A structural model of passive skeletal muscle shows two reinforcement processes in resisting deformation.
Passive skeletal muscle derives its structural response from the combination of the titin filaments in the muscle fibres, the collagen fibres in the connective tissue and incompressibility due to the high fluid content. Experiments have shown that skeletal muscle tissue presents a highly asymmetrical three-dimensional behaviour when passively loaded in tension or compression, but structural models predicting this are not available. The objective of this paper is to develop a mathematical model to study the internal mechanisms which resist externally applied deformation in skeletal muscle bulk. One cylindrical muscle fibre surrounded by connective tissue was considered. The collagenous fibres of the endomysium and perimysium were grouped and modelled as tension-only oriented wavy helices wrapped around the muscle fibre. The titin filaments are represented as non-linear tension-only springs. The model calculates the force developed by the titin molecules and the collagen network when the muscle fibre undergoes an isochoric along-fibre stretch. The model was evaluated using a range of literature based input parameters and compared to the experimental fibre-direction stress-stretch data available. Results show the fibre direction non-linearity and tension/compression asymmetry are partially captured by this structural model. The titin filament load dominates at low tensile stretches, but for higher stretches the collagen network was responsible for most of the stiffness. The oblique and initially wavy collagen fibres account for the non-linear tensile response since, as the collagen fibres are being recruited, they straighten and re-orient. The main contribution of the model is that it shows that the overall compression/tension response is strongly influenced by a pressure term induced by the radial component of collagen fibre stretch acting on the incompressible muscle fibre. Thus for along-fibre tension or compression the model predicts that the collagen network contributes to overall muscle stiffness through two different mechanisms: (1) a longitudinal force directly opposing tension and (2) a pressure force on the muscle fibres resulting in an indirect longitudinal load. Although the model presented considers only a single muscle fibre and evaluation is limited to along-fibre loading, this is the first model to propose these two internal mechanisms for resisting externally applied deformation of skeletal muscle tissue.


Breaking Lorentz reciprocity to overcome the time-bandwidth limit in physics and engineering.
A century-old tenet in physics and engineering asserts that any type of system, having bandwidth Δω, can interact with a wave over only a constrained time period Δt inversely proportional to the bandwidth (Δt·Δω ~ 2π). This law severely limits the generic capabilities of all types of resonant and wave-guiding systems in photonics, cavity quantum electrodynamics and optomechanics, acoustics, continuum mechanics, and atomic and optical physics but is thought to be completely fundamental, arising from basic Fourier reciprocity. We propose that this "fundamental" limit can be overcome in systems where Lorentz reciprocity is broken. As a system becomes more asymmetric in its transport properties, the degree to which the limit can be surpassed becomes greater. By way of example, we theoretically demonstrate how, in an astutely designed magnetized semiconductor heterostructure, the above limit can be exceeded by orders of magnitude by using realistic material parameters. Our findings revise prevailing paradigms for linear, time-invariant resonant systems, challenging the doctrine that high-quality resonances must invariably be narrowband and providing the possibility of developing devices with unprecedentedly high time-bandwidth performance.


Enhancement of the influenza A hemagglutinin (HA)-mediated cell-cell fusion and virus entry by the viral neuraminidase (NA).
The major role of the neuraminidase (NA) protein of influenza A virus is related to its sialidase activity, which disrupts the interaction between the envelope hemagglutinin (HA) protein and the sialic acid receptors expressed at the surface of infected cells. This enzymatic activity is known to promote the release and spread of progeny viral particles following their production by infected cells, but a potential role of NA in earlier steps of the viral life cycle has never been clearly demonstrated. In this study we have examined the impact of NA expression on influenza HA-mediated viral membrane fusion and virion infectivity. The role of NA in the early stages of influenza virus replication was examined using a cell-cell fusion assay that mimics HA-mediated membrane fusion, and a virion infectivity assay using HIV-based pseudoparticles expressing influenza HA and/or NA proteins. In the cell-cell fusion assay, which bypasses the endocytocytosis step that is characteristic of influenza virus entry, we found that in proper HA maturation conditions, NA clearly enhanced fusion in a dose-dependent manner. Similarly, expression of NA at the surface of pseudoparticles significantly enhanced virion infectivity. Further experiments using exogenous soluble NA revealed that the most likely mechanism for enhancement of fusion and infectivity by NA was related to desialylation of virion-expressed HA. The NA protein of influenza A virus is not only required for virion release and spread but also plays a critical role in virion infectivity and HA-mediated membrane fusion.


