A critical appraisal on AIT in childhood asthma.
Allergen immunotherapy (AIT) is the only disease-modifying treatment approved for allergic rhinitis and allergic asthma and represents a suitable therapeutic option, especially in childhood, to modify the progression of respiratory allergic diseases. Starting from the previous "generic class effect" evaluation, as testified by the numerous meta analyses, AIT is now considered a product-specific pathogenic-oriented treatment. AIT was empirically proposed more than one century ago in the subcutaneous form (SCIT), but the IgE-mediated mechanism of allergy was elucidated only after 50 years of clinical use of the treatment. The sublingual administration (SLIT) was developed during the 1980 ties, to achieve an improvement in safety and convenience. While SCIT is approved in the United States for the treatment of asthmatic patients with more than 12 years, so far few trials evaluated the clinical efficacy and safety of SLIT in children with allergic asthma, although the indications and some aspects remain unclear. Certainly, due to compliance problems, the age below 3 years may be reasonably considered a practical contraindication. Given that some specific AIT products are effective and approved as drugs (AIFA, EMA, FDA), the use in children is still debated. Some aspects still need robust confirm: (a) the safety of AIT in asthma; (b) the optimal regimen of administration; (c) the role of AIT as preventative treatment for asthma development.


A cardiac antiarrhythmic screening test using the isolated ischaemic perfused rat heart preparation.
Ventricular fibrillation was induced by myocardial ischaemia and reperfusion in the isolated perfused rat heart. The dose-response effectiveness for the prototype antiarrhythmic drugs, propranolol, quinidine and lidocaine in converting the induced ventricular fibrillation to sinus rhythm was determined. The test is easy to perform and does not require skillful surgical procedure and long time for observation. In addition, no arrhythmogenic drugs are used and the amount of substance needed for the test is very small. It is suggested that this simple test be used as a cardiac antiarrhythmic screening test for antiarrhythmic drugs.


Gene expression patterns of dengue virus-infected children from nicaragua reveal a distinct signature of increased metabolism.
Infection with dengue viruses (DENV) leads to a spectrum of disease outcomes. The pathophysiology of severe versus non-severe manifestations of DENV infection may be driven by host responses, which could be reflected in the transcriptional profiles of peripheral blood immune cells. We conducted genome-wide microarray analysis of whole blood RNA from 34 DENV-infected children in Nicaragua collected on days 3-6 of illness, with different disease manifestations. Gene expression analysis identified genes that are differentially regulated between clinical subgroups. The most striking transcriptional differences were observed between dengue patients with and without shock, especially in the expression of mitochondrial ribosomal proteins associated with protein biosynthesis. In the dengue hemorrhagic fever patients, one subset of differentially expressed genes encode neutrophil-derived anti-microbial peptides associated with innate immunity. By performing a meta-analysis of our dataset in conjunction with previously published datasets, we confirmed that DENV infection in vivo is associated with large changes to protein and nucleic acid metabolism. Additionally, whereas in vitro infection leads to an increased interferon signature, this was not consistently observed from in vivo patient samples, suggesting that the interferon response in vivo is relatively transient and was no longer observed by days 3-6 of illness. These data highlight important differences between different manifestations of severity during DENV infection as well as identify some commonalities. Compilation of larger datasets in the future across multiple studies, as we have initiated in this report, may well lead to better prediction of disease manifestation via a systems biology approach.


Reaction of lincosamide antibiotics with manganese oxide in aqueous solution.
Lincosamides are among the most frequently detected antibacterial agents in effluents from wastewater treatment plants and surface runoff at agricultural production systems. Little is known about their transformations in the environment. This study revealed that manganese oxide caused rapid and extensive decomposition of clindamycin and lincomycin in aqueous solution. The reactions occurred mainly at the pyranose ring of lincosamides, initially by formation of complexes with Mn and cleavage of the ether linkage, leading to the formation of a variety of degradation products via subsequent hydrolytic and oxidative reactions. The results of LC-MS/MS and FTIR analysis confirm cleavage of the C-O-C bond in the pyranose ring, formation of multiple carbonyl groups, and transformation of the methylthio moiety to sulfur oxide. The overall transformation was controlled by interactions of cationic species of lincosamides with MnO(2) surfaces. The presence of electrolytes (i.e., NaCl, CaCl(2), and MnCl(2)) and dissolved organic matter in aqueous solution, and increase of solution pH, diminished lincosamide binding to MnO(2) hence reducing the rate and magnitude of the transformations. Results from this study indicate that manganese dioxides in soils and sediments could contribute to the decomposition of lincosamide antibiotics released into the environment.


Transcriptional changes are tightly coupled to chromatin reorganization during cellular aging.
Human life expectancy is constantly increasing and aging has become a major risk factor for many diseases, although the underlying gene regulatory mechanisms are still unclear. Using transcriptomic and chromosomal conformation capture (Hi-C) data from human skin fibroblasts from individuals across different age groups, we identified a tight coupling between the changes in co-regulation and co-localization of genes. We obtained transcription factors, cofactors, and chromatin regulators that could drive the cellular aging process by developing a time-course prize-collecting Steiner tree algorithm. In particular, by combining RNA-Seq data from different age groups and protein-protein interaction data we determined the key transcription regulators and gene regulatory changes at different life stage transitions. We then mapped these transcription regulators to the 3D reorganization of chromatin in young and old skin fibroblasts. Collectively, we identified key transcription regulators whose target genes are spatially rearranged and correlate with changes in their expression, thereby providing potential targets for reverting cellular aging.


Influence of 8-week daily consumption of a new product combining green coffee hydroxycinnamates and beta-glucans on polyphenol bioavailability in subjects with overweight and obesity.
Nutraceuticals based on plant extracts rich in polyphenols, as well as dietary fibres, are new means to fight overweight/obesity and associated diseases. However, to understand the potential effects of polyphenols on health it is critical to study their bioavailability and metabolic fate. Consumption of a green coffee phenolic extract (GCPE) in combination with oat beta-glucan (BG) could affect the pharmacokinetic profile of the main polyphenols present in coffee (hydroxycinnamates). Moreover, the regular intake of the combination could also induce changes. Nine overweight men and women consumed a novel nutraceutical product containing 300 mg of green coffee hydroxycinnamic acids and 2.5 g of BG twice a day for 8 weeks. A pharmacokinetic study was carried out in blood and urine samples taken before (baseline) and at week 8 after the nutraceutical intervention, collecting samples at different times in a 0-24 h interval. Faecal samples were also obtained at 0 and 24 h after the intake of the nutraceutical at baseline and week 8. Phenolic metabolites were analysed by LC-MS-QToF. Results showed that polyphenols were differentially absorbed and extensively metabolized throughout the gastrointestinal tract. An apparent reduction in the excretion of small intestinal metabolites was accompanied by a tendency to increase colonic metabolites after sustained intake (p = 0.052). In conclusion, continued consumption of the GCPE/BG nutraceutical appears to enhance the absorption of hydroxycinnamates by increasing the colonic bioavailability of their derived metabolites compared to baseline, although the regular intake of the nutraceutical did not modify the metabolite profile in any of the biological samples.


A complete DNA sequence map of the ovine major histocompatibility complex.
The ovine Major Histocompatibility Complex (MHC) harbors clusters of genes involved in overall resistance/susceptibility of an animal to infectious pathogens. However, only a limited number of ovine MHC genes have been identified and no adequate sequence information is available, as compared to those of swine and bovine. We previously constructed a BAC clone-based physical map that covers entire class I, class II and class III region of ovine MHC. Here we describe the assembling of a complete DNA sequence map for the ovine MHC by shotgun sequencing of 26 overlapping BAC clones. DNA shotgun sequencing generated approximately 8-fold genome equivalent data that were successfully assembled into a finished sequence map of the ovine MHC. The sequence map spans approximately 2,434,000 nucleotides in length, covering almost all of the MHC loci currently known in the sheep and cattle. Gene annotation resulted in the identification of 177 protein-coding genes/ORFs, among which 145 were not previously reported in the sheep, and 10 were ovine species specific, absent in cattle or other mammals. A comparative sequence analyses among human, sheep and cattle revealed a high conservation in the MHC structure and loci order except for the class II, which were divided into IIa and IIb subregions in the sheep and cattle, separated by a large piece of non-MHC autosome of approximately 18.5 Mb. In addition, a total of 18 non-protein-coding microRNAs were predicted in the ovine MHC region for the first time. An ovine MHC DNA sequence map was successfully assembled by shotgun sequencing of 26 overlapping BAC clone. This makes the sheep the second ruminant species for which the complete MHC sequence information is available for evolution and functional studies, following that of the bovine. The results of the comparative analysis support a hypothesis that an inversion of the ancestral chromosome containing the MHC has shaped the MHC structures of ruminants, as we currently observed in the sheep and cattle. Identification of relative large numbers of microRNAs in the ovine MHC region helps to provide evidence that microRNAs are actively involved in the regulation of MHC gene expression and function.


A case of fatal intrahepatic cholestasis with primary AL amyloidosis: is early diagnosis possible?
Immunoglobulin light chain-associated (AL) amyloidosis is a multisystemic disorder characterized by extracellular deposition of immunoglobulin light chain produced by a proliferative plasma cell clone. Although the liver is the major organ involved in AL amyloidosis, hepatic involvement is often clinically asymptomatic and severe intrahepatic cholestasis as the primary manifestation of the disease is rare. A 60-year-old man with severe jaundice, massive ascites and highly elevated alkaline phosphatase was diagnosed with AL amyloidosis by a transjugular liver biopsy. He had undergone a yearly medical check that showed no abnormalities except for mild elevation of serum γ-glutamyltransferase at 1 year before admission. Owing to his poor condition and rapidly progressive liver and renal dysfunction, neither stem cell transplantation nor a combination of chemotherapeutic agents could be applied, and he died 1.5 months after admission. An autopsy revealed amyloid deposition in the systemic organs, and there was no evidence of multiple myeloma. Continuous elevation of γ-glutamyltransferase may be a useful marker for early diagnosis of fatal hepatic amyloidosis.


