An International Multicenter Study Assessing the Role of Ethnicity on Variation of Lumbar Facet Joint Orientation and the Occurrence of Degenerative Spondylolisthesis in Asia Pacific: A Study from the AOSpine Asia Pacific Research Collaboration Consortium.
Study Design A multinational, multiethnic, cross-sectional image-based study was performed in 33 institutions, representing 10 countries, which were part of the AOSpine Asia Pacific Research Collaboration Consortium. Objective Lumbar facet joint orientation has been reported to be associated with the development of degenerative spondylolisthesis (DS). The role of ethnicity regarding facet joint orientation remains uncertain. As such, the following study was performed across a wide-ranging population base to assess the role of ethnicity in facet joint orientation in patients with DS in the Asia Pacific region. Methods Lateral standing X-rays and axial magnetic resonance imaging scans were obtained for patients with lumbar DS. The DS parameters and facet joint angulations were assessed from L3-S1. Sex, age, body mass index (BMI), and ethnicity were also noted. Results The study included 371 patients with known ethnic origin (mean age: 62.0 years; 64% males, 36% females). The mean BMI was 25.6 kg/m(2). The level of DS was most prevalent at L4-L5 (74.7%). There were 28.8% Indian, 28.6% Japanese, 18.1% Chinese, 8.6% Korean, 6.5% Thai, 4.9% Caucasian, 2.7% Filipino, and 1.9% Malay patients. Variations in facet joint angulations were noted from L3 to S1 and between patients with and without DS (p < 0.05). No differences were noted with regards to sex and overall BMI to facet joint angulations (p > 0.05); however, increasing age was found to increase the degree of angulation throughout the lumbar spine (p < 0.05). Accounting for age and the presence or absence of DS at each level, no statistically significant differences between ethnicity and degree of facet joint angulations from L3-L5 were noted (p > 0.05). Ethnic variations were noted in non-DS L5-S1 facet joint angulations, predominantly between Caucasian, Chinese, and Indian ethnicities (p < 0.05). Conclusions This study is the first to suggest that ethnicity may not play a role in facet joint orientation in the majority of cases of DS in the Asia-Pacific region. Findings from this study may facilitate future comparative studies in other multiethnic populations. An understanding of ethnic variability may assist in identifying those patients at risk of postsurgical development or progression of DS. This study also serves as a model for large-scale multicenter studies across different ethnic groups and cultural boundaries in Asia.


New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.


Permanent magnetism of intermetallic compounds between light and heavy transition-metal elements.
First-principle calculations are used to investigate the intrinsic magnetic properties of intermetallic alloys of the type XMn, where X is a 4d or 5d element and M is Fe or Co. Emphasis is on the hexagonal C14 Laves-phase 1:2 and 1:5 alloys, the latter crystallizing in the CaCu5 structure. These series are of interest in permanent magnetism from fundamental and practical viewpoints, respectively. In the former, the unit cells form a prototypical motif where a heavy atom with high spin-orbit coupling and magnetocrystalline anisotropy is surrounded by many somewhat smaller M atoms with high magnetization, and the latter are Laves-phase derivatives of renewed interest in permanent magnetism. Our DFT calculations predict magnetic moments, magnetizations and anisotropies, as well as formation energies. The results are analyzed across the 4d and 5d series, especially with respect to hybridization effects between 3d and 4d/5d bands.


Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads.
HLA class-I alleles differ in their ability to control HIV replication through cell-mediated immune responses. No consistent associations have been found between the breadth of Cytotoxic T Lymphocytes (CTL) responses and the control of HIV-1, and it is unknown whether the size or distribution of the viral proteome-wide epitope repertoire, i.e., the intrinsic ability to present fewer, more or specific viral epitopes, could affect clinical markers of disease progression. We used an epitope prediction model to identify all epitope motifs in a set of 302 HIV-1 full-length proteomes according to each individual's HLA (Human Leukocyte Antigen) genotype. The epitope repertoire, i.e., the number of predicted epitopes per HIV-1 proteome, varied considerably between HLA alleles and thus among individual proteomes. In a subgroup of 270 chronically infected individuals, we found that lower viral loads and higher CD4 counts were associated with a larger predicted epitope repertoire. Additionally, in Gag and Rev only, more epitopes were restricted by alleles associated with low viral loads than by alleles associated with higher viral loads. This comprehensive analysis puts forth the epitope repertoire as a mechanistic component of the multi-faceted HIV-specific CTL response. The favorable impact on markers of disease status of the propensity to present more HLA binding peptides and specific proteins gives impetus to vaccine design strategies that seek to elicit responses to a broad array of HIV-1 epitopes, and suggest a particular focus on Gag.


Detection of photothermal deflection signals with conjugate masks.
A new detection technique for photothermal deflection spectroscopy and photoacoustic deflection spectroscopy is presented. The technique uses a pair of matched multiple slits placed in the path of the probe beam and oriented to block the probe light from the detector in the absence of a deflection signal. Significant improvement in the signal-to-noise ratio and in the frequency bandwidth compared with those available with current techniques is demonstrated.


Mesh complications after prosthetic reinforcement of hiatal closure: a 28-case series.
Primary laparoscopic hiatal hernia repair is associated with up to a 42% recurrence rate. This has lead to the use of mesh for crural repair, which has resulted in an improved recurrence rate (0-24%). However, mesh complications have been observed. We compiled two cases, and our senior author contacted other experienced esophageal surgeons who provided 26 additional cases with mesh-related complications. Care was taken to retrieve technical operative details concerning mesh size and shape and implantation technique used. Twenty-six patients underwent laparoscopic and two patients open surgery for large hiatal hernia (n = 28). Twenty-five patients had a concomitant Nissen fundoplication, two a Toupet fundoplication, and one a Watson fundoplication. Mesh types placed were polypropylene (n = 8), polytetrafluoroethylene (PTFE) (n = 12), biological mesh (n = 7), and dual mesh (n = 1). Presenting symptoms associated with mesh complications were dysphagia (n = 22), heartburn (n = 10), chest pain (n = 14), fever (n = 1), epigastric pain (n = 2), and weight loss (n = 4). Main reoperative findings were intraluminal mesh erosion (n = 17), esophageal stenosis (n = 6), and dense fibrosis (n = 5). Six patients required esophagectomy, two patients had partial gastrectomy, and 1 patient had total gastrectomy. Five patients did not require surgery. In this group one patient had mesh removal by endoscopy. There was no immediate postoperative mortality, however one patient has severe gastroparesis and five patients are dependent on tube feeding. Two patients died 3 months postoperatively of unknown cause. There is no apparent relationship between mesh type and configuration with the complications encountered. Complications related to synthetic mesh placement at the esophageal hiatus are more common than previously reported. Multicenter prospective studies are needed to determine the best method and type of mesh for implantation.


Repeated community-based chemotherapy for the control of Schistosoma mansoni: effect of screening and selective treatment on prevalences and intensities of infection.
The impact of repeated selective chemotherapy on prevalences and intensities of infection with Schistosoma mansoni was evaluated in Gihungwe Transversals 1 and 2 (initial prevalence 60%) and Buhandagaza/Kizina (initial prevalence 35%), two village clusters in Burundi. Surveys were carried out at months -6, -3, 0, 3, 6, 9, 12, 24, and 36, with reference to the first intervention; treatment with praziquantel (40 mg/kg) was given at months 0, 12, 24, and 36 to subjects showing parasite eggs on a single 28-mg Kato slide. A second slide was examined for monitoring purposes only. Over the pre-intervention period, the overall prevalences and intensities remained relatively stable, but important increases were observed in specific groups. The cure rate three months after the first treatment in those treated was 73% (Gihungwe) and 83% (Buhandagaza/Kizina), but the prevalence at the community level was reduced only by 50% and 46%, respectively. Fifty-six percent and 79%, respectively, of the remaining positive cases had not been treated, largely because they were (falsely) negative at the screening. Reinfection occurred mainly in Gihungwe and in younger age groups. One year after the second treatment, prevalences and intensities were further reduced in Gihungwe only; one year after the third treatment prevalences were not reduced further in either village group. The final prevalence of infection was approximately 25%, with infections with an intensity of over 100 eggs per gram of feces approximately 5%, in all four villages. Over 80% of the remaining cases had not been treated at the previous intervention; the sensitivity of the screening method appears to be a major determinant of the outcome of repeated selective treatment.


Early start to therapy preserves kidney function in spina bifida patients.
Renal scarring and renal failure remain life-threatening for children born with spinal dysraphism. We reviewed our data of spina bifida patients to evaluate whether optimal treatment of the neurogenic bladder from birth onwards can preserve kidney function. We reviewed data on all newborns with spinal dysraphism who were referred to our hospital between January 1988 and June 2001. We looked at their situations at referral and at follow-up: the type of treatment, antimuscarinic agents, clean intermittent catheterisation (CIC), antibiotic prophylaxis, and operations (sling procedures, bladder augmentations, antireflux procedures). Renal function (ultrasound, DMSA scan, serum creatinin, creatinin clearance) and bladder function (urodynamic studies) were evaluated over time. Data of 144 children of 176 could be evaluated by the end of the study: 5 patients had pre-existing renal abnormalities, 69 had an overactive sphincter, 27 had reflux, and six had renal scarring. None are currently developing end-stage renal disease. All patients with spina bifida aperta started CIC and antimuscarinic therapy shortly after birth. Five of the six patients with renal scarring were started on therapy with intermittent catheterisation and antimuscarinic therapy several months after birth. Sixty-three of 82 children with spina bifida were dry at school age (age six), although 37 of these had not had an operation. We show that an early start to therapy helps to safeguard renal function for children born with spina bifida. Our data support other recent reports that children born with spina bifida can probably use their own kidneys for a lifetime, if they are given adequate urological treatment. To protect the upper urinary tract, we need to ensure low intravesical pressure by starting children early on CIC (the preferred treatment); antimuscarinic agents to counteract detrusor instability are indispensable in most cases. Proactive treatment of risks for upper tract deterioration results in a negligible loss of renal function, even when early urinary continence is included in the treatment protocol.


