The Candida albicans biofilm gene circuit modulated at the chromatin level by a recent molecular histone innovation.
Histone H3 and its variants regulate gene expression but the latter are absent in most ascomycetous fungi. Here, we report the identification of a variant histone H3, which we have designated H3VCTG because of its exclusive presence in the CTG clade of ascomycetes, including Candida albicans, a human pathogen. C. albicans grows both as single yeast cells and hyphal filaments in the planktonic mode of growth. It also forms a three-dimensional biofilm structure in the host as well as on human catheter materials under suitable conditions. H3VCTG null (hht1/hht1) cells of C. albicans are viable but produce more robust biofilms than wild-type cells in both in vitro and in vivo conditions. Indeed, a comparative transcriptome analysis of planktonic and biofilm cells reveals that the biofilm circuitry is significantly altered in H3VCTG null cells. H3VCTG binds more efficiently to the promoters of many biofilm-related genes in the planktonic cells than during biofilm growth, whereas the binding of the core canonical histone H3 on the corresponding promoters largely remains unchanged. Furthermore, biofilm defects associated with master regulators, namely, biofilm and cell wall regulator 1 (Bcr1), transposon enhancement control 1 (Tec1), and non-dityrosine 80 (Ndt80), are significantly rescued in cells lacking H3VCTG. The occupancy of the transcription factor Bcr1 at its cognate promoter binding sites was found to be enhanced in the absence of H3VCTG in the planktonic form of growth resulting in enhanced transcription of biofilm-specific genes. Further, we demonstrate that co-occurrence of valine and serine at the 31st and 32nd positions in H3VCTG, respectively, is essential for its function. Taken together, we show that even in a unicellular organism, differential gene expression patterns are modulated by the relative occupancy of the specific histone H3 type at the chromatin level.


Anterior space relations and lower incisor alignment in 9-year-old children born in the 1960s and 1980s.
The anterior arch spaces and the effect of early loss of deciduous canines have been studied in 2 different cohorts of 9-year-old children. One group of 119 children was from Norway and consisted of 56 girls and 63 boys, and 1 group of 133 children was from Sweden and consisted of 72 girls and 61 boys. Within these cohorts, half of the children were born in the 1960s and half in the 1980s. The 1960s group has been compared with the 1980s group to look for anterior arch changes occurring during this period of time. The children who had lost a lost deciduous canine at the age of 9 years were also compared with the children with all deciduous canines remaining. Groups were compared with analysis of variance. It was found that children with a lost deciduous canine at the age of 9 years belong to a group with less available arch space and are a crowded group when compared with an earlier study. For the girls, this was also associated with larger teeth. Anterior arch space did not differ between the 1960s and the 1980s groups except for the Swedish boys, where there was less available mandibular arch space in the 1980s group. The irregularity index for the 4 mandibular incisors was increased in the 1980s group compared with the 1960s group. This could indicate a secular trend toward an increased prevalence of malocclusion in the present population.


Feasibility and safety of in-bed cycling for physical rehabilitation in the intensive care unit.
The purpose was to evaluate the feasibility and safety of in-bed cycle ergometry as part of routine intensive care unit (ICU) physical therapist (PT) practice. Between July 1, 2010, and December 31, 2011, we prospectively identified all patients admitted to a 16-bed medical ICU receiving cycling by a PT, prospectively collected data on 12 different potential safety events, and retrospectively conducted a chart review to obtain specific details of each cycling session. Six hundred eighty-eight patients received PT interventions, and 181 (26%) received a total of 541 cycling sessions (median [interquartile range {IQR}] cycling sessions per patient, 2 [1-4]). Patients' mean (SD) age was 57 (17) years, and 103 (57%) were male. The median (IQR) time from medical ICU admission to first PT intervention and first cycling session was 2 (1-4) and 4 (2-6) days, respectively, with a median (IQR) cycling session duration of 25 (18-30) minutes. On cycling days, the proportion of patients receiving mechanical ventilation, vasopressor infusions, and continuous renal replacement therapy was 80%, 8%, and 7%, respectively. A single safety event occurred, yielding a 0.2% event rate (95% upper confidence limit, 1.0%). Use of in-bed cycling as part of routine PT interventions in ICU patients is feasible and appears safe. Further study of the potential benefits of early in-bed cycling is needed.


Liver function tests in children and adolescents receiving risperidone treatment for a year: a longitudinal, observational study from Turkey.
To determine the changes in liver function tests after long-term risperidone treatment in a child and adolescent population. Weight, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatase and serum bilirubin of the patients were assessed in pre-treatment period, and at the sixth and 12th months of treatment. One hundred children and adolescents (aged between 3 and 18 years) were enrolled to the study. Liver enzyme and bilirubin levels are higher than normal in 21.0% of the patients without clinical symptoms. No cases of hepatic failure or jaundice were seen. Only in an 8-year-old boy were there ALT level increases up to three-fold and AST level increases up to two-fold. After discontinuation of the risperidone treatment, enzyme levels were normalized in this patient. Alkaline phosphatase, alanine and aspartate aminotransferases were the most frequently increased enzymes. In this study, after long-term risperidone treatment of children and adolescents there was no evidence of clinically significant increases of liver enzymes and bilirubin levels. These results indicate that risperidone treatment may rarely cause serious liver enzyme increases, and may commonly cause clinically insignificant changes in liver function tests.


Na+/H+ and HCO3-/Cl- exchange in the control of intracellular pH in vivo in the spontaneously hypertensive rat.
1. We have previously shown that the cytosolic acid concentration changes in skeletal muscle during contraction in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats in vivo. We have now found that this change was unaffected by 20% inhaled CO2 or by 4,4'-di-isothiocyanostilbene-2,2'-disulphonate. This is evidence that HCO3- exchange in vivo is not important in the control of cytosolic acid concentration during skeletal muscle contraction in either spontaneously hypertensive or Wistar-Kyoto rats. 2. We have also previously shown that the difference in cytosolic acid response during contraction between spontaneously hypertensive and Wistar-Kyoto rats is due to increased Na+/H+ antiporter activity in the spontaneously hypertensive rats. Our current findings suggest that this increase in Na+/H+ antiporter activity is more likely to be due to a change in the Km of the antiporter than to a change in the Vmax. We estimate that the Km of the antiporter changes in hypertension from pH 7.16 to 7.33. 3. We did not find any differences between adult spontaneously hypertensive and Wistar-Kyoto rats with regard to resting intracellular and extracellular pH and resting intracellular and extracellular HCO3- concentrations. In addition, we did not find any evidence of a difference in skeletal muscle HCO3-/Cl- exchange between adult spontaneously hypertensive and Wistar-Kyoto rats. 4. At rest, skeletal muscles of the spontaneously hypertensive and Wistar-Kyoto rats have the same lactate production, HCO3-/Cl- exchange and arterial partial pressure of CO2. In addition, we can also calculate that at a resting intracellular pH of 7.05 in the spontaneously hypertensive rats, the antiporter is 66% saturated.(ABSTRACT TRUNCATED AT 250 WORDS)


Nursing students' perceptions of clinical supervision: the contributions of preceptors, head preceptors and clinical lecturers.
The aims of the study were 1) to investigate to what extent nursing students were satisfied with the supervision provided by facilitators (preceptor, head preceptor, and clinical lecturer), 2) to compare nursing students' ratings of facilitators' contribution to supervision as supportive and challenging, and 3) to examine relationships between facilitators' supportive and challenging behavior in supervision and nursing students' perception of fulfillment of expected learning outcomes in clinical education. Although there are many studies on support of students in clinical education, few have addressed this from the students' point of view or made comparisons between different facilitators. A cross-sectional survey study was conducted during April to November 2010, where 107 nursing students, from a university in central Sweden, answered a questionnaire about supervision immediately after their period of clinical education. Supportive behavior in supervision was rated higher by students for all facilitator groups as compared with challenging behavior. The students rated preceptors and clinical lecturers as more supportive than head preceptors and clinical lecturers as providing more challenges than the two other facilitator groups. Supportive and challenging behavior in supervision explained 39% of the variance in students' overall learning outcomes. However, the regression coefficient was only significant for students' ratings of supportive behavior for the preceptor. Nursing students were satisfied with facilitators' supervision and by their contribution to fulfillment of overall learning outcomes. Comparisons showed that preceptors in a higher degree were perceived as supportive while clinical lecturers were perceived as more important as challengers for critical thinking, reflection and exchange of experiences between students. The model of supervision seems to be promising, but the roles across facilitators need to be made clearer, especially the head preceptor's role, which seemed to be the most unclear role in this model.


Neurometabolism of active neuropsychiatric lupus determined with proton MR spectroscopy.
To determine the neurometabolism of patients with active neuropsychiatric systemic lupus erythematosus (NPSLE) by using proton MR spectroscopy. Thirty-six patients with SLE and eight control subjects were studied with proton MR spectroscopy to measure brain metabolites. Peaks from N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and at 1.3 parts per million (ppm) lipid, macromolecules, and lactate were measured. Patients were classified as having major NPSLE (seizures, psychosis, major cognitive dysfunction, delirium, stroke, or coma) (n = 15) or minor NPSLE (headache, minor affective disorder, or minor cognitive disorder) (n = 21). Patients with major NPSLE were severely ill and hospitalized. SLE patients had lower NAA and increased metabolites at 1.3 ppm than did control subjects (NAA/Cr(SLE) = 1.90 +/- 0.35, NAA/Cr(Control) = 2.16 +/- 0.26; 1.3 ppm/Cr(SLE) = 0.49 +/- 0.41, 1.3 ppm/Cr(Control) = 0.27 +/- 0.05). NAA/Cr in patients with current or prior major NPSLE was lower than in patients without major NPSLE. Increased peaks at 1.3 ppm were present in all SLE subgroups, but particularly in patients with major NPSLE. These resonances were not evident at an echo time of 136, indicating that these signals were not lactate. Major NPSLE, past or present, is associated with decreased levels of NAA. Elevated peaks around 1.3 ppm do not represent lactate even in severely ill patients, indicating that global ischemia is not characteristic of NPSLE. Neurochemical markers determined by MR spectroscopy may be useful for determining activity and degree of brain injury in NPSLE.


