Shigella IpaC type III secretion substrate. While preventing the formation of lethal IpaC aggregates, DnaK promoted the incorporation of IpaC into large and dynamic complexes (LDCs) restricted at the bacterial pole through nucleoid occlusion. Unlike stable polymers and aggregates, LDCs show dynamic behavior indicating that nucleoid occlusion also applies to complexes formed through transient interactions. Fluorescence recovery after photobleaching analysis shows DnaK-IpaC exchanges between opposite poles and DnaKJE-mediated incorporation of immature substrates in LDCs. These findings reveal a key role for LDCs as reservoirs of functional DnaK-substrates that can be rapidly mobilized for secretion triggered upon bacterial contact with host cells.


Primary intracranial CNS lymphoma: MR manifestations.
We reviewed MR scans of 10 patients with biopsy-proved primary CNS lymphoma. Twenty-five lesions were identified in 10 patients (four with AIDS and six without AIDS). In general, the typical lesion of CNS lymphoma was found to have the following MR characteristics: they were slightly hypointense on T1-weighted images and slightly hyperintense on proton density and T2-weighted images relative to gray matter; they induced mild edema and mild to moderate mass effect. In AIDS patients, 82% of the lesions were smaller than 2 cm in diameter, and were frequently located in the temporal lobes and basal ganglia; they were often multiple. In non-AIDS patients, 75% of the lesions were larger than 2 cm in diameter and were primarily found in the deep parietal lobe; most were solitary.


The femoral stem pump in cemented hip arthroplasty: an in vitro model.
The presence of an intra-articular pump has been proposed as a central mechanism in the process of osteolysis and aseptic loosening of hip arthroplasty. It is not known if this pump exists and its mechanism remains uncharacterised. This study describes a new in vitro model of a cemented femoral stem in which cement/stem interface fluid pressures can be reliably measured under dynamic loads simulating stair climbing. A stem pump mechanism was found that generates both positive and negative clinically significant pressures (mean pressure ranges 5000-17,000 Pa). The timing of pressure peaks on the anterior and posterior aspects of the stem were in anti-phase, giving rise to oscillatory pressure gradients and potentially generating oscillatory fluid flows during the simulated physiological load cycle. The pump mechanism was shown to occur at the interface of a newly implanted polished double-tapered stem and emphasizes the importance of a complete mantle to protect the femoral bone from the raised fluid pressures.


Mechanisms for enzymatic reduction of nitric oxide to nitrous oxide - A comparison between nitric oxide reductase and cytochrome c oxidase.
Cytochrome c oxidases (CcO) reduce O2 to H2O in the respiratory chain of mitochondria and many aerobic bacteria. In addition, some species of CcO can also reduce NO to N2O and water while others cannot. Here, the mechanism for NO-reduction in CcO is investigated using quantum mechanical calculations. Comparison is made to the corresponding reaction in a "true" cytochrome c-dependent NO reductase (cNOR). The calculations show that in cNOR, where the reduction potentials are low, the toxic NO molecules are rapidly reduced, while the higher reduction potentials in CcO lead to a slower or even impossible reaction, consistent with experimental observations. In both enzymes the reaction is initiated by addition of two NO molecules to the reduced active site, forming a hyponitrite intermediate. In cNOR, N2O can then be formed using only the active-site electrons. In contrast, in CcO, one proton-coupled reduction step most likely has to occur before N2O can be formed, and furthermore, proton transfer is most likely rate-limiting. This can explain why different CcO species with the same heme a3-Cu active site differ with respect to NO reduction efficiency, since they have a varying number and/or properties of proton channels. Finally, the calculations also indicate that a conserved active site valine plays a role in reducing the rate of NO reduction in CcO.


Abnormalities in the stride length-cadence relation in parkinsonian gait.
The purpose of this investigation was to clarify abnormalities in the stride length-cadence relation in gait hypokinesia in Parkinson's disease (PD). A second aim was to investigate the effect of levodopa medication on the foot-step pattern. In the first experiment, 20 subjects with idiopathic PD and 20 age-, sex-, and height-matched controls performed a series of 10 m walking trials at cadence rates ranging from 40 steps/min to 180 steps/min. Cadence rates were set by an electronic metronome, and gait patterns were measured by using a footswitch stride-analyzer system. By instructing subjects to concentrate on walking in time to the metronome beat, the baseline stride length could be monitored for a range of velocities with the compensatory effects of cadence removed. Linear-regression analysis revealed that the mean slope for the regression of stride length against cadence was not different from normal in PD, although there was a statistically significant difference in mean intercept between the PD group (0.25) and the control group (0.59); [t (19) = -4.76; p = 0.0001]. The second experiment evaluated the effects of levodopa on stride-length regulation in 10 subjects with idiopathic PD on average 45 min before and after the first morning dose was administered. There was a statistically significant increase in stride length for all cadence rates from premedication to postmedication phases and the maximal stride length was achieved at higher cadence rates after medication. The slope of the regression of stride length against cadence did not alter according to medication status, although the mean intercept was significantly lower before levodopa (-0.06) compared with after levodopa (0.27); [t (9) = -3.83; p = 0.004]. These results suggest that defective scaling of stride length underlies gait disturbance in PD.


