Viruses in the Oceanic Basement.
Microbial life has been detected well into the igneous crust of the seafloor (i.e., the oceanic basement), but there have been no reports confirming the presence of viruses in this habitat. To detect and characterize an ocean basement virome, geothermally heated fluid samples (ca. 60 to 65°C) were collected from 117 to 292 m deep into the ocean basement using seafloor observatories installed in two boreholes (Integrated Ocean Drilling Program [IODP] U1362A and U1362B) drilled in the eastern sediment-covered flank of the Juan de Fuca Ridge. Concentrations of virus-like particles in the fluid samples were on the order of 0.2 × 105 to 2 × 105 ml-1 (n = 8), higher than prokaryote-like cells in the same samples by a factor of 9 on average (range, 1.5 to 27). Electron microscopy revealed diverse viral morphotypes similar to those of viruses known to infect bacteria and thermophilic archaea. An analysis of virus-like sequences in basement microbial metagenomes suggests that those from archaeon-infecting viruses were the most common (63 to 80%). Complete genomes of a putative archaeon-infecting virus and a prophage within an archaeal scaffold were identified among the assembled sequences, and sequence analysis suggests that they represent lineages divergent from known thermophilic viruses. Of the clustered regularly interspaced short palindromic repeat (CRISPR)-containing scaffolds in the metagenomes for which a taxonomy could be inferred (163 out of 737), 51 to 55% appeared to be archaeal and 45 to 49% appeared to be bacterial. These results imply that the warmed, highly altered fluids in deeply buried ocean basement harbor a distinct assemblage of novel viruses, including many that infect archaea, and that these viruses are active participants in the ecology of the basement microbiome.IMPORTANCE The hydrothermally active ocean basement is voluminous and likely provided conditions critical to the origins of life, but the microbiology of this vast habitat is not well understood. Viruses in particular, although integral to the origins, evolution, and ecology of all life on earth, have never been documented in basement fluids. This report provides the first estimate of free virus particles (virions) within fluids circulating through the extrusive basalt of the seafloor and describes the morphological and genetic signatures of basement viruses. These data push the known geographical limits of the virosphere deep into the ocean basement and point to a wealth of novel viral diversity, exploration of which could shed light on the early evolution of viruses.


Validity of routine surveillance data: a case study on Swedish notifications of methicillin-resistant Staphylococcus aureus.
Surveillance of communicable diseases is a public health corner stone. Routine notification data on communicable diseases are used as a basis for public health action as well as for policy making. While there are agreed standards for evaluating the performance of surveillance systems, it is rarely possible to analyse the validity of the data entered into these systems. In this study we compared data on all Swedish cases of methicillin-resistant Staphylococcus aureus (MRSA) routinely notified between 2000 and 2003 with follow-up information collected for each of these cases as part of a public health project. The variables Reason for testing (clinical sample, contact tracing, screening of risk group), Clinical presentation (disease, colonisation), Transmission setting (healthcare-acquired, community-acquired), Country of acquisition (Sweden, abroad) and Risk-occupation (yes, no) were analysed for sensitivity, positive predictive value and completeness of answers. The sensitivity varied between 23% and 83%, the positive predictive values were generally higher (55% to 97%), while missing answers varied from 11% to 59%. The proportion of community-acquired cases was markedly higher when excluding either cases of MRSA colonisation or cases found through public health-initiated activities (contact tracing or screening of risk groups). We conclude that the quality of routine surveillance data may be inadequate for in-depth epidemiological analyses. This should be taken into account when interpreting routine surveillance figures. Whether or not the case definition includes cases of MRSA colonisation may have a significant impact on population-wide estimates of MRSA occurrence.


Identification and characterization of a Streptococcus pyogenes operon involved in binding of hemoproteins and acquisition of iron.
The hemolytic Streptococcus pyogenes can use a variety of heme compounds as an iron source. In this study, we investigate hemoprotein utilization by S. pyogenes. We demonstrate that surface proteins contribute to the binding of hemoproteins to S. pyogenes. We identify an ABC transporter from the iron complex family named sia for streptococcal iron acquisition, which consists of a lipoprotein (siaA), membrane permease (siaB), and ATPase (siaC). The sia transporter is part of a highly conserved, iron regulated, 10-gene operon. SiaA, which was localized to the cell membrane, could specifically bind hemoglobin. The operon's first gene encodes a novel bacterial protein that bound hemoglobin, myoglobin, heme-albumin, and hemoglobin-haptoglobin (but not apo-haptoglobin) and therefore was named Shr, for streptococcal hemoprotein receptor. PhoZ fusion and Western blot analysis showed that Shr has a leader peptide and is found in both membrane-bound and soluble forms. An M1 SF370 strain with a polar mutation in shr was more resistant to streptonigrin and hydrogen peroxide, suggesting decreased iron uptake. The addition of hemoglobin to the culture medium increased cell resistance to hydrogen peroxide in SF370 but not in the mutant, implying the sia operon may be involved in hemoglobin-dependent resistance to oxidative stress. The shr mutant demonstrated reduced hemoglobin binding, though cell growth in iron-depleted medium supplemented with hemoglobin, whole blood, or ferric citrate was not affected, suggesting additional systems are involved in hemoglobin utilization. SiaA and Shr are the first hemoprotein receptors identified in S. pyogenes; their possible role in iron capture is discussed.


The effect of facility-based antiretroviral therapy programs on outpatient services in Kenya and Uganda.
Considerable debate exists concerning the effects of antiretroviral therapy (ART) service scale-up on non-HIV services and overall health system performance in sub-Saharan Africa. In this study, we examined whether ART services affected trends in non-ART outpatient department (OPD) visits in Kenya and Uganda. Using a nationally representative sample of health facilities in Kenya and Uganda, we estimated the effect of ART programs on OPD visits from 2007 to 2012. We modeled the annual percent change in non-ART OPD visits using hierarchical mixed-effects linear regressions, controlling for a range of facility characteristics. We used four different constructs of ART services to capture the different ways in which the presence, growth, overall, and relative size of ART programs may affect non-ART OPD services. Our final sample included 321 health facilities (140 in Kenya and 181 in Uganda). On average, OPD and ART visits increased steadily in Kenya and Uganda between 2007 and 2012. For facilities where ART services were not offered, the average annual increase in OPD visits was 4·2% in Kenya and 13·5% in Uganda. Among facilities that provided ART services, we found average annual OPD volume increases of 7·2% in Kenya and 5·6% in Uganda, with simultaneous annual increases of 13·7% and 12·5% in ART volumes. We did not find a statistically significant relationship between annual changes in OPD services and the presence, growth, overall, or relative size of ART services. However, in a subgroup analysis, we found that Ugandan hospitals that offered ART services had statistically significantly less growth in OPD visits than Ugandan hospitals that did not provide ART services. Our findings suggest that ART services in Kenya and Uganda did not have a statistically significant deleterious effects on OPD services between 2007 and 2012, although subgroup analyses indicate variation by facility type. Our findings are encouraging, particularly given recent recommendations for universal access to ART, demonstrating that expanding ART services is not inherently linked to declines in other health services in sub-Saharan Africa.


Are There Racial Ethnic Differences in Indigent, Inner-City Clients With Dual-Diagnosis?
OBJECTIVE: An exploratory, cross-sectional study examined personal, clinical, and treatment characteristics among non-Hispanic Caucasian, non-Hispanic African American, and Hispanic indigent, inner-city clients with co-occurring disorders. METHODS: Men and women, 20-50 years old who met DSM-IV criteria for concurrent mood and substance use disorders were eligible. Inpatients, persons in detoxification programs, or incarcerated inmates were excluded. Assessments covered sociodemographic characteristics, clinical diagnoses, substance use, psychosocial variables, health care utilization and treatment history. RESULTS: Two hundred volunteers were screened, and 145 were eligible to enroll. Racial ethnic group differences in the distribution of mood and substance use disorders and medical diseases were evident. Receiving psychiatric treatment and psychiatric medications significantly differed among racial ethnic groups with Caucasians more likely to receive these services than African Americans or Hispanics. African Americans and Hispanics were also more likely than Caucasians to test positive for their drug of choice and for other drugs as well. Serious medical illnesses were evident in about half of the sample, and the distributions of these illnesses significantly differed among racial ethnic groups. There were no significant differences in hospitalization or emergency room visits among racial ethnic groups. CONCLUSIONS: Indigent, inner-city clients have multiple psychiatric and medical problems that warrant continuity of care. However, few doctor's visits for medical illnesses, lack of psychotropic medications, staggering unemployment, and homelessness were common in our sample. These results present healthcare and social service professionals with potentially serious treatment challenges. Better recognition and understanding of racial ethnic needs in those with co-occurring disorders are needed.


Identification of Interacting Stromal Axes in Triple-Negative Breast Cancer.
Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC (n = 57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T, and E scores was governed by the D score. When compared with a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis. Cancer Res; 77(17); 4673-83. ©2017 AACR.


The physiological and clinical significance of nonlinear TCD waveform analysis in occlusive cerebrovascular disease.
In order to compare the results of nonlinear analysis of hemodynamically compromised and noncompromised cerebral circulations we measured consecutive transcranial Doppler (TCD) waveforms of fourteen patients with a unilateral or bilateral occlusion of the internal carotid artery. The cerebral vasomotor reactivity (VMR) to acetazolamide in both middle cerebral artery (MCA) territories was established by using TCD. Conventional TCD data and nonlinear TCD analysis of data were compared. Nonlinear analysis of the TCD time series suggested dynamical chaos based on the fractal dimension of the TCD curve and the positive Lyapunov exponents in the compromised and noncompromised MCA territories. In the areas with the compromised circulation the positive Lyapunov exponents were significantly lower compared to the noncompromised side and in some cases with a negative VMR, the Lyapunov exponent was almost zero. The latter is suggestive for periodic behavior of the impaired cerebral circulation instead of the dynamical chaos which is found under normal conditions. The TCD time series of a hemodynamic compromised cerebral territory not only shows phenomena related to a decreased perfusion pressure (such as a 'damped waveform') but also phenomena which are related to a more prominent periodicity. We speculate that conventional and nonlinear TCD analysis could be used to determine the VMR.