Y-chromosome diversity in Sweden - a long-time perspective.
Sixteen Y-chromosomal binary markers and nine Y-chromosome short tandem repeats were analyzed in a total of 383 unrelated males from seven different Swedish regions, one Finnish region and a Swedish Saami population in order to address questions about the origin and genetic structure of the present day population in Sweden. Haplogroup I1a* was found to be the most common haplogroup in Sweden and accounted, together with haplogroups R1b3, R1a1 and N3, for over 80% of the male lineages. Within Sweden, a minor stratification was found in which the northern region Västerbotten differed significantly (P < 0.05) from the other Swedish regions. A flow of N3 chromosomes into Västerbotten mainly from Saami and Finnish populations could be one explanation for this stratification. However, the demographic history of Västerbotten involving a significant male absence during the 17th Century may also have had a large impact. Immigration of young men from elsewhere to Värmland at the same time, can be responsible for a similar deviation with I1a* haplotypes. Y chromosomes within haplogroup R1b3 were found to have the highest STR variation among all haplogroups and could thus be considered to be one of the earliest major male lineages present in Sweden. Regional haplotype variation, within R1b3, also showed a difference between two regions in the south of Sweden. This can also be traced from historical time and is visible in archaeological material. Overall this Y chromosome study provides interesting information about the genetic patterns and demographic events in the Swedish population.


Ring-oxidative biotransformation and drug interactions of propofol in the livers of rats.
Propofol, an intravenous anesthetic agent, is widely used for inducing and maintaining anesthesia during surgical procedures and for sedating intensive care unit patients. In the clinic, rapid elimination is one of the major advantages of propofol. Meanwhile, the biotransformation and drug interactions of propofol in rat livers are still little known. In this study, we evaluated the ring-oxidative metabolism of propofol in phenobarbital-treated rat livers and possible drug interactions. Administration of phenobarbital to male Wistar rats significantly increased levels of hepatic cytochrome P450 (CYP) 2B1/2 and microsomal pentoxyresorufin O-dealkylase (PROD) activity. Analyses by high-performance liquid chromatography and liquid chromatography mass spectroscopy revealed that propofol was metabolized by phenobarbital-treated rat liver microsomes into 4-hydroxypropofol. In comparison, PROD activity and 4-hydroxy-propofol production from propofol metabolism were suppressed by orphenodrine, an inhibitor of CYP2B1/2, and a polyclonal antibody against rat CYP2B1/2 protein. Furthermore, exposure of rats to propofol did not affect the basal or phenobarbital-enhanced levels of hepatic CYP2B1/2 protein. Meanwhile, propofol decreased the dealkylation of pentoxyresorufin by phenobarbital-treated rat liver microsomes in a concentration-dependent manner. Taken together, this study shows that rat hepatic CYP2B1/2 plays a critical role in the ring-oxidative metabolism of propofol into 4-hydroxypropofol, and this anesthetic agent can inhibit CYP2B1/2 activity without affecting protein synthesis.


Psoriasis in Children: A Review.
Psoriasis is a chronic, immune-mediated, inflammatory systemic disease which targets primarily the skin. It presents a genetic basis, affecting 1 to 3% of the white population. Nevertheless, the existence of two psoriasis incidence peaks has been suggested (one in adolescence before 20 years of age and another in adulthood) onset may occur at any age, including childhood and adolescence, in which its prevalence ranges between 0.7% and 1.2%. As for adult psoriasis, pediatric psoriasis has recently been associated with obesity, metabolic syndrome, increased waist circumference percentiles, and metabolic laboratory abnormalities, warranting early monitoring and lifestyle modifications. In addition, due to psoriasis chronic nature and frequently occurring relapses, psoriatic patients tend to have an impaired quality of life, often requiring long-term treatment. Therefore, education of both pediatric patients and their parents is essential to successful and safe disease management. However, systemic treatment of children is challenging as the absence of standardized guidelines and the fact that evidence-based data form randomized controlled trials are very limited. This review shows an overview of the current understanding of the pathogenesis, comorbidities, differential diagnosis, treatment and prevention of pediatric psoriasis, also presenting with an emphasis on the necessity of an integrated treatment approach involving different specialists such as dermatologist, pediatricians, rheumatologists, etc.


Submicron separation of microspheres via travelling surface acoustic waves.
Submicron separation is the segregation of particles having a diameter difference of less than one micrometre. We present an acoustofluidic particle separator with submicron separation resolution to study the continuous, label-free, and contactless separation of polystyrene (PS) particles based on their acoustofluidic parameters such as size, density, compressibility and shape. In this work, the submicron separation of PS microspheres, having a marginal size difference, is achieved inside a polydimethylsiloxane (PDMS) microfluidic channel via travelling surface acoustic waves (TSAWs). The TSAWs of different frequencies (200, 192, 155, and 129 MHz), propagating normal to the fluid flow direction inside the PDMS microchannel, realized continuous separation of particles with a diameter difference as low as 200 nm. A theoretical framework based on the rigid and elastic theories is presented to support the experimental results.


Knockdown of ZBED6 is not associated with changes in murine preadipocyte proliferation or differentiation.
ZBED6 was identified as a transcription factor that affects muscle mass and fat deposition in pigs. Mechanisms mediating effects on fat mass are unclear. The objective was to determine the effect of ZBED6 mRNA knockdown on 3T3-L1 preadipocyte differentiation and gene expression. Differentiation was associated with increased mRNA abundance of CEBP/α (P < 0.05), CEBP/β (P < 0.05), CEBP/δ (P < 0.05), FASN (P < 0.05), PPARγ (P < 0.05), and SREBP-1 (P < 0.05), and decreased abundance of PREF-1 (P < 0.05). Knockdown of ZBED6 was not associated with changes in mRNA abundance of selected genes, lipid accumulation, lipid droplet size, or cell number. These results suggest that ZBED6 does not play a major role in preadipocyte differentiation.


Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1.
Hypoxia-induced replication stress is one of the most physiologically relevant signals known to activate ATM in tumors. Recently, the ATM interactor (ATMIN) was identified as critical for replication stress-induced activation of ATM in response to aphidicolin and hydroxyurea. This suggests an essential role for ATMIN in ATM regulation during hypoxia, which induces replication stress. However, ATMIN also has a role in base excision repair, a process that has been demonstrated to be repressed and less efficient in hypoxic conditions. Here, we demonstrate that ATMIN is dispensable for ATM activation in hypoxia and in contrast to ATM, does not affect cell survival and radiosensitivity in hypoxia. Instead, we show that in hypoxic conditions ATMIN expression is repressed. Repression of ATMIN in hypoxia is mediated by both p53 and HIF-1α in an oxygen dependent manner. The biological consequence of ATMIN repression in hypoxia is decreased expression of the target gene, DYNLL1. An expression signature associated with p53 activity was negatively correlated with DYNLL1 expression in patient samples further supporting the p53 dependent repression of DYNLL1. Together, these data demonstrate multiple mechanisms of ATMIN repression in hypoxia with consequences including impaired BER and down regulation of the ATMIN transcriptional target, DYNLL1.


Adapting Urban Water Systems to Manage Scarcity in the 21st Century: The Case of Los Angeles.
Acute water shortages for large metropolitan regions are likely to become more frequent as climate changes impact historic precipitation levels and urban population grows. California and Los Angeles County have just experienced a severe four year drought followed by a year of high precipitation, and likely drought conditions again in Southern California. We show how the embedded preferences for distant sources, and their local manifestations, have created and/or exacerbated fluctuations in local water availability and suboptimal management. As a socio technical system, water management in the Los Angeles metropolitan region has created a kind of scarcity lock-in in years of low rainfall. We come to this through a decade of coupled research examining landscapes and water use, the development of the complex institutional water management infrastructure, hydrology and a systems network model. Such integrated research is a model for other regions to unpack and understand the actual water resources of a metropolitan region, how it is managed and potential ability to become more water self reliant if the institutions collaborate and manage the resource both parsimoniously, but also in an integrated and conjunctive manner. The Los Angeles County metropolitan region, we find, could transition to a nearly water self sufficient system.


