Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of 'off' episodes in patients with Parkinson's disease.
Patients receiving levodopa for Parkinson's disease experience motor fluctuations and immobility ('off' episodes) between doses. This study assessed adjunctive Zelapar (selegiline orally disintegrating tablet (ODT)) for managing off episodes and for long-term safety. This open-label extension evaluated long-term safety, efficacy, and tolerability of adjunctive selegiline ODT 2.5 mg in patients who completed either of two large phase 3 double-blind studies. The study was to end after 12 months but was amended to be open-ended. Investigators could increase levodopa doses and introduce controlled-release formulations of levodopa or dopamine agonists if warranted. Additionally, results of a small randomized trial of open-label selegiline ODT 1.25 mg in comparison to conventional selegiline was added only to the safety analysis. Efficacy variables included changes in daily off time and Patient's Global Impression of Improvement (PGI-I) and Clinical Global Impressions Severity of Disease (CGI-S) ratings. Safety assessments included adverse events and oropharyngeal findings. This study enrolled 254 patients: 248 from the large phase 3 studies (efficacy analysis) and an additional six from the prior open-label comparison (safety analysis) in order to evaluate a larger population for safety purposes. Mean reduction from baseline in daily off time was 9.4% (1.6 h) for patients previously given selegiline ODT, 6.0% (1.2 h) for those switched from placebo, and 8.1% (1.4 h) overall. PGI-I and CGI-S ratings indicated little or no change from baseline. Treatment-related adverse events occurred in 132 (52%) patients. No severe oral irritations were attributed to selegiline ODT or prompted discontinuation. Long-term selegiline ODT 2.5 mg/day was effective, safe, and well tolerated in patients with Parkinson's disease experiencing off episodes during levodopa therapy.


Stomach fermentation in East African Colobus monkeys in their natural state.
The microbial fermentation in the stomachs of two monkeys, Colobus polykomos, collected in Kenya, was studied. The gas accumulated within the stomach contained H(2) but no CH(4). Volatile fatty acid concentrations were high, but accumulated acid prevented determination of the fermentation rate in untreated, incubated stomach contents. Upon addition of bicarbonate, a very rapid rate could be demonstrated. Some D- and L-lactate were in the stomach contents. Starchy seeds or fruits rather than leaves appeared to have been consumed. Microscopically, the most prominent microorganisms seen were large, very refringent cocci, possibly Sarcina ventriculi, and various smaller cocci and rods. The 28 cultured strains of bacteria included 14 Staphylococcus, 2 Streptococcus, 10 Propionibacterium, and 2 Peptostreptococcus. The culture count constituted 10 to 20% of the direct count. No protozoa or cellulolytic bacteria were found.


Long-term durability of resin dentin interface: nanoleakage vs. microtensile bond strength.
This study tested the hypothesis that long-term durability of resin bonds to dentin is directly related to the nanoleakage of dentin bonding systems. Extracted human third molars were ground flat with 600-grit SiC paper under running water to expose middle dentin. Clearfil Liner Bond 2V (LB2V) or Fluoro Bond (FB) was applied to dentin surfaces according to the manufacturer's instructions. A crown was built-up with Clearfil AP-X resin composite, and the specimens were stored in water for 24 hours at 37 degrees C. The bonded assemblies were vertically sectioned into approximately 0.7 mm thick slabs and trimmed for microtensile bond test. All slabs were immersed in individual bottles of water at 37 degrees C, which was changed every day. Specimens were incubated for one day, and three, six, and nine months, and at the specified time period, they were randomly divided to two subgroups: 50% AgNO3 and the control. In the 50% AgNO3 subgroup, the slabs were immersed for one hour in 50% AgNO3, followed by exposure in a photo-developing solution for 12 hours just prior to debonding. The specimens in the control subgroup were soaked in water until debonding. Then, all specimens were subjected to microtensile bond testing. The debonded specimens of the AgNO3 subgroup had micrographs subjected to image analysis by NIH Image PC (Scion, Fredrick, MD, USA), and the area of silver penetration was quantitated. The bond strength data and silver penetration areas were subjected to two- and three-way ANOVA and Fisher's PLSD test at the 95% level of confidence. Regression analysis was used to test the relationship between bond strengths and the silver penetration area at each time period. For both adhesive systems, the bond strengths gradually decreased over time, although there were no statistically significant differences in the FB bond strength among the four time periods tested (p>0.05). Silver penetration in specimens bonded with LB2V and FB gradually increased over time. Regression analysis showed a higher correlation between bond strength and silver penetration at 9 months for specimens bonded with LB2V (R2=0.844) than at shorter time periods. The authors speculate that hydrolytic degradation within the hybrid layer gradually increased due to water penetration through nanoleakage channels, resulting in lower bond strengths and interfacial failure after as little as nine months.


The action of stabilizing selection, mutation, and drift on epistatic quantitative traits.
For a quantitative trait under stabilizing selection, the effect of epistasis on its genetic architecture and on the changes of genetic variance caused by bottlenecking were investigated using theory and simulation. Assuming empirical estimates of the rate and effects of mutations and the intensity of selection, we assessed the impact of two-locus epistasis (synergistic/antagonistic) among linked or unlinked loci on the distribution of effects and frequencies of segregating loci in populations at the mutation-selection-drift balance. Strong pervasive epistasis did not modify substantially the genetic properties of the trait and, therefore, the most likely explanation for the low amount of variation usually accounted by the loci detected in genome-wide association analyses is that many causal loci will pass undetected. We investigated the impact of epistasis on the changes in genetic variance components when large populations were subjected to successive bottlenecks of different sizes, considering the action of genetic drift, operating singly (D), or jointly with mutation (MD) and selection (MSD). An initial increase of the different components of the genetic variance, as well as a dramatic acceleration of the between-line divergence, were always associated with synergistic epistasis but were strongly constrained by selection.


Contemporary celiac disease diagnosis: is a biopsy avoidable?
The duodenal biopsy is the gold standard for the diagnosis of celiac disease. However, given improvements in the performance of serological testing, the possibility of accurately diagnosing celiac disease without the need of a biopsy has attracted interest. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition has revised its recommendations to include a diagnostic algorithm that includes sequential serological testing and human leukocyte antigen genotyping for symptomatic children which would enable a diagnosis of celiac disease to be made in the absence of a confirmatory intestinal biopsy. Recent studies have evaluated the ESPGHAN guidelines and have mostly corroborated that celiac disease can be accurately diagnosed in specific pediatric patient populations without the need of a biopsy. However, two cautionary points have been raised that warrant further consideration - the success of this approach is highly dependent targeting a population with a high pretest probability of celiac disease, as well, the performance of serology assays must be established and the appropriate use of cutoffs is essential. The duodenal biopsy will remain the gold standard for diagnosing celiac disease in a majority of patients. However, as serology assays evolve and as a greater understanding of the genetic risk factors of celiac disease is achieved, more patients may be accurately diagnosed without the need for a biopsy.


DNMT3A Mutational Status Affects the Results of Dose-Escalated Induction Therapy in Acute Myelogenous Leukemia.
DNA methyltransferase 3A (DNMT3A) is one of the commonly mutated genes in acute myelogenous leukemia (AML). Reports on the prognostic significance of DNMT3A mutations have been inconsistent, and most of the data are available only for patients 60 years of age or younger. We hypothesized that this inconsistency is due to an interaction between the dose of anthracycline used in induction therapy and DNMT3A status. We studied whether patients with DNMT3A-mutated AML treated with standard dose anthracyclines had an inferior survival compared with patients with other mutation profiles or those who received high-dose therapy. A total of 152 patients in this retrospective cohort study (median age, 54 years) with de novo AML underwent induction therapy and next-generation sequencing of 33 commonly mutated genes in hematologic malignancies, including DNMT3A, FLT3-ITD, NPM1, and IDH1/2. Cox regression was used to know whether those with DNMT3A mutations who were treated with standard dose anthracycline had inferior survival. DNMT3A mutations, found in 32% of patients, were not associated with an inferior survival. Dose escalation of anthracycline in the induction regimen was associated with improved survival in those with DNMT3A mutations but not those with wild-type DNMT3A. Patients with DNMT3A mutations who received standard dose induction had shorter survival time than other patient groups (10.1 months vs. 19.8 months, P = 0.0129). This relationship remained significant (HR, 1.90; P = 0.006) controlling for multiple variables. Patients with DNMT3A-mutated AML have an inferior survival when treated with standard-dose anthracycline induction therapy. This group should be considered for high-dose induction therapy.


Effects of aquatic and dry land resistance training devices on body composition and physical capacity in postmenopausal women.
TO DETERMINE THE EFFECTS OF A SUPERVISED STRENGTH TRAINING PROGRAM ON BODY COMPOSITION AND PHYSICAL CAPACITY OF OLDER WOMEN USING THREE DIFFERENT DEVICES: weight machines, elastic bands, and aquatic devices that increase drag forces (ADIDF). Four groups were formed: control group, weight machine group (WMG), elastic band group (EBG) and a group that used ADIDF (ADIDFG). Body composition and physical capacity were assessed before and after the intervention period. The ADIDFG showed improvements in fat mass (FM), fat-free mass of the left arm (FFM-LA) and right arm (FFM-RA), knee push-up test (KPT), squat test (ST) and crunch test (CT) (p <0.05). Individuals in the EBG and WMG also improved their FM, fat free mass (FFM), FFM-LA, FFM-RA, KPU, ST and CT. ADIDF training improves body composition and physical capacity of postmenopausal women as does performing land-based training programs.