Role of lens extraction and laser peripheral iridotomy in treatment of glaucoma.
Lens extraction in people with coexisting cataract and open angle glaucoma is associated with a reduction in intraocular pressure (IOP). In primary angle-closure glaucoma (PACG), lens extraction and laser peripheral iridotomy (LPI) can be used to open the anterior chamber angle, increase the outflow through the trabecular meshwork and reduce the IOP. The present review will summarize the recent available literature regarding the role of both interventions for the treatment of glaucoma. Recent articles have confirmed the effect of cataract surgery as an IOP-lowering procedure in people with coexisting cataract and glaucoma, and highlight that the most important predictor for a greater decrease is a higher preoperative IOP. The probability for achieving a significant IOP reduction is highest in PACG and pseudoexfoliation glaucoma. Clear lens extraction (CLE) is associated with better clinical and quality of life outcomes than laser peripheral iridotomy (LPI) in patients with early or moderate PACG and those with primary angle closure and IOP over 30 mmHg. There is no high-quality evidence to support LPI in the treatment of pigmentary glaucoma. Evidence from the assessed period supports the IOP-lowering effect of cataract surgery in people with coexisting cataract and glaucoma. CLE is an option in the initial treatment of some patients with PACG as its superiority has been demonstrated against LPI.


Identification of the mRNA for the novel alpha 1D-adrenoceptor and two other alpha 1-adrenoceptors in vascular smooth muscle.
In situ hybridization histochemistry, radioligand binding, and in vitro contractile studies were used to characterize the vascular distribution of the recently discovered alpha 1D-adrenoceptor. In situ hybridization with an antisense probe localized the mRNA for the alpha 1D-adrenoceptor to the medial layer of the rat aorta renal and mesenteric resistance arteries. If the tissues were first treated with RNase or a sense probe was used, no specific hybridization signal was detected. The extent to which this receptor was expressed as protein was assessed with radioligand binding studies. A series of ligands used to characterize alpha 1-adrenoceptors interacted with two sites labeled by [3H]prazosin in homogenates from the aorta and mesenteric vascular bed. The high affinity site had the characteristics of an alpha 1A-adrenoceptor. However, the low affinity site had ligand binding characteristics distinct from those of the alpha 1D-adrenoceptor or any other known alpha 1-adrenoceptor subtype. mRNA for the alpha 1B- and alpha 1C-adrenoceptors was also detected in the aorta, renal arteries, and mesenteric resistance arteries. Chloroethylclonidine (CEC) (1 and 10 microM) had differential effects on phenylephrine-induced contractions of vascular smooth muscle. CEC completely inhibited the response in the aorta and caused a partial inhibition in the mesenteric resistance artery. The same concentrations of CEC had little effect on phenylephrine responses in the renal artery. The data suggest the following. 1) mRNA for the novel alpha 1D-adrenoceptor is localized in vascular smooth muscle. 2) Definitive identification of expression of this receptor was not possible; this may be related to coexpression of other subtypes of alpha 1-adrenoceptors. 3) mRNA for the alpha 1C-adrenoceptor was detected in rat peripheral vasculature. 4) The alpha 1A-adrenoceptor is also localized in the vasculature. 5) Three and possibly four alpha 1-adrenoceptors participate in vascular smooth muscle regulation.


beta-Endorphin and schizophrenia.
To study the effects of beta-endorphin in chronic schizophrenia, nine male patients participated in a double-blind crossover comparison of a single intravenous 20-mg injection of beta-endorphin and saline. Bolus injection of beta-endorphin from an albumin-coated syringe produced markedly higher plasma concentrations than did slow intravenous infusion from a non-albumin-coated syringe. Beta-endorphin intravenously injected in nine patients produced a statistically significant increase in serum prolactin levels. In one patient, both 10 mg of morphine sulfate and 20 mg of beta-endorphin produced similar increases in the alpha power of the EEG. In eight patients, beta-endorphin administration was associated with a statistically significant but not clinically obvious improvement in schizophrenic symptoms.


An evaluation of cultivated corneal limbal epithelial cells, using cell-suspension culture.
A previous report has described an ocular surface reconstruction method involving the use of cultivated corneal epithelium derived from limbal explants. In the current study, a new culture system was developed involving the in vitro propagation on amniotic membrane (AM) of epithelial cells from enzymatically dissociated limbal epithelium. The purpose of this new method is to produce a cultivated epithelial cell layer that contains stem cells and that is superior to explanted cultivated epithelium. The new cell-suspension technique was compared with the existing explant method. Limbal epithelial cells were dissociated from donor eyes by dispase and seeded on the denuded AM. Small pieces of limbal epithelium were also cultured on denuded AM as explant cultures. The cultivated epithelium was examined by electron microscopy and immunohistochemistry for cornea-specific keratins (K3 and K12). Both cell-suspension and explant culture methods produced a healthy epithelial cell layer. The cell-suspension culture had significantly (P < 0.001) more desmosomal junctions between the explant-cultured basal cells. In addition, the intercellular spaces between the cell-suspension's basal cells were significantly (P < 0.001) smaller than those between the explant-cultured basal cells. Both types of cultivated epithelium showed positive expression of K3 and K12 keratins. In the cell-suspension culture, expression of K3 and K12 keratins was more prominent in the superficial cells. Corneal epithelial cells were successfully regenerated in vitro by a cell-suspension culture system. The suspension-cultured epithelium must include some stem cells and morphologically is significantly superior to explant-cultured epithelium. Thus, this new technique is potentially more suitable for cultivated corneal limbal epithelial transplantation.


Validity and Reliability of Four Clinical Gait Measures in Patients with Multiple Sclerosis.
The gold standards for assessing ambulation are the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk (T25FW) test. In relation with these measures, we assessed the reliability and validity of four clinical gait measures: the Timed Up and Go (TUG) test, the Dynamic Gait Index (DGI), the 2-Minute Walk Test (2MWT), and the 6-Minute Walk Test (6MWT). Patient self-report of gait was also assessed using the 12-item Multiple Sclerosis Walking Scale (MSWS-12). Individuals 20 years or older with a diagnosis of multiple sclerosis (MS) and an EDSS score of 2.0 to 6.5 completed the MSWS-12, T25FW test, TUG test, DGI, 2MWT, and 6MWT. All the tests were repeated 2 weeks later at the same time of day to establish their reliability and concurrent validity. Predictive validity was established using the EDSS. Forty-two patients with MS were included. All measures showed high test-retest reliability. The TUG test, 2MWT, and 6MWT were significantly correlated with the T25FW test (Spearman ρ = -0.902, -0.919, and -0.905, respectively). The EDSS was also significantly correlated with all the walking tests. The MSWS-12 demonstrated the highest correlation to the EDSS (ρ = 0.788). The TUG test, the DGI, the 2MWT, and the 6MWT exhibited strong psychometric properties and were found to be significant predictors of the EDSS score. Use of these tests to prospectively monitor the effects of medical and rehabilitation treatment should be considered in the comprehensive care of patients with MS.


The current burden of allergic rhinitis amongst primary care practitioners and its impact on patient management.
To investigate the burden of allergic rhinitis (AR) amongst primary care practitioners (PCPs), the impact of AR on PCPs' professional lives, and the effect on their management of AR patients of PCPs' personal experience of AR. An online questionnaire was completed by 1201 PCPs (50% AR sufferers) from eight countries. 21% of PCPs reported very well controlled symptoms and 66% quite good control. Six hours work per week, on average, was missed by PCPs whose AR symptoms resulted in absence. AR symptoms affected concentration, stress level, mood, time spent with patients, physical contact with patients, and patient throughput. PCPs with AR reported a significantly higher proportion of AR patients in their practice and gave a significantly higher ranking to specific treatment requests and emotional well-being, and gave a significantly lower ranking to preventing comorbidity development and providing a treatment most likely to result in high patient compliance. This is the first study demonstrating the impact of AR on PCPs showing association with lost productivity, absenteeism and reduction in professional performance. Personal experience of AR significantly influences PCPs' management of AR and may improve their AR diagnostic ability.


Newborns should be receiving premedication before elective intubation.
Intubation is a common neonatal procedure. Premedication is accepted as a standard of care, but its use is not universal and wide variations exist in practice. To evaluate current practices for premedication use prior to elective neonatal intubation in South Africa (SA). We invited 481 clinicians to participate in a cross-sectional web-based survey. We received responses from 28.3% of the clinicians surveyed; 54.1% were from the private sector and 45.9% from the state sector. Most respondents worked in medium-sized neonatal units with six to ten beds. Most paediatricians (76.0%) worked in the private sector, and 78.6% of neonatologists in the state sector. Premedication was practised by 71.9% of the respondents, but only 38.5% of neonatal units had a written policy. Sedatives were used for premedication by 63.2% of the respondents. Midazolam (41.5%), morphine (34.0%) and ketamine (20.8%) were most commonly used. Muscle relaxants and atropine were not routinely administered. Suxamethonium was the muscle relaxant of choice. Varied combinations of agents or single agents were used. Midazolam used alone was the preferred option. This first survey of premedication for neonatal intubation in SA revealed variations in practice, with a minority of clinicians following a written policy. The findings can be used to benchmark practice and inform the design of local collaborative trials aimed at determining optimal premedication prior to neonatal intubation. The survey demonstrates clinicians' reluctance to participate in surveys, suggesting a need for a national collaborative network to obtain representative data.


Underidentification and undertreatment of dyslipidemia.
Despite increased attention placed on the identification and treatment of dyslipidemia, this condition remains undiagnosed and untreated in a significant number of patients. The recently released National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) set of cholesterol management guidelines increases to more than 65 million the number of Americans eligible for lipid-modifying therapy. Recent data, however, suggest that even with the availability of multiple regimens with proven efficacy, as many as 50% of all patients do not have their cholesterol assessed and less than 45% receive lipid-modifying therapy. In addition, less than 25% of patients are treated to their NCEP target low-density lipoprotein cholesterol (LDL-C) level. Persistence with therapy is another challenge, as more than 70% of patients fail to maintain their therapy beyond 12 months. If a realistic attempt is to be made to reduce the risk of coronary heart disease (CHD) among Americans, diagnosis of dyslipidemia and treatment to therapeutic targets must be improved. This artide discusses the underdiagnosis and undertreatment of lipid disorders and reviews the role of osteopathic physicians in strategies achieving ATP III LDL-C goals.