Risk mapping using serologic surveillance for selected One Health and transboundary diseases in Cambodian goats.
In Cambodia, goat production and meat consumption are customary among Muslim communities. Recently, goat meat has gained popularity among Cambodians. Goat farmers use a traditional management system, including grazing, requiring minimal labour. The close proximity between humans and animals could increase the risk of zoonotic disease transmission. A serological survey was undertaken to estimate the prevalence of some priority zoonoses and high-impact animal diseases in the Cambodian goat population. A total of 540 samples were collected from goats in six provinces and analysed with commercially available enzyme-linked immunosorbent assays for Brucella species, Q fever (Coxiella burnetii), Foot and Mouth Disease virus non-structural protein (FMDV NSP) and Peste des Petits Ruminants virus (PPRV). True seroprevalences with a 95% Confidence Interval (CI), taking into account imperfect tests, risk factors and odds ratios (ORs), were calculated to better understand the disease distribution and epidemiology. Independent variables used in statistical modellings included sex, body condition score, age, vaccination history, province and commune, while dependent variables were ELISA test results. The overall true prevalence of antibodies to Brucella spp., C. burnetii, FMDV and PPRV, were 0.1% (95% CI 0.0, 1.0), 7.2% (95% CI 5.3, 9.7), 57.7% (95% CI 53.1, 62.3) and 0.0% (95% CI 0.0, 0.0), respectively. There was no identified risk factor for brucellosis and PPR. The two risk factors for C. burnetii seropositivity were sex (p-value = 0.0005) and commune (p-value <0.0001). However, only the OR of C. burnetii seropositive female goat was significant at 9.7 (95% CI 2.7, 35.5) times higher than male. The risk factors of FMD NSP seropositivity were age (p-value = 0.001) and commune (p-value <0.0001). Only the age 'more than two-year-old' group with a significant OR of 6.2 (95% CI 2.1, 18.4) using the 'up to one-year-old' group as the reference. In summary, Brucella spp. seroprevalence was low, while no evidence of PPRV antibodies was detected in the goat populations. C. burnetii seroprevalence in female goats was significantly higher than for males, and there were significant differences in C. burnetii seroprevalence between communes. The overall FMDV NSP seroprevalence was high, especially in older animals. Vaccination should be advocated to protect animals from FMDV and improve productivity. As the impacts of these zoonoses on human and animal health were still unknown, further investigation of these zoonotic diseases' epidemiology is recommended.


Coupled tandem cavities based electro-absorption modulator with asymmetric tandem quantum well for high modulation performance at low driving voltage.
We propose and demonstrate a new electro-absorption modulator (EAM) based on coupled tandem cavities (CTC) having asymmetric tandem quantum well (ATQW) structure with separated electrode configuration to achieve large transmittance change over a broad spectral range at low driving voltage for high definition (HD) 3D imaging applications. Our theoretical calculations show that CTC with ATQW structure can provide large transmittance change over a wide spectral range at low driving voltage. By introducing separated electrode configuration, the fabricated EAM having CTC with ATQW structure shows a large transmittance change over 50%, almost three times larger spectral bandwidth compared to that of EAM having single cavity with a single thickness quantum well without significantly increasing the applied voltage. In addition, the CTC with ATQW structure also shows high speed modulation up to 28 MHz for the device having a large area of 2 mm x 0.5 mm. This high transmittance change, large spectral bandwidth and low voltage operation over a large device area for the EAM having CTC with ATQW demonstrates their huge potential as an optical image modulator for HD 3D imaging applications.


Reduced dose human papillomavirus vaccination: an update of the current state-of-the-art.
Human papillomavirus (HPV) infection is the primary cause of genital warts, some oropharyngeal cancers and anogenital cancers, including cervical, vagina, vulvar, anal and penile cancers. Primary prevention of cervical cancer requires the prevention of high-risk HPV infections, particularly HPV genotypes 16 and 18. Both Gardasil® and Cervarix® vaccines when administered by a three-dose schedule have been demonstrated to be effective against cervical, vulva, and vaginal cancer precursors from vaccine genotypes in phase III clinical trials, and post-marketing studies; Gardasil® vaccine also offers additional protection against anal cancer precursors. However, high costs of HPV vaccines and the logistics of delivering a three-dose schedule over 6 months are challenging in countries with limited resources. Several studies have demonstrated non-inferiority in antibody response between adolescents (9-15 years old) who received two doses (6 months apart) and women (>15 years old) who received the standard three-dose schedule. These studies provided evidence for the World Health Organization and European Medical Association to revise its recommendation to give two instead of three doses of HPV vaccine to adolescents below 15 years of age, provided the 2nd dose is given 6 months apart. Although reduced dose schedules can alleviate costs and logistics associated with HPV vaccination, especially in resource-poor countries, there are still gaps in this area of research, particularly regarding long-term protection. This review discusses the findings on antibody response and clinical outcomes in studies evaluating reduced dose HPV schedules, and highlights the important considerations of its implementation. In addition, other important immunological biomarkers that may be associated with long-term protection are highlighted and discussed.


Ocrelizumab for Treating Patients with Primary Progressive Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.
Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12 weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24 weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee's preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.


Effect of dispersive conductivity and permittivity in volume conductor models of deep brain stimulation.
The aim of this study was to examine the effect of dispersive tissue properties on the volume-conducted voltage waveforms and volume of tissue activated during deep brain stimulation. Inhomogeneous finite-element models were developed, incorporating a distributed dispersive electrode-tissue interface and encapsulation tissue of high and low conductivity, under both current-controlled and voltage-controlled stimulation. The models were used to assess the accuracy of capacitive models, where material properties were estimated at a single frequency, with respect to the full dispersive models. The effect of incorporating dispersion in the electrical conductivity and relative permittivity was found to depend on both the applied stimulus and the encapsulation tissue surrounding the electrode. Under current-controlled stimulation, and during voltage-controlled stimulation when the electrode was surrounded by high-resistivity encapsulation tissue, the dispersive material properties of the tissue were found to influence the voltage waveform in the tissue, indicated by RMS errors between the capacitive and dispersive models of 20%-38% at short pulse durations. When the dispersive model was approximated by a capacitive model, the accuracy of estimates of the volume of tissue activated was very sensitive to the frequency at which material properties were estimated. When material properties at 1 kHz were used, the error in the volume of tissue activated by capacitive approximations was reduced to -4.33% and 11.10%, respectively, for current-controlled and voltage-controlled stimulations, with higher errors observed when higher or lower frequencies were used.


Spatiotemporal clustering of malaria in southern-central Ethiopia: A community-based cohort study.
Understanding the spatiotemporal clustering of malaria transmission would help target interventions in settings of low malaria transmission. The aim of this study was to assess whether malaria infections were clustered in areas with long-lasting insecticidal nets (LLINs) alone, indoor residual spraying (IRS) alone, or a combination of LLINs and IRS interventions, and to determine the risk factors for the observed malaria clustering in southern-central Ethiopia. A cohort of 34,548 individuals residing in 6,071 households was followed for 121 weeks, from October 2014 to January 2017. Both active and passive case detection mechanisms were used to identify clinical malaria episodes, and there were no geographic heterogeneity in data collection methods. Using SaTScan software v 9.4.4, a discrete Poisson model was used to identify high rates of spatial, temporal, and spatiotemporal malaria clustering. A multilevel logistic regression model was fitted to identify predictors of spatial malaria clustering. The overall incidence of malaria was 16.5 per 1,000 person-year observations. Spatial, temporal, and spatiotemporal clustering of malaria was detected in all types of malaria infection (P. falciparum, P. vivax, or mixed). Spatial clustering was identified in all study arms: for LLIN + IRS arm, a most likely cluster size of 169 cases in 305 households [relative risk (RR) = 4.54, P<0.001]; for LLIN alone arm a cluster size of 88 cases in 103 households (RR = 5.58, P<0.001); for IRS alone arm a cluster size of 58 cases in 50 households (RR = 7.15, P<0.001), and for control arm a cluster size of 147 cases in 377 households (RR = 2.78, P<0.001). Living 1 km closer to potential vector breeding sites increased the odds of being in spatial clusters by 41.32 fold (adjusted OR = 41.32, 95% CI = 3.79-138.89). The risk of malaria infection varied significantly between kebeles, within kebeles, and even among households in areas targeted for different types of malaria control interventions in low malaria transmission setting. The results of this study can be used in planning and implementation of malaria control strategies at micro-geographic scale. PACT R2014 11000 882128 (8 September 2014).


Significant regional variation in use of implantable cardioverter-defibrillators in Denmark.
Implantable cardioverter-defibrillator (ICD) treatment prevents sudden cardiac death in high-risk patients. This study examined geographical variation in ICD implantation rates in Denmark and potential causes of variation. We obtained numbers of ICD implantations in the 5 Danish regions and 98 municipalities during 2007-13 from the Danish Pacemaker and ICD Registry. Standardized implantation rates (SIRs) were computed as ICD implantations per 1 000 000 person-years, and age- and gender-standardized to the Danish population. We examined associations of the municipal SIR with mean age and Charlson Comorbidity Index score of ICD recipients, percentage of implantations with primary prophylactic indication, and distance from patient residency to ICD implanting centre. Based on 7192 ICD implantations, the nationwide SIR was 186 [95% confidence interval (CI) 182-190], ranging from 170 (95% CI 158-183) in the North Denmark Region to 206 (95% CI 195-218) in the Region of Zealand. Municipalities with higher patient comorbidity scores, higher percentages of implantations with primary prophylactic indication, and shorter distances to ICD implanting centres, had higher SIRs [differences between SIRs of municipalities in highest and lowest quartiles 22 (95% CI 10-34), 45 (95% CI 33-58), and 35 (95% CI 24-47), respectively]. Regional differences in SIRs decreased over time and had become insignificant during 2011-13. Implantable cardioverter-defibrillator implantation rates in Denmark varied significantly between regions but variation decreased during 2007-13. Geographical variation was associated with differences in patient comorbidity score, variation in use of primary prophylactic ICD treatment, and distance to ICD implanting centre.