Initiation of sulfonylureas versus metformin is associated with higher blood pressure at one year.
To determine if incident oral antidiabetic drug (OAD) use was associated with 12-month systolic blood pressure (BP) and if this was mediated through body mass index (BMI) changes. A retrospective cohort of veterans with hypertension who initiated metformin (n = 2057) or sulfonylurea (n = 1494) between 1 January 2000 and 31 December 2007 in the Veterans Administration Mid-South Network was assembled. Patients were included if they had complete covariates, including 12-month BP and BMI, and persisted on therapy for 12 months. Linear regression was conducted to investigate the effect of OADs on 12-month systolic BP adjusting for demographics, glycated hemoglobin, creatinine, BMI, health care utilization, and comorbidities, including cardiovascular disease (CVD). A second analysis examined if these effects were mediated by BMI change. The secondary outcome was the proportion of patients who had a controlled BP (≤ 140/90 mmHg) at 12 months adjusted for baseline BP and covariates. Patients were white (82%) males (97%) with median age of 64 years (interquartile range [IQR] 57, 72), and 27% had history of CVD. Sulfonylurea users had a 1.33 mmHg (0.16, 2.50, p = 0.03) higher 12-month systolic BP than metformin users. The median change in BMI from OAD initiation to 12 months was -0.76 (IQR -1.78, 0.07) and 0.21 (IQR -0.57, 1.03) among metformin and sulfonylurea users, respectively. In a model adjusting for BMI change, the difference in 12-month systolic BP between sulfonylurea and metformin users became insignificant (0.23 (-1.00, 1.45), p = 0.72), while one BMI unit change was associated with an increase in 12-month systolic BP of 1.07 mmHg (0.74, 1.40, p < 0.0001). At 12 months, 68.3% of metformin patients had controlled BP versus 64.2% of sulfonylurea patients (p = 0.01). Compared with metformin, sulfonylurea initiation was associated with increased systolic BP at 12 months, which appears to be mediated by the differential effects of these drugs on BMI.


[Neuropathic pain treatment].
neuropathic pain is a frequent complication and results from numerous mechanisms, (infectious, post traumatic, metabolic, vascular) or toxic (i.e. medications). It is a complex entity due to its pathophysiology and its clinical features, but remains under diagnosed despite medical awareness. we reviewed the recent literature on evaluation and treatment of neuropathic pain with a focus on published guidelines. scales and questionnaires are available (DN 4, LANSS, etc.) but are not superior to anamnesis and a close physical examination. Usual treatments mostly based on empirical experiences are antidepressants, anti epileptics, calcium channels inhibitors, opioids, and cannabinoids. neuropathic pain is a complex and heterogeneous syndrome. Various medications are available but none is specific. The best choice is a drug with few interactions and side effects. Some preventive therapies are promising. We propose a practical guideline based on data from the literature.


Determination of natural killer cell function by flow cytometry.
Natural killer cells (NK cells) are a subset of peripheral blood lymphocytes that mediate non-major histocompatibility complex-restricted cytotoxicity of foreign target cells. The "gold standard" assay for NK cell activity has been the chromium release assay. This method is not easily performed in the clinical laboratory because of difficulties with disposal of radioactive and hazardous materials, short reagent half-lives, expense, and difficulties with assay standardization. We describe a flow cytometric assay for the clinical measurement of NK cell activity. This study compared the chromium release assay and the flow cytometric assay by using clinically relevant specimens. There were no significant differences between the two assays in the measurement of lytic activity for 17 peripheral blood specimens or in reproducibility in repeated samplings of healthy individuals. We also established a normal range of values for NK activity in healthy adults and identified a small cluster of individuals who have exceptionally high or low levels of NK activity. The flow cytometric assay was validated by testing specimens from subjects expected to have abnormally low levels of NK activity (pregnant women) and specimens from healthy individuals in whom the activity of NK cells was enhanced by exposure to interleukin-2 or alpha interferon. Treatment with these agents was associated with a significant increase in NK activity. These results confirm and extend those of others, showing that the flow cytometric assay is a viable alternative to the chromium release assay for measuring NK cell activity.


Setting up an ethics of ecosystem research structure based on the precautionary principle.
Ethical practices in ecological field research differ from those in laboratory research in more than the technical setting and the important distinction between population-level and individual-based concerns. The number of stakeholders affected by the conduct of field research is far larger; private landholders, public water utilities, public land managers, local industries, and communities large and small are only some of those who may be impacted. As research review boards move to establish specific ethical practices for field biologists, the process of identifying appropriate standards will affect the degree to which research will ultimately be disrupted. Standards that lead to research protocols that alienate key interests are not likely to be sustainable. Already, standards that have conflicted with the primary values of a key interest have resulted in disruptions to research and scientific progress. One way to manage this problem of deeply competing interests is to avoid the deepest offenses to any relevant interest group in the design of a proposed study. This is an application of the precautionary principle and is likely to generate a more sustainable balance among competing interests. Unfortunately, this process is also likely to be a never-ending, consensus-seeking process. Fortunately, scientists can have enormous influence on the process if they choose to engage in it early. If scientists use their expertise to function as honest brokers among affected interests, their own interest in scientific research progress is likely to be better met.


Genetic variation for outcrossing among Caenorhabditis elegans isolates.
The evolution of breeding systems results from the existence of genetic variation and selective forces favoring different outcrossing rates. In this study we determine the extent of genetic variation for characters directly related to outcrossing, such as male frequency, male mating ability, and male reproductive success, in several wild isolates of the nematode Caenorhabditis elegans. This species is characterized by an androdioecious breeding system in which males occur with hermaphrodites that can either self-fertilize or outcross with males. We find genetic variation for all characters measured, but also find that environmental variation is a large fraction of the total phenotypic variance. We further determine the existence of substantial genetic variation for population competitive performance in several laboratory environments. However, these measures are uncorrelated with outcrossing characters. The data presented here contribute to an understanding of male maintenance in natural populations through their role in outcrossing.


Labial adhesion in a reproductive aged girl.
This report describes a case of a 22-year-old girl who had labial adhesion. Her primary complaints were difficulty voiding and temporary urinary retention during menstruation for 10 years. The patient was evaluated and underwent surgical lysis of labial adhesion under regional anesthesia.


Lesbian and bisexual women in small cities--at risk for HIV? HIV Prevention Community Collaborative.
Objectives.Women who have sex with women are a relatively hidden group that has been overlooked in most AIDS research and prevention efforts, primarily because the efficiency of HIV transmission between female partners is believed to be low. Although data are scant, it is commonly assumed that members of this population are not at high risk for HIV infection. However, a recent study of lesbian and bisexual women living in the San Francisco Bay area reported a relatively high seroprevalence rate and has raised additional questions about this group's HIV risk. The present study, the first to focus on lesbian and bisexual women living outside major AIDS epicenters, provides additional evidence. It describes risk factors for HIV transmission among lesbian and bisexual women living in small cities in four geographic regions of the United States.Methods.On three consecutive evenings in 1992, members of the research team distributed anonymous structured written surveys to women patrons as they entered gay bars in each of 16 small cities.Results.Almost 17% of bisexual respondents and 0.5% of lesbians reported having had unprotected vaginal or anal sex with a male during the two months prior to the survey. Almost 10 percent of bisexual women and 8.8% of lesbians in the sample reported a history of injection drug use. Among those women surveyed who said they had been tested, 1.4% reported they were infected with HIV.Conclusions.Self-identified sexual orientation was highly consistent with recent sexual behavior. HIV risk related to sexual behavior was concentrated among self-identified bisexual women. The prevalence of injection drug use was substantial among both bisexual and lesbians. Developers of HIV risk behavior programs should take the prevalence of these risk behaviors into consideration in the design of effective HIV prevention interventions tailored to the needs of this hidden population.


Personalized HeartSteps: A Reinforcement Learning Algorithm for Optimizing Physical Activity.
With the recent proliferation of mobile health technologies, health scientists are increasingly interested in developing just-in-time adaptive interventions (JITAIs), typically delivered via notifications on mobile devices and designed to help users prevent negative health outcomes and to promote the adoption and maintenance of healthy behaviors. A JITAI involves a sequence of decision rules (i.e., treatment policies) that take the user's current context as input and specify whether and what type of intervention should be provided at the moment. In this work, we describe a reinforcement learning (RL) algorithm that continuously learns and improves the treatment policy embedded in the JITAI as data is being collected from the user. This work is motivated by our collaboration on designing an RL algorithm for HeartSteps V2 based on data collected HeartSteps V1. HeartSteps is a physical activity mobile health application. The RL algorithm developed in this work is being used in HeartSteps V2 to decide, five times per day, whether to deliver a context-tailored activity suggestion.