Choice and rejection of psychiatry as a career: surveys of UK medical graduates from 1974 to 2009.
Recruitment of adequate numbers of doctors to psychiatry is difficult. To report on career choice for psychiatry, comparing intending psychiatrists with doctors who chose other clinical careers. Questionnaire studies of all newly qualified doctors from all UK medical schools in 12 qualification years between 1974 and 2009 (33 974 respondent doctors). One, three and five years after graduation, 4-5% of doctors specified psychiatry as their first choice of future career. This was largely unchanged across the 35 years. Comparing intending psychiatrists with doctors who chose other careers, factors with a greater influence on psychiatrists' choice included their experience of the subject at medical school, self-appraisal of their own skills, and inclinations before medical school. In a substudy of doctors who initially considered but then did not pursue specialty choices, 72% of those who did not pursue psychiatry gave 'job content' as their reason compared with 33% of doctors who considered but did not pursue other specialties. Historically, more women than men have chosen psychiatry, but the gap has closed over the past decade. Junior doctors' views about psychiatry as a possible career range from high levels of enthusiasm to antipathy, and are more polarised than views about other specialties. Shortening of working hours and improvements to working practices in other hospital-based specialties in the UK may have reduced the relative attractiveness of psychiatry to women doctors. The extent to which views of newly qualified doctors about psychiatry can be modified by medical school education, and by greater exposure to psychiatry during student and early postgraduate years, needs investigation.


The heterologous expression of polysaccharidase-encoding genes with oenological relevance in Saccharomyces cerevisiae.
The main objective of this study was to develop polysaccharide-degrading wine strains of Saccharomyces cerevisiae, which are able to improve aspects of wine processing and clarification, as well as colour extraction and stabilization during winemaking. Two yeast expression/secretion gene cassettes were constructed, namely (i) a pectinase gene cassette (pPPK) consisting of the endo-polygalacturonase gene (pelE) from Erwinia chrysanthemi and the pectate lyase gene (peh1) from Erwinia carotovora and (ii) a glucanase/xylanase gene cassette (pEXS) containing the endo-beta-1,4-glucanase gene (end1) from Butyrivibrio fibrisolvens and the endo-beta-1,4-xylanase gene (xynC) from Aspergillus niger. The commercial wine yeast strain, VIN13, was transformed separately with these two gene cassettes and checked for the production of pectinase, glucanase and xylanase activities. Pinot Noir, Cinsaut and Muscat d'Alexandria grape juices were fermented using the VIN13[pPPK] pectinase- and the VIN13[pEXS] glucanase/xylanase-producing transformants. Chemical analyses of the resultant wines indicated that (i) the pectinase-producing strain caused a decrease in the concentration of phenolic compounds in Pinot Noir whereas the glucanase/xylanase-producing strain caused an increase in phenolic compounds presumably because of the degradation of the grape skins; (ii) the glucanase/xylanase-producing strain caused a decrease in wine turbidity, especially in Pinot Noir wine, as well as a clear increase in colour intensity and (iii) in the Muscat d'Alexandria and Cinsaut wines, the differences between the control wines (fermented with the untransformed VIN3 strain) and the wines produced by the two transformed strains were less prominent showing that the effect of these polysaccharide-degrading enzymes is cultivar-dependent. The recombinant wine yeasts producing pectinase, glucanase and xylanase activities during the fermentation of Pinot Noir, Cinsaut and Muscat d'Alexandria grape juice altered the chemical composition of the resultant wines in a way that such yeasts could potentially be used to improve the clarity, colour intensity and stability and aroma of wine. Aspects of commercial-scale wine processing and clarification, colour extraction and stabilization, and aroma enhancement could potentially be improved by the use of polysaccharide-degrading wine yeasts without the addition of expensive commercial enzyme preparations. This offers the potential to further improve the price:quality ratio of wine according to consumer expectations.


Protective effect of transgenic expression of porcine heat shock protein 70 on hypothalamic ischemic and oxidative damage in a mouse model of heatstroke.
Transgenic mice have been used to examine the role of heat shock protein (HSP)72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70beta gene ([+] HSP72) and transgene-negative littermate controls ([-] HSP72), under pentobarbital sodium anesthesia, were subjected to heat stress to induce heatstroke. It was found that the overexpression of HSP72 in multiple organs improved survival during heatstroke by reducing hypotension and cerebral ischemia and damage in mice. Herein we attempted to further assess the effect of heat exposure on thermoregulatory function, hypothalamic integration, and survival in unrestrained, unanesthetized [+]HSP72 and compare with those of [-]HSP72. In this research with the transgenic mice, we first conducted several biochemical, physiologic and histological determinations and then investigated the beneficial effects of HSP72 overexpression on the identified hypothalamic deficits, thermoregulatory dysfunction, and mortality during heatstroke. We report here that when [-]HSP72 mice underwent heat stress (ambient temperature 42.4 degrees C for 1 h), the fraction survival and core temperature at 4 h after heat stress were found to be 0 of 12 and 34.2 degrees C +/- 0.4 degrees C, respectively. Mice that survived to day 4 after heat stress were considered as survivors. In [+]HSP72 mice, when exposed to the same heat treatment, both fraction survival and core temperature values were significantly increased to new values of 12/12 and 37.4 degrees C +/- 0.3 degrees C, respectively. Compared to [-]HSP mice, [+]HSP72 mice displayed lower hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol) markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), pro-inflammatory cytokines (e.g., interleukin-1beta and tumor necrosis factor-alpha), and neuronal damage score evaluated 4 h after heat stress. In contrast, [+]HSP72 mice had higher hypothalamic values of antioxidant defences (e.g., glutathione peroxidase and glutathione reductase), ATP, and HSP72 expression. This study indicates that HSP72 overexpression appears to be critical to the development of thermotolerance and protection from heat-induced hypothalamic ischemic and oxidative damage.


Sport promotion policies in the European Union: results of a contents analysis.
Although sport promotion may play an important role in achieving the recommended levels of physical activity for health, until now, there has been no comprehensive assessment of how sport policies in Europe address health. This article aimed at filling this gap by reviewing and analyzing recent national policy developments in the area of sport promotion, with a focus on synergies and discrepancies with the promotion of health-enhancing physical activity. By applying various search methods, 130 documents focusing on sport and physical activity were identified in the World Health Organization (WHO) European Region. An analysis grid covering key indicators was developed for a systematic content analysis of 25 documents, selected according to established criteria. Analysis showed that general recommendations for good policy making were followed, such as establishing general goals, specifying time frame and responsible body for implementation and addressing different target groups. Furthermore, all sport strategies addressed health on an overall level and recognized the importance of Sport for All. However, in several strategies, there was a lack of measurable targets, specified budgets, and evaluation plans. The analysis showed that there is a great opportunity for health and sport sectors to work more closely together in the future, and identified areas where this could take place.


Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells.
The epithelial-to-mesenchymal transition (EMT) is an embryonic process that becomes latent in most normal adult tissues. Recently, we have shown that induction of EMT endows breast epithelial cells with stem cell traits. In this report, we have further characterized the EMT-derived cells and shown that these cells are similar to mesenchymal stem cells (MSCs) with the capacity to differentiate into multiple tissue lineages. For this purpose, we induced EMT by ectopic expression of Twist, Snail, or transforming growth factor-beta in immortalized human mammary epithelial cells. We found that the EMT-derived cells and MSCs share many properties including the antigenic profile typical of MSCs, that is, CD44(+), CD24(-), and CD45(-). Conversely, MSCs express EMT-associated genes, such as Twist, Snail, and mesenchyme forkhead 1 (FOXC2). Interestingly, CD140b (platelet-derived growth factor receptor-beta), a marker for naive MSCs, is exclusively expressed in EMT-derived cells and not in their epithelial counterparts. Moreover, functional analyses revealed that EMT-derived cells but not the control cells can differentiate into alizarin red S-positive mature osteoblasts, oil red O-positive adipocytes and alcian blue-positive chondrocytes similar to MSCs. We also observed that EMT-derived cells but not the control cells invade and migrate towards MDA-MB-231 breast cancer cells similar to MSCs. In vivo wound homing assays in nude mice revealed that the EMT-derived cells home to wound sites similar to MSCs. In conclusion, we have demonstrated that the EMT-derived cells are similar to MSCs in gene expression, multilineage differentiation, and ability to migrate towards tumor cells and wound sites.


Trends in death certification for multiple sclerosis, motor neuron disease, Parkinson's disease and epilepsy in English populations 1979-2006.
The objective of this study is to report trends in mortality, as certified on death certificates, from multiple sclerosis (MS), motor neuron disease (MND), primary Parkinson's disease (PD), and epilepsy, analysing not only the underlying cause of death but also all certified causes for each disease. Death records in the Oxford region, 1979-2006, and England, 1996-2006, were analysed for ascertaining the trends in mortality. The percentage of deaths coded as the underlying cause changed over time, coinciding with changes to the rules for selecting the underlying cause of death. Changes over time to coding rules had a large impact on apparent trends in death rates for PD when studied by underlying cause alone. They also had significant, though smaller, effects on trends in death rates for MS, MND and epilepsy. Nationally, in the last period of the study, underlying cause mortality identified 64% of deaths with a mention of MS, 88% of MND, 56% of PD, and 48% of epilepsy. In the longstanding Oxford data from 1979 to 2006, death rates based on all certified causes of death showed no significant change for MS; an upward trend for MND (notably in women over 75), though only in the last few years of the study; a significant but small decline for PD; and no significant change for epilepsy. When mortality statistics are analysed by underlying cause only, their value is reduced. A substantial percentage of neurological deaths are missed. Time trends may be misleading. All certified causes for each disease, as well as the underlying cause, should be analysed.