Expanding Role of Type II Secretion in Bacterial Pathogenesis and Beyond.
Type II secretion (T2S) is one means by which Gram-negative pathogens secrete proteins into the extracellular milieu and/or host organisms. Based upon recent genome sequencing, it is clear that T2S is largely restricted to the Proteobacteria, occurring in many, but not all, genera in the Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, and Deltaproteobacteria classes. Prominent human and/or animal pathogens that express a T2S system(s) include Acinetobacter baumannii, Burkholderia pseudomallei, Chlamydia trachomatis, Escherichia coli, Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Vibrio cholerae, and Yersinia enterocolitica T2S-expressing plant pathogens include Dickeya dadantii, Erwinia amylovora, Pectobacterium carotovorum, Ralstonia solanacearum, Xanthomonas campestris, Xanthomonas oryzae, and Xylella fastidiosa T2S also occurs in nonpathogenic bacteria, facilitating symbioses, among other things. The output of a T2S system can range from only one to dozens of secreted proteins, encompassing a diverse array of toxins, degradative enzymes, and other effectors, including novel proteins. Pathogenic processes mediated by T2S include the death of host cells, degradation of tissue, suppression of innate immunity, adherence to host surfaces, biofilm formation, invasion into and growth within host cells, nutrient assimilation, and alterations in host ion flux. The reach of T2S is perhaps best illustrated by those bacteria that clearly use it for both environmental survival and virulence; e.g., L. pneumophila employs T2S for infection of amoebae, growth within lung cells, dampening of cytokines, and tissue destruction. This minireview provides an update on the types of bacteria that have T2S, the kinds of proteins that are secreted via T2S, and how T2S substrates promote infection.


Simulation in pediatric anesthesiology.
Simulation-based training, research and quality initiatives are expanding in pediatric anesthesiology just as in other medical specialties. Various modalities are available, from task trainers to standardized patients, and from computer-based simulations to mannequins. Computer-controlled mannequins can simulate pediatric vital signs with reasonable reliability; however the fidelity of skin temperature and color change, airway reflexes and breath and heart sounds remains rudimentary. Current pediatric mannequins are utilized in simulation centers, throughout hospitals in-situ, at national meetings for continuing medical education and in research into individual and team performance. Ongoing efforts by pediatric anesthesiologists dedicated to using simulation to improve patient care and educational delivery will result in further dissemination of this technology. Health care professionals who provide complex, subspecialty care to children require a curriculum supported by an active learning environment where skills directly relevant to pediatric care can be developed. The approach is not only the most effective method to educate adult learners, but meets calls for education reform and offers the potential to guide efforts toward evaluating competence. Simulation addresses patient safety imperatives by providing a method for trainees to develop skills and experience in various management strategies, without risk to the health and life of a child. A curriculum that provides pediatric anesthesiologists with the range of skills required in clinical practice settings must include a relatively broad range of task-training devises and electromechanical mannequins. Challenges remain in defining the best integration of this modality into training and clinical practice to meet the needs of pediatric patients.


The biological relevance of direct antioxidant effects of polyphenols for cardiovascular health in humans is not established.
Human studies provide evidence for beneficial effects of polyphenol-rich foods on cardiovascular health. The antioxidant activity of polyphenols potentially explains these effects, but is the antioxidant activity a reliable predictor for these effects? An International Life Sciences Institute Europe working group addressed this question and explored the potential of antioxidant claims for polyphenols in relation to cardiovascular health by using the so-called Process for the Assessment of Scientific Support for Claims on Foods project criteria. In this process, analytical aspects of polyphenols, their occurrence in foods, dietary intake, and bioavailability were reviewed. Human studies on polyphenols and cardiovascular health were reviewed together with methods for biomarkers of oxidative damage and total antioxidant capacity (TAC). In retrospective studies, F2-isoprostanes and oxidized LDL, the most reliable biomarkers of lipid peroxidation, and measures for TAC showed the expected differences between cardiovascular disease patients and healthy controls, but prospective studies are lacking, and a causal relationship between these biomarkers and cardiovascular health could not be established. Therefore, the physiological relevance of a potential change in these biomarkers is unclear. We found limited evidence that some types of polyphenol-rich products modify these biomarkers in humans. A direct antioxidant effect of polyphenols in vivo is questionable, however, because concentrations in blood are low compared with other antioxidants and extensive metabolism following ingestion lowers their antioxidant activity. Therefore, the biological relevance of direct antioxidant effects of polyphenols for cardiovascular health could not be established. Overall, although some polyphenol-rich foods exert beneficial effects on some biomarkers of cardiovascular health, there is no evidence that this is caused by improvements in antioxidant function biomarkers (oxidative damage or antioxidant capacity).


Genetic analysis of Drosophila neurons: Shal, Shaw, and Shab encode most embryonic potassium currents.
In this study, we perform the first genetic analysis of K+ currents in Drosophila embryonic neurons revealing the identity of the currents present. Unlike muscles, where the presence of Shaker is obvious, Shaker currents are not detectable in these neurons. In contrast, we show that Shal is as important in these neuronal cell bodies as Shaker is in muscles. Only three single-channel currents were found, all of which are genetically separable. Shal encodes a 4 pS transient channel. Whole-cell Shal currents have a wide variety of inactivation rates which, in contrast to a mechanism such as heteromultimer formation, is due to single Shal channels assuming different gating modes. Shaw encodes a 42 pS noninactivating channel distinctive for its extremely low voltage sensitivity; Shaw channels have a total equivalent gating charge of 0.90 e- charges, in sharp contrast to 7 e- reported for Shaker channels. An 11 pS slowly inactivating channel also present in these neurons may be encoded by the Shab gene. Thus, of four voltage-dependent K+ channel genes now cloned in Drosophila, all except Shaker appear to be expressed in the cell bodies of these neurons. It is only in Drosophila that a study such as this one can be done. Because Drosophila contains only a single member of each of the four subfamilies of K+ channel genes (unlike mammals), we can eliminate an entire subfamily with a mutation to a single gene. Here, we have examined the effect of eliminating each of three subfamilies. Such a task is presently impossible to accomplish in any mammalian system.


Nutritional concerns of female athletes: a case study.
Some of the nutritional concerns of female athletes are highlighted in this case study of a 20-year-old woman who wants to lose 16% of her body weight to qualify for the position of coxswain on a national crew team. These concerns include adequacy of vitamin, mineral, protein, and carbohydrate intake as well as amenorrhea and pathogenic eating behaviors.