Dysregulation of in vitro cytokine production by monocytes during sepsis.
The production by monocytes of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) in intensive care unit (ICU) patients with sepsis syndrome (n = 23) or noninfectious shock (n = 6) is reported. Plasma cytokines, cell-associated cytokines within freshly isolated monocytes and LPS-induced in vitro cytokine production were assessed at admission and at regular intervals during ICU stay. TNF alpha and IL-6 were the most frequently detected circulating cytokines. Despite the fact that IL-1 alpha is the main cytokine found within monocytes upon in vitro activation of cells from healthy individuals, it was very rarely detected within freshly isolated monocytes from septic patients, and levels of cell-associated IL-1 beta were lower than those of TNF alpha. Cell-associated IL-1 beta and TNF alpha were not correlated with corresponding levels in plasma. Upon LPS stimulation, we observed a profound decrease of in vitro IL-1 alpha production by monocytes in all patients, and of IL-1 beta, IL-6, and TNF alpha in septic patients. This reduced LPS-induced production of cytokines was most pronounced in patients with gram-negative infections. Finally, monocytes from survival patients, but not from nonsurvival ones recovered their capacity to produce normal amounts of cytokines upon LPS stimulation. In conclusion, our data indicate an in vivo activation of circulating monocytes during sepsis as well as in noninfectious shock and suggest that complex regulatory mechanisms can downregulate the production of cytokines by monocytes during severe infections.


Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma: A subgroup analysis of the PETAL trial.
The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max ) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4 . For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4 , and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4 . At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.


Claudin-6, -10d and -10e contribute to seawater acclimation in the euryhaline puffer fish Tetraodon nigroviridis.
Expression profiles of claudin-6, -10d and -10e in the euryhaline teleost fish Tetraodon nigroviridis revealed claudin-6 in brain, eye, gill and skin tissue, while claudin-10d and -10e were found in brain, gill and skin only. In fishes, the gill and skin are important tissue barriers that interface directly with surrounding water, but these organs generally function differently in osmoregulation. Therefore, roles for gill and skin claudin-6, -10d and -10e in the osmoregulatory strategies of T. nigroviridis were investigated. In the gill epithelium, claudin-6, -10d and -10e co-localized with Na(+)-K(+)-ATPase immunoreactive (NKA-ir) ionocytes, and differences in sub-cellular localization could be observed in hypoosmotic (freshwater, FW) versus hyperosmotic (seawater, SW) environments. Claudin-10d and -10e abundance increased in the gills of fish acclimated to SW versus FW, while claudin-6 abundance decreased in the gills of fish acclimated to SW. Taken together with our knowledge of claudin-6 and -10 function in other vertebrates, data support the idea that in SW-acclimated T. nigroviridis, these claudins are abundant in gill ionocytes, where they contribute to the formation of a Na(+) shunt and 'leaky' epithelium, both of which are characteristic of salt-secreting SW fish gills. Skin claudin-10d and -10e abundance also increased in fish acclimated to SW versus those in FW, but so did claudin-6. In skin, claudin-6 was found to co-localize with NKA-ir cells, but claudin-10d and -10e did not. This study provides direct evidence that the gill epithelium contains salinity-responsive tight junction proteins that are abundant primarily in ionocytes. These same proteins also appear to play a role in the osmoregulatory physiology of the epidermis.


A PCR-based method for detecting the mycelia of stipitate hydnoid fungi in soil.
To reduce the reliance on sporocarp records for conservation efforts, information on the below-ground distribution of specific fungal species, such as stipitate hydnoid fungi, is required. Species-specific primers were developed within the internal transcribed spacer (ITS1 and ITS2) regions for 12 hydnoid fungal species including Bankera fuligineoalba, Hydnellum aurantiacum, H. caeruleum, H. concrescens, H. ferrugineum, H. peckii, Phellodon confluens, P. melaleucus, P. niger, P. tomentosus, Sarcodon glaucopus and S. squamosus. The specificity of the primer pairs was tested using BLAST searches and PCR amplifications. All primers amplified DNA only of the target species with the exception of those designed for P. melaleucus. In order to assess the ability of the primers to detect DNA from mycelium in soil, DNA extracted from soil samples taken from around solitary H. peckii sporocarps was amplified with the H. peckii primer 1peck and ITS2. H. peckii DNA was detected in 70% of all soil samples and up to 40 cm away from the base of individual sporocarps. The development of these species-specific primers provides a below-ground alternative for monitoring the distribution of these rare fungi.


Therapy-related longitudinal brain perfusion changes in patients with chronic pelvic pain syndrome.
The imaging method most frequently employed to identify brain areas involved in neuronal processing of nociception and brain pain perception is blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI). Arterial spin labelling (ASL), in contrast, offers advantages when slow varying changes in brain function are investigated. Chronic pelvic pain syndrome (CPPS) is a disorder of, mostly, young males that leads to altered pain perceptions in structures related to the pelvis. We aimed to investigate the potential of ASL to monitor longitudinal cranial blood flow (CBF) changes in patients with CPPS. In a randomised, placebo-controlled, double-blind single centre trial, we investigated treatment effects in CPPS after 12 weeks in patients that underwent sono-electro-magnetic therapy vs placebo. We investigated changes of CBF related to treatment outcome using pseudo-continuous arterial spin labelling (pCASL)-MRI. We observed CBF downregulation in the prefrontal cortex and anterior cingulate cortex and upregulation in the dorsolateral prefrontal cortex in responders. Nonresponders presented with CBF upregulation in the hippocampus. In patients with a history of CPPS of less than 12 months, there were significant correlations between longitudinal CBF changes and the Chronic Prostatitis Symptom Index pain subscore within the joint clusters anterior cingulate cortex and left anterior prefrontal cortex in responders, and the right hippocampus in nonresponders. We demonstrated therapy-related and stimulus-free longitudinal CBF changes in core areas of the pain matrix using ASL. ASL may act as a complementary noninvasive method to functional MRI and single-photon emission computed tomography / positron emission tomography, especially in the longitudinal assessment of pain response in clinical trials.


Lipid Raft Size and Lipid Mobility in Non-raft Domains Increase during Aging and Are Exacerbated in APP/PS1 Mice Model of Alzheimer's Disease. Predictions from an Agent-Based Mathematical Model.
A connection between lipid rafts and Alzheimer's disease has been studied during the last decades. Mathematical modeling approaches have recently been used to correlate the effects of lipid composition changes in the physicochemical properties of raft-like membranes. Here we propose an agent based model to assess the effect of lipid changes in lipid rafts on the evolution and progression of Alzheimer's disease using lipid profile data obtained in an established model of familial Alzheimer's disease. We have observed that lipid raft size and lipid mobility in non-raft domains are two main factors that increase during age and are accelerated in the transgenic Alzheimer's disease mouse model. The consequences of these changes are discussed in the context of neurotoxic amyloid β production. Our agent based model predicts that increasing sterols (mainly cholesterol) and long-chain polyunsaturated fatty acids (LCPUFA) (mainly DHA, docosahexaenoic acid) proportions in the membrane composition might delay the onset and progression of the disease.


Long-term continuous positive airway pressure therapy normalizes high exhaled nitric oxide levels in obstructive sleep apnea.
Upper airway inflammation and oxidative stress have been implicated in the pathogenesis of obstructive sleep apnea (OSA) and may be linked to cardiovascular consequences. We prospectively examined fraction of exhaled nitric oxide (FENO), a surrogate marker of upper airway inflammation using a portable nitric oxide analyzer (NIOX MINO). In consecutive adult nonsmokers with suspected OSA, FENO was measured immediately before and after polysomnographic studies, and within 1-3 months following continuous positive airway pressure (CPAP) therapy. FENO levels were increased in the 75 patients with OSA compared to the 29 controls, both before sleep (13.4 ± 6.5 ppb vs. 6.5 ± 3.5; p < 0.001) and after sleep (19.0 ± 7.7 ppb vs. 6.9 ± 3.7; p < 0.001). Furthermore, in patients with OSA, FENO levels were significantly higher post-sleep than pre-sleep (19.0 ± 7.7 ppb vs. 13.4 ± 6.5; p < 0.001), while there was no significant overnight change in patients without OSA. The rise in FENO correlated with the apnea-hypopnea index (r = 0.65, p < 0.001), nadir oxygen saturation (r = 0.54, p < 0.001), and arousal index (r = 0.52, p < 0.001). Thirty-seven of these patients underwent CPAP titration and treatment. Successful titration was associated with a lower overnight increase in FENO (7.2 ± 3.3 vs. 11.0 ± 4.3, p = 0.02). FENO levels declined after 1-3 months of CPAP therapy (11.7 ± 4.4 ppb, p < 0.001). FENO levels are elevated in OSA, correlate with severity, and decrease after positive pressure therapy. This study supports the role of upper airway inflammation in OSA pathogenesis and a possible role for FENO in monitoring CPAP therapy.


Stable epigenetic effects impact adaptation in allopolyploid orchids (Dactylorhiza: Orchidaceae).
Epigenetic information includes heritable signals that modulate gene expression but are not encoded in the primary nucleotide sequence. We have studied natural epigenetic variation in three allotetraploid sibling orchid species (Dactylorhiza majalis s.str, D. traunsteineri s.l., and D. ebudensis) that differ radically in geography/ecology. The epigenetic variation released by genome doubling has been restructured in species-specific patterns that reflect their recent evolutionary history and have an impact on their ecology and evolution, hundreds of generations after their formation. Using two contrasting approaches that yielded largely congruent results, epigenome scans pinpointed epiloci under divergent selection that correlate with eco-environmental variables, mainly related to water availability and temperature. The stable epigenetic divergence in this group is largely responsible for persistent ecological differences, which then set the stage for species-specific genetic patterns to accumulate in response to further selection and/or drift. Our results strongly suggest a need to expand our current evolutionary framework to encompass a complementary epigenetic dimension when seeking to understand population processes that drive phenotypic evolution and adaptation.


