Fab-conjugated PLGA nanoparticles effectively target cancer cells expressing human CD44v6.
Targeting of CD44 isoforms containing exon v6 (CD44v6) represents a viable strategy for the therapy and/or early diagnosis of metastatic cancers of the epithelium (e.g. gastric and colorectal cancer). We developed and characterized poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) modified with polyethylene glycol (PEG) and engrafted, by site-directed conjugation, with an engineered human Fab that specifically target human CD44v6 (v6 Fab-PLGA NPs). The v6 Fab-PLGA NPs displayed spherical morphology around 300 nm and were negatively charged. They strongly bound to a CD44v6-derived peptide and, more importantly, to cells that endogenously and exogenously express CD44v6, but not to non-expressing cells and cells expressing the standard isoform of CD44. The v6 Fab-PLGA NPs also recognized CD44v6 in tumor sections from cells grown subcutaneously within mice. The NPs had nominal cytotoxicity at 50 µg/mL and withstood simulated intestinal fluid exposure. Interestingly, v6 Fab-PLGA NPs cryopreserved in 10% trehalose and stored maintained specific cell binding. In conclusion, we envision NPs targeting CD44v6 as potential in vivo diagnostic agents and/or as anti-cancer agents in patients previously stratified with CD44v6+ carcinomas. STATEMENT OF SIGNIFICANCE: The v6 Fab-PLGA NPs displayed many favorable qualities as a potential CD44v6-targeted drug and/or diagnostic delivery agent. The NPs were designed for optimal ligand orientation and for immediate administration into humans. v6 Fab-PLGA NPs strongly bound to cells that endogenously and exogenously express CD44v6, but not to non-expressing cells and cells expressing the standard isoform of CD44. Binding ability was retained after freeze-drying and long-term storage, providing evidences on the stability of Fab-functionalized NPs. These NPs can potentially be used as an in vivo diagnostic from parenteral or oral/rectal administration.


Guidelines for the Treatment of PTSD Using Clinical EFT (Emotional Freedom Techniques).
Clinical EFT (Emotional Freedom Techniques) is an evidence-based method that combines acupressure with elements drawn from cognitive and exposure therapies. The approach has been validated in more than 100 clinical trials. Its efficacy for post-traumatic stress disorder (PTSD) has been investigated in a variety of demographic groups including war veterans, victims of sexual violence, the spouses of PTSD sufferers, motor accident survivors, prisoners, hospital patients, adolescents, and survivors of natural and human-caused disasters. Meta-analyses of EFT for anxiety, depression, and PTSD indicate treatment effects that exceed those of both psychopharmacology and conventional psychotherapy. Studies of EFT in the treatment of PTSD show that (a) time frames for successful treatment generally range from four to 10 sessions; (b) group therapy sessions are effective; (c) comorbid conditions such as anxiety and depression improve simultaneously; (d) the risk of adverse events is low; (e) treatment produces physiological as well as psychological improvements; (f) patient gains persist over time; (g) the approach is cost-effective; (h) biomarkers such as stress hormones and genes are regulated; and (i) the method can be adapted to online and telemedicine applications. This paper recommends guidelines for the use of EFT in treating PTSD derived from the literature and a detailed practitioner survey. It has been reviewed by the major institutions providing training or supporting research in the method. The guidelines recommend a stepped-care model, with five treatment sessions for subclinical PTSD, 10 sessions for PTSD, and escalation to intensive psychotherapy or psychopharmacology or both for nonresponsive patients and those with developmental trauma. Group therapy, social support, apps, and online and telemedicine methods also contribute to a successful treatment plan.


Glimepiride reduces the expression of PrPc, prevents PrPSc formation and protects against prion mediated neurotoxicity in cell lines.
A hallmark of the prion diseases is the conversion of the host-encoded cellular prion protein (PrP(C)) into a disease related, alternatively folded isoform (PrP(Sc)). The accumulation of PrP(Sc) within the brain is associated with synapse loss and ultimately neuronal death. Novel therapeutics are desperately required to treat neurodegenerative diseases including the prion diseases. Treatment with glimepiride, a sulphonylurea approved for the treatment of diabetes mellitus, induced the release of PrP(C) from the surface of prion-infected neuronal cells. The cell surface is a site where PrP(C) molecules may be converted to PrP(Sc) and glimepiride treatment reduced PrP(Sc) formation in three prion infected neuronal cell lines (ScN2a, SMB and ScGT1 cells). Glimepiride also protected cortical and hippocampal neurones against the toxic effects of the prion-derived peptide PrP82-146. Glimepiride treatment significantly reduce both the amount of PrP82-146 that bound to neurones and PrP82-146 induced activation of cytoplasmic phospholipase A(2) (cPLA(2)) and the production of prostaglandin E(2) that is associated with neuronal injury in prion diseases. Our results are consistent with reports that glimepiride activates an endogenous glycosylphosphatidylinositol (GPI)-phospholipase C which reduced PrP(C) expression at the surface of neuronal cells. The effects of glimepiride were reproduced by treatment of cells with phosphatidylinositol-phospholipase C (PI-PLC) and were reversed by co-incubation with p-chloromercuriphenylsulphonate, an inhibitor of endogenous GPI-PLC. Collectively, these results indicate that glimepiride may be a novel treatment to reduce PrP(Sc) formation and neuronal damage in prion diseases.


Atmospheric Carbon and Transport - America (ACT-America) Data Sets: Description, Management, and Delivery.
The ACT-America project is a NASA Earth Venture Suborbital-2 mission designed to study the transport and fluxes of greenhouse gases. The open and freely available ACT-America data sets provide airborne in situ measurements of atmospheric carbon dioxide, methane, trace gases, aerosols, clouds, and meteorological properties, airborne remote sensing measurements of aerosol backscatter, atmospheric boundary layer height and columnar content of atmospheric carbon dioxide, tower-based measurements, and modeled atmospheric mole fractions and regional carbon fluxes of greenhouse gases over the Central and Eastern United States. We conducted 121 research flights during five campaigns in four seasons during 2016-2019 over three regions of the US (Mid-Atlantic, Midwest and South) using two NASA research aircraft (B-200 and C-130). We performed three flight patterns (fair weather, frontal crossings, and OCO-2 underflights) and collected more than 1,140 h of airborne measurements via level-leg flights in the atmospheric boundary layer, lower, and upper free troposphere and vertical profiles spanning these altitudes. We also merged various airborne in situ measurements onto a common standard sampling interval, which brings coherence to the data, creates geolocated data products, and makes it much easier for the users to perform holistic analysis of the ACT-America data products. Here, we report on detailed information of data sets collected, the workflow for data sets including storage and processing of the quality controlled and quality assured harmonized observations, and their archival and formatting for users. Finally, we provide some important information on the dissemination of data products including metadata and highlights of applications of ACT-America data sets.


Media actors' perceptions of their roles in reporting food incidents.
Previous research has shown that the media can play a role in shaping consumer perceptions during a public health crisis. In order for public health professionals to communicate well-informed health information to the media, it is important that they understand how media view their role in transmitting public health information to consumers and decide what information to present. This paper reports the perceptions of media actors from three countries about their role in reporting information during a food incident. This information is used to present ideas and suggestions for public health professionals working with media during food incidents. Thirty three semi-structured interviews with media actors from Australia, New Zealand and the United Kingdom were conducted and analysed thematically. Media actors were recruited via purposive sampling using a sampling strategy, from a variety of formats including newspaper, television, radio and online. Media actors said that during a food incident, they play two roles. First, they play a role in communicating information to consumers by acting as a conduit for information between the public and the relevant authorities. Second, they play a role as investigators by acting as a public watchdog. Media actors are an important source of consumer information during food incidents. Public health professionals can work with media by actively approaching them with information about food incidents; promoting to media that as public health professionals, they are best placed to provide the facts about food incidents; and by providing angles for further investigation and directing media to relevant and correct information to inform such investigations. Public health professionals who adapt how they work with media are more likely to influence media to portray messages that fit what they would like the public to know and that are in line with public health recommendations and enable consumers to engage in safe and health promoting behaviours in response to food incidents.


Impact of selective alveolar decortication on bisphosphonate burdened alveolar bone during orthodontic tooth movement.
To investigate the effect of Selective Alveolar Decortication (SADc) facilitated orthodontic tooth movement (OTM) on bisphosphonate burdened alveolar bone in a rodent model. OTM was accomplished by protraction of the maxillary right first molars. Four groups were included of which two groups were pre-treated for three months with alendronate sodium (BP+TM+SADc and BP+TM group) and two groups were given saline (TM+SADc and TM group). Selective alveolar decortication surgery was performed on day 1 of appliance insertion. OTM measurements were obtained at 0, 4, and 8 weeks using in-vivo μCT. Tissues were analysed by histology and EPMA. Tooth movement of 0.39 mm and 0.75 mm in the BP+TM+SADc group at 4 and 8 weeks respectively was achieved with 113% increase in tooth movement compared to BP+TM group at 4 weeks. In comparison, SADc+TM group showed 0.63 mm and 2.1 mm of tooth movement at 4 weeks and 8 weeks respectively with only 6% increase at 4 weeks and 2% increase at 8 weeks compared to TM group. Severe interproximal and buccal bone loss around the first permanent molar in the BP+TM+SADc group was seen with μCT imaging and histology. Animals in BP+TM+SADc group histologically showed signs of osteonecrotic bone with irregular borders, loss of osteocytes and absence of osteocytic lacunae. This study demonstrated selective alveolar decortication accelerates tooth movement in a bisphosphonate burdened alveolar bone in the short term but the potential of such an invasive injury can have adverse effects.


