Measurement of the internal diameter of plastic tubes from projection MR images using a model-based least-squares fit approach.
Hyperpolarized (HP) 3He MRI is an emerging tool in the diagnosis and evaluation of pulmonary diseases involving bronchoconstriction, such as asthma. Previously, airway diameters from dynamic HP 3He MR images of the lung were assessed manually and subjectively, and were thus prone to uncertainties associated with human error and partial volume effects. A model-based algorithm capable of fully utilizing pixel intensity profile information and attaining subpixel resolution has been developed to measure surrogate airway diameters from HP 3He MR static projection images of plastic tubes. This goal was achieved by fitting ideal pixel intensity profiles for various diameter (6.4 to 19.1 mm) circular tubes to actual pixel intensity data. A phantom was constructed from plastic tubes of various diameters connected in series and filled with water mixed with contrast agent. Projection MR images were then taken of the phantom. The favorable performance of the model-based algorithm compared to manual assessment demonstrates the viability of our approach. The manual and algorithm approaches yielded diameter measurements that generally stayed within 1 x the pixel dimension. However, inconsistency of the manual approach can be observed from the larger standard deviations of its measured values. The method was then extended to HP 3He MRI, producing encouraging results at tube diameters characteristic of airways beyond the second generation, thereby justifying their application to lung airway imaging and measurement. Potential obstacles when measuring airway diameters using this method are discussed.


Pharmacology of some oral penicillins in the newborn infant.
Serum and urine concentrations of ampicillin, amoxycillin, and flucloxacillin achieved after oral administration have been measured in 27 newborn infants. Compared with adults and children, newborn infants show a delay in achieving adequate blood concentrations, presumably due to delayed absorption. However most infants achieve therapeutic concentrations in the serum. Infected newborn infants should be given these antibiotics by intramuscular injection for the first dose, but thereafter oral therapy (25 mg/lg every 6 hours begun concomitantly) should be satisfactory. The better absorption of amoxycillin compared with ampicillin reported in adults has not been confirmed in the newborn infant.


Pretreatment with neem (Azadirachta indica) leaf preparation in Swiss mice diminishes leukopenia and enhances the antitumor activity of cyclophosphamide.
Cancer chemotherapy is associated with several life threatening complications, including bone marrow suppression and leucopenia. To overcome this problem, colony stimulating factor (CSF), granulocyte colony stimulating factor (GCSF) and granulocyte macrophage colony stimulating factor (GMCSF), can be used, however, these therapeutics are expensive and have several disadvantages, including tumor growth promoting activities. This study attempted to use an immunostimulatory neem (Azadirachta indica) leaf preparation (NLP) to prevent the cyclophosphamide (CYP) induced reduction in the WBC count. Pretreatment of mice with NLP reduced the extent of leucopenia and neutropenia in normal and tumor bearing CYP treated mice. NLP pretreatment enhanced in vitro tumor cell cytotoxicity by peripheral blood mononuclear cells (PBMC) from CYP treated mice in either normal or tumor bearing conditions. Similarly, NLP pretreatment of mice enhanced the CYP mediated in vivo tumor growth inhibition and survivability of the host. Based on these observations, it is concluded that NLP would be an effective tool to reduce CYP-induced hematological complications.


The impact of structural packaging design on young adult smokers' perceptions of tobacco products.
To examine the extent that novel cigarette pack shapes and openings have on smokers' perceptions of those packs and the cigarettes contained within. Using a web-based survey, 160 young adult ever-smokers (18-29 years) were shown computer images of plain packaged cigarette packs in five different shapes. This was followed by packs illustrating five different methods of opening. Brand (prestige or budget) and size of the health warnings (30% or 70% warning size) were between-subject conditions. Respondents ranked packs on attractiveness, perceived quality of the cigarettes contained within and extent that the pack distracted from health warnings. Ratings of attractiveness and perceived quality were significantly associated in both substudies, but tendency to distract from warnings was more independent. Significant differences were found between the pack shapes on attractiveness, perceived quality and distraction from warnings. Standard, 2×10 and 4×5 packs were ranked less attractive than Bevelled and Rounded packs. 2×10 and 4×5 packs were also perceived as lower quality than Bevelled and Rounded packs. The Standard pack was less distracting to health warnings than all other shapes except the 2×10 pack. Pack openings were perceived as different on quality of cigarettes contained and extent of distraction to warnings. The Standard Flip-top was rated significantly lower in distracting from warnings than all other openings. Pack shape and pack opening affect ever-smokers' perceptions of the packs and the cigarettes they contain. This means that they have the potential to create appeal and differentiate products and thus should be regulated.


A subcellular map of the human proteome.
Resolving the spatial distribution of the human proteome at a subcellular level can greatly increase our understanding of human biology and disease. Here we present a comprehensive image-based map of subcellular protein distribution, the Cell Atlas, built by integrating transcriptomics and antibody-based immunofluorescence microscopy with validation by mass spectrometry. Mapping the in situ localization of 12,003 human proteins at a single-cell level to 30 subcellular structures enabled the definition of the proteomes of 13 major organelles. Exploration of the proteomes revealed single-cell variations in abundance or spatial distribution and localization of about half of the proteins to multiple compartments. This subcellular map can be used to refine existing protein-protein interaction networks and provides an important resource to deconvolute the highly complex architecture of the human cell.


Variants in ACPP are associated with cerebrospinal fluid Prostatic Acid Phosphatase levels.
Prostatic Acid Phosphatase (PAP) is an enzyme that is produced primarily in the prostate and functions as a cell growth regulator and potential tumor suppressor. Understanding the genetic regulation of this enzyme is important because PAP plays an important role in prostate cancer and is expressed in other tissues such as the brain. We tested association between 5.8 M SNPs and PAP levels in cerebrospinal fluid across 543 individuals in two datasets using linear regression. We then performed meta-analyses using METAL =with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets, identifying 289 candidate SNPs that affect PAP cerebrospinal fluid levels. We analyzed each of these SNPs individually and prioritized SNPs that had biologically meaningful functional annotations in wANNOVAR (e.g. non-synonymous, stop gain, 3' UTR, etc.) or had a RegulomeDB score less than 3. Thirteen SNPs met our criteria, suggesting they are candidate causal alleles that underlie ACPP regulation and expression. Given PAP's expression in the brain and its role as a cell-growth regulator and tumor suppressor, our results have important implications in brain health such as cancer and other brain diseases including neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and mental health (e.g., anxiety, depression, and schizophrenia).


Focus issue: the protein dynamics of cell signaling.
Science Signaling complements the Science special issue on protein dynamics (http://www.sciencemag.org/sciext/proteindynamics/) with several articles that highlight the dynamic nature of proteins involved in signal transduction. Not only are conformational changes in proteins important for transducing signaling information, proteins also move within the cell and interact with various partners to trigger the appropriate cellular response. Examples of each of these types of protein dynamics are highlighted in this issue.


Barriers to follow-up care of survivors in the United States and the United Kingdom.
Survivors of pediatric cancer face an increased risk of morbidity, mortality, and diminished quality of life associated with their previous cancer therapy. Because these risks are often modifiable, periodic lifetime medical follow-up is recommended for all survivors. This article assesses the current status of follow-up care in the United States and the United Kingdom. Potential barriers in both cultures and health care environments are described. A better understanding of these barriers has led to the development and testing of interventions intended to optimize the health care of survivors.


SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair.
The Sir2 chromatin regulatory factor links maintenance of genomic stability to life span extension in yeast. The mammalian Sir2 family member SIRT6 has been proposed to have analogous functions, because SIRT6-deficiency leads to shortened life span and an aging-like degenerative phenotype in mice, and SIRT6 knockout cells exhibit genomic instability and DNA damage hypersensitivity. However, the molecular mechanisms underlying these defects are not fully understood. Here, we show that SIRT6 forms a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-PK (DNA-dependent protein kinase) and promotes DNA DSB repair. In response to DSBs, SIRT6 associates dynamically with chromatin and is necessary for an acute decrease in global cellular acetylation levels on histone H3 Lysine 9. Moreover, SIRT6 is required for mobilization of the DNA-PK catalytic subunit (DNA-PKcs) to chromatin in response to DNA damage and stabilizes DNA-PKcs at chromatin adjacent to an induced site-specific DSB. Abrogation of these SIRT6 activities leads to impaired resolution of DSBs. Together, these findings elucidate a mechanism whereby regulation of dynamic interaction of a DNA repair factor with chromatin impacts on the efficiency of repair, and establish a link between chromatin regulation, DNA repair, and a mammalian Sir2 factor.


No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.
Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk. We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs. Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13). In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.


Widespread Supplement Intake and Use of Poor Quality Information in Elite Adolescent Swiss Athletes.
Compared with adult athletes, rather little is known about supplementation behavior in adolescent athletes. This study's aim was to determine elite adolescent athletes' supplement use and sources of information relating thereto. A total of 430 (87%) of 496 questioned athletes returned the anonymized questionnaire. Thereof, 84% consumed at least one weekly supplement and 97% indicated some supplement intake during the previous 4 weeks. On average, 13.3 supplement servings were consumed per week. The 25th, 50th, and 75th percentile was 4.5, 10.5, and 20.0 servings per week, with a maximum of 67. The most prevalent supplements in use were multimineral products (41% of all athletes), multivitamins (34%), Vitamin C (34%), and Vitamin D (33%). Male athletes consumed significantly more Vitamin C and D, sports drinks, protein powder, and recovery products compared with female athletes; whereas, women consumed more iron supplements. The three most important motives for supplement use were recovery support (40%), health maintenance (39%), and performance enhancement (30%). The most frequent answers to the question "who recommended that you use supplements" were family/friends (36%), a physician (27%), and a trainer/coach (25%). The main three information sources about the supplements in use were the persons who recommended the supplementation (56%), the internet (25%), and information provided by supplement suppliers (11%). A positive doping attitude was associated with the consumption of performance enhancing supplements (p = .017). In conclusion, this study among elite adolescent Swiss athletes indicates a widespread and large-scale use of dietary supplements, which was associated with a low level of information quality.