Contribution of large region joint associations to complex traits genetics.
A polygenic model of inheritance, whereby hundreds or thousands of weakly associated variants contribute to a trait's heritability, has been proposed to underlie the genetic architecture of complex traits. However, relatively few genetic variants have been positively identified so far and they collectively explain only a small fraction of the predicted heritability. We hypothesized that joint association of multiple weakly associated variants over large chromosomal regions contributes to complex traits variance. Confirmation of such regional associations can help identify new loci and lead to a better understanding of known ones. To test this hypothesis, we first characterized the ability of commonly used genetic association models to identify large region joint associations. Through theoretical derivation and simulation, we showed that multivariate linear models where multiple SNPs are included as independent predictors have the most favorable association profile. Based on these results, we tested for large region association with height in 3,740 European participants from the Health and Retirement Study (HRS) study. Adjusting for SNPs with known association with height, we demonstrated clustering of weak associations (p = 2x10-4) in regions extending up to 433.0 Kb from known height loci. The contribution of regional associations to phenotypic variance was estimated at 0.172 (95% CI 0.063-0.279; p < 0.001), which compared favorably to 0.129 explained by known height variants. Conversely, we showed that suggestively associated regions are enriched for known height loci. To extend our findings to other traits, we also tested BMI, HDLc and CRP for large region associations, with consistent results for CRP. Our results demonstrate the presence of large region joint associations and suggest these can be used to pinpoint weakly associated SNPs.


Effects of Thymus serpyllum extract on cell proliferation, apoptosis and epigenetic events in human breast cancer cells.
Thymus (T.) serpyllum (wild thyme) is an aromatic medicinal plant due to its several biological properties, including anticancer activity. Breast cancer is one of the most common malignancies and increasing evidence supports that it is not only a genetic but also an epigenetic disease. Epigenetics investigates changes in gene expression caused by mechanisms that do not involve alterations in DNA sequence. DNA methylation and histone acetylation are the most widely studied epigenetic changes in cancer cells. This study evaluated the effects of T. serpyllum on apoptosis and epigenetic events in breast cancer cells. XTT cell viability assay was used to determine cytotoxicity. DNA fragmentation and caspase 3/7 activity assays were used in the assesment of apoptosis. DNA methyltransferase (DNMT) and histone deacetylase (HDAC) activities were evaluated by ELISA and verified by qRT-PCR. T. serpyllum extract induced significant cytotoxicity in breast cancer cells (MCF-7 and MDA-MB-231) but not in normal cells. It also induced apoptosis and inhibited the DNMT and HDAC activities in MDA-MB-231 cells. In the present study, the first preliminary data on the effects of the methanolic extract of T. serpyllum in normal and breast cancer cells were obtained and suggest that T. serpyllum may be a promising candidate in the development of novel therapeutic drugs for breast cancer treatment.


Pathogenesis and outcome of extrahepatic biliary obstruction in cats.
Extrahepatic biliary obstruction (EHBO) was confirmed at surgery or necropsy in 22 cats. Biliary or pancreatic adenocarcinoma was diagnosed by histopathology in six cats and one cat had an undiagnosed mass in the common bile duct. The remaining 15 cats had at least one of a complex of inflammatory diseases including pancreatitis, cholangiohepatitis, cholelithiasis and cholecystitis. The most common clinical signs were jaundice, anorexia, lethargy, weight loss and vomiting. Hyperbilirubinaemia was present in all cases. Distension of the common bile duct and gall bladder was the most commonly observed finding on abdominal ultrasound. Nineteen cats underwent exploratory laparotomy for biliary decompression and diversion. Mortality in cats with underlying neoplasia was 100 per cent and, in those with non-neoplastic lesions, was 40 per cent. Long-term complications, in those that survived, included recurrence of cholangiohepatitis, chronic weight loss and recurrence of obstruction. Based on these findings, the prognosis for EHBO in cats must be considered guarded.


VDR and VDBP genes polymorphisms associated with susceptibility to tuberculosis in a Han Taiwanese population.
The active metabolite (1, 25-dihydroxycholecalciferol) of vitamin D (25-hydroxycholecalciferol) leads to the activation of macrophages and the deficiency of vitamin D seems to be involved in the risk of tuberculosis (TB). The effects of vitamin D are exerted by interaction with the vitamin D receptor (VDR) and vitamin D receptor binding protein (VDBP) may be influenced by polymorphisms in the VDR and VDBP genes. In this study, variation in the VDR and VDBP genes was investigated in a Taiwanese population with TB. We typed four VDR polymorphisms of restriction endonuclease sites for ApaI, TaqI, BsmI, and FokI and three VDBP polymorphisms-Thr420Lys, Asp416Glu, and Cys299Cys-in 198 patients with TB and 170 healthy volunteers. VDR TaqI, VDR BsmI, and VDBP Asp416Glu were significantly associated with TB susceptibility. Odd ratios of risk genotypes of the above three polymorphisms were 2.16 (95% confidence interval 1.01, 4.65), 2.14 (95% confidence interval 1.06, 4.31), and 2.24 (95% confidence interval 1.04, 4.80), respectively. VDBP haplotype analysis showed Gc1f carriers associated to TB. The polymorphisms in the VDR and VDBP genes appeared to be responsible for host susceptibility to human TB in a Taiwanese population.


Virtual framing: the feasibility of frameless radiosurgical planning for the Gamma Knife.
Gamma Knife (GK) treatments are typically delivered in 1 day with little opportunity to test different planning strategies. The authors demonstrate 2 methods for imposing GK coordinate systems upon imaging datasets without frame attachment to allow leisurely preprocedural planning, and discuss potential applications. A "virtual framing" is constructed by coregistering a CT scan of a Leksell frame with a patient dataset using the GammaPlan (Multiview) module. Equations for skull radii are derived by approximating the skull as an ellipsoid. No proprietary software other than that of the GK system is required. In a second method, images of fiducial markers are directly superimposed on the patient dataset. Validation of the first method was achieved by comparing the lengths of 75 line segments and 60 single shot diameters measured in the virtual coordinates with those measured in real coordinates. In addition to preplanning, 2 applications are discussed. The first is the use of GK software to aid radiosurgical planning for other devices. The second is the use of virtual framing to enhance automatic optimization algorithms. Mean (+/- standard deviation) and root-mean-square differences in lengths were 0.18 +/- 0.32 and 0.37 mm. Mean and root-mean-square differences in diameters of single-shot plans were 0.01 +/- 0.18 and 0.18 mm. Virtual framing allows exploration of radiosurgical planning strategies prior to the day of treatment using only the GK software. Other applications include enhancement of radiosurgical planning for other systems and enhancement of optimization algorithms.


Physiological and morphological changes during early and later stages of fruit growth in Capsicum annuum.
Fruit-set involves a series of physiological and morphological changes that are well described for tomato and Arabidopsis, but largely unknown for sweet pepper (Capsicum annuum). The aim of this paper is to investigate whether mechanisms of fruit-set observed in Arabidopsis and tomato are also applicable to C. annuum. To do this, we accurately timed the physiological and morphological changes in a post-pollinated and un-pollinated ovary. A vascular connection between ovule and replum was observed in fertilized ovaries that undergo fruit development, and this connection was absent in unfertilized ovaries that abort. This indicates that vascular connection between ovule and replum is an early indicator for successful fruit development after pollination and fertilization. Evaluation of histological changes in the carpel of a fertilized and unfertilized ovary indicated that increase in cell number and cell diameter both contribute to early fruit growth. Cell division contributes more during early fruit growth while cell expansion contributes more at later stages of fruit growth in C. annuum. The simultaneous occurrence of a peak in auxin concentration and a strong increase in cell diameter in the carpel of seeded fruits suggest that indole-3-acetic acid stimulates a major increase in cell diameter at later stages of fruit growth. The series of physiological and morphological events observed during fruit-set in C. annuum are similar to what has been reported for tomato and Arabidopsis. This indicates that tomato and Arabidopsis are suitable model plants to understand details of fruit-set mechanisms in C. annuum.


LipL46 is a novel surface-exposed lipoprotein expressed during leptospiral dissemination in the mammalian host.
Leptospirosis is a widespread zoonosis caused by invasive spirochaetes belonging to the genus Leptospira. Pathogenic leptospires disseminate via the bloodstream to colonize the renal tubules of reservoir hosts. Little is known about leptospiral outer-membrane proteins expressed during the dissemination stage of infection. In this study, a novel surface-exposed lipoprotein is described; it has been designated LipL46 to distinguish it from a previously described 31 kDa peripheral membrane protein, P31(LipL45), which is exported as a 45 kDa probable lipoprotein. The lipL46 gene encodes a 412 aa polypeptide with a 21 aa signal peptide. Lipid modification of cysteine at the lipoprotein signal peptidase cleavage site FSISC is supported by the finding that Leptospira interrogans intrinsically labels LipL46 during incubation in medium containing [(14)C]palmitate. LipL46 appears to be exported to the leptospiral outer membrane as a 46 kDa lipoprotein, based on Triton X-114 solubilization and phase partitioning studies, which included the outer and inner membrane controls LipL32 and LipL31, respectively. Surface immunoprecipitation and whole-cell ELISA experiments indicate that LipL46 is exposed on the leptospiral surface. Immunohistochemistry studies demonstrated expression of LipL46 by leptospires found in the bloodstream of acutely infected hamsters. Leptospires expressing LipL46 were also found in the intercellular spaces of the liver, within splenic phagocytes, and invading the glomerular hilum of the kidney. Infection-associated expression is supported by the finding that LipL46 is a major antigen recognized by sera from infected hamsters. These findings indicate that LipL46 may be important in leptospiral dissemination, and that it may serve as a useful serodiagnostic antigen.


Future premature mortality due to O3, secondary inorganic aerosols and primary PM in Europe--sensitivity to changes in climate, anthropogenic emissions, population and building stock.
Air pollution is an important environmental factor associated with health impacts in Europe and considerable resources are used to reduce exposure to air pollution through emission reductions. These reductions will have non-linear effects on exposure due, e.g., to interactions between climate and atmospheric chemistry. By using an integrated assessment model, we quantify the effect of changes in climate, emissions and population demography on exposure and health impacts in Europe. The sensitivity to the changes is assessed by investigating the differences between the decades 2000-2009, 2050-2059 and 2080-2089. We focus on the number of premature deaths related to atmospheric ozone, Secondary Inorganic Aerosols and primary PM. For the Nordic region we furthermore include a projection on how population exposure might develop due to changes in building stock with increased energy efficiency. Reductions in emissions cause a large significant decrease in mortality, while climate effects on chemistry and emissions only affects premature mortality by a few percent. Changes in population demography lead to a larger relative increase in chronic mortality than the relative increase in population. Finally, the projected changes in building stock and infiltration rates in the Nordic indicate that this factor may be very important for assessments of population exposure in the future.