Inflammatory response after implantation of a left ventricular assist device: comparison between the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device.
The implantation of a ventricular assist device (VAD) is associated with a stimulation of the inflammatory system. We compared changes in the inflammatory response after implantation of a pulsatile Novacor left (L) VAD and the axial flow MicroMed DeBakey VAD. Six consecutive patients after implantation of a Novacor LVAD (NC) and six patients after implantation of a MicroMed DeBakey VAD (MD) were included in the investigation. Patients received LVADs for medically non treatable end-stage heart failure. Tumor necrosis factor alpha (TNF), C3a, C5a, interleukin 6 (IL-6), and neutrophil elastase were measured twice a week over a period of 3 months after implantation of the device. All tests were performed with an enzyme-linked immunosorbent assay. There was no significant difference in the clinical course of the two groups. All inflammatory parameters were elevated in both groups during the entire period of the investigation. There was no difference in TNF, polynuclear leukocyte elastase, or C3a levels between the two groups; however, IL-6 (NC: 23.6+/-37.6 pg/ml vs. MD: 63+/-114 pg/ml, p < 0.001) and C5a (NC: 708+/-352 microg/L vs. MD: 1,745+/-1,305 microg/L, p < 0.001) were increased significantly more in patients following implantation of the axial flow MicroMed DeBakey VAD. Compared with the pulsatile Novacor device, the implantation of the axial flow MicroMed DeBakey LVAD seems to be associated with an increased stimulation of one part of the inflammatory system. Further investigations are necessary for evaluation of the pathophysiologic mechanism and clinical implications of these findings.


Changes in public preferences for technologically enhanced surveillance following the COVID-19 pandemic: a discrete choice experiment.
As governments attempt to navigate a path out of COVID-19 restrictions, robust evidence is essential to inform requirements for public acceptance of technologically enhanced communicable disease surveillance systems. We examined the value of core surveillance system attributes to the Australian public, before and during the early stages of the current pandemic. A discrete choice experiment was conducted in Australia with a representative group of respondents, before and after the WHO declared COVID-19 a Public Health Emergency of International Concern. We identified and investigated the relative importance of seven attributes associated with technologically enhanced disease surveillance: respect for personal autonomy; privacy/confidentiality; data certainty/confidence; data security; infectious disease mortality prevention; infectious disease morbidity prevention; and attribution of (causal) responsibility. Specifically, we explored how the onset of the COVID-19 outbreak influenced participant responses. 2008 Australians (general public) completed the experiment: 793 before COVID-19 outbreak onset (mean age 45.9 years, 50.2% male) and 1215 after onset (mean age 47.2 years, 49% male). All seven attributes significantly influenced respondents' preferences for communicable disease surveillance systems. After onset, participants demonstrated greater preference for a surveillance system that could prevent a higher number of illnesses and deaths, and were less concerned about their personal autonomy. However, they also increased their preference for a system with high data security. Public acceptance of technology-based communicable disease surveillance is situation dependent. During an epidemic, there is likely to be greater tolerance of technologically enhanced disease surveillance systems that result in restrictions on personal activity if such systems can prevent high morbidity and mortality. However, this acceptance of lower personal autonomy comes with an increased requirement to ensure data security. These findings merit further research as the pandemic unfolds and strategies are put in place that enable individuals and societies to live with SARS-CoV-2 endemicity.