Repeat variants for the SbMATE transporter protect sorghum roots from aluminum toxicity by transcriptional interplay in cis and trans.
Acidic soils, where aluminum (Al) toxicity is a major agricultural constraint, are globally widespread and are prevalent in developing countries. In sorghum, the root citrate transporter SbMATE confers Al tolerance by protecting root apices from toxic Al3+, but can exhibit reduced expression when introgressed into different lines. We show that allele-specific SbMATE transactivation occurs and is caused by factors located away from SbMATE Using expression-QTL mapping and expression genome-wide association mapping, we establish that SbMATE transcription is controlled in a bipartite fashion, primarily in cis but also in trans Multiallelic promoter transactivation and ChIP analyses demonstrated that intermolecular effects on SbMATE expression arise from a WRKY and a zinc finger-DHHC transcription factor (TF) that bind to and trans-activate the SbMATE promoter. A haplotype analysis in sorghum RILs indicates that the TFs influence SbMATE expression and Al tolerance. Variation in SbMATE expression likely results from changes in tandemly repeated cis sequences flanking a transposable element (a miniature inverted repeat transposable element) insertion in the SbMATE promoter, which are recognized by the Al3+-responsive TFs. According to our model, repeat expansion in Al-tolerant genotypes increases TF recruitment and, hence, SbMATE expression, which is, in turn, lower in Al-sensitive genetic backgrounds as a result of lower TF expression and fewer binding sites. We thus show that even dominant cis regulation of an agronomically important gene can be subjected to precise intermolecular fine-tuning. These concerted cis/trans interactions, which allow the plant to sense and respond to environmental cues, such as Al3+ toxicity, can now be used to increase yields and food security on acidic soils.


Quantitative approach using multiple single parameters versus visual assessment in dobutamine stress echocardiography.
A number of myocardial Doppler-derived velocity, strain myocardial imaging parameters (DMI) and speckle tracking imaging (STI) have been proposed for the quantification of myocardial ischemia during stress echocardiography. The purpose of the study was to identify the best single ultrasound quantitative parameter for prediction of significant coronary stenosis and compare it with visual assessment during dobutamine stress echocardiography (DSE). Prospective analysis included data of 151 patients (age 61.8 ± 9.2) who underwent dobutamine stress echocardiography for known (n = 35) or suspected coronary artery disease (CAD) (n = 36) or symptomatic chest pain (n = 80), excluding patients with previous myocardial infarction. Systolic, post-systolic and diastolic velocities, strain and strain rate parameters were obtained at rest and at peak dobutamine challenge. Derivative markers as E'/A' ratio, post-systolic index and changes from rest to stress were calculated (98 parameters overall, predominantly longitudinal). Coronary angiography was chosen as reference method considering at least one stenosis ≥70% per patient as significant CAD. The predictive value of quantitative parameters and wall motion score index (WMSI) was obtained using logistic regression and ROC analysis. The value of single parameters discriminated as independent predictors of CAD appeared to be modest (area under the curve [AUC] ranged from 0.63 to 0.72 for 16 PW-DMI, 12 CC-DMI and 12 STI markers), comparing to AUC of WMSI 0.88. Sensitivity, specificity and accuracy of visual DSE evaluation was 82.4% (95%CI 77.4%; 85.2%), 92.6% (95%CI 83.4%; 97.5%) and 86.0% (95%CI 79.5%; 89.6%), respectively, Youden index 0.75. Sensitivity, specificity and accuracy of single predictors ranged from 40.0% to 93.3% (95% CI 22.7%; 99.2%), from 34.2% to 88.7% (95% CI 25.6%; 94.1%) and from 45.8% to 80.0% (95% CI 37.5%; 87.2%) respectively, Youden index ranged from 0.20 to 0.52. Multiple single quantitative parameters showed limited predictive ability to identify significant coronary artery stenosis. Visual assessment of DSE appears to be more accurate than single velocity and strain/strain rate markers in the diagnosis of CAD.


A two-stage fuzzy chance-constrained water management model.
In this study, an inexact two-stage fuzzy gradient chance-constrained programming (ITSFGP) method is developed and applied to the water resources management in the Heshui River Basin, Jiangxi Province, China. The optimization model is established by incorporating interval programming, two-stage stochastic programming, and fuzzy gradient chance-constrained programming within an optimization framework. The hybrid model can address uncertainties represented as fuzzy sets, probability distributions, and interval numbers. It can effectively tackle the interactions between pre-regulated economic targets and the associated environmental penalties attributed to water allocation schemes and reflect the tradeoffs between economic revenues and system-failure risk. Furthermore, uncertainties associated with the decision makers' preferences are considered in decision-making processes. The obtained results can provide decision support for the local sustainable economic development and water resources allocation strategies under multiple uncertainties.


[Severe acute pancreatitis: prognosis and treatment implications].
Severe acute pancreatitis (SAP) is a very important cause of morbi-mortality inside the context of gastrointestinal diseases, and there is still some controversy in important points regarding its medical and surgical management. The present review article assesses and compares the results and conclusions of several clinical trials with respect the staging of severity, supportive measurements, prophylactic antibiotics, surgical treatment of infected and sterile necrosis and the implications that such studies have in the prognosis and management of SAP. Endoscopic techniques of treatment are beyond the scope in this review.


The replication of plant virus RNA.
The roles of plant-encoded RNA-dependent RNA polymerases and viral RNA replicases in the replication of plant viral RNA are reviewed with respect to the positive single-stranded TYMV, CPMV and BMV.


Macrophage activation induced by lymphocyte mediators.
This paper is a brief review of studies which demonstrate that lymphocyte mediators can activate macrophages in vitro. Macrophages which have been incubated in lymphocyte mediator-rich Sephadex fractions show changed morphology, metabolism and function. These changes include an increase in adherence to glass. ruffled membrane movement, phagocytosis of some particles, glucose oxidation through the hexose monophosphate shunt and an increase in the activity of a membrane enzyme, adenylate cyclase. Such mediator-activated macrophages show enhanced bacteriostasis and tumoricidal activity. In addition, studies describing the role of membrane sugars and esterases in the interaction of migration inhibition factor and macrophages are reviewed.


Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy.
Wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage, the clinical course varies substantially between individuals. There are currently no established measures of rate of disease progression. Through systematic analysis of functional, biochemical and echocardiographic disease-related variables we aimed to identify prognostic markers of disease progression in wtATTR-CM. This is a retrospective observational study of 432 patients with wtATTR-CM diagnosed at the UK NAC, none of whom received disease-modifying therapy. The association between mortality from the 12-month timepoint and change from diagnosis to 12 months in a variety of disease-related variables was explored using Cox regression. Change in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) at 12 months from diagnosis was the strongest predictor of ongoing mortality and was independent of both change in other disease-related variables (HR 1.04 per 500 ng/L increase (95% CI 1.01 to 1.07); p=0.003) and a range of known prognostic variables at the time of diagnosis (HR 1.07 per 500 ng/L increase (95% CI 1.02 to 1.13); p=0.007). An increase in NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L during the first year of follow-up occurred in 45%, 35% and 16% of patients, respectively. Change in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.


Ultrasound Guided Out-of-Plane Versus In-Plane Transpectoral Left Axillary Vein Cannulation.
The primary objective was to compare the frequency of first-attempt successful axillary vein cannulation by the Seldinger technique using out-of-plane ultrasound guidance versus in-plane imaging. Between the two ultrasound imaging planes, this study also compared the number of attempts that were necessary for the cannulation of the left axillary vein along with the number of needle redirections that had to be done for final cannulation of the vein. Incidence of complications and the number of times the procedure was abandoned also were compared between the two imaging planes. Prospective, randomized, interventional study. Tertiary care cardiac center. Cardiac surgical patients. Left axillary vein cannulation under ultrasound guidance by Seldinger technique. The left axillary vein was accessed under ultrasound guidance in 86 consecutive adult cardiac surgical patients. They were randomized to out-of-plane (Group I, n = 43) and in-plane (Group II, n = 43) groups. In group I, the number of first-attempt cannulations was very high (p < 0.01). The number of attempts to access the vein was significantly lower in this group (p < 0.05). The duration for completion of the procedure was also less in group I with out-of-plane ultrasound guidance (p < 0.01). The number of needle redirections and the incidence of complications (arterial puncture, pneumothorax hematoma formation) were similar between the groups. There was no difference in the number of times the procedure was abandoned between the two groups. With an assumption that the first 10 patients in each group would suffice for overcoming the learning curve, the above aspects were analyzed further in each group. The first-attempt cannulation success continued to be significantly higher in the out-of-plane group. Out-of-plane ultrasound imaging during axillary vein cannulation increased the chance of first-attempt successful cannulation. Axillary vein cannulation under out-of-plane ultrasound imaging also appeared to be quicker and was preferable in terms of the fewer number of attempts that were necessary for a successful vein cannulation.


Epidemiology of shoulder dislocations presenting to United States emergency departments: An updated ten-year study.
Glenohumeral dislocation is a common injury that may predispose patients to chronic pain and instability. However, there is a paucity of current data available regarding the epidemiological trends of this injury. To provide an updated, comparative assessment of the epidemiology of shoulder dislocations presenting to emergency departments in the United States. We also sought to analyze patient demographic risk factors and consumer products associated with dislocation events. Data were obtained from the national electronic injury surveillance system database for glenohumeral dislocations between 2012 and 2021. Incidence, age, sex, and injury characteristics were analyzed using weighted population statistics as well as incidence rates and 95% confidence intervals (CI). In total, an estimated 773039 shoulder dislocations (CI: 640598-905481) presented to emergency rooms across the United States during the study period. The annual incidence rate was 23.96 per 100000 persons and the average patient age at the time of injury was 37.1 years. Significantly more male patients sustained dislocations than female patients (537189, 69.5%, vs 235834, 30.5%, P < 0.001). With regard to associated consumer products, sports and recreation equipment were involved in the highest proportion of incidents (44.31%), followed by home structures and construction materials (21.22%), and home furnishings, fixtures, and accessories (21.21%). Regarding product sub-groups, stairs, ramps, landings, floors was cited in the greatest number of cases (131745). The national annual incidence rate of glenohumeral dislocations throughout the study period was approximately 23.92 per 100000 persons. Male adolescents sustained the highest proportion of dislocations, with a peak incidence in age group 15-20 years, predominantly secondary to participation in sporting and recreational activities. Conversely, women experienced a relatively consistent incidence of dislocation throughout their lifespan. After age 63, the incidence rate of dislocations in females was found to surpass that observed in males.