Severe hemorrhagic colitis in a patient with chronic myeloid leukemia in the blastic phase after dasatinib use.
Dasatinib is a second-line tyrosine kinase inhibitor used in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia. Gastrointestinal bleeding may occur in up to 7% of patients using dasatinib, although, severe dasatinib-related acute colitis had rarely been reported. Here, we present the case of a 36-year-old female who progressed to acute myeloid leukemia after fourteen months of receiving imatinib for CML in the chronic phase and was treated with a dasatinib-containing chemotherapy regimen. On day 34 of treatment, the patient developed moderate abdominal pain and bloody diarrhea with mucous. Analyses of stool specimens were negative for parasites, Clostridium difficile, and other pathogenic bacteria. The cytomegalovirus pp65 antigen was negative in her blood leukocytes. A colonoscopy revealed acute colitis, and a mucosal biopsy showed nonspecific colitis. The patient was treated with broad-spectrum antibiotics, bowel rest and hydration, and dasatinib treatment was stopped. Her bloody diarrhea improved within 72 h. After confirming cytological remission, the patient received initial course of consolidation, and dasatinib treatment was reinstated. However, hemorrhagic colitis recurred. After discontinuing dasatinib, herhemorrhagic colitis drastically improved and did not recur following the administration of nilotinib. The characteristics of our patient suggest that dasatinib treatment can lead to hemorrhagic colitis, which typically resolves after discontinuation of the drug.


Energy transfer in light-harvesting complexes LHCII and CP29 of spinach studied with three pulse echo peak shift and transient grating.
Three pulse echo peak shift and transient grating (TG) measurements on the plant light-harvesting complexes LHCII and CP29 are reported. The LHCII complex is by far the most abundant light-harvesting complex in higher plants and fulfills several important physiological functions such as light-harvesting and photoprotection. Our study is focused on the light-harvesting function of LHCII and the very similar CP29 complex and reveals hitherto unresolved excitation energy transfer processes. All measurements were performed at room temperature using detergent isolated complexes from spinach leaves. Both complexes were excited in their Chl b band at 650 nm and in the blue shoulder of the Chl a band at 670 nm. Exponential fits to the TG and three pulse echo peak shift decay curves were used to estimate the timescales of the observed energy transfer processes. At 650 nm, the TG decay can be described with time constants of 130 fs and 2.2 ps for CP29, and 300 fs and 2.8 ps for LHCII. At 670 nm, the TG shows decay components of 230 fs and 6 ps for LHCII, and 300 fs and 5 ps for CP29. These time constants correspond to well-known energy transfer processes, from Chl b to Chl a for the 650 nm TG and from blue (670 nm) Chl a to red (680 nm) Chl a for the 670 nm TG. The peak shift decay times are entirely different. At 650 nm we find times of 150 fs and 0.5-1 ps for LHCII, and 360 fs and 3 ps for CP29, which we can associate mainly with Chl b <--> Chl b energy transfer. At 670 nm we find times of 140 fs and 3 ps for LHCII, and 3 ps for CP29, which we can associate with fast (only in LHCII) and slow transfer between relatively blue Chls a or Chl a states. From the occurrence of both fast Chl b <--> Chl b and fast Chl b --> Chl a transfer in CP29, we conclude that at least two mixed binding sites are present in this complex. A detailed comparison of our observed rates with exciton calculations on both CP29 and LHCII provides us with more insight in the location of these mixed sites. Most importantly, for CP29, we find that a Chl b pair must be present in some, but not all, complexes, on sites A(3) and B(3). For LHCII, the observed rates can best be understood if the same pair, A(3) and B(3), is involved in both fast Chl b <--> Chl b and fast Chl a <--> Chl a transfer. Hence, it is likely that mixed sites also occur in the native LHCII complex. Such flexibility in chlorophyll binding would agree with the general flexibility in aggregation form and xanthophyll binding of the LHCII complex and could be of use for optimizing the role of LHCII under specific circumstances, for example under high-light conditions. Our study is the first to provide spectroscopic evidence for mixed binding sites, as well as the first to show their existence in native complexes.


Estradiol increases spine density and NMDA-dependent Ca2+ transients in spines of CA1 pyramidal neurons from hippocampal slices.
To investigate the physiological consequences of the increase in spine density induced by estradiol in pyramidal neurons of the hippocampus, we performed simultaneous whole cell recordings and Ca2+ imaging in CA1 neuron spines and dendrites in hippocampal slices. Four- to eight-days in vitro slice cultures were exposed to 17beta-estradiol (EST) for an additional 4- to 8-day period, and spine density was assessed by confocal microscopy of DiI-labeled CA1 pyramidal neurons. Spine density was doubled in both apical and basal dendrites of the CA1 region in EST-treated slices; consistently, a reduction in cell input resistance was observed in EST-treated CA1 neurons. Double immunofluorescence staining of presynaptic (synaptophysin) and postsynaptic (alpha-subunit of CaMKII) proteins showed an increase in synaptic density after EST treatment. The slopes of the input/output curves of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) postsynaptic currents were steeper in EST-treated CA1 neurons, consistent with the observed increase in synapse density. To characterize NMDA-dependent synaptic currents and dendritic Ca2+ transients during Schaffer collaterals stimulation, neurons were maintained at +40 mV in the presence of nimodipine, picrotoxin, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). No differences in resting spine or dendritic Ca2+ levels were observed between control and EST-treated CA1 neurons. Intracellular Ca2+ transients during afferent stimulation exhibited a faster slope and reached higher levels in spines than in adjacent dendrites. Peak Ca2+ levels were larger in both spines and dendrites of EST-treated CA1 neurons. Ca2+ gradients between spine heads and dendrites during afferent stimulation were also larger in EST-treated neurons. Both spine and dendritic Ca2+ transients during afferent stimulation were reversibly blocked by D, L-2-amino-5-phosphonovaleric acid (D,L-APV). The increase in spine density and the enhanced NMDA-dependent Ca2+ signals in spines and dendrites induced by EST may underlie a threshold reduction for induction of NMDA-dependent synaptic plasticity in the hippocampus.


Biosynthesis of C9-aldehydes in the moss Physcomitrella patens.
After wounding, the moss Physcomitrella patens emits fatty acid derived volatiles like octenal, octenols and (2E)-nonenal. Flowering plants produce nonenal from C18-fatty acids via lipoxygenase and hydroperoxide lyase reactions, but the moss exploits the C20 precursor arachidonic acid for the formation of these oxylipins. We describe the isolation of the first cDNA (PpHPL) encoding a hydroperoxide lyase from a lower eukaryotic organism. The physiological pathway allocation and characterization of a downstream enal-isomerase gives a new picture for the formation of fatty acid derived volatiles from lower plants. Expression of a fusion protein with a yellow fluorescent protein in moss protoplasts showed that PpHPL was found in clusters in membranes of plastids. PpHPL can be classified as an unspecific hydroperoxide lyase having a substrate preference for 9-hydroperoxides of C18-fatty acids but also the predominant substrate 12-hydroperoxy arachidonic acid is accepted. Feeding experiments using arachidonic acid show an increase in the 12-hydroperoxide being metabolized to C8-aldehydes/alcohols and (3Z)-nonenal, which is rapidly isomerized to (2E)-nonenal. PpHPL knock out lines failed to emit (2E)-nonenal while formation of C8-volatiles was not affected indicating that in contrast to flowering plants, PpHPL is only involved in formation of a specific subset of volatiles.


PHC re-engineering may relieve overburdened tertiary hospitals in South Africa.
Under the National Health Insurance, a hospital is expected to provide service to patients based on its category. However, in reality the tertiary hospitals offer every level of care, resulting in poor quality of care and over-expenditure. The Polokwane/Mankweng Hospital Complex is a provincial tertiary hospital that delivers tertiary care as well as dealing with some secondary and primary care cases. This study evaluated the hospital casualty department in the Polokwane/Mankweng Hospital Complex. A sample of 250 patients' records was selected by simple random sampling from a cohort of 14 113 patients who attended the Polokwane Hospital Casualty Department during the 1-year study period. Most patients were admitted in the casualty department as a result of injuries (25%). Only 20% (N=51) of the patients were referred from other health facilities. Half of the patients could have been managed at a regional or district hospital. The overall expenditure for the casualty unit during the 1-year study period was R10 321 401.42 and the combined unit cost was estimated at R731.34 per single emergency care patient excluding the capital costs. Referral systems must be strengthened to manage patients at regional and district level to reduce the burden on the Polokwane/Mankweng Hospital Complex. It is hoped that the Primary Health Care (PHC) Re-engineering Policy will address this by strengthening the referral system in PHC facilities.


Measurement of tumour protein synthesis in vivo in human colorectal and breast cancer and its variability in separate biopsies from the same tumour.
1. A method is described for measuring the rates of protein synthesis in vivo in human colorectal and breast tumours by the intravenous injection of L-[1-13C]leucine as a 'flooding dose'. 2. The incorporation of isotope into colorectal tumour protein was measured in six patients, whose tumours were biopsied after the injection. Fractional rates of protein synthesis were calculated from the enrichment of leucine in protein and the average free leucine enrichment in plasma. The range of rates obtained was 17.2-33.9%/day, with a mean rate (+/- SEM) of 22.5 +/- 2.6%/day. 3. Tumour protein synthesis rates were also measured in 15 patients with breast cancer. The range of rates obtained was 5.3-15.9%/day, with a mean rate (+/- SEM) of 10.3 +/- 0.8%/day. These rates are significantly lower than those obtained with colorectal tumours (P less than 0.001). 4. In 9 of the breast cancer patients, protein synthesis was measured in multiple random biopsies taken from the same tumour. The mean (+/- SEM) difference between the highest and lowest rates in biopsies from the same tumour was only 1.1 +/- 0.3%/day. Only 13% of the variation in protein synthesis between separate tumours could be explained by sampling error because of variation within the tumour itself, the remainder being genuine variation between individual tumours.