Tracing of cells of the avian thymus through embryonic life in interspecific chimeras.
Differences in the structure of the interphase nucleus between two species of birds, the Japanese quail (Coturnix coturnix japonica) and the chick (Gallus gallus) has been used to distinguish cells from different origins in interspecies combinations. This biological cell marking technique was applied to thymus histogenesis. Using various combinations between components of quail and chick thymic rudiments, the respective contribution of endodermal epithelium, mesenchyme, and blood-borne extrinsic elements to the histogenesis of thymus was analyzed. It was demonstrated that the whole lymphoid population of the thymus is derived from immigrant blood-borne stem cells which are chemically attracted by the endoderm of the 3rd and 4th pharyngeal pouch. The latter is determined to differentiate into thymic epithelial reticulum as soon as the 15-somite stage, and is able to attract blood stem cells even when transplanted in an heterotopic position such as the ventral body wall of the embryo. It was shown that the thymic mesenchyme originates from the neural crest mesectoderm which colonizes early the 3rd and 4th branchial arches. It participates in the formation of perivascular mesenchyme, but does not give rise to lymphocytes. From heterospecific transplantations of quail thymuses into chick embryo (and inversely) at various stages of development is appeared that the thymic rudiment becomes attractive for lymphoid stem cells at a precise stage of its evolution for each species. The attractivity period lasts about 24 h for the quail and 36 h for the chick. Then, the inflow of stem cells becomes very low until the end of the incubation period. At this time, a second wave of lymphocytoblasts invades the thymus and the primitive embryonic lymphoid population is completely renewed around the hatching time. Competent thymic stem cells are present in the blood before and after the period of physiological thymic attractivity. The identity of basophilic cells appearing in the thymus during its histogenesis and lymphoid stem cells has been demonstrated from the analysis of quail-chick chimeric thymuses.


Validity over time of self-reported anthropometric variables during follow-up of a large cohort of UK women.
In prospective epidemiological studies, anthropometry is often self-reported and may be subject to reporting errors. Self-reported anthropometric data are reasonably accurate when compared with measurements made at the same time, but reporting errors and changes over time in anthropometric characteristics could potentially generate time-dependent biases in disease-exposure associations. In a sample of about 4000 middle-aged UK women from a large prospective cohort study, we compared repeated self-reports of weight, height, derived body mass index, and waist and hip circumferences, obtained between 1999 and 2008, with clinical measurements taken in 2008. For self-reported and measured values of each variable, mean differences, correlation coefficients, and regression dilution ratios (which measure relative bias in estimates of linear association) were compared over time. For most variables, the differences between self-reported and measured values were small. On average, reported values tended to be lower than measured values (i.e. under-reported) for all variables except height; under-reporting was greatest for waist circumference. As expected, the greater the elapsed time between self-report and measurement, the larger the mean differences between them (each P < 0.001 for trend), and the weaker their correlations (each P < 0.004 for trend). Regression dilution ratios were in general close to 1.0 and did not vary greatly over time. Reporting errors in anthropometric variables may result in small biases to estimates of associations with disease outcomes. Weaker correlations between self-reported and measured values would result in some loss of study power over time. Overall, however, our results provide new evidence that self-reported anthropometric variables remain suitable for use in analyses of associations with disease outcomes in cohort studies over at least a decade of follow-up.


Handoff communication from the emergency department to primary care.
Handoff communication deficiencies between the emergency department (ED) and primary care have been recognized as the result of delays and/or omissions in follow-up care for patients. This quality improvement project addresses the gaps in follow-up care for patients with low-risk chest pain by implementing an electronic Emergency Provider Written Plan of Discharge (eEPWPD) template to notify primary care providers (PCPs) that follow-up care is needed for their patients. This retrospective study evaluated effectiveness of the template in providing additional diagnostic and follow-up care. Results indicated that following the implementation of the eEPWPD template, follow-up for this population increased significantly. This study provides evidence that standardizing handoff communication from the ED to PCP can improve the quality of patient care by ensuring timely diagnostic and follow-up care.


Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight.
From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.


Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 × 107/kg (range, 4.6 to 27.9) and CD34+ dose of 3.1 × 105/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.


A meta-analytic review of cognitive processing therapy for adults with posttraumatic stress disorder.
Numerous studies have demonstrated the efficacy of cognitive processing therapy (CPT) for treating posttraumatic stress disorder (PTSD). Two prior meta-analyses of studies are available but used approaches that limit conclusions that can be drawn regarding the impact of CPT on PTSD outcomes. The current meta-analysis reviewed outcomes of trials that tested the efficacy of CPT for PTSD in adults and evaluated potential moderators of outcomes. All published trials comparing CPT against an inactive control condition (i.e. psychological placebo or wait-list) or other active treatment for PTSD in adults were included, resulting in 11 studies with a total of 1130 participants. CPT outperformed inactive control conditions on PTSD outcome measures at posttreatment (mean Hedges' g = 1.24) and follow-up (mean Hedges' g = 0.90). The average CPT-treated participant fared better than 89% of those in inactive control conditions at posttreatment and 82% at follow-up. Results also showed that CPT outperformed inactive control conditions on non-PTSD outcome measures at posttreatment and follow-up and that CPT outperformed other active treatments at posttreatment but not at follow-up. Effect sizes of CPT on PTSD symptoms were not significantly moderated by participant age, number of treatment sessions, total sample size, length of follow-up, or group versus individual treatment; but, older studies had larger effect sizes and percent female sex moderated the effect of CPT on non-PTSD outcomes. These meta-analytic findings indicate that CPT is an effective PTSD treatment with lasting benefits across a range of outcomes.