Psychological aspects of bone marrow transplantation: a retrospective study of 17 long-term survivors.
In a retrospective study 17 patients were interviewed 1-5 years after bone marrow transplantation (BMT) about their emotional experiences and about the information and support given to them. In all patients the illness, the BMT and its consequences created severe emotional strain; their psychological state was closely linked to their physical condition. Yet, most patients showed a surprising emotional elasticity and affective adjustment. Although the patients were overwhelmingly positive about the information and support they had received, an important number of them felt inadequately prepared for the emotional and sexual problems they had to face in the first period after discharge. The results of this study have led to structural changes in the psychiatric and psychosocial approach to the BMT patients.


Watch Out for Your Neighbor: Climbing onto Shrubs Is Related to Risk of Cannibalism in the Scorpion Buthus cf. occitanus.
The distribution and behavior of foraging animals usually imply a balance between resource availability and predation risk. In some predators such as scorpions, cannibalism constitutes an important mortality factor determining their ecology and behavior. Climbing on vegetation by scorpions has been related both to prey availability and to predation (cannibalism) risk. We tested different hypotheses proposed to explain climbing on vegetation by scorpions. We analyzed shrub climbing in Buthus cf. occitanus with regard to the following: a) better suitability of prey size for scorpions foraging on shrubs than on the ground, b) selection of shrub species with higher prey load, c) seasonal variations in prey availability on shrubs, and d) whether or not cannibalism risk on the ground increases the frequency of shrub climbing. Prey availability on shrubs was compared by estimating prey abundance in sticky traps placed in shrubs. A prey sample from shrubs was measured to compare prey size. Scorpions were sampled in six plots (50 m x 10 m) to estimate the proportion of individuals climbing on shrubs. Size difference and distance between individuals and their closest scorpion neighbor were measured to assess cannibalism risk. The results showed that mean prey size was two-fold larger on the ground. Selection of particular shrub species was not related to prey availability. Seasonal variations in the number of scorpions on shrubs were related to the number of active scorpions, but not with fluctuations in prey availability. Size differences between a scorpion and its nearest neighbor were positively related with a higher probability for a scorpion to climb onto a shrub when at a disadvantage, but distance was not significantly related. These results do not support hypotheses explaining shrub climbing based on resource availability. By contrast, our results provide evidence that shrub climbing is related to cannibalism risk.


Semiconductor diode laser device adjuvanting intradermal vaccine.
A brief exposure of skin to a low-power, non-tissue damaging laser light has been demonstrated to augment immune responses to intradermal vaccination. Both preclinical and clinical studies show that this approach is simple, effective, safe and well tolerated compared to standard chemical or biological adjuvants. Until now, these laser exposures have been performed using a diode-pumped solid-state laser (DPSSL) devices, which are expensive and require labor-intensive maintenance and special training. Development of an inexpensive, easy-to-use and small device would form an important step in translating this technology toward clinical application. Here we report that we have established a handheld, near-infrared (NIR) laser device using semiconductor diodes emitting either 1061, 1258, or 1301nm light that costs less than $4000, and that this device replicates the adjuvant effect of a DPSSL system in a mouse model of influenza vaccination. Our results also indicate that a broader range of NIR laser wavelengths possess the ability to enhance vaccine immune responses, allowing engineering options for the device design. This small, low-cost device establishes the feasibility of using a laser adjuvant approach for mass-vaccination programs in a clinical setting, opens the door for broader testing of this technology with a variety of vaccines and forms the foundation for development of devices ready for use in the clinic.


A Bayesian network model to assess the public health risk associated with wet weather sewer overflows discharging into waterways.
Overflows from sanitary sewers during wet weather, which occur when the hydraulic capacity of the sewer system is exceeded, are considered a potential threat to the ecological and public health of the waterways which receive these overflows. As a result, water retailers in Australia and internationally commit significant resources to manage and abate sewer overflows. However, whilst some studies have contributed to an increased understanding of the impacts and risks associated with these events, they are relatively few in number and there still is a general lack of knowledge in this area. A Bayesian network model to assess the public health risk associated with wet weather sewer overflows is presented in this paper. The Bayesian network approach is shown to provide significant benefits in the assessment of public health risks associated with wet weather sewer overflows. In particular, the ability for the model to account for the uncertainty inherent in sewer overflow events and subsequent impacts through the use of probabilities is a valuable function. In addition, the paper highlights the benefits of the probabilistic inference function of the Bayesian network in prioritising management options to minimise public health risks associated with sewer overflows.


Glutamate transport asymmetry in renal glutamine metabolism.
D-Glutamate (Glu) was previously shown to block L-Glu uptake and accelerate glutaminase flux in cultured kidney cells [Welbourne, T. C., and D. Chevalier. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E367-E370, 1997]. To test whether D-Glu would be taken up by the intact functioning kidney and effect the same response in vivo, male Sprague-Dawley rats were infused with D-Glu (2.6 mumol/min), and renal uptake of D- and L-Glu was determined from chemical and radiolabeled arteriovenous Glu concentration differences times renal plasma flow. The amount removed was then compared with that amount filtered to obtain the antiluminal contribution. In the controls, L-Glu uptake measured as net removal was 33% of the arterial L-Glu load and not different from that filtered, 27%; however, the unidirectional uptake was actually 58% of the arterial load, indicating that antiluminal uptake contributes at least half to the overall Glu consumption. Surprisingly, the kidneys showed a more avid removal of D-Glu, removing 73% of the arterial load, indicating uptake predominantly across the antiluminal cell surface. Furthermore, uptake of D-Glu was associated with a 55% reduction in L-Glu uptake, with the residual amount taken up equivalent to that filtered; D-Glu did not increase the excretion of the L-isomer. However, elevating plasma L-Glu concentration reduced uptake of the D-isomer, suggesting a shared antiluminal transporter. Thus there is an apparent asymmetrical distribution of the D-Glu transporter. Under these conditions, kidney cortex L-Glu content decreased 44%, whereas net glutamine (Gln) uptake increased sevenfold (170 +/- 89 to 1,311 +/- 219 nmol/min, P < 0.01) and unidirectional uptake nearly threefold (393 +/- 121 to 1,168 +/- 161 nmol/min, P < 0.05); this large Gln consumption was paralleled by an increase in ammonium production so that the ratio of production to consumption approaches 2, consistent with accelerated Gln deamidation and subsequent Glu deamination. These results point to a functional asymmetry (antiluminal vs. luminal) for Glu transporter activity, which potentially plays an important role in modulating Gln metabolism and renal function.


Reconstruction of the pinna using pre-auricular flaps.
The pre-auricular skin reservoir provides an excellent source of full thickness skin for reconstruction of defects of the pinna. Pre-auricular flaps may be based superiorly or inferiorly. The skin texture and color match is ideal for pinna reconstruction.


A New, Noninvasive Accelerometric Method for Diagnosing Acid andNon-Acid Gastroesophageal Reflux in Premature Infants: Proof of Concept.
Non-acid reflux is common in premature neonates. Current methods of diagnosing gastroesophageal reflux (GER) such as pH probes, multichannel impedance monitoring, X-rays, or endoscopy are either invasive or unable to diagnose non-acid reflux. Passage of a naso-esophageal tube is uncomfortable. Imaging studies are of short duration and may miss reflux entirely. Herein, we present proof of concept of a noninvasive accelerometric device that detects acid and non-acid reflux in premature infants. An accelerometer was taped over the subxiphoid process in patients suspected of having GER who were already scheduled for pH probe or multichannel impedance monitoring. The largest cohort was preterm infants, but term infants and toddlers were also studied. Low-frequency subaudible signals were obtained on a digital recorder (sampling rate 200 Hz) signals. Fast Fourier transforms graphically displayed the frequency and amplitude of signals. Data were then resampled at a rate of 60 Hz to create a spectrogram with a focused range of 0-30 Hz representing reflux-associated events. Proof of concept was attained through successful comparison with results from concurrent pH probes, multichannel impedance recordings, and ultrasound studies. We have thus validated accelerometry as a noninvasive method for assessing both acid and non-acid GER. The noninvasiveness of this diagnostic modality allows for repeated testing to assess the efficacy of anti-reflux medications, even when patients remain on antacids. This technology allows for more rational management of patients with GER and represents a major advance in the diagnosis and treatment of GER.


Predicting the likelihood of hemorrhage in patients with stroke.
To identify those clinical findings that independently help differentiate intracranial hemorrhage from cerebral infarction, we studied patients who were admitted to a hospital with acute focal neurologic deficits after strokes during a 17-month period. The predictive strength of a decision-making aid incorporating these findings was then assessed by studying patients who were admitted to a different hospital after experiencing strokes. The decision-making aid stratified the patients into groups having probabilities of intracranial hemorrhage ranging from 5% to 67%. The results of this study may facilitate more discriminating test selection during the early evaluation of patients who have had strokes.