Change in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics.
When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes. This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time. Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 ± 1.19, RISP = -0.03 ± 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 ± 1.38, ZIP = 0.25 ± 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ = -0.31 ± 1.59, HAL = -0.69 ± 1.56, p = 0.011) and over the long-term (OLZ = 0.10 ± 1.50, HAL = -0.32 ± 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or haloperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS). Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy. clinicaltrials.gov identifier NCT00088049; NCT00036088.


Protocol for the study of cervical cancer screening technologies in HIV-infected women living in Rwanda.
The optimal method(s) for screening HIV-infected women, especially for those living in sub-Saharan Africa, for cervical precancer and early cancer has yet to be established. A convenience sample of >5000 Rwandan women, ages 30-54 years and living with HIV infection, is being consented and enroled into a cross-sectional study of cervical cancer screening strategies. Participants are completing an administered short risk factor questionnaire and being screened for high-risk human papillomavirus (hrHPV) using the Xpert HPV assay (Cepheid, Sunnyvale, California, USA), unaided visual inspection after acetic acid (VIA) and aided VIA using the Enhanced Visual Assessment (EVA) system (Mobile ODT, Tel Aviv, Israel). Women positive for hrHPV and/or by unaided VIA undergo colposcopy, which includes the collection of two cervical specimens prior to undergoing a four-quadrant microbiopsy protocol. The colposcopy-collected specimens are being tested by dual immunocytochemical staining for p16INK4a and Ki-67 (CINtec PLUS Cytology, Ventana, Tucson, Arizona, USA) and for E6 or E7 oncoprotein for 8 hrHPV genotypes (HPV16, 18, 31, 33, 35, 45, 52 and 58) using the next-generation AV Avantage hrHPV E6/E7 test (Arbor Vita Corporation, Freemont, California, USA). Women with a local pathology diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+) or pathology review diagnosis of CIN grade three or more severe (CIN3+) will receive treatment. Clinical performance and cost-effectiveness (eg, sensitivity, specificity and predictive values) of different screening strategies and algorithms will be evaluated. The protocol was approved by local and institutional review boards for human subjects research. At the completion of the study, results will be disseminated to the scientific community through peer-reviewed publication and to the Rwandan stakeholders through an external advisory panel.


The mechanism underlying the central glucagon-induced hyperglycemia and anorexia in chicks.
We investigated the mechanism underlying central glucagon-induced hyperglycemia and anorexia in chicks. Male 8-day-old chicks (Gallus gallus) were used in all experiments. Intracerebroventricular administration of glucagon in chicks induced hyperglycemia and anorexia from 30 min after administration. However, the plasma insulin level did not increase until 90 min after glucagon administration, suggesting that glucose-stimulated insulin secretion from pancreatic beta cells may be suppressed by central glucagon. The plasma corticosterone concentration significantly increased from 30 min to 120 min after administration, suggesting that central glucagon activates the hypothalamic pituitary adrenal (HPA) axis in chicks. However, central administration of corticotropin-releasing factor (CRF), which activates the HPA axis in chicken hypothalamus, significantly reduced not only food intake but also plasma glucose concentration, suggesting that CRF and the activation of the HPA axis are related to the glucagon-induced anorexia but not hyperglycemia in chicks. Phentolamine, an α-adrenergic receptor antagonist, significantly attenuated the glucagon-induced hyperglycemia, suggesting that glucagon induced hyperglycemia at least partly via α-adrenergic neural pathway. Co-administration of phentolamine and α-helical CRF, a CRF receptor antagonist, significantly attenuated glucagon-induced hyperglycemia and anorexia. It is therefore likely that central administration of glucagon suppresses food intake at least partly via CRF-induced anorexigenic pathway in chicks.


Genomics of bacterial and archaeal viruses: dynamics within the prokaryotic virosphere.
Prokaryotes, bacteria and archaea, are the most abundant cellular organisms among those sharing the planet Earth with human beings (among others). However, numerous ecological studies have revealed that it is actually prokaryotic viruses that predominate on our planet and outnumber their hosts by at least an order of magnitude. An understanding of how this viral domain is organized and what are the mechanisms governing its evolution is therefore of great interest and importance. The vast majority of characterized prokaryotic viruses belong to the order Caudovirales, double-stranded DNA (dsDNA) bacteriophages with tails. Consequently, these viruses have been studied (and reviewed) extensively from both genomic and functional perspectives. However, albeit numerous, tailed phages represent only a minor fraction of the prokaryotic virus diversity. Therefore, the knowledge which has been generated for this viral system does not offer a comprehensive view of the prokaryotic virosphere. In this review, we discuss all families of bacterial and archaeal viruses that contain more than one characterized member and for which evolutionary conclusions can be attempted by use of comparative genomic analysis. We focus on the molecular mechanisms of their genome evolution as well as on the relationships between different viral groups and plasmids. It becomes clear that evolutionary mechanisms shaping the genomes of prokaryotic viruses vary between different families and depend on the type of the nucleic acid, characteristics of the virion structure, as well as the mode of the life cycle. We also point out that horizontal gene transfer is not equally prevalent in different virus families and is not uniformly unrestricted for diverse viral functions.


Beam monitoring system for simultaneous measurement of near and far field patterns in high repetition rate KrF lasers.
A computer-controlled beam monitoring system for KrF excimer lasers was developed for simultaneous measurement of near and far field patterns and pointing stability of the laser beam at a 250 Hz repetition rate. The system and results obtained are described.


Supervised practice program guided by the Accreditation Council for Education in Nutrition and Dietetics standards improves potential employability of nutrition/dietetics graduates: perspective of employers and preceptors.
This study investigated employers' perspectives on the impact of a supervised practice program (SPP), guided by international accreditation standards on the skill development and potential employability of dietetics students. This study was based on qualitative research. Fifteen potential employers, who also served as SPP preceptors, participated in this study. Participants were interviewed using semi-structured questionnaire. All interviews were conducted face-to-face by a trained interviewer. Participates were invited to discuss their own experiences in the current SPP, their perceptions of the impact of SPP on skills and attributes of graduates, and their overall ideas of how SPP may contribute to the employability of graduates. This study found that the SPP program guided by international accreditation standards shaped the duties and responsibilities of preceptors/supervisors and promoted a beneficial relationship between preceptors and SPP students. The benefits to graduates include bridging the gap between classroom didactic knowledge and practice; improving workplace self-confidence; developing competencies such as critical-thinking, communication, interviewing, and counselling skills in various multidisciplinary and multicultural settings. In addition, the preceptors suggested that accreditation-guided SPP contributes to the employability of graduates. Also, they opined that it reduced the need for orientation and shortened the probation time because students were familiar with the work environment and work flow. This lead to the improved preparedness for work. SPP based on set of competencies guided by international accreditation standards provides an up-to-date curriculum, improves the quality of the nutrition and dietetics services, and increases the potential employability of the graduates.


Ploidy Variation in Kluyveromyces marxianus Separates Dairy and Non-dairy Isolates.
Kluyveromyces marxianus is traditionally associated with fermented dairy products, but can also be isolated from diverse non-dairy environments. Because of thermotolerance, rapid growth and other traits, many different strains are being developed for food and industrial applications but there is, as yet, little understanding of the genetic diversity or population genetics of this species. K. marxianus shows a high level of phenotypic variation but the only phenotype that has been clearly linked to a genetic polymorphism is lactose utilisation, which is controlled by variation in the LAC12 gene. The genomes of several strains have been sequenced in recent years and, in this study, we sequenced a further nine strains from different origins. Analysis of the Single Nucleotide Polymorphisms (SNPs) in 14 strains was carried out to examine genome structure and genetic diversity. SNP diversity in K. marxianus is relatively high, with up to 3% DNA sequence divergence between alleles. It was found that the isolates include haploid, diploid, and triploid strains, as shown by both SNP analysis and flow cytometry. Diploids and triploids contain long genomic tracts showing loss of heterozygosity (LOH). All six isolates from dairy environments were diploid or triploid, whereas 6 out 7 isolates from non-dairy environment were haploid. This also correlated with the presence of functional LAC12 alleles only in dairy haplotypes. The diploids were hybrids between a non-dairy and a dairy haplotype, whereas triploids included three copies of a dairy haplotype.


Superoxide induced by a high-glucose concentration attenuates production of angiogenic growth factors in hypoxic mouse mesenchymal stem cells.
Previous reports have shown that the paracrine system may be an important mediator in bone-marrow-derived mesenchymal stem cell (MSC) therapy for ischemic diseases. Hyperglycemia and hypoxia have been associated with increased levels of reactive oxygen species; oxidative stress may therefore influence the paracrine effects of MSCs under hypoxic conditions in diabetic patients, although the mechanism underlying this effect remains unknown. Hypoxia-inducible factor 1α (HIF-1α) regulates the transcription of hypoxia-inducible genes. We determined the effect of high-glucose concentrations on the production of angiogenic growth factors via HIF-1α induction in hypoxic MSCs. MSCs were cultured with different glucose concentration (5.6, 11, 20, or 30 mM) for 24 h. The cells were then incubated in a hypoxic chamber (5% O₂) or under normoxia (21% O₂) for 6 or 24 h. Protein levels of HIF-1α, vascular endothelial growth factor A₁₆₅ (VEGF-A₁₆₅), and platelet-derived growth factor B (PDGF-B) were attenuated by glucose in hypoxic MSCs in a dose-dependent manner. Treatment with MG132, a specific inhibitor of proteasome activity, significantly reversed the inhibitory effect of high-glucose concentrations in hypoxic MSCs. 4-Hydroxyl-tetramethylpiperidin-oxyl (a cell-permeable superoxide scavenger) or Apocynin (a NADPH oxidase inhibitor) significantly reversed glucose-induced attenuation of VEGF-A₁₆₅, PDGF-B, and HIF-1α protein levels. Stimulation with a high-glucose concentration (30 mM) significantly increased intracellular superoxide levels in hypoxic MSCs. Our results suggest that in hypoxic MSCs the increase in intracellular superoxide levels induced by high-glucose concentrations may attenuate hypoxia-induced HIF-1α expression, which in turn attenuates hypoxia-induced VEGF-A₁₆₅ and PDGF-B transcription.