Empirical Optimization of Interactions between Proteins and Chemical Denaturants in Molecular Simulations.
Chemical denaturants are the most commonly used perturbation applied to study protein stability and folding kinetics as well as the properties of unfolded polypeptides. We build on recent work balancing the interactions of proteins and water, and accurate models for the solution properties of urea and guanidinium chloride, to develop a combined force field that is able to capture the strength of interactions between proteins and denaturants. We use solubility data for a model tetraglycine peptide in each denaturant to tune the protein-denaturant interaction by a novel simulation methodology. We validate the results against data for more complex sequences: single-molecule Förster resonance energy transfer data for a 34-residue fragment of the globular protein CspTm and photoinduced electron transfer quenching data for the disordered peptides C(AGQ)nW in denaturant solution as well as the chemical denaturation of the mini-protein Trp cage. The combined force field model should aid our understanding of denaturation mechanisms and the interpretation of experiment.


Decline in US stroke mortality. Demographic trends and antihypertensive treatment.
Stroke mortality has been falling rapidly in this country since 1973. To investigate age-race-sex effects on stroke mortality, we studied US vital statistics during 1950-1972 and 1973-1981 in 55-64-, 65-74-, and 75-84-year-old race-sex groups. The accelerated rate of decline in stroke mortality since 1973 has had a substantial public health impact, with greater than 200,000 fewer stroke deaths than would otherwise have occurred. For all groups, stroke mortality declined at a greater rate (p less than 0.05) in 1973-1981 than during 1950-1972. The rates of decline during 1973-1981 were greater with increasing age (p less than 0.05) and were more substantial for younger blacks. There were no consistent differences in the rate of decline by sex. The greater rate of decline in absolute stroke mortality in the older age groups and blacks was explained by higher baseline mortality in these groups. Overall, stroke mortality decreased by approximately 2%/yr in 1950-1972 and by approximately 7%/yr after 1973. Rank order of average annual percent decline after 1973 by age-race-sex groups did not correspond to rates of change in treatment or control of hypertension obtained from three national surveys. The accelerated rate of decline after 1973 may have resulted from improved antihypertensive therapy, but our findings fail to confirm this hypothesis and suggest that treatment of hypertension may not be the principal reason for the decline in stroke mortality.


Short-term choroidal thickness changes in patients treated with either ranibizumab or aflibercept: a comparative study.
To compare, in neovascular age-related macular degeneration (AMD) patients, short-term choroidal thickness changes in eyes treated using ranibizumab with those in eyes treated using aflibercept. This retrospective, observational study included 240 eyes from 240 patients who had been diagnosed with treatment-naive neovascular AMD and treated using three monthly injections of either ranibizumab (ranibizumab group) or aflibercept (aflibercept group). The choroidal thickness change between the time of diagnosis and 3 months later was compared between the two groups. Eyes were then classified into three disease groups: typical neovascular AMD, polypoidal choroidal vasculopathy (PCV) and retinal angiomatous proliferation (RAP). Within each disease group, choroidal thickness change was again compared between the two treatment groups. In the ranibizumab group (n=155), the mean choroidal thicknesses at diagnosis and at 3 months were 255.3±103.9 μm and 242.9±104.8 μm, respectively. In the aflibercept group (n=85), the values were 277.5±119.1 μm and 254.7±114.5 μm, respectively. The decrease was significantly greater in the aflibercept group (p<0.001). In the PCV group, the decrease was greater in the aflibercept group (p=0.001), whereas the difference was not significant in either the typical neovascular AMD group or the RAP group. A greater decrease in choroidal thickness was noted in eyes treated with aflibercept than in eyes treated with ranibizumab. This difference was more marked in PCV than in other subtypes of neovascular AMD.


Maternal and neonatal outcomes among obese women with weight gain below the new Institute of Medicine recommendations.
To estimate whether weight loss or low gestational weight gain in class I-III obese women is associated with adverse maternal and neonatal outcomes compared with gestational weight gain within the new Institute of Medicine recommendations. This was a population-based cohort study, which included 32,991 obesity class I, 10,068 obesity class II, and 3,536 obesity class III women who were divided into four gestational weight gain categories. Women with low (0-4.9 kg) or no gestational weight gain were compared with women gaining the recommended 5-9 kg concerning obstetric and neonatal outcome after suitable adjustments. Women in obesity class III who lost weight during pregnancy had a decreased risk of cesarean delivery (24.4%; odds ratio [OR] 0.77, 95% confidence interval [CI] 0.60-0.99), large-for-gestational-age births (11.2%, OR 0.64, 95% CI 0.46-0.90), and no significantly increased risk for pre-eclampsia, excessive bleeding during delivery, instrumental delivery, low Apgar score, or fetal distress compared with obese (class III) women gaining within the Institute of Medicine recommendations. There was an increased risk for small for gestational age, 3.7% (OR 2.34, 95% CI 1.15-4.76) among women in obesity class III losing weight, but there was no significantly increased risk of small for gestational age in the same group with low weight gain. Obese women (class II and III) who lose weight during pregnancy seem to have a decreased or unaffected risk for cesarean delivery, large for gestational age, pre-eclampsia, excessive postpartum bleeding, instrumental delivery, low Apgar score, and fetal distress. The twofold increased risk of small for gestational age in obesity class III and weight loss (3.7%) is slightly above the overall prevalence of small-for-gestational-age births in Sweden (3.6%).


X-ray emission spectroscopy of nitrogen-rich compounds.
Nonresonant X-ray emission spectroscopy was used to compare the nitrogen-rich compounds ammonium nitrate, trinitrotoluene, and cyclotrimethylene-trinitramine. They are representative of crystalline and molecular structures of special importance in industrial and military applications. The spectral signature of each substance was analyzed and correlated with features in the electronic structure of the systems. This analysis was accomplished by means of theoretical simulations of the emission spectra and a detailed examination of the molecular orbitals and densities of states. We find that the two theoretical methods used (frozen-orbital density functional theory and real-space Green's function simulations) account semiquantitatively for the observed spectra and are able to predict features arising from distinct chemical complexes. A comparison of the calculations and the data provides insight into the electronic contributions of specific molecular orbitals, as well as the features due to bandlike behavior. With some additional refinements, these methods could be used as an alternative to reference compounds.


APOA2, dietary fat, and body mass index: replication of a gene-diet interaction in 3 independent populations.
Nutrigenetics studies the role of genetic variation on interactions between diet and health, aiming to provide more personalized dietary advice. However, replication has been low. Our aim was to study interaction among a functional APOA2 polymorphism, food intake, and body mass index (BMI) in independent populations to replicate findings and to increase their evidence level. Cross-sectional, follow-up (20 years), and case-control analyses were undertaken in 3 independent populations. We analyzed gene-diet interactions between the APOA2 -265T>C polymorphism and saturated fat intake on BMI and obesity in 3462 individuals from 3 populations in the United States: the Framingham Offspring Study (1454 whites), the Genetics of Lipid Lowering Drugs and Diet Network Study (1078 whites), and Boston-Puerto Rican Centers on Population Health and Health Disparities Study (930 Hispanics of Caribbean origin). Prevalence of the CC genotype in study participants ranged from 10.5% to 16.2%. We identified statistically significant interactions between the APOA2 -265T>C and saturated fat regarding BMI in all 3 populations. Thus, the magnitude of the difference in BMI between the individuals with the CC and TT+TC genotypes differed by saturated fat. A mean increase in BMI of 6.2% (range, 4.3%-7.9%; P = .01) was observed between genotypes with high- (> or =22 g/d) but not with low- saturated fat intake in all studies. Likewise, the CC genotype was significantly associated with higher obesity prevalence in all populations only in the high-saturated fat stratum. Meta-analysis estimations of obesity for individuals with the CC genotype compared with the TT+TC genotype were an odds ratio of 1.84 (95% confidence interval, 1.38-2.47; P < .001) in the high-saturated fat stratum, but no association was detected in the low-saturated fat stratum (odds ratio, 0.81; 95% confidence interval, 0.59-1.11; P = .18). For the first time to our knowledge, a gene-diet interaction influencing BMI and obesity has been strongly and consistently replicated in 3 independent populations.


Human Hepatocyte Metabolism of Novel Synthetic Cannabinoids MN-18 and Its 5-Fluoro Analog 5F-MN-18.
In 2014, 2 novel synthetic cannabinoids, MN-18 and its 5-fluoro analog, 5F-MN-18, were first identified in an ongoing survey of novel psychoactive substances in Japan. In vitro pharmacological assays revealed that MN-18 and 5F-MN-18 displayed high binding affinities to human CB1 and CB2 receptors, with Ki being 1.65-3.86 nmol/L. MN-18 and 5F-MN-18 were scheduled in Japan and some other countries in 2014. Despite increasing prevalence, no human metabolism data are currently available, making it challenging for forensic laboratories to confirm intake of MN-18 or 5F-MN-18. We incubated 10 μmol/L of MN-18 and 5F-MN-18 in human hepatocytes for 3 h and analyzed the samples on a TripleTOF 5600+ high-resolution mass spectrometer to identify appropriate marker metabolites. Data were acquired via full scan and information-dependent acquisition-triggered product ion scans with mass defect filter. In total, 13 MN-18 metabolites were detected, with the top 3 abundant metabolites being 1-pentyl-1H-indazole-3-carboxylic acid, pentyl-carbonylated MN-18, and naphthalene-hydroxylated MN-18. For 5F-MN-18, 20 metabolites were observed, with the top 3 abundant metabolites being 5'-OH-MN-18, MN-18 pentanoic acid, and 1-(5-fluoropentyl)-1H-indazole-3-carboxylic acid. We have characterized MN-18 and 5F-MN-18 metabolism with human hepatocytes and high-resolution mass spectrometry, and we recommend characteristic major metabolites for clinical and forensic laboratories to identify MN-18 and 5F-MN-18 intake and link observed adverse events to these novel synthetic cannabinoids.