Updating of visual orientation in a gravity-based reference frame.
The brain can use multiple reference frames to code line orientation, including head-, object-, and gravity-centered references. If these frames change orientation, their representations must be updated to keep register with actual line orientation. We tested this internal updating during head rotation in roll, exploiting the rod-and-frame effect: The illusory tilt of a vertical line surrounded by a tilted visual frame. If line orientation is stored relative to gravity, these distortions should also affect the updating process. Alternatively, if coding is head- or frame-centered, updating errors should be related to the changes in their orientation. Ten subjects were instructed to memorize the orientation of a briefly flashed line, surrounded by a tilted visual frame, then rotate their head, and subsequently judge the orientation of a second line relative to the memorized first while the frame was upright. Results showed that updating errors were mostly related to the amount of subjective distortion of gravity at both the initial and final head orientation, rather than to the amount of intervening head rotation. In some subjects, a smaller part of the updating error was also related to the change of visual frame orientation. We conclude that the brain relies primarily on a gravity-based reference to remember line orientation during head roll.


Abnormal functional connectivity in autism spectrum disorders during face processing.
Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning adults with ASD and 21 age-and IQ-matched control adults. Activation during identification of previously viewed faces and houses using a one-back paradigm was compared. The fusiform face area (FFA) was individually localized in each participant and used as the seed point for functional connectivity analyses. The degree of correlation between FFA and the extended neural circuitry involved in face identification was tested. A whole brain analysis was also conducted in order to determine whether connectivity from the FFA to aberrant brain locations was present in the ASD group. Measures of clinical severity (ADOS social score and ADI-R social score) were included as independent variables into the functional connectivity analyses. Significant FFA-amygdala and FFA-superior temporal sulcus functional connectivity was found in both the ASD and control participants. However, the control group had significantly increased connectivity to the left amygdala and the posterior cingulate compared to ASD. Post hoc analyses additionally found increased connectivity to the thalamus in the controls. A significant relationship between abnormal functional connectivity and clinical severity in the ASD group was observed. Specifically, greater social impairment was associated with reduced FFA-amygdala connectivity and increased FFA-right inferior frontal connectivity. These results suggest that abnormal neural connections within the limbic system may contribute to the social impairments observed in ASD.


Changes in asthma prevalence: two surveys 15 years apart.
In 1973 a survey was conducted among 12 year old children living in a defined area of South Wales. In 1988 the survey was repeated in the same area, again among 12 year old children. Questionnaires were completed for all 965 children in the population sample; peak expiratory flow rates were performed on them all, and repeated (except for five children) after an exercise provocation test. The prevalence of a history of wheeze at any time had increased from 17% to 22%, while that of a history of asthma at any time had increased from 6% to 12%. Current asthma had increased from 4% to 9%, but wheezing in the past year not attributed to asthma had remained at 6%. The exercise provocation tests suggested that both mild and severe asthma had become more common. Increases had also occurred in the frequencies of a history of eczema (from 5% to 16%) and of hay fever (from 9% to 15%). It seems that the prevalence of asthma has risen, and that this cannot be wholly explained by a greater readiness to diagnose the disease.


Between- and within-day variability in physical activity and inactivity in 9- and 15-year-old European children.
To examine differences in levels of physical activity (PA), time spent at moderate-to-vigorous intensity PA (MVPA) and time spent sedentary between and within days in children from four European countries, 1954 9 - and 15-year-olds were included. PA was measured during 2 weekdays and 2 weekend days using the manufacturing technology-incorporated (MTI) accelerometer. Average count per minute, time spent sedentary, time spent at MVPA and the proportion of children accumulating > or =60 min of MVPA were calculated. Data were compared between weekdays and weekend days and between school time and leisure-time. Although not entirely consistent across countries, overall PA, time spent sedentary and the proportion of children accumulating > or =60 min of MVPA were higher during weekdays compared with weekend days. Differences in overall PA between school time and leisure-time were highly inconsistent between countries. Few children (4-31%) accumulated > or =60 min of MVPA either during school time or during leisure-time. Differences in activity patterns between weekdays and weekend days are explained by less accumulated time in MVPA during weekend days. Weekend days and leisure-time during weekdays seem appropriate targets when promoting PA in order to increase the proportion of children achieving current recommendations on health-enhancing PA.


Ant pupae employ acoustics to communicate social status in their colony's hierarchy.
The possession of an efficient communication system and an ability to distinguish between young stages are essential attributes that enable eusocial insects to live in complex integrated societies. Although ants communicate primarily via chemicals, it is increasingly clear that acoustical signals also convey important information, including status, between adults in many species. However, all immature stages were believed to be mute. We confirm that larvae and recently formed pupae of Myrmica ants are mute, yet once they are sclerotized, the pupae possess a fully functioning stridulatory organ. The sounds generated by worker pupae were similar to those of workers but were emitted as single pulses rather than in the long sequences characteristic of adults; both induced the same range and intensity of benevolent behaviors when played back to unstressed workers. Both white and sclerotized pupae have a higher social status than larvae within Myrmica colonies, but the latter's status fell significantly after they were made mute. Our results suggest that acoustical signals supplant semiochemicals as a means of identification in sclerotized pupae, perhaps because their hardened integuments block the secretion of brood pheromones or because their developing adult secretions initially differ from overall colony odors.


Complete Genome Sequence of Pseudorabies Virus Reference Strain NIA3 Using Single-Molecule Real-Time Sequencing.
Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease in pigs. PRV strains are also used as model organisms for the study of alphaherpesvirus biology or for neuronal pathway studies. We present here the complete genome of the virulent wild-type PRV reference strain NIA3, determined by single-molecule real-time sequencing.