Survival after single versus bilateral lung transplantation for high-risk patients with pulmonary fibrosis.
Whether single lung transplantation (SLT) or bilateral lung transplantation (BLT) is optimal for patients with severe idiopathic pulmonary fibrosis (IPF) is unknown. We examine a large multi-institutional cohort of high-risk IPF patients to address this question. We retrospectively reviewed United Network for Organ Sharing data to identify 1,256 lung transplant (LTx) recipients with IPF between 2005 and 2007. Risk of 30-day, 90-day, and 1-year mortality for SLT versus BLT was examined across levels of the lung allocation score (LAS [both continuous with incorporation of interaction terms and categorized by LAS quartiles]). Multivariable analysis was conducted through Cox proportional hazards regression. Lung allocation score quartiles were as follows: quartile 1, 29.8 to 37.8, n = 315; quartile 2, 37.9 to 42.4, n = 313; quartile 3, 42.5 to 51.9, n = 314; and quartile 4, 52.0 to 94.1, n = 314. Overall, 21.1% more patients received BLT in the highest LAS quartile (59.5%) than in the lowest LAS quartile (38.4%, p < 0.05). In patients at highest risk, BLT was associated with a 14.4% decrease in mortality at 1 year after LTx. This survival benefit was confirmed on univariate analysis (hazard ratio 1.90 [95% confidence interval: 1.16 to 3.13], p = 0.01) and multivariable analysis (hazard ratio 2.09 [95% confidence interval: 1.07 to 4.10], p = 0.03) as well as in sensitivity analyses incorporating pulmonary hypertension and maximizing follow-up. There were no differences in the risk of death with SLT at 30 or 90 days after LTx in any quartile on unadjusted or multivariable adjusted analysis. We provide an initial examination of survival by procedure type and LAS score for LTx recipients with IPF. Bilateral LTx appears to offer advantages over SLT for high-risk patients.


Navigational decision making in Drosophila thermotaxis.
A mechanistic understanding of animal navigation requires quantitative assessment of the sensorimotor strategies used during navigation and quantitative assessment of how these strategies are regulated by cellular sensors. Here, we examine thermotactic behavior of the Drosophila melanogaster larva using a tracking microscope to study individual larval movements on defined temperature gradients. We discover that larval thermotaxis involves a larger repertoire of strategies than navigation in smaller organisms such as motile bacteria and Caenorhabditis elegans. Beyond regulating run length (i.e., biasing a random walk), the Drosophila melanogaster larva also regulates the size and direction of turns to achieve and maintain favorable orientations. Thus, the sharp turns in a larva's trajectory represent decision points for selecting new directions of forward movement. The larva uses the same strategies to move up temperature gradients during positive thermotaxis and to move down temperature gradients during negative thermotaxis. Disrupting positive thermotaxis by inactivating cold-sensitive neurons in the larva's terminal organ weakens all regulation of turning decisions, suggesting that information from one set of temperature sensors is used to regulate all aspects of turning decisions. The Drosophila melanogaster larva performs thermotaxis by biasing stochastic turning decisions on the basis of temporal variations in thermosensory input, thereby augmenting the likelihood of heading toward favorable temperatures at all times.


Toward a planning scheme for emission guided radiation therapy (EGRT): FDG based tumor tracking in a metastatic breast cancer patient.
Emission guided radiation therapy (EGRT) is a new modality that uses PET emissions in real-time for direct tumor tracking during radiation delivery. Radiation beamlets are delivered along positron emission tomography (PET) lines of response (LORs) by a fast rotating ring therapy unit consisting of a linear accelerator (Linac) and PET detectors. The feasibility of tumor tracking and a primitive modulation method to compensate for attenuation have been demonstrated using a 4D digital phantom in our prior work. However, the essential capability of achieving dose modulation as in conventional intensity modulated radiation therapy (IMRT) treatments remains absent. In this work, the authors develop a planning scheme for EGRT to accomplish sophisticated intensity modulation based on an IMRT plan while preserving tumor tracking. The planning scheme utilizes a precomputed LOR response probability distribution to achieve desired IMRT planning modulation with effects of inhomogeneous attenuation and nonuniform background activity distribution accounted for. Evaluation studies are performed on a 4D digital patient with a simulated lung tumor and a clinical patient who has a moving breast cancer metastasis in the lung. The Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm. The IMRT plan is optimized for a planning target volume (PTV) that encompasses the tumor motion using the MOSEK package and a Pinnacle3™ workstation (Philips Healthcare, Fitchburg, WI) for digital and clinical patients, respectively. To obtain the emission data for both patients, the Geant4 application for tomographic emission (GATE) package and a commercial PET scanner are used. As a comparison, 3D and helical IMRT treatments covering the same PTV based on the same IMRT plan are simulated. 3D and helical IMRT treatments show similar dose distribution. In the digital patient case, compared with the 3D IMRT treatment, EGRT achieves a 15.1% relative increase in dose to 95% of the gross tumor volume (GTV) and a 31.8% increase to 50% of the GTV. In the patient case, EGRT yields a 15.2% relative increase in dose to 95% of the GTV and a 20.7% increase to 50% of the GTV. The organs at risk (OARs) doses are kept similar or lower for EGRT in both cases. Tumor tracking is observed in the presence of planning modulation in all EGRT treatments. As compared to conventional IMRT treatments, the proposed EGRT planning scheme allows an escalated target dose while keeping dose to the OARs within the same planning limits. With the capabilities of incorporating planning modulation and accurate tumor tracking, EGRT has the potential to greatly improve targeting in radiation therapy and enable a practical and effective implementation of 4D radiation therapy for planning and delivery.


Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses.
With the global spread of the 2009 pandemic H1N1 (pH1N1) influenza virus, there are increasing worries about evolution through antigenic drift. One way previous seasonal H1N1 and H3N2 influenza strains have evolved over time is by acquiring additional glycosylations in the globular head of their hemagglutinin (HA) proteins; these glycosylations have been believed to shield antigenically relevant regions from antibody immune responses. We added additional HA glycosylation sites to influenza A/Netherlands/602/2009 recombinant (rpH1N1) viruses, reflecting their temporal appearance in previous seasonal H1N1 viruses. Additional glycosylations resulted in substantially attenuated infection in mice and ferrets, whereas deleting HA glycosylation sites from a pre-pandemic virus resulted in increased pathogenicity in mice. We then more directly investigated the interactions of HA glycosylations and antibody responses through mutational analysis. We found that the polyclonal antibody response elicited by wild-type rpH1N1 HA was likely directed against an immunodominant region, which could be shielded by glycosylation at position 144. However, rpH1N1 HA glycosylated at position 144 elicited a broader polyclonal response able to cross-neutralize all wild-type and glycosylation mutant pH1N1 viruses. Moreover, mice infected with a recent seasonal virus in which glycosylation sites were removed elicited antibodies that protected against challenge with the antigenically distant pH1N1 virus. Thus, acquisition of glycosylation sites in the HA of H1N1 human influenza viruses affected not only their pathogenicity and ability to escape from polyclonal antibodies elicited by previous influenza virus strains but also their ability to induce cross-reactive antibodies against drifted antigenic variants.


The Urgent Need for Clinical Research Reform to Permit Faster, Less Expensive Access to New Therapies for Lethal Diseases.
High costs of complying with drug development regulations slow progress and contribute to high drug prices and, hence, mounting health care costs. If it is exorbitantly expensive to bring new therapies to approval, fewer agents can be developed with available resources, impeding the emergence of urgently needed treatments and escalating prices by limiting competition. Excessive regulation produces numerous speed bumps on the road to drug authorization. Although an explosion of knowledge could fuel rapid advances, progress has been slowed worldwide by inefficient regulatory and clinical research systems that limit access to therapies that prolong life and relieve suffering. We must replace current compliance-centered regulation (appropriate for nonlethal diseases like acne) with "progress-centered regulation" in lethal diseases, where the overarching objective must be rapid, inexpensive development of effective new therapies. We need to (i) reduce expensive, time-consuming preclinical toxicology and pharmacology assessments, which add little value; (ii) revamp the clinical trial approval process to make it fast and efficient; (iii) permit immediate multiple-site trial activation when an eligible patient is identified ("just-in-time" activation); (iv) reduce the requirement for excessive, low-value documentation; (v) replace this excessive documentation with sensible postmarketing surveillance; (vi) develop pragmatic investigator accreditation; (vii) where it is to the benefit of the patient, permit investigators latitude in deviating from protocols, without requiring approved amendments; (viii) confirm the value of predictive biomarkers before requiring the high costs of IDE/CLIA compliance; and (ix) approve agents based on high phase I-II response rates in defined subpopulations, rather than mandating expensive, time-consuming phase III trials.


Diagnostic performance of fecal quantitative real-time polymerase chain reaction for detection of Lawsonia intracellularis-associated proliferative enteropathy in nursery pigs.
Quantitative polymerase chain reaction (qPCR) tests for detection and quantification of Lawsonia intracellularis in feces from pigs have been developed. The objective of the current study was to evaluate the diagnostic performance of a fecal qPCR test for detection of nursery pigs with L. intracellularis-associated proliferative enteropathy (PE) under field conditions. Furthermore, the diagnostic performance for different subpopulations of pigs was investigated, including pigs infected or noninfected with Porcine circovirus-2, Brachyspira pilosicoli, and Escherichia coli. The diagnostic performance was evaluated in terms of diagnostic sensitivity and specificity. Data from pigs originating from 20 herds with antibiotic treatment requiring diarrhea outbreaks from a prior study were reused. Before treatment, pigs were randomly selected for histological and immunohistochemical examination of intestinal segments and fecal quantification of L. intracellularis by qPCR. A total of 313 pigs (157 without diarrhea, 156 with diarrhea) were included in the statistical analysis, and 37 pigs (11.8%) were classified as PE positives (defined as proliferative histological lesions in combination with L. intracellularis demonstration by immunohistochemistry). Lawsonia intracellularis was detected by qPCR in feces from 91 pigs (29.1%). A nonparametric receiver operating characteristic (ROC) analysis provided an area under the ROC curve (0.93) and an optimal cutoff value of 4.8 log10 L. intracellularis bacteria/g feces. This cutoff provided a diagnostic sensitivity of 0.84 and diagnostic specificity of 0.93. The diagnostic sensitivity and specificity were significantly different between herds (P < 0.0001). Numerically, diagnostic sensitivity and specificity were different between subpopulations of pigs, but no significant differences were demonstrated.