Topical steroid for chronic rhinosinusitis without polyps.
Topical corticosteroid is used as part of a comprehensive medical treatment for chronic rhinosinusitis (CRS) without polyps. Nevertheless, there is insufficient evidence to show a clear overall benefit. Trials studying the efficacy of topical corticosteroid use various delivery methods in patients who have or have not had sinus surgery, which directly impacts on topical delivery and distribution. To assess the effects of topical steroid in patients with CRS without nasal polyps and perform a meta-analysis of symptom improvement data, including subgroup analysis by sinus surgery status and topical delivery methods. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the most recent search was 9 July 2010. All randomised trials in which a topically administered corticosteroid was compared with either a placebo, no treatment or alternative topically administered corticosteroid for the treatment of CRS without polyps in patients of any age. Two authors reviewed the search results and selected trials meeting the eligibility criteria, obtaining full texts and contacting authors where necessary. We documented our justification for the exclusion of studies. Two authors extracted data using a pre-determined standardised data form. Ten studies (590 patients) met the inclusion criteria. The trials were of low (six trials) and medium (four trials) risk of bias. The primary outcome was sino-nasal symptoms. When compared to placebo, topical steroid improved symptom scores (standardised mean difference -0.37; 95% confidence interval (CI) -0.60 to -0.13, P = 0.002; five trials, n = 286) and had a greater proportion of responders (risk ratio 1.69; 95% CI 1.21 to 2.37, P = 0.002; four trials, n = 263). With a limited number of studies, the subgroup analyses of patients who had received sinus surgery versus those who had not was not significant (P = 0.35). Subgroup analyses by topical delivery method revealed more benefit when steroid was administered directly to the sinuses than with simple nasal delivery (P = 0.04). There were no differences between groups for quality of life and adverse events. Topical steroid is a beneficial treatment for CRS without polyps and the adverse effects are minor. It may be included in a comprehensive treatment of CRS without polyps. Direct delivery of steroid to the sinuses may bring more beneficial effect. Further studies comparing different topical drug delivery methods to the sinuses, with appropriate treatment duration (longer than 12 weeks), are required.


HF-UNet: Learning Hierarchically Inter-Task Relevance in Multi-Task U-Net for Accurate Prostate Segmentation in CT Images.
Accurate segmentation of the prostate is a key step in external beam radiation therapy treatments. In this paper, we tackle the challenging task of prostate segmentation in CT images by a two-stage network with 1) the first stage to fast localize, and 2) the second stage to accurately segment the prostate. To precisely segment the prostate in the second stage, we formulate prostate segmentation into a multi-task learning framework, which includes a main task to segment the prostate, and an auxiliary task to delineate the prostate boundary. Here, the second task is applied to provide additional guidance of unclear prostate boundary in CT images. Besides, the conventional multi-task deep networks typically share most of the parameters (i.e., feature representations) across all tasks, which may limit their data fitting ability, as the specificity of different tasks are inevitably ignored. By contrast, we solve them by a hierarchically-fused U-Net structure, namely HF-UNet. The HF-UNet has two complementary branches for two tasks, with the novel proposed attention-based task consistency learning block to communicate at each level between the two decoding branches. Therefore, HF-UNet endows the ability to learn hierarchically the shared representations for different tasks, and preserve the specificity of learned representations for different tasks simultaneously. We did extensive evaluations of the proposed method on a large planning CT image dataset and a benchmark prostate zonal dataset. The experimental results show HF-UNet outperforms the conventional multi-task network architectures and the state-of-the-art methods.


Measurement of Choroidal Thickness Following Caffeine Intake in Healthy Subjects.
The aim of this study is to investigate the effect of 200 mg caffeine on subfoveal choroidal thickness (CT) in the macular area as measured by enhanced depth imaging optical coherence tomography (EDI-OCT) in healthy subjects. Fifty healthy individuals (study group) and 50 healthy individuals (control group) were enrolled in study. In the study group, participants received a 200 mg caffeine capsule and the control group consisted of subjects who received plasebo capsule. The subfoveal CT was measured by EDI-OCT before the caffeine intake and at 30 min, 1 h, 2 h, 3 h, 4 h and 6 h following caffeine intake. SFCT after caffeine intake was significantly decreased at 30 min, 1 h, 2 h, 3 h and 4 h compared to the baseline measurement, while the difference between baseline and 6 h was not statistically significant in the study group. There were no significant differences between the baseline and the other measurement times in the control group (p > 0.05). The thinning of CT begins about 30 min after the oral ingestion of 200 mg of caffeine and lasts for about four hours.


Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells.
Butyrate and its structural analogues have recently entered clinical trials as a potential drug for differentiation therapy of advanced prostate cancer. To better understand the molecular mechanism(s) involved in prostate cancer differentiation, we used mRNA differential display to identify the gene(s) induced by butyrate. We found that the androgen-independent prostate cancer cell line PC-3 undergoes terminal differentiation and apoptosis after treatment with sodium butyrate (NaBu). A novel cDNA designated carboxypeptidase A3 (CPA3), which was up-regulated in NaBu-treated PC-3 cells, was identified and characterized. This gene expresses a 2795-bp mRNA encoding a protein with an open reading frame of 421 amino acids. CPA3 has 37-63% amino acid identity with zinc CPs from different mammalian species. It also shares 27-43% amino acid similarity with zinc CPs from several nonmammalian species, including Escherichia coli, yeast, Caenorhabditis elegans, and Drosophila. The structural similarity between CPA3 and its closest homologues indicates that the putative CPA3 protein contains a 16-residue signal peptide sequence, a 95-residue NH2-terminal activation segment, and a 310-residue CP enzyme domain. The consistent induction of CPA3 by NaBu in several prostate cancer cell lines led us to investigate the signaling pathway involved in the induction of CPA3 mRNA. Trichostatin A, a potent and specific inhibitor of histone deacetylase, also induced CPA3 mRNA expression, suggesting that CPA3 gene induction is mediated by histone hyperacetylation. We demonstrated that CPA3 induction was a downstream effect of the treatment with butyrate or trichostatin A, but that the induction of p21(WAF1/CIP1) occurred immediately after these treatments. We also demonstrated that the induction of CPA3 mRNA by NaBu was inhibited by p21(WAF1/CIP1) antisense mRNA expression, indicating that p21 transactivation is required for the induction of CPA3 by NaBu. Our data demonstrate that the histone hyperacetylation signaling pathway is activated during NaBu-mediated differentiation of PC-3 cells, and the new gene, CPA3, is involved in this pathway.


Causes and timing of death in extremely premature infants from 2000 through 2011.
Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families. We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences. The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days. We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).


Tissue Destruction in Bullous Pemphigoid Can Be Complement Independent and May Be Mitigated by C5aR2.
Bullous pemphigoid (BP), the most frequent autoimmune bullous disorder, is a paradigmatic autoantibody-mediated disease associated with autoantibodies against BP180 (type XVII collagen, Col17). Several animal models have been developed that reflect important clinical and immunological features of human BP. Complement activation has been described as a prerequisite for blister formation, however, the recent finding that skin lesions can be induced by anti-Col17 F(ab')2 fragments indicates complement-independent mechanisms to contribute to blister formation in BP. Here, C5-/- mice injected with anti-Col17 IgG showed a reduction of skin lesions by about 50% associated with significantly less skin-infiltrating neutrophils compared to wild-type mice. Reduction of skin lesions and neutrophil infiltration was seen independently of the employed anti-Col17 IgG dose. Further, C5ar1-/- mice were protected from disease development, whereas the extent of skin lesions was increased in C5ar2-/- animals. Pharmacological inhibition of C5a receptor 1 (C5aR1) by PMX53 led to reduced disease activity when applied in a prophylactic setting. In contrast, PMX-53 treatment had no effect when first skin lesions had already developed. While C5aR1 was critically involved in neutrophil migration in vitro, its role for Col17-anti-Col17 IgG immune complex-mediated release of reactive oxygen species from neutrophils was less pronounced. Our data demonstrate that complement-dependent and -independent mechanisms coexist in anti-Col17-autoantibody-mediated tissue destruction. C5aR1 and C5aR2 seem to play opposing roles in this process with C5aR1 exerting its primary effect in recruiting inflammatory cells to the skin during the early phase of the disease. Further studies are required to fully understand the role of C5aR2 in autoantibody-mediated skin inflammation.


Phylogeny and genetic diversity of the banana Fusarium wilt pathogen Fusarium oxysporum f. sp. cubense in the Indonesian centre of origin.
Fusarium oxysporum f. sp. cubense (Foc), the causal agent of Fusarium wilt or Panama disease on banana, is one of the major constraints in banana production worldwide. Indonesia is the centre of origin for wild and cultivated bananas, which likely co-evolved with Foc. This study explored the widest possible genetic diversity of Foc by sampling across Indonesia at 34 geographically and environmentally different locations in 15 provinces at six islands. This resulted in a comprehensive collection of ∼200 isolates from 40 different local banana varieties. Isolates were identified and assessed using sequence analysis of the translation elongation factor-1alpha (tef1), the RNA polymerase II largest subunit (rpb1), and the RNA polymerase II second largest subunit (rpb2). Phylogenetic analyses of these genes allowed the identification of 180 isolates of Fusarium oxysporum f. sp. cubense (Foc), and 20 isolates of the Fusarium fujikuroi species complex (FFSC), the Fusarium incarnatum-equiseti species complex (FIESC), and the Fusarium sambucinum species complex (FSSC). Further analyses, incorporating a worldwide collection of Foc strains, revealed nine independent genetic lineages for Foc, and one novel clade in the Fusarium oxysporum species complex (FOSC). Selected isolates from each lineage were tested on the banana varieties Gros Michel and Cavendish to characterise their pathogenicity profiles. More than 65 % of the isolates were diagnosed as Tropical Race 4 (Foc-TR4) due to their pathogenicity to Cavendish banana, which supports the hypothesis that Foc-TR4 is of Indonesian origin. Nine independent genetic lineages for Foc are formally described in this study. This biodiversity has not been studied since the initial description of Foc in 1919. This study provides a detailed overview of the complexity of Fusarium wilt on banana and its diversity and distribution across Indonesia.


