Noncoding RNAs as emerging regulators of Plasmodium falciparum virulence gene expression.
The eukaryotic unicellular pathogen Plasmodium falciparum tightly regulates gene expression, both during development and in adaptation to dynamic host environments. This regulation is evident in the mutually exclusive expression of members of clonally variant virulence multigene families. While epigenetic regulators have been selectively identified at active or repressed virulence genes, their specific recruitment remains a mystery. In recent years, noncoding RNAs (ncRNAs) have emerged as lynchpins of eukaryotic gene regulation; by binding to epigenetic regulators, they provide target specificity to otherwise non-specific enzyme complexes. Not surprisingly, there is great interest in understanding the role of ncRNA in P. falciparum, in particular, their contribution to the mutually exclusive expression of virulence genes. The current repertoire of P. falciparum ncRNAs includes, but is not limited to, subtelomeric ncRNAs, virulence gene-associated ncRNAs and natural antisense RNA transcripts. Continued improvement in high-throughput sequencing methods is sure to expand this repertoire. Here, we summarize recent advances in P. falciparum ncRNA biology, with an emphasis on ncRNA-mediated epigenetic modes of gene regulation.


Rational design of anticytoadherence inhibitors for Plasmodium falciparum based on the crystal structure of human intercellular adhesion molecule 1.
Adhesion of Plasmodium falciparum-infected erythrocytes (IE) to host endothelium has been associated with pathology in malaria. Although the interaction with endothelial cells can be complex due to the relatively large number of host receptors available for binding, specific proteins have been identified that are more commonly used than others. For example, binding to intercellular adhesion molecule 1 (ICAM 1) is found frequently in parasites from pediatric cases of malaria. The binding site for P. falciparum-infected erythrocytes on ICAM 1 has been mapped in some detail and is distinct from the site for lymphocyte function-associated antigen 1 (LFA-1). Part of the ICAM 1 binding site for P. falciparum-infected erythrocytes (the DE loop) was used to screen a library of compounds based on its structure (derived from the crystal structure of human ICAM 1). This resulted in the identification of 36 structural mimeotopes as potential competitive inhibitors of binding. One of these compounds, (+)-epigalloyl-catechin-gallate [(+)-EGCG], was found to inhibit IE adhesion to ICAM 1 in a dose-dependent manner with two variant ICAM 1-binding parasite lines, providing the first example of a potential mimeotope-based anticytoadherence inhibitor for Plasmodium falciparum.


Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families.
Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene have been reported in 15-40% of FIPA patients. Limited data are available on the functional consequences of the mutations or regarding the regulation of the AIP gene. We describe a large cohort of FIPA families and characterize missense and silent mutations using minigene constructs, luciferase and beta-galactosidase assays, as well as in silico predictions. Patients with AIP mutations had a lower mean age at diagnosis (23.6+/-11.2 years) than AIP mutation-negative patients (40.4+/-14.5 years). A promoter mutation showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein-protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In summary, exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in our FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants.


Accelerating invasion rate in a highly invaded estuary
Biological invasions are a major global environmental and economic problem. Analysis of the San Francisco Bay and Delta ecosystem revealed a large number of exotic species that dominate many habitats in terms of number of species, number of individuals and biomass, and a high and accelerating rate of invasion. These factors suggest that this may be the most invaded estuary in the world. Possible causes include a large number and variety of transport vectors, a depauperate native biota, and extensive natural and anthropogenic disturbance.


Cardiopulmonary effects of positive pressure ventilation during acute lung injury.
To assess the gas exchange and hemodynamic effects of pressure-limited ventilation (PLV) strategies in acute lung injury (ALI). We hypothesized that in ALI, the reduction of plateau airway pressure (Paw) would be associated with less alveolar overdistention and thus have better hemodynamic and gas exchange characteristics than larger tidal volume (Vr) ventilation. Laboratory. Prospective time-controlled sequential animal study. Right atrial, pulmonary artery, left atrial, arterial, lateral pleural (Ppl), and pericardial (Ppc) pressures, Paw, ventricular stroke volume, mean expired CO2, and arterial and mixed venous oxygen contents. Airway resistance and static lung compliance were also measured. Intermittent positive pressure ventilation (IPPV) given before (control) and after induction of ALI by oleic acid infusion (0.1 mL/kg). IPPV at FIO2 of 1, VT of 12 mL/kg, and frequency adjusted to maintain normocarbia. ALI PLV was given during ALI and defined as that VT which gave a similar plateau Paw to that of control IPPV. High-frequency jet ventilation (HFJV) and ALI HFJV were also given and defined as frequency within 10% of heart rate and mean Paw similar to that during control IPPV. After ALI, static lung compliance, PaO2, and pH decreased, whereas airway resistance and PaCO2 increased. For a constant lung volume, Ppl and Ppc were not different between control and ALI. Both absolute dead space (VD) and intrapulmonary shunt fraction increased after ALI, but absolute VD was lower with ALI PLV and ALI HFJV when compared with ALI IPPV. Ventilation did not alter hemodynamics during ALI. Changes in lung volume determine Ppc and Ppl. PLV strategies do not alter hemodynamics but result in less of an increase in VD/VT than would be predicted from the obligatory decrease in VT.


Automated Quantitative Assessment of Coronary Calcification Using Intravascular Ultrasound.
Coronary calcification represents a challenge in the treatment of coronary artery disease by stent placement. It negatively affects stent expansion and has been related to future adverse cardiac events. Intravascular ultrasound (IVUS) is known for its high sensitivity in detecting coronary calcification. At present, automated quantification of calcium as detected by IVUS is not available. For this reason, we developed and validated an optimized framework for accurate automated detection and quantification of calcified plaque in coronary atherosclerosis as seen by IVUS. Calcified lesions were detected by training a supported vector classifier per IVUS A-line on manually annotated IVUS images, followed by post-processing using regional information. We applied our framework to 35 IVUS pullbacks from each of the three commonly used IVUS systems. Cross-validation accuracy for each system was >0.9, and the testing accuracy was 0.87, 0.89 and 0.89 for the three systems. Using the detection result, we propose an IVUS calcium score, based on the fraction of calcium-positive A-lines in a pullback segment, to quantify the extent of calcified plaque. The high accuracy of the proposed classifier suggests that it may provide a robust and accurate tool to assess the presence and amount of coronary calcification and, thus, may play a role in image-guided coronary interventions.


Prediction of function for the polyprenyl transferase subgroup in the isoprenoid synthase superfamily.
The number of available protein sequences has increased exponentially with the advent of high-throughput genomic sequencing, creating a significant challenge for functional annotation. Here, we describe a large-scale study on assigning function to unknown members of the trans-polyprenyl transferase (E-PTS) subgroup in the isoprenoid synthase superfamily, which provides substrates for the biosynthesis of the more than 55,000 isoprenoid metabolites. Although the mechanism for determining the product chain length for these enzymes is known, there is no simple relationship between function and primary sequence, so that assigning function is challenging. We addressed this challenge through large-scale bioinformatics analysis of >5,000 putative polyprenyl transferases; experimental characterization of the chain-length specificity of 79 diverse members of this group; determination of 27 structures of 19 of these enzymes, including seven cocrystallized with substrate analogs or products; and the development and successful application of a computational approach to predict function that leverages available structural data through homology modeling and docking of possible products into the active site. The crystallographic structures and computational structural models of the enzyme-ligand complexes elucidate the structural basis of specificity. As a result of this study, the percentage of E-PTS sequences similar to functionally annotated ones (BLAST e-value ≤ 1e(-70)) increased from 40.6 to 68.8%, and the percentage of sequences similar to available crystal structures increased from 28.9 to 47.4%. The high accuracy of our blind prediction of newly characterized enzymes indicates the potential to predict function to the complete polyprenyl transferase subgroup of the isoprenoid synthase superfamily computationally.


Hydrogen in Patients With Corticosteroid-Refractory/Dependent Chronic Graft-Versus-Host-Disease: A Single-Arm, Multicenter, Open-Label, Phase 2 Trial.
Chronic graft-versus-host-disease (cGVHD) is the leading cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation(HSCT). There is no standard therapy for patients refractory or dependent to corticosteroid treatment. We hypothesized that hydrogen may exert therapeutic effects on cGVHD patients with few side effects. A prospective open-label phase 2 study of hydrogen was conducted. Patients received hydrogen-rich water 4ml/kg orally three times a day. Responses were graded in the skin, mouth, Gastrointestinal(GI), liver, eyes, lungs and joints and fascia every 3 months. A total of 24 patients (median age 27) were enrolled. Of the 24 patients, 18 (75%; 95% CI, 55.1% to 88%) had an objective response. No significant toxicity was observed. The estimated 4-year overall survival rate was 74.7%(95% CI, 54.9%-94.5%). The survival time was significantly prolonged in the response group. The survival rate at 4 years in the response group is significantly higher than the nonresponse group (86.6% vs 0%; p= 0.000132). Hydrogen showed great efficacy on cGVHD patients and long-term administration of hydrogen was not associated with significant toxic effects. The trial was registered at www.ClinicalTrials.Gov, NCT02918188.


Investigating perceptual features of electrode stimulation via a multidimensional scaling paradigm.
To achieve the most effective speech processing for individuals with cochlear implants, it is important to understand the perceptual features associated with the stimulation parameters. In general, when electrodes are stimulated in order from apex to base, the pitch of the perceived sound changes in an orderly fashion from low to high. Some deviations from this assumed order have been documented. Also, pitch is the dominant perceptual attribute of a sound when the stimuli associated with different electrodes have been accurately loudness balanced. In this study, the results of a multidimensional scaling (MDS) paradigm were compared to the results of a pitch-ranking procedure for six subjects implanted with multichannel cochlear prostheses. Results indicate that there may be multiple percepts that change with electrode location. Not surprisingly, the dominant percept is strongly correlated with pitch. The results also indicate that the structure of the second percept is consistent across subjects, although not interpretable using the data measured in this study. Furthermore, results indicate that MDS data can be used to pinpoint indiscriminable electrodes more accurately than pitch data. The results of this study may have importance for the design of the next generation of speech processors.


Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction.
To determine (1) clinical features that distinguish maculopathy due to the R345W substitution in fibulin-3 from other forms of inherited or early-onset drusen, (2) the phenotypic variability, and (3) the extent of retinal disease in those with a positive molecular diagnosis. Affected individuals underwent ophthalmic examination, digital color fundus photography, fundus autofluorescence (AF) imaging, and psychophysical testing with automated photopic and dark-adapted perimetry and fine matrix mapping. Blood samples were taken for DNA extraction and screening for the R345W mutation in fibulin-3. Patients were subsequently divided into mutation-positive and -negative groups, to compare the identified phenotypic findings in these two sets of subjects. Twenty-nine subjects from 19 families were ascertained with inherited or early-onset drusen. Twenty-four (83%) subjects from 15 families were found to harbor the R345W fibulin-3 mutation. Peripapillary deposition and a radial distribution of macular drusen were consistent, distinguishing signs in the mutation-positive group. Subretinal neovascular membrane (SRNVM) was a rare occurrence, affecting only 1 of 48 eyes, whereas hyperpigmentation and atrophy of the retinal pigment epithelium (RPE) were common in older mutation-positive patients. Increased AF corresponding to the drusen was detected in both the mutation-positive and -negative groups. The phenotype in the group of patients positive for the R345W mutation was extremely variable, with evidence of interocular, intrafamilial, and interfamilial variability in visual loss, natural history, ophthalmoscopic findings, autofluorescence imaging, and psychophysical data. The novel finding of nonpenetrance was observed in a 62-year-old asymptomatic, mutation-positive man. The findings from detailed perimetry performed on a subset of subjects were consistent with the presence of widespread retinal dysfunction not isolated to the macula. Marked inter- and intrafamilial variation associated with the fibulin-3 R345W mutation in terms of retinal appearance, severity, progression, and nonpenetrance were identified. It was noted that SRNVM is a rare occurrence in R345W fibulin-3 maculopathy. These findings are helpful for advice regarding prognosis and for genetic counseling. The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation.


Efficacy of phototherapy in non-haemolytic hyperbilirubinaemia.
Clinical experience of phototherapy for non-haemolytic hyperbilirubinaemia in 3999 infants in Kandang Kerbau Hospital, Singapore, is documented. Phototherapy was most effective in extremely preterm infants with very low birth weight (gestation less than or equal to 32 weeks, birth weight less than or equal to 1500 g) and least effective in full term infants with very low birth weight (gestation greater than or equal to 37 weeks, birth weight less than or equal to 1500 g) and large preterm infants (gestation less than 37 weeks, birth weight greater than 2270 g). Overall, phototherapy was effective in almost all the infants, with a failure rate of only 2.00/1000 infants. No characteristic features common to all the failures could be detected. The bilirubin rebound was usually mild; repeat phototherapy was required in only 30 infants (7.50/1000), with the response to the second exposure comparable to that to the first. No infant required a third exposure. All the infants tolerated phototherapy well, none developing any illness that could be attributed to the treatment. This clinical experience shows that phototherapy for the treatment of nonhaemolytic hyperbilirubinaemia is effective and safe.


Risk-benefit assessment of oral phosphodiesterase type 5 inhibitors for treatment of erectile dysfunction: a multiple criteria decision analysis.
Erectile dysfunction (ED) is a common male sexual disorder worldwide. Three oral phosphodiesterase type 5 inhibitors (PDE5Is) - sildenafil, tadalafil and vardenafil - are available for treatment of ED. This study quantitatively evaluated the therapeutic efficacy and safety of these medications to assist treatment decision making. We used multiple criteria decision analysis (MCDA) to assess the totality of risk-benefit of PDE5Is. We created two models: (i) the overall model included 'overall improvement in erections' and 'any adverse events' and (ii) the detailed model included 'erectile function domain', 'ability for sexual intercourse', 'duration of erection last', 'serious adverse events', 'headache', 'flushing' and 'dyspepsia'. We calculated a synthetic utility for each drug accounting for all of its benefits and risks. Considering the overall risk-benefit, vardenafil had the highest synthetic utility among three medications; in the order of synthetic utilities: vardenafil (0.568), tadalafil (0.478) and sildenafil (0.437). However, when specific risk and benefit criteria were assessed, tadalafil had the highest synthetic utility (0.602) according to the conjoint evaluation (synthetic utility for vardenafil is 0.491 and sildenafil is 0.442, respectively). The sensitivity analysis based on the uncertainties of weight on risks of any adverse events (including serious adverse events and headache) suggested our results were robust. This study provides a useful approach that comprehensively and systematically assesses and compares the risk-benefit of several treatment alternatives. Our study not only rank treatment alternatives by synthetic utilities based on the risk-benefit balance but also compare specific risk and benefit criteria between these medicines. Our results provide valuable evidence that can guide clinicians and patients in making treatment decisions.


Retrospective analysis of prognostic factors associated with response and overall survival by baseline marrow blast percentage in patients with myelodysplastic syndromes treated with decitabine.
After the World Health Organization (WHO) changed the definition of acute myeloid leukemia (AML) to ≥ 20% blasts, the International Working Group (IWG) response criteria for myelodysplasia were updated. This retrospective analysis evaluated response to decitabine using updated IWG criteria in patients pooled from 2 decitabine trials. Outcomes for patients with myelodysplastic syndrome (MDS) with baseline marrow blasts ≥ 20% and < 30% (RAEB-t group) and < 20% (MDS group) were compared. Patients with RAEB-t (n = 26) had a significantly shorter time from diagnosis to study treatment (7.3 vs. 18.3 months), a higher International Prognostic Scoring System (IPSS) risk (77% vs. 16% high-risk patients), and lower median baseline platelet count (62.3 vs. 112.7 × 10(3)/μL) vs. patients with MDS (n = 157), yet no significant difference in overall response rate (ORR) (15.4% vs. 28.0%). Patients with MDS had better duration of response (9.9 vs. 5 months; P = .024) and overall survival (OS) (16.6 vs. 9.0 months; P = .021) compared with patients with RAEB-t. Decitabine is active in and may benefit patients with > 20% blasts (RAEB-t).


Adherence to evidence-based therapies after acute coronary syndrome: a retrospective population-based cohort study linking hospital, outpatient, and pharmacy health information systems in Valencia, Spain.
Pharmacological secondary prevention in patients after an acute coronary syndrome (ACS) has contributed substantially to reductions in cardiovascular morbidity and mortality and, overall, has undergone important improvements in recent years. Nevertheless, there is still a considerable adherence gap and opportunity for improvement. To assess, in a cohort of patients who survived an ACS, adherence to commonly prescribed secondary prevention drugs, factors associated to adherence, and variations among health care delivery areas. We combined the medical and pharmacy databases from a regional public health service in Valencia, Spain, to construct a population-based cohort of patients discharged alive after an emergency admission for an ACS to any hospital of the Valencia Health Agency in 2008. We evaluated medication adherence by determining the proportion of days covered (PDC) for each therapeutic group (antiplatelet agents, beta-blockers, angiotensin antagonists, and statins) in the 9 months following hospital discharge. Fully adherent patients were defined as those having enough treatment to cover 75% (PDC75) of the follow-up period. The study cohort consisted of 7,462 patients. PDC75 was reached by 69.9% of patients taking antiplatelet agents, 43.3% taking beta-blockers, 45.4% taking angiotensin antagonists, and 58.8% taking statins. Approximately 18% of patients did not reach PDC75 with any treatment, while 47.6% did so for 3 or more therapeutic groups. Lower adherence was found in diagnoses other than myocardial infarction. Other factors associated with nonadherence were older age, women, having copayment, foreign born, and most comorbidities (except for hypertension and hyperlipidemia, which were inversely associated, and diabetes and peripheral disease, which were not significantly associated). Health care delivery areas showed certain variability in their performance on these adherence measures that remained after the adjustment for covariates, although confidence intervals overlapped except between areas at the extremes. The proportion of fully adherent patients remains suboptimal, and important improvements are still possible in secondary prevention of ischemic heart disease. The combination of electronic health information systems may be very useful for monitoring adherence and evaluating the effectiveness of adherence and other quality improvement interventions.


Hepatitis A immunisation in persons not previously exposed to hepatitis A.
In many parts of the world, hepatitis A infection represents a significant cause of morbidity and socio-economic loss. Whilst hepatitis A vaccines have the potential to prevent disease, the degree of protection afforded against clinical outcomes and within different populations remains uncertain. There are two types of hepatitis A virus (HAV) vaccine, inactivated and live attenuated. It is important to determine the efficacy and safety for both vaccine types. To determine the clinical protective efficacy, sero-protective efficacy, and safety and harms of hepatitis A vaccination in persons not previously exposed to hepatitis A. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and China National Knowledge Infrastructure (CNKI) up to November 2011. Randomised clinical trials comparing HAV vaccine with placebo, no intervention, or appropriate control vaccines in participants of all ages. Data extraction and risk of bias assessment were undertaken by two authors and verified by a third author. Where required, authors contacted investigators to obtain missing data. The primary outcome was the occurrence of clinically apparent hepatitis A (infectious hepatitis). The secondary outcomes were lack of sero-protective anti-HAV immunoglobulin G (IgG), and number and types of adverse events. Results were presented as relative risks (RR) with 95% confidence intervals (CI). Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence interval (CI), using intention-to-treat analysis. We conducted assessment of risk of bias to evaluate the risk of systematic errors (bias) and trial sequential analyses to estimate the risk of random errors (the play of chance). We included a total of 11 clinical studies, of which only three were considered to have low risk of bias; two were quasi-randomised studies in which we only addressed harms. Nine randomised trials with 732,380 participants addressed the primary outcome of clinically confirmed hepatitis A. Of these, four trials assessed the inactivated hepatitis A vaccine (41,690 participants) and five trials assessed the live attenuated hepatitis A vaccine (690,690 participants). In the three randomised trials with low risk of bias (all assessing inactivated vaccine), clinically apparent hepatitis A occurred in 9/20,684 (0.04%) versus 92/20,746 (0.44%) participants in the HAV vaccine and control groups respectively (RR 0.09, 95% CI 0.03 to 0.30). In all nine randomised trials, clinically apparent hepatitis A occurred in 31/375,726 (0.01%) versus 505/356,654 (0.18%) participants in the HAV vaccine and control groups respectively (RR 0.09, 95% CI 0.05 to 0.17). These results were supported by trial sequential analyses. Subgroup analyses confirmed the clinical effectiveness of both inactivated hepatitis A vaccines (RR 0.09, 95% CI 0.03 to 0.30) and live attenuated hepatitis A vaccines (RR 0.07, 95% CI 0.03 to 0.17) on clinically confirmed hepatitis A. Inactivated hepatitis A vaccines had a significant effect on reducing the lack of sero-protection (less than 20 mIU/L) (RR 0.01, 95% CI 0.00 to 0.03). No trial reported on a sero-protective threshold less than 10 mIU/L. The risk of both non-serious local and systemic adverse events was comparable to placebo for the inactivated HAV vaccines. There were insufficient data to draw conclusions on adverse events for the live attenuated HAV vaccine. Hepatitis A vaccines are effective for pre-exposure prophylaxis of hepatitis A in susceptible individuals. This review demonstrated significant protection for at least two years with the inactivated HAV vaccine and at least five years with the live attenuated HAV vaccine. There was evidence to support the safety of the inactivated hepatitis A vaccine. More high quality evidence is required to determine the safety of live attenuated vaccines.