Peripheral vascular decoupling in porcine endotoxic shock.
Cardiac output measurement from arterial pressure waveforms presumes a defined relationship between the arterial pulse pressure (PP), vascular compliance (C), and resistance (R). Cardiac output estimates degrade if these assumptions are incorrect. We hypothesized that sepsis would differentially alter central and peripheral vasomotor tone, decoupling the usual pressure wave propagation from central to peripheral sites. We assessed arterial input impedance (Z), C, and R from central and peripheral arterial pressures, and aortic blood flow in an anesthetized porcine model (n = 19) of fluid resuscitated endotoxic shock induced by endotoxin infusion (7 μg·kg⁻¹·h⁻¹ increased to 14 and 20 μg·kg⁻¹·h⁻¹ every 10 min and stopped when mean arterial pressure <40 mmHg or Sv(O₂) < 45%). Aortic, femoral, and radial artery pressures and aortic and radial artery flows were measured. Z was calculated by FFT of flow and pressure data. R and C were derived using a two-element Windkessel model. Arterial PP increased from aortic to femoral and radial sites. During stable endotoxemia with fluid resuscitation, aortic and radial blood flows returned to or exceeded baseline while mean arterial pressure remained similarly decreased at all three sites. However, aortic PP exceeded both femoral and radial arterial PP. Although Z, R, and C derived from aortic and radial pressure and aortic flow were similar during baseline, Z increases and C decreases when derived from aortic pressure whereas Z decreases and C increases when derived from radial pressure, while R decreased similarly with both pressure signals. This central-to-peripheral vascular tone decoupling, as quantified by the difference in calculated Z and C from aortic and radial artery pressure, may explain the decreasing precision of peripheral arterial pressure profile algorithms in assessing cardiac output in septic shock patients and suggests that different algorithms taking this vascular decoupling into account may be necessary to improve their precision in this patient population.


Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses.
The pathophysiology of bipolar disorder is likely to involve both genetic and environmental risk factors. In our study, we aimed to perform a systematic search of environmental risk factors for BD. In addition, we assessed possible hints of bias in this literature, and identified risk factors supported by high epidemiological credibility. We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases up to 7 October 2016 to identify systematic reviews and meta-analyses of observational studies that assessed associations between putative environmental risk factors and BD. For each meta-analysis, we estimated its summary effect size by means of both random- and fixed-effects models, 95% confidence intervals (CIs), the 95% prediction interval, and heterogeneity. Evidence of small-study effects and excess of significance bias was also assessed. Sixteen publications met the inclusion criteria (seven meta-analyses and nine qualitative systematic reviews). Fifty-one unique environmental risk factors for BD were evaluated. Six meta-analyses investigated associations with a risk factor for BD. Only irritable bowel syndrome (IBS) emerged as a risk factor for BD supported by convincing evidence (k=6; odds ratio [OR]=2.48; 95% CI=2.35-2.61; P<.001), and childhood adversity was supported by highly suggestive evidence. Asthma and obesity were risk factors for BD supported by suggestive evidence, and seropositivity to Toxoplasma gondii and a history of head injury were supported by weak evidence. Notwithstanding that several environmental risk factors for BD were identified, few meta-analyses of observational studies were available. Therefore, further well-designed and adequately powered studies are necessary to map the environmental risk factors for BD.


Vasectomy and prostate cancer in US blacks and whites.
A large population-based case-control study was carried out to investigate the association between vasectomy and prostate cancer risk in black and in white men in the United States. Study subjects resided in the geographic areas covered by the population-based cancer registries of the Georgia Center for Cancer Statistics, or the Metropolitan Detroit Cancer Surveillance System, or in 10 counties included in the cancer registry of the New Jersey State Health Department. Cases for this study were men aged 40-79 years identified from pathology and outpatient records at hospitals covered by these registries, newly diagnosed with pathologically confirmed prostate cancer between August 1, 1986, and April 30, 1989. Population controls less than age 65 years were selected at periodic intervals by random digit dialing. Older controls were systematically selected (after a random start) from computerized records of the Health Care Finance Administration. A statistically nonsignificant excess risk (odds ratio (OR) = 1.6, 95% confidence interval (CI) 0.5-4.8) for prostate cancer associated with vasectomy was noted in blacks. Overall, the risk for prostate cancer associated with vasectomy in whites was not elevated (OR = 1.1, 95% CI 0.8-1.7). An increase in risk was found, however, for white men who had had a vasectomy 20 years or more prior to study (OR = 1.7, 95% CI 0.9-3.3) or who had had a vasectomy at less than age 35 years (OR = 2.2, 95% CI 1.0-4.4). For the total study group, the odds ratio associated with men who had a vasectomy 20 or more years prior to study was 1.5 (95% CI 0.8-2.7), and the odds ratio associated with men who had had a vasectomy at less than age 35 years was 2.0 (95% CI 1.0-4.0). Further detailed analysis showed that young age at vasectomy (less than age 35 years) was a more important risk factor than was years since vasectomy.


The feasibility of trace element supplementation for stable operation of wheat stillage-fed biogas tank reactors.
The aim of this study was to investigate the effect of trace element supplementation on operation of wheat stillage-fed biogas tank reactors. The stillage used was a residue from bio-ethanol production, containing high levels of sulfate. In biogas production, high sulfate content has been associated with poor process stability in terms of low methane production and accumulation of process intermediates. However, the results of the present study show that this problem can be overcome by trace element supplementations. Four lab-scale wheat stillage-fed biogas tank reactors were operated for 345 days at a hydraulic retention time of 20 days (37 degrees C). It was concluded that daily supplementation with Co (0.5 mg L(-1)), Ni (0.2 mg L(-1)) and Fe (0.5 g L(-1)) were required for maintaining process stability at the organic loading rate of 4.0 g volatile solids L(-1) day(-1).


Structure from motion with wide circular field of view cameras.
This paper presents a method for fully automatic and robust estimation of two-view geometry, autocalibration, and 3D metric reconstruction from point correspondences in images taken by cameras with wide circular field of view. We focus on cameras which have more than 180 degrees field of view and for which the standard perspective camera model is not sufficient, e.g., the cameras equipped with circular fish-eye lenses Nikon FC-E8 (183 degrees), Sigma 8mm-f4-EX (180 degrees), or with curved conical mirrors. We assume a circular field of view and axially symmetric image projection to autocalibrate the cameras. Many wide field of view cameras can still be modeled by the central projection followed by a nonlinear image mapping. Examples are the above-mentioned fish-eye lenses and properly assembled catadioptric cameras with conical mirrors. We show that epipolar geometry of these cameras can be estimated from a small number of correspondences by solving a polynomial eigenvalue problem. This allows the use of efficient RANSAC robust estimation to find the image projection model, the epipolar geometry, and the selection of true point correspondences from tentative correspondences contaminated by mismatches. Real catadioptric cameras are often slightly noncentral. We show that the proposed autocalibration with approximate central models is usually good enough to get correct point correspondences which can be used with accurate noncentral models in a bundle adjustment to obtain accurate 3D scene reconstruction. Noncentral camera models are dealt with and results are shown for catadioptric cameras with parabolic and spherical mirrors.


Overestimating resistance in field testing of malaria parasites: simple methods for estimating high EC50 values using a Bayesian approach.
Conventional methods of assessing in-vitro antimalarial drug-concentration effect relationships in field testing of fresh isolates assess each parasite isolate individually. This leads to systematic overestimation of EC50 values for the most resistant isolates, and thus overestimation of the degree of resistance. In antimalarial drug-susceptibility studies conducted on the north-western border of Thailand the overestimation of EC50 for the most resistant isolate ranged from 15% for artesunate to 43% for mefloquine. If isolates cannot be stored for re-testing, more accurate estimations of the degree of resistance can be obtained using a Bayesian approach to data analysis which is described here.


Complex protein interactions within the human polyadenylation machinery identify a novel component.
Polyadenylation of mRNA precursors is a two-step reaction requiring multiple protein factors. Cleavage stimulation factor (CstF) is a heterotrimer necessary for the first step, endonucleolytic cleavage, and it plays an important role in determining the efficiency of polyadenylation. Although a considerable amount is known about the RNA binding properties of CstF, the protein-protein interactions required for its assembly and function are poorly understood. We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other. Unexpectedly, small regions of two of the subunits participate in multiple interactions. In CstF-77, a proline-rich domain is necessary not only for binding both other subunits but also for self-association, an interaction consistent with genetic studies in Drosophila. In CstF-64, a small region, highly conserved in metazoa, is responsible for interactions with two proteins, CstF-77 and symplekin, a nuclear protein of previously unknown function. Intriguingly, symplekin has significant similarity to a yeast protein, PTA1, that is a component of the yeast polyadenylation machinery. We show that multiple factors, including CstF, cleavage-polyadenylation specificity factor, and symplekin, can be isolated from cells as part of a large complex. These and other data suggest that symplekin may function in assembly of the polyadenylation machinery.


