Ischemia-induced epicardial vasoconstriction. A potential mechanism for distant myocardial ischemia.
This study evaluated the effects of transient coronary occlusion on the diameter of a nonischemic vessel or a nonischemic coronary segment proximal to the site of occlusion. Awake mongrel dogs chronically instrumented with dimension crystals, Doppler flow probes, and distal pneumatic occluders on the circumflex coronary arteries were subjected to transient 2-minute circumflex occlusions (n = 9) under constant heart rate (120 beats/min). Left ventricular end-diastolic pressure increased by 60% (from 10 +/- 1 to 16 +/- 2 mm Hg), and dP/dt decreased by 8% (from 2,048 +/- 130 to 1,885 +/- 110 mm Hg/sec); systemic hemodynamics were unaltered. Epicardial coronary diameter proximal to the site of occlusion decreased by 4.37% (from 3.62 +/- 0.25 to 3.46 +/- 0.29 mm, p less than 0.05). Constriction began 15-20 seconds after the onset of ischemia and progressed to maximum in 1-2 minutes. Combined alpha- and beta-receptor blockade (n = 8) with phentolamine (2 mg/kg) and propranolol (1 mg/kg) or cyclooxygenase inhibition (n = 5) with indomethacin (7.5 mg/kg) did not attenuate the ischemia-induced vasoconstriction response. Transient 2-minute occlusion of the left anterior descending coronary artery (n = 6) also elicited significant epicardial vasoconstriction in the circumflex coronary artery in the first minute (from 3.88 +/- 0.31 to 3.81 +/- 0.31 mm, p less than 0.05); the constriction was attenuated subsequently by an increase (25.5%) in circumflex flow. When left anterior descending occlusion was repeated (n = 6) with circumflex flow held constant, the ischemia-induced circumflex constriction was augmented; diameter decreased 3.7% (from 3.83 +/- 0.29 to 3.69 +/- 0.29 mm, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Glycerol, ethylene glycol and propanediol elicit pimaricin biosynthesis in the PI-factor-defective strain Streptomyces natalensis npi287 and increase polyene production in several wild-type actinomycetes.
Production of pimaricin by Streptomyces natalensis ATCC 27448 is elicited by the PI-factor, an autoinducer secreted by the producer strain during the rapid growth phase. Exogenous PI-factor restored pimaricin production in a mutant strain npi287 defective in PI-factor biosynthesis. During purification of the PI-factor, a second pimaricin-inducing fraction different from PI-factor was isolated from the culture broth of wild-type S. natalensis ATCC 27448. After purification by HPLC and analysis by MS and NMR, this active fraction was shown to contain glycerol and lactic acid. Pure glycerol restored pimaricin production in liquid cultures of the autoinducer-defective npi287 mutant. A similar effect was exerted by ethylene glycol, 1,2-propanediol and 1,3-propanediol but not by higher polyalcohols or by glycerol acetate or glycerol lactate esters. Glycerol stimulated (30-270 %) the production of six different polyene macrolide antibiotics by their respective producer strains. Addition of glycerol to the inducer-defective npi287 strain restored pimaricin production but did not result in extracellular or intracellular accumulation of PI-factor. Exogenously added PI-factor was internalized by the cells in the presence of glycerol, and a mixture of both PI-factor and glycerol produced a slightly higher inducing effect on pimaricin production than PI-factor alone. In summary, glycerol, ethylene glycol and propanediol exert a bypass of the PI-factor inducing effect on pimaricin biosynthesis.


Post-transplantation lymphoproliferative disorder with gastrointestinal involvement.
Post-transplantation lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that are the second most common tumors in adult transplant recipients. Most cases of PTLD are attributed to Epstein-Barr virus, which induces B-cell proliferation and occurs in the setting of severe immunosuppression after solid organ or bone marrow transplantation. The disorder is seen in 1-3% of liver transplant recipients and has a variable presentation chronology. Herein, we chronicle a case of aggressive B-cell lymphoma (PTLD WHO class-3) presenting with isolated gastrointestinal involvement in an Epstein-Barr virus-negative patient with living-donor liver transplantation, 4 years after receiving the transplant. While typical symptoms may be elusive in the immunocompromised setting, clinicians should be vigilant for underlying PTLD with isolated gastrointestinal involvement. Prompt detection and characterization by endoscopic evaluation with biopsy should be particularly stressed in such patients.


Strategies and tools to reduce workplace violence.
The U.S. health care system is in the beginning of a crisis that can barely be comprehended. If projections are accurate, the demand for nurses will increase 40% and a 400,000-hour full-time equivalent registered nurse shortfall will occur by 2020. Not only are nurses leaving the field, but fewer candidates are entering. The reasons are unclear, but research has shown that nursing is a dangerous occupation--four times more dangerous than most other occupations. Protection from an unsafe workplace is guaranteed under Occupational Safety and Health Administration regulations, and many national and international groups call for zero tolerance of workplace violence. Health care worksites must develop specific plans to minimize and prevent workplace violence. Additional research is necessary to determine which methods are most effective. This article examines the necessary components of a workplace violence prevention program.


Issues affecting therapist workforce and service delivery in the disability sector in rural and remote New South Wales, Australia: perspectives of policy-makers, managers and senior therapists.
The disability sector encompasses a broad range of conditions and needs, including children and adults with intellectual and developmental disabilities, people with acquired disabilities, and irreversible physical injuries. Allied health professionals (therapists), in the disability sector, work within government and funded or charitable non-government agencies, schools, communities, and private practice. This article reports the findings of a qualitative study of therapist workforce and service delivery in the disability sector in rural and remote New South Wales (NSW), Australia. The aim was to investigate issues of importance to policy-makers, managers and therapists providing services to people with disabilities in rural and remote areas. The project gathered information via semi-structured interviews with individuals and small groups. Head office and regional office policy-makers, along with managers and senior therapists in western NSW were invited to participate. Participants included 12 policy-makers, 28 managers and 10 senior therapists from NSW government agencies and non-government organisations (NGOs) involved in providing services and support to people with disabilities in the region. Information was synthesised prior to using constant comparative analysis within and across data sets to identify issues. Five broad themes resonated across participants' roles, locations and service settings: (1) challenges to implementing policy in rural and remote NSW; (2) the impact of geographic distribution of workforce and clients; (3) workforce issues - recruitment, support, workloads, retention; (4) equity and access issues for rural clients; and (5) the important role of the NGO sector in rural service delivery and support. Although commitment to providing best practice services was universal, policy-related information transfer between organisations and employees was inconsistent. Participants raised some workforce and service delivery issues that are similar to those reported in the rural health literature but rarely in the context of allied health and disability services. Relatively recent innovations such as therapy assistants, information technology, and trans-disciplinary approaches, were raised as important service delivery considerations within the region. These and other innovations were expected to extend the coverage provided by therapists. Non-government organisations played a significant role in service delivery and support in the region. Participants recognised the need for therapists working for different organisations, in rural areas, to collaborate both in terms of peer support and service delivery to clients.


Topological comparison of methods for predicting transcriptional cooperativity in yeast.
The cooperative interaction between transcription factors has a decisive role in the control of the fate of the eukaryotic cell. Computational approaches for characterizing cooperative transcription factors in yeast, however, are based on different rationales and provide a low overlap between their results. Because the wealth of information contained in protein interaction networks and regulatory networks has proven highly effective in elucidating functional relationships between proteins, we compared different sets of cooperative transcription factor pairs (predicted by four different computational methods) within the frame of those networks. Our results show that the overlap between the sets of cooperative transcription factors predicted by the different methods is low yet significant. Cooperative transcription factors predicted by all methods are closer and more clustered in the protein interaction network than expected by chance. On the other hand, members of a cooperative transcription factor pair neither seemed to regulate each other nor shared similar regulatory inputs, although they do regulate similar groups of target genes. Despite the different definitions of transcriptional cooperativity and the different computational approaches used to characterize cooperativity between transcription factors, the analysis of their roles in the framework of the protein interaction network and the regulatory network indicates a common denominator for the predictions under study. The knowledge of the shared topological properties of cooperative transcription factor pairs in both networks can be useful not only for designing better prediction methods but also for better understanding the complexities of transcriptional control in eukaryotes.


Evidence for 14 homeobox gene clusters in human genome ancestry.
The arrangement of Hox genes into physical clusters is fundamental to the patterning of animal body plans. Other homeobox genes are often described as dispersed, with only occasional examples of linkage reported, such as the amphioxus ParaHox and Drosophila 93D/E clusters. This clustering is unlikely to be the derived condition, as the genes of the ParaHox and 93D/E clusters are phylogenetically widespread. To assess whether clustering is retained in mammals, and to infer its history, we considered the distribution of ANTP superclass homeobox genes in human and mouse genomes. We postulate four ancient arrays of ANTP superclass genes in animal genomes, denoted 'extended Hox' (Hox, Evx and Mox), NKL (including NK1, NK3, NK4, Lbx, Tlx, Emx, Vax, Hmx, NK6, Msx), ParaHox (Cdx, Xlox, Gsx) and EHGbox (En, HB9, Gbx). Each of these duplicated in the ancestry of the human genome to yield four Hox, four NKL, four ParaHox and at least two EHGbox clusters or arrays. Two of the human NKL clusters (four in mouse) have subsequently been split by chromosome rearrangement, as has one human EHGbox array. We date all cluster duplications to early chordate evolution and infer that three clusters (Hox, NKL, EHGbox) resided on the same chromosome before duplication.