Synthetic fragments of Vibrio cholerae O1 Inaba O-specific polysaccharide bound to a protein carrier are immunogenic in mice but do not induce protective antibodies.
Development of Vibrio cholerae lipopolysaccharide (LPS) as a cholera vaccine immunogen is justified by the correlation of vibriocidal anti-LPS response with immunity. Two V. cholerae O1 LPS serotypes, Inaba and Ogawa, are associated with endemic and pandemic cholera. Both serotypes induce protective antibody following infection or vaccination. Structurally, the LPSs that define the serotypes are identical except for the terminal perosamine moiety, which has a methoxyl group at position 2 in Ogawa but a hydroxyl group in Inaba. The terminal sugar of the Ogawa LPS is a protective B-cell epitope. We chemically synthesized the terminal hexasaccharides of V. cholerae serotype Ogawa, which comprises in part the O-specific polysaccharide component of the native LPS, and coupled the oligosaccharide at different molar ratios to bovine serum albumin (BSA). Our initial studies with Ogawa immunogens showed that the conjugates induced protective antibody. We hypothesized that antibodies specific for the terminal sugar of Inaba LPS would also be protective. Neoglycoconjugates were prepared from synthetic Inaba oligosaccharides (disaccharide, tetrasaccharide, and hexasaccharide) and BSA at different levels of substitution. BALB/c mice responded to the Inaba carbohydrate (CHO)-BSA conjugates with levels of serum antibodies of comparable magnitude to those of mice immunized with Ogawa CHO-BSA conjugates, but the Inaba-specific antibodies (immunoglobulin M [IgM] and IgG1) were neither vibriocidal nor protective in the infant mouse cholera model. We hypothesize that the anti-Inaba antibodies induced by the Inaba CHO-BSA conjugates have enough affinity to be screened via enzyme-linked immunosorbent assay but not enough to be protective in vivo.


Vegan-mycoprotein concentrate from pea-processing industry byproduct using edible filamentous fungi.
Currently around one billion people in the world do not have access to a diet which provides enough protein and energy. However, the production of one of the main sources of protein, animal meat, causes severe impacts on the environment. The present study investigates the production of a vegan-mycoprotein concentrate from pea-industry byproduct (PpB), using edible filamentous fungi, with potential application in human nutrition. Edible fungal strains of Ascomycota (Aspergillus oryzae, Fusarium venenatum, Monascus purpureus, Neurospora intermedia) and Zygomycota (Rhizopus oryzae) phyla were screened and selected for their protein production yield. A. oryzae had the best performance among the tested fungi, with a protein yield of 0.26 g per g of pea-processing byproduct from the bench scale airlift bioreactor cultivation. It is estimated that by integrating the novel fungal process at an existing pea-processing industry, about 680 kg of fungal biomass attributing to about 38% of extra protein could be produced for each 1 metric ton of pea-processing byproduct. This study is the first of its kind to demonstrate the potential of the pea-processing byproduct to be used by filamentous fungi to produce vegan-mycoprotein for human food applications. The pea-processing byproduct (PpB) was proved to be an efficient medium for the growth of filamentous fungi to produce a vegan-protein concentrate. Moreover, an industrial scenario for the production of vegan-mycoprotein concentrate for human nutrition is proposed as an integrated process to the existing PPI production facilities.


The Operational Canine and K9 Tactical Emergency Casualty Care Initiative.
Approximately 20% to 25% of trauma-related, prehospital fatalities in humans are due to preventable deaths. Data are lacking, however, on the nature and the prevalence of operational canine (OC) prehospital deaths. It is plausible that OCs engaged in high-threat operations are also at risk for suffering some type of preventable death. Tactical Combat Casualty Care has significantly reduced human fatality rates on the battlefield. Standardized guidelines specifically for prehospital trauma care have not been developed for the OC caregiver. An initiation has been approved by the Committee for Tactical Emergency Casualty Care to form a K9-Tactical Emergency Casualty Care (TECC) working group to develop such guidelines. The intent of the K9-TECC initiative is to form best practice recommendations for the civilian high-risk OC caregiver. These recommendations are to focus on interventions that (1) eliminate the major causes of canine out-of-hospital preventable deaths, (2) are easily learned and applied by any civilian first responder, and (2) minimize resource consumption.


Total and functional parasite specific IgE responses in Plasmodium falciparum-infected patients exhibiting different clinical status.
There is an increase of serum levels of IgE during Plasmodium falciparum infections in individuals living in endemic areas. These IgEs either protect against malaria or increase malaria pathogenesis. To get an insight into the exact role played by IgE in the outcome of P. falciparum infection, total IgE levels and functional anti-parasite IgE response were studied in children and adults, from two different endemic areas Gabon and India, exhibiting either uncomplicated malaria, severe non cerebral malaria or cerebral malaria, in comparison with control individuals. Blood samples were collected from controls and P. falciparum-infected patients before treatment on the day of hospitalization (day 0) in India and, in addition, on days 7 and 30 after treatment in Gabon. Total IgE levels were determined by ELISA and functional P. falciparum-specific IgE were estimated using a mast cell line RBL-2H3 transfected with a human Fcepsilon RI alpha-chain that triggers degranulation upon human IgE cross-linking. Mann Whitney and Kruskall Wallis tests were used to compare groups and the Spearman test was used for correlations. Total IgE levels were confirmed to increase upon infection and differ with level of transmission and age but were not directly related to the disease phenotype. All studied groups exhibited functional parasite-specific IgEs able to induce mast cell degranulation in vitro in the presence of P. falciparum antigens. Plasma IgE levels correlated with those of IL-10 in uncomplicated malaria patients from Gabon. In Indian patients, plasma IFN-gamma , TNF and IL-10 levels were significantly correlated with IgE concentrations in all groups. Circulating levels of total IgE do not appear to correlate with protection or pathology, or with anti-inflammatory cytokine pattern bias during malaria. On the contrary, the P. falciparum-specific IgE response seems to contribute to the control of parasites, since functional activity was higher in asymptomatic and uncomplicated malaria patients than in severe or cerebral malaria groups.


An association study of RGS4 polymorphisms with clinical phenotypes of schizophrenia in a Chinese population.
The regulator of G-protein signaling 4 (RGS4) has been suggested as a candidate gene for schizophrenia. However, following an initial positive report, subsequent association studies between RGS4 and schizophrenia have yielded inconclusive results. Also, few studies have investigated the association of RGS4 polymorphisms with the phenotypic subgroups of schizophrenia. To further clarify the role of RGS4 in this disease, we performed a case-control study (504 cases and 531 controls of Han Chinese descent) to examine the association of RGS4 with schizophrenia and with clinical and neurocognitive profiles. The four markers (SNPs 1, 4, 7, and 18) implicated in the original association study were genotyped. We detected significant association of four-marker haplotypes with schizophrenia (UNPHASED: global P = 0.037; PHASE: global P = 0.048). The haplotype G-G-G-G, which was implicated in at least three previous studies, was the major risk haplotype (UNPHASED: P = 0.019; PHASE: P = 0.010). Regarding the clinical phenotypes, the Wechsler Adult Intelligence Test (WAIS) information subtest score was associated with SNP4 genotypes (P = 0.001). PANSS total and global psychopathology scores were also associated with SNP4, but may not reliably reflect the general severity of disease as the scores may be affected by confounders like medication response. Our study provides further support for a role of RGS4 in the pathogenesis of schizophrenia. We identified G-G-G-G as the risk haplotype in our Chinese sample. The association with information subtest score suggests an effect of RGS4 on premorbid functioning, which may be related to neurodevelopmental processes. Further independent studies are required to verify our findings.


Short term respiratory health effects of ambient air pollution: results of the APHEA project in Paris.
To quantify the short term respiratory health effects of ambient air pollution in the Paris area. Time series analysis of daily pollution levels using Poisson regression. Paris, 1987-92. Air pollution was monitored by measurement of black smoke (BS) (15 monitoring stations), sulphur dioxide (SO2), nitrogen dioxide (NO2), particulate matter less than 13 microns in diameter (PM13), and ozone (O3) (4 stations). Daily mortality and general admissions to public hospitals due to respiratory causes were considered. The statistical analysis was based on a time series procedure using linear regression modelling followed by a Poisson regression. Meterological variables, epidemics of influenza A and B, and strikes of medical staff were included in the models. The mean daily concentration of PM13 and daily 1 hour maximum of SO2 significantly affected daily mortality from respiratory causes. An increase in the concentration of PM13 of 100 micrograms/m3 above its 5th centile value increased the risk of respiratory death by 17%. PM13 and BS were also associated with hospital admissions due to all respiratory diseases (4.1% increased risk when the BS level exceeded its 5th centile value by 100 micrograms/m3). SO2 levels consistently influenced hospital admissions for all respiratory diseases, chronic obstructive pulmonary disease, and asthma. Asthma was also correlated with NO2 levels. These results indicate that even though the relative risk is weak in areas with low levels of pollution, ambient air pollution, and especially particulate matter and SO2, nonetheless require attention because of the number of people exposed and the existence of high risk groups.