METS-IR, a novel score to evaluate insulin sensitivity, is predictive of visceral adiposity and incident type 2 diabetes.
We developed a novel non-insulin-based fasting score to evaluate insulin sensitivity validated against the euglycemic-hyperinsulinemic clamp (EHC). We also evaluated its correlation with ectopic fact accumulation and its capacity to predict incident type 2 diabetes mellitus (T2D). The discovery sample was composed by 125 subjects (57 without and 68 with T2D) that underwent an EHC. We defined METS-IR as Ln((2*G0)+TG0)*BMI)/(Ln(HDL-c)) (G0: fasting glucose, TG0: fasting triglycerides, BMI: body mass index, HDL-c: high-density lipoprotein cholesterol), and compared its diagnostic performance against the M-value adjusted by fat-free mass (MFFM) obtained by an EHC. METS-IR was validated in a sample with EHC data, a sample with modified frequently sampled intravenous glucose tolerance test (FSIVGTT) data and a large cohort against HOMA-IR. We evaluated the correlation of the score with intrahepatic and intrapancreatic fat measured using magnetic resonance spectroscopy. Subsequently, we evaluated its ability to predict incident T2D cases in a prospective validation cohort of 6144 subjects. METS-IR demonstrated the better correlation with the MFFM (ρ = -0.622, P < 0.001) and diagnostic performance to detect impaired insulin sensitivity compared to both EHC (AUC: 0.84, 95% CI: 0.78-0.90) and the SI index obtained from the FSIVGTT (AUC: 0.67, 95% CI: 0.53-0.81). METS-IR significantly correlated with intravisceral, intrahepatic and intrapancreatic fat and fasting insulin levels (P < 0.001). After a two-year follow-up, subjects with METS-IR in the highest quartile (>50.39) had the highest adjusted risk to develop T2D (HR: 3.91, 95% CI: 2.25-6.81). Furthermore, subjects with incident T2D had higher baseline METS-IR compared to healthy controls (50.2 ± 10.2 vs 44.7 ± 9.2, P < 0.001). METS-IR is a novel score to evaluate cardiometabolic risk in healthy and at-risk subjects and a promising tool for screening of insulin sensitivity.


The acidic macromolecules in rabbit cortical bone tissue.
Rabbit cortical bone powder was extracted with EDTA solutions at neutral pH and the soluble constituents fractionated by DEAE-cellulose chromatography. The acidic fractions obtained were further investigated by gel chromatography and chemical analysis. Two classes of proteoglycans were present; one containing chondroitin sulphate and the other containing material resembling keratan sulphate mixed with a smaller amount of chondroitin sulphate. Sialoglycoproteins were detected by specific chemical introduction of tritium label into the sialic acid residues of the acidic glycoprotein fraction. Following sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography, the presence of numerous distinct sialoglycoprotein components was demonstrated.


[MSDs and job security of employees aged 50 years and over: a challenge for occupational health and public health].
Work-related musculoskeletal disorders of the upper limbs (MSDs) are the first cause of occupational illness in France, as in Europe. A pilot network for epidemiological surveillance system of MSDs has been implemented in France's Loire Valley region to assess the prevalence of MSDs and their risk factors in the working population, namely the ageing workforce. The surveillance was based on a network of occupational physicians and used the recommendations of a group of European experts ('Saltsa Criteria document' consensus). Between 2002 and 2004, 3710 men and women (aged 20-59) representative of the regional workforce were randomly selected. Exposure to risk factors of MSDs was evaluated by the use of a self-administered questionnaire which aimed to assess bio-mechanical and psychosocial risk factors. With at least one of the six primary MSDs of the upper limbs having been clinically diagnosed using a rigorous protocol, the prevalence of clinically-diagnosed MSDs was high: about 11% of male and 15% of female workers suffered from at least one of the MSDs studied. After age fifty, about 19% of male and 27% of female workers suffered from at least one MSD and 4% of male and 6% of female workers from at least two disorders. Blue-collar workers were the most affected, regardless of age or gender, followed by office employees. Exposure to MSD risk factors of remained high after age fifty: 77% of male and 72% of female blue-collar workers were exposed to at least two MSD risk factors. The implications for the prevention of MSDs and job security of workers are discussed. The high prevalence of specific MSDs of the upper limb combined with a high exposure to risk factors of MSDs in ageing workers emphasizes the need to implement comprehensive prevention programs in most sectors to reduce the exposure to risk, the prevalence of MSDs and ensure the capacity to keep employees suffering from MSDs working, or at least to quickly return to work after recovery.


Behavioural hypervolumes of spider communities predict community performance and disbandment.
Trait-based ecology argues that an understanding of the traits of interactors can enhance the predictability of ecological outcomes. We examine here whether the multidimensional behavioural-trait diversity of communities influences community performance and stability in situ We created experimental communities of web-building spiders, each with an identical species composition. Communities contained one individual of each of five different species. Prior to establishing these communities in the field, we examined three behavioural traits for each individual spider. These behavioural measures allowed us to estimate community-wide behavioural diversity, as inferred by the multidimensional behavioural volume occupied by the entire community. Communities that occupied a larger region of behavioural-trait space (i.e. where spiders differed more from each other behaviourally) gained more mass and were less likely to disband. Thus, there is a community-wide benefit to multidimensional behavioural diversity in this system that might translate to other multispecies assemblages.


Establishment of a clonal human chondrosarcoma cell line with cartilage phenotypes.
A clonal cell line with cartilage phenotypes and tumorigenicity during more than 3 years in culture was established from a human chondrosarcoma. In sparse cultures, the clonal line, named HCS-2/8, consisted of slightly elongated polygonal cells, which proliferated with a doubling time of 3.5 days. The cells became polygonal to spherical as they became confluent. After reaching confluence, the cells continued to proliferate slowly and formed nodules, which showed metachromasia when stained with toluidine blue. The nodules were three-dimensional in structure; cells were multilayered in the surface regions, overlying a thick layer of extracellular matrix, which showed metachromasia. Electron microscopically, the cells resembling chondrocytes in vivo were surrounded by an extracellular matrix consisting of thin collagen-like fibrils with numerous fine granules, presumably of proteoglycans. The cells actively synthesized proteoglycans as determined by [35S]sulfate incorporation. The hydrodynamic size of major proteoglycan monomers synthesized by the cells was that of so-called cartilage-specific proteoglycans, as determined by glycerol gradient centrifugation. Immunostaining identified type II collagen but not type I collagen. Fluorography and immunoblotting of collagens separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis also demonstrated the synthesis of type II collagen but not type I collagen. Inoculation of HCS-2/8 cells into athymic mice resulted in the formation of chondrosarcomas that resembled the original tumor. Because of having these characters, HCS-2/8 cells should be useful not only in studies on the differentiated phenotypes of human chondrocytes but also in basic studies on the diagnosis, treatment, and etiology of human chondrosarcomas.


Changes in the gene expression profile during spontaneous migraine attacks.
Migraine attacks are delimited, allowing investigation of changes during and outside attack. Gene expression fluctuates according to environmental and endogenous events and therefore, we hypothesized that changes in RNA expression during and outside a spontaneous migraine attack exist which are specific to migraine. Twenty-seven migraine patients were assessed during a spontaneous migraine attack, including headache characteristics and treatment effect. Blood samples were taken during attack, two hours after treatment, on a headache-free day and after a cold pressor test. RNA-Sequencing, genotyping, and steroid profiling were performed. RNA-Sequences were analyzed at gene level (differential expression analysis) and at network level, and genomic and transcriptomic data were integrated. We found 29 differentially expressed genes between 'attack' and 'after treatment', after subtracting non-migraine specific genes, that were functioning in fatty acid oxidation, signaling pathways and immune-related pathways. Network analysis revealed mechanisms affected by changes in gene interactions, e.g. 'ion transmembrane transport'. Integration of genomic and transcriptomic data revealed pathways related to sumatriptan treatment, i.e. '5HT1 type receptor mediated signaling pathway'. In conclusion, we uniquely investigated intra-individual changes in gene expression during a migraine attack. We revealed both genes and pathways potentially involved in the pathophysiology of migraine and/or migraine treatment.


An organizing framework for informal caregiver interventions: detailing caregiving activities and caregiver and care recipient outcomes to optimize evaluation efforts.
Caregiver interventions may help improve the quality of informal care. Yet the lack of a systematic framework specifying the targets and outcomes of caregiver interventions hampers our ability to understand what has been studied, to evaluate existing programs, and to inform the design of future programs. Our goal was to develop an organizing framework detailing the components of the caregiving activities and the caregiver and care recipient outcomes that should be affected by an intervention. In so doing, we characterize what has been measured in the published literature to date and what should be measured in future studies to enable comparisons across interventions and across time. Our data set comprises 121 reports of caregiver interventions conducted in the United States and published between 2000 and 2009. We extracted information on variables that have been examined as primary and secondary outcomes. These variables were grouped into categories, which then informed the organizing framework. We calculated the frequency with which the interventions examined each framework component to identify areas about which we have the most knowledge and under-studied areas that deserve attention in future research. The framework stipulates that caregiver interventions seek to change caregiving activities, which in turn affect caregiver and care recipient outcomes. The most frequently assessed variables have been caregiver psychological outcomes (especially depression and burden) and care recipient physical and health care use outcomes. Based on the organizing framework, we make three key recommendations to guide interventions and inform research and policy. First, all intervention studies should assess quality and/or quantity of caregiving activities to help understand to what extent and how well the intervention worked. Second, intervention studies should assess a broad range of caregiver and care recipient outcomes, including considering whether expanding to economic status and health care use of the caregiver can be accommodated, to ease subsequent economic evaluations of caregiving. Third, intervention studies should measure a common set of outcomes to facilitate cross-time and cross-study comparisons of effectiveness.