Decision mechanisms underlying mood-congruent emotional classification.
There is great interest in understanding whether and how mood influences affective processing. Results in the literature have been mixed: some studies show mood-congruent processing but others do not. One limitation of previous work is that decision components for affective processing and responses biases are not dissociated. The present study explored the roles of affective processing and response biases using a drift-diffusion model (DDM) of simple choice. In two experiments, participants decided if words were emotionally positive or negative while listening to music that induced positive or negative mood. The behavioural results showed weak, inconsistent mood-congruency effects. In contrast, the DDM showed consistent effects that were selectively driven by an a-priori bias in response expectation, suggesting that music-induced mood influences expectations about the emotionality of upcoming stimuli, but not the emotionality of the stimuli themselves. Implications for future studies of emotional classification and mood are subsequently discussed.


A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle.
Drug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K-dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.


Deep proteome of human nNOS/NOS1-positive versus MOCK SH-SY5Y neuroblastoma cells under full nutrition, serum free starvation and rapamycin treatment.
Upregulations of neuronal nitric oxide synthase (nNOS/NOS1) in the mouse brain upon aging suggest a role in age-associated changes of protein homeostasis. We generated a cell model, in which constitutive expression of nNOS in SH-SY5Y cells at a level comparable to mouse brain replicates the aging phenotype i.e. slowing of cell proliferation, cell enlargement and expression of senescence markers. nNOS+ and MOCK cells were exposed to proteostasis stress by treatment with rapamycin or serum-free starvation. The proteomes were analyzed per SILAC or label-free using hybrid liquid chromatography/mass spectrometry (LC/MS). Full scan MS-data were acquired using Xcalibur, and raw mass spectra were analyzed using the proteomics software MaxQuant. The human reference proteome from uniprot was used as template to identify peptides and proteins and quantify protein expression. The DiB data file contains essential MaxQuant output tables and includes peptide and protein identification, accession numbers, protein and gene names, sequence coverage and quantification values of each sample. Differences in protein expression in MOCK versus nNOS+ SH-SY5Y cells and interpretation of results are presented in Valek et al. (2018). Raw mass spectra and MaxQuant output files have been deposited to the ProteomeXchange Consortium (Vizcaino et al., 2014) via the PRIDE partner repository with the dataset identifier PRIDE: PXD010538.


Expression of a Mr 41,000 glycoprotein associated with thrombin-independent platelet aggregation in high metastatic variants of murine B16 melanoma.
In the previous study, we generated a monoclonal antibody, 8F11, against NL-17, a high metastatic clone derived from a metastatic variant of murine colon adenocarcinoma 26. 8F11 inhibited platelet aggregation induced by NL-17 and recognized a Mr 44,000 membrane protein as antigen. In the present study, the reactivity of 8F11 to murine B16 melanoma and its metastatic variants was examined, and the antigen recognized by 8F11 on the cell surface was characterized. 8F11 was found to strongly react with 3 metastatic variants of B16 melanoma. In contrast, only slight reactivity was observed with parent B16 melanoma. The reactivity of the antibody to these cells was in the order B16F10 greater than B16BL-6 greater than B16F1 much greater than B16. Western blot analysis showed a Mr 41,000 protein as the antigen recognized by 8F11 on the cell surface of B16F10 cells. The Mr 41,000 antigen appeared to be a glycoprotein that bound to wheat germ agglutinin as has been observed for the Mr 44,000 antigen of NL-17. To elucidate the functional role of the Mr 41,000 antigen in B16 melanoma, platelet aggregation induced by B16 and B16F10 was compared. B16 was reported to stimulate platelet aggregation by the generation of thrombin, whereas B16F10 was found to activate platelet by at least 2 mechanisms: one dependent on thrombin and the other independent on thrombin. The activity of B16 and its metastatic variants to induce platelet aggregation in the presence of MD805, a synthetic antagonist of thrombin, well correlated with the reactivity of 8F11 to these cells. 8F11 blocked platelet activation by B16F10 under conditions preventing thrombin activity such as enzymatic formation of lysolecithin through the treatment of the cell surface with phospholipase A2 or in the presence of MD805. These data indicate that Mr 41,000 glycoprotein recognized by 8F11 on metastatic variants of B16 melanoma is involved in the thrombin-independent platelet aggregation. A positive correlation was observed between the levels of Mr 41,000 glycoprotein expression of B16 and its metastatic variants and their pulmonary metastasis after i.v. injection, suggesting Mr 41,000 glycoprotein, as well as other factors reported previously, may play an important role in the hematogenous spread of B16 melanoma.


Carbon Sources for Polyhydroxyalkanoates and an Integrated Biorefinery.
Polyhydroxyalkanoates (PHAs) are a group of bioplastics that have a wide range of applications. Extensive progress has been made in our understanding of PHAs' biosynthesis, and currently, it is possible to engineer bacterial strains to produce PHAs with desired properties. The substrates for the fermentative production of PHAs are primarily derived from food-based carbon sources, raising concerns over the sustainability of their production in terms of their impact on food prices. This paper gives an overview of the current carbon sources used for PHA production and the methods used to transform these sources into fermentable forms. This allows us to identify the opportunities and restraints linked to future sustainable PHA production. Hemicellulose hydrolysates and crude glycerol are identified as two promising carbon sources for a sustainable production of PHAs. Hemicellulose hydrolysates and crude glycerol can be produced on a large scale during various second generation biofuels' production. An integration of PHA production within a modern biorefinery is therefore proposed to produce biofuels and bioplastics simultaneously. This will create the potential to offset the production cost of biofuels and reduce the overall production cost of PHAs.


Encouraging Physical Activity during and after Pregnancy in the COVID-19 Era, and beyond.
Physical activity is known to decline during pregnancy and the postnatal period, yet physical activity is recommended during this time due to the significant health benefits for mothers and their offspring. As a result of the COVID-19 pandemic and the restrictions imposed to reduce infection rates, pregnant and postnatal women have experienced disruption not just to their daily lives but also to their pregnancy healthcare experience and their motherhood journey with their new infant. This has included substantial changes in how, when and why they have engaged with physical activity. While some of these changes undoubtedly increased the challenge of being sufficiently active as a pregnant or postnatal woman, they have also revealed new opportunities to reach and support women and their families. This commentary details these challenges and opportunities, and highlights how researchers and practitioners can, and arguably must, harness these short-term changes for long-term benefit. This includes a call for a fresh focus on how we can engage and support those individuals and groups who are both hardest hit by COVID-19 and have previously been under-represented and under-served by antenatal and postnatal physical activity research and interventions.


Controlling the kinetics of the non-covalent functionalization of carbon nanotubes using sub-cmc dilutions in a co-surfactant environment.
We investigate the origin of the slow kinetics of functionalization processes in micellar environments. We show that the ionic nature of the surfactants used to solubilize small molecules and nano-objects plays a central role in the slowness of the kinetics. In order to solve this issue, we have developed an innovative method that we apply to the hybrid compound porphyrin molecule/carbon nanotube. We use two ionic surfactants to solubilize the molecules and the nanotubes respectively. Passing the molecule suspension below the cmc allows circumventing the stability of the ionic surfactant while keeping the benefit of working with highly concentrated solutions. This method allows fine control of the functionalization reaction and tuning of the kinetics characteristic time over more than two orders of magnitude.


Medical student and junior doctors' tolerance of ambiguity: development of a new scale.
The practice of medicine involves inherent ambiguity, arising from limitations of knowledge, diagnostic problems, complexities of treatment and outcome and unpredictability of patient response. Research into doctors' tolerance of ambiguity is hampered by poor conceptual clarity and inadequate measurement scales. We aimed to create and pilot a measurement scale for tolerance of ambiguity in medical students and junior doctors that addresses the limitations of existing scales. After defining tolerance of ambiguity, scale items were generated by literature review and expert consultation. Feedback on the draft scale was sought and incorporated. 411 medical students and 75 foundation doctors in Exeter, UK were asked to complete the scale. Psychometric analysis enabled further scale refinement and comparison of scale scores across subgroups. The pilot study achieved a 64% response rate. The final 29 item version of the Tolerance of Ambiguity in Medical Students and Doctors (TAMSAD) scale had good internal reliability (Cronbach's α 0.80). Tolerance of ambiguity was higher in foundation year 2 doctors than first, third and fourth year medical students (-5.23, P = 0.012; -5.98, P = 0.013; -4.62, P = 0.035, for each year group respectively). The TAMSAD scale offers a valid and reliable alternative to existing scales. Further work is required in different settings and in longitudinal studies but this study offers intriguing provisional insights.


Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease.
To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.


What epidemiology has told us about risk factors and aetiopathogenesis in rheumatic diseases.
This article will review how epidemiological studies have advanced our knowledge of both genetic and environmental risk factors for rheumatic diseases over the past decade. The major rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, osteoarthritis, gout, and fibromyalgia, and chronic widespread pain, will be covered. Advances discussed will include how a number of large prospective studies have improved our knowledge of risk factors, including diet, obesity, hormones, and smoking. The change from small-scale association studies to genome-wide association studies using gene chips to reveal new genetic risk factors will also be reviewed.