Active learning with point supervision for cost-effective panicle detection in cereal crops.
Panicle density of cereal crops such as wheat and sorghum is one of the main components for plant breeders and agronomists in understanding the yield of their crops. To phenotype the panicle density effectively, researchers agree there is a significant need for computer vision-based object detection techniques. Especially in recent times, research in deep learning-based object detection shows promising results in various agricultural studies. However, training such systems usually requires a lot of bounding-box labeled data. Since crops vary by both environmental and genetic conditions, acquisition of huge amount of labeled image datasets for each crop is expensive and time-consuming. Thus, to catalyze the widespread usage of automatic object detection for crop phenotyping, a cost-effective method to develop such automated systems is essential. We propose a point supervision based active learning approach for panicle detection in cereal crops. In our approach, the model constantly interacts with a human annotator by iteratively querying the labels for only the most informative images, as opposed to all images in a dataset. Our query method is specifically designed for cereal crops which usually tend to have panicles with low variance in appearance. Our method reduces labeling costs by intelligently leveraging low-cost weak labels (object centers) for picking the most informative images for which strong labels (bounding boxes) are required. We show promising results on two publicly available cereal crop datasets-Sorghum and Wheat. On Sorghum, 6 variants of our proposed method outperform the best baseline method with more than 55% savings in labeling time. Similarly, on Wheat, 3 variants of our proposed methods outperform the best baseline method with more than 50% of savings in labeling time. We proposed a cost effective method to train reliable panicle detectors for cereal crops. A low cost panicle detection method for cereal crops is highly beneficial to both breeders and agronomists. Plant breeders can obtain quick crop yield estimates to make important crop management decisions. Similarly, obtaining real time visual crop analysis is valuable for researchers to analyze the crop's response to various experimental conditions.


Impact of DNA-Encoded Chemical Library Technology on Drug Discovery.
DNA-Encoded Chemical Libraries (DELs) have gained momentum over the recent years for the discovery of small-molecule ligands and the technology has been integrated in most of the larger pharmaceutical companies. With this perspective we would like to summarize the development of DEL technology and present some representative DEL-derived hits which may soon enter the pharmaceutical market.


BET protein inhibitor JQ1 attenuates Myc-amplified MCC tumor growth in vivo.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin currently with no cure. In this study, we have first demonstrated that c-Myc overexpression is common in MCC. By targeting c-Myc, bromodomain inhibitors have demonstrated antitumor efficacy in several preclinical human cancer models. Thus, we interrogated the role of c-Myc inhibition in MCC with c-Myc amplification by using the BET inhibitor JQ1. We have uncovered that c-Myc can be regulated by JQ1 in MCC cells with pathologic c-Myc activation. Moreover, JQ1 potently abrogates c-Myc expression in MCC cells and causes marked G1 cell-cycle arrest. Mechanistically, JQ1-induced cell-cycle arrest coincides with downregulation of cyclin D1 and upregulation of p21, p27, and p57, whereas JQ1 exerts no effect on apoptosis in MCC cells. Further knockdown of p21, p27, or p57 by shRNA partially protects cells from JQ1-induced cell-cycle arrest. In addition, c-Myc knockdown by shRNA generates significant cell-cycle arrest, suggesting that c-Myc overexpression plays a role in MCC pathogenesis. Most importantly, JQ1 significantly attenuates tumor growth in xenograft MCC mouse models. Our results provide initial evidence, indicating the potential clinical utility of BET protein inhibitors in the treatment of MCC with pathologic activation of c-Myc.


Tetracycline-labeled human bone from ancient Sudanese Nubia (A.D. 350).
Nubian bone recovered from an X-group cemetery (A.D. 350 to 550) exhibits a pattern of fluorescence identical to that of modern tetracycline-labeled bone. When it is viewed under ultraviolet light at 490 angstroms, fluorophors are visible as a characteristic yellow-green fluorescence on surfaces that were actively mineralizing at the time of exposure. Contamination of stored grains provided the proper environment for cultivation of tetracycline-producing Streptomycetes. Evidence for exposure to antibiotics in an archeological population is relevant to studies of the evolution of R factors and to the interpretation of health and disease within the population.


Atomistic amorphous/crystalline interface modelling for superlattices and core/shell nanowires.
In this paper we present a systematic and well controlled procedure for building atomistic amorphous/crystalline interfaces in silicon, dedicated to the molecular dynamics simulations of superlattices and core/shell nanowires. The obtained structures depend on the technique used to generate the amorphous phase and their overall quality is estimated through comparisons with structural information and interfacial energies available from experimental and theoretical results. While most of the related studies focus on a single planar interface, we consider here both the generation of multiple superlattice planar interfaces and core/shell nanowire structures. The proposed method provides periodic homogeneous and reproducible, atomically sharp and defect free interface configurations at low temperature and pressure. We also illustrate how the method may be used to predict the thermal transport properties of composite crystalline/amorphous superlattices.


The impact of hospital harm on length of stay, costs of care and length of person-centred episodes of care: a retrospective cohort study.
There is a lack of data in Canada on the longitudinal effects of adverse events that occur in hospital, specifically in the period after discharge. Our objective was to quantify the impact of adverse events on hospital length of stay, length of person-centred episodes of care (PCEs) and costs of PCEs, as well as their impact on the total health system. We conducted a population-based, retrospective cohort study using linked health administrative databases. We included adults in Ontario who had an acute hospital admission between Apr. 1, 2015, and Mar. 31, 2016. We grouped hospital admissions into 1 of 9 episode types and used the Canadian Institute for Health Information methodology for hospital harm to measure adverse events. We specified generalized linear models to estimate the impact of hospital harm on the following: incremental length of index acute hospital admission, incremental length of the PCE, and incremental costs of the PCE. Out of 610 979 hospital admissions, 36 004 (5.9%) involved an occurrence of harm. The impact of harm on the incremental length of hospital stay ranged from 0.4 to 24.2 days (p < 0.001); the incremental length of the PCE ranged from 0.3 to 30.2 days (p < 0.001); and the incremental costs of the PCE ranged from $800 to $51 067 (p < 0.001). Total hospital days attributable to hospital harm amounted to 407 696, and the total attributable cost to the Ontario health system amounted to $1 088 330 376. We found that experiencing harm in hospital significantly affects both in-hospital and post-discharge use of health services and costs of care, and constitutes an enormous expense to Ontario's publicly funded health system.


Comparison of clinical course of Mpox among HIV-negative and HIV-positive patients: A 2022 cohort of hospitalized patients in Central Europe.
Mpox has become the most significant orthopoxviral infection among humans. Since May 2022, there has been a multicountry outbreak of mpox across six continents. Retrospective observational cohort study of 94 patients with probable or confirmed mpox of whom 86.2% were hospitalized in Hospital for Infectious Diseases in Warsaw, Poland between May 16 and October 30, 2022. Most patients were young (median age: 31, IQR: 25-43 years), predominantly (88.3%) Polish men who have sex with men exposed most commonly in Poland (82.7%), Spain (6.2%), or Germany (4.9%). The median observed mpox incubation period was 7 (IQR: 4-8) days with the median hospitalization time of 7 (range: 2-24, IQR: 5-11) days. History of sexually transmitted infections (STIs) was common in the group (previous syphilis or hepatitis C virus in 33.3% and 17.3%, respectively, 6.2% of early syphilis or gonorrhea). A significant proportion (n = 43, 45.7%) of mpox cases were people with human immunodeficiency virus (HIV), all except one were on stable and virologically effective (88.4% with HIV viral load <50 copies/mL) antiretroviral treatment. Chemsex was reported in 34.6% of hospitalized cases, more commonly among people with HIV (48.5% vs. 25.0%, p = 0.029). None of the mpox infected patients presented with advanced HIV infection. Despite the fact that 6.3% of cases presented with >50 skin lesions the course of the disease was self-limited with no severe cases or deaths. There were no significant clinical or laboratory differences or complication rates between patients with and without HIV coinfection. Epidemiological and clinical characteristics of mpox in Poland are similar to other countries, but there were no targeted, population oriented interventions or vaccination programs. Mpox diagnosis provided an opportunity to screen and diagnose other STIs. As Central European populations, including refugees from Ukraine, are largely unvaccinated against mpox access to preventive vaccinations and antiviral therapy should be maximized.


Cost-effectiveness of minimally invasive midline lumbar interbody fusion versus traditional open transforaminal lumbar interbody fusion.
The midline transforaminal lumbar interbody fusion (MIDLIF) using cortical screw fixation is a novel, minimally invasive procedure that may offer enhanced recovery over traditional open transforaminal lumbar interbody fusion (TLIF). Little information is available regarding the comparative cost-effectiveness of the MIDLIF over conventional TLIF. The purpose of this study was to compare cost-effectiveness of minimally invasive MIDLIF with open TLIF. From a prospective, multisurgeon, surgical database, a consecutive series of patients undergoing 1- or 2-level MIDLIF for degenerative lumbar conditions was identified and propensity matched to patients undergoing TLIF based on age, sex, smoking status, BMI, diagnosis, American Society of Anesthesiologists Physical Status Classification System (ASA) class, and levels fused. Direct costs at 1 year were collected, including costs associated with the index surgical visit as well as costs associated with readmission. Improvement in health-related quality of life was measured using EQ-5D and SF-6D. Of 214 and 181 patients undergoing MIDLIF and TLIF, respectively, 33 cases in each cohort were successfully propensity matched. Consistent with propensity matching, there was no difference in age, sex, BMI, diagnosis, ASA class, smoking status, or levels fused. Spondylolisthesis was the most common indication for surgery in both cohorts. Variable direct costs at 1 year were $2493 lower in the MIDLIF group than in the open TLIF group (mean $15,867 vs $17,612, p = 0.073). There was no difference in implant (p = 0.193) or biologics (p = 0.145) cost, but blood utilization (p = 0.015), operating room supplies (p < 0.001), hospital room and board (p < 0.001), pharmacy (p = 0.010), laboratory (p = 0.004), and physical therapy (p = 0.009) costs were all significantly lower in the MIDLIF group. Additionally, the mean length of stay was decreased for MIDLIF as well (3.21 vs 4.02 days, p = 0.05). The EQ-5D gain at 1 year was 0.156 for MIDLIF and 0.141 for open TLIF (p = 0.821). The SF-6D gain at 1 year was 0.071 for MIDLIF and 0.057 for open TLIF (p = 0.551). Compared with patients undergoing traditional open TLIF, those undergoing MIDLIF have similar 1-year gains in health-related quality of life, with total direct costs that are $2493 lower. Although the findings were not statistically significant, minimally invasive MIDLIF showed improved cost-effectiveness at 1 year compared with open TLIF.