The geometry of musical chords.
A musical chord can be represented as a point in a geometrical space called an orbifold. Line segments represent mappings from the notes of one chord to those of another. Composers in a wide range of styles have exploited the non-Euclidean geometry of these spaces, typically by using short line segments between structurally similar chords. Such line segments exist only when chords are nearly symmetrical under translation, reflection, or permutation. Paradigmatically consonant and dissonant chords possess different near-symmetries and suggest different musical uses.


Neuroprotective FK506 does not alter in vivo nitric oxide production during ischemia and early reperfusion in rats.
Previous studies have demonstrated that the immunosuppressant FK506 provides neuroprotection in experimental brain injury and suggest that this action may be mediated by suppression of neuronal nitric oxide synthase activation that occurs after ischemic depolarization. We sought to determine whether FK506 reduces histological injury after middle cerebral artery occlusion (MCAO) in the rat and whether the neuroprotective effect is mediated via suppression of in vivo nitric oxide (NO) production during ischemia or early reperfusion. Under controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of MCAO by the intraluminal occlusion technique in a blinded, randomized experimental trial. Ipsilateral parietal cortical laser-Doppler flowmetry was monitored throughout ischemia. Animals were randomly assigned to 4 pretreatment groups: intravenous FK506 0.3 mg/kg or 1. 0 mg/kg, vehicle (cremaphor), or an equivalent volume of saline administered 30 minutes before MCAO. Infarction volume was assessed by a triphenyltetrazolium chloride staining at 22 hours of reperfusion. In separate experiments, microdialysis probes were placed bilaterally into the striatum. Rats were perfused with artificial cerebrospinal fluid containing 3 micromol/L [14C]- L-arginine for 3 hours and then subjected to 2 hours of right MCAO. Intravenous 0.3 mg/kg FK506 or cremaphor was given 30 minutes before right MCAO. Right-left differences between [14C]-L-citrulline in the effluent were assumed to reflect differences in NO production. All values are mean+/-SE. FK506 at 0.3 mg/kg reduced infarction volume in cortex: 40+/-12 mm3 compared with saline (109+/-15 mm3) and cremaphor vehicle (148+/-23) (P<0.05). Striatal infarction was also reduced by low-dose FK506: 16+/-4 mm3 versus 36+/-4 mm3 and 34+/-4 mm3 in saline and vehicle groups, respectively (P<0.05). High-dose treatment reduced infarction volume in cortex (61+/-14 mm3, P<0.05 from saline and vehicle groups) and in striatum (22+/-5 mm3, P<0.05 from saline and vehicle groups). [14C]-L-citrulline recovery via microdialysis was markedly enhanced in ischemic compared with nonischemic striatum. However, ischemia-evoked [14C]-L-citrulline recovery was not different in FK506-treated rats compared with vehicle-treated animals. These data demonstrate that FK506 provides robust neuroprotection against transient focal cerebral ischemia in the rat. The mechanism of protection in vivo is not through attenuation of ischemia-evoked NO production during MCAO and early reperfusion.


A Rare Case of Intraductal Tubulopapillary Neoplasm of the Pancreas Rupturing and Causing Acute Peritonitis.
An intraductal tubulopapillary neoplasm (ITPN) is a very rare pancreatic tumor. Here we report an extremely rare case of an ITPN rupturing and causing acute peritonitis. A 50-year-old woman presented with left flank pain and vomiting. A computed tomography (CT) scan revealed gigantic multilocular cysts in the pancreatic tail and massive fluid collection in the abdominal cavity. The serum, urine, and abdominal fluid amylase levels were highly elevated, so she was conservatively treated with intraperitoneal drainage and antibiotics for a diagnosis of ruptured pancreatic cysts. After this patient recovered, a CT scan revealed a 2-cm low-density mass located in the body of the pancreas. This was diagnosed as a pancreatic ductal adenocarcinoma of the pancreatic body with an intraductal papillary mucinous neoplasm, and a distal pancreatectomy was performed. The tumor was composed of cuboidal high-grade dysplastic cells proliferating in a tubulopapillary growth pattern without mucin production. An immunohistochemical examination revealed that the tumor cells were positive for MUC1 and CK7, but negative for MUC5AC. These features led to the final diagnosis of ITPN. In this case, the solid ITPN growth obstructed the lumen of the main pancreatic duct, and the intraductal pressure of the distal side rose gradually. Then, pancreatic cysts formed and burst into the abdominal cavity when the intraductal pressure was at its maximum. However, an ITPN consists of high-grade atypical cells derived from the pancreatic ductal epithelium in principle, so the rupture may be an independent risk factor for peritonitis carcinomatosa in the future.


Experimental model of hypochloremic metabolic alkalosis caused by diversion of abomasal outflow in sheep.
Hypochloremic metabolic alkalosis accompanied by hypokalemia and hyponatremia was induced experimentally in 7 adult sheep by diversion (loss) of gastric contents through an Ivan and Johnston cannula placed in the cranial part of the duodenum just distal to the pylorus. Cannula placement was easily accomplished, and cannulae were tolerated well by the sheep. Volume of effluent produced during the 60- to 120-hour period of diversion ranged from 7.7 to 14.9 L and tended to be greatest during the first 24 hours. All sheep became dehydrated, with mean PCV and plasma total protein concentration increases of 94.2 and 61.7%, respectively. Plasma chloride concentration decreased in linear fashion from a prediversion mean of 113 mEq/L (range, 111 to 117 mEq/L) to an end-point mean of 54 mEq/L (range, 45 to 65 mEq/L). Plasma sodium and potassium concentrations also decreased, though potassium concentration increased terminally. There were rapid increases in arterial blood pH and bicarbonate and base excess concentrations during the first 48 hours after diversion. However, during the final stages of diversion, sheep developed superimposed metabolic acidosis with increased plasma lactate concentration and high anion gap.


Genome-wide analysis reveals selection for important traits in domestic horse breeds.
Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse.


Molecular mechanisms of the anti-obesity effect of bioactive compounds in tea and coffee.
Obesity is a serious health problem in adults and children worldwide. However, the basic strategies for the management of obesity (diet, exercise, drugs and surgery) have limitations and side effects. Therefore, many researchers have sought to identify bioactive components in food. Tea and coffee are the most frequently consumed beverages in the whole world. Their health benefits have been studied for decades, especially those of green tea. The anti-obesity effect of tea and coffee has been studied for at least ten years. The results have shown decreased lipid accumulation in cells via the regulation of the cell cycle during adipogenesis, changes in transcription factors and lipogenesis-related proteins in the adipose tissue of animal models, and decreased body weight and visceral fat in humans. Tea and coffee also influence the gut microbiota in obese animals and humans. Although the anti-obesity mechanism of tea and coffee still needs further clarification, they may have potential as a new strategy to prevent or treat obesity.


Gamblers seeking treatment: Who does and who doesn't?
As only a minority of pathological gamblers (PGr) presents for treatment, further knowledge about help-seeking behavior is required in order to enhance treatment utilization. The present study investigated factors associated with treatment participation in gamblers in Germany. As subclinical pathological gamblers (SPGr, fulfilling one to four DSM-IV-criteria) are target of early intervention due to high risk of transition to pathological gambling, they were subject of special interest. The study analyzed data from a general population survey (n = 234, SPGr: n = 198, PGr: n = 36) and a treatment study (n = 329, SPGr: n = 22, PGr: n = 307). A two-step weighting procedure was applied to ensure comparability of samples. Investigated factors included socio-demographic variables, gambling behavior, symptoms of pathological gambling and substance use. In PGr, regular employment and non-German nationality were positively associated with being in treatment while gambling on the Internet and gaming machines and fulfilling more DSM-IV-criteria lowered the odds. In SPGr, treatment attendance was negatively associated with married status and alcohol consumption and positively associated with older age, higher stakes, more fulfilled DSM-IV criteria and regular smoking. In accordance to expectations more severe gambling problems and higher problem awareness and/or external pressure might facilitate treatment entry. There are groups with lower chances of being in treatment: women, ethnic minorities, and SPGr. We propose target group specific offers, use of Internet-based methods as possible adaptions and/or extensions of treatment offers that could enhance treatment attendance.


The parenting attitudes and the stress of mothers predict the asthmatic severity of their children: a prospective study.
To examine relationships between a mother's stress-related conditions and parenting attitudes and their children's asthmatic status. 274 mothers of an asthmatic child 2 to 12 years old completed a questionnaire including questions about their chronic stress/coping behaviors (the "Stress Inventory"), parenting attitudes (the "Ta-ken Diagnostic Test for Parent-Child Relationship, Parent Form"), and their children's disease status. One year later, a follow-up questionnaire was mailed to the mothers that included questions on the child's disease status. 223 mothers (81%) responded to the follow-up survey. After controlling for non-psychosocial factors including disease severity at baseline, multiple linear regression analysis followed by multiple logistic regression analysis found chronic irritation/anger and emotional suppression to be aggravating factors for children aged < 7 years; for children aged 7 and over, the mothers' egocentric behavior was a mitigating factor while interference was an aggravating factor. Different types of parental stress/coping behaviors and parenting styles may differently predict their children's asthmatic status, and such associations may change as children grow.


The prevalence of ADHD, ODD, depression, and anxiety in a community sample of 4-year-olds.
Few studies have examined the epidemiology of preschoolers' psychopathology. This study included 796 4-year-old children recruited from schools and pediatric practices in a diverse, urban area. Psychiatric disorder was assessed by a structured interview adapted for preschool children and by questionnaire. The most common disorders were oppositional defiant disorder (ODD) and attention deficit hyperactivity disorder (ADHD). Generalized anxiety disorder (GAD) and depressive disorders were reported in less than 1% of the sample. Race/ethnicity differences were not significant. Gender differences showed ADHD-inattentive type more common among boys, with no gender differences for GAD, major depressive disorder, dysthymia, separation anxiety disorder, or ODD at any level of impairment. The overall comorbidity rate was 6.4%. Approximately 3% of individuals receiving a diagnosis had received mental health services.