Helix dynamics in a membrane transport protein: comparative simulations of the glycerol-3-phosphate transporter and its constituent helices.
The glycerol-3-phosphate transporter (GlpT) is a member of the major facilitator superfamily (MFS). GlpT is an organic phosphate/inorganic phosphate antiporter. It shares a similar fold with other MFS transporters (e.g. LacY and EmrD) consisting of 12 transmembrane (TM) helices which form two domains (each of six TM helices) surrounding a central ligand-binding cavity. The TM helices (especially the cavity-lining helices) contain a large number of proline and glycine residues, which may aid in the conformational changes believed to underline the transport mechanism. Molecular dynamics simulations in a phospholipid bilayer have been used to compare the conformational properties of the isolated TM helices with those in the intact GlpT protein. Analysis of these simulations focuses on the role of proline-induced flexibility in the TM helices. Our results are consistent with the proposed rocker switch mechanism for transport by GlpT. In particular, the simulations highlight the cavity-lining helices (H4, H5, H10 and H11) as being significantly flexible, suggesting that the transport mechanism may involve intra-helix motions in addition to pseudo-rigid body motions of the N- and C-terminal domains relative to one another.


Integrated Service Delivery and Health-Related Quality of Life of Individuals in Permanent Supportive Housing Who Were Formerly Chronically Homeless.
To investigate the impact of an integrated care model on the health-related quality of life (HRQOL) of formerly chronically homeless individuals in permanent supportive housing. From 2014 to 2017, eligible individuals in Houston, Texas (n = 323), were placed in 1 of 2 permanent supportive housing service delivery models. Both models included coordinated care teams. In the intervention group, teams had a single plan of care with the partnering clinic. The 9-item Patient Health Questionnaire and 36-item Short Form Survey were administered at baseline and every 6 months for 30 months. We assessed intervention group emergency department use at 2 years. We evaluated change by using hierarchical linear growth models. There was a significant and clinically meaningful increase in HRQOL in the intervention group, with the intervention group reporting improvement over the comparison group. Intervention group emergency department use decreased by 70% (no comparison group). Those in the intervention group with a single, coordinated plan of care reported significant and clinically meaningful increases in their HRQOL. Public Health Implications. Coordinated care models have potential to reduce societal costs and increase HRQOL, providing a financial and humanitarian justification for the continued investment in collaborative care in permanent supportive housing.


Prognostic significance of P27 (Kip 1) and MUC1 in papillary transitional cell carcinoma of the urinary bladder.
To examine p27 (Kip 1) and MUC1 expression in specimens of papillary transitional cell carcinoma (PTCC) of the urinary bladder and to correlate their expression with the tumor grades,stages and outcome. Paraffin sections from previously diagnosed PTCC bladder were graded, staged and the patients were followed up for 5 years. Ten non-neoplastic urological lesions diagnosed as polypoid cystitis were taken as control. Three sections of 4 um thickness were obtained from every case. One was hematoxylin and eosin (H and E) stained for diagnosis, reviewing and confirmation. The other two sections were immunohistochemically stained for both p27and MUC1. The data of immunohistochemical results were correlated with the following conventional prognostic variables: tumor grade, stage, distant metastasis and 5 year survival. The results showed a highly significant and an insignificant relationship between p27 expression and tumor grade and stage (P<0.01 and P>0.05), respectively. Correlating p27 expression with distant metastasis and overall survival showed a significant relationship with distant metastasis (P<0.05) and a highly significant one with overall survival (P<0.01). The results showed also a significant relationship between MUC1 expression and both tumor grade (P<0.01) and overall survival (P<0.05). p27 and MUC1 immunohistochemistry augment the classic histochemistry for the prognosis of PTCC of the bladder as well as improving the prediction of the patient outcome and survival.


Methodology of the global and regional burden of stroke study.
Setting priorities for the prevention of stroke requires an empirical understanding of the pattern of disease burden and exposure to major risk factors. In this manuscript we aim to report the methodology of a systematic review of the epidemiological literature on stroke and how this information will be synthesized to produce updated estimates of the global burden of stroke. We will use multi-state models implemented in the software program DisMod III to estimate age-specific prevalence, incidence, and early case-fatality (defined as either 28-day, 30-day or 1-month case fatality) for stroke by the 21 global burden of disease (GBD) regions as well as by gender and pathological stroke type based on information obtained from a systematic review. We conducted a two-stage search strategy in order to identify studies published between 1980 and 2011 for the GBD stroke review. Eligible studies: (a) distinguished between stroke and transient ischaemic attack (TIA); (b) distinguished between 1st ever and recurrent stroke; (c) reported on age-specific rates; (d) if reported, provided survival status within 28 days, 30 days or 1 month of onset for fatal and nonfatal events; (e) specified methods for ascertaining stroke cases, and (f) described imaging modalities to determine stroke subtypes. Details of included studies were recorded on a detailed data extraction form by trained reviewers. We will gather information on demographics, natural history and clinical outcomes (e.g. Rankin scale, Glasgow Coma Scale), after stroke which will be used to facilitate the estimation of epidemiological parameters. Reporting and methodological quality was rated. Populations were coded as urban, rural, or combined and studies classified as national, subnational, healthcare system-based, or community level. Studies published in non-English languages were translated and coded centrally. In international health research, there is a crucial need for accurate assessment of global health patterns. A thorough GBD reassessment of stroke will ensure that global health policy decisions are based on the most up-to-date, valid and reliable epidemiological information available.


Feasibility and Conceptualization of an e-Mental Health Treatment for Depression in Older Adults: Mixed-Methods Study.
Depression is one of the most common mental disorders in older adults. Unfortunately, it often goes unrecognized in the older population. The aim of this study was to identify how Web-based apps can recognize and help treat depression in older adults. Focus groups were conducted with mental health care experts. A Web-based survey of 56 older adults suffering from depression was conducted. Qualitative interviews were conducted with 2 individuals. Results of the focus groups highlighted that there is a need for a collaborative care platform for depression in old age. Findings from the Web-based study showed that younger participants (aged 50 to 64 years) used electronic media more often than older participants (aged 65 years and older). The interviews pointed in a comparable direction. Overall, an e-mental (electronic mental) health treatment for depression in older adults would be well accepted. Web-based care platforms should be developed, evaluated, and in case of evidence for their effectiveness, integrated into the everyday clinic.


Diaphragm and lung-preserving surgery with hyperthermic chemotherapy for malignant pleural mesothelioma: A 10-year experience.
The best surgical treatment for malignant pleural mesothelioma is still under a debate, but recent evidence points toward a less-invasive approach to reduce morbidity and mortality. We reported our 10-year experience of a limited surgical approach associated with hyperthermic intrathoracic chemotherapy (HITHOC). Between 2005 and 2014, patients with epithelioid or biphasic malignant pleural mesothelioma were treated with lung-diaphragm-pericardium-sparing pleurectomy associated with double-drug HITHOC; at least 3 cycles of adjuvant chemotherapy were then administered. The primary outcome examined was the feasibility of the procedure, whereas secondary outcomes were overall survival and disease-free interval. Among 49 patients, 41 were male. Median age was 68 years (35-76 years). Histology was epithelioid in 43 cases. Pathologic stage I, II, III, and IV occurred in 12, 14, 20, and 3 cases, respectively. No intraoperative complications or postoperative mortality occurred, whereas morbidity rate was 46.9%. Median hospital stay was 8 days (5-45 days). Actuarial median overall survival was 22 months and a 1-, 2-, and 5-year survival accounted for 79.6%, 45.7%, and 9.9%, respectively. Disease-free survival after surgery was 62%, 37.5%, and 18.5% at 1, 2, and 5 years, respectively. Risk factors analysis for overall survival confirmed a significant role for early stages, epithelioid histology, and fibrinogen serum levels. Cytoreductive surgery associated with HITHOC and adjuvant chemotherapy appears feasible and safe, with no mortality and low morbidity. Preserving lung and diaphragmatic function might warrant an acceptable long-term outcome.


Enhancement of astaxanthin production using Haematococcus pluvialis with novel LED wavelength shift strategy.
Haematococcus pluvialis is a green microalga of particular interest, since it is considered the best potential natural source of astaxanthin, which is widely used as an additive for natural pigmentation. In addition, astaxanthin has recently garnered commercial interest as a nutraceutical, cosmetic, and pharmaceutical. However, producing astaxanthin from H. pluvialis necessitates separation with distinctive culture conditions, dividing between the microalgae growth and the astaxanthin production stages. Light-emitting diodes (LEDs) have emerged as a replacement for traditional light sources, and LED applications are now rapidly expanding to multiple areas in fields such as biotechnology. However, further detail application into microalgae biotechnology remains limited. In this study, we have attempted to establish new protocols based on the specific wavelength of LEDs for the cultivation and production of astaxanthin using H. pluvialis. Specifically, we applied red LEDs for microalgae cell growth and then switched to blue LEDs to induce astaxanthin biosynthesis. The result showed that astaxanthin productions based on a wavelength shift from red to blue were significantly increased, compared to those with continuous illumination using red LEDs. Furthermore, additional increase of astaxanthin production was achieved with simultaneous application of exogenous carbon with blue LED illumination. Our approach based on the proper manipulation of LED wavelengths upon H. pluvialis cell stages will enable the improvement of biomass and enhance astaxanthin production using H. pluvialis.