Visual acuity improvements after implantation of toric intraocular lenses in cataract patients with astigmatism: a systematic review.
Cataracts are a common and significant cause of visual impairment globally. We aimed to evaluate uncorrected distance visual acuity (UDVA) as an outcome in treating astigmatic cataract patients to assist clinicians or ophthalmologists in their decision making process regarding available interventions. Medline, Embase and Evidence Based Reviews were systematically reviewed to identify relevant studies reporting changes in UDVA, UIVA and UNVA after cataract surgery in presbyopic patients. Strict inclusion/exclusion criteria were used to exclude any non-relevant studies. Relevant outcomes (UDVA, UIVA and UNVA) were identified from the studies retrieved through the systematic review process. The systematic review identified 11 studies which reported UCVA. All 11 studies reported UDVA. Four brands of toric intraocular lenses (IOLs) were reported in these studies. All studies identified in the literature search reported improvements in UDVA following surgical implant of a toric IOL. The largest improvements in VA were reported using the Human Optics MicroSil toric IOL (0.74 LogMAR, UDVA) and the smallest improvements were also reported using the Human Optics MicroSil toric IOL (0.23 LogMAR, UDVA) in a different study. The results of this systematic review showed the aggregate of studies reporting a beneficial increase in UDVA with the use of toric IOLs in cataract patients with astigmatism.


PI 3-kinase regulation of dopamine uptake.
The magnitude and duration of dopamine (DA) signaling is defined by the amount of vesicular release, DA receptor sensitivity, and the efficiency of DA clearance, which is largely determined by the DA transporter (DAT). DAT uptake capacity is determined by the number of functional transporters on the cell surface as well as by their turnover rate. Here we show that inhibition of phosphatidylinositol (PI) 3-kinase with LY294002 induces internalization of the human DAT (hDAT), thereby reducing transport capacity. Acute treatment with LY294002 reduced the maximal rate of [(3) H]DA uptake in rat striatal synaptosomes and in human embryonic kidney (HEK) 293 cells stably expressing the hDAT (hDAT cells). In addition, LY294002 caused a significant redistribution of the hDAT from the plasma membrane to the cytosol. Conversely, insulin, which activates PI 3-kinase, increased [(3)H]DA uptake and blocked the amphetamine-induced hDAT intracellular accumulation, as did transient expression of constitutively active PI 3-kinase. The LY294002-induced reduction in [(3)H]DA uptake and hDAT cell surface expression was inhibited by expression of a dominant negative mutant of dynamin I, indicating that dynamin-dependent trafficking can modulate transport capacity. These data implicate DAT trafficking in the hormonal regulation of dopaminergic signaling, and suggest that a state of chronic hypoinsulinemia, such as in diabetes, may alter synaptic DA signaling by reducing the available cell surface DATs.


Interleukin-1 stimulates diglyceride accumulation in the absence of protein kinase C activation.
Despite advances in the knowledge of the intracellular signalling in response to extracellular messengers, the mechanism of action of interleukin-1 (IL-1) has remained an enigma. In the present study, we have employed human dermal fibroblasts (Detroit 532 cells) to investigate IL-1 beta-induced changes in intracellular signals. Both recombinant human IL-1 beta and a native preparation purified from human placental tissue were employed. Cyclic AMP levels in cell monolayers were unaltered by IL-1 beta. Also, IL-1 beta did not influence significantly the levels of phosphatidylinositol, phosphatidylinositol 4-monophosphate, and phosphatidylinositol 4,5-bisphosphate in the membrane, nor the water-soluble inositol phosphates, inositol monophosphate, inositol bisphosphate and inositol trisphosphate, in cells prelabelled with myo-[3H]inositol. In addition, intracellular calcium as measured by Quin2 was unaffected by interleukin-1. However, in cells labelled with [3H]glycerol or [3H]arachidonic acid, IL-1 beta caused an immediate rise in diglyceride (DG) accumulation. As the effects of IL-1 beta have been reported to be mimicked by tumour-promoting phorbol esters, this rise in DG suggested the involvement of protein kinase C (PKC). However, repeated experiments failed to reveal any acute effect of IL-1 beta on the activity of this enzyme. Furthermore, IL-1 beta did not cause the translocation of PKC between the membrane and the cytosol as has been found in response to other extracellular signals. Rather, IL-1 beta appeared to increase the synthesis of PKC in both membrane and cytosol preparations, an effect which could be prevented by coincubation with cycloheximide. These findings suggest that the diglyceride formed in response to IL-1 beta does not activate protein kinase C.


Syk-dependent phosphorylation of microtubules in activated B-lymphocytes.
Syk is a protein-tyrosine kinase that is essential for B-lymphocyte development and B-cell signaling. Syk phosphorylates tubulin on tyrosine both in vitro and in intact lymphocytes. Here we show that (alpha)-tubulin present within the cytoskeletal microtubule network was phosphorylated in a Syk-dependent manner following the activation of B-cells by engagement of the B-cell antigen receptor or by treatment with the phosphotyrosine phosphatase inhibitor, pervanadate. Immunofluorescence staining of microtubule cytoskeletons and western blotting studies with antibodies to phosphotyrosine confirmed the phosphorylation of polymerized tubulin in Syk-expressing, but not Syk-deficient, cells. At low concentrations of pervanadate, centrosomes appeared to be preferentially tyrosine-phosphorylated. Tubulin phosphorylated to a high stoichiometry on tyrosine assembled into microtubules in vitro, and preassembled microtubules were also phosphorylated by Syk kinase in vitro. Thus, Syk has the capacity to interact with microtubule networks within the B-lymphocyte and catalyzes the phosphorylation of the (alpha)-tubulin subunit. Syk-dependent phosphorylation of microtubules may affect the ability of the microtubule cytoskeleton to serve as a platform upon which signaling complexes are assembled.


Identification of adrafinil and its main metabolite modafinil in human hair. Self-administration study and interpretation of an authentic case.
For several years, the misuse of stimulant substances is increasingly observed both in the field of sport, to improve the functions of the body and therefore to be more performant, and also by non-athletes to make life more tolerable on a daily basis. Adrafinil, 2-((diphenylmethyl)sulfinyl)-N-hydroxyacetamide, is a drug designed for the treatment of narcolepsy by promoting an awakened state, and to treat alertness and neurological symptoms in the elderly. It is primarily metabolized in vivo to an active form, i.e. modafinil, 2-((diphenylmethyl)sulfinyl)acetamide. The World Anti-Doping Agency (WADA) banned these two drugs in sports in 2004. The authors report an authentic case involving adrafinil and modafinil. The laboratory was requested to test for adrafinil in a hair strand collected from a woman found in possession of vials of adrafinil and suspected of trafficking. A specific method was developed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unlike modafinil (varying from 6.8 to 13.9 ng/mg), adrafinil was not identified in the strand. The interpretation of the results was difficult because this is the first case describing human hair analysis. In order to be able to interpret the results, a self-administration study was conducted after an oral administration to a volunteer (200 mg) whose beard hair was collected 10 days after administration. The analysis of this specimen highlighted the presence of adrafinil at 0.8 ng/mg and modafinil at 0.5 ng/mg. These results demonstrate the dual identification of both compounds after a single consumption, even after administration of a low dose. According to these results, the analysis of the hair strand from the authentic case does not match with a consumption of adrafinil, in accordance with abuse of modafinil alone. Intelligence considered that this was a trafficking case of adrafinil, with no self-consumption.


Patient and public involvement in paediatric medical education.
The benefits of involving patients and the public in medical education are well documented, however there is a need to further explore how this can be translated to the setting of paediatric medical education. This article aims to identify how organisations can facilitate the involvement of paediatric patients and their parents/carers.While involving children in research can present challenges, we describe examples where organisations have successfully involved young people in clinical research and selection of research topics.Involving paediatric patients and their parents/carers in medical education helps develop a patient centred approach to practice for medical students. Participation of paediatric patients in objective structured clinical examination (OSCE) examinations is employed by many medical schools, however allowing them the ability to provide a 'global score' may have the potential to assess skills such as communication and empathy in addition to medical knowledge.The Royal College of Paediatrics and Child Health (RCPCH) have provided a framework on how to involve children in health services, addressing practical considerations such as funding and facilities. This framework could be applied by organisations seeking to actively involve children in paediatric medical education. Potential barriers and facilitators are explored in this article.During the COVID-19 pandemic, involving young people and their families in medical student teaching became challenging. We describe virtual bedside teaching sessions which actively involved paediatric patients and their families, which showed that many patients and parents prefer virtual consultations.Involving paediatric patients and their families in medical education is strongly advocated by the General Medical Council (GMC) and RCPCH. Organisations should actively seek out opportunities to become involved in the development of medical education resources as we describe in this paper.


β-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto-Kakizaki rat.
A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto-Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin-angiotensin-aldosterone system (RAAS) overactivation.