[A controlled clinical study on the efficacy of recombinant human interleukin-2 in the treatment of pulmonary tuberculosis].
To study and evaluate the efficacy and safety of recombinant human interleukin-2 (IL-2) in the treatment of pulmonary tuberculosis. Two hundred and nine cases with re-treated Mycobacterium tuberculosis-positive pulmonary tuberculosis were randomly divided into a trial group (106 cases, treated with 3PaZ (TH)L(2)VE(AK) + IL-2/4PaL(2)V) and a control group (103 cases, treated with 3PaZ(TH)L(2)VE(AK)/4PaL(2)V). The efficacy of 203 cases was available for evaluation when the course was completed (trial group 103 cases, control group 100 cases). The sputum smear-negative conversion rates at the 1st and the 2nd month of therapy were 33.3% and 69.4% in the trial group, and 7.2% and 44.9% in the control group (P < 0.01). At the completion of the therapy, the X-ray resolution rates were 64.1% and 36.0% respectively for the trial and the control groups, the difference being significant (P < 0.001). There were significant differences in CD(4) T cells, the ratio of CD(4)/CD(8) and NK cells between the two groups (P < 0.01). The level of soluble interleukin-2 receptor (sIL-2R) was significantly different between the two groups after treatment for 3 months (P < 0.05). IL-2 associated side effects were rare and mild. As an effective and relatively safe biological agent, IL-2 can be added to the standard chemotherapy for pulmonary tuberculosis.


A high biotin diet improves the impaired glucose tolerance of long-term spontaneously hyperglycemic rats with non-insulin-dependent diabetes mellitus.
The Otsuka Long-Evans Tokushima Fatty (OLETF) rat, serving as a spontaneously diabetic model with non-insulin-dependent diabetes mellitus (NIDDM), exhibits impaired glucose tolerance (IGT) at about 16 weeks of age. In this study, we investigated whether or not biotin, a water-soluble vitamin, improved the IGT of OLETF rats. To this end, we administered diets containing one of three levels of biotin, a high-biotin diet (BH), a normal-biotin diet (BN) and a basal-biotin diet (BB), to OLETF rats up to 24 weeks of age. An oral glucose tolerance test (OGTT) was performed four times between 13 and 22 weeks of age. The administration of a BH corrected the IGT of OLETF rats. Upon further investigation, we found that insulin secretion in the OLETF-BH rats was decreased to a significant extent, signaling that the hyperinsulinemia typical to the OLETF-BH rats had clearly improved. Body weights were significantly lower in the OLETF-BH group than in the other OLETF groups, even though the OLETF-BH rats showed a significantly higher average daily food intake. The body weight gain of the OLETF-BH rats followed the same tendency as the control-LETO (Long Evans Tokushima Otsuka) rats (LETO-BB and LETO-BN). These results demonstrate that a high-level biotin diet can improve the glucose handicap in NIDDM rats.


[Animal models of hereditary diseases].
A large number of genetic diseases are found both in humans and in one or several animal species. The mouse is a species of choice since, in addition to hundreds of spontaneous mutations which have been described, it is now possible to produce at will a mutation in any gene. This strategy has been used to generate genetically engineered mice which carry genetic defects found in human molecular pathology. Animal models are an invaluable tool to study the pathophysiology of diseases and to test new therapies. However, they are rarely exact replicates of the human disease. Possible origins for these differences are discussed in detail.


Pretargeting for the implantation of stimulation electrodes into the subthalamic nucleus: a comparative study of magnetic resonance imaging and ventriculography.
The optimal imaging modality for preoperative targeting of the subthalamic nucleus (STN) for high-frequency stimulation is controversially discussed. Commonly used methods were stereotactic magnetic resonance imaging (MRI), stereotactic ventriculography, and fusion between MRI and stereotactic computer tomography. All of these techniques not only have their own advantages but also specific limitations and drawbacks. The purpose of this study was to evaluate the accuracy of the preoperative MRI targeting as compared with ventriculography in terms of both the STN target as well as the internal landmarks. Thirty patients with Parkinson's disease who underwent bilateral surgery for STN-high-frequency stimulation received both stereotactic ventriculography and stereotactic MRI. The theoretical target was determined by each of these two imaging modalities. The final electrode placement was performed after extensive electrophysiological evaluation using microrecording and microstimulation. The real target was assumed to be given by the electrode contact with the best clinical result assessed by the United Parkinson's Disease Rating Scale in the postoperative follow-up. In addition, the coordinates of the two landmarks, anterior commissure and posterior commissure, were determined using both imaging methods. The mean targeting error was 4.1 +/- 1.7 mm (mean +/- standard deviation) for MRI and 2.4 +/- 1.1 mm for ventriculography (P < 0.0001). The mean target mismatch between the two imaging methods was 2.9 +/- 1.2 mm. The length of the anterior commissure-posterior commissure distance differed significantly (P < 0.0001) between MRI (27.6 +/- 1.6 mm) and ventriculography (25.0 +/- 1.3 mm). The mismatch was mainly induced by an anterior diplacement of the anterior commissure by 1.9 +/- 2.2 mm (P < 0.0001) in MRI determination, as compared with ventriculography. Our findings show that the indirect targeting of the STN using coordinates based on radiological landmarks is more accurate than the direct targeting using anatomic visualization of the target structure. Regardless of the imaging procedure, electrophysiological mapping is required for optimal electrode placement, although in 20% of cases, the target determined by MRI falls out of the radius explored by electrophysiology.


Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling.
The effect of glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide] on membrane potential, whole-cell ATP-sensitive potassium channel (K[ATP]) and Ca2+ currents, cytoplasmic Ca2+ concentration, and exocytosis was explored in single human beta-cells. GLP-1(7-36) amide induced membrane depolarization that was associated with inhibition of whole-cell K(ATP) current. In addition, GLP-1(7-36) amide (and forskolin) produced greater than fourfold potentiation of Ca2+-dependent exocytosis. The latter effect resulted in part (40%) from acceleration of Ca2+ influx through voltage-dependent (L-type) Ca2+ channels. More importantly, GLP-1(7-36) amide (via generation of cyclic AMP and activation of protein kinase A) potentiated exocytosis at a site distal to a rise in the cytoplasmic Ca2+ concentration. Photorelease of caged cAMP produced a two- to threefold potentiation of exocytosis when the cytoplasmic Ca2+ concentrations were clamped at > or =170 nmol/l. The effect of GLP-1(7-36) amide was antagonized by the islet hormone somatostatin. Similar effects on membrane potential, ion conductances, and exocytosis were observed with glucose-dependent insulinotropic polypeptide (GIP), the second major incretin. The present data suggest that the strong insulinotropic action of GLP-1(7-36) amide and GIP in humans results from its interaction with several proximal as well as distal important regulatory steps in the stimulus-secretion coupling.


Anytime Exploration for Multi-armed Bandits using Confidence Information.
We introduce anytime Explore-m, a pure exploration problem for multi-armed bandits (MAB) that requires making a prediction of the top-m arms at every time step. Anytime Explore-m is more practical than fixed budget or fixed confidence formulations of the top-m problem, since many applications involve a finite, but unpredictable, budget. However, the development and analysis of anytime algorithms present many challenges. We propose AT-LUCB (AnyTime Lower and Upper Confidence Bound), the first nontrivial algorithm that provably solves anytime Explore-m. Our analysis shows that the sample complexity of AT-LUCB is competitive to anytime variants of existing algorithms. Moreover, our empirical evaluation on AT-LUCB shows that AT-LUCB performs as well as or better than state-of-the-art baseline methods for anytime Explore-m.


The Association Between Perceived Stress and Mortality Among People With Multimorbidity: A Prospective Population-Based Cohort Study.
Multimorbidity is common and is associated with poor mental health and high mortality. Nevertheless, no studies have evaluated whether mental health may affect the survival of people with multimorbidity. We investigated the association between perceived stress and mortality in people with multimorbidity by following a population-based cohort of 118,410 participants from the Danish National Health Survey 2010 for up to 4 years. Information on perceived stress and lifestyle was obtained from the survey. We assessed multimorbidity using nationwide register data on 39 conditions and identified 4,229 deaths for the 453,648 person-years at risk. Mortality rates rose with increasing levels of stress in a dose-response relationship (P-trend < 0.0001), independently of multimorbidity status. Mortality hazard ratios (highest stress quintile vs. lowest) were 1.51 (95% confidence interval (CI): 1.25, 1.84) among persons without multimorbidity, 1.39 (95% CI: 1.18, 1.64) among those with 2 or 3 conditions, and 1.43 (95% CI: 1.18, 1.73) among those with 4 or more conditions, when adjusted for disease severities, lifestyle, and socioeconomic status. The numbers of excess deaths associated with high stress were 69 among persons without multimorbidity, 128 among those with 2 or 3 conditions, and 255 among those with 4 or more conditions. Our findings suggested that perceived stress contributes significantly to higher mortality rates in a dose-response pattern, and more stress-associated deaths occurred in people with multimorbidity.