Role of fibronectin in the migration of fibroblasts into plasma clots.
The adhesion and migration of human diploid fibroblasts on plasma clots were measured. The role of plasma fibronectin was examined by depleting plasma of fibronectin before clotting. Fibronectin was not essential for cell adhesion and spreading, although rates were slightly slower on depleted clots. Rates of migration on the surface of clots were unaffected by fibronectin depletion. In contrast, fibronectin was an absolute requirement for migration of cells into plasma clots. Cells migrated rapidly into control clots but completely failed to penetrate the surface of fibronectin-depleted clots. The effect of depletion could only be reversed by adding fibronectin to depleted plasma before clotting. Adsorption of fibronectin after clotting failed to reverse the effect of depletion, suggesting that fibronectin had to be cross-linked by transglutaminase during the clotting process.


Multi-PIE.
A close relationship exists between the advancement of face recognition algorithms and the availability of face databases varying factors that affect facial appearance in a controlled manner. The CMU PIE database has been very influential in advancing research in face recognition across pose and illumination. Despite its success the PIE database has several shortcomings: a limited number of subjects, single recording session and only few expressions captured. To address these issues we collected the CMU Multi-PIE database. It contains 337 subjects, imaged under 15 view points and 19 illumination conditions in up to four recording sessions. In this paper we introduce the database and describe the recording procedure. We furthermore present results from baseline experiments using PCA and LDA classifiers to highlight similarities and differences between PIE and Multi-PIE.


Clinical pharmacology of bleomycin and cisplatin.
Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs, with activity for head and neck tumors, that were introduced into clinical use in the past ten years. Bleomycin is used primarily in the chemotherapy of squamous cell carcinomas, lymphomas, and testicular carcinoma, while cisplatin possesses significant activity against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (terminal phase half-life = 2-4 h), although enzymatic inactivation also occurs in many tissues. Cisplatin is nonenzymatically converted to highly protein bound metabolites, which then undergo renal elimination, but total body clearance occurs much more slowly than with bleomycin (terminal phase half-life = 40-50 h). Both agents have acute and chronic toxicities; the acute toxicities are generally reversible but cause a great deal of patient discomfort, while the chronic toxicities are often irreversible and dose-limiting. For bleomycin, the acute toxicities are mucocutaneous are pyretic; severe nausea and vomiting represents the major acute toxicity of cisplatin therapy. Cumulative dose-related pulmonary toxicity is the most serious chronic toxicity of bleomycin. The clinical, radiographic, and pathologic presentations are nonspecific, although identification of high risk patients may be possible with serial pulmonary function tests. Cumulative nephrotoxicity occurs with cisplatin use, and its incidence and severity can be reduced by maintaining adequate hydration and diuresis during and following administration of the drug.


Simultaneous determination of 44 pesticides in tobacco by UPLC/MS/MS and a modified QuEChERS procedure.
A novel, simple, and rapid method for determination of the residues of 44 commonly used pesticides in tobacco was developed based on modified Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) procedures. The pesticides were extracted with acetonitrile and purified on a mixed sorbents column of primary secondary amine, C18, and graphitized carbon black. Quantitative determination of all pesticides was performed by ultra-performance LC/MS/MS in the positive or negative ionization mode by a single run due to the fast polarity switching capability of the mass spectrometer. Two precursor-product ion transitions were monitored for each compound in the multiple reaction monitoring mode. Quantification was carried out using matrix-matched standard calibration. The method has been validated by various tobacco cultivars, such as Burley, Oriental, and Virginia from different countries. Recoveries of the proposed method for spiked samples ranged from 71.1 to 109.8%, and RSD values were below 10%. The LOQ values were are all below the guidance residue levels proposed by the Agrochemical Advisory Committee of Cooperation Center for Scientific Research Relative to Tobacco. This method is valuable for measurement of pesticide residues in tobacco for QC and monitoring.


Acute hepatitis C virus structural gene sequences as predictors of persistent viremia: hypervariable region 1 as a decoy.
We hypothesized that hepatitis C virus (HCV) persistence is related to the sequence variability of putative envelope genes. This hypothesis was tested by characterizing quasispecies in specimens collected every six months from a cohort of acutely HCV-infected subjects (mean duration of specimen collection, 72 months after seroconversion). We evaluated 5 individuals who spontaneously cleared viremia and 10 individuals with persistent viremia by cloning 33 1-kb amplicons that spanned E1 and the 5' half of E2, including hypervariable region 1 (HVR1). To assess the quasispecies complexity and to detect variants for sequencing, the first PCR-positive sample was examined by using a previously described method that combines heteroduplex analysis and analysis of single-stranded conformational polymorphisms. The ratio of nonsynonymous to synonymous substitutions (dN/dS) within each sample was evaluated as an indicator of relative selective pressure. Amino acid sequences were analyzed for signature patterns, glycosylation signals, and charge. Quasispecies complexity was higher and E1 dN/dS ratios (selective pressure) were lower in those with persistent viremia; the association with persistence was strengthened by the presence of a combination of both characteristics. In contrast, a trend toward higher HVR1 dN/dS ratios was detected among those with persistent viremia. We did not detect any such association for factors that may affect complexity such as serum HCV RNA concentration. HVR1 had a lower positive charge in subjects with persistent viremia, although no consistent motifs were detected. Our data suggest that HCV persistence is associated with a complex quasispecies and immune response to HVR1.


Does age matter in song bird vocal interactions? Results from interactive playback experiments.
The song of oscines provides an extensively studied model of age-dependent behaviour changes. Male and female receivers might use song characteristics to obtain information about the age of a signaller, which is often related to its quality. Whereas most of the age-dependent song changes have been studied in solo singing, the role of age in vocal interactions is less well understood. We addressed this issue in a playback study with common nightingales (Luscinia megarhynchos). Previous studies showed that male nightingales had smaller repertoires in their first year than older males and males adjusted their repertoire towards the most common songs in the breeding population. We now compared vocal interaction patterns in a playback study in 12 one year old and 12 older nightingales (cross-sectional approach). Five of these males were tested both in their first and second breeding season (longitudinal approach). Song duration and latency to respond did not differ between males of different ages in either approach. In the cross-sectional approach, one year old nightingales matched song types twice as often as did older birds. Similarly, in the longitudinal approach all except one bird reduced the number of song type matches in their second season. Individuals tended to overlap songs at higher rates in their second breeding season than in their first. The higher levels of song type matches in the first year and song overlapping by birds in their second year suggest that these are communicative strategies to establish relationships with competing males and/or choosy females.


The combined impact of cold smoking and natural antioxidants on quality and shelf life of dolphinfish (Coryphaena hippurus) fillets.
This study aimed to produce new value-added products from dolphinfish (Coryphaena hippurus) as fillets when using cold smoking combined with natural antioxidants, obtained from Halocnemum strobilaceum a plant belonging to halophytes. The fillet treatments were controlled (untreated), immersed in standard brine (STD), treated with NaCI and antioxidant before freezing (Aox-pre) and treated with NaCl and antioxidant after thawing (Aox-post). The quality of dolphinfish fillets was assessed using sensory, biochemical, microbiological, and technological parameters. Treating fillets with antioxidants before freezing and cold smoking (Aox-pre) enhanced significantly the shelf life, as well as improved the biochemical, microbiological, and sensory aspects of the product. Aox-pre fillets had the lowest peroxide values (PV) and malondialdehyde (MDA) content, demonstrating that the immediate treatment of fillets with the polyphenols protected lipids from peroxidation. The smoking process, together with antioxidant treatment, significantly reduced microbial counts after 15 days of storage, compared to the control. Overall, combining antioxidant treatments with cold smoking has a positive effect on the quality of Aox-pre fillets with respect to both sensory components and biochemical parameters associated with shelf life. Consequently, Aox-pre treatment enhances the marketability of this species, promoting local and seasonal products, contributing to costal fisheries sustainability.


Respiratory problems in myasthenia gravis.
We evaluated our experience involving 27 patients with myasthenia gravis with particular reference to the various respiratory problems encountered. These included restriction of ventilation, respiratory tract infections, aspiration due to bulbar weakness, respiratory failure requiring mechanical ventilation, and post-thymectomy pulmonary complications.