Effective physician-patient communication and health outcomes: a review.
To ascertain whether the quality of physician-patient communication makes a significant difference to patient health outcomes. The MEDLINE database was searched for articles published from 1983 to 1993 using "physician-patient relations" as the primary medical subject heading. Several bibliographies and conference proceedings were also reviewed. Randomized controlled trials (RCTs) and analytic studies of physician-patient communication in which patient health was an outcome variable. The following information was recorded about each study: sample size, patient characteristics, clinical setting, elements of communication assessed, patient outcomes measured, and direction and significance of any association found between aspects of communication and patient outcomes. Of the 21 studies that met the final criteria for review, 16 reported positive results, 4 reported negative (i.e., nonsignificant) results, and 1 was inconclusive. The quality of communication both in the history-taking segment of the visit and during discussion of the management plan was found to influence patient health outcomes. The outcomes affected were, in descending order of frequency, emotional health, symptom resolution, function, physiologic measures (i.e., blood pressure and blood sugar level) and pain control. Most of the studies reviewed demonstrated a correlation between effective physician-patient communication and improved patient health outcomes. The components of effective communication identified by these studies can be used as the basis both for curriculum development in medical education and for patient education programs. Future research should focus on evaluating such educational programs.


Cell seeding into calcium phosphate cement.
To improve the effectiveness of calcium phosphate cement (CPC), we have developed a method to seed osteoblasts into the cement. CPC powder is mixed with water to form a paste that can be shaped to fit a bone defect in situ. The paste hardens in 30 min, reacts to form hydroxyapatite, and is replaced with new bone. Reacted CPC is biocompatible but unreacted CPC paste was found to have toxic effects when placed on cell monolayers (MC3T3-E1 cells). In contrast, when cells were indirectly exposed to CPC paste using a porous membrane or by placing a coverslip containing adherent cells onto a bed of CPC paste, the unreacted CPC was nontoxic. These results suggested that gel encapsulation of the cells might protect them from the CPC paste. Thus, cells were encapsulated in alginate beads (3.6-mm diameter), mixed with CPC paste, and incubated overnight. Both vital staining (calcein-AM and ethidium homodimer-1) and the Wst-1 assay (measures dehydrogenase activity) showed that cell survival in alginate beads that were mixed with CPC was similar to survival in untreated control beads. These results suggest that gel encapsulation could be used as a mechanism to protect cells for seeding into CPC.


Content validation of the Patient-Reported Hamilton Inventory for Complex Regional Pain Syndrome: Validité de contenu du Hamilton Inventory for Complex Regional Pain Syndrome, une mesure des résultats déclarés par le patient.
Complex regional pain syndrome (CRPS) is a perplexing neurological condition, and persons with CRPS experience substantial loss of daily roles and activities. A condition-specific measure is being developed to evaluate CRPS. We describe the use of cognitive interviews to examine content validity of this patient-reported outcome measure for CRPS. Interviews with 44 persons with CRPS were analyzed to identify problems with wording and support content validation. Item-total correlations were calculated for proposed subscales, and scores were plotted to consider floor/ceiling effects. Interviews identified questions where respondents considered factors unrelated to the construct of interest or were underaddressed by the questionnaire, including depression and skin temperature. The symptoms, daily function, and coping/social impact scales demonstrated satisfactory correlations (Cronbach's alpha 0.76-0.86). Despite a sampling bias of severity, no frank floor/ceiling effects were noted. This study builds a foundation for continuing development and evaluation of the measurement properties of the Patient-Reported Hamilton Inventory for CRPS. It makes explicit the iterative decisions involved in rigorous instrument development.


A Prospective, International Cohort Study of Invasive Mold Infections in Children.
Invasive mold infections (IMIs) are a leading cause of mortality in immunocompromised children, yet there has never been an international epidemiologic investigation of pediatric IMIs. This international, prospective cohort study was performed to characterize the epidemiology, antifungal therapy, and outcomes of pediatric IMIs. Children (≤18 years) with proven or probable IMIs were enrolled between August 2007 and May 2011 at 22 sites. Risk factors, underlying diagnoses, and treatments were recorded. Outcomes were assessed at 12 weeks after diagnosis using European Organization for Research and Treatment of Cancer/Mycoses Study Group response criteria. One hundred thirty-one pediatric patients with IMIs were enrolled; the most common IMI was invasive aspergillosis ([IA] 75%). Children with IA and those with other types of IMIs had similar underlying risk factors, except that children with IMIs caused by non-Aspergillus species were more likely to have received mold-active antifungal agents preceding diagnosis. The most commonly used antifungal classes after diagnosis were triazoles (82%) and polyenes (63%). Combination therapy was used in 53% of patients. Use of combination therapy was associated with an increased risk of adverse events (risk ratio, 1.98; 95% confidence interval, 1.06-3.68; P = .031), although there was no detectable difference in outcome. Although risk factors for IMIs are similar across specific subtypes, preceding antifungal therapy may be an important modifier. Combination antifungal therapy requires further study to determine its true risks and benefits.


Guaraná, a Highly Caffeinated Food, Presents in vitro Antitumor Activity in Colorectal and Breast Cancer Cell Lines by Inhibiting AKT/mTOR/S6K and MAPKs Pathways.
The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPKs) pathways are frequently upregulated in cancer. Some authors have reported that some antioxidant molecules could be potential inhibitors of these pathways. Therefore, we investigated the in vitro antitumor effect of guaraná by inhibiting the AKT/mTOR/S6K and MAPKs pathways. Colorectal and breast cancer cell lineages, HT-29 and MCF-7 cells, respectively, were exposed to different guaraná concentrations (0.1, 1, 10, and 100 µg/mL) as well as its main bioactive molecule, caffeine, in proportional concentrations to those found in the extract. Western blot, clonogenic assay, and growth curve were performed. Moreover, we investigated the potential cytotoxic effect of guaraná in normal cells. The results revealed that guaraná and caffeine inhibited some MAPKs proteins (p-p38 and p-HSP27) in MCF-7 cells. However, they did not affect this pathway in HT-29 cells. Furthermore, guaraná inhibited mTORC1 (p-S6K) and mTORC2 (p-AKT) in MCF-7 cells, but only mTORC1 in HT-29 cells. Caffeine only inhibited the mTOR pathway in MCF-7 cells. Guaraná decreased the colony formation and cell growth in MCF-7 and HT-29 cells. Guaraná did not affect normal cells. In conclusion, guaraná could be an important agent in antitumor pharmacologic therapies by inhibiting the mTOR and MAPKs pathways.


Cultivation-independent characterization of methylobacterium populations in the plant phyllosphere by automated ribosomal intergenic spacer analysis.
Bacteria of the genus Methylobacterium are widespread in the environment, but their ecological role in ecosystems, such as the plant phyllosphere, is not very well understood. To gain better insight into the distribution of different Methylobacterium species in diverse ecosystems, a rapid and specific cultivation-independent method for detection of these organisms and analysis of their community structure is needed. Therefore, 16S rRNA gene-targeted primers specific for this genus were designed and evaluated. These primers were used in PCR in combination with a reverse primer that binds to the tRNA(Ala) gene, which is located upstream of the 23S rRNA gene in the 16S-23S intergenic spacer (IGS). PCR products that were of different lengths were obtained due to the length heterogeneity of the IGS of different Methylobacterium species. This length variation allowed generation of fingerprints of Methylobacterium communities in environmental samples by automated ribosomal intergenic spacer analysis. The Methylobacterium communities on leaves of different plant species in a natural field were compared using this method. The new method allows rapid comparisons of Methylobacterium communities and is thus a useful tool to study Methylobacterium communities in different ecosystems.


AxonQuant: A Microfluidic Chamber Culture-Coupled Algorithm That Allows High-Throughput Quantification of Axonal Damage.
Published methods for imaging and quantitatively analyzing morphological changes in neuronal axons have serious limitations because of their small sample sizes, and their time-consuming and nonobjective nature. Here we present an improved microfluidic chamber design suitable for fast and high-throughput imaging of neuronal axons. We developed the AxonQuant algorithm, which is suitable for automatic processing of axonal imaging data. This microfluidic chamber-coupled algorithm allows calculation of an 'axonal continuity index' that quantitatively measures axonal health status in a manner independent of neuronal or axonal density. This method allows quantitative analysis of axonal morphology in an automatic and nonbiased manner. Our method will facilitate large-scale high-throughput screening for genes or therapeutic compounds for neurodegenerative diseases involving axonal damage. When combined with imaging technologies utilizing different gene markers, this method will provide new insights into the mechanistic basis for axon degeneration. Our microfluidic chamber culture-coupled AxonQuant algorithm will be widely useful for studying axonal biology and neurodegenerative disorders.