Intervening transcribed spacer region 1 variability in Cyclospora cayetanensis.
Cyclospora cayetanensis is an apicomplexan protozoan parasite which has emerged as an important cause of epidemic and endemic diarrhea. Water-borne as well as food-borne outbreaks have occurred, including a large number of U.S. cases associated with raspberries imported from Guatemala. Molecular markers exist for tracing the epidemiology of many of the bacterial pathogens associated with water-borne or food-borne diarrhea, such as serotyping and pulsed-field electrophoresis. However, there are currently no molecular markers available for C. cayetanensis. The intervening transcribed spacer (ITS) regions between the small- and large-subunit rRNA genes demonstrate much greater sequence variability than the small-subunit rRNA sequence itself and have been useful for the molecular typing of other organisms. Thus, ITS1 variability might allow the identification of different genotypes of C. cayetanensis. In order to determine the degree of ITS1 variability among C. cayetanensis isolates, the ITS1 sequences of C. cayetanensis isolates from a variety of sources, including raspberry-associated cases, cases from Guatemala, and pooled and individual isolates from Peru, were obtained. The ITS1 sequences of all five raspberry-associated isolates were identical, consistent with their origin from a single source. In contrast, one of the two Guatemala isolates and two Peruvian isolates contained multiple ITS1 sequences. These multiple sequences could represent multiple clones from a single clinical source or, more likely, variability of the ITS1 region within the genome of a single clone.


Relationship between device acceptance and patient-reported outcomes in Left Ventricular Assist Device (LVAD) recipients.
The number of Left Ventricular Assist Devices (LVADs) implanted each year is rising. Nevertheless, there are minimal data on device acceptance after LVAD implant, and on its relationship with patient-reported outcomes. We designed a cross-sectional study to address this knowledge gap and test the hypothesis that low device acceptance is associated with poorer quality of life, depression and anxiety. Self-report questionnaires were administered to assess quality of life (12-item Kansas City Cardiomyopathy Questionnaire quality of life subscale), level of anxiety (7-item Generalized Anxiety Disorder; GAD-7), level of depression (9-item Patient Health Questionnaire; PHQ-9) and device acceptance (Florida Patient Acceptance Survey; FPAS) to 101 consecutive patients presenting to LVAD clinic. Regression analysis showed a strong correlation between device acceptance and both psychological distress (p < 0.001) and quality of life (p < 0.001). Analysis of the sub-scales of the FPAS showed that patients had significant body image concerns, but return to function and device-related distress were the main drivers of the observed correlation between device acceptance and patient well-being. Younger age was associated with lower device acceptance (r = 0.36, p < 0.001) and lower quality of life (r = 0.54, p < 0.001). These findings suggest that interventions targeting device acceptance should be explored to improve outcomes in LVAD recipients.


Inverse visualization concept for RGB-D augmented C-arms.
X-ray is still the essential imaging for many minimally-invasive interventions. Overlaying X-ray images with an optical view of the surgery scene has been demonstrated to be an efficient way to reduce radiation exposure and surgery time. However, clinicians are recommended to place the X-ray source under the patient table while the optical view of the real scene must be captured from the top in order to see the patient, surgical tools, and the surgical site. With the help of a RGB-D (red-green-blue-depth) camera, which can measure depth in addition to color, the 3D model of the real scene is registered to the X-ray image. However, fusing two opposing viewpoints and visualizing them in the context of medical applications has never been attempted. In this paper, we propose first experiences of a novel inverse visualization technique for RGB-D augmented C-arms. A user study consisting of 16 participants demonstrated that our method shows a meaningful visualization with potential in providing clinicians multi-modal fused data in real-time during surgery.


Influence of Lactobacillus brevis 15 and Lactobacillus plantarum 13 on blood glucose and body weight in rats after high-fructose diet.
In recent years, many authors have investigated the possible antidiabetic effect of lactic acid bacteria. Lactobacillus species constitute a major part of the lactic acid bacteria group and have been found to exhibit beneficial effects on the development of diabetes and its complications. In the current study, we investigated the effects of newly characterised Bulgarian Lactobacillus strains, Lactobacillus brevis 15 and Lactobacillus plantarum 13, on blood glucose levels and body weight of rats fed a fructose-enriched diet. An experiment was conducted over a period of 8 weeks with 24 2-month-old Wistar rats randomly assigned to receive a standard diet (Con, control group), fructose-enriched diet (Fr group), standard diet with probiotics given twice a week (Pro group), and fructose-enriched diet with probiotics given twice a week (Pro+Fr group). At the end of the experimental period, a statistically significant increase in body weight was observed in all experimental groups (P<0.0001). The highest rise was seen in the fructose group (Fr, 169±19 g), followed by the Pro+Fr group (153±15 g), Pro group (149±13 g), and Con group (141±5 g). Moreover, the final blood glucose levels had risen significantly in the groups receiving fructose either without (Fr; P<0.0001) or with lactobacilli (Pro+Fr; P=0.002), while the rise was insignificant in the group of rats given probiotic supplementation only (Pro, P=0.071) and inexistent in the Con group (P=0.999). The highest elevation of blood glucose levels was observed in the Fr group (3.18 mmol/l), followed by the Pro+Fr group (2.00 mmol/l) whereas the Pro group showed the lowest levels (0.60 mmol/l). The results of our study suggest that the newly characterised Bulgarian Lactobacillus strains, L. brevis 15 and L. plantarum 13, could be considered as possible probiotics and might be able to prevent some metabolic disturbances.


A comparison of three strategies for reducing the public stigma associated with stuttering.
The effects of three anti-stigma strategies for stuttering-contact (hearing personal stories from an individual who stutters), education (replacing myths about stuttering with facts), and protest (condemning negative attitudes toward people who stutter)-were examined on attitudes, emotions, and behavioral intentions toward people who stutter. Two hundred and twelve adults recruited from a nationwide survey in the United States were randomly assigned to one of the three anti-stigma conditions or a control condition. Participants completed questionnaires about stereotypes, negative emotional reactions, social distance, discriminatory intentions, and empowerment regarding people who stutter prior to and after watching a video for the assigned condition, and reported their attitude changes about people who stutter. Some participants completed follow-up questionnaires on the same measures one week later. All three anti-stigma strategies were more effective than the control condition for reducing stereotypes, negative emotions, and discriminatory intentions from pretest to posttest. Education and protest effects for reducing negative stereotypes were maintained at one-week follow-up. Contact had the most positive effect for increasing affirming attitudes about people who stutter from pretest to posttest and pretest to follow-up. Participants in the contact and education groups, but not protest, self-reported significantly more positive attitude change about people who stutter as a result of watching the video compared to the control group. Advocates in the field of stuttering can use education and protest strategies to reduce negative attitudes about people who stutter, and people who stutter can increase affirming attitudes through interpersonal contact with others.


Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys.
The dopamine hypothesis of schizophrenia posits that dopamine dysregulation plays a key role in the etiology of schizophrenia. In line with this hypothesis, repeated amphetamine (AMPH) exposure has been shown to alter dopamine systems and induce behaviors reminiscent of positive-like and negative-like symptoms in both human and nonhuman primates. The mechanisms by which AMPH produces disturbances in brain function and behavior are not fully understood. The present study has employed a novel AMPH regimen, 12 weeks of intermittent escalating low doses of AMPH, to produce a nonhuman primate model for the purpose of elucidating the behavioral and neural consequences of excessive dopamine exposure. Behavioral responses to acute AMPH challenge (0.4-0.46 mg/kg) were assessed prior to and following the chronic 12-week treatment regimen, and, at present monkeys have been followed out to 28 months post-treatment. After chronic treatment, enhanced behavioral responses to AMPH challenge were readily apparent at 5 days postwithdrawal, and, were still present at 28 months postwithdrawal. The enhanced behavioral responses to low-dose AMPH challenge that were observed in the present study resemble closely the behavioral profile that has been described for chronic high-dose AMPH treatment in monkeys; i.e., hallucinatory-like behaviors, static posturing, and fine-motor stereotypies were all exacerbated in response to AMPH injection. In some animals, acute challenges after chronic AMPH evoked aberrant behavioral responses that lasted for 4 days. AMPH-treated monkeys also exhibited a significant decrease in the incidence of motor stereotypies in the off-drug periods between challenges. The present results are the first to document persistent long-term behavioral effects of intermittent exposure to repeated low-dose AMPH treatment in nonhuman primates. These findings may lay the groundwork for the development of a primate mode of psychosis with possible positive-like and negative-like symptoms.


Ionizing radiation: future etiologic research and preventive strategies.
Estimates of cancer risks following exposure to ionizing radiation traditionally have been based on the experience of populations exposed to substantial (and known) doses delivered over short periods of time. Examples include survivors of the atomic bombings at Hiroshima and Nagasaki, and persons treated with radiation for benign or malignant disease. Continued follow-up of these populations is important to determine the long-term effects of exposure in childhood, to characterize temporal patterns of excess risk for different types of cancer, and to understand better the interactions between radiation and other host and environmental factors. Most population exposure to radiation occurs at very low dose rates. For low linear energy transfer (LET) radiations, it often has been assumed that cancer risks per unit dose are lower following protracted exposure than following acute exposure. Studies of nuclear workers chronically exposed over a working lifetime provide data that can be used to test this hypothesis, and preliminary indications are that the risks per unit dose for most cancers other than leukemia are similar to those for acute exposure. However, these results are subject to considerable uncertainty, and further information on this question is needed. Residential radon is the major source of population exposure to high-LET radiation. Current estimates of the risk of lung cancer due to residential exposure to radon and radon daughters are based on the experience of miners exposed to much higher concentrations. Data indicate that lung cancer risk among miners is inversely associated with exposure rate, and also is influenced by the presence of other lung carcinogens such as arsenic in the mine environment. Further study of populations of radon-exposed miners would be informative, particularly those exposed at below-average levels. More direct evidence on the effects of residential exposure to radon also is desirable but might be difficult to come by, as risks associated with radon levels found in most homes might be too low to be quantified accurately in epidemiological studies.