Deep brain stimulation for psychiatric disorders: where we are now.
Fossil records showing trephination in the Stone Age provide evidence that humans have sought to influence the mind through physical means since before the historical record. Attempts to treat psychiatric disease via neurosurgical means in the 20th century provided some intriguing initial results. However, the indiscriminate application of these treatments, lack of rigorous evaluation of the results, and the side effects of ablative, irreversible procedures resulted in a backlash against brain surgery for psychiatric disorders that continues to this day. With the advent of psychotropic medications, interest in invasive procedures for organic brain disease waned. Diagnosis and classification of psychiatric diseases has improved, due to a better understanding of psychiatric patho-physiology and the development of disease and treatment biomarkers. Meanwhile, a significant percentage of patients remain refractory to multiple modes of treatment, and psychiatric disease remains the number one cause of disability in the world. These data, along with the safe and efficacious application of deep brain stimulation (DBS) for movement disorders, in principle a reversible process, is rekindling interest in the surgical treatment of psychiatric disorders with stimulation of deep brain sites involved in emotional and behavioral circuitry. This review presents a brief history of psychosurgery and summarizes the development of DBS for psychiatric disease, reviewing the available evidence for the current application of DBS for disorders of the mind.


Epidemiological, clinical, haematological and biochemical characteristics of canine hypothyroidism.
Hypothyroidism was diagnosed in 50 dogs and excluded in 86 dogs suspected of hypothyroidism, on the basis of the results of bovine thyrotropin response tests. Breed, pedigree, sex or neutering status did not significantly influence the likelihood of the dogs being hypothyroid. The hypothyroid dogs were significantly older than the non-hypothyroid dogs referred to the University of Glasgow during the same period. However, when dogs under two years of age were excluded from the statistical analyses there was no significant difference in age between the two groups. The most common clinical characteristics associated with hypothyroidism were metabolic signs (84 per cent of cases), particularly lethargy (76 per cent), obesity or weight gain (44 per cent), and exercise intolerance (24 per cent); and dermatological abnormalities (80 per cent), including alopecia (56 per cent), poor coat quality (30 per cent) and hyperpigmentation (20 per cent). When compared with the laboratory reference limits the most common biochemical and haematological abnormalities were increased concentrations of triglycerides (88 per cent), cholesterol (78 per cent), glucose (49 per cent), and fructosamine (43 per cent), and increased activities of creatine kinase (35 per cent), and decreased concentrations of inorganic phosphate (63 per cent), and a low red blood cell count (40 per cent). When compared with reference limits derived from the euthyroid dogs the most common abnormalities were increased concentrations of gamma-glutamyltransferase (21 per cent), cholesterol (18 per cent), and aspartate aminotransferase (15 per cent) and a decreased red blood cell count (29 per cent), and decreased neutrophils (18 per cent) and decreased activity of creatine kinase (15 per cent). Assessment of cholesterol, creatine kinase, aspartate aminotransferase, gamma-glutamyltransferase, and red blood cell and neutrophil counts may be particularly useful in distinguishing hypothyroid dogs from euthyroid animals with similar clinical signs.


Asymptomatic atherosclerosis and insulin resistance.
High plasma insulin has been shown to be associated with the risk of coronary heart disease in nondiabetic subjects in prospective population studies. Furthermore, insulin resistance measured by the euglycemic glucose clamp technique has been shown to be related to lipid and lipoprotein changes favoring atherosclerosis and to high blood pressure. No study, however, has demonstrated that insulin resistance per se is directly associated with atherosclerosis. With this aim, we studied 30 middle-aged nonobese subjects with asymptomatic atherosclerosis in the femoral or carotid arteries and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were only slightly and nonsignificantly higher in subjects with atherosclerosis than in controls, and during the oral glucose tolerance test 1- and 2-hour glucose, insulin, and C-peptide levels were similar in both groups. During the euglycemic hyperinsulinemic (1,200 pmol/l) clamp studies, subjects with atherosclerosis had a 20% reduced whole-body glucose uptake (58 +/- 2 versus 71 +/- 4 mumol/kg/min, p = 0.004). Glucose oxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. In contrast, nonoxidative glucose disposal was significantly reduced in patients compared with that in controls (37 +/- 2 versus 50 +/- 4 mumol/kg/min, p = 0.004). When glucose uptakes were matched during the hyperglycemic clamp studies, the rate of nonoxidative glucose uptake was normalized in the patients. These results provide the first direct evidence that asymptomatic atherosclerosis is associated with insulin resistance. This insulin resistance is characterized by reduced whole-body and nonoxidative glucose uptake. In contrast, glucose and lipid oxidation, potassium disposal, and suppression of free fatty acid levels during hyperinsulinemia did not differ between the subjects with and without atherosclerosis.


Recurring mutations found by sequencing an acute myeloid leukemia genome.
The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known. We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome. We identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis. By comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.


What can Google Trends and Wikipedia-Pageview analysis tell us about the landscape of epilepsy surgery over time?
Epilepsy surgery is an effective treatment for drug-resistant epilepsy. Some centers have noticed changes in referral patterns. The aim of this study was to determine if online infodemiological data related to epilepsy surgery reflect reported changes in referrals to surgical centers. Google Trends and Pageview analysis of temporal trends of searches conducted in Google and Wikipedia for epilepsy surgery, using key search terms such as "epilepsy surgery" and terms related to pathology, operation type, and investigative practice. Over the 15-year time period studied by Google trend analysis, when the initial three-year epoch and final three-year epoch are compared, a 56.1% decline in search volume for "epilepsy surgery" was observed. Vagus nerve stimulation and laser ablation are increasingly searched items. Pageview analysis shows that temporal lobe epilepsy remains the most commonly searched subtype of epilepsy and hippocampal sclerosis was searched for more than focal cortical dysplasia. This study suggests a lower search interest over time in epilepsy surgery, and various associated terms, with increased interest in vagus nerve stimulation and laser ablation procedures over time. There is no clear indication from these data regarding the apparent shift from mesial temporal cases to an increase in extratemporal case workload.


Oxidative stress in toxicology: established mammalian and emerging piscine model systems.
Interest in the toxicological aspects of oxidative stress has grown in recent years, and research has become increasingly focused on the mechanistic aspects of oxidative damage and cellular responses in biological systems. Toxic consequences of oxidative stress at the subcellular level include lipid peroxidation and oxidative damage to DNA and proteins. These effects are often used as end points in the study of oxidative stress. Typically, mammalian species have been used as models to study oxidative stress and to elucidate the mechanisms underlying cellular damage and response, largely because of the interest in human health issues surrounding oxidative stress. However, it is becoming apparent that oxidative stress also affects aquatic organisms exposed to environmental pollutants. Research in fish has demonstrated that mammalian and piscine systems exhibit similar toxicological and adaptive responses to oxidative stress. This suggests that piscine models, in addition to traditional mammalian models, may be useful for further understanding the mechanisms underlying the oxidative stress response.


Upregulation of the vascular endothelial growth factor/vascular endothelial growth factor receptor system in experimental background diabetic retinopathy of the rat.
Vascular endothelial growth factor (VEGF) is a major contributor to retinal neovascularization. The possible participation of VEGF and its high-affinity tyrosine kinase receptors, flk-1 and flt-1, in early background diabetic retinopathy was studied in the streptozotocin-induced diabetic rat model of experimental retinopathy using in situ hybridization, blotting techniques, and immunohistochemistry. Diabetic retinopathy was assessed by quantitative morphometry of retinal digest preparations. The number of acellular capillaries increased 2.7-fold in diabetic animals with diabetes' duration of 6 months compared with nondiabetic controls. VEGF expression was not detectable by in situ hybridization in nondiabetic rats but was highly increased in the ganglion cell layer and in the inner and outer nuclear layers of retinas from diabetic animals. VEGF protein was extractable only from diabetic retinas, and a strong immunolabeling was detected in vascular and perivascular structures. Increased flk-1 and flt-1 mRNA levels were also found in the ganglion cell and both nuclear layers of diabetic samples only. Dot blot and Western blot analyses confirmed the increase in flk-1 mRNA and protein in diabetic retinas. Also, flk-1 immunoreactivity was associated with vascular and nonvascular structures of the inner retinas from diabetic animals. These data obtained from a rodent model in which retinal neovascularization does not occur support the concept that the VEGF/VEGF receptor system is upregulated in early diabetic retinopathy.


The relationships between age, associative memory performance, and the neural correlates of successful associative memory encoding.
Using functional magnetic resonance imaging, subsequent memory effects (greater activity for later remembered than later forgotten study items) predictive of associative encoding were compared across samples of young, middle-aged, and older adults (total N = 136). During scanning, participants studied visually presented word pairs. In a later test phase, they discriminated between studied pairs, "rearranged" pairs (items studied on different trials), and new pairs. Subsequent memory effects were identified by contrasting activity elicited by study pairs that went on to be correctly judged intact or incorrectly judged rearranged. Effects in the hippocampus were age-invariant and positively correlated across participants with associative memory performance. Subsequent memory effects in the right inferior frontal gyrus (IFG) were greater in the older than the young group. In older participants only, both left and, in contrast to prior reports, right IFG subsequent memory effects correlated positively with memory performance. We suggest that the IFG is especially vulnerable to age-related decline in functional integrity and that the relationship between encoding-related activity in right IFG and memory performance depends on the experimental context.