Association between happiness and psychopathology in an elderly regional rural population in Crete.
Research has shown that socio-demographic profile and psychopathology symptoms are related to levels of happiness in old age. The aims of this cross-sectional study were: 1) to investigate the effect of recent stressful life events and socio-demographic factors on psychopathological symptoms in elderly residents in mountain regions of Crete, Greece and 2) to explore the mechanism which underlies the relationship between socio-demographic factors and psychopathological symptoms, with levels of happiness in old age. To this end, we used the nine psychopathology dimensions of symptoms as defined in the Symptom Checklist-90-R (SCL-90), while the Holmes and Rahe stress inventory was administered to quantify the stressful life events. A sample of 205 elderly men and women (age=77.1±6.7 years) living in 10 remote rural and isolated villages participated in this study. Data was collected through questionnaires completed upon individual meetings with each participant, with the interviewer's assistance. Each questionnaire included the two aforesaid scales alongside questions on individual socio-demographic characteristics. Analysis of variance was applied to detect socio-demographic factors that have a significant effect on specific psychopathological symptoms. Then, path analysis was applied to quantify the direct and indirect effect of the selected socio-demographic factors on happiness levels. Stressful life events were found to have no statistically significant effect on the presence of specific symptoms (somatization, psychoticism, anxiety) in elderly adults. Furthermore, certain socio-demographic factors (marital status, smoking, family income and social activity) were found to influence happiness, which varied according to the level of psycho-emotional tension. The results suggest that somatization, psychoticism, and phobic anxiety symptoms are psychic reactions independent of recent stressful life events. Our study,despite its regional character, may contribute in the development of appropriate clinical assessment tools and interventions, helping primary care practitioners to approach elderly people living in remote villages in a more appropriate and holistic manner, improving thereby the effectiveness of their interventions.


p53 Specifically Binds Triplex DNA In Vitro and in Cells.
Triplex DNA is implicated in a wide range of biological activities, including regulation of gene expression and genomic instability leading to cancer. The tumor suppressor p53 is a central regulator of cell fate in response to different type of insults. Sequence and structure specific modes of DNA recognition are core attributes of the p53 protein. The focus of this work is the structure-specific binding of p53 to DNA containing triplex-forming sequences in vitro and in cells and the effect on p53-driven transcription. This is the first DNA binding study of full-length p53 and its deletion variants to both intermolecular and intramolecular T.A.T triplexes. We demonstrate that the interaction of p53 with intermolecular T.A.T triplex is comparable to the recognition of CTG-hairpin non-B DNA structure. Using deletion mutants we determined the C-terminal DNA binding domain of p53 to be crucial for triplex recognition. Furthermore, strong p53 recognition of intramolecular T.A.T triplexes (H-DNA), stabilized by negative superhelicity in plasmid DNA, was detected by competition and immunoprecipitation experiments, and visualized by AFM. Moreover, chromatin immunoprecipitation revealed p53 binding T.A.T forming sequence in vivo. Enhanced reporter transactivation by p53 on insertion of triplex forming sequence into plasmid with p53 consensus sequence was observed by luciferase reporter assays. In-silico scan of human regulatory regions for the simultaneous presence of both consensus sequence and T.A.T motifs identified a set of candidate p53 target genes and p53-dependent activation of several of them (ABCG5, ENOX1, INSR, MCC, NFAT5) was confirmed by RT-qPCR. Our results show that T.A.T triplex comprises a new class of p53 binding sites targeted by p53 in a DNA structure-dependent mode in vitro and in cells. The contribution of p53 DNA structure-dependent binding to the regulation of transcription is discussed.


An analysis of the explosion limits of hydrogen/oxygen mixtures with nonlinear chain reactions.
The ignition boundary of hydrogen/oxygen mixtures is a Z-shaped curve in the pressure-temperature space, demonstrating the existence of three explosion limits. In this study, a general analysis governing all the three explosion limits in an isothermal environment is performed by considering both linear chain reactions (reactant-radical reactions) and nonlinear chain reactions (radical-radical reactions), in addition to the zeroth-order reactant-reactant reactions. For the nonlinear reactions, it is further shown that the linear-nonlinear coupling has the major influence, while the effect of nonlinear-nonlinear coupling is negligible. Phenomenologically, at low pressures, the competition between linear branching and linear termination as well as wall destruction determines the first and second explosion limits, while the nonlinear chain reactions are unimportant because of the small radical concentrations under these conditions. However, at higher pressures, both linear and nonlinear chain reactions are needed to accurately describe the third limit, which would be underpredicted by considering the linear chain reactions alone. For intermediate and high pressures, the dominant species are HO2 and H2O2, respectively. Mechanistically, the concentration of HO2 becomes higher at higher pressures due to the three-body recombination reaction, H + O2 + M → HO2 + M, such that the radical-radical reactions involving HO2 become important, while the reaction HO2 + HO2 → H2O2 + O2 renders HO2 nonessential at the third limit, with the H2O2 radical generated by the nonlinear chain reactions becoming the controlling species.


Short-term training increases human muscle MCT1 and femoral venous lactate in relation to muscle lactate.
We examined the effects of increasing a known lactate transporter protein, monocarboxylate transporter 1 (MCT1), on lactate extrusion from human skeletal muscle during exercise. Before and after short-term bicycle ergometry training [2 h/day, 7 days at 65% maximal oxygen consumption (VO2max)], subjects (n = 7) completed a continuous bicycle ergometer ride at 30% VO2max (15 min), 60% VO2max (15 min), and 75% VO2max (15 min). Muscle biopsy samples (vastus lateralis) and arterial and femoral venous blood samples were obtained before exercise and at the end of each workload. After 7 days of training the MCT1 content in muscle was increased (+18%; P < 0.05). The concentrations of both muscle lactate and femoral venous lactate were reduced during exercise (P < 0.05) that was performed after training. High correlations were observed between muscle lactate and venous lactate before training (r = 0.92, P < 0.05) and after training (r = 0.85, P < 0.05), but the slopes of the regression lines between these variables differed markedly. Before training, the slope was 0.12 +/- 0.01 mM lactate.mmol lactate-1.kg muscle dry wt-1, and this was increased by 33% after training to 0.18 +/- 0.02 mM lactate.mmol lactate-1.kg muscle dry wt-1. This indicated that after training the femoral venous lactate concentrations were increased for a given amount of muscle lactate. These results suggest that lactate extrusion from exercising muscles is increased after training, and this may be associated with the increase in skeletal muscle MCT1.


Factors Associated with Vitamin D Deficiency and Inadequacy among Women of Childbearing Age in the United States.
Objective. To examine the prevalence and correlates of vitamin D deficiency and inadequacy among US women of childbearing age. Methods. Data from 1,814 female participants (20-44 y) in the 2003-2006 NHANES were analyzed to estimate the age-adjusted prevalence and prevalence ratios with 95% confidence intervals (CIs) for vitamin D deficiency (defined as serum 25-hydroxyvitamin D [25(OH)D] <12.0 ng/mL) and inadequacy (defined as 25(OH)D: 12.0-<20.0 ng/mL). Results. The age-adjusted prevalence was 11.1% (95% CI: 8.8-14.0%) for vitamin D deficiency and 25.7% (95% CI: 22.3-29.5%) for vitamin D inadequacy. Race/ethnicity other than non-Hispanic white and obesity were associated with increased risks, whereas dietary supplement use, milk consumption of ≥1 time/day, and potential sunlight exposure during May-October were associated with decreased risks for both vitamin D deficiency and inadequacy (P < 0.05). Current smoking and having histories of diabetes and cardiovascular disease were also associated with an increased risk for vitamin D deficiency (P < 0.05). Conclusions. Among women of childbearing age, periconceptional intervention programs may focus on multiple risk factors for vitamin D deficiency and inadequacy to ultimately improve their vitamin D nutrition.


Mild Aerobic Exercise Training Hardly Affects the Diaphragm of mdx Mice.
In the mdx mice model of Duchenne Muscular Dystrophy (DMD), mild endurance exercise training positively affected limb skeletal muscles, whereas few and controversial data exist on the effects of training on the diaphragm. The diaphragm was examined in mdx (C57BL/10ScSn-Dmdmdx) and wild-type (WT, C57BL/10ScSc) mice under sedentary conditions (mdx-SD, WT-SD) and during mild exercise training (mdx-EX, WT-EX). At baseline, and after 30 and 45 days (training: 5 d/wk for 6 weeks), diaphragm muscle morphology and Cx39 protein were assessed. In addition, tissue levels of the chaperonins Hsp60 and Hsp70 and the p65 subunit of nuclear factor-kB (NF-kB) were measured in diaphragm, gastrocnemius, and quadriceps in each experimental group at all time points. Although morphological analysis showed unchanged total area of necrosis/regeneration in the diaphragm after training, there was a trend for larger areas of regeneration than necrosis in the diaphragm of mdx-EX compared to mdx-SD mice. However, the levels of Cx39, a protein associated with active regeneration in damaged muscle, were similar in the diaphragm of mdx-EX and mdx-SD mice. Hsp60 significantly decreased at 45 days in the diaphragm, but not in limb muscles, in both trained and sedentary mdx compared to WT mice. In limb muscles, but not in the diaphragm, Hsp70 and NF-kB p65 levels were increased in mdx mice irrespective of training at 30 and 45 days. Therefore, the diaphragm of mdx mice showed little inflammatory and stress responses over time, and appeared hardly affected by mild endurance training. J. Cell. Physiol. 232: 2044-2052, 2017. © 2016 Wiley Periodicals, Inc.


Comparison of clinical and economic outcomes of two antibiotic prophylaxis regimens for sternal wound infection in high-risk patients following coronary artery bypass grafting surgery: a prospective randomised double-blind controlled trial.
Prospective studies show a 10% incidence of sternal wound infection (SWI) after 90 days of follow-up, compared with infection rates of 5% reported by the National Nosocomial Infections Surveillance System after only 30 days of follow-up. This incidence increases 2-3 times in high-risk patients. Prospective randomised double-blind controlled clinical trial. Cardiothoracic centre, UK. Patients were eligible if they were undergoing median sternotomy for primary isolated coronary artery bypass grafting, with at least one internal thoracic artery used for coronary grafting and having one or more of the following three risk factors: (1) obesity, defined as body mass index 30 kg/m(2); (2) diabetes mellitus; or (3) bilateral internal thoracic artery grafts (ie, the use of the other internal thoracic artery). The study group received a single dose of gentamicin 2 mg/kg, rifampicin 600 mg and vancomycin 15 mg/kg, with three further doses of 7.5 mg/kg at 12-hour intervals. The control group received cefuroxime 1.5 g at induction and three further doses of 750 mg at 8-hour intervals. The primary end point was the incidence of SWI at 90 days. The secondary end point was the antibiotic and hospital costs. During the study period, 486 patients underwent isolated coronary artery bypass grafting with a 30-day SWI of 7.6%. 186 high-risk patients were recruited and analysed: 87 in the study group and 99 in the control group. 90-day SWI was significantly reduced in 8 patients in the study group (9.2%; 95% CI 3.5% to 15.3%) compared with 25 patients in the control group (25.2%; 95% CI 19.5% to 39.4%; p = 0.004). The study group had a significantly lower cost of antibiotics (21.2% reduction--US$96/patient; p<0.001), and a significantly lower hospital cost (20.4% reduction in cost--US$3800/patient; p = 0.04). Longer and broader-spectrum antibiotic prophylaxis significantly reduces the incidence of SWI in high-risk patients, with a significant economic benefit in costs of antibiotics as well as hospital costs.