Organic component vapor pressures and hygroscopicities of aqueous aerosol measured by optical tweezers.
Measurements of the hygroscopic response of aerosol and the particle-to-gas partitioning of semivolatile organic compounds are crucial for providing more accurate descriptions of the compositional and size distributions of atmospheric aerosol. Concurrent measurements of particle size and composition (inferred from refractive index) are reported here using optical tweezers to isolate and probe individual aerosol droplets over extended timeframes. The measurements are shown to allow accurate retrievals of component vapor pressures and hygroscopic response through examining correlated variations in size and composition for binary droplets containing water and a single organic component. Measurements are reported for a homologous series of dicarboxylic acids, maleic acid, citric acid, glycerol, or 1,2,6-hexanetriol. An assessment of the inherent uncertainties in such measurements when measuring only particle size is provided to confirm the value of such a correlational approach. We also show that the method of molar refraction provides an accurate characterization of the compositional dependence of the refractive index of the solutions. In this method, the density of the pure liquid solute is the largest uncertainty and must be either known or inferred from subsaturated measurements with an error of <±2.5% to discriminate between different thermodynamic treatments.


Antigenic heterogeneity of gonococcal pili.
Pili were isolated from two different strains of gonococci (33 and 2686) and demonstrated to be pure by the criteria of electron microscopy and polyacrylamide gel electrophoresis in sodium dodecyl sulfate. Each purified pili preparation was studied for its ability to inhibit; (a) binding of 124-I-labeled purified 2686 pili by antibody to 2686 pili, and (b) binding of 125-I-labeled purified 33 pili by antibody to 33 pili. In each instance progressive inhibition of binding was produced by homologous pili type, but no significant inhibition was observed using comparable weights of the heterologous pili type. These results indicate that the pili of strains 2686 and 33 are antigenically different.


[Acute lymphoblastic leukemia in children with initial leucocytosis above 50,000/mm3: summary of treatment results of Polish Pediatric Leukemia/Lymphoma Study Group].
Initial leucocytosis, presence of t(9;22) and t(4;11) translocations and poor response to therapy with steroids or induction chemotherapy are still included to poor risk factors group. From 1981 to 1986, children with acute lymphoblastic leukemia (ALL) and initial WBC above 50,000/mm3, achieved significantly worse treatment results than children with lower WBC: over 6-year disease-free survival were respectively 33% and 60%. In attempt to improve treatment results in children with hyperleucocytosis, modified American protocols called: New York (1987), New York I (1997), and New York II (1999) were introduced consecutively in the centers of Polish Pediatric Leukemia/ Lymphoma Study Group. Actually treatment results obtained with those protocols in three groups of patients: group I: 214 children (1987-1996), group II: 58 children (1997-1999), and group III: 77 children (1999-2001) are presented. The observation was completed in March 31, 2004. In evaluated groups the first complete remissions (CR) were achieved in 91%, 95%, and 96% of patients, respectively. Relapses occurred in 72 patients of group I (37%), in 12 patients of group II (21%), and in 13 patients of group III (18%). The 5-year overall survivals were: 62%, 79%, and 78% (p=0.05) respectively; 5 year event-free survivals (EFS) were: 52%, 74%, and 69% (p=0.01) respectively. A significant improvement in treatment results in second compared with first group was achieved. Treatment results obtained with New York II are comparable with results obtained with New York I. The analysis of treatment results achieved shows the improvement of the prognosis in children with ALL and initial WBC above 50 000/mm3 in comparison with patients treated before 1987. There is strong necessity of unification of risk group qualification criteria in childhood ALL in term of comparable estimation treatment results achieved in different centers all over the world.


A critical public-health ethics analysis of Canada's international response to HIV.
As interconnections between health, ideology and politics become increasingly acknowledged, gaps in the literature also become visible in terms of analytic frameworks to engage these issues and empirical studies to understand the complexities. 'Critical public-health ethics' provides such an analytic lens. This article presents the results of a critical public-health ethics analysis of the government of Canada's international response to HIV. This qualitative study involved in-depth, semi-structured interviews with 23 experts on Canada's international response over time. Descriptive, thematic and theoretical analyses revealed an underlying dilemma between Canada's philanthropic desire to 'do the right thing' for the broader public good and Canada's commitment to its own economic growth and other forms of self-interest. Related to this tension were four conspicuous areas of silence in the data: (1) The relative absence of moral vocabulary for discussing Canada's duty to respond to the global HIV pandemic. (2) Scant reference to solutions based on poverty reduction. (3) Little awareness about the dominance of neoliberal economic rationality and its impact on HIV. (4) Limited understanding of Canada's function within the international economic order in terms of its role in poverty creation. Our study has implications for Canada and other rich nations through its empirical contribution to the chorus of calls challenging the legitimised, institutionalised and normative practice of considering the economic growth of wealthy countries as the primary objective of global economic policy.


Retrospective Outcome Monitoring of ADHD and Nutrition (ROMAN): The Effectiveness of the Few-Foods Diet in General Practice.
Double-blind placebo-controlled studies investigating the effect of a few-foods diet (FFD) on attention-deficit/hyperactivity disorder (ADHD) have provided consistent evidence that ADHD can be triggered by foods, indicating the existence of a food-induced ADHD subtype. In 2001 the "few-foods" approach was included in an ADHD treatment protocol. This approach consists of (a) determining, by means of an FFD, whether food is a trigger of ADHD; (b) reintroducing, in FFD responders, foods to assess which foods are incriminated; (c) finally composing a personalised diet eliminating the involved foods only. In the Netherlands the few-foods approach is applied in practice. We aimed to retrospectively assess its effectiveness on ADHD and oppositional defiant disorder (ODD) in real life. Data from all children who started the few-foods approach in three specialised healthcare facilities during three consecutive months were included. Behavior was assessed at start and end of the 5-week FFD, using the ADHD Rating Scale and a structured psychiatric interview. Clinical responders (behavioral improvements ≥40%) proceeded with the reintroduction phase. Data of 57 children, 27 taking medication and 15 following some elimination diet at start, were available. No differences were noted between parental scores of children with and without medication or some elimination diet at start. 21/27 (78%) children stopped taking medication during the FFD. 34/57 (60%) children were ADHD responders, 20/29 (65%) children meeting ODD criteria were ODD responders. 26/34 (76%) ADHD responders started the reintroduction phase; 14/26 (54%) still participated at six months. Teacher data were available of 18/57 (32%) children. 9/18 (50%) children were ADHD responders. The FFD, if applied by trained specialists, may lead to clinically relevant reduction of ADHD and ODD symptoms in general practice, and a concomitant decrease of ADHD medication. These results corroborate the existence of an ADHD subgroup with food-induced ADHD. Defining and eliminating the incriminated foods, i.e. the underlying causal triggers, may result in secondary prevention of food-induced ADHD. Research into underlying mechanism(s) is of vital importance: finding an easier method or biomarkers for diagnosing food-induced ADHD and ascertaining the incriminated foods may lead to redundancy of the few-foods approach.


From denial to awareness: a conceptual model for obtaining equity in healthcare.
Although Swedish legislation prescribes equity in healthcare, studies have reported inequalities, both in face-to-face encounters and in telephone nursing. Research has suggested that telephone nursing has the capability to increase equity in healthcare, as it is open to all and not limited by long distances. However, this requires an increased awareness of equity in healthcare among telephone nurses. The aim of this study was to explore and describe perceptions of equity in healthcare among Swedish telephone nurses who had participated in an educational intervention on equity in health, including which of the power constructs gender, ethnicity and age they commented upon most frequently. Further, the aim was to develop a conceptual model for obtaining equity in healthcare, based on the results of the empirical investigation. A qualitative method was used. Free text comments from questionnaires filled out by 133 telephone nurses before and after an educational intervention on equity in health, as well as individual interviews with five participants, were analyzed qualitatively. The number of comments related to inequity based on gender, ethnicity or age in the free text comments was counted descriptively. Gender was the factor commented upon the least and ethnicity the most. Four concepts were found through the qualitative analysis: Denial, Defense, Openness, and Awareness. Some informants denied inequity in healthcare in general, and in telephone nursing in particular. Others acknowledged it, but argued that they had workplace routines that protected against it. There were also examples of an openness to the fact that inequity existed and a willingness to learn and prevent it, as well as an already high awareness of inequity in healthcare. A conceptual model was developed in which the four concepts were divided into two qualitatively different blocks, with Denial and Defense on one side of a continuum and Openness and Awareness on the other. In order to reach equity in healthcare, action is also needed, and that concept was therefore added to the model. The result can be used as a starting point when developing educational interventions for healthcare personnel.