Frequency Dependence of Polarization of Pulsar CP 0328.
The circularly polarized emission from the pulsar CP 0328 has an approximately flat spectrum in the 1-megahertz band centered at 113.6 megahertz, whereas the linearly polarized emission varies with frequency and from pulse to pulse. A simple model for the source that has a constant Faraday rotation measure fits some of the linearly polarized spectra observed for individual pulses, but changes in the rotation measure of as much as 30 radians per square meter are required between adjacent pulses. The simple model does not fit the average spectrum of the linearly polarized emission, although the average spectrum had the same form on two nights.


Proteins isolated with TRIzol are compatible with two-dimensional electrophoresis and mass spectrometry analyses.
TRIzol is used for RNA isolation but also permits protein recovery. We investigated whether proteins prepared with TRIzol were suitable for two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization mass spectrometry. Proteins from TRIzol-treated SH-SY5Y cells produced 2-DE spot patterns similar to those from an equivalent untreated sample. Subsequent identification of TRIzol-treated proteins using peptide mass fingerprinting was successful. TRIzol exposure altered neither the mass of myoglobin extracted from sodium dodecyl sulfate (SDS) gels nor the masses of myoglobin peptides produced by in-gel trypsin digestion. These findings suggest that proteins isolated with TRIzol remain amenable to proteomic analyses.


Rapid Formation of Aggregates with Uniform Numbers of Cells Based on Three-dimensional Dielectrophoresis.
We applied a fabrication method for the formation of island organization of cells based on a three-dimensional (3D) device for negative dielectrophoresis (n-DEP) to produce cell aggregates with uniform numbers of cells rapidly and simply. The intersections formed by rotating the interdigitated array (IDA) with two combs of band electrodes on the upper substrate by 90° relative to the IDA with two combs on the lower substrate were prepared in the device. The AC voltage was applied to a comb on the upper substrate and a comb on the lower substrate, while AC voltage with opposite phase was applied to another comb on the upper substrate and another comb on the lower substrate. Cells dispersed randomly were directed toward the intersections with relatively lower electric fields due to n-DEP, which formed by AC voltage applied bands with the identical phase, resulting in the formation of island patterns of cells. The cells accumulated at intersections were promoted to form the cell aggregates due to the close contact together. The production of cell aggregations adhered together was easily found by the dispersion behavior after switching the applied frequency to convert the cellular pattern. When cells were accumulated at the intersections by n-DEP for 45 min, almost accumulations of cells were adhered together, and hence a formations of cell aggregations. By using the present method, we can rapidly and simply fabricate cell aggregations with a uniform number of cells.


Management of ingested foreign bodies in children: a clinical report of the NASPGHAN Endoscopy Committee.
Foreign body ingestions in children are some of the most challenging clinical scenarios facing pediatric gastroenterologists. Determining the indications and timing for intervention requires assessment of patient size, type of object ingested, location, clinical symptoms, time since ingestion, and myriad other factors. Often the easiest and least anxiety-producing decision is the one to proceed to endoscopic removal, instead of observation alone. Because of variability in pediatric patient size, there are less firm guidelines available to determine which type of object will safely pass, as opposed to the clearer guidelines in the adult population. In addition, the imprecise nature of the histories often leaves the clinician to question the timing and nature of the ingestion. Furthermore, changes in the types of ingestions encountered, specifically button batteries and high-powered magnet ingestions, create an even greater potential for severe morbidity and mortality among children. As a result, clinical guidelines regarding management of these ingestions in children remain varied and sporadic, with little in the way of prospective data to guide their development. An expert panel of pediatric endoscopists was convened and produced the present article that outlines practical clinical approaches to the pediatric patient with a variety of foreign body ingestions. This guideline is intended as an educational tool that may help inform pediatric endoscopists in managing foreign body ingestions in children. Medical decision making, however, remains a complex process requiring integration of clinical data beyond the scope of these guidelines. These guidelines should therefore not be considered to be a rule or to be establishing a legal standard of care. Caregivers may well choose a course of action outside of those represented in these guidelines because of specific patient circumstances. Furthermore, additional clinical studies may be necessary to clarify aspects based on expert opinion instead of published data. Thus, these guidelines may be revised as needed to account for new data, changes in clinical practice, or availability of new technology.


Training-based interventions in motor rehabilitation after stroke: theoretical and clinical considerations.
Basic neuroscience research on brain plasticity, motor learning and recovery has stimulated new concepts in neurological rehabilitation. Combined with the development of set methodological standards in clinical outcome research, these findings have led to a double-paradigm shift in motor rehabilitation: (a) the move towards evidence-based procedures for the assessment of clinical outcome & the employment of disablement models to anchor outcome parameters, and (b) the introduction of practice-based concepts that are derived from testable models that specify treatment mechanisms. In this context, constraint-induced movement therapy (CIT) has played a catalytic role in taking motor rehabilitation forward into the scientific arena. As a theoretically founded and hypothesis-driven intervention, CIT research focuses on two main issues. The first issue is the assessment of long-term clinical benefits in an increasing range of patient groups, and the second issue is the investigation of neuronal and behavioural treatment mechanisms and their interactive contribution to treatment success. These studies are mainly conducted in the research environment and will eventually lead to increased treatment benefits for patients in standard health care. However, gradual but presumably more immediate benefits for patients may be achieved by introducing and testing derivates of the CIT concept that are more compatible with current clinical practice. Here, we summarize the theoretical and empirical issues related to the translation of research-based CIT work into the clinical context of standard health care.


Guiding-center soliton in optical fibers.
For a relatively long optical pulse in a fiber with a dispersion distance z(0) much larger than the loss distance, a soliton cannot exist in an ideal sense. However, with a proper choice of the initial amplitude and amplifier distance z(a), a nonlinear pulse (a guiding-center soliton) propagates like a soliton over a distance much larger than the dispersion distance when it is periodically amplified at distances much shorter than the dispersion distance. The guidingcenter soliton is shown to satisfy the nonlinear Schrodinger equation with a correction of order (z(a)/z(0))(2). Numerical examples supported by analytical results are presented for distortionless propagation of the guiding-center solitons with a pulse width of 40 psec in a dispersion-shifted fiber of D = 1 psec/(nm-km).


Expression of Insulin-like Growth Factors in a Mouse Model of Salicylate Ototoxicity.
Insulin-like growth factors (IGFs) are known to be neurotrophic factors, and they efficiently signal to cells to grow, differentiate and survive. The purpose of study was to identify the expressions of IGFs in mice with salicylate ototoxicity, which is a typical reversible hearing loss model. The mice were given intraperitoneal injections of salicylate (400 mg/kg) and about a 30 dB threshold shift was achieved at 3 hours. The expressions of IGF-1 and 2 were confirmed by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Localization of IGFs was confirmed using confocal immunofluorescence imaging. For in-vitro study on the HEI-OC1 auditory cells, the cell viability was calculated and the apoptotic features of the nuclei were observed with Hoechst staining. The expressions of the IGFs mRNA and protein were significantly increased in the salicylate ototoxicity groups compared with that of the normal control group. Salicylate induced apoptosis and decreased viability of the HEI-OC1 auditory cells in a time- and dose-dependent manner. The expressions of IGFs were localized in the stria vascularis, and these IGFs play a protective role in the in-vivo condition of salicylate ototoxicity. IGFs were highly expressed in the mice with salicylate ototoxicity, and this expression was mainly focused in the stria vascularis in the salicylate intoxicated mice. The systemic action of IGFs, which were expressed in the vascular-rich stria vascularis, can act as a major protective mechanism in a mouse model of salicylate ototoxicity.


Chorionic villus sampling for abnormal screening compared to historical indications: prevalence of abnormal karyotypes.
To determine the prevalence of abnormal karyotype results in women undergoing chorionic villus sampling (CVS) for abnormal first trimester screening compared to CVS for historical indications (advanced maternal age (AMA) or prior aneuploidy). Retrospective cohort of all patients undergoing CVS at Oregon Health & Science University from January 2006 to June 2010. Patients were separated based on CVS indication: (1) positive ultrasound (U/S) or serum screening; or (2) AMA or prior aneuploidy with normal or no screening. Prevalence of abnormal karyotype results were compared between groups. Fetal karyotyping was successful in 500 of 506 CVS procedures performed. 203 CVS were performed for positive screening with 69 abnormal karyotypes (34.0%). 264 CVS were performed for historical indications with 11 abnormal karyotypes (4.2%). This difference was statistically significant (χ(2) 71.9, p < 0.001; OR 11.8 [95% CI 5.8, 24.6]). There were two age-related aneuplodies in AMA women without positive screening. 42 out of 44 AMA women diagnosed with aneuploidy (95.5%) had abnormal U/S and/or serum screening (35 U/S, 4 serum, 3 U/S and serum). Combined ultrasound and serum screening should be recommended to all women, including AMA women, prior to undergoing invasive testing to improve risk-based counseling and minimize morbidity.


Ruptured distal AICA pseudoaneurysm presenting years after vestibular schwannoma resection and radiation.
Distal anterior inferior cerebellar artery (AICA) pseudoaneurysms are very rare lesions. Although cases have been previously reported, only a few have been reported as a result of vestibular schwannoma (VS) radiation, none have been reported as a result of VS resection, and only one has been reported as treated with parent vessel occlusion (PVO) with n-butyl cyanoacrylate (nBCA). We report a case of a 65-year-old man with a history of right-sided VS surgery and radiation who presented years later with a ruptured pseudoaneurysm of the distal right AICA and was treated with endovascular PVO using nBCA. The aneurysm was completely obliterated and the patient had no worsening of symptoms or neurological exam. The case illustrates a very rare complication of VS surgery and radiation as well as an effective treatment for distal AICA aneurysms.