High-end normal adrenocorticotropic hormone and cortisol levels are associated with specific cardiovascular risk factors in pediatric obesity: a cross-sectional study.
The hypothalamic-pituitary-adrenal (HPA) axis, and in particular cortisol, has been reported to be involved in obesity-associated metabolic disturbances in adults and in selected populations of adolescents. The aim of this study was to investigate the association between morning adrenocorticotropic hormone (ACTH) and cortisol levels and cardiovascular risk factors in overweight or obese Caucasian children and adolescents. This cross-sectional study of 450 obese children and adolescents (aged 4 to 18 years) was performed in a tertiary referral center. ACTH, cortisol, cardiovascular risk factors (fasting and post-challenge glucose, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, and hypertension) and insulin resistance were evaluated. All analyses were corrected for confounding factors (sex, age, puberty, body mass index), and odds ratios were determined. ACTH and cortisol levels were positively associated with systolic and diastolic blood pressure, triglycerides, fasting glucose and insulin resistance. Cortisol, but not ACTH, was also positively associated with LDL-cholesterol. When adjusted for confounding factors, an association between ACTH and 2 h post-oral glucose tolerance test glucose was revealed. After stratification according to cardiovascular risk factors and adjustment for possible confounding factors, ACTH levels were significantly higher in subjects with triglycerides ≥90th percentile (P <0.02) and impaired fasting glucose or glucose tolerance (P <0.001). Higher cortisol levels were found in subjects with blood pressure ≥95th percentile and LDL-cholesterol ≥90th percentile. Overall, the highest tertiles of ACTH (>5.92 pmol/l) and cortisol (>383.5 nmol/l) although within the normal range were associated with increases in cardiovascular risk factors in this population. In obese children and adolescents, high morning ACTH and cortisol levels are associated with cardiovascular risk factors. High ACTH levels are associated with high triglyceride levels and hyperglycemia, while high cortisol is associated with hypertension and high LDL-cholesterol. These specific relationships suggest complex mechanisms through which the HPA axis may contribute to metabolic impairments in obesity, and merit further investigations.


Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids.
Asthma is associated with remodeling of the extracellular matrix (ECM) and increased airway obstruction, and the mechanisms of this process are unknown. Matrix metalloproteinases (MMPs) are a group of enzymes capable of degrading the ECM. They are released along with their inhibitors, tissue inhibitor of MMP (TIMP). s: To determine whether severe, persistent asthma is associated with increased levels of MMP-9 in the airway compared with mild asthma, and to assess the effect of both allergen exposure and steroid treatment on MMP-9 and TIMP-1 levels. Prospective analysis of levels and activity of MMP-9 and TIMP-1 in BAL fluid (BALF) and induced sputum obtained from asthmatics of differing disease severity. In patients with mild asthma, MMP-9 and TIMP-1 levels were studied in induced sputum following allergen challenge and in BALF after inhaled steroid therapy. Eighteen patients with mild asthma, 10 patients with severe asthma, and 10 nonsmoking, atopic subjects had their sputum studied. Fourteen of the patients with mild asthma underwent allergen challenge. BAL was collected from 16 patients with mild asthma before and after 4 weeks treatment with inhaled budesonide, 800 micro g bid, or placebo. Patients with severe asthma had increased levels and activity of sputum MMP-9 in their sputum compared with patients with mild asthma and normal subjects. Allergen challenge increased the MMP-9/TIMP-1 ratio and MMP-9 activity. Inhaled budesonide had no effect on MMP-9 or TIMP-1 in patients with mild asthma. MMP-9 may play a role in chronic airway inflammation and remodeling in asthma, as concentrations are increased in severe, persistent asthma and following allergen challenge. Inhaled steroids may not affect MMP-9 and TIMP in patients with mild asthma, and additional studies in patients with more severe asthma are needed.


Carrier photogeneration, drift and recombination in a semiconducting carbon nanotube network.
Charge carrier photogeneration, drift and recombination in thin film networks of polymer-wrapped (6,5)-single-wall carbon nanotubes (SWNTs) blended with phenyl-C61-butyric acid methyl ester (PCBM) have been investigated by using transient photocurrent and time-delayed collection field (TDCF) techniques. Three distinct transient photocurrent components on the nano- and microsecond timescales have been identified. We attribute the dominant (>50% of total extracted charge) ultrashort photocurrent component with a decay time below our experimental time-resolution of 2 ns to the intratube hole motion. The second component on the few microsecond timescale is attributed to the intertube hole transfer, while the slowest component is assigned to the electron drift within the PCBM phase. The hole drift distance appears to be limited by gaps in the nanotube percolation network rather than by hole trapping or recombination. Photocurrent saturation was observed when excitation densities reached more than one charge pair per nanotube; we attribute this to the local electric field screening.


Automatic null ellipsometry with an interferometer.
A new approach to automatic null ellipsometry is described in which the analyzer of a traditional polarizer compensator sample analyzer (PCSA) null ellipsometer is replaced with a heterodyne Michelson interferometer. One arm of this interferometer is modified such that it produces a fixed, linearly polarized reference beam, irrespective of the input polarization state. This beam is recombined interferometrically with the measurement beam and spatially separated into its p and s polarizations. The relative phase of the resulting temporal fringes is a linear function of the polarizer azimuthal angle P, and thus this component can be driven to its null position without iteration. Once at null, the azimuthal angle of the reflected, linearly polarized light is trivially determined from the relative amplitude of the fringes. Measurements made with this instrument on a native oxide film on a silicon wafer were in excellent agreement with those made with a traditional PCSA null ellipsometer.


Are quality improvement collaboratives effective? A systematic review.
Quality improvement collaboratives (QIC) have proliferated internationally, but there is little empirical evidence for their effectiveness. We searched Medline, Embase, CINAHL, PsycINFO and the Cochrane Library databases from January 1995 to December 2014. Studies were included if they met the criteria for a QIC intervention and the Cochrane Effective Practice and Organisation of Care (EPOC) minimum study design characteristics for inclusion in a review. We assessed study bias using the EPOC checklist and the quality of the reported intervention using a subset of SQUIRE 1.0 standards. Of the 220 studies meeting QIC criteria, 64 met EPOC study design standards for inclusion. There were 10 cluster randomised controlled trials, 24 controlled before-after studies and 30 interrupted time series studies. QICs encompassed a broad range of clinical settings, topics and populations ranging from neonates to the elderly. Few reports fully described QIC implementation and methods, intensity of activities, degree of site engagement and important contextual factors. By care setting, an improvement was reported for one or more of the study's primary effect measures in 83% of the studies (32/39 (82%) hospital based, 17/20 (85%) ambulatory care, 3/4 nursing home and a sole ambulance QIC). Eight studies described persistence of the intervention effect 6 months to 2 years after the end of the collaborative. Collaboratives reporting success generally addressed relatively straightforward aspects of care, had a strong evidence base and noted a clear evidence-practice gap in an accepted clinical pathway or guideline. QICs have been adopted widely as an approach to shared learning and improvement in healthcare. Overall, the QICs included in this review reported significant improvements in targeted clinical processes and patient outcomes. These reports are encouraging, but most be interpreted cautiously since fewer than a third met established quality and reporting criteria, and publication bias is likely.