Is cumulated pyrethroid exposure associated with prediabetes? A cross-sectional study.
Pyrethroids are a class of insecticides used widely for vector control programs. Acute pyrethroid poisoning is rare, but well documented, whereas effects of cumulative exposure are insufficiently described, including possible negative effect on glucose regulation. The objective of this study was to investigate an association between exposure to pyrethroids and abnormal glucose regulation (prediabetes or diabetes). A cross-sectional study was performed among 116 pesticide sprayers from public vector control programs in Bolivia and 92 nonexposed controls. Pesticide exposure (duration, intensity, cumulative exposure) was assessed from questionnaire data. Participants were asked about symptoms of diabetes. Blood samples were analyzed for glycosylated hemoglobin (HbA1c), a measure of glucose regulation. No association was found between pyrethroid exposure and diabetes symptoms. The prevalence of abnormal glucose regulation (defined as HbA1c ≥ 5.6%) was 61.1% among sprayers and 7.9% among nonexposed controls, corresponding to an adjusted odds ratio (OR [95% confidence interval]) for all sprayers of 11.8 [4.2-33.2] and 18.5 [5.5-62.5] for pyrethroid-exposed only. Among sprayers who had only used pyrethroids, a significant positive trend was observed between cumulative pesticide exposure (total number of hours sprayed) and adjusted OR of abnormal glucose regulation, with OR 14.7 [0.9-235] in the third exposure quintile. The study found a severely increased prevalence of prediabetes among Bolivian pesticide sprayers compared with a control group, but the relevance of the control group is critical. Within the spraying group, an association between cumulative exposure to pyrethroids and abnormal glucose regulation was seen. Further studies are needed to confirm this association.


Effect of glandular kallikrein on renin release in isolated rat glomeruli.
Numerous studies have suggested that a functional relationship may exist between the kallikrein-kinin and the renin-angiotensin systems within the kidney. We investigated the effects of glandular kallikrein on renin release by using an in vitro preparation of isolated rat glomeruli with their attendant arterioles. The effect of kallikrein was studied in the presence or absence of 0.1% bovine serum albumin (BSA) in Krebs superfusion fluid. We also studied the effect of inactivating kallikrein by treatment with phenylmethylsulfonyl fluoride or by inhibiting it with aprotinin. In the absence of BSA, kallikrein caused a 12-fold increase in renin release, from 5.1 +/- 1.2 ng angiotensin I (ANG I)/min to 66.0 +/- 2.27 ng ANG I/min (p less than 0.025). In the presence of BSA, renin release increased twofold, from 13.0 +/- 1.8 ng ANG I/min to 24.3 +/- 4.8 ng ANG I/min (p less than 0.025). The basal level of renin measured when the glomeruli were superfused with BSA-Krebs was two to three times greater than when they were superfused with Krebs alone (p less than 0.001). This finding suggests that media protein inhibited renin loss during either the superfusion or storage of renin samples. Neither phenylmethylsulfonyl fluoride-inactivated nor aprotinin-inhibited kallikrein stimulated renin release. We propose that kallikrein can stimulate renin release in isolated glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)


Liquid calories and the failure of satiety: how good is the evidence?
Increasing rates of obesity and overweight have been attributed to the growing proportion of dietary energy that is consumed in liquid form. Liquids reportedly fail to trigger physiological satiety mechanisms so that compensation for energy consumed as beverages may be imprecise and incomplete. Sweetened beverages have come under particular scrutiny, as their consumption exceeds that of milk and fruit and vegetable juices. However, the evidence that liquids have less impact on satiety than do solid foods remains inconclusive. Some published studies have reported that liquids are less satiating than solids, whereas other studies have reported that solids are less satiating than liquids. In laboratory studies, the degree of energy compensation following pre-load ingestion was influenced by subject characteristics, pre-load volume, or the time lag between the pre-load and the next meal. Such factors appear to interact with pre-load texture in their impact on hunger and satiety and later food consumption.


Changes in Pre- and Post-Exercise Gene Expression among Patients with Chronic Kidney Disease and Kidney Transplant Recipients.
Decreased insulin sensitivity blunts the normal increase in gene expression from skeletal muscle after exercise. In addition, chronic inflammation decreases insulin sensitivity. Chronic kidney disease (CKD) is an inflammatory state. How CKD and, subsequently, kidney transplantation affects skeletal muscle gene expression after exercise are unknown. Study cohort: non-diabetic male/female 4/1, age 52±2 years, with end-stage CKD who underwent successful kidney transplantation. The following were measured both pre-transplant and post-transplant and compared to normals: Inflammatory markers, euglycemic insulin clamp studies determine insulin sensitivity, and skeletal muscle biopsies performed before and within 30 minutes after an acute exercise protocol. Microarray analyses were performed on the skeletal muscle using the 4x44K Whole Human Genome Microarrays. Since nuclear factor of activated T cells (NFAT) plays an important role in T cell activation and calcineurin inhibitors are mainstay immunosuppression, calcineurin/NFAT pathway gene expression was compared at rest and after exercise. Log transformation was performed to prevent skewing of data and regression analyses comparing measures pre- and post-transplant performed. Markers of inflammation significantly improved post-transplantation. Insulin infusion raised glucose disposal slightly lower post-transplant compared to pre-transplant, but not significantly, thus concluding differences in insulin sensitivity were similar. The overall pattern of gene expression in response to exercise was reduced both pre-and post-transplant compared to healthy volunteers. Although significant changes were observed among NFAT/Calcineurin gene at rest and after exercise in normal cohort, there were no significant differences comparing NFAT/calcineurin pathway gene expression pre- and post-transplant. Despite an improvement in serum inflammatory markers, no significant differences in glucose disposal were observed post-transplant. The reduced skeletal muscle gene expression, including NFAT/calcineurin gene expression, in response to a single bout of exercise was not improved post-transplant. This study suggests that the improvements in inflammatory mediators post-transplant are unrelated to changes of NFAT/calcineurin gene expression.


Characterization of Macrophage/Microglial Activation and Effect of Photobiomodulation in the Spared Nerve Injury Model of Neuropathic Pain.
Neuropathic pain is common and debilitating with limited effective treatments. Macrophage/microglial activation along ascending somatosensory pathways following peripheral nerve injury facilitates neuropathic pain. However, polarization of macrophages/microglia in neuropathic pain is not well understood. Photobiomodulation treatment has been used to decrease neuropathic pain, has anti-inflammatory effects in spinal injury and wound healing models, and modulates microglial polarization in vitro. Our aim was to characterize macrophage/microglia response after peripheral nerve injury and modulate the response with photobiomodulation. Adult male Sprague-Dawley rats were randomly assigned to sham (N = 13), spared nerve injury (N = 13), or injury + photobiomodulation treatment groups (N = 7). Mechanical hypersensitivity was assessed with electronic von Frey. Photobiomodulation (980 nm) was applied to affected hind paw (output power 1 W, 20 s, 41cm above skin, power density 43.25 mW/cm 2 , dose 20 J), dorsal root ganglia (output power 4.5W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 85.5 J), and spinal cord regions (output power 1.5 W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 28.5 J) every other day from day 7-30 post-operatively. Immunohistochemistry characterized macrophage/microglial activation. Injured groups demonstrated mechanical hypersensitivity 1-30 days post-operatively. Photobiomodulation-treated animals began to recover after two treatments; at day 26, mechanical sensitivity reached baseline. Peripheral nerve injury caused region-specific macrophages/microglia activation along spinothalamic and dorsal-column medial lemniscus pathways. A pro-inflammatory microglial marker was expressed in the spinal cord of injured rats compared to photobiomodulation-treated and sham group. Photobiomodulation-treated dorsal root ganglion macrophages expressed anti-inflammatory markers. Photobiomodulation effectively reduced mechanical hypersensitivity, potentially through modulating macrophage/microglial activation to an anti-inflammatory phenotype.


The Role of Biofilms Developed under Different Anthropogenic Pressure on Recruitment of Macro-Invertebrates.
Microbial biofilms can be key mediators for settlement of macrofoulers. The present study examines the coupled effects of microbial biofilms and local environmental conditions on the composition, structure and functioning of macrofouling assemblages. Settlement of invertebrates over a gradient of human-impacted sites was investigated on local biofilms and on biofilms developed in marine protected areas (MPAs). Special attention was given to the presence of non-indigenous species (NIS), a global problem that can cause important impacts on local assemblages. In general, the formation of macrofouling assemblages was influenced by the identity of the biofilm. However, these relationships varied across levels of anthropogenic pressure, possibly influenced by environmental conditions and the propagule pressure locally available. While the NIS Watersipora subatra seemed to be inhibited by the biofilm developed in the MPA, Diplosoma cf. listerianum seemed to be attracted by biofilm developed in the MPA only under mid anthropogenic pressure. The obtained information is critical for marine environmental management, urgently needed for the establishment of prevention and control mechanisms to minimize the settlement of NIS and mitigate their threats.


Mineralogical and chemical characterization of iron-, manganese-, and copper-containing synthetic hydroxyapatites.
The National Aeronautics and Space Administration's (NASA) Advanced Life Support (ALS) Program is evaluating the use of Fe-, Mn-, and Cu-containing synthetic hydroxyapatite (SHA) as a slow release fertilizer for crops that might be grown on the International Space Station or at Lunar and Martian outposts. Separate Fe-, Mn-, and Cu-containing SHA materials along with a transition-metal free SHA (pure-SHA) were synthesized using a precipitation method. Chemical and mineralogical analyses determined if and how Fe, Mn, and Cu were incorporated into the SHA structure. X-ray diffraction (XRD), Rietveld refinement, and transmission electron microscopy (TEM) confirmed that SHA materials with the apatite structure were produced. Chemical analyses indicated that the metal containing SHA materials were deficient in Ca relative to pure-SHA. The shift in the infrared PO4-mu 3 vibrations, smaller unit cell parameters, smaller particle size, and greater structural strain for Fe-, Mn-, and Cu-containing SHA compared with pure-SHA suggested that Fe, Mn, and Cu were incorporated into SHA structure. Rietveld analyses revealed that Fe, Mn, and Cu substituted into the Ca2 site of SHA. An Fe-rich phase was detected by TEM analyses and backscattered electron microscopy in the Fe-containing SHA material with the greatest Fe content. The substitution of metals into SHA suggests that metal-SHA materials are potential slow-release sources of micronutrients for plant uptake in addition to Ca and P.