In vitro wear of primary and permanent enamel. Simultaneous erosion and abrasion.
To evaluate the wear differences between primary and permanent enamel caused by the association of abrasion and erosion. Fragments of 40 human teeth (20 primary and 20 permanent) were cast in acrylic rings, polished to expose a flat enamel area, and evaluated with a 3D profiler. Antagonists were made from primary and permanent molars. The specimens were distributed into four groups (n = 10) according to type of substrate and slurry (neutral and acidic), and cycled 100,000 times in the OHSU oral wear simulator. Specimens were cleaned and re-profiled. Volume loss and maximum depth were determined on the polished specimens. Data were submitted to ANOVA and Tukey's test. The area of the wear facet on the antagonist was measured. Primary enamel showed more wear than permanent enamel, regardless of the slurry type. The acidic environment increased the wear rate compared to the neutral slurry. The association of abrasion and erosion increased the wear rate for the primary teeth only. There was no significant difference among groups for cusp wear and no correlation between cusp wear and the enamel wear.


Increased activation of frontal areas during arm movement in idiopathic torsion dystonia.
Most positron emission tomography (PET) studies of regional cerebral function in idiopathic torsion dystonia (ITD) have failed to show abnormalities, but there have been few studies of the changes in regional cerebral blood flow (rCBF) that occur during movement in dystonia. Using PET, we have studied six patients with familial generalized ITD both at rest and while moving a joystick with the right hand. The patterns of CBF change obtained were compared with those in six age-matched control subjects. In the dystonia group, free selection of movement was associated with relative increases in rCBF above that observed in control subjects in the left premotor area, the supplementary motor area (SMA), the anterior cingulate cortex, and the left dorsolateral prefrontal area. Subcortical increases were observed within the cerebellum and the putamen. There was a relative decrease in flow through the contralateral primary sensorimotor cortex. These findings contrast with those reported in patients with Parkinson's disease undertaking the same task in which the activity in the SMA and putamen was decreased. We suggest that arm dystonia in ITD is associated with overactivity of the premotor areas, including the SMA, and that this results from release of the thalamus from the normal inhibitory influence of the globus pallidus internal segment. Other abnormalities of basal ganglia control of brain stem centers may be involved in axial dystonia.


Emerging plasmonic nanostructures for controlling and enhancing photoluminescence.
Localised surface plasmon resonance endows plasmonic nanostructures with unique, powerful properties such as photoluminescence enhancement, which is a phenomenon based on the interaction between light and a metal nanostructure. In particular, photoluminescence modulation and enhancement are of importance to many research fields such as photonics, plasmonics and biosensing. In this minireview, we introduce basic principles of plasmonic-nanostructure photoluminescence and recently reported plasmonic nanostructures exhibiting surface-enhanced fluorescence and direct photoluminescence, with one-photon photoluminescence being of particular interest. Gaining insights into these systems not only helps understand the fundamental concepts of plasmonic nanostructures but also advances and extends their applications.


Background mutation frequency in microsatellite-unstable colorectal cancer.
Microsatellite instability (MSI) is observed in approximately 12% of colorectal cancers. Genes containing a mononucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumorigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumors. Much less attention has been paid to background mutation frequencies, and no work has focused on nontranscribed regions. Here, we studied 114 nontranscribed intergenic A/T and C/G repeats 6 to 10 bp in length, located distant from known genes, to examine background mutation frequencies in MSI colorectal cancers. A strong correlation with tract length was observed, and mutation frequencies of up to 87% were observed in 8 to 10 bp tracts. Subsequently, to compare the background mutation rate in transcribed and nontranscribed noncoding repeats, we screened nine randomly selected intronic C/G8 repeats. In addition, the coding repeats of seven suggested MSI target genes, and nine previously published intronic A8 and G8 repeats were analyzed. Intronic repeats seemed to mutate less frequently than nontranscribed intergenic repeats. Our results show that strand slippage mutations in mismatch repair-deficient cells are as abundant in short intergenic repeats as in many proposed MSI target genes. However, under mismatch repair deficiency, strand slippage mutations in transcribed sequences seem to be repaired more efficiently than in intergenic nontranscribed sequences. The mechanisms causing these differences are not yet understood and should be a subject for further studies. For MSI target gene identification, repeats in transcribed sequences seem to be the most appropriate reference group for coding region repeat mutations.


Phytochemicals Rosmarinic Acid, Ampelopsin, and Amorfrutin-A Can Modulate Age-Related Phenotype of Serially Passaged Human Skin Fibroblasts in vitro.
One of the aims of the EU-funded Research and Innovation Action (RIA), titled "Ageing with Elegans" (AwE) is to enhance better understanding of the factors causing health and disease in aging and develop evidence-based preventive, diagnostic, therapeutic, and other strategies. The work package-5 of this project is focused on testing the effects of phytochemicals of natural and synthetic origin on aging, longevity, and health of human cells in vitro, after the initial screening using the animal model systems of nematodes and rats and mice. Accordingly, the first series of three compounds, rosmarinic acid (ROSM), ampelopsin (AMPEL), and amorfrutin-A (AMOR), were selected to test for their short-term and long-term effects on human skin fibroblasts undergoing aging and senescence in vitro. The lifelong modulatory effects of these compounds were tested individually at two doses (0.5 and 1.0 μM), selected after a short-term dose response check of a 20,000-fold range (0.01-200 μM). The results show that these compounds do have some beneficial effects in terms of supporting the long-term lifelong growth and enhanced stress tolerance of serially passaged cells. These effects seem to be achieved by reducing the extent of loss of telomeres, of 5-methyl-cytosine (5-mC) and of 5-hydroxymethyl-cytosine (5-hmC), by reducing the accumulation of oxidative DNA damage product 8-OHdG. There is also some indication that these compounds induce at least one of the stress responses in terms of the increased synthesis of heat shock protein Hsp70. Thus, these phytochemicals may be potential hormetins, which bring about their health beneficial effects by the phenomenon of mild stress-induced hormesis.


Functional characterization and modified rescue of novel AE1 mutation R730C associated with overhydrated cation leak stomatocytosis.
We report the novel, heterozygous AE1 mutation R730C associated with dominant, overhydrated, cation leak stomatocytosis and well-compensated anemia. Parallel elevations of red blood cell cation leak and ouabain-sensitive Na(+) efflux (pump activity) were apparently unaccompanied by increased erythroid cation channel-like activity, and defined ouabain-insensitive Na(+) efflux pathways of nystatin-treated cells were reduced. Epitope-tagged AE1 R730C at the Xenopus laevis oocyte surface exhibited severely reduced Cl(-) transport insensitive to rescue by glycophorin A (GPA) coexpression or by methanethiosulfonate (MTS) treatment. AE1 mutant R730K preserved Cl(-) transport activity, but R730 substitution with I, E, or H inactivated Cl(-) transport. AE1 R730C expression substantially increased endogenous oocyte Na(+)-K(+)-ATPase-mediated (86)Rb(+) influx, but ouabain-insensitive flux was minimally increased and GPA-insensitive. The reduced AE1 R730C-mediated sulfate influx did not exhibit the wild-type pattern of stimulation by acidic extracellular pH (pH(o)) and, unexpectedly, was partially rescued by exposure to sodium 2-sulfonatoethyl methanethiosulfonate (MTSES) but not to 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) or 2-(trimethylammonium)ethyl methanethiosulfonate bromide (MTSET). AE1 R730E correspondingly exhibited acid pH(o)-stimulated sulfate uptake at rates exceeding those of wild-type AE1 and AE1 R730K, whereas mutants R730I and R730H were inactive and pH(o) insensitive. MTSES-treated oocytes expressing AE1 R730C and untreated oocytes expressing AE1 R730E also exhibited unprecedented stimulation of Cl(-) influx by acid pH(o). Thus recombinant cation-leak stomatocytosis mutant AE1 R730C exhibits severely reduced anion transport unaccompanied by increased Rb(+) and Li(+) influxes. Selective rescue of acid pH(o)-stimulated sulfate uptake and conferral of acid pH(o)-stimulated Cl(-) influx, by AE1 R730E and MTSES-treated R730C, define residue R730 as critical to selectivity and regulation of anion transport by AE1.


Transient and cyclic responses of strain-generated potential in rabbit patellar tendon are frequency and pH dependent.
The goal of this study was to expand understanding of strain-generated potential (SGP) in ligamentous or tendinous tissues. Most SGP studies in the past have focused on cartilage or bone. Herein, rabbit patellar tendon (PT) was used as a model. Each patellar tendon had two Ag/AgCl electrodes inserted at axial positions of 1/4 and 1/2 from patellar to tibial insertions. Each specimen was electrically isolated, gripped in a servohydraulic test system, and then subjected to a short session of uniaxial haversine tension (2.5 percent maximum strain) at a frequency of 0.5, 1.0, 2.0, or 5.0 Hz. A cyclic (sinusoidal) electrical potential superimposed upon a larger transient (exponentially asymptotic) potential was consistently observed. Upon termination of loading, the cyclic SGP ended, and the shifted baseline of the SGP exponentially decayed and asymptotically returned to a residual potential which over all specimens was not different than the original potential. The transient and cyclic SGPs were frequency dependent (P < 0.001, P = 0.06, respectively). To our knowledge, this transient portion of the SGP, although theoretically predicted by Suh (1996, Biorheology, 33, pp. 289-304) and Chen (1996, Ph.D. thesis, University of Wisconsin-Madison) has not been observed in other experiments using different protocols. Additional PTs were dehydrated and the rehydrated in solution at different pH levels. The magnitude of SGPs increased in basic solution (pH 9.5) but diminished in pH 4.7 buffer. This pH dependency suggests that electrokinetics is the dominant mechanism for the transient and cyclic responses of the SGPs, although this study does not provide direct evidence.