Interleukin-19 downregulates interleukin-4-induced eotaxin production in human nasal fibroblasts.
Interleukin-19 (IL-19), a member of the IL-10 family, is characterized as the cytokine suppressing the release and function of several proinflammatory cytokines. For regulation of local reaction in allergic rhinitis (AR), IL-19 might play an especially important role. We examined effects of IL-19 on IL-4-induced eotaxin production by human nasal fibroblasts. Early receptor-mediated events (expression of the suppressors of cytokine signaling (SOCS) and phosphorylation of signal transducer and activator of transcription 6 [STAT6]) by IL-19 was examined. Knockdown methods by RNAi were administered to investigate the involvement of those signal transductions. Pretreatment with IL-19 downregulates IL-4-induced eotaxin production, but not interferon-γ(IFN-γ)-induced RANTES. Pretreatment with IL-19 suppressed the IL-4-induced STAT6 phosphorylation. The IL-19 induced SOCS-1, but not SOCS-3 or SOCS-5. The SOCS-1 knockdown by RNAi diminished pretreatment with IL-19-induced down-regulation of eotaxin production. These results suggest that IL-19 down-regulates IL-4-induced eotaxin production via SOCS-1 in human nasal fibroblasts. In non-hematopoietic cells in AR, IL-19 might be an immunosuppressive factor.


Clinical implications of pharmacogenetic variation on the effects of statins.
The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80 million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5, and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1), which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its application in medicine to individualize drug therapy has been previously shown to be clinically and economically beneficial through quality-adjusted life-year assessment. Therefore, polymorphisms affecting the pharmacokinetic and pharmacodynamic profiles of statins, which are widely used in therapy, with their potential application in the personalized prescribing of statin therapy, need further research. In this review, we update the recent literature with respect to genetic polymorphisms that may influence the pharmacokinetics and pharmacodynamics of statin therapy, and consider the relevance of these findings to the efficacy of treatment, prevention of ADRs and what this may mean for patient tolerance and compliance.


Effects of warm-up on hamstring muscles stiffness: Cycling vs foam rolling.
This study investigated the effects of active and/or passive warm-up tasks on the hamstring muscles stiffness through elastography and passive torque measurements. On separate occasions, fourteen males randomly completed four warm-up protocols comprising Control, Cycling, Foam rolling, or Cycling plus Foam rolling (Mixed). The stiffness of the hamstring muscles was assessed through shear wave elastography, along with the passive torque-angle relationship and maximal range of motion (ROM) before, 5, and 30 minutes after each experimental condition. At 5 minutes, Cycling and Mixed decreased shear modulus (-10.3% ± 5.9% and -7.7% ± 8.4%, respectively; P≤.0003, effect size [ES]≥0.24) and passive torque (-7.17% ± 8.6% and -6.2% ± 7.5%, respectively; P≤.051, ES≥0.28), and increased ROM (+2.9% ± 2.9% and +3.2% ± 3.5%, respectively; P≤.001, ES≥0.30); 30 minutes following Mixed, shear modulus (P=.001, ES=0.21) and passive torque (P≤.068, ES≥0.2) were still slightly decreased, while ROM increased (P=.046, ES=0.24). Foam rolling induced "small" immediate short-term decreases in shear modulus (-5.4% ± 5.7% at 5 minutes; P=.05, ES=0.21), without meaningful changes in passive torque or ROM at any time point (P≥.12, ES≤0.23). These results suggest that the combined warm-up elicited no acute superior effects on muscle stiffness compared with cycling, providing evidence for the key role of active warm-up to reduce muscle stiffness. The time between warm-up and competition should be considered when optimizing the effects on muscle stiffness.


The Female Sexual Distress Scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal distress in women.
Recent consensus-based characterizations of female sexual dysfunction have emphasized personal distress as an essential component of their definition. To assist researchers and clinicians, we developed a new scale, the Female Sexual Distress Scale, to measure sexually related personal distress in women. In this article, we describe the initial stages in the development and validation of this instrument. Three studies involving a total of approximately 500 women were performed to evaluate the reliability and validity of the scale in different samples of sexually functional and dysfunctional women. Results indicated a unidimensional factor structure in both the original 20-item version and in a "polished" 12-item version. We observed a high degree of internal consistency and test-retest reliability in both versions across all three studies. Additionally, the scale showed a high degree of discriminative ability to distinguish between sexually dysfunctional and functional women in each of the studies. One study also showed a strong sensitivity to treatment response. Finally, we observed moderate positive correlations with other conceptually related nonsexual measures of distress, supporting the construct validity of the scale. Overall, these findings provide solid support for the FSDS as a valid and reliable measure for assessing sexually related personal distress in women.


Using 'candidacy' as a framework for understanding access to mainstream psychological treatment for people with intellectual disabilities and common mental health problems within the English Improving Access to Psychological Therapies service.
The Improving Access to Psychological Therapies (IAPT) service was established to address common mental health problems among the English population in a timely manner in order to counter the social and economic disadvantage accompanying such difficulties. Using the concept of candidacy, we examined how the legitimacy of claims by people with intellectual disabilities to use this service is facilitated or impeded. We used a sequential mixed methods design. We completed 21 interviews with a range of stakeholders, including people with intellectual disabilities and their carers. Themes from the interviews were used to design an online survey questionnaire that was returned by 452 staff from IAPT and specialist intellectual disability services. Using the candidacy framework, we noted that eligibility and access to IAPT were achieved through dynamic and iterative processes of negotiation involving people with intellectual disabilities and their supporters on one side and IAPT staff and service structures on the other. Barriers and facilitators were apparent throughout the seven dimensions of candidacy (identification, navigation, permeability of services, appearances, adjudications, offers and resistance and operating conditions) and were linked to discourses relating to the character and purpose of IAPT and specialist intellectual disability services. Opportunities exist for some people with intellectual disabilities to assert their candidacy for IAPT input, although there are barriers at individual, professional, organisational and structural levels. More attention needs to be paid to how principles of inclusiveness are operationalised within IAPT teams and to the mental health facilitation role of specialist intellectual disability staff.


Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities.
The endothelium is essential for the maintenance of vascular homeostasis. Central to this role is the production of endothelium-derived nitric oxide (EDNO), synthesized by the endothelial isoform of nitric oxide synthase (eNOS). Endothelial dysfunction, manifested as impaired EDNO bioactivity, is an important early event in the development of various vascular diseases, including hypertension, diabetes, and atherosclerosis. The degree of impairment of EDNO bioactivity is a determinant of future vascular complications. Accordingly, growing interest exists in defining the pathologic mechanisms involved. Considerable evidence supports a causal role for the enhanced production of reactive oxygen species (ROS) by vascular cells. ROS directly inactivate EDNO, act as cell-signaling molecules, and promote protein dysfunction, events that contribute to the initiation and progression of endothelial dysfunction. Increasing data indicate that strategies designed to limit vascular ROS production can restore endothelial function in humans with vascular complications. The purpose of this review is to outline the various ways in which ROS can influence endothelial function and dysfunction, describe the redox mechanisms involved, and discuss approaches for preventing endothelial dysfunction that may highlight future therapeutic opportunities in the treatment of cardiovascular disease.


The surgeon general report on smoking and health 50 years later: breast cancer and the cost of increasing caution.
Despite the Surgeon General's strong track record and the rapidly expanding body of solid scientific work demonstrating that smoking caused a wide range of diseases, the decision making process for concluding "causality" in Surgeon General reports has become increasingly cautious and defensive. Whereas, the 1964 report did not conclude that smoking caused heart disease, it recommended that "from the public health viewpoint [one should] assume that the established association has causative meaning rather than to suspend judgment until no uncertainty remains," the de facto practice has become to do just the opposite. In particular, the 2004 report reached an affirmative negative conclusion that active smoking did not cause breast cancer and the 2006 report on passive smoking only found the link "suggestive." In contrast, in 2005 the California EPA found both active and passive smoking caused breast cancer in younger women. The evidence has continued to strengthen since 2005: there are now 12 large cohort studies that consistently demonstrate a dose-response relationship with smoking before first birth and increased breast cancer risk. The Surgeon General's increasing caution is preventing young women around the world from appreciating the risks that smoking and secondhand smoke pose for developing breast cancer.


Conceptual Model Formalization in a Semantic Interoperability Service Framework: Transforming Relational Database Schemas to OWL.
Healthcare information is distributed through multiple heterogeneous and autonomous systems. Access to, and sharing of, distributed information sources are a challenging task. To contribute to meeting this challenge, this paper presents a formal, complete and semi-automatic transformation service from Relational Databases to Web Ontology Language. The proposed service makes use of an algorithm that allows to transform several data models of different domains by deploying mainly inheritance rules. The paper emphasizes the relevance of integrating the proposed approach into an ontology-based interoperability service to achieve semantic interoperability.


Putting scales into evolutionary time: the divergence of major scale insect lineages (Hemiptera) predates the radiation of modern angiosperm hosts.
The radiation of flowering plants in the mid-Cretaceous transformed landscapes and is widely believed to have fuelled the radiations of major groups of phytophagous insects. An excellent group to test this assertion is the scale insects (Coccomorpha: Hemiptera), with some 8,000 described Recent species and probably the most diverse fossil record of any phytophagous insect group preserved in amber. We used here a total-evidence approach (by tip-dating) employing 174 morphological characters of 73 Recent and 43 fossil taxa (48 families) and DNA sequences of three gene regions, to obtain divergence time estimates and compare the chronology of the most diverse lineage of scale insects, the neococcoid families, with the timing of the main angiosperm radiation. An estimated origin of the Coccomorpha occurred at the beginning of the Triassic, about 245 Ma [228-273], and of the neococcoids 60 million years later [210-165 Ma]. A total-evidence approach allows the integration of extinct scale insects into a phylogenetic framework, resulting in slightly younger median estimates than analyses using Recent taxa, calibrated with fossil ages only. From these estimates, we hypothesise that most major lineages of coccoids shifted from gymnosperms onto angiosperms when the latter became diverse and abundant in the mid- to Late Cretaceous.