Effects of hypothyroidism and hypertension on myocardial perfusion and vascularity in rabbits.
We considered the role of thyroid hormones in the growth of the coronary microvasculature during various levels of afterload. Arterial pressure was increased for 3 mo in hypothyroid and euthyroid rabbits via the Page (1-kidney, 1-wrap) method. Systolic pressures (mmHg +/- SE) indicated that the groups could be characterized as follows: euthyroid sham normotensive (103 +/- 5), euthyroid Page hypertensive (158 +/- 24), hypothyroid Page normotensive (110 +/- 5), and hypothyroid sham hypotensive (87 +/- 5). The hypothyroid groups were characterized by bradycardia. Left ventricular weight-to-body weight ratios were higher in the Page groups than in the controls. Minimal coronary vascular resistance (MCVR) was elevated in the euthyroid Page group but was not affected by hypothyroidism. Lumen diameters of the major resistance vessels tended to be larger in the hypertensive rabbits. Capillary length density was greater in the hypothyroid than in the euthyroid groups. We conclude that 1) the elevated MCVR in the hypertensive rabbits is due mainly to a failure of the major resistance vessels to increase in size or number rather than to a decrease in vascular lumen diameter, and 2) hypothyroidism does not affect maximal myocardial perfusion or lumen diameter of resistance vessels but facilitates capillary growth. The latter may be due to the presence of bradycardia.


Prevalence of Peri-implant Disease According to Periodontal Probing Depth and Bleeding on Probing: A Systematic Review and Meta-Analysis.
To compare changes in the prevalence of peri-implantitis when the unit of analysis is the subject and when the unit of analysis is the implant, by means of meta-analysis with subgroup and sensitivity analyses, according to the case definition and cutoffs. Periodontal probing depth (PPD) and bleeding on probing (BOP) were considered the primary variables. Electronic and manual searches of observational studies of implants with loading of more than 6 months were conducted. The quality of the studies was evaluated, and finally, a description (qualitative analysis) and a meta-analysis (quantitative analysis) of the available studies were performed. Fifty-five studies were included in this systematic review, 32 of which met the criteria for evaluation of disease based on PPD and BOP. A total of 2,734 subjects and 7,849 implants were evaluated. The prevalence of peri-implantitis, defined by PPD and BOP, was 17% when the unit of analysis was the subject, and 11% when it was the implant. If the clinical criterion was PPD ≥ 4 mm, the prevalence by subject was 34% and by implant 11%. If PPD was ≥ 5 mm, the prevalence by subject was 12% and by implant 10%. Finally, if the clinical criterion was PPD ≥ 6 mm, the prevalence by subject was 18% and by implant 10%. The prevalence of peri-implantitis is influenced by the criteria used for the case definition, and the true prevalence may currently be incorrectly estimated.


Transient inhibition of the human motor cortex by capsaicin-induced pain. A study with transcranial magnetic stimulation.
Motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) of the left motor cortex were recorded from the right first dorsal interosseous (FDI), abductor pollicis brevis (APB), abductor digiti minimi (ADM), flexor carpi radialis (FCR), extensor carpi radialis (ECR) in 17 normal subjects, before and after painful application of capsaicin on the skin overlying the right FDI and FCR muscles. The amplitude of MEPs from the FDI and FCR was significantly reduced from 20 to 30 min after the application of capsaicin over the FDI and FCR muscles, respectively, then progressively returned to the basal values. A similar trend of MEPs inhibition was observed for APB and FCR muscles, but this reduction was not significant. Indices of peripheral nerve (M-wave) and spinal cord excitability (F and H waves) did not change throughout the experiments. Motor cortex inhibition induced by tonic cutaneous pain is maximal to muscles adjacent to the painful area. This inhibition may be due to the activation of the C fibres which mediate 'slow' nociception and might be important to alert subject to possible phasic nociceptive events that may occur close to the painful area.


Application of mesenchymal stem cells in bone regenerative procedures in oral implantology. A literature review.
The aim of this work was to review de literature about the role of mesenchymal stem cells in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration. [corrected] A bibliographic search was carried out in PUBMED with a combination of different key words. Animal and human studies that assessed histomorphometrically the influence of mesenchymal stem cells on bone regeneration procedures in oral implantology surgeries were examined. Reults: - Alveolar regeneration: Different controlled histomorphometric animal studies showed that bone regeneration is faster using stem cells seeded in scaffolds than using scaffolds or platelet rich plasma alone. Human studies revealed that stem cells increase bone regeneration. - Maxillary sinus lift: Controlled studies in animals and in humans showed higher bone regeneration applying stem cells compared with controls. - Periimplantary bone regeneration and alveolar distraction: Studies in animals showed higher regeneration when stem cells are used. In humans, no evidence of applying mesenchymal stem cells in these regeneration procedures was found. Stem cells may promote bone regeneration and be useful in bone regenerative procedures in oral implantology, but no firm conclusions can be drawn from the rather limited clinical studies so far performed. Key words:Mesenchymal stem cells, bone regeneration, dental implants, oral surgery, tissue engineering.


Survival of knee arthroplasties for rheumatoid arthritis.
During a 15-year period, 498 primary knee arthroplasties for chronic rheumatoid and related arthritides were performed. Ninety arthroplasties where prosthetic components were added, removed or replaced were recorded as failures. Eighty-one revisions were exchange arthroplasties, eight attempted arthrodeses and one an above-the-knee amputation. Survival rates were calculated with a life table technique. The cumulative 5-year survival rate was 76 per cent for tibial hemiprostheses, 78 per cent for unicompartment prostheses, 100 per cent for tricompartment prostheses, 87 per cent for stabilized prostheses and 84 per cent for hinge prostheses. Continuous deterioration was observed in the tibial hemiprostheses. The improved surgical technique, with guide instruments and release procedures for better alignment and stability, and to some extent the improved prosthetic design may explain the good early results with tricompartment prostheses.


The Influence of Data Resolution on Predicted Distribution and Estimates of Extent of Current Protection of Three 'Listed' Deep-Sea Habitats.
Modelling approaches have the potential to significantly contribute to the spatial management of the deep-sea ecosystem in a cost effective manner. However, we currently have little understanding of the accuracy of such models, developed using limited data, of varying resolution. The aim of this study was to investigate the performance of predictive models constructed using non-simulated (real world) data of different resolution. Predicted distribution maps for three deep-sea habitats were constructed using MaxEnt modelling methods using high resolution multibeam bathymetric data and associated terrain derived variables as predictors. Model performance was evaluated using repeated 75/25 training/test data partitions using AUC and threshold-dependent assessment methods. The overall extent and distribution of each habitat, and the percentage contained within an existing MPA network were quantified and compared to results from low resolution GEBCO models. Predicted spatial extent for scleractinian coral reef and Syringammina fragilissima aggregations decreased with an increase in model resolution, whereas Pheronema carpenteri total suitable area increased. Distinct differences in predicted habitat distribution were observed for all three habitats. Estimates of habitat extent contained within the MPA network all increased when modelled at fine scale. High resolution models performed better than low resolution models according to threshold-dependent evaluation. We recommend the use of high resolution multibeam bathymetry data over low resolution bathymetry data for use in modelling approaches. We do not recommend the use of predictive models to produce absolute values of habitat extent, but likely areas of suitable habitat. Assessments of MPA network effectiveness based on calculations of percentage area protection (policy driven conservation targets) from low resolution models are likely to be fit for purpose.


Chemo- and site-selective derivatizations of natural products enabling biological studies.
Bioactive natural products and derivatives remain an enduring starting point for the discovery of new cellular targets for disease intervention and lead compounds for the development of new therapeutic agents. The former goal is accomplished through the synthesis of bioactive cellular probes from natural products, enabling insights into the mechanism of action of these natural products by classical affinity chromatography or more recent proteome profiling methods. However, the direct and selective modification of native natural products for these purposes remains a challenge due to the structural complexity and the wide functional group diversity found in these natural substances. The lack of selective synthetic methods available to directly manipulate unprotected complex small molecules, in particular to perform structure-activity relationship studies and prepare appropriate cellular probes, has recently begun to be addressed, benefitting from the broader emerging area of chemoselective synthetic methodology. Thus, new reagents, catalysts and reaction processes are enabling both chemo- and site-selective modifications of complex, native natural products. In this review, we describe selected recent examples of these functionalization strategies in this emerging area.


Distribution patterns of hepatitis B surface antigen (HBsAg) in the liver of hepatitis patients.
One hundred liver biopsies from 100 hepatitis patients were examined by the indirect immunofluorescent technique for the detection of HBsAg. Of the 60 positive specimens 52 were diagnosed as various types of chronic hepatitis and 8 were acute hepatitis. Four main distribution patterns of HBsAg were obtained: full cytoplasmic fluorescence with diffuse lobular distribution; cytoplasmic fluorescence with spotty distribution; peripheral fluorescence in the cell membrane and/or cell peripheries; and focal cytoplasmic positivity. There was an inverse relationship between the number of positive hepatocytes and the extent of liver cell necrosis. The distribution patterns of HBsAg were distinctive in each type of chronic hepatitis and in acute hepatitis. Homogeneous full cytoplasmic fluorescence, distributed diffusely in the whole liver lobule, was observed in chronic persistent hepatitis and in cirrhosis with little activity whereas peripheral liver cell membrane and/or peripheral cytoplasmic fluorescence associated with cytoplasmic positivity in a smaller number of hepatocytes was a characteristic finding in chronic aggressive hepatitis, active cirrhosis, and acute hepatitis with possible transition to chronicity. Focal cytoplasmic fluorescence was observed in acute hepatitis and a group of biopsies in chronic hepatitis in which HBsAg was detected in the liver but no antigen was detectable in the serum. The results show that the different patterns of distribution of HBsAg in the liver biopsy are helpful for the histological diagnosis of different types of HBAg positive viral hepatitis and are consistent with the hypothesis of the role of specific immune response in the pathogenesis of type B viral hepatitis.


Fine structure of changes produced in cultured cells sampled at specified intervals during a single growth cycle of polio virus.
Primary suspended cultures of rhesus monkey kidney cells were infected with poliomyelitis virus, type 1 (Brunhilde strain). The release of virus from these cells over a one-step growth curve was correlated with their change in fine structure, as seen in the electron microscope. Most of the cells were infected nearly simultaneously, and morphological changes developed in the cells were sufficiently synchronous to be classified into three stages. The earliest change (stage I) became visible at a time when virus release into the culture fluid begins, some 3 hours after adsorption. Accentuation of the abnormal characteristics soon occurs, at 4 to 7 hours after adsorption, and results in stage II. Stage III represents the appearance of cells after their rate of virus release had passed its maximum, and probably the abnormal morphology of these cells reflects non-specific physiological damage. There seems to be consistency between the previously described cellular changes as seen under the light microscope and the finer scale changes reported here. Cytoplasmic bodies, called U bodies, were seen in large number at the time when the virus release was the most rapid (stage II). While these bodies are not of proper size to be considered polio virus, they seem to be specifically related to the infection. No evidence was found for the presence of particles that could even be presumptively identified with those of polio virus.