A Network-Based Mixed Methods Approach to Analyze Current Perspectives on Personalized Oncological Medicine in Austria.
Personalized medicine (PM) to tailor healthcare (HC) to the individual, is a promising but challenging concept. So far, no study exists investigating stakeholders' perspectives on PM in oncology in Austria potentially hindering implementation, which was the aim of this study. We performed semi-structured interviews among experts (n = 14) and cancer patients (n = 2) of the Vienna General Hospital and the Medical University of Vienna and analyzed them by a mixed methods network theoretical approach. Study results show a great variety of topics addressed by the interviewees. Clear differences in the topic selection between patients and experts could be observed. Patient-doctor relationship was the most prominent theme among experts, whereas HC systems and public health in PM was more relevant for the patients. Although promising new molecular pathology methods were explicitly mentioned, the experts believed that their practical implementation and the implementation of PM in standard care will take a long time in Austria. A variety of concerns regarding PM were mentioned by the experts, including communication issues and knowledge gaps. Besides important insights into the current situation of PM in Austria, the study has shown that network theory is a powerful tool for analyzing qualitative interview data.


Evaluation of mucoadhesive PLGA microparticles for nasal immunization.
In this study, hepatitis B surface antigen (HBsAg) loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared and coated with chitosan and trimethyl chitosan (TMC) to evaluate the effect of coating material for nasal vaccine delivery. The developed formulations were characterized for size, zeta potential, entrapment efficiency, and mucin adsorption ability. Plain PLGA microparticles demonstrated negative zeta potential. However, coated microparticles showed higher positive zeta potential. Results indicated that TMC microparticles demonstrated substantially higher mucin adsorption when compared to chitosan-coated microparticles and plain PLGA microparticles. The coated and uncoated microparticles showed deposition in nasal-associated lymphoid tissue under fluorescence microscopy. The coated and uncoated microparticles were then administered intranasally to mice. Immune-adjuvant effect was determined on the basis of specific antibody titer observed in serum and secretions using enzyme-linked immunosorbent assay. It was observed that coated particles showed a markedly increased anti-HBsAg titer as compared to plain PLGA microparticles, but the results were more pronounced with the TMC-coated PLGA microparticles.


Comparison of the Diagnostic Performance of Fibulin-3 and Mesothelin in Patients with Pleural Effusions from Malignant Mesothelioma.
In the literature, there exist conflicting data on the value of fibulin-3 (FBLN3) for the diagnosis of pleural effusion (PE) in malignant pleural mesothelioma (MPM). Therefore we compared the diagnostic performance of FBLN3 against that of soluble mesothelin-related peptide (SMRP) in a cohort of Italian patients. FBLN3 and SMRP were detected in PE from 33 patients with MPM, 64 with pleural benign lesions and 23 with non-MPM pleural metastases using a commercial enzyme-linked-immunosorbent(ELISA)-assay kit according to manufacturers' instructions. Levels of FBLN3 were similar in PE from MPM and PE from other pathologies (geometric mean=68.1 vs. 66.2 ng/ml; p=0.872) in contrast to SMRP levels, which were significantly higher in PE from MPM (geometric mean=14.6 vs. 3.2 nM; p<0.001). Receiver operating characteristic analysis confirmed that SMRP showed a good performance (area under the curve=0.79, p<0.001), whereas FBLN3 was not able to discriminate MPM from other pathologies (area under the curve=0.44, p=0.838). FBLN3 detection in PE, in contrast to SMRP detection, is not useful as a biomarker for the diagnosis of PE from MPM.


Genome-Wide Association Study of Root-Lesion Nematodes Pratylenchus Species and Crown Rot Fusarium culmorum in Bread Wheat.
Triticum aestivum L., also known as common wheat, is affected by many biotic stresses. Root diseases are the most difficult to tackle due to the complexity of phenotypic evaluation and the lack of resistant sources compared to other biotic stress factors. Soil-borne pathogens such as the root-lesion nematodes caused by the Pratylenchus species and crown rot caused by various Fusarium species are major wheat root diseases, causing substantial yield losses globally. A set of 189 advanced spring bread wheat lines obtained from the International Maize and Wheat Improvement Center (CIMMYT) were genotyped with 4056 single nucleotide polymorphisms (SNP) markers and screened for root-lesion nematodes and crown rot resistance. Population structure revealed that the genotypes could be divided into five subpopulations. Genome-Wide Association Studies were carried out for both resistances to Pratylenchus and Fusarium species. Based on our results, 11 different SNPs on chromosomes 1A, 1B, 2A, 3A, 4A, 5B, and 5D were significantly associated with root-lesion nematode resistance. Seven markers demonstrated association with P. neglectus, while the remaining four were linked to P. thornei resistance. In the case of crown rot, eight different markers on chromosomes 1A, 2B, 3A, 4B, 5B, and 7D were associated with Fusarium crown rot resistance. Identification and screening of root diseases is a challenging task; therefore, the newly identified resistant sources/genotypes could be exploited by breeders to be incorporated in breeding programs. The use of the identified markers in marker-assisted selection could enhance the selection process and cultivar development with root-lesion nematode and crown rot resistance.


Assessment of cerebrovascular reactivity during major depression and after remission of disease.
There are a growing number of studies suggesting that depression may increase the risk of stroke. Impaired autoregulation of vascular tone may contribute to a higher risk of developing cerebrovascular diseases. Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is an important mechanism that ensures constant cerebral blood flow. There is a hypothesis that CVR is reduced in major depression, which would explain the association between depression and stroke. The aim of this study was to investigate the effect of depression on CVR in cerebral vessels by comparing CVR during the depression phase with that during remission. Using the apnea test, we assessed CVR in 16 patients with unipolar depression during disease and after remission of disease by calculating the increase in cerebral blood flow velocity after breath-holding (the apnea test). Blood flow velocities were measured by transcranial Doppler ultrasound (TCD). CVR was significantly reduced in the depression phase in comparison to that in the remission phase. However, this change was not seen in all the patients. CVR was reduced in most of the depressed patients. The decreased CVR, as indicated by the changes in peak systolic velocity (PSV) and mean flow velocity (MFV) of the middle cerebral artery, in depressed patients was more marked on the right side, which could point to a vascular basis for some kinds of depression. We recommend that other studies, with larger samples, be done; future studies should assess whether the changes in the CVR varies with the severity and type of depression.


Detailed assessment of the hemodynamic response to psychosocial stress using real-time MRI.
To demonstrate that combining the Montreal Imaging Stress Task (MIST) with real-time cardiac magnetic resonance imaging (MRI) allows detailed assessment of the cardiovascular mental stress response. 22 healthy volunteers (1:1 M:F, 26-64 years) underwent MRI during rest and the MIST. Real-time spiral phase contrast MR, accelerated with sensitivity encoding (SENSE) was used to assess stroke volume (SV), and radial k-t SENSE was used to assess ventricular volumes. Simultaneous heart rate (HR) and blood pressure (BP) measures allowed calculation of cardiac output (CO), systemic vascular resistance (SVR), and arterial compliance (TAC). Endocrine responses were assessed using salivary cortisol. In response to stress, BP increased due to increased CO and reduced TAC but not increased SVR, which fell. HR, not SV, determined CO increases. Greater BP responses occurred in men due to greater CO increases and relatively higher SVR. Older participants had greater BP responses due to greater falls in TAC. Greater cortisol response was correlated with greater falls in TAC but resting cortisol and TAC were not related. This new approach allows detailed, accurate assessment of stress physiology. Preliminary findings suggest stress exposes relationships, not seen at rest, of cardiovascular function with age, sex, and endocrine function.


Protective effect of a purified polyphenolic extract from Ecklonia cava against noise-induced hearing loss: Prevention of temporary threshold shift.
Noise is one of the most common causes of hearing loss. Approximately 16% of American teenagers (12-19 years) have hearing loss caused by loud noise. The implication of noise-induced hearing loss (NIHL) in teenagers has received increasing attention. Although temporary threshold shift (TTS), a type of NIHL, is a transient hearing loss, it can accelerate age-related hearing loss. Reactive oxygen species are a primary cause of TTS. As the polyphenols from Ecklonia cava are known to have potent antioxidant effects, we investigated the protective effects of a purified polyphenolic extract of Ecklonia cava (PPEE) against TTS in mice. The radical-scavenging activity of PPEE was evaluated using the 1,1-diphenyl-2-picrylhydrazyl assay. The PPEE + Noise and Saline + Noise groups were administered intraperitoneal PPEE (100 mg/kg) and saline, respectively, for 5 days before exposure to noise at 100 dB SPL for 60 min. Hearing ability was assessed following noise exposure using auditory brainstem responses and distortion product otoacoustic emissions. PPEE exhibited significant radical scavenging activity. The ABR threshold shifts 1 day after exposure to noise at 16 kHz and 1, 7, and 14 days after exposure to noise at 32 kHz, were significantly less in the PPEE + Noise than in the Saline + Noise group. One day after noise exposure, mice in the PPEE + Noise group showed a significant degree of protection in relation to their DPOAE level at f2, 17, and 28 kHz. These findings suggest that PPEE may be a potential preventive agent against TTS. In addition, as a food ingredient approved by the United States Food and Drug Administration, PPEE may be administered to those who are exposed to noise inevitably with little likelihood of adverse effects, thereby contributing to the prevention of TTS.