Umbelliferone Inhibits Migration, Invasion and Inflammation of Rheumatoid Arthritis Fibroblast-Like Synoviocytes and Relieves Adjuvant-Induced Arthritis in Rats by Blockade of Wnt/β-Catenin Signaling Pathway.
Umbelliferone (UMB), a natural coumarin compound, has been reported to possess anti-rheumatic effects on rheumatoid arthritis (RA) experimental models, but its potential role of UMB in regulating migration, invasion and inflammation of RA fibroblast-like synoviocytes (FLS) remain unclear. Herein, MTT assay was performed to confirm the non-cytotoxic concentrations (10, 20, and 40[Formula: see text][Formula: see text]M) and the treatment time (24[Formula: see text]h) of UMB on TNF-[Formula: see text]-stimulated RA FLS (MH7A cells) in vitro. Results of wound-healing, transwell and phalloidin staining assays revealed that UMB inhibited TNF-[Formula: see text]-induced migration, invasion and F-actin cytoskeletal reorganization in MH7A. Results of ELISA, western blot and gelatin zymography indicated that UMB decreased the productions of pro-inflammatory factors, including IL-1[Formula: see text], IL-6, IL-8, MMP-2 and MMP-9, and inhibited MMP-2 activity in TNF-[Formula: see text]-stimulated MH7A cells. In vivo, UMB (25[Formula: see text]mg/kg and 50[Formula: see text]mg/kg) relieved the joint damage and synovial inflammation in rats with adjuvant-induced arthritis (AIA). Mechanistically, UMB could suppress Wnt/[Formula: see text]-catenin signaling both in TNF-[Formula: see text]-induced MH7A cells and in AIA rat synovium, evidenced by decreasing Wnt1 protein level, activating GSK-3[Formula: see text] kinase by blocking GSK-3[Formula: see text] (Ser9) phosphorylation, and reducing the protein level and nuclear translocation of [Formula: see text]-catenin. Importantly, combined use of lithium chloride (a Wnt/[Formula: see text]-catenin signaling agonist) eliminated the inhibitory effects of UMB on migration, invasion and inflammation in vitro and the anti-arthritic effects of UMB in vivo. We concluded that UMB inhibited TNF-[Formula: see text]-induced migration, invasion and inflammation of RA FLS and attenuated the severity of rat AIA through its ability to block Wnt/[Formula: see text]-catenin signaling pathway.


SWOT analysis of a pediatric rehabilitation programme: a participatory evaluation fostering quality improvement.
To present the results of a strengths, weaknesses, opportunities and threats (SWOT) analysis used as part of a process aimed at reorganising services provided within a pediatric rehabilitation programme (PRP) in Quebec, Canada and to report the perceptions of the planning committee members regarding the usefulness of the SWOT in this process. Thirty-six service providers working in the PRP completed a SWOT questionnaire and reported what they felt worked and what did not work in the existing model of care. Their responses were used by a planning committee over a 12-month period to assist in the development of a new service delivery model. Committee members shared their thoughts about the usefulness of the SWOT. Current programme strengths included favourable organisational climate and interdisciplinary work whereas weaknesses included lack of psychosocial support to families and long waiting times for children. Opportunities included working with community partners, whereas fear of losing professional autonomy with the new service model was a threat. The SWOT results helped the planning committee redefine the programme goals and make decisions to improve service coordination. SWOT analysis was deemed as a very useful tool to help guide service reorganisation. SWOT analysis appears to be an interesting evaluation tool to promote awareness among service providers regarding the current functioning of a rehabilitation programme. It fosters their active participation in the reorganisation of a new service delivery model for pediatric rehabilitation.


A review of pesticide exposure and cancer incidence in the Agricultural Health Study cohort.
We reviewed epidemiologic evidence related to occupational pesticide exposures and cancer incidence in the Agricultural Health Study (AHS) cohort. Studies were identified from the AHS publication list available at http://aghealth.nci.nih.gov as well as through a Medline/PubMed database search in March 2009. We also examined citation lists. Findings related to lifetime-days and/or intensity-weighted lifetime-days of pesticide use are the primary focus of this review, because these measures allow for the evaluation of potential exposure-response relationships. We reviewed 28 studies; most of the 32 pesticides examined were not strongly associated with cancer incidence in pesticide applicators. Increased rate ratios (or odds ratios) and positive exposure-response patterns were reported for 12 pesticides currently registered in Canada and/or the United States (alachlor, aldicarb, carbaryl, chlorpyrifos, diazinon, dicamba, S-ethyl-N,N-dipropylthiocarbamate, imazethapyr, metolachlor, pendimethalin, permethrin, trifluralin). However, estimates of association for specific cancers were often imprecise because of small numbers of exposed cases, and clear monotonic exposure-response patterns were not always apparent. Exposure misclassification is also a concern in the AHS and may limit the analysis of exposure-response patterns. Epidemiologic evidence outside the AHS remains limited with respect to most of the observed associations, but animal toxicity data support the biological plausibility of relationships observed for alachlor, carbaryl, metolachlor, pendimethalin, permethrin, and trifluralin. Continued follow-up is needed to clarify associations reported to date. In particular, further evaluation of registered pesticides is warranted.


High school science fair and research integrity.
Research misconduct has become an important matter of concern in the scientific community. The extent to which such behavior occurs early in science education has received little attention. In the current study, using the web-based data collection program REDCap, we obtained responses to an anonymous and voluntary survey about science fair from 65 high school students who recently competed in the Dallas Regional Science and Engineering Fair and from 237 STEM-track, post-high school students (undergraduates, 1st year medical students, and 1st year biomedical graduate students) doing research at UT Southwestern Medical Center. Of the post-high school students, 24% had competed in science fair during their high school education. Science fair experience was similar overall for the local cohort of Dallas regional students and the more diverse state/national cohort of post-high school students. Only one student out of 122 reported research misconduct, in his case making up the data. Unexpectedly, post-high school students who did not participate in science fair anticipated that carrying out science fair would be much more difficult than actually was the case, and 22% of the post-high school students anticipated that science fair participants would resort to research misconduct to overcome obstacles. No gender-based differences between students' science fair experiences or expectations were evident.


Effect of eplerenone, a selective aldosterone blocker, on the development of diabetic nephropathy in type 2 diabetic rats.
Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats. ANIMALS WERE DIVIDED INTO SIX GROUPS AS FOLLOWS: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks. Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-β1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups. Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.


Identification of two small regulatory RNAs linked to virulence in Brucella abortus 2308.
Hfq is an RNA-binding protein that functions in post-transcriptional gene regulation by mediating interactions between mRNAs and small regulatory RNAs (sRNAs). Two proteins encoded by BAB1_1794 and BAB2_0612 are highly over-produced in a Brucella abortus hfq mutant compared with the parental strain, and recently, expression of orthologues of these proteins in Agrobacterium tumefaciens was shown to be regulated by two sRNAs, called AbcR1 and AbcR2. Orthologous sRNAs (likewise designated AbcR1 and AbcR2) have been identified in B. abortus 2308. In Brucella, abcR1 and abcR2 single mutants are not defective in their ability to survive in cultured murine macrophages, but an abcR1 abcR2 double mutant exhibits significant attenuation in macrophages. Additionally, the abcR1 abcR2 double mutant displays significant attenuation in a mouse model of chronic Brucella infection. Quantitative proteomics and microarray analyses revealed that the AbcR sRNAs predominantly regulate genes predicted to be involved in amino acid and polyamine transport and metabolism, and Northern blot analyses indicate that the AbcR sRNAs accelerate the degradation of the target mRNAs. In an Escherichia coli two-plasmid reporter system, overexpression of either AbcR1 or AbcR2 was sufficient for regulation of target mRNAs, indicating that the AbcR sRNAs from B. abortus 2308 perform redundant regulatory functions.


Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial.
The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease. The purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy. COMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit. High-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months. In patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.


Superamphiphobic coatings based on liquid-core microcapsules with engineered capsule walls and functionality.
Microcapsules with specific functional properties, related to the capsule wall and core, are highly desired in a number of applications. In this study, hybrid cellulose microcapsules (1.2 ± 0.4 µm in diameter) were prepared by nanoengineering the outer walls of precursor capsules. Depending on the preparation route, capsules with different surface roughness (raspberry or broccoli-like), and thereby different wetting properties, could be obtained. The tunable surface roughness was achieved as a result of the chemical and structural properties of the outer wall of a precursor capsule, which combined with a new processing route allowed in-situ formation of silica nanoparticles (30-40 nm or 70 nm in diameter). By coating glass slides with "broccoli-like" microcapsules (30-40 nm silica nanoparticles), static contact angles above 150° and roll-off angles below 6° were obtained for both water and low surface-tension oil (hexadecane), rendering the substrate superamphiphobic. As a comparison, coatings from raspberry-like capsules were only strongly oleophobic and hydrophobic. The liquid-core of the capsules opens great opportunities to incorporate different functionalities and here hydrophobic superparamagnetic nanoparticles (SPIONs) were encapsulated. As a result, magnetic broccoli-like microcapsules formed an excellent superamphiphobic coating-layer on a curved geometry by simply applying an external magnetic field.


Ottawa Panel evidence-based clinical practice guidelines on therapeutic massage for neck pain.
To update evidence-based clinical practice guideline (EBCPG) on the use of massage compared to a control or other treatments for adults (>18 years) suffering from sub-acute and chronic neck pain. A literature search was performed from January 1, 1948 to December 31, 2010 for relevant articles. The Ottawa Panel created inclusion criteria focusing on high methodological quality and grading methods. Recommendations were assigned a grade (A, B, C, C+, D, D+, D-) based on strength of evidence. A total of 45 recommendations from ten articles were developed including 8 positive recommendations (6 grade A and 2 grade C+) and 23 neutral recommendations (12 grade C and 11 grade D). Therapeutic massage can decrease pain, tenderness, and improve range of motion for sub-acute and chronic neck pain. The Ottawa Panel was able to demonstrate that the massage interventions are effective for relieving immediate post-treatment neck pain symptoms, but data is insufficient for long-term effects.