Modulation of Host Immunity by the Human Metapneumovirus.
Globally, as a leading agent of acute respiratory tract infections in children <5 years of age and the elderly, the human metapneumovirus (HMPV) has gained considerable attention. As inferred from studies comparing vaccinated and experimentally infected mice, the acquired immune response elicited by this pathogen fails to efficiently clear the virus from the airways, which leads to an exaggerated inflammatory response and lung damage. Furthermore, after disease resolution, there is a poor development of T and B cell immunological memory, which is believed to promote reinfections and viral spread in the community. In this article, we discuss the molecular mechanisms that shape the interactions of HMPV with host tissues that lead to pulmonary pathology and to the development of adaptive immunity that fails to protect against natural infections by this virus.


Inflammation in CRPS: role of the sympathetic supply.
Acute Complex Regional Pain Syndrome (CRPS) is associated with signs of inflammation such as increased skin temperature, oedema, skin colour changes and pain. Pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-1beta, IL-6) are up-regulated, whereas anti-inflammatory cytokines (IL-4, IL-10) are diminished. Adaptive immunity seems to be involved in CRPS pathophysiology as many patients have autoantibodies directed against β2 adrenergic and muscarinic-2 receptors. In an animal tibial fracture model changes in the innate immune response such as up-regulation of keratinocytes are also found. Additionally, CRPS is accompanied by increased neurogenic inflammation which depends mainly on neuropeptides such as CGRP and Substance P. Besides inflammatory signs, sympathetic nervous system involvement in CRPS results in cool skin, increased sweating and sympathetically-maintained pain. The norepinephrine level is lower in the CRPS-affected than contralateral limb, but sympathetic sprouting and up-regulation of alpha-adrenoceptors may result in an adrenergic supersensitivity. The sympathetic nervous system and inflammation interact: norepinephrine influences the immune system and the production of cytokines. There is substantial evidence that this interaction contributes to the pathophysiology and clinical presentation of CRPS, but this interaction is not straightforward. How inflammation in CRPS might be exaggerated by sympathetic transmitters requires further elucidation.


Comparison of outcome among double, bifoil and Inoue balloon techniques for percutaneous mitral valvuloplasty in mitral stenosis.
The efficacy and complications of three different methods of percutaneous mitral valvuloplasty (PMV) were evaluated in 245 patients with mitral stenosis (MS). Eight six patients (35%) had severe MS defined in the mitral valve area (MVA) less than 1.0 cm2 (0.8 +/- 0.2) and Echoscore greater than or equal to 8(8.9 +/- 1.1). The results including post MCA greater than or equal to 1.5cm2 and complications, i.e, increment of mitral regurgitation (MR) greater than or equal to +1 and atrial septal defect (ASD) with Qp/Qs greater than or equal to 1.5 were compared in overall and in severe MS groups. There was no statistically significant difference in size of MVA before and after PMV between overall patients group and severe mitral stenosis group (0.8 +/- 0.1 vs 1.7 +/- 0.4cm2 in the double technique, 0.8 +/- 0.2 vs 1.5 +/- 0.3cm2 in the Bifoil technique and 0.7 +/- 0.2 vs 1.8 +/- 0.3cm2 in the Inoue technique. p: NS). However, a significantly larger number of patients in the severe MS group had better MVA with the double than the Bifoil technique [MVA greater than or equal to 1.5cm2; 42 (72%) vs 6 (46%), p less than 0.005] whereas higher complications were observed with the Bifoil than the Inoue technique (MR greater than or equal to +1; 9 (69%) vs 4 (27%), ASD (Qp/Qs greater than or equal to 1.5' 6 (46%) vs 2 (13%) p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)


Search for high-mass e+e- resonances in pp collisions at sqrt[s]=1.96 TeV.
A search for high-mass resonances in the e+e- final state is presented based on 2.5 fb(-1) of sqrt[s]=1.96 TeV pp collision data from the CDF II detector at the Fermilab Tevatron. The largest excess over the standard model prediction is at an e+e- invariant mass of 240 GeV/c2. The probability of observing such an excess arising from fluctuations in the standard model anywhere in the mass range of 150-1000 GeV/c2 is 0.6% (equivalent to 2.5sigma). We exclude the standard model coupling Z' and the Randall-Sundrum graviton for k/MPl=0.1 with masses below 963 and 848 GeV/c2 at the 95% credibility level, respectively.


Depressive symptoms in intellectual disability: does gender play a role?
Gender issues remain largely unaddressed in the dual diagnosis arena, even in the area of depression where there is a 2:1 female to male ratio in the general population. This paper argues that women with intellectual disability (ID) report higher levels of depressive symptoms than men with ID and that risk factors for depression identified for women in the general population are relevant to this group. Findings are based on structured interviews with 99 men and women with ID, with corroborative information provided from caregivers and casebook reviews. Overall, women reported higher levels of depression than men. Individuals with higher depression scores were more lonely and had higher stress levels than individuals with lower scores. Women with higher depression scores were more likely to report coming from abusive situations, to have poor social support from family and to be unemployed when compared to women with lower scores, but similar differences were not found when comparing men with higher and lower depression scores. Men and women who report experiencing these psychosocial correlates of depression should be a target group for future prevention efforts, taking gender specific concerns into consideration.


A DNA integrity network in the yeast Saccharomyces cerevisiae.
A network governing DNA integrity was identified in yeast by a global genetic analysis of synthetic fitness or lethality defect (SFL) interactions. Within this network, 16 functional modules or minipathways were defined based on patterns of global SFL interactions. Modules or genes involved in DNA replication, DNA-replication checkpoint (DRC) signaling, and oxidative stress response were identified as the major guardians against lethal spontaneous DNA damage, efficient repair of which requires the functions of the DNA-damage checkpoint signaling and multiple DNA-repair pathways. This genome-wide genetic interaction network also identified novel components (DIA2, NPT1, HST3, HST4, and the CSM1 module) that potentially contribute to mitotic DNA replication and genomic stability and revealed novel functions of well-studied genes (the CTF18 module) in DRC signaling. This network will guide more detailed characterization of mechanisms governing DNA integrity in yeast and other organisms.


Misophonia is associated with altered brain activity in the auditory cortex and salience network.
Misophonia is characterized by intense rage and disgust provoked by hearing specific human sounds resulting in social isolation due to avoidance. We exposed patients with symptom provoking audiovisual stimuli to investigate brain activity of emotional responses. 21 patients with misophonia and 23 matched healthy controls were recruited at the psychiatry department of the Amsterdam UMC. Participants were presented with three different conditions, misophonia related cues (video clips with e.g. lip smacking and loud breathing), aversive cues (violent or disgusting clips from movies), and neutral cues (video clips of e.g. someone meditating) during fMRI. Electrocardiography was recorded to determine physiological changes and self-report measures were used to assess emotional changes. Misophonic cues elicited anger, disgust and sadness in patients compared to controls. Emotional changes were associated with increases in heart rate. The neuroimaging data revealed increased activation of the right insula, right anterior cingulate cortex and right superior temporal cortex during viewing of the misophonic video clips compared to neutral clips. Our results demonstrate that audiovisual stimuli trigger anger and physiological arousal in patients with misophonia, associated with activation of the auditory cortex and salience network.


Wanting and liking: Separable components in problematic eating behavior?
Some individuals may have an addictive-like response to certain foods, possibly contributing to problematic eating. Highly processed foods, with added fats and/or refined carbohydrates, are suggested to be most associated with addictive-like eating. The incentive sensitization theory suggests that wanting (e.g. craving) may drive compulsive drug use rather than liking (e.g. enjoyment), but it is unknown whether highly processed foods elicit similar wanting and liking patterns as drugs of abuse, or whether individual differences exist. The current study examines the association of highly processed foods with craving and liking, and whether these relationships differ by food addiction symptomology, cognitive restraint, or body mass index (BMI). Participants (n = 216) reported craving and liking for 35 foods and completed the Yale Food Addiction Scale (YFAS) and Three Factor Eating Questionnaire (TFEQ). Highly processed foods were craved more overall. Craving of highly processed foods was predicted negatively by restraint and positively by YFAS score. Liking of highly processed foods was predicted negatively by restraint and positively by BMI. In conclusion, craving and liking appear distinct with respect to highly processed foods, and may be influenced by addictive-like eating, cognitive restraint, and BMI. This suggests that the incentive sensitization framework may also be relevant for problematic food consumption, especially for individuals reporting food addiction symptoms.


Immunity to malaria.
Malaria remains prevalent throughout tropical and subtropical regions and almost a third of the World's population is exposed to the risk of infection. There is currently a serious resurgence of the disease in Asia and Central America. The failure of global eradication measures based upon the use of insecticides and chemotherapy has resulted from difficulties of practical implementation compounded by the spread of insecticide and drug resistance. Repeated natural infection does not produce detectable resistance to the exo-erythrocytic cycle of malaria in man. Irradiated sporzoite vaccines do, however, induce stage specific immunity in murine malaria and in a proportion of human subjects. Vaccinated individuals remain susceptible to blood stage infection which causes clinical malaria. In addition the vaccine is unstable and must be administered by intravenous inoculation. Since neither sporogonic nor exo-erythrocytic parasite development is cyclical in human malarias, there is little prospect for vaccine production through cultivation of these stages. The inhabitants of hyperendaemic areas become increasingly resistant to malaria during childhood and adolescence, through the slow development of specific, acquired immunity to asexual blood stage parasites. Immunity is mediated by antibody, which blocks merozoite invasion of red cells, as well as by cell mediated mechanisms and non-specific cytotoxic agents. Vaccination with merozoites induces long lasting immunity of broad serological specificity active against the blood-stage of the parasite. Merozoite vaccines can be preserved by freeze drying and harvested from continuous cultures of blood stage parasites. The major problem in development of a human merozoite vaccine concerns the requirement for Freund's complete adjuvant which is not acceptable for man. The effective immunity induced by vaccination contrasts with the slow development of incomplete resistance which follows repeated natural infection. The latter is associated with the generation of immune suppressor cells, lymphoid cell mitogens and soluble antigens, and in some species by the occurrence of antigenic variation--all of which may favour parasite survival. It is probable that vaccination with non-viable antigen of appropriate composition, induces immune effector processes without activating mechanisms which allow parasites to escape the consequences of immunity. Many effective vaccines such as those against measles, poliomyelitis, tetanus and rabies are commercially available but barely used in the developing world. The affected nations cannot afford their purchase, nor do the means exist for their distribution. It follows that if a safe and effective malaria vaccine were to be developed, its bulk manufacture and administration would require massive international support and cooperation.