The use of zygomatic implants for the rehabilitation of atrophic maxillas with 2 different techniques: Stella and Extrasinus.
The zygomatic implant anchorage is a surgical technique that provides a new perspective for patients with severe maxillary atrophy, increasing predictability and reduced cost of treatment, besides being a tool for the hardships of the rehabilitation of such a challenging region. This article describes 2 clinical cases with zygomatic implants with different techniques (Stella and Extrasinus) and both with immediate loading and accompanying clinical radiographic follow-up procedures of 12 and 24 months, respectively.


Microholographic multilayer optical disk data storage.
Micrometer-sized reflection holograms can be written into a rapidly rotating homogeneous photopolymer disk at the focus of a high-numerical-aperture beam and its retroreflection to implement high-capacity multilayer digital data storage. This retroreflection is generated by an optical system with positive unity magnification to ensure passive alignment of the counterpropagating beam. Analysis reveals that the storage capacity and transfer rate of this bit-based holographic storage system compare favorably with traditional page-based systems but at a fraction of the system complexity and cost. The analysis is experimentally validated at 532 nm by writing and reading 12 layers of microholograms in a 125-microm photopolymer disk continuously rotating at 3600 rpm. The experimental results predict a capacity limit of 140 Gbytes in a millimeter-thick disk or over 1 Tbyte with the wavelength and numerical aperture of Blu-Ray.


Cooperative computation of stereo disparity.
The extraction of stereo-disparity information from two images depends upon establishing a correspondence between them. In this article we analyze the nature of the correspondence computation and derive a cooperative algorithm that implements it. We show that this algorithm successfully extracts information from random-dot stereograms, and its implications for the psychophysics and neurophysiology of the visual system are briefly discussed.


Dynamic changes in the tear film in dry eyes.
To examine the dynamics of the tear film in patients with dry eye by measuring the wavefront aberrations of the anterior surface of the film. Anterior surface aberrations for a 7-mm pupil were determined in 13 patients with dry eye at 1-second time intervals, for 15 seconds after a blink. The aberrations were calculated from the elevations provided by corneal topography. All data were decomposed using Zernike polynomials. Total, spherical, and comalike aberrations terms were studied separately. Results were compared with those in normal eyes. Outcome measures included comparison with clinical tear breakup time measurements. The total root mean square (RMS) wavefront aberration in patients with dry eye passed through in a minimum of 2.9 +/- 0.4 seconds after a blink in comparison to the minimum at 6.1 +/- 0.5 seconds in normal patients. In both groups, the minimum in total aberration appeared to be associated with similar changes in comalike aberrations, rather than in spherical aberrations, which increased monotonically with time. The time at which minimum RMS aberration occurred correlated reasonably well with the measured tear breakup times. Measurements of the dynamic changes in the optical aberrations introduced by the anterior tear film surface give valuable insights into tear film changes and may provide a convenient objective method for the diagnosis of dry eye.


Beyond language impairment: Profiles of apathy in primary progressive aphasia.
Primary progressive aphasia (PPA) is characterised by predominant language and communication impairment. However, behavioural changes, such as apathy, are increasingly recognised. Apathy is defined as a reduction in motivation and goal-directed behaviour. Recent theoretical models have suggested that apathy can be delineated into multiple dimensions: executive apathy (i.e., deficits in maintaining goals and organisation), emotional apathy (i.e., emotional blunting and indifference) and initiation apathy (i.e., reduced self-initiation). Whether the nature of apathy differs between clinical variants of PPA, and across early and late disease stages, remains to be established. Here, carers/informants of 20 semantic variant PPA (svPPA), 15 non-fluent variant PPA (nfvPPA), 16 logopenic variant PPA (lvPPA) and 25 healthy older controls completed the Dimensional Apathy Scale to quantify executive, emotional and initiation apathy. Voxel-based morphometry was used to identify associations between dimensions of apathy and regions of grey matter intensity decrease. Our behavioural results showed greater executive and initiation apathy in late svPPA than in late nfvPPA patients, while late svPPA had greater emotional apathy than both late nfvPPA and late lvPPA groups. Executive and initiation apathy were significantly higher than premorbid levels in all PPA subtypes, while elevated emotional apathy was only seen in early and late svPPA. Distinct neural correlates were identified across apathy dimensions. Executive apathy correlated with grey matter intensity of the left dorsolateral prefrontal and inferior parietal cortices; emotional apathy with the left medial prefrontal, insular and cerebellar regions; and initiation apathy with right parietal areas. Our findings are the first to reveal evidence of the dimensional nature of apathy in PPA, with different clinical signatures observed for each subtype. From a clinical standpoint, these results will inform the development of targeted interventions for specific aspects of apathy which emerge in PPA.


Strategies for obtaining unpublished drug trial data: a qualitative interview study.
Authors of systematic reviews have difficulty obtaining unpublished data for their reviews. This project aimed to provide an in-depth description of the experiences of authors in searching for and gaining access to unpublished data for their systematic reviews, and to give guidance on best practices for identifying, obtaining and using unpublished data. This is a qualitative study analyzing in-depth interviews with authors of systematic reviews who have published Cochrane reviews or published systematic reviews outside of The Cochrane Library. We included participants who 1) were the first or senior author of a published systematic review of a drug intervention, 2) had expertise in conducting systematic reviews, searching for data, and assessing methodological biases, and 3) were able to participate in an interview in English. We used non-random sampling techniques to identify potential participants. Eighteen Cochrane authors were contacted and 16 agreed to be interviewed (89% response rate). Twenty-four non-Cochrane authors were contacted and 16 were interviewed (67% response rate). Respondents had different understandings of what was meant by unpublished data, including specific outcomes and methodological details. Contacting study authors was the most common method used to obtain unpublished data and the value of regulatory agencies as a data source was underappreciated. Using the data obtained was time consuming and labor intensive. Respondents described the collaboration with other colleagues and/or students required to organize, manage and use the data in their reviews, generally developing and using templates, spreadsheets and computer programs for data extraction and analysis. Respondents had a shared belief that data should be accessible but some had concerns about sharing their own data. Respondents believed that obtaining unpublished data for reviews has important public health implications. There was widespread support for government intervention to ensure open access to trial data. Respondents uniformly agreed that the benefit of identifying unpublished data was worth the effort and was necessary to identify the true harms and benefits of drugs. Recent actions by government, such as increased availability of trial data from the European Medicines Agency, may make it easier to acquire critical drug trial data.


Vascular air embolism: A silent hazard to patient safety.
To narratively review published information on prevention, detection, pathophysiology, and appropriate treatment of vascular air embolism (VAE). MEDLINE, SCOPUS, Cochrane Central Register and Google Scholar databases were searched for data published through October 2016. The Manufacturer and User Facility Device Experience (MAUDE) database was queried for "air embolism" reports (years 2011-2016). VAE may be introduced through disruption in the integrity of the venous circulation that occurs during insertion, maintenance, or removal of intravenous or central venous catheters. VAE impacts pulmonary circulation, respiratory and cardiac function, systemic inflammation and coagulation, often with serious or fatal consequences. When VAE enters arterial circulation, air emboli affect cerebral blood flow and the central nervous system. New medical devices remove air from intravenous infusions. Early recognition and treatment reduce the clinical sequelae of VAE. An organized team approach to treatment including clinical simulation can facilitate preparedness for VAE. The MAUDE database included 416 injuries and 95 fatalities from VAE. Data from the American Society of Anesthesiologists Closed Claims Project showed 100% of claims for VAE resulted in a median payment of $325,000. VAE is an important and underappreciated complication of surgery, anesthesia and medical procedures.


Comparative pharmacokinetics of intravenous and intramuscular cefquinome sulfate administration in ducklings and goslings.
To compare the pharmacokinetics of cefquinome sulfate in ducklings and goslings after IV or IM administration of a single dose. 216 healthy Muscovy ducklings (Cairina moschata) and 216 healthy Sichuan white goslings (Anser cygnoides). Ducklings and goslings were each randomly assigned to 3 groups (n = 72/group) that received a single dose (2 mg/kg) of injectable cefquinome sulfate administered IV or IM or of injectable cefquinome sulfate suspension administered IM. Blood samples were collected at various points after drug administration (n = 6 birds/time point). Plasma cefquinome concentrations were measured by high-performance liquid chromatography with UV detection, and pharmacokinetic parameters were calculated with a 2-compartment model method. After IV injection, mean distribution half-life of cefquinome was longer in goslings (0.446 hours) than in ducklings (0.019 hours), whereas volume of distribution at steady state was greater (0.432 vs 0.042 L/kg) and elimination half-life was slower (1.737 vs 0.972 hours). After IM administration of injectable cefquinome sulfate, bioavailability of the drug was higher in goslings (113.9%) than in ducklings (67.5%). After IM administration of injectable cefquinome sulfate suspension, bioavailability was also higher in goslings (123.1%) than in ducklings (96.8%), whereas elimination half-life was slower (6.917 vs 1.895 hours, respectively). In goslings, IV administration of cefquinome resulted in slower distribution and metabolism of the drug than in ducklings and IM administration resulted in higher bioavailability. The delayed-release effect of the injectable cefquinome sulfate suspension when administered IM was observed only in goslings.