Laserlight visual cueing device for freezing of gait in Parkinson's disease: a case study of the biomechanics involved.
Freezing of gait (FOG) is a serious gait disorder affecting up to two-thirds of people with Parkinson's disease (PD). Cueing has been explored as a method of generating motor execution using visual transverse lines on the floor. However, the impact of a laser light visual cue remains unclear. To determine the biomechanical effect of a laser cane on FOG in a participant with PD compared to a healthy age- and gender-matched control. The participant with PD and healthy control were given a task of initiating gait from standing. Electromyography (EMG) data were collected from the tibialis anterior (TA) and the medial gastrocnemius (GS) muscles using an 8-channel system. A 10-camera system (Qualisys) recorded movement in 6 degrees of freedom and a calibrated anatomical system technique was used to construct a full body model. Center of mass (COM) and center of pressure (COP) were the main outcome measures. The uncued condition showed that separation of COM and COP took longer and was of smaller magnitude than the cued condition. EMG activity revealed prolonged activation of GS, with little to no TA activity. The cued condition showed earlier COM and COP separation. There was reduced fluctuation in GS, with abnormal, early bursts of TA activity. Step length improved in the cued condition compared to the uncued condition. Laserlight visual cueing improved step length beyond a non-cued condition for this patient indicating improved posture and muscle control.


Evaluating Alternative Risk Adjusters for Medicare.
In this study the authors use 3 years of the Medicare Current Beneficiary Survey (MCBS) to evaluate alternative demographic, survey, and claims-based risk adjusters for Medicare capitation payment. The survey health-status models have three to four times the predictive power of the demographic models. The risk-adjustment model derived from claims diagnoses has 75-percent greater predictive power than a comprehensive survey model. No single model predicts average expenditures well for all beneficiary subgroups of interest, suggesting a combined model may be appropriate. More data are needed to obtain stable estimates of model parameters. Advantages and disadvantages of alternative risk adjusters are discussed.


Hyperbaric oxygenation promotes neural stem cell proliferation and protects the learning and memory ability in neonatal hypoxic-ischemic brain damage.
The aim of our study was to evaluate whether hyperbaric oxygenation (HBO) was an effective therapy for neonatal hypoxic ischemic brain damage (HIBD). Seven-day-old rat pups were divided into 3 groups: sham, hypoxia-ischemia (HI) control and HI-HBO group. HBO was administered for HI rats daily. The pathologic changes in brain tissues were observed by hematoxylin-eosin (H-E) staining. The immunohistochemical staining was applied to detect the Nestin and 5-bromo-2-deoxyuridine (BrdU) positive cells in hippocampal dentate gyrus region. The learning and memory function of rats was examined by Morris water maze. The HI rats showed obvious pathologic changes accompanied by levels decreasing and disorder arrangement of pyramidal cells, glial cells proliferation in postoperative, and nerve nuclei broken, while pathologic changes of rats in sham group was approximate to that in the HI + HBO group that was opposite to the HI group. Compared with the sham group, the Nestin and BrdU positive cells in HBO + HI group at different time points increased significantly (P < 0.01). Learning and memory function of rats in HI group was poor compared with the sham/HI + HBO group (P < 0.01), while that in HI + HBO group was approximate to that in sham group (P > 0.05). HBO treatment improved the learning and memory ability of the HI rats. HBO therapy may be effective for neonatal HIBD treatment.


Head injury does not alter disease progression or neuropathologic outcomes in ALS.
To study the effects of head injury on disease progression and on neuropathologic outcomes in amyotrophic lateral sclerosis (ALS). Patients with ALS were surveyed to obtain head injury history, and medical records were reviewed. Linear regression was performed to determine if head injury was a predictor for mean monthly decline of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R), while controlling for confounders. Head injury history was obtained from family members of ALS autopsy cases. The frequency of tau proteinopathy, brain TDP-43 inclusions, and pathologic findings of Alzheimer disease (AD) were examined in ALS cases with head injury compared to cases without. Logistic regression was performed with each neuropathologic diagnosis as an outcome measure and head injury as a predictor variable. No difference was seen in rate of decline of the ALSFRS-R between patients with head injury (n = 24) and without (n = 76), with mean monthly decline of -0.9 for both groups (p = 0.18). Of 47 ALS autopsy cases (n = 9 with head injury, n = 38 without), no significant differences were seen in the frequency of tau proteinopathy (11% with head injury; 24% without), TDP-43 in the brain (44% with head injury; 45% without), or AD pathology (33% with head injury; 26% without). Independent logistic regression models showed head injury was not a predictor of tau pathology (p = 0.42) or TDP-43 in the brain (p = 0.99). Head injury was not associated with faster disease progression in ALS and did not result in a specific neuropathologic phenotype. The tau pathology described with chronic traumatic encephalopathy was found in ALS autopsy cases both with and without head injury.


Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma.
Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood. We analyzed the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interaction. We found that TIMP-1 is aberrantly overexpressed in tumor-associated fibroblasts (TAFs) in ADC compared to SCC. Mechanistically, TIMP-1 overexpression was mediated by the selective hyperactivity of the pro-fibrotic TGF-β1/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-β1-activated ADC-TAFs is both necessary and sufficient to enhance growth and invasion of ADC cancer cells in culture, and that tumor cell expression of CD63 was required for these effects. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced SMAD3 or TIMP-1 expression into immunocompromised mice attenuated tumor aggressiveness compared to tumors bearing parental fibroblasts. We also found that high TIMP1 and CD63 mRNA levels combined define a stronger prognostic biomarker than TIMP1 alone. Our results identify an excessive stromal TIMP-1 within the tumor microenvironment selectively in lung ADC, and implicate it in a novel tumor-promoting TAF-carcinoma crosstalk, thereby pointing to TIMP-1/CD63 interaction as a novel therapeutic target in lung cancer.


Antibiotic resistance in urinary tract bacteria in Ouagadougou.
The present study aimed to ascertain for the current situation of antimicrobial resistance of major urinary tract bacteria in Saint Camille Medical Centre. During two consecutive years, 794 urine specimens were analyzed for microorganism isolation and identification. The microorganisms were identified by conventional methods used in the centre and antimicrobial assays were performed by the NCCLS agar disk diffusion. Pathogenic microorganism's isolation was attempted for 89.04% samples. Escherichia coli (32.76%) was the most frequently isolated microorganism followed by Staphylococcus aureus (22.74%) and Klebsiella pneumoniae (10.45%). The antimicrobial screenings revealed very high antimicrobial resistance, to beta-lactams. The resistance rates recorded with E. coli were 76.64, 74.01, 25 and 74.34% for ampicillin, amoxicillin amoxicillin/clavulanic acid and trimethoprime-sulfamethoxazole, respectively. Microorganisms were still susceptible to quinolones however, attention should be paid, because, the resistance rate already reached 10% for nalidixic acid and ciprofloxacin. Periodic performance of prevalence studies is a useful tool to know the current situation of microorganisms and their resistance patterns in an institution and it helps to access the emergence and the spread of antibiotic resistance.


Vasodilatory Actions of Glucagon-Like Peptide 1 Are Preserved in Skeletal and Cardiac Muscle Microvasculature but Not in Conduit Artery in Obese Humans With Vascular Insulin Resistance.
Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans. Fifteen obese adults received intravenous infusion of either saline or GLP-1 (1.2 pmol/kg/min) for 150 min with or without a euglycemic insulin clamp (1 mU/kg/min) superimposed over the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity and blood flow, brachial artery diameter and blood flow, and pulse wave velocity (PWV) were determined. Insulin failed to change MBV or flow in either skeletal or cardiac muscle, confirming the presence of microvascular insulin resistance. GLP-1 infusion alone increased MBV by ∼30% and ∼40% in skeletal and cardiac muscle, respectively, with no change in flow velocity, leading to a significant increase in microvascular blood flow in both skeletal and cardiac muscle. Superimposition of insulin to GLP-1 infusion did not further increase MBV or flow in either skeletal or cardiac muscle but raised the steady-state glucose infusion rate by ∼20%. Insulin, GLP-1, and GLP-1 + insulin infusion did not alter brachial artery diameter and blood flow or PWV. The vasodilatory actions of GLP-1 are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes. In obese humans with microvascular insulin resistance, GLP-1's vasodilatory actions are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.