Identifying the relationship between the non-PV triggers and the critical CFAE sites post-PVAI to curtail the extent of atrial ablation in longstanding persistent AF.
Complex fractionated atrial electrograms (CFAE) ablation has been performed in addition to pulmonary veins (PV) isolation to increase the success rate of atrial fibrillation (AF) ablation in patients with longstanding (LS) persistent AF. The mechanism underlying the clinical benefit of CFAE ablation remains, however, poorly understood. We compared the impact of CFAE ablation on the prevalence of non-PV atrial triggers inducing AF in 2 groups of patients with LS persistent AF. One group underwent PVAI alone, and the other group underwent PVAI plus CFAE ablation. In addition, we correlated the site of non-PV triggers with the presence of CFAE. A total of 98 consecutive patients with symptomatic drug refractory LS persistent AF presenting for ablation had a preablation electroanatomic CFAE map. Patients randomized to either isolation of the PVs and posterior wall (PVAI) (group I, n = 48 pts) or PVAI and biatrial ablation of CFAEs (group II, 50 pts). After ablation, infusion of isoproterenol up to 30 mcg/min was given to reveal non PV foci inducing AF. Those foci were mapped and correlated with CFAE regions and ablated. A total of 19 patients (76%) with PV foci inducing AF were associated with either stable or transient CFAE after PVAI, respectively, in 12 patients (48%) and 7 patients (28%). A total of 20 (42%) non-PV triggers were observed in group I versus 5 (10%) in group II (P < 0.001) in 18 and 5 patients, respectively. After a mean f/u of 17.2 ± 5.2 months, 33 (69%) patients in group I and 36 (72%) patients in group II were in SR (P = NS). Non-PV triggers inducing AF post-PVAI were associated with the presence of stable or transient CFAE in 48% and 28% of cases, respectively, in LS persistent AF. CFAE ablation after PVAI was associated with a significantly higher elimination of those non-PV triggers. This suggests that at least part of the beneficial effect achieved by CFAE ablation reflects elimination of non-PV AF triggers.


The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt.
In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch. The IGF-1/Akt pathway has a dual effect on huntingtin-induced toxicity, since activation of this pathway also results in a decrease in the formation of intranuclear inclusions of mutant huntingtin. We demonstrate that huntingtin is a substrate of Akt and that phosphorylation of huntingtin by Akt is crucial to mediate the neuroprotective effects of IGF-1. Finally, we show that Akt is altered in Huntington's disease patients. Taken together, these results support a potential role of the Akt pathway in Huntington's disease.


An adipogenic gel for surgical reconstruction of the subcutaneous fat layer in a rat model.
'Off-the-shelf' tissue-engineered skin alternatives for epidermal and dermal skin layers are available; however, no such alternative for the subdermal fat layer exists. Without this well-vascularized layer, skin graft take is variable and grafts may have reduced mobility, contracture and contour defects. In this study a novel adipose-derived acellular matrix (Adipogel) was investigated for its properties to generate subdermal fat in a rat model. In a dorsal thoracic site, a 1 × 1 cm Adipogel implant was inserted within a subdermal fat layer defect. In a dorsal lumbar site, an Adipogel implant was inserted in a subfascial pocket. Contralateral control defects remained empty. At 8 weeks wound/implant sites were evaluated histologically, immunohistochemically and morphometrically. Identifiable thoracic Adipogel implants lost volume in vivo over 8 weeks. Neovascularization and adipogenesis were evident within implants and adipocyte percentage volume was 33.07 ± 6.55% (mean ± SEM). A comparison of entire cross-sections of thoracic wounds demonstrated a significant increase in total wound fat in Adipogel-implanted wounds (37.19 ± 4.48%, mean ± SEM) compared to control (16.53 ± 4.60%; p = 0.0092), indicating that some Adipogel had been completely converted to normal fat. At the lumbar site, Adipogel also lost volume, appearing flattened, although fat generation and angiogenesis occurred. At both sites macrophage infiltration was mild, whilst many infiltrating cells were PDGFRβ-positive mesenchymal cells. Adipogel is adipogenic and angiogenic and is a promising candidate for subcutaneous fat regeneration; it has the potential to be a valuable adjunct to wound-healing therapy and reconstructive surgery practice. Copyright © 2015 John Wiley & Sons, Ltd.


Characterization and cardioprotective activity of anthocyanins from Nitraria tangutorum Bobr. by-products.
The Nitraria tangutorum Bobr. fruit is an indigenous berry of the shrub belonging to the Zygophyllaceae family which grows at an altitude of over 3000 m in the Tibetan Plateau, and has been used as a native medicinal food for treating weakness of the spleen, stomach syndrome, dyspepsia, neurasthenia, dizziness, etc. for thousands of years. Nowadays, N. tangutorum industrial juice by-products generated from health food production can be a potential low cost source of some unique bioactive ingredients. In a prior study, we established a simultaneous microwave/ultrasonic assisted enzymatic extraction method for extracting antioxidant ingredients from the industrial by-products of N. tangutorum juice. In this study, these ingredients were selectively fractionated by cation-exchange resin chromatography to obtain an anthocyanin fraction namely NJBAE. NJBAE was found to be composed of 16 anthocyanins derived from six anthocyanidins by HPLC-ESI-MS, and has an appreciable cardioprotective effect on doxorubicin-induced injured H9c2 cardiomyocytes. The cardioprotective mechanism research showed that NJBAE could directly scavenge ROS, restrict further generation of ROS, promote the activity of key antioxidase, enhance glutathione redox cycling, then affect the apoptotic signaling changes in a positive way, and finally mediate caspase-dependent cell death pathways. Therefore, NJBAE has great potential to be used for preventing and treating cardiovascular disease in the food, pharmaceutical and other emerging industries.


Cycling for transport and public health: a systematic review of the effect of the environment on cycling.
Active transport policies are being developed across Europe designed to have health and environmental benefits. There is little evidence of impact on physical activity of active transport strategies which modify the built environment. Cycling represents one virtually carbon-neutral form of transport that can help to address declining levels of exercise. A systematic literature review of experimental or observational studies that objectively evaluated the effect of the built environment on cycling. A total of 21 studies met the inclusion criteria, all of which were observational studies. Eleven studies identified objectively measured environmental factors with a significant positive association with cycling. The environmental factors identified as being positively associated with cycling included presence of dedicated cycle routes or paths, separation of cycling from other traffic, high population density, short trip distance, proximity of a cycle path or green space and for children projects promoting 'safe routes to school'. Negative environmental factors were perceived and objective traffic danger, long trip distance, steep inclines and distance from cycle paths. Of the seven studies which focused primarily on the impact of cycle routes, four demonstrated a statistically significant positive association. Although the study identified environmental factors with positive and negative associations with cycling behaviour, many other types of environmental policies and interventions have yet to be rigorously evaluated. Policies promoting cycle lane construction appear promising but the socio-demographic distribution of their effects on physical activity is unclear. The wider impact of active transport policies on health and inequalities across Europe must be explored.


Unusual sign of meningitis: acute globe vesicalis.
We report a rare case of urinary retention secondary to meningitis. A 15-year-old previously healthy male patient admitted to our clinic with complaint of fever, inability to urinate and vomiting, with a two-day history of clavulanate amoxicillin usage. Lumbar puncture was performed, demonstrating a cloudy cerebrospinal fluid (CSF), with protein concentration of 86 mg/dl and glucose concentration of 72 mg/dl, and simultaneous blood glucose of 137 mg/dl. Cell count was 170/microL (neutrophil 154, lymphocyte 11), latex agglutination was negative and no microorganism was detected with Gram stain; there were few polymorphonuclear leukocytes with Wright stain. Cranial tomography was normal and CSF culture and blood culture did not yield any microorganisms. He was treated with ceftriaxone as empirical therapy for bacterial meningitis. In just six days after admission, voiding inability had recovered completely. Although acute urinary retention in patients with meningitis may be self-limited and there is no evidence that any treatment affects its clinical course, physicians should be aware of acute urinary retention as a rare but critical manifestation of meningitis.


Microbial contamination of preservative free eye drops in multiple application containers.
The majority of eye drops used in the United Kingdom contain preservatives and are bottled in plastic containers. Preservative free drops are used to avoid ocular irritation and allergies in certain individuals. The aim of this study was to investigate the incidence of microbial contamination of preservative free drops dispensed from multiusage containers. Eye drop bottles were collected from patients attending the Tennent Institute of Ophthalmology outpatient and inpatient departments. The bottles were collected on day 3 (for inpatients) and day 7 (for outpatients) of use. The drops were inoculated onto different culture plates (chocolate agar, blood agar, fungal culture media, and enriched media) and the resulting microbial growth was identified using standard microbial identification techniques. 95 eye drop bottles were collected, containing a variety of 10 different eye drops. Significant bacterial growth was found in eight bottles. In total, seven different types of organism were identified from the eye drops. The organisms identified were Staphylococcus aureus, coagulase negative staphylococcus, Bacillus spp, Serattia spp, Klebsiella oxytoca, Enterobacter cloacae, and alpha streptococcus. Staph aureus was the commonest microbial organism. Preservative free eye drops in multiple application containers are at risk of contamination by potentially pathogenic micro-organisms.


Early increase in marker of neuronal integrity with antidepressant treatment of major depression: 1H-magnetic resonance spectroscopy of N-acetyl-aspartate.
Increasing interest surrounds potential neuroprotective or neurotrophic actions of antidepressants. While growing evidence points to important early clinical and neuropsychological effects of antidepressants, the time-course of any effect on neuronal integrity is unclear. This study used magnetic resonance spectroscopy to assess effects of short-term treatment with escitalopram on N-acetyl-aspartate (NAA), a marker of neuronal integrity. Thirty-nine participants with major depression were randomly assigned to receive either 10 mg escitalopram or placebo daily in a double-blind, parallel group design. On the seventh day of treatment, PRESS data were obtained from a 30×30×20 mm voxel placed in medial frontal cortex. Age and gender-matched healthy controls who received no treatment were also scanned. Levels of NAA were significantly higher in patients treated with escitalopram than in either placebo-treated patients (p<0.01) or healthy controls (p<0.01). Our findings are consistent with the proposition that antidepressant treatment in depressed patients can produce early changes in neuronal integrity.