Point-of-care creatinine tests to assess kidney function for outpatients requiring contrast-enhanced CT imaging: systematic reviews and economic evaluation.
Patients with low estimated glomerular filtration rates may be at higher risk of post-contrast acute kidney injury following contrast-enhanced computed tomography imaging. Point-of-care devices allow rapid measurement of estimated glomerular filtration rates for patients referred without a recent estimated glomerular filtration rate result. To assess the clinical effectiveness and cost-effectiveness of point-of-care creatinine tests for outpatients without a recent estimated glomerular filtration rate measurement who need contrast-enhanced computed tomography imaging. Three systematic reviews of test accuracy, implementation and clinical outcomes, and economic analyses were carried out. Bibliographic databases were searched from inception to November 2018. Studies comparing the accuracy of point-of-care creatinine tests with laboratory reference tests to assess kidney function in adults in a non-emergency setting and studies reporting implementation and clinical outcomes were included. Risk of bias of diagnostic accuracy studies was assessed using a modified version of the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Probabilities of individuals having their estimated glomerular filtration rates correctly classified were estimated within a Bayesian framework and pooled using a fixed-effects model. A de novo probabilistic decision tree cohort model was developed to characterise the decision problem from an NHS and a Personal Social Services perspective. A range of alternative point-of-care testing approaches were considered. Scenario analyses were conducted. Fifty-four studies were included in the clinical reviews. Twelve studies reported diagnostic accuracy for estimated glomerular filtration rates; half were rated as being at low risk of bias, but there were applicability concerns for most. i-STAT (Abbott Point of Care, Inc., Princeton, NJ, USA) and ABL (Radiometer Ltd, Crawley, UK) devices had higher probabilities of correctly classifying individuals in the same estimated glomerular filtration rate categories as the reference laboratory test than StatSensor® devices (Nova Biomedical, Runcorn, UK). There was limited evidence for epoc® (Siemens Healthineers AG, Erlangen, Germany) and Piccolo Xpress® (Abaxis, Inc., Union City, CA, USA) devices and no studies of DRI-CHEM NX 500 (Fujifilm Corporation, Tokyo, Japan). The review of implementation and clinical outcomes included six studies showing practice variation in the management decisions when a point-of-care device indicated an abnormal estimated glomerular filtration rate. The review of cost-effectiveness evidence identified no relevant studies. The de novo decision model that was developed included a total of 14 strategies. Owing to limited data, the model included only i-STAT, ABL800 FLEX and StatSensor. In the base-case analysis, the cost-effective strategy appeared to be a three-step testing sequence involving initially screening all individuals for risk factors, point-of-care testing for those individuals with at least one risk factor, and including a final confirmatory laboratory test for individuals with a point-of-care-positive test result. Within this testing approach, the specific point-of-care device with the highest net benefit was i-STAT, although differences in net benefit with StatSensor were very small. There was insufficient evidence for patients with estimated glomerular filtration rates < 30 ml/minute/1.73 m2, and on the full potential health impact of delayed or rescheduled computed tomography scans or the use of alternative imaging modalities. A three-step testing sequence combining a risk factor questionnaire with a point-of-care test and confirmatory laboratory testing appears to be a cost-effective use of NHS resources compared with current practice. The risk of contrast causing acute kidney injury to patients with an estimated glomerular filtration rate of < 30 ml/minute/1.73 m2 is uncertain. Cost-effectiveness of point-of-care testing appears largely driven by the potential of point-of-care tests to minimise delays within the current computed tomography pathway. Studies evaluating the impact of risk-stratifying questionnaires on workflow outcomes in computed tomography patients without recent estimated glomerular filtration rate results are needed. This study is registered as PROSPERO CRD42018115818. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 39. See the NIHR Journals Library website for further project information.


An updated atlas of human helminth infections: the example of East Africa.
Reliable and updated maps of helminth (worm) infection distributions are essential to target control strategies to those populations in greatest need. Although many surveys have been conducted in endemic countries, the data are rarely available in a form that is accessible to policy makers and the managers of public health programmes. This is especially true in sub-Saharan Africa, where empirical data are seldom in the public domain. In an attempt to address the paucity of geographical information on helminth risk, this article describes the development of an updated global atlas of human helminth infection, showing the example of East Africa. Empirical, cross-sectional estimates of infection prevalence conducted since 1980 were identified using electronic and manual search strategies of published and unpublished sources. A number of inclusion criteria were imposed for identified information, which was extracted into a standardized database. Details of survey population, diagnostic methods, sample size and numbers infected with schistosomes and soil-transmitted helminths were recorded. A unique identifier linked each record to an electronic copy of the source document, in portable document format. An attempt was made to identify the geographical location of each record using standardized geolocation procedures and the assembled data were incorporated into a geographical information system. At the time of writing, over 2,748 prevalence surveys were identified through multiple search strategies. Of these, 2,612 were able to be geolocated and mapped. More than half (58%) of included surveys were from grey literature or unpublished sources, underlining the importance of reviewing in-country sources. 66% of all surveys were conducted since 2000. Comprehensive, countrywide data are available for Burundi, Rwanda and Uganda. In contrast, information for Kenya and Tanzania is typically clustered in specific regions of the country, with few records from areas with very low population density and/or environmental conditions which are unfavourable for helminth transmission. Information is presented on the prevalence and geographical distribution for the major helminth species. For all five countries, the information assembled in the current atlas provides the most reliable, up-to-date and comprehensive source of data on the distribution of common helminth infections to guide the rational implementation of control efforts.