Synaptic inputs to retinal ganglion cells that set the circadian clock.
Melanopsin-containing retinal ganglion cells (RGCs) project to the suprachiasmatic nuclei (SCN) and mediate photoentrainment of the circadian system. Melanopsin is a novel retinal-based photopigment that renders these cells intrinsically photosensitive (ip). Although genetic ablation of melanopsin abolishes the intrinsic light response, it has a surprisingly minor effect on circadian photoentrainment. This and other non-visual responses to light are lost only when the melanopsin deficiency is coupled with mutations that disable classical rod and cone photoreceptors, suggesting that melanopsin-containing RGCs also receive rod- and cone-driven synaptic inputs. Using whole-cell patch-clamp recording, we demonstrate that light triggers synaptic currents in ipRGCs via activation of ionotropic glutamate and gamma-aminobutyric acid (GABA) receptors. Miniature postsynaptic currents (mPSCs) were clearly observed in ipRGCs, although they were less robust and were seen less frequently than those seen in non-ip cells. Pharmacological treatments revealed that the majority of ipRGCs receive excitatory glutamatergic inputs that were blocked by DNQX and/or kynurenic acid, as well as inhibitory GABAergic inputs that were blocked by bicuculline. Other ipRGCs received either glutamatergic or GABAergic inputs nearly exclusively. Although strychnine (Strych)-sensitive mPSCs were evident on many non-ipRGCs, indicating the presence of glycinergic inputs, we saw no evidence of Strych-sensitive events in ipRGCs. Based on these results, it is clear that SCN-projecting RGCs can respond to light both via an intrinsic melanopsin-based signaling cascade and via a synaptic pathway driven by classical rod and/or cone photoreceptors. It remains to be determined how the ipRGCs integrate these temporally distinct inputs to generate the signals that mediate circadian photoentrainment and other non-visual responses to light.


Interventions for the management of mandibular fractures.
Fractures of the mandible (lower jaw) are a common occurrence and usually related to interpersonal violence or road traffic accidents. Mandibular fractures may be treated using open (surgical) and closed (non-surgical) techniques. Fracture sites are immobilized with intermaxillary fixation (IMF) or other external or internal devices (i.e. plates and screws) to allow bone healing. Various techniques have been used, however uncertainty exists with respect to the specific indications for each approach. The objective of this review is to provide reliable evidence of the effects of any interventions either open (surgical) or closed (non-surgical) that can be used in the management of mandibular fractures, excluding the condyles, in adult patients. We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 28 February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1), MEDLINE via OVID (1950 to 28 February 2013), EMBASE via OVID (1980 to 28 February 2013), metaRegister of Controlled Trials (to 7 April 2013), ClinicalTrials.gov (to 7 April 2013) and the WHO International Clinical Trials Registry Platform (to 7 April 2013). The reference lists of all trials identified were checked for further studies. There were no restrictions regarding language or date of publication. Randomised controlled trials evaluating the management of mandibular fractures without condylar involvement. Any studies that compared different treatment approaches were included. At least two review authors independently assessed trial quality and extracted data. Results were to be expressed as random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals. Heterogeneity was to be investigated to include both clinical and methodological factors. Twelve studies, assessed as high (six) and unclear (six) risk of bias, comprising 689 participants (830 fractures), were included. Interventions examined different plate materials and morphology; use of one or two lag screws; microplate versus miniplate; early and delayed mobilization; eyelet wires versus Rapid IMF™ and the management of angle fractures with intraoral access alone or combined with a transbuccal approach. Patient-oriented outcomes were largely ignored and post-operative pain scores were inadequately reported. Unfortunately, only one or two trials with small sample sizes were conducted for each comparison and outcome. Our results and conclusions should therefore be interpreted with caution. We were able to pool the results for two comparisons assessing one outcome. Pooled data from two studies comparing two miniplates versus one miniplate revealed no significant difference in the risk of post-operative infection of surgical site (risk ratio (RR) 1.32, 95% CI 0.41 to 4.22, P = 0.64, I(2) = 0%). Similarly, no difference in post-operative infection between the use of two 3-dimensional (3D) and standard (2D) miniplates was determined (RR 1.26, 95% CI 0.19 to 8.13, P = 0.81, I(2) = 27%). The included studies involved a small number of participants with a low number of events. This review illustrates that there is currently inadequate evidence to support the effectiveness of a single approach in the management of mandibular fractures without condylar involvement. The lack of high quality evidence may be explained by clinical diversity, variability in assessment tools used and difficulty in grading outcomes with existing measurement tools. Until high level evidence is available, treatment decisions should continue to be based on the clinician's prior experience and the individual circumstances.


A cross-sectional examination of the clinical significance of autistic traits in individuals experiencing a first episode of psychosis.
Autism traits are found at elevated rates in individuals with schizophrenia spectrum disorders, however, there is a lack of evidence regarding potential clinical impact. The current research aimed to examine potential associations between autism traits and symptoms of psychosis, social and role functioning, and quality of life. 99 individuals experiencing a first episode of psychosis took part in a cross-sectional interview and self-report questionnaire which assessed current symptoms of psychosis, autism traits, functioning, and quality of life. Participants were found to have a high level of autism traits. Higher autism traits were associated with poorer quality of life, functioning, and current psychotic symptoms. Receiver operating characteristic curve (ROC) analyses indicated that optimal AQ cut-off scores to predict severity of psychosis symptoms, functioning, and quality of life were lower than those used to suggest likely autism-spectrum diagnosis. Results suggest that autism traits are associated with poorer clinical presentation in first-episode psychosis populations, even in those whose traits fall below potentially diagnostic thresholds for autism. Psychosis services should be prepared to adequately address the needs of individuals with higher autism traits.


Fascicles from energy-storing tendons show an age-specific response to cyclic fatigue loading.
Some tendons, such as the human Achilles and equine superficial digital flexor tendon (SDFT), act as energy stores, stretching and recoiling to increase efficiency during locomotion. Our previous observations of rotation in response to applied strain in SDFT fascicles suggest a helical structure, which may provide energy-storing tendons with a greater ability to extend and recoil efficiently. Despite this specialization, energy-storing tendons are prone to age-related tendinopathy. The aim of this study was to assess the effect of cyclic fatigue loading (FL) on the microstructural strain response of SDFT fascicles from young and old horses. The data demonstrate two independent age-related mechanisms of fatigue failure; in young horses, FL caused low levels of matrix damage and decreased rotation. This suggests that loading causes alterations to the helix substructure, which may reduce their ability to recoil and recover. By contrast, fascicles from old horses, in which the helix is already compromised, showed greater evidence of matrix damage and suffer increased fibre sliding after FL, which may partially explain the age-related increase in tendinopathy. Elucidation of helix structure and the precise alterations occurring owing to both ageing and FL will help to develop appropriate preventative and repair strategies for tendinopathy.


Adaptations in urea ammonium excretion in metabolic acidosis in the rat: a reinterpretation.
1. The effects of oral hydrochloric acid, ammonium chloride, sodium bicarbonate and ammonium bicarbonate on urea and ammonium excretion in rats on a constant diet were studied. 2. Hydrochloric acid acidosis significantly reduced urea excretion in the rat, with an equimolar increase in NH+4 excretion and no change in their sum. In ammonium chloride acidosis, most of the additional nitrogen intake is excreted as NH+4 and a small percentage as urea. The converse holds true after administration of ammonium bicarbonate. The physiological significance of this is discussed. 3. The shift in nitrogen excretion from urea to NH+4 in acidosis is interpreted on the basis of bicarbonate production and utilization. Urea formation utilizes HCO-3. For amino acid sources, this utilization is offset by the metabolism of the carbon skeleton, which gives rise to HCO-3. When waste nitrogen is excreted as NH+4, no bicarbonate is utilized and the new HCO-3, generated by the carbon skeleton, hels to maintain hydrogen ion homeostasis.


Detecting Methamphetamine in Aerosols by Electroanalysis in a Soap Bubble Wall.
We present a facile method to detect methamphetamine in aerosols by trapping aerosols in a soap bubble wall for electroanalysis. A microwire was placed through a soap bubble wall as a sensing electrode along with a 1 mm diameter platinum wire as the counter/reference electrode. The resulting electrochemical cell and electrode geometry are unique and allow for reproducible electrochemistry between bubble walls. We first provide a thorough investigation of the cell and electrode geometry and an electrochemical characterization of ferrocene methanol in a soap bubble wall composed of 0.1 M KCl and 0.1% Triton X-100 (v/v). To visualize the boundary where the bubble wets the microwire (the effective electrode area) with tens of nanometer resolution, we electrodeposited platinum on carbon microwire. Scanning electron microscopy and energy dispersive X-ray spectroscopy revealed the bubble contact (i.e., cylindrical electrode height) is 157 ± 30 μm. Correlated digital microscopy suggests that the wetting reaches r ∼ 125 μm along the bubble wall laterally from the microwire. Beyond the wetting region, the bubble thickness is 18 ± 1 μm, as indicated by ultraviolet-visible spectroscopy experiments probing dissolved bis(bipyridine)ruthenium(II) chloride. We illustrate that the voltammetric character in this system is highly dependent on the bubble wetting parameters, which are tuned by changing the microwire material. We then applied this system to the collection and electrochemical detection of methamphetamine in liquid aerosols, where the bubble wall acts as a low volume collector.