Use of simulation to assess electronic health record safety in the intensive care unit: a pilot study.
To establish the role of high-fidelity simulation training to test the efficacy and safety of the electronic health record (EHR)-user interface within the intensive care unit (ICU) environment. Prospective pilot study. Medical ICU in an academic medical centre. Postgraduate medical trainees. A 5-day-simulated ICU patient was developed in the EHR including labs, hourly vitals, medication administration, ventilator settings, nursing and notes. Fourteen medical issues requiring recognition and subsequent changes in management were included. Issues were chosen based on their frequency of occurrence within the ICU and their ability to test different aspects of the EHR-user interface. ICU residents, blinded to the presence of medical errors within the case, were provided a sign-out and given 10 min to review the case in the EHR. They then presented the case with their management suggestions to an attending physician. Participants were graded on the number of issues identified. All participants were provided with immediate feedback upon completion of the simulation. To determine the frequency of error recognition in an EHR simulation. To determine factors associated with improved performance in the simulation. 38 participants including 9 interns, 10 residents and 19 fellows were tested. The average error recognition rate was 41% (range 6-73%), which increased slightly with the level of training (35%, 41% and 50% for interns, residents, and fellows, respectively). Over-sedation was the least-recognised error (16%); poor glycemic control was most often recognised (68%). Only 32% of the participants recognised inappropriate antibiotic dosing. Performance correlated with the total number of screens used (p=0.03). Despite development of comprehensive EHRs, there remain significant gaps in identifying dangerous medical management issues. This gap remains despite high levels of medical training, suggesting that EHR-specific training may be beneficial. Simulation provides a novel tool in order to both identify these gaps as well as foster EHR-specific training.


Low Doses of Glyphosate/Roundup Alter Blood-Testis Barrier Integrity in Juvenile Rats.
It has been postulated that glyphosate (G) or its commercial formulation Roundup (R) might lead to male fertility impairment. In this study, we investigated the possible effects of G or R treatment of juvenile male rats on blood-testis barrier function and on adult male sperm production. Pups were randomly assigned to the following groups: control group (C), receiving water; G2 and G50 groups, receiving 2 and 50 mg/kg/day G respectively; and R2 and R50 groups receiving 2 and 50 mg/kg/day R respectively. Treatments were performed orally from postnatal day (PND) 14 to 30, period of life that is essential to complete a functional blood-testis barrier. Evaluation was done on PND 31. No differences in body and testis weight were observed between groups. Testis histological analysis showed disorganized seminiferous epithelium, with apparent low cellular adhesion in treated animals. Blood-testis barrier permeability to a biotin tracer was examined. A significant increase in permeable tubules was observed in treated groups. To evaluate possible mechanisms that could explain the effects on blood-testis barrier permeability, intratesticular testosterone levels, androgen receptor expression, thiobarbituric acid reactive substances (TBARS) and the expression of intercellular junction proteins (claudin11, occludin, ZO-1, connexin43, 46, and 50 which are components of the blood-testis barrier) were examined. No modifications in the above-mentioned parameters were detected. To evaluate whether juvenile exposure to G and R could have consequences during adulthood, a set of animals of the R50 group was allowed to grow up until PND 90. Histological analysis showed that control and R50 groups had normal cellular associations and complete spermatogenesis. Also, blood-testis barrier function was recovered and testicular weight, daily sperm production, and epididymal sperm motility and morphology did not seem to be modified by juvenile treatment. In conclusion, the results presented herein show that continuous exposure to low doses of G or R alters blood-testis barrier permeability in juvenile rats. However, considering that adult animals treated during the juvenile stage showed no differences in daily sperm production compared with control animals, it is feasible to think that blood-testis barrier impairment is a reversible phenomenon. More studies are needed to determine possible damage in the reproductive function of human juvenile populations exposed to low doses of G or R.


Randomization-Based Inference within Principal Strata.
In randomized studies, treatment comparisons conditional on intermediate post-randomization outcomes using standard analytic methods do not have a causal interpretation. An alternate approach entails treatment comparisons within principal strata defined by the potential outcomes for the intermediate outcome that would be observed under each treatment assignment. In this paper, we develop methods for randomization-based inference within principal strata. The proposed methods are compared with existing large-sample methods as well as traditional intent-to-treat approaches. This research is motivated by HIV prevention studies where few infections are expected and inference is desired within the always-infected principal stratum, i.e., all individuals who would become infected regardless of randomization assignment.


Autonomic pathophysiology in heart failure: carotid baroreceptor-cardiac reflexes.
We evaluated reflex cardiac responses mediated by carotid baroreceptors in 14 patients with treated congestive heart failure and 14 age-matched healthy subjects. We used a neck chamber to deliver two types of pressure change: 5 s of continuous 50-mmHg suction and an R wave triggered, ramped neck pressure-suction sequence. Reflex latencies (functions of baroreflex arc duration) were comparable in heart failure patients and healthy subjects. However, the average maximum baroreflex slope (gain) was less in heart failure patients than healthy subjects (2.0 vs. 3.5 ms/mmHg, P less than 0.010), the R-R interval response range was smaller (91 vs. 188 ms, P = 0.002), and the resting R-R interval position on stimulus-response relation (operational point) was significantly (13 vs. 40%, P = 0.001) closer to threshold. Stepwise regression analysis suggested that baseline R-R interval variability, used as an index of ongoing vagal-cardiac nerve traffic, and the inverse of antecubital vein plasma norepinephrine level, used as an index of sympathetic nerve activity, contributed significantly to the prediction of abnormal carotid baroreceptor-cardiac reflex responses. Thus our results suggest that in heart failure patients, carotid baroreceptor-cardiac reflex abnormalities are related significantly to ongoing abnormalities of vagal and sympathetic cardiovascular outflow.


Expression of Trichoderma reesei β-mannanase in tobacco chloroplasts and its utilization in lignocellulosic woody biomass hydrolysis.
Lignocellulosic ethanol offers a promising alternative to conventional fossil fuels. One among the major limitations in the lignocellulosic biomass hydrolysis is unavailability of efficient and environmentally biomass degrading technologies. Plant-based production of these enzymes on large scale offers a cost-effective solution. Cellulases, hemicellulases including mannanases and other accessory enzymes are required for conversion of lignocellulosic biomass into fermentable sugars. β-mannanase catalyzes endo-hydrolysis of the mannan backbone, a major constituent of woody biomass. In this study, the man1 gene encoding β-mannanase was isolated from Trichoderma reesei and expressed via the chloroplast genome. PCR and Southern hybridization analysis confirmed site-specific transgene integration into the tobacco chloroplast genomes and homoplasmy. Transplastomic plants were fertile and set viable seeds. Germination of seeds in the selection medium showed inheritance of transgenes into the progeny without any Mendelian segregation. Expression of endo-β-mannanase for the first time in plants facilitated its characterization for use in enhanced lignocellulosic biomass hydrolysis. Gel diffusion assay for endo-β-mannanase showed the zone of clearance confirming functionality of chloroplast-derived mannanase. Endo-β-mannanase expression levels reached up to 25 units per gram of leaf (fresh weight). Chloroplast-derived mannanase had higher temperature stability (40 °C to 70 °C) and wider pH optima (pH 3.0 to 7.0) than E.coli enzyme extracts. Plant crude extracts showed 6-7 fold higher enzyme activity than E.coli extracts due to the formation of disulfide bonds in chloroplasts, thereby facilitating their direct utilization in enzyme cocktails without any purification. Chloroplast-derived mannanase when added to the enzyme cocktail containing a combination of different plant-derived enzymes yielded 20% more glucose equivalents from pinewood than the cocktail without mannanase. Our results demonstrate that chloroplast-derived mannanase is an important component of enzymatic cocktail for woody biomass hydrolysis and should provide a cost-effective solution for its diverse applications in the biofuel, paper, oil, pharmaceutical, coffee and detergent industries.


Archival fixed histologic and cytologic specimens including stained and unstained materials are amenable to RT-PCR.
Formalin-fixed and paraffin-embedded tissues are increasingly used for analysis of gene expression. However, a large proportion of archival fixed histologic specimens including spare paraffin sections and stained slides, as well as archival cytologic materials, have not been investigated for their suitability for RNA-based analysis. The current study addressed this issue by reverse transcription and polymerase chain reaction (RT-PCR) of the glucose-6-phosphate dehydrogenase (G6PD) transcript in a series of archival histologic and cytologic specimens. The histologic specimens included freshly prepared paraffin sections, spare paraffin sections, hematoxylin and eosin-stained slides, immunostained slides, and decalcified bone marrow trephines. The cytologic specimens comprised cervical smears and various stained and unstained needle aspirates and cell sediments. The G6PD was amplified for five different fragment sizes ranging from 67 bp to 453 bp. It was found that the majority of archival materials were amenable to RT-PCR of small fragments with the overall success rates of 95% and 79% for 67 bp and 151 bp of the G6PD mRNA, respectively. Neither staining nor prolonged storage up to 15 years had major negative effects on RT-PCR, although fine-needle aspirates showed a higher rate of RT-PCR of 242-bp fragment than other types of cytologic specimens and so did Papanicolaou-stained samples than May Grounwald and Giemsa-stained samples. RT-PCR of minute cell populations microdissected from immunostained sections of tonsils and t(11;18)-positive mucosa-associated lymphoid tissue lymphomas showed that as few as 100 cells were adequate for RT-PCR of G6PD and translocation-associated fusion transcript as long as the target fragment was limited to less than 150 bp. Our results demonstrate that archival fixed histologic and cytologic specimens are valuable resources for RT-PCR-based molecular investigations.