Deep Reinforcement Learning Controller for 3D Path Following and Collision Avoidance by Autonomous Underwater Vehicles.
Control theory provides engineers with a multitude of tools to design controllers that manipulate the closed-loop behavior and stability of dynamical systems. These methods rely heavily on insights into the mathematical model governing the physical system. However, in complex systems, such as autonomous underwater vehicles performing the dual objective of path following and collision avoidance, decision making becomes nontrivial. We propose a solution using state-of-the-art Deep Reinforcement Learning (DRL) techniques to develop autonomous agents capable of achieving this hybrid objective without having a priori knowledge about the goal or the environment. Our results demonstrate the viability of DRL in path following and avoiding collisions towards achieving human-level decision making in autonomous vehicle systems within extreme obstacle configurations.


Neurogenesis in the ependymal layer of the adult rat 3rd ventricle.
Neurogenesis has been described in limited regions of the adult mammalian brain. In this study, we showed that the ependymal layer of the 3rd ventricle is a neurogenic region in the adult rat brain. DiI labeling of the 3rd ventricle revealed that neural progenitor cells were derived from cells at the ependymal layer of the adult 3rd ventricle. The mitosis of these progenitor cells at the ependymal layer was promoted by bFGF administration. Combination of BrdU administration, nestin/GFAP immunohistochemistry, and labeling by GFP-recombinant adenoviral infection (vGFP) indicated that at least some tanycytes might be neural progenitor cells in the ependymal layer of the 3rd ventricle. Tracing by vGFP indicated that neural progenitor cells may have migrated from the 3rd ventricle to the hypothalamic parenchyma, where they were integrated into neural networks by forming synapses. In addition, some BrdU(+) neurons had immunoreactivity for orexin A in the hypothalamus. These results indicate that neural progenitor cells exist in the ependymal layer of the adult rat 3rd ventricle and that they may differentiate into neurons functioning in the hypothalamus.


A physical map of the papaya genome with integrated genetic map and genome sequence.
Papaya is a major fruit crop in tropical and subtropical regions worldwide and has primitive sex chromosomes controlling sex determination in this trioecious species. The papaya genome was recently sequenced because of its agricultural importance, unique biological features, and successful application of transgenic papaya for resistance to papaya ringspot virus. As a part of the genome sequencing project, we constructed a BAC-based physical map using a high information-content fingerprinting approach to assist whole genome shotgun sequence assembly. The physical map consists of 963 contigs, representing 9.4x genome equivalents, and was integrated with the genetic map and genome sequence using BAC end sequences and a sequence-tagged high-density genetic map. The estimated genome coverage of the physical map is about 95.8%, while 72.4% of the genome was aligned to the genetic map. A total of 1,181 high quality overgo (overlapping oligonucleotide) probes representing conserved sequences in Arabidopsis and genetically mapped loci in Brassica were anchored on the physical map, which provides a foundation for comparative genomics in the Brassicales. The integrated genetic and physical map aligned with the genome sequence revealed recombination hotspots as well as regions suppressed for recombination across the genome, particularly on the recently evolved sex chromosomes. Suppression of recombination spread to the adjacent region of the male specific region of the Y chromosome (MSY), and recombination rates were recovered gradually and then exceeded the genome average. Recombination hotspots were observed at about 10 Mb away on both sides of the MSY, showing 7-fold increase compared with the genome wide average, demonstrating the dynamics of recombination of the sex chromosomes. A BAC-based physical map of papaya was constructed and integrated with the genetic map and genome sequence. The integrated map facilitated the draft genome assembly, and is a valuable resource for comparative genomics and map-based cloning of agronomically and economically important genes and for sex chromosome research.


Evaluation and prediction of the HIV-1 central polypurine tract influence on foamy viral vectors to transduce dividing and growth-arrested cells.
Retroviral vectors are potent tools for gene delivery and various biomedical applications. To accomplish a gene transfer task successfully, retroviral vectors must effectively transduce diverse cell cultures at different phases of a cell cycle. However, very promising retroviral vectors based on the foamy viral (FV) backbone lack the capacity to efficiently transduce quiescent cells. It is hypothesized that this phenomenon might be explained as the inability of foamy viruses to form a pre-integration complex (PIC) with nuclear import activity in growth-arrested cells, which is the characteristic for lentiviruses (HIV-1). In this process, the HIV-1 central polypurine tract (cPPT) serves as a primer for plus-strand synthesis to produce a "flap" element and is believed to be crucial for the subsequent double-stranded cDNA formation of all retroviral RNA genomes. In this study, the effects of the lentiviral cPPT element on the FV transduction potential in dividing and growth-arrested (G1/S phase) adenocarcinomic human alveolar basal epithelial (A549) cells are investigated by experimental and theoretical methods. The results indicated that the HIV-1 cPPT element in a foamy viral vector background will lead to a significant reduction of the FV transduction and viral titre in growth-arrested cells due to the absence of PICs with nuclear import activity.


Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: mechanistic study.
Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [(3)H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD.


Sustained bromocriptine therapy in previously untreated patients with Parkinson's disease.
The progress of 50 previously untreated patients with idiopathic Parkinson's disease taking maximum tolerated doses of bromocriptine is compared with patients who had taken levodopa. Twenty-eight of the bromocriptine treated patients showed sustained benefit for at least one year and in five this persisted longer than five years. Fewer of the late complications of levodopa therapy occurred in those taking bromocriptine; drug-induced dyskinesia was seen in only one patient and oscillations in performance were not observed. There was a tendency for deterioration to develop after two years treatment when patients then failed to respond well to levodopa. It was not possible to extend the period of effective control of disabilities by first giving bromocriptine.