Cultural adaptation resources for nutrition and health in new immigrants in Central North Carolina.
This paper presents results of a study that was conducted for the purposes of describing available human services resources relating to nutrition, physical health, and behavioral health for new and recent immigrants (predominantly Mexican immigrants, but groups from Southeast Asia and continental Africa as well) in Guilford County, NC. Sixty-five service providers were determined to represent cultural adaptation resources providing either direct and/or ancillary assistance to limited English proficient immigrants. Seventeen direct assistance providers specialized in food and nutrition programs, but only 2 had targeted programs for addressing food scarcity, insecurity, and nutritional deficiencies in immigrant households. Four of 15 direct physical health services providers had clinical care or specialty programs for immigrants. Finally, 5 of 16 direct behavioral health care providers offered mental health treatment and counseling services adapted specifically for targeted immigrant groups. These findings highlight the limited development of the existing human services network to increase its capacity to provide nutrition and health related services to a growing community of diverse immigrant groups. These descriptive results underscore a need for additional local level or community based resources to be directed towards increasing the community's ability to provide essential human services to population groups not yet language proficient and acculturated to "American community standards."


Projected neurodegenerative disease mortality among minorities in the United States, 1990-2040.
Between 1992 and 2040, the United States nonwhite elderly population is expected to grow from 3.3 to 14.1 million. In order to assess the implications of this increase on the mortality from neurodegenerative diseases in the United States, we used Census Bureau population estimates to formulate projections of the annual number of deaths from neurodegenerative diseases and from six comparison conditions (liver cirrhosis, colon cancer, lung cancer, cancer of the female breast, multiple sclerosis, and malignant melanoma), assuming that the United States disease-age-gender-specific death rates for 1985-1988 remain constant between 1990 and 2040. We find that neurodegenerative disease mortality increases by 281-524%, depending on the model of population growth used. For the 'middle' population growth model, the increase in annual neurodegenerative disease mortality is 373%. The major component of this increase is the rise in deaths attributed to dementia. For the six comparison diseases, the increases in mortality range from 130 (multiple sclerosis) to 288% (colon cancer). Given the current level of underascertainment of neurodegenerative disease mortality, particularly among minorities, and the conservative nature of the Census Bureau estimates of future population, it is likely that these projections are under-estimates. The implications of these data are discussed.


On the Role of Proprioception in Making Free Throws in Basketball.
The aim of this article was to investigate the role that proprioception of the upper limb plays in making basketball free throws. We designed an experiment to directly correlate the performance of basketball players in a free-throw task and an elbow- and wrist-joint position sense task. We found a moderately high correlation between the free-throw success rate and wrist-joint position sense and a moderate correlation between the free-throw success rate and elbow-joint position sense. In both cases, the most successful shooters also had the best proprioceptive results. The results indicate that free-throw success is, at least partly, determined by players' ability to sense the position of the distal joints of their throwing upper limb. From a motor-control point of view, this suggests that basketball players may organize the compensatory behavior between the joints of their free-throwing arm on the basis of proprioception. From a practical point of view, it points toward new training techniques to enhance free-throwing efficiency.