Approaches to education of pharmaceutical biotechnology in faculties of pharmacy.
Pharmaceutical biotechnology is developing rapidly both in academic institutions and in the biopharmaceutical industry. For this reason, FIP Special Interest Group of Pharmaceutical Biotechnology decided to develop a questionnaire concerning pharmaceutical biotechnology education. After preliminary studies were completed, questionnaires were sent to the leading scientists in academia and research directors or senior managers of various Pharmaceutical Biotechnology Companies in order to gather their views about how to create a satisfactory program. The objectives of this study were as follows: -To review all of the graduate and undergraduate courses which are presently available worldwide on pharmaceutical biotechnology in Faculties of Pharmacy. -To review all of the text books, references and scientific sources available worldwide in the area of pharmaceutical biotechnology. When replying to the questionnaires, the respondents were asked to consider the present status of pharmaceutical biotechnology education in academia and future learning needs in collaboration with the biotechnology industry. The data from various pharmacy faculties and biotechnology industry representatives from Asia, Europe and America were evaluated and the outcome of the survey showed that educational efforts in training qualified staff in the rapidly growing field of pharmaceutical biotechnology is promising. Part of the results of this questionnaire study have already been presented at the 57th International Congress of FIP Vancouver, Canada in 1997.


Can hyperbaric oxygen be used to prevent deep infections in neuro-muscular scoliosis surgery?
The prevalence of postoperative wound infection in patients with neuromuscular scoliosis surgery is significantly higher than that in patients with other spinal surgery. Hyperbaric oxygen has been used as a supplement to treat postsurgical infections. Our aim was to determine beneficiary effects of hyperbaric oxygen treatment in terms of prevention of postoperative deep infection in this specific group of patients in a retrospective study. Forty two neuromuscular scoliosis cases, operated between 2006-2011 were retrospectively reviewed. Patients who had presence of scoliosis and/or kyphosis in addition to cerebral palsy or myelomeningocele, postoperative follow-up >1 year and posterior only surgery were the subjects of this study. Eighteen patients formed the Hyperbaric oxygen prophylaxis (P-HBO) group and 24, the control group. The P-HBO group received 30 sessions of HBO and standard antibiotic prophylaxis postoperative, and the control group (received standard antibiotic prophylaxis). In the P-HBO group of 18 patients, the etiology was cerebral palsy in 13 and myelomeningocele in 5 cases with a mean age of 16.7 (11-27 yrs). The average follow-up was 20.4 months (12-36mo). The etiology of patients in the control group was cerebral palsy in 17, and myelomeningocele in 7 cases. The average age was 15.3 years (8-32 yrs). The average follow-up was 38.7 months (18-66mo). The overall incidence of infection in the whole study group was 11.9% (5/42). The infection rate in the P-HBO and the control group were 5.5% (1/18), and 16.6% (4/24) respectively. The use of HBO was found to significantly decrease the incidence of postoperative infections in neuromuscular scoliosis patients. In this study we found that hyperbaric oxygen has a possibility to reduce the rate of post-surgical deep infections in complex spine deformity in high risk neuromuscular patients.


Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal.
Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability.


Inhibition of cyclooxygenase activity, platelet aggregation and thromboxane B2 production by two environmental toxicants: m- and o-cresol.
Cresol is a well-known environmental pollutant, toluene metabolite, uremic toxicant and accidental poisoning product. Formocresol, a preparation of formalin and cresol, is also used as a root canal medicament and for pulpotomy of primary teeth. However, little is known about its effect on cardiovascular system. In this study, m-cresol inhibited the AA-induced platelet aggregation by 43-97% at concentrations ranging from 0.25 to 1 mM. Collagen-induced platelet aggregation was also inhibited by 0.25-1 mM of m-cresol by 47-98%. Accordingly, o-cresol (0.1-0.5 mM) also inhibited the AA-induced platelet aggregation by 46-96% and the collagen-induced platelet aggregation by 35-88% at concentrations of 0.1-1 mM. AA- and collagen-induced platelet thromboxane B(2) (TXB(2)) production was inhibited by even 0.1 mM of m-cresol with 88 and 54% of inhibition, respectively. The o-cresol (0.1 mM) also inhibited the AA- and collagen-induced platelet TXB(2) production with 91 and 97% respectively. Although m- and o-cresol (<1 mM) showed little effect on thrombin-induced platelet aggregation, they effectively inhibited the thrombin-induced platelet TXB(2) production. The m-cresol (2 and 5 mM) inhibited the COX-1 activity by 55-99%, but showed little effect on COX-2 enzyme activity. Moreover, o-cresol (0.5 and 1 mM) inhibited the COX-1 activity by 40-95%. COX-2 enzyme activity was inhibited by 68% at a concentration of 5 mM o-cresol. These results indicate that acute cresol-poisoning, direct root canal medication with formocresol or long-term occupational exposure to cresol and toluene may potentially suppress blood clot formation and lead to tissue hemorrhage via inhibition of platelet aggregation, TXB(2) production and COX enzyme activity.


Theoretical Kinetics Analysis for Ḣ Atom Addition to 1,3-Butadiene and Related Reactions on the Ċ4H7 Potential Energy Surface.
The oxidation chemistry of the simplest conjugated hydrocarbon, 1,3-butadiene, can provide a first step in understanding the role of polyunsaturated hydrocarbons in combustion and, in particular, an understanding of their contribution toward soot formation. On the basis of our previous work on propene and the butene isomers (1-, 2-, and isobutene), it was found that the reaction kinetics of Ḣ-atom addition to the C═C double bond plays a significant role in fuel consumption kinetics and influences the predictions of high-temperature ignition delay times, product species concentrations, and flame speed measurements. In this study, the rate constants and thermodynamic properties for Ḣ-atom addition to 1,3-butadiene and related reactions on the Ċ4H7 potential energy surface have been calculated using two different series of quantum chemical methods and two different kinetic codes. Excellent agreement is obtained between the two different kinetics codes. The calculated results including zero-point energies, single-point energies, rate constants, barrier heights, and thermochemistry are systematically compared among the two quantum chemical methods. 1-Methylallyl (Ċ4H71-3) and 3-buten-1-yl (Ċ4H71-4) radicals and C2H4 + Ċ2H3 are found to be the most important channels and reactivity-promoting products, respectively. We calculated that terminal addition is dominant (>80%) compared to internal Ḣ-atom addition at all temperatures in the range 298-2000 K. However, this dominance decreases with increasing temperature. The calculated rate constants for the bimolecular reaction C4H6 + Ḣ → products and C2H4 + Ċ2H3 → products are in excellent agreement with both experimental and theoretical results from the literature. For selected C4 species, the calculated thermochemical values are also in good agreement with literature data. In addition, the rate constants for H atom abstraction by Ḣ atoms have also been calculated, and it is found that abstraction from the central carbon atoms is the dominant channel (>70%) at temperatures in the range of 298-2000 K. Finally, by incorporating our calculated rate constants for both Ḣ atom addition and abstraction into our recently developed 1,3-butadiene model, we show that laminar flame speed predictions are significantly improved, emphasizing the value of this study.


Sjögren's syndrome (SS) and Epstein-Barr virus (EBV) reactivation.
Recent reports have shown that dry eye in Sjögren's syndrome (SS) is associated with reactivation of Epstein-Barr virus (EBV) in lacrimal glands. However, the number of patients examined were few and it has not been determined whether dry eye in the absence of SS is also related to EBV reactivation. The authors examined the serum antibody titers to EBV in three groups of patients: (1) simple dry eye (SDE)-dry eye with no circulating autoantibodies (n = 157), (2) autoimmune positive dry eye (ADE)-dry eye with circulating autoantibodies (n = 68), and (3) Sjögren's syndrome (SS)-dry eye associated with Sjögren's syndrome (n = 62). Healthy volunteers were recruited as controls (n = 47). In SS, the mean antibody titers to EBV nuclear antigen (anti-EBNA), early antigen (anti-EA-IgG), and virus capsid antigen (anti-VCA-IgG) were significantly elevated compared to those of controls. No significant differences in antibody titers were found among ADE, SDE, and the controls. The EBV reactivated pattern was found in 17.7% of SS, which was significantly higher than the 4.4% in ADE, 1.9% in SDE, 0% in controls. These findings suggest an association of EBV with SS, but not ADE or SDE.


Pulmonary vascular pathophysiology.
Knowledge of pulmonary vascular pathophysiology is crucial to understand the various disease processes and their medical management. Pulmonary vascular system constitutes the right sided circulation which is distinct from the left side circulation and facilitates unique hemodynamic properties to adapt to a multitude of external demands and circumstances. With growing prevalence and increasing ability to diagnose and treat pulmonary diseases, this review becomes more relevant.


Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.
Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal-recessive disease that affects young children. It presents as a severe hyperinflammatory syndrome with activated macrophages and T lymphocytes. Mutations in the perforin 1 gene (PRF1) were found in FHL-2 in 15-50% of all cases. Defective granule exocytosis caused by mutations in the hMunc13-4 gene (UNC13D) has been described in FHL-3. FHL-4 patients have mutations in STX11, a t-SNARE involved in intracellular trafficking. We analyzed a large group of 63 unrelated patients with FHL of different geographic origins (Turkey:32; Germany:23; others:8) for mutations in STX11, PRF1, and UNC13D. We identified mutations in 38 samples (20 in PRF1, 12 in UNC13D, and six in STX11). Of 32 patients from Turkey, 14 had mutations in PRF1, six had mutations in UNC13D, and six had mutations in STX11. The mutation Trp374X in PRF1 was found in 12 patients from Turkey and was associated with a very early onset of the disease below the age of 3 months in all cases. In contrast, three of 23 and four of 23 patients from Germany, and three of eight and two of eight from other origins showed mutations in PRF1 and UNC13D, respectively, but none in STX11. Thus, FHL-2, FHL-3, and FHL-4 account for 80% of the HLH cases of Turkish origin, and for 30% of German patients. Furthermore, we identified mutations in RAB27A in three patients with FHL-related Griscelli syndrome type 2. In functional studies using a mammalian two-hybrid system we found that missense mutations Ala87Pro in Rab27a and Leu403Pro in hMunc13-4 each prevented the formation of a stable hMunc13-4/Rab27a complex in vitro. Our findings demonstrate extensive genetic and allelic heterogeneity in FHL and delineate an approach for functionally characterizing missense mutations in RAB27A and UNC13D.


Zolmitriptan nasal spray in the acute treatment of cluster headache: a double-blind study.
To evaluate the efficacy and tolerability of zolmitriptan 5 mg and 10 mg nasal spray (ZNS) vs placebo in the acute treatment of cluster headache. Design/ We conducted a multicenter, double-blind, randomized, three-period crossover study using ZNS 5 mg, ZNS 10 mg, and placebo. Headache intensity was rated by a 5-point scale: none, mild, moderate, severe, or very severe. The primary efficacy measure was headache response (pain reduced from moderate, severe, or very severe at baseline, to mild or none) at 30 minutes. Logistic regression was used to account for treatment period effect as well as for cluster headache subtype effect. A total of 52 adult patients treated 151 attacks. For the primary endpoint, both doses reached significance at 30 minutes (placebo = 30%, ZNS 5 mg = 50%, ZNS 10 mg = 63.3%). For headache relief, ZNS 10 mg separated from placebo at 10 minutes (24.5% vs 10%). Zolmitriptan 5 mg separated from placebo at 20 minutes (38.5% vs 20%). For pain-free status, ZNS 10 mg was superior to placebo at 15 minutes (22.0% vs 6%). Both doses had higher pain-free rates than placebo at 30 minutes (placebo = 20%, ZNS 5 mg = 38.5%, ZNS 10 mg = 46.9%). Side effects were mild and seen in 16% of those attacks treated with placebo, 25% of attacks treated with ZNS 5 mg, and 32.7% treated with ZNS 10 mg. Zolmitriptan nasal spray, at doses of 5 and 10 mg, is effective and tolerable for the acute treatment of cluster headache.


Harm to Others Acts as a Negative Reinforcer in Rats.
Empathy, the ability to share another individual's emotional state and/or experience, has been suggested to be a source of prosocial motivation by attributing negative value to actions that harm others. The neural underpinnings and evolution of such harm aversion remain poorly understood. Here, we characterize an animal model of harm aversion in which a rat can choose between two levers providing equal amounts of food but one additionally delivering a footshock to a neighboring rat. We find that independently of sex and familiarity, rats reduce their usage of the preferred lever when it causes harm to a conspecific, displaying an individually varying degree of harm aversion. Prior experience with pain increases this effect. In additional experiments, we show that rats reduce the usage of the harm-inducing lever when it delivers twice, but not thrice, the number of pellets than the no-harm lever, setting boundaries on the magnitude of harm aversion. Finally, we show that pharmacological deactivation of the anterior cingulate cortex, a region we have shown to be essential for emotional contagion, reduces harm aversion while leaving behavioral flexibility unaffected. This model of harm aversion might help shed light onto the neural basis of psychiatric disorders characterized by reduced harm aversion, including psychopathy and conduct disorders with reduced empathy, and provides an assay for the development of pharmacological treatments of such disorders. VIDEO ABSTRACT.


Does touch massage facilitate recovery after stroke? A study protocol of a randomized controlled trial.
Despite high quality stroke care, decreased sensorimotor function, anxiety and pain often remain one year after stroke which can lead to impaired health and dependence, as well as higher healthcare costs. Touch massage (TM) has been proven to decrease anxiety and pain, and improve quality of health in other conditions of reduced health, where reduced anxiety seems to be the most pronounced benefit. Thus there are reasons to believe that TM may also reduce anxiety and pain, and improve quality of life after stroke. Further, several studies indicate that somatosensory stimulation can increase sensorimotor function, and it seems feasible to believe that TM could increase independence after stroke. In this study we will evaluate effects of TM after stroke compared to sham treatment. This is a prospective randomized open-labelled control trial with blinded evaluation (PROBE-design). Fifty patients with stroke admitted to stroke units will be randomized (1:1) to either a TM intervention or a non-active transcutaneous electrical nerve stimulation (non-TENS) control group. Ten sessions of 30 min treatments (TM or control) will be administered during two weeks. Assessment of status according to the International Classification of Functioning, Disability and Health (ICF), including body function, activity, and participation. Assessment of body function will include anxiety, pain, and stress response (heart rate variability and salivary cortisol), where anxiety is the primary outcome. Activity will be assessed by means of sensorimotor function and disability, and participation by means of health-related quality of life. Assessments will be made at baseline, after one week of treatment, after two weeks of treatment, and finally a follow-up after two months. The trial has been approved by the Regional Ethical Review Board. TM seems to decrease anxiety and pain, increase health-related quality of life, and improve sensorimotor functions after stroke, but the field is largely unexplored. Considering the documented pleasant effects of massage in general, absence of reported adverse effects, and potential effects in relation to stroke, it is essential to evaluate effects of TM during the sub-acute phase after stroke. The results of this project will hopefully provide important knowledge for evidence-based care. ClinicalTrials.gov: NTC01883947.


Cortical operational synchrony during audio-visual speech integration.
Information from different sensory modalities is processed in different cortical regions. However, our daily perception is based on the overall impression resulting from the integration of information from multiple sensory modalities. At present it is not known how the human brain integrates information from different modalities into a unified percept. Using a robust phenomenon known as the McGurk effect it was shown in the present study that audio-visual synthesis takes place within a distributed and dynamic cortical networks with emergent properties. Various cortical sites within these networks interact with each other by means of so-called operational synchrony (Kaplan, Fingelkurts, Fingelkurts, & Darkhovsky, 1997). The temporal synchronization of cortical operations processing unimodal stimuli at different cortical sites reveals the importance of the temporal features of auditory and visual stimuli for audio-visual speech integration.


SU-E-T-136: Comparison of TomoScanner™ 2D Water Phantom versus IBA Helix for Tomotherapy Profile Measurements.
To compare the differences in measured data using Tomotherapy's TomoScanner™ 2D Water Phantom versus IBA's Blue Phantom Helix taken during commissioning of the Tomotherapy HD unit. IBA Helix was used with CC04 ion chamber to measure Inline (jaw-size width), Crossline (40 cm width) and Percent Depth Dose (PDD). Data was analyzed using IBA Omni-Pro 7.3 software. Measurements were performed at 85 SSD for field sizes 5×40 cm2 , 2.5×40 cm2 , and 1.0×40 cm2 . All field sizes were measured at 1.5 cm (nominal dmax), 5 cm, 10 cm and 15 cm depths. Scans were performed at a continuous speed setting of 0.5 cm/sec. Setup and data measurements were performed twice on separate occasions for consistency and repeatability. Data measurements were normalized to 10 cm depth and compared to commissioning data taken from TomoScanner™ and Tomotherapy's Twinning Data. For all jaws, the profiles measured at 5 cm, 10 cm, and 15 cm depth using IBA Helix matched the profiles of the TomoScanner™ data within 1%. Profile variance at 1.5 cm depth showed a deviation of up to 3%. For all jaws, the PDD comparisons displayed 3-5% deviation from the surface to 2 cm depth and within 1% deviation at 2 cm to 15 cm depth. Measurements performed using CC04 ion chamber versus A1SL ion chamber (used by Standard Imaging) showed data differences of less than 0.5%. Discrepancies in Tomotherapy beam profiles were observed between different water phantoms. Further investigation is required to determine the cause of variances between IBA and Tomotherapy data sets such as investigating geometrical differences between the water tanks and software dissimilarities in collecting and correcting raw data. It is recommended that independent commissioning data be taken when TomoScanner™ is not the clinical site's standard water phantom.


Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease.
The immune system's ability to distinguish self and nonself is essential for both host defense against foreign agents and protection of self-antigens from autoimmune destruction. Such discrimination is complicated by extensive structural homology shared between foreign and self antigens. One hypothesis to explain the development of an autoimmune response is that some B cells activated by foreign antigen acquire, through somatic mutation, specificity for both the eliciting foreign antigen and self antigen. If such clones arise frequently, there must be a mechanism for their elimination. We have analyzed the extent of autoreactivity arising in a nonautoimmune host during the response to a foreign antigen. To overcome the process of apoptosis in primary B cells that might routinely eliminate autoreactive clones, we generated B-cell hybridomas from spleen cells of immunized mice by using a fusion partner constitutively expressing bcl-2. Multiple lines were obtained that recognize simultaneously the hapten phosphorylcholine and the self antigen double-stranded DNA. This dual specificity was not present early but was detected by day 10 after immunization. Some of these cross-reactive antibodies deposit in kidneys in a pattern similar to what is seen in autoimmune disease. These results demonstrate that autoantibodies arise at a high frequency as part of a response to foreign antigen. It has previously been shown that autoreactivity is regulated by central deletion; these data demonstrate a need for negative selection in peripheral lymphoid organs also, to regulate autoantibodies acquiring their self-specificity by somatic mutation.


Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect.
Angiogenesis is required for the growth and progression of malignancies. Recent studies have demonstrated that genetic alterations may accompany acquisition of the angiogenic phenotype. The tumor suppressor gene p53 is most frequently mutated in human cancers and is also known to be a transcriptional regulator of a variety of genes. Here, we investigated the antiangiogenic effect of the wild-type p53 (wt-p53) gene transfer on a human non-small cell lung cancer cell line. Mutant p53-expressing H226Br non-small cell lung cancer cells were transduced with the wt-p53 gene using a recombinant adenoviral vector (Ad5CMVp53) and applied to semiquantitative reverse transcription-PCRs for the detection of altered mRNA expression of angiogenic and/or antiangiogenic factors. In vivo neovascularization assay of Ad5CMVp53-infected cells was then performed using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice. We also evaluated the effect of Ad5CMVp53-infected H226Br cells on nontransduced tumor cells in vivo by s.c. inoculating mixture of cells into nu/nu mice. Ad5CMVp53 infection markedly inhibited the expression of an angiogenic factor, vascular endothelial growth factor, and increased the expression of a novel antiangiogenic factor, brain-specific angiogenesis inhibitor 1, resulting in reduced neovascularization in vivo. Mixing experiments showed that tumor cells transduced with the wt-p53 gene inhibited the in vivo tumor growth of adjacent nontransduced cells. Our data suggest that a recombinant adenovirus expressing the wt-p53 gene is antiangiogenic, which may explain, in part, the mechanism of the bystander effect induced by the wt-p53 gene transfer on adjacent tumor cells.


Evidence for the involvement of the mammillary bodies and cingulum bundle in allocentric spatial processing by rats.
Comparisons were made between the behavioural effects of lesions in three inter-related limbic structures: the mammillary bodies, the fornix and the cingulum bundle/cingulate cortex. Cytotoxic lesions of the mammillary nuclei produced a marked deficit on reinforced T-maze alternation, but performance gradually improved with practice. Subsequent tests in a cross-maze and a radial-arm maze showed that the animals with mammillary body lesions failed to use allocentric cues, but were able to perform normally in an egocentric discrimination. Three groups of rats with different patterns of either crossed or unilateral radio frequency lesions of the cingulate region were given the same tasks. The profile of results indicated that disruption of those fibres in the cingulum bundle connecting the anterior thalamic nuclei with the hippocampal/retrohippocampal region was responsible for the observed impairments to T-maze alternation and radial-arm maze performance. There was also evidence that disconnection of frontal connections in the cingulum bundle might affect perseverative behaviour, but not allocentric processing. The results add support to the notion of a functional circuit that involves projections from the hippocampus to the mammillary bodies and anterior thalamic nuclei, and from there back to hippocampal/retrohippocampal regions via the cingulum bundle. This circuit appears to be vital for normal allocentric processing.


Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach.
This study allocated the symptoms identified during acute hypoglycemia objectively to the autonomic or neuroglycopenic groups of symptoms by the use of factor analysis. Twenty-five nondiabetic subjects, 14 newly diagnosed insulin-dependent diabetic patients, and 16 insulin-dependent diabetic patients with diabetes greater than 4 yr duration were studied. Acute hypoglycemia was induced with insulin (2.5 mU.kg-1 body wt.min-1 i.v.), and symptoms of hypoglycemia were recorded with a seven-point scale at regular time points throughout the studies. Factor analysis of the symptom scores at the time of the acute autonomic reaction with principal component analysis followed by Varimax rotation was used to separate those symptoms that might belong to neuroglycopenic and autonomic groups. Hypoglycemia was induced to a mean +/- SE plasma glucose nadir of 1.3 +/- 0.1 mM in nondiabetic subjects, to 2.0 +/- 0.3 mM in newly diagnosed diabetic patients, and 1.4 +/- 0.2 mM in patients with diabetes of greater than 4 yr duration. The most frequently reported autonomic symptoms were sweating, trembling, and warmness, and the most frequently reported neuroglycopenic symptoms were inability to concentrate, weakness, and drowsiness. Neuroglycopenic symptoms were reported more commonly at the onset of hypoglycemia, which was identified by the development of symptoms. Factor analysis grouped trembling, anxiety, sweating, warmness, and nausea together, and this grouping was labeled an autonomic factor. A second factor was identified that included dizziness, confusion, tiredness, difficulty in speaking, shivering, drowsiness, and inability to concentrate, which was labeled a neuroglycopenic factor. This study demonstrated the high frequency with which neuroglycopenic symptoms occur at the onset of hypoglycemia and the symptoms that could be used by an individual patient as a warning of the development of acute hypoglycemia, although the rapid reduction of plasma glucose is faster than experienced by the ambulant diabetic patient. Factor analysis assisted with the allocation of symptoms to either the autonomic or neuroglycopenic groupings, but the allocation of some symptoms remained undefined, and care must be taken when assessing symptoms such as hunger, weakness, blurred vision, and drowsiness when comparing the frequency of autonomic versus neuroglycopenic symptoms. To reduce the confusion resulting from the use of different symptom questionnaires in studies of hypoglycemia, a sample questionnaire is presented, the development of which was assisted by our analysis.


Derivation of traceable and transplantable photoreceptors from mouse embryonic stem cells.
Retinal degenerative diseases resulting in the loss of photoreceptors are one of the major causes of blindness. Photoreceptor replacement therapy is a promising treatment because the transplantation of retina-derived photoreceptors can be applied now to different murine retinopathies to restore visual function. To have an unlimited source of photoreceptors, we derived a transgenic embryonic stem cell (ESC) line in which the Crx-GFP transgene is expressed in photoreceptors and assessed the capacity of a 3D culture protocol to produce integration-competent photoreceptors. This culture system allows the production of a large number of photoreceptors recapitulating the in vivo development. After transplantation, integrated cells showed the typical morphology of mature rods bearing external segments and ribbon synapses. We conclude that a 3D protocol coupled with ESCs provides a safe and renewable source of photoreceptors displaying a development and transplantation competence comparable to photoreceptors from age-matched retinas.


Clinical features of organophosphate poisoning: A review of different classification systems and approaches.
The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms. However, several other manifestations are described. We review the spectrum of symptoms and signs in OP poisoning as well as the different approaches to clinical features in these patients. Articles were obtained by electronic search of PubMed(®) between 1966 and April 2014 using the search terms organophosphorus compounds or phosphoric acid esters AND poison or poisoning AND manifestations. Of the 5026 articles on OP poisoning, 2584 articles pertained to human poisoning; 452 articles focusing on clinical manifestations in human OP poisoning were retrieved for detailed evaluation. In addition to the traditional approach of symptoms and signs of OP poisoning as peripheral (muscarinic, nicotinic) and central nervous system receptor stimulation, symptoms were alternatively approached using a time-based classification. In this, symptom onset was categorized as acute (within 24-h), delayed (24-h to 2-week) or late (beyond 2-week). Although most symptoms occur with minutes or hours following acute exposure, delayed onset symptoms occurring after a period of minimal or mild symptoms, may impact treatment and timing of the discharge following acute exposure. Symptoms and signs were also viewed as an organ specific as cardiovascular, respiratory or neurological manifestations. An organ specific approach enables focused management of individual organ dysfunction that may vary with different OP compounds. Different approaches to the symptoms and signs in OP poisoning may better our understanding of the underlying mechanism that in turn may assist with the management of acutely poisoned patients.


The use of carbohydrates during exercise as an ergogenic aid.
Carbohydrate and fat are the two primary fuel sources oxidized by skeletal muscle tissue during prolonged (endurance-type) exercise. The relative contribution of these fuel sources largely depends on the exercise intensity and duration, with a greater contribution from carbohydrate as exercise intensity is increased. Consequently, endurance performance and endurance capacity are largely dictated by endogenous carbohydrate availability. As such, improving carbohydrate availability during prolonged exercise through carbohydrate ingestion has dominated the field of sports nutrition research. As a result, it has been well-established that carbohydrate ingestion during prolonged (>2 h) moderate-to-high intensity exercise can significantly improve endurance performance. Although the precise mechanism(s) responsible for the ergogenic effects are still unclear, they are likely related to the sparing of skeletal muscle glycogen, prevention of liver glycogen depletion and subsequent development of hypoglycemia, and/or allowing high rates of carbohydrate oxidation. Currently, for prolonged exercise lasting 2-3 h, athletes are advised to ingest carbohydrates at a rate of 60 g·h⁻¹ (~1.0-1.1 g·min⁻¹) to allow for maximal exogenous glucose oxidation rates. However, well-trained endurance athletes competing longer than 2.5 h can metabolize carbohydrate up to 90 g·h⁻¹ (~1.5-1.8 g·min⁻¹) provided that multiple transportable carbohydrates are ingested (e.g. 1.2 g·min⁻¹ glucose plus 0.6 g·min⁻¹ of fructose). Surprisingly, small amounts of carbohydrate ingestion during exercise may also enhance the performance of shorter (45-60 min), more intense (>75 % peak oxygen uptake; VO(₂peak)) exercise bouts, despite the fact that endogenous carbohydrate stores are unlikely to be limiting. The mechanism(s) responsible for such ergogenic properties of carbohydrate ingestion during short, more intense exercise bouts has been suggested to reside in the central nervous system. Carbohydrate ingestion during exercise also benefits athletes involved in intermittent/team sports. These athletes are advised to follow similar carbohydrate feeding strategies as the endurance athletes, but need to modify exogenous carbohydrate intake based upon the intensity and duration of the game and the available endogenous carbohydrate stores. Ample carbohydrate intake is also important for those athletes who need to compete twice within 24 h, when rapid repletion of endogenous glycogen stores is required to prevent a decline in performance. To support rapid post-exercise glycogen repletion, large amounts of exogenous carbohydrate (1.2 g·kg⁻¹·h⁻¹) should be provided during the acute recovery phase from exhaustive exercise. For those athletes with a lower gastrointestinal threshold for carbohydrate ingestion immediately post-exercise, and/or to support muscle re-conditioning, co-ingesting a small amount of protein (0.2-0.4 g·kg⁻¹·h⁻¹) with less carbohydrate (0.8 g·kg⁻¹·h⁻¹) may provide a feasible option to achieve similar muscle glycogen repletion rates.