Growth inhibition and recovery of Lemna gibba after pulse exposure to sulfonylurea herbicides.
The exposure of non-target aquatic organisms to pesticides often happens as short-term, high exposure events (pulses) and effects of these must be addressed in the current regulation in the EU. It is, however, questionable whether the effects of pulse exposures are adequately covered by the standardized ecotoxicological tests used in environmental effect assessments, since these aim at maintaining constant exposure concentrations during the incubation. Therefore, we investigated the effects of four sulfonylurea herbicides (flupyrsulfuron-methyl, metsulfuron-methyl, rimsulfuron, and thifensulfuron-methyl) on the growth of Lemna gibba over a 6-day period after 24h of pulse exposure, and compared with effects observed in standard OECD tests with continuous exposure. It was observed that concentrations around the E(y)C50-values found in OECD tests did not affect the growth in the 6 days post-exposure period. Slightly higher concentrations initially resulted in lower growth in pulse exposure tests, but the growth rate of the plants reached the level of untreated plants during the 6 days post-exposure period. The 24h pulse exposure tests gave 2-6 times higher E(y)C50-values than the OECD 7-d continuous exposure tests. The approach of this study enables experimentally based comparisons between observations of effects between the two exposure regimes. We propose that results obtained in this way be applied in effect assessments for intermittent releases.


Studies of PPLO infection. II. The neurotoxin of Mycoplasma neurolyticum.
Rolling disease has been produced and studied in rats and mice, using the exotoxin of the A strain of Mycoplasma neurolyticum. The primary lesion of the brain consists of spongiform degeneration, associated with vesicle formation in the cortex and underlying white matter of the cerebral hemispheres, and in the molecular layer of the cerebellum. The brains of animals surviving 2 days or longer show extensive necrotizing lesions resembling ischemic necrosis, in both cerebral hemispheres. The brains of rats and mice with rolling disease become deeply stained by intraperitoneally injected trypan blue, indicating early disruption of the blood brain barrier. The toxin appears to be a thermolabile protein with a molecular weight exceeding 200,000. It is only active when injected by vein, and causes no disease when injected intracerebrally, intraperitoneally or subcutaneously, suggesting the existence of specific receptors within the vascular bed of the central nervous system. Protection is afforded by rabbit antibody against the toxin, but only when antibody is injected within less than 3 min after intravenous injection of toxin, indicating rapid fixation to receptors in the brain. The toxin is inactivated by incubation for 10 min at 37 degrees C with suspensions of the sedimentable component of normal brain. The inactivating factor in brain sediment is very thermostable, not affected by trypsin, and eliminated by treatment with periodate. Similar inactivation of toxin is demonstrable with water-soluble gangliosides of brain. A theoretical concept to explain the action of the toxin is proposed.


A Cytoscape app for motif enumeration with ISMAGS.
We present a Cytoscape app for the ISMAGS algorithm, which can enumerate all instances of a motif in a graph, making optimal use of the motif's symmetries to make the search more efficient. The Cytoscape app provides a handy interface for this algorithm, which allows more efficient network analysis. The Cytoscape app for ISMAGS can be freely downloaded from the Cytoscape App store http://apps.cytoscape.org/apps/ismags. Source code and documentation for ISMAGS are available at https://github.com/biointec/ismags. Source code and documentation for the Cytoscape app are available at https://gitlab.psb.ugent.be/thpar/ISMAGS_Cytoscape. firstname.lastname@example.com or email@example.com Supplementary data are available at Bioinformatics online.


Learning about pain: the neural substrate of the prediction error for aversive events.
Associative learning is thought to depend on detecting mismatches between actual and expected experiences. With functional magnetic resonance imaging (FMRI), we studied brain activity during different types of mismatch in a paradigm where contrasting-colored lights signaled the delivery of painful heat, nonpainful warmth, or no stimulation. When painful heat stimulation was unexpected, there was increased FMRI signal intensity in areas of the hippocampus, superior frontal gyrus, cerebellum, and superior parietal gyrus that was not found with mismatch between expectation and delivery of nonpainful warmth stimulation. When painful heat stimulation was unexpectedly omitted, the FMRI signal intensity decreased in the left superior parietal gyrus and increased in the other regions. These contrasting activation patterns correspond to two different mismatch concepts in theories of associative learning (Rescorla-Wagner, temporal difference vs. Pearce-Hall, Mackintosh). Searching for interventions to specifically modulate activation of these brain regions therefore offers an approach to identifying new treatments for chronic pain, which often has a substantial associative learning component.


G-CSF induction early in uropathogenic Escherichia coli infection of the urinary tract modulates host immunity.
Uropathogenic Escherichia coli (UPEC), the causative agent of approximately 85% of urinary tract infections (UTI), is a major health concern primarily affecting women. During infection, neutrophils infiltrate the bladder, but the mechanism of recruitment is not well understood. Here, we investigated the role of UPEC-induced cytokine production in neutrophil recruitment and UTI progression. We first examined the kinetics of cytokine expression during UPEC infection of the bladder, and their contribution to neutrophil recruitment. We found that UPEC infection induces expression of several pro-inflammatory cytokines including granulocyte colony-stimulating factor (G-CSF, CSF-3), not previously known to be involved in the host response to UTI. G-CSF induces neutrophil emigration from the bone marrow; these cells are thought to be critical for bacterial clearance during infection. Upon neutralization of G-CSF during UPEC infection, we found fewer circulating neutrophils, decreased neutrophil infiltration into the bladder and, paradoxically, a decreased bacterial burden in the bladder. However, depletion of G-CSF resulted in a corresponding increase in macrophage-activating cytokines, such as monocyte chemotactic protein-1 (MCP-1, CCL-2) and Il-1beta, which may be key in host response to UPEC infection, potentially resolving the paradoxical decreased bacterial burden. Thus, G-CSF acts in a previously unrecognized role to modulate the host inflammatory response during UPEC infection.


Increased genetic susceptibility to renal damage in the stroke-prone spontaneously hypertensive rat.
The spontaneously hypertensive rat (SHR) develops much less renal damage than the stroke-prone strain of SHR (SHRsp) after salt-supplementation, and it has been proposed that these strains differ in their genetic susceptibility to renal damage. However, radiotelemetric BP measurements have shown that salt-supplementation results in more severe and accelerated hypertension in the SHRsp. Therefore, it is unclear whether the differences in renal damage are due to differences in BP exposure or true differences in intrinsic (genetic) renal susceptibility to hypertensive damage. Kidney cross transplantation was performed between the SHR and SHRsp strains in uninephrectomized recipients to allow an investigation of the susceptibility to renal damage in SHR and SHRsp kidneys maintained in the same host and exposed to the same BP profile and metabolic environment. Following transplantation, BP was radiotelemetrically monitored before and after an 8% NaCl diet given to accelerate hypertension and renal damage. Then the kidneys were removed and renal damage was assessed histologically. In the SHR recipients, the SHRsp donor kidneys exhibited more hypertensive damage than the contralateral native SHR kidneys, but histologic evidence of mild cellular immunologic rejection also was observed that could have facilitated the increased renal damage. However, even in SHRsp recipients, the native SHRsp kidneys exhibited twice the damage seen in the contralateral transplanted SHR kidneys. These data unequivocally demonstrate that the SHRsp kidneys are intrinsically more susceptible than the SHR kidneys to renal damage when exposed to exactly the same BP and metabolic environment.


Development and Evaluation of an Automated, Home-Based, Electronic Questionnaire for Detecting COPD Exacerbations.
Collaboration between patients and their medical and technical experts enabled the development of an automated questionnaire for the early detection of COPD exacerbations (AQCE). The questionnaire consisted of fourteen questions and was implemented on a computer system for use by patients at home in an un-supervised environment. Psychometric evaluation was conducted after a 6-month field trial. Fifty-two patients were involved in the development of the questionnaire. Reproducibility was studied using 19 patients (ICC = 0.94). Sixteen out of the 19 subjects started the 6 month-field trial with the computer application. Cronbach's alpha of 0.81 was achieved. In the concurrent validity analysis, a correlation of 0.80 (p = 0.002) with the CCQ was reported. The results suggest that AQCE is a valid and reliable questionnaire, showing that an automated home-based electronic questionnaire may enable early detection of exacerbations of COPD.


Liana abundance, diversity, and distribution on Barro Colorado Island, Panama.
Lianas are a key component of tropical forests; however, most surveys are too small to accurately quantify liana community composition, diversity, abundance, and spatial distribution - critical components for measuring the contribution of lianas to forest processes. In 2007, we tagged, mapped, measured the diameter, and identified all lianas ≥1 cm rooted in a 50-ha plot on Barro Colorado Island, Panama (BCI). We calculated liana density, basal area, and species richness for both independently rooted lianas and all rooted liana stems (genets plus clones). We compared spatial aggregation patterns of liana and tree species, and among liana species that varied in the amount of clonal reproduction. We also tested whether liana and tree densities have increased on BCI compared to surveys conducted 30-years earlier. This study represents the most comprehensive spatially contiguous sampling of lianas ever conducted and, over the 50 ha area, we found 67,447 rooted liana stems comprising 162 species. Rooted lianas composed nearly 25% of the woody stems (trees and lianas), 35% of woody species richness, and 3% of woody basal area. Lianas were spatially aggregated within the 50-ha plot and the liana species with the highest proportion of clonal stems more spatially aggregated than the least clonal species, possibly indicating clonal stem recruitment following canopy disturbance. Over the past 30 years, liana density increased by 75% for stems ≥1 cm diameter and nearly 140% for stems ≥5 cm diameter, while tree density on BCI decreased 11.5%; a finding consistent with other neotropical forests. Our data confirm that lianas contribute substantially to tropical forest stem density and diversity, they have highly clumped distributions that appear to be driven by clonal stem recruitment into treefall gaps, and they are increasing relative to trees, thus indicating that lianas will play a greater role in the future dynamics of BCI and other neotropical forests.