The tsetse fly Glossina fuscipes fuscipes (Diptera: Glossina) harbours a surprising diversity of bacteria other than symbionts.
Three different bacterial species are regularly described from tsetse flies. However, no broad screens have been performed to investigate the existence of other bacteria in this medically and agriculturally important vector insect. Utilising both culture dependent and independent methods we show that Kenyan populations of Glossina fuscipes fuscipes harbour a surprising diversity of bacteria. Bacteria were isolated from 72% of flies with 23 different bacterial species identified. The Firmicutes phylum dominated with 16 species of which seven belong to the genus Bacillus. The tsetse fly primary symbiont, Wigglesworthia glossinidia, was identified by the culture independent pathway. However, neither the secondary symbiont Sodalis nor Wolbachia was detected with either of the methods used. Two other bacterial species were identified with the DNA based method, Bacillus subtilis and Serratia marcescens. Further studies are needed to determine how tsetse flies, which only ever feed on vertebrate blood, pick up bacteria and to investigate the possible impact of these bacteria on Glossina longevity and vector competence.


Characterization of a cDNA encoding the 70-kDa single-stranded DNA-binding subunit of human replication protein A and the role of the protein in DNA replication.
Replication protein A (RP-A) is a three-subunit single-stranded DNA-binding protein that has been isolated from human cells. RP-A is essential for SV40 DNA replication and may also be important in genetic recombination. The sequence of a cDNA encoding the 70-kDa subunit of human RP-A is reported. The 616-amino acid predicted open reading frame of the human protein is 31% identical with the 621-amino acid open reading frame of the 70-kDa subunit of RP-A from the yeast Saccharomyces cerevisiae. Both proteins share a highly conserved putative metal binding domain of the 4-cysteine type. The human cDNA directs production in Escherichia coli of a 70-kDa protein that reacts with a monoclonal antibody directed against the 70-kDa subunit of human RP-A. The recombinant 70-kDa subunit, purified from bacteria, exhibits single-stranded DNA binding activity comparable to that of the complete RP-A complex. The 70-kDa subunit is able to substitute for the complete human RP-A complex in stimulating the activity of DNA polymerase alpha-primase on a poly(dA).oligo(dT) template. However, the 70-kDa subunit alone cannot substitute for the complete RP-A complex in SV40 DNA replication in vitro, suggesting an important functional role for the other subunits.


Response of putative indices of copper status to copper supplementation in human subjects.
No sensitive functional index is currently available to assess Cu status in healthy human populations. This study evaluated the effect of Cu supplementation on putative indices of Cu status in twelve women and twelve men, aged between 22 and 45 years, who participated in a double-blind placebo controlled crossover study. The study consisted of three 6-week supplementation regimens of 3 mg CuSO4, 3 mg Cu-glycine chelate and 6 mg Cu-glycine chelate, each separated by placebo periods of equal length. Women had significantly higher caeruloplasmin oxidase activity (P < 0.001), caeruloplasmin protein concentration (P < 0.05), and serum diamine oxidase activity (P < 0.01) at baseline than men. Erythrocyte and leucocyte superoxide dismutase activity, leucocyte cytochrome c oxidase activity, and erythrocyte glutathione peroxidase activity did not respond to Cu supplementation. Platelet cytochrome c oxidase activity was significantly higher (P < 0.01), after supplementation with 6 mg Cu-glycine chelate in the total group and in women but did not change in men. Caeruloplasmin oxidase activity was significantly higher (P < 0.05), in men after supplementation with 3 mg Cu-glycine chelate, while caeruloplasmin protein concentration was significantly lower in men after supplementation with 6 mg Cu-glycine chelate (P < 0.05). Serum diamine oxidase activity was significantly higher after all supplementation regimens in the total group and in both men and women (P < 0.01). These results indicate that serum diamine oxidase activity is sensitive to changes in dietary Cu intakes and may also have the potential to evaluate changes in Cu status in healthy adult human subjects.


Trimming of silicon ring resonator by electron beam induced compaction and strain.
Silicon is becoming the preferable platform for future integrated components, mostly due to the mature and reliable fabrication capabilities of electronics industry. Nevertheless, even the most advanced fabrication technologies suffer from non-uniformity on wafer scale and on chip scale, causing variations in the critical dimensions of fabricated components. This is an important issue since photonic circuits, and especially cavities such as ring resonators, are extremely sensitive to these variations. In this paper we present a way to circumvent these problems by trimming using electron beam induced compaction of oxide in silicon on insulator. Volume compaction of the oxide cladding causes both changes in the refractive index and creates strain in the silicon lattice. We demonstrate a resonance wavelength red shift 4.91 nm in a silicon ring resonator.


Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease.
Detailed knowledge of protein changes in cerebrospinal fluid (CSF) across healthy and diseased individuals would provide a better understanding of the onset and progression of neurodegenerative disorders. In this study, we selected 20 brain-enriched proteins previously identified in CSF by antibody suspension bead arrays (SBA) to be potentially biomarkers for Alzheimer's disease (AD) and verified these using an orthogonal approach. We examined the same set of 94 CSF samples from patients affected by AD (including preclinical and prodromal), mild cognitive impairment (MCI), non-AD dementia and healthy individuals, which had previously been analyzed by SBA. Twenty-eight parallel reaction monitoring (PRM) assays were developed and 13 of them could be validated for protein quantification. Antibody profiles were verified by PRM. For seven proteins, the antibody profiles were highly correlated with the PRM results (r > 0.7) and GAP43, VCAM1 and PSAP were identified as potential markers of preclinical AD. In conclusion, we demonstrate the usefulness of targeted mass spectrometry as a tool for the orthogonal verification of antibody profiling data, suggesting that these complementary methods can be successfully applied for comprehensive exploration of CSF protein levels in neurodegenerative disorders.