The effects of body mass index on the treatment of the patients with migraine headaches.
Migraine is a prevalent disease which is classified into two groups of migraine with aura and without aura. Eighteen percent of women and 6.5 percent of men in United States have migraine headache. Migraine headache is prevalent in all age groups but it usually subsides in adults above fifty. Migraine has many risk factors such as stress, light, tiredness, special foods and beverages. The aim of this study was the evaluation of the effects of body mass index (BMI) on the treatment of migraine headaches. All patients assigned to four groups according to their BMI. Patients with more than three attacks per month received nortriptyline and propranolol for eight weeks. The frequency, duration and severity of pain were measured by visual analogue scale (VAS) and behavioral rating scale (BRS-6) in regular intervals. 203 patients completed the study. 153(75%) subjects were women and 50(25%) were men. Mean age of patients was 30.5 ± 7.1 years. Mean weight was 80.4 ± 14.1 kg and mean height was 1.67 ± 0.07 m. Pain frequency and duration showed statistically significant differences among four groups with better response in patients with lower BMI (P < 0.0001). VAS and BRS-6 scales showed statistically significant differences among four groups in favor of patients with lower BMI (P < 0.0001). This study showed that obesity has a direct influence on the treatment of migraine headaches. It could be recommended to patients to reduce their weight for better response to treatment. In addition, care should be taken about migraine drugs which make a tendency for increased appetite.


Recent advances in the pharmacological management of acute and chronic pain.
This review focuses on newer medications for the treatment of pain as well as on new guidelines and indications for the use of established medications. With regard to classical analgesics, the use of non-opioids and opioids is reviewed. Here are relevant new data on the use of the old substance acetaminophen as well as on non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and the newer COX-2 selective agents, which continue to be misunderstood. Amongst the opioids the new compound tapentadol with a new mechanism of action is presented as well as a number of new opioid preparations aiming to increase speed of onset of effect and to reduce abuse and diversion. Many medications, which were not originally developed to treat pain, are now used as components of multimodal analgesia or in specific indications. Here are of relevance anticonvulsants such as pregabalin and gabapentin, which were initially used for neuropathic pain, but are now used successfully in a wide range of indications from postoperative pain to fibromyalgia. The reason for this increased range of indications is the realization of the relevance of central sensitization processes for all pain states. Similarly, the use of antidepressants and the old dissociative anesthetic ketamine is increasing for the same reasons. Calcitonin has also found some new indications in difficult to treat pain conditions, while the discussion on the role of cannabinoids in pain management continues, partially driven by political issues. For localized neuropathic pain, there is increasing interest in topical preparations such as lidocaine and capsaicin patches, in particular in view of their minimal systemic adverse effects. Overall, recent advances in the pharmacological management of pain are not so much the result of new 'miracle' drugs, but new preparations and new ways to use old drugs in a variety of settings, often as components of a multimodal approach to pain relief.


Structural characterization and immunomodulatory effects of polysaccharides from Phellinus linteus and Phellinus igniarius on the IL-6/IL-10 cytokine balance of the mouse macrophage cell lines (RAW 264.7).
Phellinus linteus and igniarius (L.) Quel. have been used in traditional Asian medicine for over two centuries against a variety of diseases. Polysaccharides from their fruiting bodies show strong immunomodulatory activity. In this study we characterized the structure and composition of polysaccharides from Phellinus linteus and Phellinus igniarius by HPLC, GC-MS and NMR (1-H, 13-C, COSY, NOESY and TOCSY). The polysaccharides from P. linteus and P. igniarius mainly contained glucose with minor proportions of mannose, galactose, xylose, arabinose and rhamnose. Methylation analyses showed that the glycosidic linkages were mostly 1 → 3, 1 → 6 or 1 → 3,6. The two-dimensional COSY, NOESY and TOCSY confirmed that these polysaccharides have a main chain of →3)-β-D-Glcp-(1→ with →6)-β-D-Glcp-(1→ side chain. In vitro assays by RT-PCR and ELISA showed that (1 → 3; 1 → 6)-β-D-polysaccharides from P. linteus and P. igniarius decreased TNF-α in RAW 264.7 cells, suggesting an immuno-suppressive activity. Furthermore, these polysaccharides stimulated a high IL-10 response and induced strong suppression of transcription of IL-6. The results suggest that polysaccharides from P. linteus and P. igniarius could possibly find applications in restoring the IL-6/IL-10 balance, the disturbance of which is thought to be related to chronic inflammatory disease, obesity, diabetes type 2, and to mania and depression.


Defluvicoccus vanus gen. nov., sp. nov., a novel Gram-negative coccus/coccobacillus in the 'Alphaproteobacteria' from activated sludge.
A novel Gram-negative coccus/coccobacillus, strain Ben 114(T), growing in tetrads, clusters or aggregates, was isolated from activated sludge by micromanipulation. 16S rRNA gene sequence analysis revealed that it belonged to the 'Alphaproteobacteria', with no close relatives among cultured bacterial isolates. On the basis of phylogenetic data, this organism is considered to belong to a new genus, Defluvicoccus, represented by the species Defluvicoccus vanus sp. nov., a name chosen because of the distinctive staining properties of this organism; only the cell wall stained strongly with a wide range of stains, giving the cell a hollow and empty appearance. No intracellular polyphosphate granules could be detected after staining, but poly-beta-hydroxyalkanoate inclusions were detected using Nile blue A staining. Because of its taxonomic distance from its closest relatives among the 'Alphaproteobacteria', namely members of the genera Azospirillum, Phaeospirillum, Rhodospirillum, Rhodocista, Magnetospirillum and Rhodospira, D. vanus is considered to represent a new phylogenetic lineage within subgroup 1 of the 'Alphaproteobacteria', the D. vanus subgroup. The type strain is Ben 114(T) (=NCIMB 13612(T)=CIP 107350(T)).


Breast feeding and cognitive development at age 1 and 5 years.
To examine whether duration of breast feeding has any effect on a child's cognitive or motor development in a population with favourable environmental conditions and a high prevalence of breast feeding. In 345 Scandinavian children, data on breast feeding were prospectively recorded during the first year of life, and neuromotor development was assessed at 1 and 5 years of age. Main outcome measures were Bayley's Scales of Infant Development at age 13 months (Mental Index, MDI; Psychomotor Index, PDI), Wechsler Preschool and Primary Scales of Intelligence (WPPSI-R), and Peabody Developmental Scales at age 5. Children breast fed for less than 3 months had an increased risk, compared to children breast fed for at least 6 months, of a test score below the median value of MDI at 13 months and of WPPSI-R at 5 years. Maternal age, maternal intelligence (Raven score), maternal education, and smoking in pregnancy were significant confounders, but the increased risk of lower MDI and total IQ scores persisted after adjustment for each of these factors. We found no clear association between duration of breast feeding and motor development at 13 months or 5 years of age. Our data suggest that a longer duration of breast feeding benefits cognitive development.


Online Graph Completion: Multivariate Signal Recovery in Computer Vision.
The adoption of "human-in-the-loop" paradigms in computer vision and machine learning is leading to various applications where the actual data acquisition (e.g., human supervision) and the underlying inference algorithms are closely interwined. While classical work in active learning provides effective solutions when the learning module involves classification and regression tasks, many practical issues such as partially observed measurements, financial constraints and even additional distributional or structural aspects of the data typically fall outside the scope of this treatment. For instance, with sequential acquisition of partial measurements of data that manifest as a matrix (or tensor), novel strategies for completion (or collaborative filtering) of the remaining entries have only been studied recently. Motivated by vision problems where we seek to annotate a large dataset of images via a crowdsourced platform or alternatively, complement results from a state-of-the-art object detector using human feedback, we study the "completion" problem defined on graphs, where requests for additional measurements must be made sequentially. We design the optimization model in the Fourier domain of the graph describing how ideas based on adaptive submodularity provide algorithms that work well in practice. On a large set of images collected from Imgur, we see promising results on images that are otherwise difficult to categorize. We also show applications to an experimental design problem in neuroimaging.


Beta-microseminoprotein in serum correlates with the levels in seminal plasma of young, healthy males.
Beta-microseminoprotein (MSP) is one of the most abundant proteins secreted by the prostate gland. Because MSP is also synthesized in nonreproductive organs, the establishment of a solid relationship between the levels of MSP in serum and semen is crucial for future studies connecting MSP with aging or diseases of the prostate gland. We developed a specific, competitive, europium-based immunoassay to measure MSP in serum and seminal plasma. We also produced recombinant MSP in insect cells using baculo virus and purified it to homogeneity by a novel approach with ethanol extraction and gel filtration. The median values of MSP in 205 young men were 12 microg/L (2.5-97.5 percentile, 4.9-26 microg/L) in serum and 0.53 g/L (2.5-97.5 percentile, 0.13-2.0 g/L) or 1.8 mg (2.5-97.5 percentile, 0.32-6.6 mg) in seminal plasma. MSP in serum showed significant correlation to MSP in seminal plasma (r = .50, P < .001). Significant correlations were also found in seminal plasma between MSP and prostate-specific antigen (PSA) (r = .65, P < .001) and between MSP and Zn(2+) (r = .54, P < .001). The yield of recombinant MSP in culture medium was 35 mg/L or higher, and recovery following ethanol extraction was 80%-90%. MSP in serum reflects the prostate secretion of MSP, and correlations were also found in seminal plasma between MSP and PSA and Zn(2+). This suggests that MSP in serum can be used as a marker of prostate secretion, despite the contribution from extra prostatic tissues.