The family and peer origins of coercion within adult romantic relationships: A longitudinal multimethod study across relationships contexts.
Using coercive strategies to resolve conflicts with romantic partners has toxic effects on relationships. Coercion predicts relationship dissatisfaction, instability, and intimate partner violence. The early adult romantic relationships model hypothesizes that such strategies first emerge within the family and continue to affect romantic relationships into adulthood. We tested whether adolescent antisocial behaviors and deviancy training with peers mediated between early disruptive parenting and adult romantic relationship coercion. Furthermore, we tested the impact of trauma in this longitudinal model. We studied 230 adults in committed relationships, whom we initially recruited and studied when they were age 11. We collected videotaped observations with friends (when participants were ages 16-17) and with intimate partners (when participants were ages 28-30). As hypothesized, disruptive parenting predicted antisocial behaviors and deviancy training with friends in adolescence, which in turn predicted coercion within intimate adult relationships. Moreover, disruptive parenting in early adolescence also directly predicted romantic partner coercion 15 years later. No significant effects were found for trauma. Findings suggest the promise of promoting healthy adult intimate relationships through early relationships with parents and friends. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Virus-specific TRM cells of both donor and recipient origin reside in human kidney transplants.
Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.


Risks of carcinogenesis from electromagnetic radiation of mobile telephony devices.
Intensive implementation of mobile telephony technology in everyday human life during last two decades has given a possibility for epidemiological estimation of long-term effects of chronic exposure of human organism to low-intensive microwave (MW) radiation. Latest epidemiological data reveal a significant increase in risk of development of some types of tumors in chronic (over 10 years) users of mobile phone. It was detected a significant increase in incidence of brain tumors (glioma, acoustic neuroma, meningioma), parotid gland tumor, seminoma in long-term users of mobile phone, especially in cases of ipsilateral use (case-control odds ratios from 1.3 up to 6.1). Two epidemiological studies have indicated a significant increase of cancer incidence in people living close to the mobile telephony base station as compared with the population from distant area. These data raise a question of adequacy of modern safety limits of electromagnetic radiation (EMR) exposure for humans. For today the limits were based solely on the conception of thermal mechanism of biological effects of RF/MW radiation. Meantime the latest experimental data indicate the significant metabolic changes in living cell under the low-intensive (non-thermal) EMR exposure. Among reproducible biological effects of low-intensive MWs are reactive oxygen species overproduction, heat shock proteins expression, DNA damages, apoptosis. The lack of generally accepted mechanism of biological effects of low-intensive non-ionizing radiation doesn't permit to disregard the obvious epidemiological and experimental data of its biological activity. Practical steps must be done for reasonable limitation of excessive EMR exposure, along with the implementation of new safety limits of mobile telephony devices radiation, and new technological decisions, which would take out the source of radiation from human brain.


The use of a computerized database to monitor vaccine safety in Viet Nam.
Health information systems to monitor vaccine safety are used in industrialized countries to detect adverse medical events related to vaccinations or to prove the safety of vaccines. There are no such information systems in the developing world, but they are urgently needed. A large linked database for the monitoring of vaccine-related adverse events has been established in Khanh Hoa province, Viet Nam. Data collected during the first 2 years of surveillance, a period which included a mass measles vaccination campaign, were used to evaluate the system. For this purpose the discharge diagnoses of individuals admitted to polyclinics and hospitals were coded according to the International Classification of Diseases (ICD)-10 guidelines and linked in a dynamic population database with vaccination histories. A case-series analysis was applied to the cohort of children vaccinated during the mass measles vaccination campaign. The study recorded 107,022 immunizations in a catchment area with a population of 357,458 and confirmed vaccine coverage of 87% or higher for completed routine childhood vaccinations. The measles vaccination campaign immunized at least 86% of the targeted children aged 9 months to 10 years. No medical event was detected significantly more frequently during the 14 days after measles vaccination than before it. The experience in Viet Nam confirmed the safety of a measles vaccination campaign and shows that it is feasible to establish health information systems such as a large linked database which can provide reliable data in a developing country for a modest increase in use of resources.


Using co-design to develop an intervention to improve communication about the heart failure trajectory and end-of-life care.
The aim of this paper was to describe the development of an intervention that is developed to improve communication about the heart failure (HF) trajectory and end-of-life care. We also present data that provides a first insight in specific areas of feasibility of the intervention. Co-design was used and patients, family members and health care professionals were constructive participants in the design process of the intervention. Feasibility of the intervention was tested in two areas; acceptability and limited efficacy. Two communication tools were designed and evaluated; 1) a Question Prompt List (QPL) for patients and family members and 2) a communication course for professionals which was web -based with one face-to-face training day with simulation. Data on feasibility was collected with questionnaires that were developed for this study, from the 13 participants who completed the course (all nurses). They reported improved knowledge, confidence and skills to discuss the HF trajectory and end-of-life care. The QPL was evaluated to be a useful tool in communication with patients and family members. In a co-design process, future users identified the need for a QPL and a communication course. These communication tools can be used as a dual intervention to improve communication about the HF trajectory and end-of-life care. The QPL can help patients and families to ask questions about the HF trajectory and end-of-life care. The communication course can prepare the professionals to be knowledgeable, confident and skilled to discuss the questions in the QPL. Before the tools are ready for implementation in clinical practice, further studies testing the feasibility of the intervention are needed, including also patients and their families.


A genetic characterization of the nadC gene of Salmonella typhimurium.
The nadC gene of Salmonella encodes the pyridine biosynthetic enzyme PRPP-quinolinate phosphoribosyltransferase. Using a combination of genetic techniques, a deletion map for the Salmonella nadC gene has been generated which includes over 100 point mutants and 18 deletion intervals. The nadC alleles obtained by hydroxylamine mutagenesis include those suppressed by either amber, ochre, or UGA nonsense suppressors as well as alleles suppressed by the missense suppressor, sumA. Deletions were obtained by three separate protocols including spontaneous selection for loss of the nearby aroP gene, recombination between aroP::MudA and nadC::MudA insertion alleles, and selection for spontaneous loss of tetracycline resistance in a nearby guaC::Tn10dTc insertion mutant allele. The nadC mutants comprise one complementation group and the nadC+ allele is dominant to simple, nadC auxotrophic mutant alleles. Intragenic complementation of two nadC alleles, nadC493 and nadC494, mapping to deletion intervals 17 and 18, respectively, suggests that nadC encodes a multimeric enzyme. Both nadC and the nearby aroP locus are transcribed counterclockwise on the standard genetic map of Salmonella, in opposite orientation to the direction of chromosome replication.


Postpartum mental health service utilization in women with Human Immunodeficiency Virus (HIV): a population-based study.
Women with HIV have higher rates of psychiatric disorders than HIV-negative women, yet little is known about their postpartum mental health and associated service use. The purpose of this study was to characterize HIV-positive women's use of ambulatory and acute mental health services in the first year postpartum, relative to HIV-negative women. Using health administrative data, we identified 861,365 women who had a live birth delivery from April 1, 2002 to March 31, 2012 in Ontario, Canada, of whom 530 were identified to be HIV-positive. We described their use of mental health services, including outpatient mental health visits, psychiatric emergency department (ED) visits and hospitalizations using adjusted odds ratios (aORs) and 95% confidence intervals (CIs). HIV-positive women were more likely to access outpatient mental health services (31.5% vs. 21.0%, aOR, 1.26; 95% CI, 1.03-1.55), but more likely to remain engaged in psychiatrist services only (15.6% vs. 6.5%, aOR, 2.35; 95% CI, 1.41-3.72). They were also more likely to require a psychiatric ED visit or hospitalization (3.3% vs. 1.1%, aOR, 2.74; 95% CI, 1.72-4.12). Our findings highlight the importance of considering postpartum mental health as part of comprehensive reproductive health care for women with HIV.


Identifying priority conservation landscapes and actions for the Critically Endangered Javan leopard in Indonesia: Conserving the last large carnivore in Java Island.
With the extirpation of tigers from the Indonesian island of Java in the 1980s, the endemic and Critically Endangered Javan leopard is the island's last remaining large carnivore. Yet despite this, it has received little conservation attention and its population status and distribution remains poorly known. Using Maxent modeling, we predicted the locations of suitable leopard landscapes throughout the island of Java based on 228 verified Javan leopard samples and as a function of seven environmental variables. The identified landscapes covered over 1 million hectares, representing less than 9% of the island. Direct evidence of Javan leopard was confirmed from 22 of the 29 identified landscapes and included all national parks, which our analysis revealed as the single most important land type. Our study also emphasized the importance of maintaining connectivity between protected areas and human-modified landscapes because adjacent production forests and secondary forests were found to provide vital extensions for several Javan leopard subpopulations. Our predictive map greatly improves those previously produced by the Government of Indonesia's Javan Leopard Action Plan and the IUCN global leopard distribution assessment. It shares only a 32% overlap with the IUCN range predictions, adds six new priority landscapes, all with confirmed presence of Javan leopard, and reveals an island-wide leopard population that occurs in several highly fragmented landscapes, which are far more isolated than previously thought. Our study provides reliable information on where conservation efforts must be prioritized both inside and outside of the protected area network to safeguard Java's last remaining large carnivore.


Cleavage of Arabidopsis PBS1 by a bacterial type III effector.
Plant disease-resistance (R) proteins are thought to function as receptors for ligands produced directly or indirectly by pathogen avirulence (Avr) proteins. The biochemical functions of most Avr proteins are unknown, and the mechanisms by which they activate R proteins have not been determined. In Arabidopsis, resistance to Pseudomonas syringae strains expressing AvrPphB requires RPS5, a member of the class of R proteins that have a predicted nucleotide-binding site and leucine-rich repeats, and PBS1, a protein kinase. AvrPphB was found to proteolytically cleave PBS1, and this cleavage was required for RPS5-mediated resistance, which indicates that AvrPphB is detected indirectly via its enzymatic activity.