Multiple links between the NuA4 histone acetyltransferase complex and epigenetic control of transcription.
NuA4 is an essential histone H4/H2A acetyltransferase complex that interacts with activators and stimulates transcription in vitro. We have identified three novel NuA4 subunits: Act3/Arp4, an actin-related protein implicated in epigenetic control of transcription, Act1, and Epl1, a protein homologous to Drosophila Enhancer of Polycomb. Act3/Arp4 binds nucleosomes in vitro and is required for NuA4 integrity in vivo. Mutations in ACT3 and acetyltransferase-encoding ESA1 cause gene-specific transcription defects. Accordingly, NuA4 is localized in precise loci within the nucleus and does not overlap with the silent chromatin marker Sir3. These data along with the known epigenetic roles of Act3/Arp4 and homologs of Epl1 and Esa1 strongly support an essential role for chromatin structure modification by NuA4 in transcription regulation in vivo.


Stunting induced by cucumber mosaic cucumovirus-infected Nicotiana glutinosa is determined by a single amino acid residue in the coat protein.
R-CMV, a subgroup II strain of cucumber mosaic cucumovirus (CMV) induces a very strong stunting response in Nicotiana glutinosa plants, while Trk7-CMV causes green mosaic in this host. The genetic determinant of this phenotype was mapped to a 534-nucleotide region at the 3' end of RNA3 with biologically active, full-length cDNA clones of R-CMV and Trk7-CMV and RNA3 chimeras of the two strains. Within this region, R-CMV differs from Trk7-CMV by a single amino acid at position 193 in the coat protein. Changing the codon for Lys at this position to Asn or Ser, by site-directed mutagenesis, also changed the phenotype of the viruses from green mosaic to induction of stunting. Profound differences in both the spread and the accumulation of the viruses causing stunting and green mosaic were observed, although these did not correlate with the host specificity of stunting. Since expression of R-CMV coat protein with the PVX vector did not cause stunting, the data suggest that the presence of other CMV components is necessary for the induction of this symptom.


Distribution and regulation of aromatase activity in the ram hypothalamus and amygdala.
Conversion of androgen to estrogen within the brain by cytochrome P450 aromatase is a component of the system controlling the display of normal male reproductive behavior and negative feedback inhibition of LH secretion in rams. In the present study, we used the highly sensitive 3H2O assay to measure aromatase activity in microdissected regions of the basal diencephalon and amygdala of intact and castrated rams. We found that aromatase activity was heterogeneously distributed. The highest activity was found in the medial amygdala, cortical amygdala, and bed nucleus of the stria terminalis. Intermediate levels of aromatase activity were found within the medial preoptic area/anterior hypothalamus, periventricular preoptic area, lateral preoptic area/anterior hypothalamus, ventromedial hypothalamus, and lateral hypothalamus. The lowest activity was present in the septum, infundibulum/median eminence, and dorsal medial hypothalamus. After castration, aromatase was significantly reduced in the medial preoptic area/anterior hypothalamus, periventricular preoptic area, lateral preoptic area/anterior hypothalamus, and infundibular nucleus/median eminence. In contrast, levels in castrate rams were unchanged in several other regions, most notably the bed nucleus of the stria terminalis and medial and cortical amygdala. These results provide a quantitative profile of aromatase activity in discrete regions of the ram hypothalamus and limbic system. They also demonstrate that aromatase activity is reduced in some, but not all brain regions after castration which suggests that different regulatory mechanisms control aromatase within different neuronal populations of the ram.


Mold: "tsara'at," Leviticus, and the history of a confusion.
The noun tsara'at appears about two dozen times in the Hebrew Bible, almost exclusively in Leviticus, where it is used to describe a state of ritual defilement manifested as a scaly condition of the skin, a condition of cloth, leather, and the walls of houses. In the Septuagint, the Greek translation of the Hebrew Bible, negac tsara'at was translated as aphe lepras; in the Latin Vulgate, this became plega leprae. These words in Greek and Latin implied a condition that spread over the body, not a term of ritual impurity. Tsara'at has continued to be translated as "leprosy," even though this term is not appropriate, as there was no leprosy as we know it in the Middle East during the time period the Hebrew Bible was written. Others have suggested that the proper translation of tsara'at is "mold." The recent identification of a specific mold (Stachybotrys sp.) that contaminates buildings and causes respiratory distress, memory loss, and rash, and the fact that mold has been present for millennia, lend support to the translation of tsara'at as "mold."


Are readmission rates on a neurosurgical service indicators of quality of care?
The goal of this study was to examine the reasons for early readmissions within 30 days of discharge to a major academic neurosurgical service. A database of readmissions within 30 days of discharge between April 2009 and September 2010 was retrospectively reviewed. Clinical and administrative variables associated with readmission were examined, including age, sex, race, days between discharge and readmission, and insurance type. The readmissions were then assigned independently by 2 neurosurgeons into 1 of 3 categories: scheduled, adverse event, and unrelated. The adverse event readmissions were further subcategorized into patients readmitted although best practices were followed, those readmitted due to progression of their underlying disease, and those readmitted for preventable causes. These variables were compared descriptively. A total of 348 patients with 407 readmissions were identified, comprising 11.5% of the total 3552 admissions. The median age of readmitted patients was 55 years (range 16-96 years) and patients older than 65 years totaled 31%. There were 216 readmissions (53% of 407) for management of an adverse event that was classified as either preventable (149 patients; 37%) or unpreventable (67 patients; 16%). There were 113 patients (28%) who met readmission criteria but who were having an electively scheduled neurosurgical procedure. Progression of disease (48 patients; 12%) and treatment unrelated to primary admission (30 patients; 7%) were additional causes for readmission. There was no significant difference in the proportion of early readmissions by payer status when comparing privately insured patients and those with public or no insurance (p = 0.09). The majority of early readmissions within 30 days of discharge to the neurosurgical service were not preventable. Many of these readmissions were for adverse events that occurred even though best practices were followed, or for progression of the natural history of the neurosurgical disease requiring expected but unpredictably timed subsequent treatment. Judicious care often requires readmission to prevent further morbidity or death in neurosurgical patients, and penalties for readmission will not change these patient care obligations.