Clinical and histologic evaluation of anorganic bovine bone collagen with or without a collagen barrier.
This study evaluated an anorganic bovine-derived xenograft (Bio-Oss Collagen) in the treatment of human periodontal defects. Four patients with intrabony defects on teeth that were treatment planned for extraction were enrolled in the study. Presurgical measurements of probing depth, attachment level, and recession were recorded. The surgical procedure consisted of flap reflection, debridement of the osseous defects and root surface, placement of a notch through calculus into the root surface, topical application of a tetracycline paste to the root surface, grafting with Bio-Oss Collagen, and flap closure. Three of the eight defects examined received a resorbable collagen barrier (Bio-Gide) in addition to the bone graft. Patients were seen every 2 weeks for plaque control and review of oral hygiene measures. Six months postsurgery, clinical parameters were rerecorded prior to en bloc resection of teeth and adjacent graft sites. The majority of sites showed a favorable clinical response with respect to probing depth reduction and clinical attachment gain. Histologic analysis demonstrated new bone, cementum, and periodontal ligament coronal to the reference notch in two of the eight specimens. Two sites demonstrated new attachment, and four showed a long junctional epithelium. Periodontal regeneration is possible following a bone-replacement graft of Bio-Oss Collagen.


International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.


Age and gender variations of sleep in subjects without sleep disorders.
Although sleep is a biomarker for general health and pathological conditions, its changes across age and gender are poorly understood. Subjective evaluation of sleep was assessed by questionnaires in 5,064 subjects, and 2,966 were considered without sleep disorders. Objective evaluation was performed by polysomnography in 2,160 subjects, and 1,147 were considered without sleep disorders. Only subjects without sleep disorders were included (aged 40-80 years). Aging was strongly associated with morning preference. Older subjects, especially women, complained less about sleepiness, and pathological sleepiness was significantly lower than in younger subjects. Self-reported sleep quality and daytime functioning improved with aging. Sleep latency increased with age in women, while sleep efficiency decreased with age in both genders. Deep slow-wave sleep decreased with age, but men were more affected. Spectral power densities within slow waves (< 5 Hz) and fast spindles (14-14.75 Hz) decreased, while theta-alpha (5-1 Hz) and beta (16.75-25 Hz) power in non-rapid eye movement sleep increased with aging. In REM sleep, aging was associated with a progressive decrease in delta (1.25-4.5 Hz) and increase in higher frequencies. Our findings indicate that sleep complaints should not be viewed as part of normal aging but should prompt the identification of underlying causes.


Psychosocial and immune effects of self-hypnosis training for stress management throughout the first semester of medical school.
This study was a 19-week prospective conducted to determine the effectiveness of a self-hypnosis/relaxation intervention to relieve symptoms of psychological distress and moderate immune system reactivity to examination stress in 35 first-year medical students. Twenty-one subjects were randomly selected for training in the use of self-hypnosis as a coping skill and were encouraged to practice regularly and to maintain daily diary records related to mood, sleep, physical symptoms, and frequency of relaxation practice. An additional 14 subjects received no explicit training in stress-reduction strategies, but completed similar daily diaries. Self-report psychosocial and symptom measures, as well as blood draws, were obtained at four time points: orientation, late semester, examination period, and postsemester recovery. It was found that significant increases in stress and fatigue occurred during the examination period, paralleled by increases in counts of B lymphocytes and activated T lymphocytes, PHA-induced and PWM-induced blastogenesis, and natural killer cell (NK) cytotoxicity. No immune decreases were observed. Subjects in the self-hypnosis condition reported significantly less distress and anxiety than their nonintervention counterparts, but the two groups did not differ with respect to immune function. Nevertheless, within the self-hypnosis group, the quality of the exercises (ie, relaxation ratings) predicted both the number of NK cells and NK activity. It was concluded that stress associated with academic demands affects immune function, but immune suppression is not inevitable. Practice of self-hypnosis reduces distress, without differential immune effects. However, individual responses to the self-hypnosis intervention appear to predict immune outcomes.


Impact of CPR Quality and Adherence to Advanced Cardiac Life Support Guidelines on Patient Outcomes in In-Hospital Cardiac Arrest.
Sudden cardiac arrest is a major cause of death worldwide. Performance of prompt, high-quality cardiopulmonary resuscitation improves patient outcomes. To evaluate the association between patient survival of in-hospital cardiac arrest and 2 independent variables: adherence to resuscitation guidelines and patient severity of illness, as indicated by the number of organ supportive therapies in use before cardiac arrest. An observational study was conducted using prospectively collected data from a convenience sample. Cardiopulmonary arrest forms and medical records were evaluated at an academic medical center. Adherence to resuscitation guidelines was measured with the ZOLL R Series monitor/defibrillator using RescueNet Code Review software. The primary outcome was patient survival. Of 200 cases, 37% of compressions were in the recommended range for rate (100-120/min) and 63.9% were in range for depth. The average rate was above target 55.7% of the time. The average depth was above and below target 1.4% and 34.7% of the time, respectively. Of the 200 patients, 125 (62.5%) attained return of spontaneous circulation. Of those, 94 (47%) were alive 24 hours after resuscitation. Fifty patients (25%) were discharged from the intensive care unit alive and 47 (23.5%) were discharged from the hospital alive. These exploratory data reveal overall survival rates similar to those found in previous studies. The number of pauses greater than 10 seconds during resuscitation was the one consistent factor that impacted survival. Despite availability of an audiovisual feedback system, rescuers continue to perform compressions that are not at optimal rate and depth.


Circulating microRNAs as potentially new diagnostic biomarkers of idiopathic sudden sensorineural hearing loss.
Early detection of inner ear cell damage can reduce the chances of permanent damage to hearing ability. However, current inner ear cell damage detection methods can detect damage only after the patient has lost hearing ability. MicroRNA expression levels in circulating systems are affected in diseases or conditions arising from the distant lesions. Therefore, detection of circulating microRNA expression levels could be one of the best ways to obtain information on inaccessible lesion sites. This study aims to establish a method for monitoring idiopathic sudden sensorineural hearing loss (ISSNHL) by analyzing circulating microRNA expression levels. 21 ISSNHL patients and 24 healthy controls were enrolled. Real-time quantitative polymerase chain reaction was performed for detecting expression levels of circulating microRNAs. Among eight circulating microRNAs, expression levels of five circulating microRNAs significantly differed between ISSNHL patients and healthy controls. circulating microRNA expression levels correlates with treatment outcomes and hearing ability. Using methods combining the evaluation of miR-183, miR-210, miR-18b, and miR-23a cut-off values identified in ISSNHL patients and healthy controls during receiver operating characteristic curve analysis, sensitivity and specificity of 80.95% (17/21) and 87.50% (21/24) were obtained, respectively.


Zinc metallopeptidase inhibitors. A novel antihypertensive treatment.
Inhibitors of two zinc metallopeptidases, angiotensin I converting enzyme (ACE) and neutral metalloendopeptidase-24.11 (EP-24.11), are antihypertensive agents. In this issue of Hypertension, Genden and Molineaux report that yet another peptidase inhibitor, metalloendopeptidase-24.15, EC 184.108.40.206 (EP-24.15), lowers blood pressure in normotensive rats. In this editorial we discuss the possible role of kinins as common mediators of part of the vasodepressor action of these peptidase inhibitors. Genden and Molineaux report that the marked fall in blood pressure caused by the EP-24.15 inhibitor is almost abolished by a kinin receptor antagonist, supporting the hypothesis that kinins play a role in the regulation of normal blood pressure. We have confirmed that the EP-24.15 inhibitor used by these investigators lowers blood pressure. Up to now, EP-24.15 has not been implicated in in vivo metabolism of kinins. Although a number of kininases have been identified, our own previous work indicated that the metabolic pathway responsible for clearing kinins from the circulation involves the action of kininase II (angiotensin I converting enzyme) and renal peptidases. Nevertheless, the main metabolic pathway involved some other unidentified enzyme, since in these experiments disappearance of kinins from the circulation was only marginally reduced by a "cocktail" of inhibitors of ACE, EP-24.11, and carboxypeptidase N. It could be that EP-24.15 is involved in kinin metabolism. However, a number of questions need to be answered with regard to the mechanism by which the EP-24.15 inhibitor lowers blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility.
A glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a two-nucleotide deletion in the open reading frame, which generates an abnormal mRNA. The allele frequency of this variant sequence was high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or a wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from del/del carriers exhibited an 84% reduction in the rate of penetration of a hyaluronic acid gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in hyaluronic acid gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. Nevertheless, DEFB126 genotype and lectin binding were correlated with sperm performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. This common sequence variation in DEFB126, and its apparent effect of impaired reproductive function, will allow a better understanding, clinical evaluation, and possibly treatment of human infertility.


Collinearity analysis of Brassica A and C genomes based on an updated inferred unigene order.
This data article includes SNP scoring across lines of the Brassica napus TNDH population based on Illumina sequencing of mRNA, expanded to 75 lines. The 21, 323 mapped markers defined 887 recombination bins, representing an updated genetic linkage map for the species. Based on this new map, 5 genome sequence scaffolds were split and the order and orientation of scaffolds updated to establish a new pseudomolecule specification. The order of unigenes and SNP array probes within these pseudomolecules was determined. Unigenes were assessed for sequence similarity to the A and C genomes. The 57, 246 that mapped to both enabled the collinearity of the A and C genomes to be illustrated graphically. Although the great majority was in collinear positions, some were not. Analyses of 60 such instances are presented, suggesting that the breakdown in collinearity was largely due to either the absence of the homoeologue on one genome (resulting in sequence match to a paralogue) or multiple similar sequences being present. The mRNAseq datasets for the TNDH lines are available from the SRA repository (ERA283648); the remaining datasets are supplied with this article.