Patients' and caregivers' attributes in a meaningful care encounter: similarities and notable differences.
In today's healthcare system, there is an imbalance between what patients expect of caregivers' care and their perception of the care they get. How is it possible to reduce this imbalance? The aim of this paper was to describe attributes associated with meaningful encounters in the Swedish healthcare system based on patients' and caregivers' written narratives and to note the differences and similarities between the attributes identified by the two groups. This paper is a qualitative descriptive study. The analysis was guided by qualitative content analyses. Based on patients' narratives, attributes associated with a meaningful encounter fell into four categories: the kind-hearted caregiver, the thoughtful caregiver, the mutually oriented caregiver, and the helpful caregiver. Based on caregivers' narratives, the attributes were categorized as being humane, caring through physical contact, caring by nurturing communication, joy and laughter in care, and a sense of mutuality. The results show that there are both similarities and differences in patients' and caregivers' opinions about the attributes of a meaningful encounter. Knowing more about the attributes associated with meaningful encounters makes it possible for caregivers to individualize care for patients and makes it easier to help and support patients in what they most need support with.


Training pharmacists to deliver a complex information technology intervention (PINCER) using the principles of educational outreach and root cause analysis.
To describe the training undertaken by pharmacists employed in a pharmacist-led information technology-based intervention study to reduce medication errors in primary care (PINCER Trial), evaluate pharmacists' assessment of the training, and the time implications of undertaking the training. Six pharmacists received training, which included training on root cause analysis and educational outreach, to enable them to deliver the PINCER Trial intervention. This was evaluated using self-report questionnaires at the end of each training session. The time taken to complete each session was recorded. Data from the evaluation forms were entered onto a Microsoft Excel spreadsheet, independently checked and the summary of results further verified. Frequencies were calculated for responses to the three-point Likert scale questions. Free-text comments from the evaluation forms and pharmacists' diaries were analysed thematically. All six pharmacists received 22 h of training over five sessions. In four out of the five sessions, the pharmacists who completed an evaluation form (27 out of 30 were completed) stated they were satisfied or very satisfied with the various elements of the training package. Analysis of free-text comments and the pharmacists' diaries showed that the principles of root cause analysis and educational outreach were viewed as useful tools to help pharmacists conduct pharmaceutical interventions in both the study and other pharmacy roles that they undertook. The opportunity to undertake role play was a valuable part of the training received. Findings presented in this paper suggest that providing the PINCER pharmacists with training in root cause analysis and educational outreach contributed to the successful delivery of PINCER interventions and could potentially be utilised by other pharmacists based in general practice to deliver pharmaceutical interventions to improve patient safety.


Multisensory temporal integration in autism spectrum disorders.
The new DSM-5 diagnostic criteria for autism spectrum disorders (ASDs) include sensory disturbances in addition to the well-established language, communication, and social deficits. One sensory disturbance seen in ASD is an impaired ability to integrate multisensory information into a unified percept. This may arise from an underlying impairment in which individuals with ASD have difficulty perceiving the temporal relationship between cross-modal inputs, an important cue for multisensory integration. Such impairments in multisensory processing may cascade into higher-level deficits, impairing day-to-day functioning on tasks, such as speech perception. To investigate multisensory temporal processing deficits in ASD and their links to speech processing, the current study mapped performance on a number of multisensory temporal tasks (with both simple and complex stimuli) onto the ability of individuals with ASD to perceptually bind audiovisual speech signals. High-functioning children with ASD were compared with a group of typically developing children. Performance on the multisensory temporal tasks varied with stimulus complexity for both groups; less precise temporal processing was observed with increasing stimulus complexity. Notably, individuals with ASD showed a speech-specific deficit in multisensory temporal processing. Most importantly, the strength of perceptual binding of audiovisual speech observed in individuals with ASD was strongly related to their low-level multisensory temporal processing abilities. Collectively, the results represent the first to illustrate links between multisensory temporal function and speech processing in ASD, strongly suggesting that deficits in low-level sensory processing may cascade into higher-order domains, such as language and communication.


Long-term changes in motor cortical organisation after recovery from subcortical stroke.
The present study has investigated the long-term changes in the organisation of the corticomotor projection to the hand in a group of subjects who had sustained a subcortical hemispheric stroke up to 15 years previously and had subsequently recovered normal or near-normal motor function. Transcranial magnetic cortical stimulation (TMCS) was employed to map the topography of the primary corticomotor projection to the hand and to obtain measures of cortical motor threshold, long-latency intracortical inhibition and corticospinal conduction. Changes in motor threshold and in motor-evoked potential (MEP) amplitude and latency in keeping with persisting impairment of conduction in the corticospinal pathway were still present in the majority of subjects, whereas the duration of the post-MEP silent period, reflecting the strength of long-latency intracortical inhibition, was usually normal. Topographic shifts in the corticomotor representation relative to the unaffected side were found in the majority of subjects. In some the shifts were in the mediolateral axis suggesting reorganisation within the primary motor cortex, while in the others anteroposterior shifts were present in keeping with recruitment of premotor or postcentral cortex. The present findings indicate that changes in the physiological properties of the corticomotor projection to the hand are frequently present in subjects who have recovered motor function after a subcortical stroke and may persist indefinitely. We postulate that these changes are the result of reorganisation at cortical level and that cortical reorganisation is one of the processes which contribute to motor recovery after a subcortical lesion and which may compensate for persisting impairment of conduction in the corticospinal pathway.


Hospital downsizing and trends in health care use among elderly people in British Columbia.
There has been considerable downsizing of acute care services in British Columbia over the past 2 decades. In this population-based study we examined changes in the proportion of elderly people who used acute care, long-term care and home care services between 1986-1988 and 1993-1995 to explore whether the downsizing has influenced use. Changes in death rates were also examined. The British Columbia Linked Health Database was used to select all British Columbia residents aged 65 years, 75-76 years, 85-87 years or 90-93 years as of Jan. 1, 1986 (cohort 1), and Jan. 1, 1993 (cohort 2). Each person was assigned to 1 of 6 mutually exclusive categories of health care use reflecting different intensities of use (i.e., hospital, long-term or home care). The proportions of people within each category were compared between the 2 periods, as were the age-standardized death rates. There were 79,175 people in cohort 1 and 92,320 in cohort 2. Overall, the relative proportion of people in each use category was similar between the 2 study periods. The most substantial changes were an increase of 2 percentage points in the proportion of people who received no facility or home care services and a decrease of 2 to 3 percentage points in the proportion who received some acute care but no facility-based continuing care. The age-adjusted all-cause death rates for the earlier and later cohorts were virtually identical (15.7% and 15.8% respectively), although the rate increased from 63.6% to 70.1% among those in the "full-time facility with acute care" group. Overall changes in health care use were small, which suggests that the repercussions of the decline in acute care services for elderly people have been minimal. The higher age-adjusted death rates in the later cohort in full-time care suggests that long-term stays are becoming reserved for a sicker group of elderly people than in the past.


Reflection in the training of nurses in clinical practice settings: a scoping review protocol.
This scoping review will seek to find answers for the following questions which will focus on the use of reflection in the education of nurses in clinical settings:The review will also extract and map data regarding: i) what outcomes have been found in relation to the use of different tools and approaches (e.g. dialogues, diaries, case studies); ii) how approaches and tools have been implemented as interventions; iii) details of the topic or focus of reflection (e.g. ethical issues, care of older adults etc.); iv) details about the participants involved in reflection activities (e.g. first or second year undergraduate nursing students etc.); and v) barriers/challenges to the use of reflection approaches/tools. Additional details may also be extracted and mapped during the process of the scoping review and this will be explained in the final scoping review report.


Mitochondrial therapies for Parkinson's disease.
Parkinson's disease (PD) is marked by widespread neurodegeneration in the brain in addition to a selective yet prominent and progressive loss of nigrostriatal dopaminergic neurons. Of the multiple theories suggested in the pathogenesis of PD, mitochondrial dysfunction takes a center stage in both sporadic and familial forms of illness. Deficits in mitochondrial functions due to impaired bioenergetics, aging associated increased generation of reactive oxygen species, damage to mitochondrial DNA, impaired calcium buffering, and alterations in mitochondrial morphology may contribute to improper functioning of the CNS leading to neurodegeneration. These mitochondrial alterations suggest that a potential target worth exploring for neuroprotective therapies are the ones that can preserve mitochondrial functions in PD. Here, we provide a recent update on potential drugs that are known to block mitochondrial dysfunctions in various experimental models and those that are currently under clinical trials for PD. We also review novel mitochondrial survival pathways that provide hope and promise for innovative neuroprotective therapies in the future that can be explored as possible therapeutic intervention for PD pathogenesis.


The health impacts and economic value of wildland fire episodes in the U.S.: 2008-2012.
Wildland fires degrade air quality and adversely affect human health. A growing body of epidemiology literature reports increased rates of emergency departments, hospital admissions and premature deaths from wildfire smoke exposure. Our research aimed to characterize excess mortality and morbidity events, and the economic value of these impacts, from wildland fire smoke exposure in the U.S. over a multi-year period; to date no other burden assessment has done this. We first completed a systematic review of the epidemiologic literature and then performed photochemical air quality modeling for the years 2008 to 2012 in the continental U.S. Finally, we estimated the morbidity, mortality, and economic burden of wildland fires. Our models suggest that areas including northern California, Oregon and Idaho in the West, and Florida, Louisiana and Georgia in the East were most affected by wildland fire events in the form of additional premature deaths and respiratory hospital admissions. We estimated the economic value of these cases due to short term exposures as being between $11 and $20B (2010$) per year, with a net present value of $63B (95% confidence intervals $6-$170); we estimate the value of long-term exposures as being between $76 and $130B (2010$) per year, with a net present value of $450B (95% confidence intervals $42-$1200). The public health burden of wildland fires-in terms of the number and economic value of deaths and illnesses-is considerable.


Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice.
The objectives of our studies are to characterize the ability of dietary soybean components to inhibit the growth of prostate cancer in mice and alter tumor biomarkers associated with angiogenesis. Soy isoflavones (genistein or daidzein) or soy phytochemical concentrate inhibit the growth of prostate cancer cells LNCaP, DU 145 and PC-3 in vitro, but only at supraphysiologic concentrations, i.e., 50% inhibitory concentration (IC(50)) > 50 micromol/L. G2-M arrest and DNA fragmentation consistent with apoptosis of prostate cancer cells are also observed at concentrations causing growth inhibition. In contrast, the in vitro proliferation of vascular endothelial cells was inhibited by soy phytochemcials at much lower concentrations. We evaluated the ability of dietary soy phytochemical concentrate and soy protein isolate to inhibit the growth of the LNCaP human prostate cancer in severe combined immune-deficient mice. Mice inoculated subcutaneously with LNCaP cells (2 x 10(6)) were randomly assigned to one of the six dietary groups based on the AIN-76A formulation for 3 wk. A 2 x 3 factorial design was employed with two protein sources (20%, casein vs. soy protein) and three levels of soy phytochemical concentrate (0, 0.2 and 1.0% of the diet). Soy components did not alter body weight gain or food intake. Compared with casein-fed controls, the tumor volumes after 3 wk were reduced by 11% (P = 0.45) by soy protein, 19% (P = 0.17) by 0.2% soy phytochemical concentrate, 28% by soy protein with 0.2% soy phytochemical concentrate (P < 0.05), 30% by 1.0% soy phytochemical concentrate (P < 0.05) and 40% by soy protein with 1.0% soy phytochemical concentrate (P < 0.005). Histologic examination of tumor tissue showed that consumption of soy products significantly reduced tumor cell proliferation, increased apoptosis and reduced microvessel density. The angiogenic protein insulin-like growth factor-I was reduced in the circulation of mice fed soy protein and phytochemical concentrate. Our data suggest that dietary soy products may inhibit experimental prostate tumor growth through a combination of direct effects on tumor cells and indirect effects on tumor neovasculature.


Ultrasound assessment of transversus abdominis muscle contraction ratio during abdominal hollowing: a useful tool to distinguish between patients with chronic low back pain and healthy controls?
Spine stabilisation exercises, in which patients are taught to preferentially activate the transversus abdominus (TrA) during "abdominal hollowing" (AH), are a popular treatment for chronic low back pain (cLBP). The present study investigated whether performance during AH differed between cLBP patients and controls to an extent that would render it useful diagnostic tool. 50 patients with cLBP (46.3 ± 12.5 years) and 50 healthy controls (43.6 ± 12.7 years) participated in this case-control study. They performed AH in hook-lying. Using M-mode ultrasound, thicknesses of TrA, and obliquus internus and externus were determined at rest and during 5 s AH (5 measures each body side). The TrA contraction-ratio (TrA-CR) (TrA contracted/rest) and the ability to sustain the contraction [standard deviation (SD) of TrA thickness during the stable phase of the hold] were investigated. There were no significant group differences for the absolute muscle thicknesses at rest or during AH, or for the SD of TrA thickness. There was a small but significant difference between the groups for TrA-CR: cLBP 1.35 ± 0.14, controls 1.44 ± 0.24 (p < 0.05). However, Receiver Operator Characteristics (ROC) analysis revealed a poor and non-significant ability of TrA-CR to discriminate between cLBP patients and controls on an individual basis (ROC area under the curve, 0.60 [95% CI 0.495; 0.695], p = 0.08). In the patient group, TrA-CR showed a low but significant correlation with Roland Morris score (Spearman Rho = 0.328; p = 0.02). In conclusion, the difference in group mean values for TrA-CR was small and of uncertain clinical relevance. Moreover, TrA-CR showed a poor ability to discriminate between control and cLBP subjects on an individual basis. We conclude that the TrA-CR during abdominal hollowing does not distinguish well between patients with chronic low back pain and healthy controls.


The critical link between health care and jails.
As a group, jail-involved individuals, which we define here as people with a history of arrest and jail admission in the recent past, carry a heavy illness burden, with high rates of infectious and chronic disease as well as mental illness and substance use. Because these people have tended to also be uninsured, jail frequently has been their only regular source of health care. Three thousand three hundred local and county jails processed 11.6 million admissions during the twelve-month period ending midyear 2012. The Urban Institute estimated as much as 30 percent of some local corrections budgets is allocated to inmate health care services. This investment is largely lost when people are released back into the community, where they typically do not get treatment. For people with untreated substance use or mental illness, this issue reaches beyond public health, because without treatment, these people are at heightened risk of cycling into and out of jail for low-level, nonviolent offenses. This article offers eight policy recommendations to build a continuum of care that will ensure that jail-involved people get the care they need, regardless of where they reside. With the expansion of Medicaid eligibility under the Affordable Care Act, there is now a critical opportunity to bring the jail-involved population into the mainstream health care system, which benefits the health care and criminal justice systems and society at large.


A shared alloantigenic determinant on Ia antigens encoded by the I-A and I-E subregions: evidence for I region gene duplication.
Two monoclonal antibodies to mouse Ia antigens were produced by fusion of xenoimmune rat spleen cells with the NSI myeloma. These monoclonal antibodies detect polymorphic determinants present on B cells and activated T lymphocytes from mice carrying the H-2b, H-2d, H-2k, H-2r, and H-2q haplotypes but not from mice carrying the H-2s or H-2r haplotypes. Antigenic site number determinations showed the positive haplotypes can be divided into 2 groups. Mice bearing the H-2b, H-2d, and H-2q haplotypes express a high number--40,000 to 80,000--of antigenic sites per B lymphocyte, and monoclonal antibody plus complement can lyse B cells from these mice. In contrast, mice bearing the H-2k and H-2r haplotypes express a low number of antigenic sites--about 5000 per cell. Spleen cells from mice carrying the latter haplotypes are not lysed with monoclonal antibody and complement. Genetic mapping demonstrated that high and low expression map to the I-A and I-E subregions, respectively. The monoclonal antibodies detect an Ia specificity on I-Ab, I-Ad, I-Ed, and I-Ek molecules. These observations were confirmed using several different experimental approaches, i.e., cytotoxicity, fluorescent staining, competitive inhibition of monoclonal antibody binding, and 2-dimensional gel electrophoresis of immunoprecipitates. The avidity for A alpha b A beta b and E alpha k E beta k is 5 to 7 x 10(-9) M-1. The antigenic determinant is heat labile, which suggests that it is not carbohydrate. The results imply that Ia antigens encoded by distinct subregions share sequence homology, which may be a consequence of ancestral gene duplication.


Motion integration and postdiction in visual awareness.
In the flash-lag illusion, a flash and a moving object in the same location appear to be offset. A series of psychophysical experiments yields data inconsistent with two previously proposed explanations: motion extrapolation (a predictive model) and latency difference (an online model). We propose an alternative in which visual awareness is neither predictive nor online but is postdictive, so that the percept attributed to the time of the flash is a function of events that happen in the approximately 80 milliseconds after the flash. The results here show how interpolation of the past is the only framework of the three models that provides a unified explanation for the flash-lag phenomenon.


Diabetic ketoacidosis charges relative to medical charges of adult patients with type I diabetes.
To determine the medical charges for treating diabetic ketoacidosis (DKA) episodes relative to direct medical care charges of adult patients with type I diabetes. Using data from an electronic medical record system, we identified adult patients with type I diabetes who had received inpatient or outpatient care on at least two occasions between 1 January 1993 and 30 June 1994. Resources and charges for hospitalizations, emergency room visits, outpatient visits, and pharmaceuticals were recorded during this period. One additional year of information was collected to assess the resources and charges associated with multiple DKA episodes. A total of 200 patients were identified, of whom 72 (36.0%) experienced a total of 161 DKA episodes. The direct medical care charges associated with DKA episodes represented 28.1% of the direct medical care charges for the cohort of patients with type I diabetes. The average charge per DKA episode was $6,444. The estimated annual medical care charge for each patient was $7,855 ($13,096 per patient experiencing a DKA episode versus $4,907 per patient not experiencing an episode). Multiple DKA episodes were experienced by 24 (12.0%) of the study patients and accounted for 55.6% of the direct medical care charges for these patients. DKA episodes represented more than $1 of every $4 spent on direct medical care for adult patients with type I diabetes and $1 of every $2 in those patients experiencing multiple episodes. Interventions that are capable of even a modest reduction in the number of DKA episodes could produce substantial cost savings in a health care system and could be particularly cost-effective in adult patients with recurrent DKA.


Relationship Between Carotid Intima-Media Thickness with some Inflammatory Biomarkers, Ghrelin and Adiponectin in Iranians with and without Metabolic Syndrome in Isfahan Cohort Study.
Recent studies have confirmed inflammatory factors and metabolic syndrome (MetS) as important cardiovascular disease (CVD) risk factors. Recently measurement of carotid intima-media thickness (IMT) has been used for evaluation of early atherosclerosis. This study was designed to assess the correlation between IMT with some inflammatory biomarkers, ghrelin and adiponectin in people with and without MetS in a cohort sample in Isfahan province. Among participants of Isfahan Cohort Study (ICS) by random sampling, 88 participants were selected and divided into case (with MetS) and control (without MetS) groups. A questionnaire including demographic data and CVD risk factors was completed for all of the participants. Physical examination and blood pressure, height, weight and waist circumference measurements were done for all subjects. Vascular echocardiography was done for evaluation of IMT of each carotid artery of both sides. Interlukin-6 (IL-6), interlukin-10 (IL-10), highly sensitive C-reactive protein (hs-CRP), ghrelin and adiponectin levels were measured using ELIZA method. Data were entered in SPSS(15) software and analyzed by t-test, chi square, Pearson correlation and linear regression analyze. The mean waist circumference, BMI, systolic blood pressure, diastolic blood pressure, hs-CRP and IMT of left carotid artery were significantly higher in participants with Mets. There was significant correlation between left carotid IMT and IL-6 level in all patients (P = 0.03). After adjustment for age and sex, significant relationship in groups with MetS was only reported between the left IMT and IL-6 (P = 0.02). There was no relation between IMT and other inflammatory markers in subjects with and without MetS. Significant correlation between IL-6 and IMT was reported in patients with MetS. While no significant correlation between IL-10, adiponectin and ghrelin with IMT was observed in metabolic syndrome group.