Noninvasive ankle distraction: relationship between force, magnitude of distraction, and nerve conduction abnormalities.
Seven healthy volunteers (14 ankles; four males, 3 females) with no history of ankle or foot pathology were placed in a modified beach chair position on an operating table for ankle distraction using a noninvasive ankle distractor. In-line traction of 0 to 225 N (50 lb) in 22.5-N (5-lb) increments was applied to the ankle. A direct lateral radiograph was obtained at each distraction force. The joint space was measured on the lateral radiographs using electronic microcalipers. Surface recordings of the superficial peroneal, deep peroneal dorsal digital cutaneous, and sural nerves were obtained. The ankle joint space increased progressively from an average 3.1 mm with no force applied to an average 4.2 mm with 225 N (50 lb) distraction force applied. The maximum joint distraction averaged 1.3 mm (range, 0.35 to 2.35 mm). The sensory amplitudes were diminished or absent with increasing time and force of distraction. The decreased amplitudes were most marked after 1 hour of distraction with 135 N (30 lb) or greater distraction force. This correlated with symptoms of paresthesias. The superficial and deep peroneal cutaneous nerves were affected to a much greater extent than the sural nerve. The amplitudes quickly returned to normal values with the weight being released from the ankle. The noninvasive ankle distractor safely increased ankle joint space by more than 1 mm. Distraction with 135 N (30 lb) or more for 1 hour is associated with reversible nerve conduction changes. Based on these findings, we recommend using the noninvasive ankle distraction apparatus for ankle arthroscopy, with up to 135 N (30 lb) of traction applied to the foot for up to 1 hour. Greater force, applied for longer periods, is associated with increasing nerve conduction abnormalities.


Comparison of API and Minitek to Center for Disease Control methods for the biochemical characterization of anaerobes.
Two commercially available micromethod multitest systems (API, Analytab Products, Inc., Minitek-Bioquest) were compared with conventional tests suggested by the Center for Disease Control for the identification of anaerobes. Anaerobiosis for the microsystems was achieved using GasPak system (BBL), A total of 175 anaerobes, including 158 clinical isolates and 17 reference strains, were used. Gram morphology, gas-liquid chromatography data, and biochemical reactions from the Center for Disease Control and Virginia Polytechnic Institute anaerobic manuals were used to identify the organisms. The Minitek system included a new anaerobe inoculum broth and two new disks, dextrose without nitrate and nitrate reductase disks. The percentage of correlation of 12 biochemicals using Minitek and 11 biochemicals using the API were compared with the Center for Disease Control reactions. The percentage of correlation of both positive and negative reactions with the API anaerobic strip ranged from 70.8 to 99.4% and with the Minitek from 97.1 to 100%. The microsystems were also evaluated as to the ease of use, adaptabilty to a clinical laboratory, time, and cost.


A conceptual framework for assessing interorganizational integration and interprofessional collaboration.
The need for collaboration in health and social welfare is well documented internationally. It is related to the improvement of services for the users, particularly target groups with multiple problems. However, there is still insufficient knowledge of the complex area of collaboration, and the interprofessional literature highlights the need to develop adequate research approaches for exploring collaboration between organizations, professionals and service users. This paper proposes a conceptual framework based on interorganizational and interprofessional research, with focus on the concepts of integration and collaboration. Furthermore, the paper suggests how two measurement instruments can be combined and adapted to the welfare context in order to explore collaboration between organizations, professionals and service users, thereby contributing to knowledge development and policy improvement. Issues concerning reliability, validity and design alternatives, as well as the importance of management, clinical implications and service user involvement in future research, are discussed.


Effect of methanol in controlling defunctionalization of the propyl side chain of phenolics from catalytic upstream biorefining.
In recent years, lignin valorization has gained upward momentum owing to advances in both plant bioengineering and catalytic processing of lignin. In this new horizon, catalysis is now applied to the 'pulping process' itself, creating efficient methods for lignocellulose fractionation or deconstruction (here referred to as Catalytic Upstream Biorefining or 'CUB'). These processes render, together with delignified pulps, lignin streams of low molecular weight (Mw) and low molecular diversity. Recently, we introduced a CUB process based on Early-stage Catalytic Conversion of Lignin (ECCL) through H-transfer reactions catalyzed by RANEY® Ni. This approach renders a lignin stream obtained as a viscous oil, comprising up to 60 wt% monophenolic compounds (Mw < 250 Da). The remaining oil fraction (40 wt%) is mainly composed of lignin oligomers, and as minor products, holocellulose-derived polyols and lignin-derived species of high Mw (0.25-2 kDa). Simultaneously, the process yields a holocellulose pulp with a low content of residual lignin (<5 wt%). Despite the efficiency of aqueous solutions of 2-propanol as a solvent for lignin fragments and an H-donor, there is scant information regarding the CUB process carried out in the presence of primary alcohols, which often inhibit the catalytic activity of RANEY® Ni, as revealed in model compound studies performed at low temperature. Considering the composition of the lignin oils obtained from CUB based on ECCL, the processes commonly render ortho-(di)methoxy-4-propylphenol derivatives with a varied degree of defunctionalization of the propyl side chain. In this contribution, we present the role of the alcohol solvent (methanol or 2-propanol) and Ni catalyst (Ni/C or RANEY® Ni) in control over selectivity of phenolic products. The current results indicate that solvent effects on the catalytic processes could hold the key for improving control over the degree of functionalization of the propyl side-chain in the lignin oil obtained from CUB, offering new avenues for lignin valorization at the extraction step.


Normal host prion protein necessary for scrapie-induced neurotoxicity.
Accumulation of the prion protein PrPSc, a pathological and protease-resistant isoform of the normal host protein PrPC, is a feature of prion disease such as scrapie. It is still unknown whether scrapie pathology comes about by neurotoxicity of PrPSc, acute depletion of PrPC, or some other mechanism. Here we investigate this question by grafting neural tissue overexpressing PrPC into the brain of PrP-deficient mice which are scrapie-resistant and do not propagate infectivity. After intracerebral inoculation with scrapie prions, the grafts accumulated high levels of PrPSc and infectivity and developed the severe histopathological changes characteristic of scrapie. Moreover, substantial amounts of graft-derived PrPSc migrated into the host brain. Even 16 months after inoculation no pathological changes were seen in PrP-deficient tissue, not even in the immediate vicinity of the grafts. Therefore, in addition to being resistant to scrapie infection, brain tissue devoid of PrPC is not damaged by exogenous PrPSc.


Carbamazepine inhibits ATP-sensitive potassium channel activity by disrupting channel response to MgADP.
In pancreatic β-cells, K(ATP) channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion. Sulfonylureas, insulin secretagogues used to treat type II diabetes, inhibit K(ATP) channel activity primarily by abolishing the stimulatory effect of MgADP endowed by SUR1. In addition, sulfonylureas have been shown to function as pharmacological chaperones to correct channel biogenesis and trafficking defects. Recently, we reported that carbamazepine, an anticonvulsant known to inhibit voltage-gated sodium channels, has profound effects on K(ATP) channels. Like sulfonylureas, carbamazepine corrects trafficking defects in channels bearing mutations in the first transmembrane domain of SUR1. Moreover, carbamazepine inhibits the activity of K(ATP) channels such that rescued mutant channels are unable to open when the intracellular ATP/ADP ratio is lowered by metabolic inhibition. Here, we investigated the mechanism by which carbamazepine inhibits K(ATP) channel activity. We show that carbamazepine specifically blocks channel response to MgADP. This gating effect resembles that of sulfonylureas. Our results reveal striking similarities between carbamazepine and sulfonylureas in their effects on K(ATP) channel biogenesis and gating and suggest that the 2 classes of drugs may act via a converging mechanism.


Milk: the new sports drink? A Review.
There has been growing interest in the potential use of bovine milk as an exercise beverage, especially during recovery from resistance training and endurance sports. Based on the limited research, milk appears to be an effective post-resistance exercise beverage that results in favourable acute alterations in protein metabolism. Milk consumption acutely increases muscle protein synthesis, leading to an improved net muscle protein balance. Furthermore, when post-exercise milk consumption is combined with resistance training (12 weeks minimum), greater increases in muscle hypertrophy and lean mass have been observed. Although research with milk is limited, there is some evidence to suggest that milk may be an effective post-exercise beverage for endurance activities. Low-fat milk has been shown to be as effective, if not more effective, than commercially available sports drinks as a rehydration beverage. Milk represents a more nutrient dense beverage choice for individuals who partake in strength and endurance activities, compared to traditional sports drinks. Bovine low-fat fluid milk is a safe and effective post exercise beverage for most individuals, except for those who are lactose intolerant. Further research is warranted to better delineate the possible applications and efficacy of bovine milk in the field of sports nutrition.