Efficient cross-species capture hybridization and next-generation sequencing of mitochondrial genomes from noninvasively sampled museum specimens.
The ability to uncover the phylogenetic history of recently extinct species and other species known only from archived museum material has rapidly improved due to the reduced cost and increased sequence capacity of next-generation sequencing technologies. One limitation of these approaches is the difficulty of isolating and sequencing large, orthologous DNA regions across multiple divergent species, which is exacerbated for museum specimens, where DNA quality varies greatly between samples and contamination levels are often high. Here we describe the use of cross-species DNA capture hybridization techniques and next-generation sequencing to selectively isolate and sequence partial to full-length mitochondrial DNA genomes from the degraded DNA of museum specimens, using probes generated from the DNA of a single extant species. We demonstrate our approach on specimens from an enigmatic gliding mammal, the Sunda colugo, which is widely distributed throughout Southeast Asia. We isolated DNA from 13 colugo specimens collected 47-170 years ago, and successfully captured and sequenced mitochondrial DNA from every specimen, frequently recovering fragments with 10%-13% sequence divergence from the capture probe sequence. Phylogenetic results reveal deep genetic divergence among colugos, both within and between the islands of Borneo and Java, as well as between the Malay Peninsula and different Sundaic islands. Our method is based on noninvasive sampling of minute amounts of soft tissue material from museum specimens, leaving the original specimen essentially undamaged. This approach represents a paradigm shift away from standard PCR-based approaches for accessing population genetic and phylogenomic information from poorly known and difficult-to-study species.


Linkage analysis of quantitative traits in an interspecific cross of tomato (lycopersicon esculentum x lycopersicon pimpinellifolium) by means of genetic markers.
Linkage relationships between loci affecting quantitative traits (QTL) and marker loci were examined in an interspecific cross between Lycopersicon esculentum and Lycopersicon pimpinellifolium. Parental lines differed for six morphological markers and for four electrophoretic markers. Almost 1700 F-2 plants were scored with respect to the genetic markers and also with respect to 18 quantitative traits. Major genes affecting the quantitative traits were not found, but out of 180 possible marker x trait combinations, 85 showed significant quantitative effects associated with the genetic markers. The average marker-associated main effect was on the order of 6% of the mean value of the trait. Most of the main effects were apparently due to linkage of QTL to the marker loci rather than to pleiotropy. Fourteen of the traits showed at least one highly significant effect of opposite sign to the overall difference between the parental lines, demonstrating the ability of this design to uncover cryptic genetic variation. Significant variance and skewness effects on the quantitative traits were found to be associated with the genetic markers, suggesting the possible presence of loci affecting the variance and shape of quantitative trait distribution in a population. Most marker-associated quantitative effects showed some degree of dominance, generally in the direction of the L. pimpinellifolium parent. When the significant marker-associated effects were examined in pairs, 12% showed significant interaction effects. The results of this study illustrate the potential usefulness of this type of analysis for the detailed genetic investigation of quantitative trait variation in suitably marked populations.


Genetic variation at the IGF1 locus shows association with post-stroke outcome and to circulating IGF1.
In humans, serum IGF1 (s-IGF1) is associated with outcome after ischemic stroke (IS). Therefore variation at the IGF1 locus could also associate with both IS and s-IGF1. We investigated whether genetic variation at the IGF1 locus is associated with i) s-IGF1, ii) IS occurrence, iii) IS severity, and iv) post-stroke outcome. Patients (n=844; 66% males, mean age 56 years) and community controls (n=668) were included from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Post-stroke outcome was evaluated with the modified Rankin Scale at 3 and 24 months after index stroke, and baseline stroke severity with the Scandinavian Stroke Scale. s-IGF1 was determined in patients and after random selection in 40 of the controls. Eleven single nucleotide polymorphisms (SNPs) were selected in the IGF1 gene. In healthy controls the major allele of rs7136446 was associated with higher s-IGF1, whereas in patients no such association was found. No SNP was associated with IS, nor with stroke severity. After multivariate correction for presence of diabetes, smoking, and hypertension, the major allele of rs7136446 was associated with favorable functional outcome 24-months post-stroke (odds ratio 1.46; 95% CI 1.09-1.96). Variation in rs7136446 of the IGF1 gene associates with post-stroke outcome in relatively young IS patients. Also, rs7136446 associates with s-IGF1 in controls but not in IS, which indicates that IS perturbs a normal genetic impact on s-IGF1 levels.


Prevalidation of salivary biomarkers for oral cancer detection.
Oral cancer is the sixth most common cancer with a 5-year survival rate of approximately 60%. Presently, there are no scientifically credible early detection techniques beyond conventional clinical oral examination. The goal of this study is to validate whether the seven mRNAs and three proteins previously reported as biomarkers are capable of discriminating patients with oral squamous cell carcinomas (OSCC) from healthy subjects in independent cohorts and by a National Cancer Institute (NCI)-Early Detection Research Network (EDRN)-Biomarker Reference Laboratory (BRL). Three hundred and ninety-five subjects from five independent cohorts based on case controlled design were investigated by two independent laboratories, University of California, Los Angeles (Los Angeles, CA) discovery laboratory and NCI-EDRN-BRL. Expression of all seven mRNA and three protein markers was increased in OSCC versus controls in all five cohorts. With respect to individual marker performance across the five cohorts, the increase in interleukin (IL)-8 and subcutaneous adipose tissue (SAT) was statistically significant and they remained top performers across different cohorts in terms of sensitivity and specificity. A previously identified multiple marker model showed an area under the receiver operating characteristic (ROC) curve for prediction of OSCC status ranging from 0.74 to 0.86 across the cohorts. The validation of these biomarkers showed their feasibility in the discrimination of OSCCs from healthy controls. Established assay technologies are robust enough to perform independently. Individual cutoff values for each of these markers and for the combined predictive model need to be further defined in large clinical studies. Salivary proteomic and transcriptomic biomarkers can discriminate oral cancer from control subjects.


ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case-control study.
Carriage of a non-O ABO blood group and colonization by Helicobacter pylori are thought to be risk factors for pancreatic cancer. We examined these associations in a population-based case-control study of 373 case patients and 690 control subjects frequency matched on sex and age. Control subjects were selected by random-digit dialing. Seropositivity for H pylori and its virulence protein CagA was determined by enzyme-linked immunosorbent assay (ELISA). Increased risk of pancreatic cancer was associated with non-O blood group (adjusted odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.02 to 1.83, P = .034) and CagA-negative H pylori seropositivity (OR = 1.68, 95% CI = 1.07 to 2.66, P = .025), but no association was observed for CagA seropositivity (OR = 0.77, 95% CI = 0.52 to 1.16). An association between pancreatic cancer risk and CagA-negative H pylori seropositivity was found among individuals with non-O blood type but not among those with O blood type (OR = 2.78, 95% CI = 1.49 to 5.20, P = .0014; OR = 1.28, 95% CI = 0.62 to 2.64, P = .51, respectively). This study demonstrates an association between pancreatic cancer and H pylori colonization, particularly for individuals with non-O blood types.


Adolescents' experience of complex persistent pain.
Persistent (chronic) pain is a common phenomenon in adolescents. When young people are referred to a pain clinic, they usually have amplified pain signals, with pain syndromes of unconfirmed ethology, such as fibromyalgia and complex regional pain syndrome (CRPS). Pain is complex and seems to be related to a combination of illness, injury, psychological distress, and environmental factors. These young people are found to have higher levels of distress, anxiety, sleep disturbance, and lower mood than their peers and may be in danger of entering adulthood with mental and physical problems. In order to understand the complexity of persistent pain in adolescents, there seems to be a need for further qualitative research into their lived experiences. The aim of this study was to explore adolescents' experiences of complex persistent pain and its impact on everyday life. The study has an exploratory design with individual in-depth interviews with six youths aged 12-19, recruited from a pain clinic at a main referral hospital in Norway. A narrative approach allowed the informants to give voice to their experiences concerning complex persistent pain. A hermeneutic analysis was used, where the research question was the basis for a reflective interpretation. Three main themes were identified: (1) a life with pain and unpleasant bodily expressions; (2) an altered emotional wellbeing; and (3) the struggle to keep up with everyday life. The pain was experienced as extremely strong, emerging from a minor injury or without any obvious causation, and not always being recognised by healthcare providers. The pain intensity increased as the suffering got worse, and the sensation was hard to describe with words. Parts of their body could change in appearance, and some described having pain-attacks or fainting. The feeling of anxiety was strongly connected to the pain. Despair and uncertainty contributed to physical disability, major sleep problems, school absence, and withdrawal from leisure activities. Their parents were supportive, but sometimes more emotionally affected than themselves. The adolescents described how they strived for normality and to not become an outsider. Being met with necessary facilitation from school was important, as well as keeping up with friends. These adolescents had all been treated by an interdisciplinary pain team, and stated that they had an optimistic view of the future, despite still having some symptoms. The study provides new insights into adolescents' own experiences of complex persistent pain occurring unexpectedly, developing dramatically over time, and influencing all parts of their everyday lives. The adolescents entered vicious cycles, with despair and decreased physical and social functioning, with the risk of isolation and role-loss. However, these young people seem to have a strong motivation to strive for normalcy. These findings may encourage healthcare providers to perceive adolescents' persistent pain through the lenses of a biopsychosocial approach. We suggest that further research into adolescents with persistent pain should include longitudinal studies of quality of life and gender perspectives.


Serologic survey of hantavirus in a rural population from the northern State of Mato Grosso, Brazil.
Hantavirus is a genus of ribonucleic acid (RNA) viruses included in the family Bunyaviridae. Hantaviruses are rodent-borne zoonoses that, in the last 18 years, became an emergent public health problem in the Americas, causing a severe cardiopulmonary syndrome. This disease has no specific treatment and has a high case fatality. The transmission of hantavirus to man occurs by inhaling aerosols of rodent excreta. The aim of this study was to determine the prevalence of antibodies to hantavirus in the population of the rural settlement of Tupã in the county of Marcelândia, state of Mato Grosso, Brazil. The participants of the serologic survey were visited at their homes and selected randomly among the settlement population. Blood samples of the participants were collected by venopuncture. The serum samples were tested by an IgG-ELISA using an N recombinant protein of Araraquara hantavirus as antigen, using the protocol previously established by Figueiredo et al. IgG antibodies to hantavirus were detected in 7 (13%) of the 54 participants. The positivity was higher among men. It was observed that there was an association of seropositivity to hantavirus within the participants born in the south of Brazil. The results suggest that, in this rural area, everyone is exposed to the same risk of becoming infected with hantavirus, and, therefore, there is a need to intensify surveillance activities and education of the local people to prevent this viral infection.