Directed differentiation of embryonic stem cells into motor neurons.
Inductive signals and transcription factors involved in motor neuron generation have been identified, raising the question of whether these developmental insights can be used to direct stem cells to a motor neuron fate. We show that developmentally relevant signaling factors can induce mouse embryonic stem (ES) cells to differentiate into spinal progenitor cells, and subsequently into motor neurons, through a pathway recapitulating that used in vivo. ES cell-derived motor neurons can populate the embryonic spinal cord, extend axons, and form synapses with target muscles. Thus, inductive signals involved in normal pathways of neurogenesis can direct ES cells to form specific classes of CNS neurons.


Modulation of human chondrocyte metabolism by recombinant human interferon gamma: in-vitro effects on basal and IL-1-stimulated proteinase production, cartilage degradation and DNA synthesis.
Human articular chondrocytes in monolayer culture and fragments of human articular cartilage were treated with recombinant human interferon gamma (IFN-gamma) both alone and in combination with interleukin 1 (IL-1). IFN-gamma alone inhibits metalloproteinase production, as measured in the caseinase assay, and decreases glycosaminoglycan release from cartilage fragments in culture. The synthesis of DNA, as measured by [3H]thymidine incorporation, is stimulated by IFN-gamma. Similar effects are seen in the presence of IL-1. Thus, IFN-gamma opposes the stimulatory effect of IL-1 on caseinase production and decreases IL-1-stimulated cartilage degradation, as measured by glycosaminoglycan release. In contrast, IFN-gamma has no effect on IL-1-stimulated prostaglandin production, and acts synergistically with IL-1 to cause a large stimulation of DNA synthesis. These results show that IFN-gamma has a number of effects on articular chondrocytes in-vitro and suggest a possible role for IFN-gamma in limiting cartilage degradation in inflammatory joint conditions.


Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery.
Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers as well as nonsmokers. Numerous animal and human studies now indicate that nicotine and a variety of nAChR ligands have the potential to improve multiple domains of cognition including attention, spatial learning, working memory, recognition memory, and executive function. The purpose of this review is to (1) discuss several pharmacologic strategies that have been developed to enhance nAChR activity (eg, agonist, partial agonist, and positive allosteric modulator) and improve cognitive function, (2) provide a brief overview of some of the more common rodent behavioral tasks with established translational validity that have been used to evaluate nAChR ligands for effects on cognitive function, and (3) briefly discuss some of the topics of debate regarding the development of optimal therapeutic strategies using nAChR ligands. Because of their densities in the mammalian brain and the amount of literature available, the review primarily focuses on ligands of the high-affinity α4β2* nAChR ("*" indicates the possible presence of additional subunits in the complex) and the low-affinity α7 nAChR. The behavioral task discussion focuses on representative methods that have been designed to model specific domains of cognition that are relevant to human neuropsychiatric disorders and often evaluated in human clinical trials. The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.


The impact of continuity editing in narrative film on event segmentation.
Filmmakers use continuity editing to engender a sense of situational continuity or discontinuity at editing boundaries. The goal of this study was to assess the impact of continuity editing on how people perceive the structure of events in a narrative film and to identify brain networks that are associated with the processing of different types of continuity editing boundaries. Participants viewed a commercially produced film and segmented it into meaningful events, while brain activity was recorded with functional magnetic resonance imaging (MRI). We identified three degrees of continuity that can occur at editing locations: edits that are continuous in space, time, and action; edits that are discontinuous in space or time but continuous in action; and edits that are discontinuous in action as well as space or time. Discontinuities in action had the biggest impact on behavioral event segmentation, and discontinuities in space and time had minor effects. Edits were associated with large transient increases in early visual areas. Spatial-temporal changes and action changes produced strikingly different patterns of transient change, and they provided evidence that specialized mechanisms in higher order perceptual processing regions are engaged to maintain continuity of action in the face of spatiotemporal discontinuities. These results suggest that commercial film editing is shaped to support the comprehension of meaningful events that bridge breaks in low-level visual continuity, and even breaks in continuity of spatial and temporal location.


Effect of oligonucleic acid (ONA) backbone features on assembly of ONA-star polymer conjugates: a coarse-grained molecular simulation study.
Understanding the impact of incorporating new physical and chemical features in oligomeric DNA mimics, termed generally as "oligonucleic acids" (ONAs), on their structure and thermodynamics will be beneficial in designing novel materials for a variety of applications. In this work, we conduct coarse-grained molecular simulations of ONA-star polymer conjugates with varying ONA backbone flexibility, ONA backbone charge, and number of arms in the star polymer at a constant ONA strand volume fraction to elucidate the effect of these design parameters on the thermodynamics and assembly of multi-arm ONA-star polymer conjugates. We quantify the thermo-reversible behavior of the ONA-star polymer conjugates by quantifying the hybridization of the ONA strands in the system as a function of temperature (i.e. melting curve). Additionally, we characterize the assembly of the ONA-star polymer conjugates by tracking cluster formation and percolation as a function of temperature, as well as cluster size distribution at temperatures near the assembly transition region. The key results are as follows. The melting temperature (Tm) of the ONA strands decreases upon going from a neutral to a charged ONA backbone and upon increasing flexibility of the ONA backbone. Similar behavior is seen for the assembly transition temperature (Ta) with varying ONA backbone charge and flexibility. While the number of arms in the ONA-star polymer conjugate has a negligible effect on the ONA Tm in these systems, as the number of ONA-star polymer arms increase, the assembly temperature Ta increases and local ordering in the assembled state improves. By understanding how factors like ONA backbone charge, backbone flexibility, and ONA-star polymer conjugate architecture impact the behavior of ONA-star polymer conjugate systems, we can better inform how the selection of ONA chemistry will influence resulting ONA-star polymer assembly.


Evolution of nickel hyperaccumulation and serpentine adaptation in the Alyssum serpyllifolium species complex.
Metal hyperaccumulation is an uncommon but highly distinctive adaptation found in certain plants that can grow on metalliferous soils. Here we review what is known about evolution of metal hyperaccumulation in plants and describe a population-genetic analysis of the Alyssum serpyllifolium (Brassicaceae) species complex that includes populations of nickel-hyperaccumulating as well as non-accumulating plants growing on serpentine (S) and non-serpentine (NS) soils, respectively. To test whether the S and NS populations belong to the same or separate closely related species, we analysed genetic variation within and between four S and four NS populations from across the Iberian peninsula. Based on microsatellites, genetic variation was similar in S and NS populations (average Ho=0.48). The populations were significantly differentiated from each other (overall FST=0.23), and the degree of differentiation between S and NS populations was similar to that within these two groups. However, high S versus NS differentiation was observed in DNA polymorphism of two genes putatively involved in adaptation to serpentine environments, IREG1 and NRAMP4, whereas no such differentiation was found in a gene (ASIL1) not expected to play a specific role in ecological adaptation in A. serpyllifolium. These results indicate that S and NS populations belong to the same species and that nickel hyperaccumulation in A. serpyllifolium appears to represent a case of adaptation to growth on serpentine soils. Further functional and evolutionary genetic work in this system has the potential to significantly advance our understanding of the evolution of metal hyperaccumulation in plants.


Satellite Images Combined with Field Data Reveal Negative Changes in the Distribution of Babassu Palms after Clearing off Amazonian Forests.
When the Amazonian rain forest is cut to create pasture, some of the original vegetal species survive clearing, even expressing their ability to invade agro-systems. It is true of the babassu palm, which can be considered, paradoxically, a natural resource by the "Interstate Movement of Babassu Fruit Breaker Women" or as native weed by land owners-farmers. To manage potential conflict of land uses, we study here the current density of this palm tree in different habitats, based on a combination of field data and remote sensing data. Firstly, we checked that the field survey methodology (i.e., counting free-trunk palm trees over 20 cm in circumference) provides density values compatible with those stemming from satellite images interpretation. We can see then that, a PA-Benfica Brazilian territory revealed an average density of the babassu lower in pastures (2.86 ind/ha) than in the dense forest (4.72 ind/ha) from which they originate and than in fallow land (4.31 ind/ha). We analyze in detail density data repartition in three habitats and we discuss results from the literature on the density of this palm tree versus its resilience at different developmental stages after forest clearing, depending on anthropogenic-or not-factors, including solar radiation, fire, weeding, clear cutting, burying fruit, and competition with forage grass. All these results can be exploited for the design of future management plans for the babassu palm and we think that the linked methodology and interdisciplinary approach can be extended to others palms and trees species in similar problematic issues.


A cost-effectiveness analysis of anal cancer screening in HIV-positive women.
Anal cancer rates have increased in HIV+ patients. The prevalence of anal intraepithelial neoplasias (AINs) and progression to anal cancer in HIV+ men who have sex with men has been well described, and screening is cost-effective. Our objective was to determine whether anal cancer screening in HIV+ women is cost-effective. A Markov model analysis of 100 HIV+ women was constructed. All women had a CD4 count less than 200 and were assumed to be on antiretrovirals. Rates of AIN were based on previous studies. Progression rates were extrapolated from previous data on HIV+ men who have sex with men. The 5-year model included 3 screening approaches: none, annual, and biennial. Anoscopy and biopsy were performed after an abnormal cytologic result. Low-grade AIN was followed with repeat cytology, and high-grade AIN was treated surgically. Anal cancer was treated surgically followed by chemotherapy and radiation. Sensitivity analyses (SAs) were performed to account for variable rates of AIN progression, anal cancer mortality, and anal cancer and HIV quality-adjusted life years. The incremental cost-effectiveness ratio of biennial anal cancer screening compared to no screening was $34,763. Cost-effectiveness was maintained across all assumptions in SA except for decreased progression rate of high-grade AIN to anal cancer. Biennial anal cancer screening in HIV+ women with CD4 counts less than 200 is cost-effective. Annual screening was not cost-effective, likely because of the slow progression of AIN to anal cancer. Further data on rates of AIN progression in HIV+ women based on CD4 count are needed to determine whether screening is cost-effective in women with higher CD4 counts.