High-Throughput Analysis of Ovarian Cycle Disruption by Mixtures of Aromatase Inhibitors.
Combining computational toxicology with ExpoCast exposure estimates and ToxCast™ assay data gives us access to predictions of human health risks stemming from exposures to chemical mixtures. We explored, through mathematical modeling and simulations, the size of potential effects of random mixtures of aromatase inhibitors on the dynamics of women's menstrual cycles. We simulated random exposures to millions of potential mixtures of 86 aromatase inhibitors. A pharmacokinetic model of intake and disposition of the chemicals predicted their internal concentration as a function of time (up to 2 y). A ToxCast™ aromatase assay provided concentration-inhibition relationships for each chemical. The resulting total aromatase inhibition was input to a mathematical model of the hormonal hypothalamus-pituitary-ovarian control of ovulation in women. Above 10% inhibition of estradiol synthesis by aromatase inhibitors, noticeable (eventually reversible) effects on ovulation were predicted. Exposures to individual chemicals never led to such effects. In our best estimate, ∼10% of the combined exposures simulated had mild to catastrophic impacts on ovulation. A lower bound on that figure, obtained using an optimistic exposure scenario, was 0.3%. These results demonstrate the possibility to predict large-scale mixture effects for endocrine disrupters with a predictive toxicology approach that is suitable for high-throughput ranking and risk assessment. The size of the effects predicted is consistent with an increased risk of infertility in women from everyday exposures to our chemical environment. https://doi.org/10.1289/EHP742.


Black/white differences in hypertension in the elderly: an epidemiologic analysis in central North Carolina.
Hypertension in blacks, compared with whites, occurs at higher prevalence rates, is more severe, and carries a worse prognosis for cardiovascular morbidity and mortality. The authors examined the degree to which black/white differences in hypertension in the elderly are explained by demographic variables, income, health behavior (smoking, obesity), health service use, and comorbid diabetes. The study population consisted of subjects participating in the Duke site of the Established Populations for Epidemiologic Studies of the Elderly, initiated in 1984. Cross-sectional data reported here were collected between January 1986 and July 1987. Subjects were aged 65 years or older and were not institutionalized. Blacks were oversampled. Of 5,223 eligible persons, 4,163 (80%) agreed to be interviewed; 16% of the study subjects were white men, 30% white women, 19% black men, and 35% black women. The mean age for all groups was approximately 73 years. Forty-four percent of white men, 52% of white women, 50% of black men, and 66% of black women had hypertension. Eighty percent of hypertensives were receiving pharmacologic therapy. Older age, female sex, lower socioeconomic status, obesity, and diabetes mellitus were associated with hypertension. After adjusting for covariables, black race/ethnicity remained an independent risk factor for high blood pressure in the elderly, with an adjusted odds ratio of 1.30.


Comparison of clinical signs, diagnostic findings, organisms isolated, and clinical outcome in dogs with bacterial pneumonia: 93 cases (1986-1991).
Medical records were reviewed for 93 dogs with bacterial pneumonia from which transtracheal aspiration samples were obtained for culturing of Mycoplasma spp and aerobic bacteria. On the basis of culture results, there were 65 Mycoplasma-positive dogs, including 7 dogs for which only Mycoplasma spp were isolated, and 28 Mycoplasma-negative dogs. Most dogs were > 5 years old, and differences in breed or gender distribution among the 3 groups of dogs were not detected. Hematologic and serum biochemical analysis results did not differ significantly between Mycoplasma-positive and Mycoplasma-negative dogs. Fifty-three of 93 (57%) dogs had a concurrent medical problem that may have predisposed them to developing bacterial pneumonia as a sequelae to aspiration or immunosuppression. Mycoplasma-positive dogs were significantly (P < 0.005) more likely to have > 1 species of bacteria isolated from their transtracheal aspiration samples. Clinical outcome was favorable when antimicrobials were selected on the basis of antimicrobial susceptibility results for the other bacterial isolates and not on results of the antimicrobial activity against Mycoplasma spp. It could not be determined whether Mycoplasma spp were primary pathogens or only opportunists.


Cellular Angiofibroma of the Nasopharynx.
Angiofibroma is a common tumor of the nasopharynx region but cellular type is extremely rare in head and neck. A 13-year-old boy presented with frequent epistaxis and nasal obstruction persisting for 6 months. According to the clinical symptoms and imaging studies juvenile angiofibroma was suspected. Following angiographic embolization total excision of the lesion by midfacial degloving approach was performed. Histological examination revealed that the tumor consisted of staghorn blood vessels and irregular fibrous stroma. Stellate fibroblasts with small pyknotic to large vesicular nuclei were seen in a highly cellular stroma. These findings identified cellular angiofibroma mimicking juvenile angiofibroma. This article is about a very rare patient of cellular angiofibroma of nasopharynx.


Anaerobic Threshold in Children.
The ventilatory anaerobic threshold (VAT) occurs when there is an isolated increase in the slope for ventilator equivalent for oxygen consumption (VE/VO2) with no change in the slope for ventilatoiy equivalent for carbon dioxide production (VE/VCO2) when both are plotted against time. The concept of anaerobic threshold remains controversial. However, it is a clinically useful tool in evaluating the exercise capacity of children. This paper will review the history, biochemistry, and methodology involved in determining the anaerobic threshold, as well as the ventilatory anaerobic threshold in children.


Autism screening and diagnosis in low resource settings: Challenges and opportunities to enhance research and services worldwide.
Most research into the epidemiology, etiology, clinical manifestations, diagnosis and treatment of autism is based on studies in high income countries. Moreover, within high income countries, individuals of high socioeconomic status are disproportionately represented among participants in autism research. Corresponding disparities in access to autism screening, diagnosis, and treatment exist globally. One of the barriers perpetuating this imbalance is the high cost of proprietary tools for diagnosing autism and for delivering evidence-based therapies. Another barrier is the high cost of training of professionals and para-professionals to use the tools. Open-source and open access models provide a way to facilitate global collaboration and training. Using these models and technologies, the autism scientific community and clinicians worldwide should be able to work more effectively and efficiently than they have to date to address the global imbalance in autism knowledge and at the same time advance our understanding of autism and our ability to deliver cost-effective services to everyone in need.


Combined anaerobic/aerobic (UASB + UBAF) system for organic matter and nitrogen removal from a high strength industrial wastewater.
The paper presents the experimental results collected from seven months of operation of a combined anaerobic/aerobic system treating an industrial effluent with averaged content of organic matter and nitrogen of 10.4 g COD/L and 790 mg NKT/L, respectively. The system was formed by an upflow anaerobic sludge blanket (UASB) and an upflow biological aerated filter (UBAF) connected in series, with a recycling line of the UBAF effluent into the UASB for its denitrification. The best results were obtained when operating the two reactors, UASB and UBAF, with hydraulic retention times (HRT) of 3.3 and 1.3 days, respectively, and a recycling ratio of 6.7. Under these conditions the system removed 98% of the organic matter and ammonia and 91% of the total nitrogen entering the system. The activity of the different microorganisms was followed through activity assays consisting of measuring the consumption or production rate of any specific substrate or metabolism product. Thus when operating the system under the aforementioned conditions the reported values for the specific activity of methanogenic microorganisms and denitrifiers coexisting in the UASB were 1.05 g COD/g VS d and 32.08 mg NO3-N/g VS d, respectively. While the activity of ammonia and nitrite oxidizers within the UBAF were 47.65 and 4.36 mg O2/g VS h, respectively.


Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient's Body Mass Index.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer recurrences. Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI). We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n = 529 with, n = 298 without) or diclofenac (n = 787 with, n = 220 without). The BMI subgroups were defined as less than 25 kg/m2 (lean) and 25 or more kg/m2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two-sided. The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio [aHR]= 0.59, 95% confidence interval [CI] = 0.37 to 0.96, P = .03). In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR = 0.55, 95% CI = 0.31 to 0.96, P = .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups. These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI. Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies.


[Spanish adaptation of the Stress Manifestations Scale of the Student Stress Inventory (SSI-SM)].
The aim of the present study was to translate into Spanish and to describe the psychometric properties of the Stress Manifestations Scale of the Student Stress Inventory (SSI-SM), developed by Fimian, Fastenau, Tashner and Cross to identify the main manifestations of stress in adolescents. The scale was applied to a sample of 1,002 pupils from years one and two of Secondary Education. The paper reports the factor structure, an item analysis, the internal consistency, differences by sex and academic year, external evidence of validity, and norms for scoring the scale. The results reveal a factor structure based on three first-order factors (emotional manifestations, physiological manifestations and behavioural manifestations) and one second-order factor (indicative of stress manifestations). In terms of external validity, there was a positive association with measures of perceived stress, aggressiveness, internalized/externalized symptoms, and a negative association with life satisfaction. The results show that the scale is an adequate tool for evaluating stress manifestations in adolescents.


Individual susceptibility to alcoholic pancreatitis.
The observation that only a minority of heavy drinkers develop pancreatitis has prompted an intensive search for a trigger factor/cofactor/susceptibility factor that may precipitate a clinical attack. Putative susceptibility factors examined so far include diet, smoking, amount and type of alcohol consumed, the pattern of drinking and lipid intolerance. In addition, a range of inherited factors have been assessed including blood group antigens, human leukocyte antigen serotypes, alpha-1-antitrypsin phenotypes and several genotypes. The latter group comprises mutations/polymorphisms in genes related to alcohol-metabolizing enzymes, detoxifying enzymes, pancreatic digestive enzymes, pancreatic enzyme inhibitors, cystic fibrosis and cytokines. Disappointingly, despite this concerted research effort, no clear association has been established between the above factors and alcoholic pancreatitis. Experimentally, the secretagogue cholecystokinin (CCK) has been investigated as a candidate 'trigger' for alcoholic pancreatitis. However, the clinical relevance of CCK as a trigger factor has to be questioned, as it is difficult to envisage a situation in humans where abnormally high levels of CCK would be released into the circulation to trigger pancreatitis in alcoholics. In contrast, bacterial endotoxemia is a candidate cofactor that does have relevance to the clinical situation. Plasma lipopolysaccharide (LPS, an endotoxin) levels are significantly higher in drinkers (either after chronic alcohol intake or a single binge) compared to non-drinkers. We have recently shown that alcohol-fed animals challenged with otherwise innocuous doses of LPS exhibit significant pancreatic injury. Moreover, repeated LPS exposure in alcohol-fed rats leads to progressive injury to the gland characterized by significant pancreatic fibrosis. These studies support the concept that endotoxin may be an important factor in the initiation and progression of alcoholic pancreatitis. Scope remains for further studies examining proteins related to cellular anti-oxidant defenses, minor cystic fibrosis (CF) mutations and trans-heterozygosity involving a combination of mutations of different genes (such as CFTR alterations combined with SPINK1 or PRSS1 variants), as potential triggers of alcoholic pancreatitis.


Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain.
In addition to their well-established role in signaling rewarding outcomes and reward-predictive cues and in mediating positive reinforcement, there is growing evidence that nucleus accumbens (NAc) neurons also signal aversive events and cues that predict them. Here we use diffusion tractography to subdivide the right NAc into lateral-rostral (putative core, pcore) and medial-caudal (putative shell, pshell) subdivisions in humans. The two subregions exhibited differential structural connectivity, based on probabilistic tractography, to prefrontal cortical and subcortical limbic regions. We also demonstrate unique roles for each of the two subdivisions for monetary reward and thermal pain perception tasks: pshell signaling impending pain and value predictions for monetary gambles and pcore activating with anticipation of cessation of thermal pain (signaling reward value of analgesia). We examined functional connectivity for resting state, monetary reward, and thermal pain tasks, and for all three conditions observed that pcore and pshell of right NAc exhibit distinct patterns of synchrony (functional connectivity) to prefrontal cortical and subcortical limbic targets within the right hemisphere. To validate the NAc segregation, we mirrored the coordinates of right NAc pcore and pshell onto the left hemisphere and examined structural and resting state connectivity in the left hemisphere. This latter analysis closely replicated target-specific connections we obtained for the right hemisphere. Overall, we demonstrate that the human NAc can be parceled based on structural and functional connectivity, and that activity in these subdivisions differentially encodes values for expected pain relief and for expected monetary reward.


The use of B vitamin supplements and peripheral arterial disease risk in men are inversely related.
Peripheral arterial disease (PAD) causes morbidity and is associated with mortality. B vitamin intake has been inversely associated with coronary heart disease, but their effects on PAD are not known. We examined prospectively the relationships between dietary folate, vitamin B-6 and B-12 and PAD risk in 51529 male U.S. health professionals, aged 40 to 75 y, who answered a detailed 131-item questionnaire to assess diet and vitamin supplement use. The study population consisted of 46036 men free of PAD, cardiovascular disease and diabetes at baseline followed for 12 y during which we documented 308 incident PAD cases. For every 400 microg/d increment of folate intake, the multivariate adjusted PAD risk decreased by 21% [relative risk (RR) = 0.79, 95% CI 0.64-0.96]. Men in the top category of folate intake (median = 840 micro g) were at 33% lower risk of PAD than men in the bottom category (median = 244 microg) (RR = 0.67, 95% CI 0.45-0.96, P-value, test for trend = 0.03) after multivariate adjustment. There were weak inverse associations between intake of vitamin B-6 and PAD risk (RR = 0.70, 95% CI 0.48-1.02, P-value, test for trend = 0.06) and B-12 (RR = 0.77, 95% CI 0.54-1.11, P-value, test for trend = 0.12). These results suggest that higher consumption of folate may contribute to the prevention of PAD.


Anastomoses between lower cranial and upper cervical nerves: a comprehensive review with potential significance during skull base and neck operations, part I: trigeminal, facial, and vestibulocochlear nerves.
Descriptions of the anatomy of the neural communications among the cranial nerves and their branches is lacking in the literature. Knowledge of the possible neural interconnections found among these nerves may prove useful to surgeons who operate in these regions to avoid inadvertent traction or transection. We review the literature regarding the anatomy, function, and clinical implications of the complex neural networks formed by interconnections among the lower cranial and upper cervical nerves. A review of germane anatomic and clinical literature was performed. The review is organized in two parts. Part I concerns the anastomoses between the trigeminal, facial, and vestibulocochlear nerves or their branches with any other nerve trunk or branch in the vicinity. Part II concerns the anastomoses among the glossopharyngeal, vagus, accessory and hypoglossal nerves and their branches or among these nerves and the first four cervical spinal nerves; the contribution of the autonomic nervous system to these neural plexuses is also briefly reviewed. Part I is presented in this article. An extensive anastomotic network exists among the lower cranial nerves. Knowledge of such neural intercommunications is important in diagnosing and treating patients with pathology of the skull base.


Developmental expression of histone deacetylase 11 in the murine brain.
Recent studies indicate that neural cell development in the central nervous system (CNS) correlates with a reduction in acetylation of histone core proteins. Moreover, histone hypoacetylation is thought to be important to oligodendrocyte lineage development. The mechanisms mediating the reduction in acetylation during postnatal neural development remain to be defined. To begin to understand these mechanisms, we investigated the expression of histone deacetylase 11 (HDAC11), a newly identified HDAC, in mouse brain during postnatal development. We show that HDAC11 was widely expressed in the brain and that this expression gradually increased in a region-specific pattern between birth and 4 weeks of age. At the cellular level HDAC11 protein was predominately localized in the nuclei of mature oligodendrocytes but only minimally in astrocytes. Although dentate gyrus granule neurons abundantly expressed HDAC11, granule neuron precursors in the subgranule layer exhibited little HDAC11 immunoreactivity. Double-immunostaining of the corpus callosum and dentate gyrus demonstrated that HDAC11 and Ki67, a cell-proliferating marker, are rarely colocalized in same cells. Our data show that HDAC11 was expressed in the developing brain in a temporal and spatial pattern that correlates with the maturation of neural cells, including cells of the oligodendrocyte lineage. These findings support a role for HDAC11 in CNS histone deacetylation and the development of oligodendrocytes and neurons during postnatal development.


Baroreceptor reflex control of arterial hemodynamics in the dog.
The regional differentiation of carotid sinus control of arterial pressure-flow relationships was studied in chloralose-anesthetized dogs. Simulatneous pressure-flow measurements were made in the ascending aorta, the celiac artery, the cranial mesenteric artery, the renal artery, and the femoral artery. The carotid sinuses were bilaterally isolated and perfused with pulsatile pressure. The open-loop reflex gain was not symmetrical about and was maximum at pressures below the closed loop operating point pressure. Changes in both peripheral resistance and cardiac output contributed significantly to the open-loop gain with the former predominating. Aortic impedance for frequencies above 3 Hz was at a minimum at the closed-loop operating point and increased for both higher and lower values of carotid sinus pressure. For the frequency range from 3 to 9 Hz, regional impedance in all of the beds varied inversely with carotid sinus pressure. The sensitivity of the various beds to changes in carotid sinus pressure around the operating point increased in the order celiac less than mesenteric less than renal less than femoral. Following vagotomy, operating point values of regional resistance and sensitivity were significantly increased. This fact suggests that the aortic arch receptors exert a significant influence on regional vascular impedance at operating point pressures. The fraction of cardiac output in the celiac, mesenteric, and renal beds was nearly independent of carotid sinus pressure before and after vagotomy, but that in the femoral bed increased with carotid sinus pressure. These results demonstrate the nonuniform nature of carotid sinus and aortic arch baroreceptor control of regional blood flow.


Proactive prevention: Act now to disrupt the impending non-communicable disease crisis in low-burden populations.
Non-communicable disease (NCD) prevention efforts have traditionally targeted high-risk and high-burden populations. We propose an alteration in prevention efforts to also include emphasis and focus on low-risk populations, predominantly younger individuals and low-prevalence populations. We refer to this approach as "proactive prevention." This emphasis is based on the priority to put in place policies, programs, and infrastructure that can disrupt the epidemiological transition to develop NCDs among these groups, thereby averting future NCD crises. Proactive prevention strategies can be classified, and their implementation prioritized, based on a 2-dimensional assessment: impact and feasibility. Thus, potential interventions can be categorized into a 2-by-2 matrix: high impact/high feasibility, high impact/low feasibility, low impact/high feasibility, and low impact/low feasibility. We propose that high impact/high feasibility interventions are ready to be implemented (act), while high impact/low feasibility interventions require efforts to foster buy-in first. Low impact/high feasibility interventions need to be changed to improve their impact while low impact/low feasibility might be best re-designed in the context of limited resources. Using this framework, policy makers, public health experts, and other stakeholders can more effectively prioritize and leverage limited resources in an effort to slow or prevent the evolving global NCD crisis.


Reiki brief report: using Reiki to reduce stress levels in a nine-year-old child.
A nine-year-old female with a history of perinatal stroke, seizures, and type-I diabetes was seen for six weeks of Reiki to determine the effects of Reiki on relaxation, and in turn, the prevention of future seizures. The secondary and tertiary aims were to determine the effects of Reiki on sleep patterns and the stress levels of the mother. There was a decrease in stress in both the child and the mother, as measured by a modified Perceived Stress Scale and a Perceived Stress Scale, respectively. There was no change in the child's overall sense of well-being, as measured by a global questionnaire. There was a positive change in sleep patterns on 33.3% of the nights during which the study occurred, as reported on a sleep log kept by the mother. The child and the Reiki Master (a Reiki practitioner who has completed all three levels of Reiki certification training and trains and certifies individuals in the practice of Reiki as well as provides Reiki to individuals) experienced warmth and tingling sensations on the same area of the child during the Reiki sessions. The child relaxed within the first five to seven minutes of each session as reported by the Reiki Master. There were no reports of seizures during this study. Reiki may be a useful adjunct for children with increased stress levels and sleep disturbances secondary to their medical condition. Further research is warranted to evaluate the use of Reiki in children, particularly with a large sample size, and to evaluate the long-term use of Reiki and its effects on adequate sleep.