Development of a reference database for assessing dietary nitrate in vegetables.
Nitrate from vegetables improves vascular health with short-term intake. Whether this translates into improved long-term health outcomes has yet to be investigated. To enable reliable analysis of nitrate intake from food records, there is a strong need for a comprehensive nitrate content of vegetables database. A systematic literature search (1980-2016) was performed using Medline, Agricola and Commonwealth Agricultural Bureaux abstracts databases. The nitrate content of vegetables database contains 4237 records from 255 publications with data on 178 vegetables and 22 herbs and spices. The nitrate content of individual vegetables ranged from Chinese flat cabbage (median; range: 4240; 3004-6310 mg/kg FW) to corn (median; range: 12; 5-1091 mg/kg FW). The database was applied to estimate vegetable nitrate intake using 24-h dietary recalls (24-HDRs) and food frequency questionnaires (FFQs). Significant correlations were observed between urinary nitrate excretion and 24-HDR (r = 0.4, P = 0.013), between 24-HDR and 12 month FFQs (r = 0.5, P < 0.001) as well as two 4 week FFQs administered 8 weeks apart (r = 0.86, P < 0.001). This comprehensive nitrate database allows quantification of dietary nitrate from a large variety of vegetables. It can be applied to dietary records to explore the associations between nitrate intake and health outcomes in human studies.


Education and occupations preceding Parkinson disease: a population-based case-control study.
To investigate the association of Parkinson disease (PD) with education and occupations using a case-control study design. The authors used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control. The authors collected information about education and occupations using two independent sources of data: a review of the complete medical records in the system and a telephone interview. Occupations were coded using the 1980 Standard Occupational Classification. Subjects with 9 or more years of education were at increased risk of PD (OR = 2.0; 95% CI = 1.1 to 3.6; p = 0.02), and there was a trend of increasing risk with increasing education (test for linear trend, p = 0.02; medical records data). Physicians were at significantly increased risk of PD using both sources of occupational data. By contrast, four occupational groups showed a significantly decreased risk of PD using one source of data: construction and extractive workers (e.g., miners, oil well drillers), production workers (e.g., machine operators, fabricators), metal workers, and engineers. These associations with increased or decreased risk did not change noticeably after adjustment for education. Subjects with higher education and physicians have an increased risk of Parkinson disease (PD), while subjects with some occupations presumed to involve high physical activity have a decreased risk of PD.


An electron microscope study of the epithelium in the normal mature and immature mouse cornea.
1. An electron microscope study at high resolution of the corneal epithelium of the normal mature and immature mouse revealed new information regarding the submicroscopic appearance of these cells. 2. Two thin dense lines separated by a less dense area constituted the structure of the limiting surface membrane of epithelial cells; the thickness of this membrane was about 80 A. 3. Some differences in the appearance of the cytoplasm and mitochondria of cells from the immature mouse cornea and the appearance of the cytoplasm and mitochondria of cells from the adult mouse cornea were observed. 4. The basement membrane appeared as a dense band about 600 A wide separating the basal epithelial cells from the substantia propria. Suggestions of periodicity were seen in some phosphotungstic acid-treated specimens. 5. Round bodies believed to be bacteria were seen on the surface of the outer epithelial cells in the adult mouse cornea but not in the immature, unopened eye.


The NGFI-B protein, an inducible member of the thyroid/steroid receptor family, is rapidly modified posttranslationally.
The NGFI-B gene is rapidly activated by a variety of stimuli that induce cells to differentiate or proliferate. It encodes a protein with a predicted molecular mass of congruent to 61 kDa and is a member of the thyroid/steroid hormone receptor gene family. To characterize this protein, monoclonal antibodies were raised against a bacterial TrpE-NGFI-B fusion protein that encompasses a large portion (Glu-410 to Leu-527) of the carboxy-terminal domain of NGFI-B. These antibodies detected a protein that was rapidly synthesized in response to nerve growth factor (NGF) and migrated as a broad band on sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular mass that ranged from 63 to 88 kDa. Pulse-chase analysis demonstrated that NGFI-B was rapidly posttranslationally modified and was a short-lived protein. NGFI-B was found to be a phosphorylated protein, and the multiple NGFI-B species coalesced into a single, more rapidly migrating species when treated with alkaline phosphatase. PC12 cells grown in the absence of NGF contained low levels of NGFI-B that was underphosphorylated. Epidermal growth factor, phorbol ester, and the calcium ionophore A23187 stimulated the synthesis of NGFI-B that was composed largely of underphosphorylated, rapidly migrating species. In contrast, basic fibroblast growth factor, which promotes differentiation of PC12 cells, induced the synthesis of NGFI-B species similar to those synthesized in response to NGF treatment. The underphosphorylated NGFI-B found in uninduced PC12 cells was found only in the nucleus, whereas NGFI-B in NGF-stimulated PC12 cells was present in approximately equal quantities in the cytoplasm and nucleus. Consistent with the cellular distribution observed in nonstimulated PC12 cells, the highly phosphorylated species were predominantly cytoplasmic whereas the more rapidly migrating forms were nuclear.


Efficacy of local lidocaine application on anxiety and depression and its curative effect on patients with chronic tension-type headache.
Tension-type headache (TTH) is a primary headache disorder. In this study, the efficacy of local lidocaine application on anxiety and depression and its curative effect in patients with chronic TTH was investigated. Forty-eight patients (24 local lidocaine injection, 24 local saline injection group) with chronic TTH were enrolled in our study. Injections were applied to the trigger points of the muscles that are innervated by C1-C3 and the trigeminal nerve, exit points of the fifth cranial nerve, and around the superior cervical ganglion. Each patient underwent one session every 3 days. Patients were evaluated before and 3 months after the treatment. In both groups, the number of painful days in a month, visual analogue scale values, amount of analgesic use in a month, Hamilton depression score, and Hamilton anxiety score decreased after the treatment. As a result, all of the parameters were found to have improved in both groups (p < 0.05), the results were statistically significant, and the lidocaine group's response to the treatment was better than the placebo group (p < 0.001). Our findings suggest that local lidocaine administration can be an effective method in the treatment of chronic TTH.


Color coding in the primate visual pathway: a historical view.
The physiology and anatomy of the primate visual pathway are reviewed from a historical perspective, especially in relation to color vision. From the work of the last decades, certain issues have been selected which remain unresolved and still pose a challenge for neurobiologists and psychophysicists. It is suggested that the structure of the primate visual pathway has been colored by the evolution of trichromacy and that many features of the parvocellular pathway represent adaptations to this end.


Mitochondrial dysfunction in Parkinson's disease.
Parkinson's disease (PD) is a progressive, neurodegenerative condition that has increasingly been linked with mitochondrial dysfunction and inhibition of the electron transport chain. This inhibition leads to the generation of reactive oxygen species and depletion of cellular energy levels, which can consequently cause cellular damage and death mediated by oxidative stress and excitotoxicity. A number of genes that have been shown to have links with inherited forms of PD encode mitochondrial proteins or proteins implicated in mitochondrial dysfunction, supporting the central involvement of mitochondria in PD. This involvement is corroborated by reports that environmental toxins that inhibit the mitochondrial respiratory chain have been shown to be associated with PD. This paper aims to illustrate the considerable body of evidence linking mitochondrial dysfunction with neuronal cell death in the substantia nigra pars compacta (SNpc) of PD patients and to highlight the important need for further research in this area.


Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years.
The incidence of nonmelanoma skin cancer is increasing rapidly among elderly persons, but little is known about its incidence in the population younger than 40 years. To estimate the sex- and age-specific incidences of basal cell carcinoma and squamous cell carcinoma in persons younger than 40 years in Olmsted County, Minnesota, and to evaluate change in incidence over time; to describe the clinical presentation, rate of recurrence and metastasis, and histologic characteristics of these tumors in this population-based sample. Population-based retrospective incidence case review. Residents of Olmsted County, Minnesota, a population with comprehensive medical records captured through the Rochester Epidemiology Project. Patients younger than 40 years with basal cell carcinoma or squamous cell carcinoma diagnosed between 1976 and 2003. Incident basal cell carcinomas and squamous cell carcinomas and change in incidence of these tumors over time. During the study period, 451 incident basal cell carcinomas were diagnosed in 417 patients and 70 incident squamous cell carcinomas were diagnosed in 68 patients. Of these tumors, 328 were histologically confirmed basal cell carcinomas and 51 were histologically confirmed squamous cell carcinomas. Overall, the age-adjusted incidence of basal cell carcinoma per 100,000 persons was 25.9 (95% confidence interval [CI], 22.6-29.2) for women and 20.9 (95% CI, 17.8-23.9) for men. The incidence of basal cell carcinoma increased significantly during the study period among women (P<.001) but not men (P = .19). Nodular basal cell carcinoma was the most common histologic subtype; 43.0% of tumors were solely nodular basal cell carcinoma and 11.0% had a mixed composition, including the nodular subtype. The incidence of squamous cell carcinoma was similar in men and women, with an average age- and sex-adjusted incidence per 100 000 persons of 3.9 (95% CI, 3.0-4.8); the incidence of squamous cell carcinoma increased significantly over the study period among both women (P = .01) and men (P = .04). This population-based study demonstrated an increase in the incidence of nonmelanoma skin cancer among young women and men residing in Olmsted County, Minnesota. There was a disproportionate increase in basal cell carcinoma in young women. This increase may lead to an exponential increase in the overall occurrence of nonmelanoma skin cancers over time as this population ages, which emphasizes the need to focus on skin cancer prevention in young adults.