Factors Associated With Self-Reported Concussion History in Middle School Athletes.
Identifying personal characteristics associated with sustaining a concussion is of great interest, yet only a few have examined this in children. The purpose of this study was to examine the association between sex, neurodevelopmental disorders, health history, and lifetime history of self-reported concussion in 12- and 13-year-old athletes. Cross-sectional study. Middle schools. Participants were 1744 twelve- and thirteen-year-old student athletes who completed preseason Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) testing, including a self-report questionnaire about previous concussions, developmental diagnoses, and previous medical treatment. Age, sex, attention-deficit/hyperactivity disorder (ADHD), learning disabilities (LDs), and previous treatment for migraine. Self-reported history of concussion. A minority of athletes (13.7%) reported previous concussions (1 concussion, n = 181; 2 concussions, n = 41; and 3+ concussions, n = 17). A small proportion reported a history of ADHD (4.4%), LD (2.8%) or migraine treatment (4.0%). Higher rates of self-reported previous concussions were associated with male sex [16.9% vs 9.1%; χ(1) = 21.47, P < 0.001] and previous migraine treatment [31.9% vs 13.0%; χ(1) = 20.08, P < 0.001]. There were no differences in self-reported concussion history between 12- and 13-year olds (P = 0.18) and those with/without ADHD (P = 0.41) or LDs (P = 0.06). The overall logistic regression model was statistically significant [χ(5) = 42.01, P < 0.001] but explained only 4.3% of the variance. Previous treatment for migraine [P < 0.001, Exp(B) = 3.30] and male sex [P < 0.001, Exp(B) = 2.06] were independently associated with a self-reported concussion history, whereas age, LD, and ADHD were not (P's > 0.05). Male sex and previous migraine treatment were associated with higher rates of self-reported previous concussions in both independent and multivariate models in middle school athletes, whereas age, ADHD, and LDs were not.


Adverse drug reaction profile of daily regimen antituberculosis treatment.
The objective was to estimate the proportion of adverse drug reactions (ADRs) to daily regimen antituberculosis treatment (ATT) among the ADRs received in the ADR monitoring center (AMC) of the institution and to describe its pattern. This was a descriptive study conducted in the Department of Pharmacology of a Government Medical College in Central Kerala and the period under study was October 2017-June 2020. The data on ADR were entered into a structured pro forma and data were analyzed using SPSS for Windows Version 16.0 (SPSS Inc., Chicago, USA). Of the 643 ADRs, 98 (15.24%) were suspected to be due to the daily regimen of ATT. The most common organ system affected was hepatobiliary 46 (46.9%) namely hepatitis in 35 and asymptomatic elevated liver enzymes in 11 followed by eye with 26 reports of decreased vision. In 96 (97.95%), the suspected ADR had probable causality and in 2 (2.04%) it was possible. Seventy-seven (78.6%) ADR reports were serious as well as moderate-level 4b in severity and 57 (58.16%) were probably preventable. The mean days of onset of ADR after starting the ATT regimen were 56.40 ± 58.29 days (range 1-180). Decrease in vision with a mean duration of 125.23 ± 55.46 days had the longest latency in onset among all the ADRs. Of all the ADRs reported to AMC 15.24% were due to the daily regimen of ATT. Hepatitis was the most common ADR encountered followed by decrease in vision. The majority of the ADRs were probable in causality, serious, moderate-level 4b in severity, and probably preventable.


Self-regulation, alcohol consumption, and consequences in college student heavy drinkers: a simultaneous latent growth analysis.
Lower levels of self-regulation have been associated with higher rates of alcohol-related consequences. Self-regulation refers to the effortful ability to plan and achieve delayed adaptive outcomes through goal-directed behavior, and this skill may play a role in adaptive behavioral change. The purpose of this prospective, longitudinal study was to test predictions from self-regulation theory about the relationship among self-regulation and weekly alcohol consumption and alcohol-related consequences over 12 months. Participants were 170 heavy drinking college students who provided data on alcohol use and consequences at baseline and at 1-, 6-, and 12-month assessments. Using a simultaneous latent growth model, self-regulation ability predicted the amount of initial alcohol-related consequences, the rate of change for alcohol-related consequences, and the rate of change for drinks per week. In contrast, self-regulation was not related to the initial level of alcohol use. Collectively, these results suggest that lower self-regulation ability functions as a risk factor for experiencing alcohol-related consequences and attenuates naturally occurring reductions in alcohol use and consequences over time for heavier drinking college students.


Indoor air pollution (PM2.5) due to secondhand smoke in selected hospitality and entertainment venues of Karachi, Pakistan.
To determine particulate matter smaller than 2.5 μm (PM(2.5)) levels at various hospitality and entertainment venues of Karachi, Pakistan. This was a descriptive cross-sectional study conducted at various locations in Karachi, during July 2009. Sampling was performed at 20 enclosed public places, including hospitality (restaurants and cafés) and entertainment (snooker/billiard clubs and gaming zones) venues. PM(2.5) levels were measured using an aerosol monitor. All entertainment venues had higher indoor PM(2.5) levels as compared to the immediate outdoors. The indoor PM(2.5) levels ranged from 25 to 390 μg/m(3) and the outdoor PM(2.5) levels ranged from 18 to 96 μg/m(3). The overall mean indoor PM(2.5) level was 138.8 μg/m(3) (± 112.8). Among the four types of venues, the highest mean indoor PM(2.5) level was reported from snooker/billiard clubs: 264.7 μg/m(3) (± 85.4) and the lowest from restaurants: 66.4 μg/m(3) (± 57.6) while the indoor/outdoor ratio ranged from 0.97 to 10.2, highest being at the snooker/billiard clubs. The smoking density ranged from 0.21 to 0.57, highest being at gaming zones. The indoor PM(2.5) concentration and smoking density were not significantly correlated (Spearman's correlation coefficient = 0.113; p = 0.636). This study demonstrates unacceptably high levels of PM(2.5) exposure associated with secondhand smoke (SHS) at various entertainment venues of Karachi even after 8 years since the promulgation of smoke-free ordinance (2002) in Pakistan; however, better compliance may be evident at hospitality venues. The results of this study call for effective implementation and enforcement of smoke-free environment at public places in the country.


Hypocretin (orexin) cell loss in Parkinson's disease.
It has recently been reported that Parkinson's disease (PD) is preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behaviour disorder, hallucinations and depression, symptoms which are frequently as troublesome as the motor symptoms of PD. All these symptoms are present in narcolepsy, which is linked to a selective loss of hypocretin (Hcrt) neurons. In this study, the Hcrt system was examined to determine if Hcrt cells are damaged in PD. The hypothalamus of 11 PD (mean age 79 +/- 4) and 5 normal (mean age 77 +/- 3) brains was examined. Sections were immunostained for Hcrt-1, melanin concentrating hormone (MCH) and alpha synuclein and glial fibrillary acidic protein (GFAP). The substantia nigra of 10 PD brains and 7 normal brains were used for a study of neuromelanin pigmented cell loss. The severity of PD was assessed using the Hoehn and Yahr scale and the level of neuropathology was assessed using the Braak staging criteria. Cell number, distribution and size were determined with stereologic techniques on a one in eight series. We found an increasing loss of hypocretin cells with disease progression. Similarly, there was an increased loss of MCH cells with disease severity. Hcrt and MCH cells were lost throughout the anterior to posterior extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage I (23%) and was maximal in stage V (62%). Similarly, the percentage loss of MCH cells was lowest in stage I (12%) and was highest in stage V (74%). There was a significant increase (P = 0.0006, t = 4.25, df = 15) in the size of neuromelanin containing cells in PD patients, but no difference in the size of surviving Hcrt (P = 0.18, t = 1.39, df = 14) and MCH (P = 0.28, t = 1.39, df = 14) cells relative to controls. In summary, we found that PD is characterized by a massive loss of Hcrt neurons. Thus, the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and may be ameliorated by treatments aimed at reversing the Hcrt deficit. We also saw a substantial loss of hypothalamic MCH neurons. The losses of Hcrt and MCH neurons are significantly correlated with the clinical stage of PD, not disease duration, whereas the loss of neuromelanin cells is significantly correlated only with disease duration. The significant correlations that we found between the loss of Hcrt and MCH neurons and the clinical stage of PD, in contrast to the lack of a relationship of similar strength between loss of neuromelanin containing cells and the clinical symptoms of PD, suggests a previously unappreciated relationship between hypothalamic dysfunction and the time course of the overall clinical picture of PD.


Cyst volume changes measured with a 3D reconstruction after decompression of a mandibular dentigerous cyst with an impacted third molar.
The aim of this article is to describe a large mandibular cyst treated with decompression followed by surgical enucleation. Furthermore, we described the utility of cyst volume measurements by using a 3D reconstruction on Cone Beam Computed Tomography (CBCT). The dentigerous cyst is the most common cyst type of epithelial origin, arising from remnants of odontogenic epithelium, asymptomatic and associated with the crown of an unerupted or partially or completely impacted tooth. However, after a long duration and extension of the cyst volume it may provoke significant bone resorption, cortical expansion, tooth displacement and the vitality of neighboring teeth may be affected. The regular treatment of this lesion is enucleation and extraction of the involved tooth. Marsupialization and decompression are proposed when the volume of the cyst is well developed to release the cystic pressure and allow the bone cavity to progressively decrease in volume with the gradual apposition of bone. This report presents a large dentigerous cyst related to impacted mandibular third molar of a 21-year-old male patient. The cyst was treated successfully by decompression and later by surgical enucleation with surgical extraction of the related molar. In conclusion, the combination of decompression and surgical approach showed on the three-dimensional CBCT investigation a significant correlation between the treatment and volume reduction of the cyst. The clinical case described allows us to observe bone formation after decompression and surgical enucleation was performed with less risk on vital anatomic elements.


Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial.
Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters. Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test. A subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance. Our data suggest melatonin as an aid during benzodiazepine withdrawal for patients distressed by disrupted circadian rest-activity cycles. Benzodiazepine tapering might result in diminished sedentary behavior but further research is needed. ClinicalTrials NCT01431092 , clinicaltrials.gov. Registered 31 August 2011.


ISHNE/EHRA expert consensus on remote monitoring of cardiovascular implantable electronic devices (CIEDs).
We are in the midst of a rapidly evolving era of technology-assisted medicine. The field of telemedicine provides the opportunity for highly individualized medical management in a way that has never been possible before. Evolving medical technologies using cardiac implantable devices with capabilities for remote monitoring permit evaluation of multiple parameters of cardiovascular physiology and risk, including cardiac rhythm, device function, blood pressure values, the presence of myocardial ischaemia, and the degree of compensation of congestive heart failure. Cardiac risk, device status, and response to therapies can now be assessed with these electronic systems of detection and reporting. This document reflects the extensive experience from investigators and innovators around the world who are shaping the evolution of this rapidly expanding field, focusing in particular on implantable pacemakers, implantable cardioverter defibrillators, devices for cardiac resynchronization therapy (both with and without defibrillation properties), loop recorders, and hemodynamic monitoring devices. This document covers the basic methodologies, guidelines for their use, experience with existing applications, and the legal and reimbursement aspects associated with their use. To adequately cover this important emerging topic, the International Society for Holter and Noninvasive Electrocardiology and the European Heart Rhythm Association combined their expertise in this field. We hope that the development of this field can contribute to improve care of our cardiovascular patients.


L-DOPA and serotonergic neurons: functional implication and therapeutic perspectives in Parkinson's disease.
L-DOPA is the gold standard medication of Parkinson's disease, a neurological disorder consequent upon the degeneration of mesencephalic dopaminergic neurons. The therapeutic efficacy of L-DOPA has been related to its ability to restore dopamine (DA) extracellular levels in the Parkinsonian brain. The origin of the L-DOPA-induced rise in DA has been the object of numerous studies and controversies but the data collectively point to serotonergic (5-HT) neurons as being most significant in the release. Here, we review biochemical and behavioral evidence supporting serotonergic neurons as playing the main role in the actions of L-DOPA, considered from two points of view. The main aspect concerns the biochemical demonstration that 5-HT neurons are almost solely implicated in the release of DA induced by L-DOPA. The mechanism of action of L-DOPA inside 5-HT neurons will be thoroughly dissected on the basis of L-DOPA effects on extracellular versus tissue DA levels. The unique contribution of 5-HT neurons in mediating the release of newly synthesised DA from L-DOPA will be discussed in parallel with DA-dependent behaviors induced by L-DOPA. The other, and neglected, aspect concerns the possible deleterious impact of the presence of L-DOPA inside 5-HT neurons on 5-HT neuronal function. Overall, the fact that 5-HT neurons release the newly synthesised DA from L-DOPA in multiple brain regions beyond the striatum gives new insight into the large impact of L-DOPA in the Parkinsonian brain and strengthens therapeutic perspectives targeting the 5-HT system to reduce both motor and non-motor complications of L-DOPA medication.


Infection control hazards associated with the use of forced-air warming in operating theatres.
A review is presented of the published experimental and clinical research into the infection control hazards of using forced air-warming (FAW) in operating theatres to prevent inadvertent hypothermia. This evidence has been reviewed with emphasis on the use of ultra-clean ventilation, any interaction it has with different types of patient warming (and FAW in particular), and any related increased risk of surgical site infection (SSI). We conclude that FAW does contaminate ultra-clean air ventilation; however, there appears to be no definite link to an increased risk of SSI based on current research. Nevertheless, whereas this remains unproven, we recommend that surgeons should at least consider alternative patient-warming systems in areas where contamination of the operative field may be critical. Although this is not a systematic review of acceptable randomized controlled clinical trials, which do not exist, it does identify that there is a need for definitive research in this field.


G protein-coupled receptor-mediated activation of p110β by Gβγ is required for cellular transformation and invasiveness.
Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110β is specifically implicated in various physiological and pathophysiological processes, such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110β-dependent functions, we identified the site in p110β that binds to the Gβγ subunit of G proteins. Mutation of this site eliminated Gβγ-dependent activation of PI3Kβ (a dimer of p110β and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110β-Gβγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kβ in fibroblasts and reduced the proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kβ could provide a therapeutic approach for tumors that depend on p110β for growth and metastasis.


Sublethal toxicity of the Prestige oil spill on yellow-legged gulls.
The Prestige oil spill in November 2002 is considered the biggest large-scale catastrophe of its type in Europe, thousands of seabirds dying in the subsequent months. Here, the total concentration of 16 polycyclic aromatic hydrocarbons (TPAH) was measured in the blood cell fraction of adult and chick yellow-legged gulls (Larus michahellis) from unoiled and oiled coastal areas in North Western Spain. In addition, hematocrit, plasma metabolites, electrolytes and enzymes, as well as body mass were determined in the same individuals. Our results strongly suggest the presence of health damages of sublethal nature in adult gulls breeding in oiled colonies 17 months after the Prestige oil spill. This is supported by the following evidences: (1) gulls sampled in unoiled and oiled colonies differed in blood TPAH levels, (2) gulls sampled in unoiled and oiled colonies differed in several blood parameters indicative of physiological disorders, and (3) TPAH in blood was significantly related to several of these parameters. Differences in the level of asparatate aminotransferase (AST), gamma-glutamyl transferase (GGT), total protein, glucose and inorganic phosphorus suggest damages on some vital organs (i.e. liver and kidney) in adult birds from oiled areas. Meanwhile, chicks presented weaker effects than adults, showing only between-area differences in hematocrit. Since TPAH levels in blood did not differ between both age-groups, the stronger effects on adults should be due to their longer exposure to these pollutants and/or to severe exposure in the months following the spill. The presence of PAHs in chicks indicates that these pollutants were incorporated into the food chain because nestlings would have been only exposed to contaminated organisms in the diet (e.g. fishes and crustaceans). Our findings support the view that PAHs may deeply alter the physiology of seabirds, and emphasize the necessity of quantifying the circulating levels of these compounds in order to evaluate the sublethal effects associated to large oil spills.


Inactivation of indicator microorganisms and biological hazards by standard and/or alternative processing methods in Category 2 and 3 animal by-products and derived products to be used as organic fertilisers and/or soil improvers.
The European Commission requested EFSA to assess if different thermal processes achieve a 5 log10 reduction in Enterococcus faecalis or Salmonella Senftenberg (775W) and (if relevant) a 3 log10 reduction in thermoresistant viruses (e.g. Parvovirus) as well as if different chemical processes achieve a 3 log10 reduction of eggs of Ascaris sp., in eight groups of Category 2 and 3 derived products and animal by-products (ABP). These included (1) ash derived from incineration, co-incineration and combustion; (2) glycerine derived from the production of biodiesel and renewable fuels; (3) other materials derived from the production of biodiesel and renewable fuels; (4) hides and skins; (5) wool and hair; (6) feathers and down; (7) pig bristles; and (8) horns, horn products, hooves and hoof products. Data on the presence of viral hazards and on thermal and chemical inactivation of the targeted indicator microorganisms and biological hazards under relevant processing conditions were extracted via extensive literature searches. The evidence was assessed via expert knowledge elicitation. The certainty that the required log10 reductions in the most resistant indicator microorganisms or biological hazards will be achieved for each of the eight groups of materials mentioned above by the thermal and/or chemical processes was (1) 99-100% for the two processes assessed; (2) 98-100% in Category 2 ABP, at least 90-99% in Category 3 ABP; (3) 90-99% in Category 2 ABP; at least 66-90% in Category 3 ABP; (4) 10-66% and 33-66%; (5) 1-33% and 10-50%; (6) 66-90%; (7) 33-66% and 50-95%; (8) 66-95%, respectively. Data generation on the occurrence and reduction of biological hazards by thermal and/or chemical methods in these materials and on the characterisation of the usage pathways of ABP as organic fertilisers/soil improvers is recommended.


Neurotransmitter phenotype-specific expression changes in developing sympathetic neurons.
During late developmental phases individual sympathetic neurons undergo a switch from noradrenergic to cholinergic neurotransmission. This phenomenon of plasticity depends on target-derived signals in vivo and is triggered by neurotrophic factors in neuronal cultures. To analyze genome-wide expression differences between the two transmitter phenotypes we employed DNA microarrays. RNA expression profiles were obtained from chick paravertebral sympathetic ganglia, treated with neurotrophin 3, glial cell line-derived neurotrophic factor or ciliary neurotrophic factor, all of which stimulate cholinergic differentiation. Results were compared with the effect of nerve growth factor, which functions as a pro-noradrenergic stimulus. The gene set common to all three comparisons defined the noradrenergic and cholinergic synexpression groups. Several functional categories, such as signal transduction, G-protein-coupled signaling, cation transport, neurogenesis and synaptic transmission, were enriched in these groups. Experiments based on the prediction that some of the identified genes play a role in the neurotransmitter switch identified bone morphogenetic protein signaling as an inhibitor of cholinergic differentiation.