Metronomics chemotherapy: time for computational decision support.
Over the last decade, metronomic chemotherapy has been increasingly considered as an attractive strategy for treating cancer in a variety of settings. Beside pharmaco-economic considerations making metronomics a unique opportunity in low- or middle-income countries, revisiting dosing schedules using continuous low doses of cytotoxics should theoretically permit to reduce the incidence of treatment-related toxicities, while offering unexpected novel mechanisms of actions such as antiangiogenic or immuno-stimulating properties. Consequently, a number of clinical trials sought to evaluate to what extent switching to metronomic schedules could actually impact indeed on the efficacy/toxicity balance of a variety of anticancer drugs in both adults and pediatric oncology. Vinorelbine is a vinca-alcaloïd that remains the backbone of several regimens to treat patients with metastatic breast cancer or non-small cell lung cancer. Additionally, vinorelbine is widely used to treat a variety of solid tumors in children such as rhabdomyosarcomas and acute leukemia. The recent approval of an oral formulation of vinorelbine has open the way to developing alternative metronomic schedules with this drug. Consequently, a number of clinical trials investigating on metronomic vinorelbine have been performed over the last few years, with seemingly inconsistent results to date. Of note, all the studies published thus far were based upon empirical determination of the metronomic schedule, both in terms of doses, drug-free intervals and repartition of the administrations throughout time. Because the very concept of «low, repeated doses with little or no drug-free interval» covers numerous possible combinations, determining the optimal protocol using traditional under-powered empirical design looks like an unreachable goal. In this context, mathematical modeling offers invaluable in silico tools to help determining the optimal metronomic schedule among a variety of possibilities. This review covers the latest clinical trials investigating on metronomic vinorelbine and proposes alternative strategies for developing computational decision support to make metronomics a scientific-grounded strategy, rather than an empirical practice at the bedside. In particular, mathematical simulations using an original pharmacokinetics/pharmacodynamics constraint models provide clues for exploring new paths in the way metronomic vinorelbine could be scheduled in patients with lung cancer.


Performance of commercially available deformable image registration platforms for contour propagation using patient-based computational phantoms: A multi-institutional study.
To investigate the performance of various algorithms for deformable image registration (DIR) to propagate regions of interest (ROIs) using multiple commercial platforms. Thirteen institutions participated in the study with six commercial platforms: RayStation (RaySearch Laboratories, Stockholm, Sweden), MIM (Cleveland, OH, USA), VelocityAI and Smart Adapt (Varian Medical Systems, Palo Alto, CA, USA), Mirada XD (Mirada Medical Ltd, Oxford, UK), and ABAS (Elekta AB, Stockholm, Sweden). The DIR algorithms were tested on synthetic images generated with the ImSimQA package (Oncology Systems Limited, Shrewsbury, UK) by applying two specific Deformation Vector Fields (DVF) to real patient data-sets. Head-and-neck (HN), thorax, and pelvis sites were included. The accuracy of the algorithms was assessed by comparing the DIR-mapped ROIs from each center with those of reference, using the Dice Similarity Coefficient (DSC) and Mean Distance to Conformity (MDC) metrics. Statistical inference on validation results was carried out in order to identify the prognostic factors of DIR performances. DVF intensity, anatomic site and participating center were significant prognostic factors of DIR performances. Sub-voxel accuracy was obtained in the HN by all algorithms. Large errors, with MDC ranging up to 6 mm, were observed in low-contrast regions that underwent significant deformation, such as in the pelvis, or large DVF with strong contrast, such as the clinical tumor volume (CTV) in the lung. Under these conditions, the hybrid DIR algorithms performed significantly better than the free-form intensity based algorithms and resulted robust against intercenter variability. The performances of the systems proved to be site specific, depending on the DVF type and the platforms and the procedures used at the various centers. The pelvis was the most challenging site for most of the algorithms, which failed to achieve sub-voxel accuracy. Improved reproducibility was observed among the centers using the same hybrid registration algorithm.


Hypogonadism and renal failure: An update.
The prevalence of both hypogonadism and renal failure is increasing. Hypogonadism in men with renal failure carries with it significant morbidity, including anemia and premature cardiovascular disease. It remains unclear whether testosterone therapy can affect the morbidity and mortality associated with renal failure. As such, in this review, we sought to evaluate the current literature addressing hypogonadism and testosterone replacement, specifically in men with renal failure. The articles chosen for this review were selected by performing a broad search using Pubmed, Embase and Scopus including the terms hypogonadism and renal failure from 1990 to the present. This review is based on both primary sources as well as review articles. Hypogonadism in renal failure has a multifactorial etiology, including co-morbid conditions such as diabetes, hypertension, old age and obesity. Renal failure can lead to decreased luteinizing hormone production and decreased prolactin clearance that could impair testosterone production. Given the increasing prevalence of hypogonadism and the potential morbidity associated with hypogonadism in men with renal failure, careful evaluation of serum testosterone would be valuable. Testosterone replacement therapy should be considered in men with symptomatic hypogonadism and renal failure, and may ameliorate some of the morbidity associated with renal failure. Patients with all stages of renal disease are at an increased risk of hypogonadism that could be associated with significant morbidity. Testosterone replacement therapy may reduce some of the morbidity of renal failure, although it carries risk.


Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B.
Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1+ and Vδ2+γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3hiCD4- Vδ2+γδT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vδ2+γδT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vδ1+γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2+γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1+γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2+γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.


Intestinal apolipoprotein AI gene transcription is regulated by multiple distinct DNA elements and is synergistically activated by the orphan nuclear receptor, hepatocyte nuclear factor 4.
We have used apolipoprotein genes to investigate the signal transduction mechanisms involved in the control of intestinal specific gene expression. The human apoAI, apoCIII, and apoAIV genes are tandemly organized within a 15-kb DNA segment and are expressed predominantly in the liver and intestine. Transient transfection of various human apoAI gene plasmid constructs into human hepatoma (HepG2) and colon carcinoma (Caco-2) cells showed that apoAI gene transcription is under the control of two separate and distinct cell-specific promoters. The region between nucleotides -192 and -41 is essential for expression in HepG2 cells, whereas the region from -595 to -192 is essential for expression in Caco-2 cells. A third 0.6 kb DNA fragment in the apoCIII gene promoter region, approximately 5 kb down-stream from the human apoAI gene, enhances transcription mediated by either of these two tissue-specific apoAI promoters. In Caco-2 cells, expression of the apoAI gene and activation by the distal enhancer required the presence of a nuclear hormone receptor response element (NHRRE) located in the -214 to -192 apoAI promoter region. Overexpression of the orphan receptor hepatocyte nuclear factor 4 (HNF-4), which binds to the NHRRE, dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 cells. Maximal stimulation of transcription by HNF-4 in Caco-2 cells required the presence of both the intestinal specific promoter, the NHRRE, and distal enhancer elements. Transactivation by HNF-4 thus appears to result from functional synergy between the NHRRE binding HNF-4 and distal DNA elements containing intestinal-specific DNA binding activities. The apoAI gene provides a model system to define the mechanism(s) governing intestinal cell specific gene regulation and the role of nuclear hormone receptors in the establishment and regulation of enterocytic gene transcription.


Hedgehog signaling: from the cuirass to the heart of pancreatic cancer.
Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and carries a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistence is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drug delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. In particular, this subpopulation is resistant to classic cytotoxic therapies, and seems to be responsible for disease renewal. Hedgehog signaling (HH) is implicated in pancreatic gland development during embryogenesis and is reactivated during tumorigenesis and the maintenance of pancreatic cancer. Some studies demonstrated that the Hedgehog-secreted signaling proteins are overexpressed in both the stromal and CSCs pools, implying an abnormal activation of HH in the main compartment of pancreatic cancer. For this reason, the Hedgehog pathway could be an interesting target for clinical trials to increase drug concentration in neoplastic cells and hence deplete the stroma and directly kill tumor-initiating cells.


Sensitive naked eye detection of hydrogen sulfide and nitric oxide by aza-BODIPY dyes in aqueous medium.
With an objective to develop optical probes for biologically important anions and neutral molecules, we synthesized three novel NIR absorbing aza-BODIPY derivatives, 3a-3c, and have systematically tuned their photophysical properties by changing the peripheral substitution. A profound red-shift was observed in the absorption and fluorescence spectra of the aza-BODIPY dyes with the change in substitution from azido (3a) to amino (3b) to dimethylamino (3c) groups. Theoretical calculations of 3a-3c showed a consistent decrease in bandgap, which supports the observed spectral changes. The study of their interactions with various analytes revealed that the azido-aza-BODIPY 3a selectively interacts with hydrogen sulfide (H2S) when compared to other molecules. Uniquely, the detection of H2S can be visualized through a change in color from bright blue to purple with a detection limit of 0.5 ppm. The sensitivity of the probe was observed to be ~20-fold higher than the allowed exposure limits of H2S as defined by EPA (10 ppm). The aza-BODIPY derivative 3b, on the other hand, exhibited selective interactions with nitrite ions (NO2(-)) and nitric oxide (NO) in aqueous medium through a visible color change from blue to green with a sensitivity of 20 and 0.15 ppb, respectively. In contrast, the dimethylamino-aza-BODIPY derivative, 3c, showed negligible affinity for the anions and neutral molecules tested. By tuning the photophysical properties through the judicious functionalization, the aza-BODIPY dyes thus synthesized can be utilized for the sensitive on-site detection and analysis of H2S, NO2(-), and NO in the aqueous medium.


Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases.
Tyrosine kinases relay signals from diverse leukocyte antigen receptors, innate immune receptors, and cytokine receptors, and therefore mediate the recruitment and activation of various leukocyte populations. Non-receptor tyrosine kinases of the Jak, Src, Syk, and Btk families play major roles in various immune-mediated disorders, and small-molecule tyrosine kinase inhibitors are emerging novel therapeutics in a number of those diseases. Autoimmune and inflammatory skin diseases represent a broad spectrum of immune-mediated diseases. Genetic and pharmacological studies in humans and mice support the role of tyrosine kinases in several inflammatory skin diseases. Atopic dermatitis and psoriasis are characterized by an inflammatory microenvironment which activates cytokine receptors coupled to the Jak-Stat signaling pathway. Jak kinases are also implicated in alopecia areata and vitiligo, skin disorders mediated by cytotoxic T lymphocytes. Genetic studies indicate a critical role for Src-family kinases and Syk in animal models of autoantibody-mediated blistering skin diseases. Here, we review the various tyrosine kinase signaling pathways and their role in various autoimmune and inflammatory skin diseases. Special emphasis will be placed on identification of potential therapeutic targets, as well as on ongoing preclinical and clinical studies for the treatment of inflammatory skin diseases by small-molecule tyrosine kinase inhibitors.