Regulation of Chlamydia psittaci (strain guinea pig inclusion conjunctivitis) growth in McCoy cells by amino acid antagonism.
Chlamydiae have amino acid requirements for growth in tissue culture as defined by those amino acids whose individual omission from the growth medium prevents chlamydial multiplication. We have tested the hypothesis that this inhibition of growth arises as a result of antagonism between particular amino acids such that inhibition occurs when the concentration of one amino acid is reduced in the presence of the antagonist amino acid at high concentration. Using the Chlamydia psittaci strain guinea pig inclusion conjunctivitis (GPIC), in the presence of cycloheximide, the requirement for valine was abrogated by the simultaneous omission of isoleucine, that for phenylalanine by simultaneous omission of tryptophan and that for leucine by simultaneous omission of isoleucine plus valine. The antagonism shown between leucine and isoleucine plus valine appears to be unique among bacteria. In the absence of cycloheximide, GPIC had an additional need for tryptophan, tyrosine and isoleucine; these amino acid requirements were shown for both infected McCoy, HeLa and BHK cells. The results are consistent with a mechanism for regulation of parasite growth which depends on the balance of amino acid concentrations in the extracellular environment.


Reduced toxicological activity of cigarette smoke by the addition of ammonium magnesium phosphate to the paper of an electrically heated cigarette: smoke chemistry and in vitro cytotoxicity and genotoxicity.
The effects of the addition of ammonium magnesium phosphate (AMP) to the paper of an electrically heated cigarette (EHC) prototype on smoke composition and toxicity were quantified and the underlying mechanisms investigated. Smoke from EHC prototypes with and without AMP and from conventional cigarettes, i.e. the University of Kentucky Standard Reference Cigarette 1R4F and eight American-blend market cigarettes, was compared. Endpoints for comparison were smoke chemistry, where toxic constituents were measured, cytotoxic activity, as measured in murine fibroblasts embryo cells by the Neutral Red Uptake Assay, and genotoxic activity, as measured in bacteria by the Salmonella Reverse Mutation Assay and in murine lymphoma cells by the TK Assay. The addition of AMP to the EHC led to a reduction of toxic substances and toxicological activity of approximately 30% compared to the EHC without AMP. Compared to the conventional cigarettes, the EHC with AMP showed reductions of 75-90%. Smoke from the EHCs generated in nitrogen atmospheres supplemented with different concentrations of ammonia and oxygen was assayed for its in vitro cytotoxicity and genotoxicity. The results indicate that the ammonia released by AMP at the heating site of the EHC is responsible for the reductions in cytotoxicity and mutagenicity for the EHC with AMP compared with the EHC without AMP. Thus, while the EHC approach distinctly reduces toxic smoke constituents compared to conventional cigarettes, the use of AMP in the paper of an EHC leads to further distinct reductions. In the study presented here, in vitro assays were used as quantitative tools to investigate toxicity-related mechanisms.


Effectiveness of an intervention in groups of family caregivers of dependent patients for their application in primary health centers. Study protocol.
Although Primary Health Care (PHC) Teams are used to deal with prevention and treatment of sanitary problems in adults with chronic diseases, they usually have a lack of experience in development of psychotherapeutic interventions. However, these interventions are the ones that achieve better results to reduce symptomatology and improve emotional state of caregivers.The study aims to evaluate the effectiveness of an intervention of psychotherapy in improving the mental health and Quality of life of caregivers. This intervention is based on theoretical approaches to care adjusted to cognitive theory, in order to be applied in primary health care centres. This is multicentre clinical trials study, randomized in two parallel groups, carry out in two PHC, Study population: 150 caregivers will be included by consecutive sampling and they will be randomized the half to experimental group and the other half to control group. They provide mostly all the assistance to care-dependent familiars receiving attention in PHC Centers. Each caregiver will be evaluated on a personal interview. The caregivers' assessment protocol: 1) Assessment of different socio-demographic related to care, and caregiver's personal situation. 2)Care-dependent individuals will also be assessed by Barthel Index and Pfeiffer Questionnaire (SPMSQ). 3)Change in caregivers will be the principal measure: family function (Family APGAR Questionnaire), burden short questionnaire (Short Zarit Burden Interview), quality of life (Ruiz & Baca: 1993 Questionnaire), the Duke-UNK Functional Social Support Questionnaire, the General Health Questionnaire-12, and changes in Dysfunctional Thoughts about caring. 4) Intervention implementation measures will also be assessed. A psychotherapeutic intervention will be 8 sessions of 90 minutes in groups. This intervention has been initially developed for family caregivers of patients with dementia. Psychotherapeutic interventions have been proved to obtain better results to reduce symptomatology and improve emotional state of caregivers. Moreover, this intervention has been proved to be effective in a different setting other than PHC, and was developed by professionals of Mental Health. If we found that this intervention is effective in PHC and with our professionals, it would be an important instrument to offer to caregivers of care-dependent patients. ClinicalTrials.gov Identifier NCT01177696.


Over-the-counter access, changing WHO guidelines, and contraindicated oral contraceptive use in Mexico.
This study examines the prevalence of contraindications to the use of oral contraceptives in Mexico by sociodemographic characteristics and by whether this family planning method was obtained with or without a doctor's prescription. Using data on smoking behavior and blood-pressure measurements from the 2000 Mexican National Health Survey, the authors found that, under the 1996 World Health Organization (WHO) medical eligibility guidelines, the prevalence of contraindications is low and that no significant differences in contraindications exist at any level between those who obtain oral contraceptives at clinics and those who obtain them at pharmacies. In 2000, however, WHO substantially revised its criteria regarding the level of hypertension that would constitute a contraindication for oral contraceptive use. Applying the new guidelines, the authors found that 10 percent of pill users younger than 35 and 33 percent aged 35 and older have health conditions that are either relative or absolute (Category 3 or 4) contraindications. The relevance of these findings to the larger debate concerning screening and over-the-counter access to oral contraceptives is discussed.


Eleven distinct VH gene families and additional patterns of sequence variation suggest a high degree of immunoglobulin gene complexity in a lower vertebrate, Xenopus laevis.
Lower vertebrate species, including Xenopus laevis, exhibit restricted antibody diversity relative to higher vertebrates. We have analyzed more than 180 VH gene-containing recombinant clones from an unamplified spleen cDNA library by selective sequencing of JH and CH positive clones following iterative hybridization screening with family-specific VH probes, 11 unique families of VH genes, each associated with a unique genomic Southern blot hybridization pattern, are described and compared. Considerable variation in the number of hybridizing components detected by each probe is evident. The nucleotide sequence difference between VH families is as great as, if not more than, that reported in other systems, including representatives of the mammalian, avian, and elasmobranch lineages. Some Xenopus Ig gene families encode alternative amino acids at positions that are otherwise invariant or very rarely substituted in known Igs. Furthermore, variations in complementarity determining region sequences among members of the same gene family and high degrees of DH and JH region complexity are described, suggesting that in at least this lower vertebrate species, the diversity of expressed Ig VH genes is not restricted.


Identification of a Helical Segment within the Intrinsically Disordered Region of the PCSK9 Prodomain.
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of lipid metabolism by degrading liver LDL receptors. Structural studies have provided molecular details of PCSK9 function. However, the N-terminal acidic stretch of the PCSK9 prodomain (Q31-T60) has eluded structural investigation, since it is in a disordered state. The interest in this region is intensified by the presence of human missense mutations associated with low and high LDL-c levels (E32K, D35Y, and R46L, respectively), as well as two posttranslationally modified sites, sulfated Y38 and phosphorylated S47. Herein we show that a segment within this region undergoes disorder-to-order transition. Experiments with acidic stretch-derived peptides demonstrated that the folding is centered at the segment Y38-L45, which adopts an α-helix as determined by NMR analysis of free peptides and by X-ray crystallography of peptides in complex with antibody 6E2 (Ab6E2). In the Fab6E2-peptide complexes, the structured region features a central 2 1/4-turn α-helix and encompasses up to 2/3 of the length of the acidic stretch, including the missense mutations and posttranslationally modified sites. Experiments with helix-breaking proline substitutions in peptides and in PCSK9 protein indicated that Ab6E2 specifically recognizes the helical conformation of the acidic stretch. Therefore, the observed quantitative binding of Ab6E2 to native PCSK9 from various cell lines suggests that the disorder-to-order transition is a true feature of PCSK9 and not limited to peptides. Because the helix provides a constrained spatial orientation of the missense mutations and the posttranslationally modified residues, it is probable that their biological functions take place in the context of an ordered conformational state.


An acetylcholinesterase-inspired biomimetic toxicity sensor.
This work demonstrates the ability of an acetylcholinesterase-inspired biomimetic sensor to accurately predict the toxicity of acetylcholinesterase (AChE) inhibitors. In surface waters used for municipal drinking water supplies, numerous pesticides and other anthropogenic chemicals have been found that inhibit AChE; however, there is currently no portable toxicity assay capable of determining the potential neurotoxicity of water samples and complex mixtures. Biological assays have been developed to determine the toxicity of unknown samples, but the short shelf-life of cells and other biological materials often make them undesirable for use in portable assays. Chemical methods and structure-activity-relationships, on the other hand, require prior knowledge on the compounds of interest that is often unavailable when analyzing environmental samples. In the toxicity assay presented here, the acetylcholinesterase enzyme has been replaced with 1-phenyl-1,2,3-butanetrione 2-oxime (PBO) a biomimetic compound that is structurally similar to the AChE active site. Using a biomimetic compound in place of the native enzyme allows for a longer shelf-life while maintaining the selective and kinetic ability of the enzyme itself. Previous work has shown the success of oxime-based sensors in the selective detection of AChE inhibitors and this work highlights the ability of an AChE-inspired biomimetic sensor to accurately predict the toxicity (LD50 and LC50) for a range of AChE inhibitors. The biomimetic assay shows strong linear correlations to LD50 (oral, rat) and LC50 (fish) values. Using a test set of eight AChE inhibitors, the biomimetic assay accurately predicted the LC50 value for 75% of the inhibitors within one order of magnitude.