Evaluation of microalbuminuria in relation to asymptomatic bacteruria in Nigerian patients with sickle cell anemia.
Studies have identified microalbuminuria (MA) and asymptomatic bacteruria (ASB) as co-morbid factors in sickle cell anemia (SCA). However, the relationship between these comorbid factors remains unclear and data are lacking for Nigerian patients. This study determined the prevalence of MA and ASB in a cohort of patients with SCA in a steady state, in Lagos, Nigeria. Early morning mid-stream urine samples were collected in sterile bottles from 103 patients comprising 48 males and 55 females with a mean age of 10.4 years. Aerobic culture and colony count of organisms was done using conventional methods. Serum creatinine and hematological indices, including irreversibly sickled cells (ISC), were also assayed. Of the 103 urine samples screened, 23 (22.3%) had albuminuria (ALB), and consisted of nine males and 14 females (P > 0.05); 16.5% of the cases had MA (P <0.05). Age at onset of MA was seven years, and children accounted for 23.5% of all cases with ALB (P >0.05). The prevalence of confirmed ASB was 14.6%, with females accounting for 14 of 19 probable ASB cases (P <0.05). Univariate regression analysis demonstrated a significant (P <0.05) association between age at onset of MA, hemoglobin level, reticulocyte count, ISC and occurrence of ASB, but with only ISC evolving as an independent predictor. Twenty-eight bacterial isolates predominated by Escherichia coli (39.3%; P <0.05), of whom 89.3% were multi-drug resistant, were recovered from the ASB urine samples. In conclusion, both MA and ASB are common in Nigerian SCA patients, with the former occurring from the first decade of life.


Delayed Galectin-3-Mediated Reprogramming of Microglia After Stroke is Protective.
Galectin-3 (Gal-3), a β-galactoside-binding lectin, has recently emerged as a molecule with immunoregulatory functions. We investigated the effects of Gal-3 on microglia morphology, migration, and secretory profile under physiological conditions and in the context of ischemic injury. We show that in the control conditions, exposure to recombinant Gal-3 increases microglial ramification and motility in vitro and in vivo via an IL-4-dependent mechanism. Importantly, after stroke, Gal-3 exerted marked immune-modulatory properties. Delivery of Gal-3 at 24 h after middle cerebral artery occlusion (MCAO) was associated with an increase in Ym1-positive microglia and decrease in iNOS. Analysis of cytokine profiles at the protein level revealed downregulation of pro-inflammatory cytokines and a marked upregulation of the anti-inflammatory cytokine, IL-4, 24 h after i.c.v. injection of Gal-3. Importantly, the observed shift in cytokines in microglia was associated with a significant decrease in the infarct size. Taken together, our results suggest that when delivered well after ischemic injury, Gal-3 might fine tune innate immunity and induce a therapeutic shift in microglia polarization.


Fasting hyperglycemia upon hospital admission is associated with higher pneumonia complication rates among the elderly.
Hyperglycemia is an independent predictor of adverse outcomes during hospitalization. In patients who have pneumonia, significant hyperglycemia is associated with poor outcomes. This study evaluates the interaction of the degree of hyperglycemia and complication rates stratified by age in non-critically ill patients admitted to the hospital for care of community-acquired pneumonia. Retrospective review of patient records coded for pneumonia. Analysis included 501 non-critically ill patients admitted to a tertiary care hospital in New York City. Data were stratified by diabetes status, age (less than 65 and 65 and over), and fasting blood glucose (FBG) within the first 24 hours of hospitalization. Among patients with no history of diabetes, FBG was stratified as "normal" [FBG </=100 mg/dl (5.6 mmol/l)], "mild-hyperglycemia" [101-125 mg/dl (5.7-6.9 mmol/l)], and "severe-hyperglycemia" [>/=126 mg/dl (7 mmol/l)]. The diabetic group included known diabetics regardless of FBG. The Pneumonia Severity Index (PSI) was calculated for all patients. Complications rates, hospital length of stay and mortality were compared among the groups. In patients age 65 and older, complication rates were 16.7% in normoglycemics, 27.5% in the "mild-hyperglycemia" group, 28.6% in the "severe hyperglycemia" group, and 25.5% in those with known diabetes. The mild and severe-hyperglycemics had similar complication rates (p = 0.94). Compared to the normal group, mild and severe groups had higher rates of complications, p = 0.05 and p = 0.03, respectively. PSI tended to be higher in those over the age of 65. PSI was not significantly different when the normal, mild, severe, and known diabetes groups were compared. PSI did not predict complications for new hyperglycemia (normals' mean score 87, mild 84.7, severe 93.9, diabetics 100). Hospital mortality did not differ among groups. Length of stay was longer (p = 0.05) among mild-hyperglycemics (days = 8.4 s.e. 14.3) vs. normals (days = 6.2 s.e.6.5). This study shows that FBS between 101-125 mg/dl (5.7-6.9 mmol/l) on hospital admission increases pneumonia complication rates among the elderly with no previous diagnosis of diabetes.


Genomic Profiling for Piroplasms in Feeding Ixodid Ticks in the Eastern Cape, South Africa.
Importation of tick-infected animals and the uncontrollable migration of birds and wild animals across borders can lead to geographical expansion and redistribution of ticks and pathogen vectors, thus leading to the emergence and re-emergence of tick-borne diseases in humans and animals. Comparatively, little is known about the occurrence of piroplasms in ixodid ticks in the Eastern Cape, South Africa, thus necessitating this study, which is aimed at detecting piroplasms (Theileria and Babesia) from feeding tick samples collected from cattle, sheep, and goats in selected sites in the Eastern Cape, South Africa. A total of 1200 feeding ixodid ticks collected from farm animals at selected homesteads were first subjected to molecular identification using mitochondrial 12S ribosomal RNA (rRNA) gene by PCR and were further tested for the presence of piroplasms through amplification of the 18S rRNA gene via nested-PCR followed by sequencing of the PCR products. The results indicated that 853 (71.1%) corresponded to the genus Rhipicephalus, 335 (27.9%) corresponded to genus Amblyomma, and 12 (1%) corresponded to genus Haemaphysalis. Amblyomma hebraeum and Rhipicephalus appendiculatus were the most common identified ticks from this study. The 18S rRNA nested-PCR revealed that 44 (3.7%) samples were confirmed positive for Theileria. A homology search for the generated sequences revealed a high percentage identity of 98-98.9% similarity to T. buffeli, T. orientalis, and T. sergenti in the GenBank. Based on the results obtained herein, we conclude that there is a big diversity of Theileria species; therefore, we suggest that this research should cover more geographical areas in order to reveal the true prevalence of this pathogen in the studied area because this will be a great step in the possible prevention of an outbreak that could have devastating effects on livestock production and human health in both the studied areas and South Africa at large.


Rhomboid flap dynamics.
The rhomboid flap is a reliable, versatile, and widely used tool in head and neck surgery. Although its geometry is well described, the mechanics of the flap have not been scientifically investigated. For example, there is disagreement whether the maximum tension is located at the closure of the donor site or at the tip of the flap. An experimental model using piglets and stabilized force gauges has been developed to measure the distribution of tension in a standard Limberg flap (60 degrees rhomboid). Variables evaluated include the size of the rhomboid, the amount of undermining, and the position of the flap on the animal. Consistent measurements show tension at the closure of the donor site to represent the majority of tension around the flap (58% average); the size of the rhomboid and degree of undermining do not change relative tensions. A composite figure discloses the relationship of the initially outlined flap to the final result and quantifies the observable changes in the length of sides.


Calcium response to retinohypothalamic tract synaptic transmission in suprachiasmatic nucleus neurons.
Glutamate released from retinohypothalamic tract (RHT) synapses with suprachiasmatic nucleus (SCN) neurons induces phase changes in the circadian clock presumably by using Ca2+ as a second messenger. We used electrophysiological and Ca2+ imaging techniques to simultaneously record changes in the membrane potential and intracellular calcium concentration ([Ca2+]i) in SCN neurons after stimulation of the RHT at physiologically relevant frequencies. Stimulation of the RHT sufficient to generate an EPSP did not produce detectable changes in [Ca2+]i, whereas EPSP-induced action potentials evoked an increase in [Ca2+]i, suggesting that the change in postsynaptic somatic [Ca2+]i produced by synaptically activated glutamate receptors was the result of membrane depolarization activating voltage-dependent Ca2+ channels. The magnitude of the Ca2+ response was dependent on the RHT stimulation frequency and duration, and on the SCN neuron action potential frequency. Membrane depolarization-induced changes in [Ca2+]i were larger and decayed more quickly in the dendrites than in the soma and were attenuated by nimodipine, suggesting a compartmentalization of Ca2+ signaling and a contribution of L-type Ca2+ channels. RHT stimulation at frequencies that mimicked the output of light-sensitive retinal ganglion cells (RGCs) evoked [Ca2+]i transients in SCN neurons via membrane depolarization and activation of voltage-dependent Ca2+ channels. These data suggest that for Ca2+ to induce phase advances or delays, light-induced signaling from RGCs must augment the underlying oscillatory somatic [Ca2+]i by evoking postsynaptic action potentials in SCN neurons during a period of slow spontaneous firing such as occurs during nighttime.