Association of host cell intermediate filaments with Toxoplasma gondii cysts in murine astrocytes in vitro.
Toxoplasma gondii is an intracellular parasite that is a common opportunistic infection of AIDS patients where it causes a severe and often fatal encephalitis. Toxoplasmic encephalitis in AIDS patients results from a reactivation of the cyst stage of Toxoplasma gondii in the brain. A previous study found an association of host cell intermediate filaments with parasitophorous vacuoles and some studies have suggested the host cell cytoskeletal elements are incorporated into the cyst wall. In this study, the interaction of glial filaments with Toxoplasma gondii cysts was studied in cysts derived in vitro in mouse astrocytes and in cysts isolated from mouse brains. Glial filaments, detected by immunostaining of the glial fibrillary acidic protein, were found to accumulate around the perimeter of the cysts as they developed in mouse astrocytes. Transmission electron microscopy revealed a layer of glial filaments was wrapped around the cytoplasmic side of the cyst. The glial filaments were present in close apposition to the cyst wall and arranged around the cysts in a concentric layer, measuring 5-10 microns in thickness. The layer of glial filaments excluded host cell mitochondria and endoplasmic reticulum from the cytoplasmic surface of the cyst. Colocalisation of glial fibrillary acidic protein and the cyst wall via confocal and immunoelectron microscopy, confirmed that there was no glial fibrillary acidic protein present within the cyst wall. The cyst wall of cysts isolated from mouse brains were also found to be negative for glial fibrillary acidic protein. In conclusion, we found no evidence of structural integration of the host cell intermediate filaments in the cyst wall, but glial filaments were found to encase the cysts in the host cell during cyst development in host cells in vitro. The glial filaments wrapping of cysts may play a role in bradyzoite differentiation and/or cyst stabilisation in the host cell cytoplasm.


Cross-talk between SOX2 and TGFβ Signaling Regulates EGFR-TKI Tolerance and Lung Cancer Dissemination.
Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFβ signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFβ stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFβ signaling affects EGFR-TKI tolerance and lung cancer dissemination. SIGNIFICANCE: These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFβ stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination.


Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.
Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.


The Neuropsychological Profile of Comorbid Post-Traumatic Stress Disorder in Adult ADHD.
ADHD and post-traumatic stress disorder (PTSD) are often comorbid yet despite the increased comorbidity between the two disorders, to our knowledge, no data have been published regarding the neuropsychological profile of adults with comorbid ADHD and PTSD. Likewise, previous empirical studies of the neuropsychology of PTSD did not control for ADHD status. We sought to fill this gap in the literature and to assess the extent to which neuropsychological test performance predicted psychosocial functioning, and perceived quality of life. Participants were 201 adults with ADHD attending an outpatient mental health clinic between 1998 and 2003 and 123 controls without ADHD. Participants completed a large battery of self-report measures and psychological tests. Diagnoses were made using data obtained from structured psychiatric interviews (i.e., Structured Clinical Interview for DSM-IV, Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiologic Version). Differences emerged between control participants and participants with ADHD on multiple neuropsychological tests. Across all tests, control participants outperformed participants with ADHD. Differences between the two ADHD groups emerged on seven psychological subtests including multiple Wechsler Adult Intelligence Scale-Third edition and Rey-Osterrieth Complex Figure Test measures. These test differences did not account for self-reported quality of life differences between groups. The comorbidity with PTSD in adults with ADHD is associated with weaker cognitive performance on several tasks that appear related to spatial/perceptual abilities and fluency. Neuropsychological test performances may share variance with the quality of life variables yet are not mediators of the quality of life ratings.


[Protective effect of compound tongfu granule on intestinal mucosal barrier in patients with cirrhosis of decompensation stage].
To explore the intestinal mucosal barrier protective effect of herbal medicine Compound Tongfu Granule (CTG) in patients with liver cirrhosis of decompensation stage. Fifty patients enrolled were randomly assigned to the control group (26 cases) and the CTG group (24 cases), and 30 healthy adults were set up as normal control. After 2-week treatment, the intestinal permeability (IP, represented by urinary lactulose/mannitol excretion rate), plasma endotoxin (EDT) level, and change of enteric bacteria (EB) in patients were observed before and after treatment, and compared with those in the normal control. Before treatment, cirrhotic patients showed significantly higher levels of IP, EDT, and intestinal bacilli, but a lower amount of enteric bifidobacteria as compared with those the normal control. After 2-week treatment, levels of EDT and urinary excretion rate of lactulose in the CTG group were lowered more significantly than those in the control group (P < 0.05), while the amount of bifidobacteria in the CTG group increased accompanied with intestinal bacilli significantly lowered to near the levels in the normal control (P < 0.05, P < 0.01). CTG can improve the intestinal barrier function, correct the intestinal bacteria disturbance, and significantly reduce the entero-derived endotoxemia in cirrhotic patients of decompensation stage.


Diagnostic value of culture and serological tests in the diagnosis of histoplasmosis in HIV and non-HIV Colombian patients.
We determined the value of culture and serological tests used to diagnose histoplasmosis. The medical records of 391 histoplasmosis patients were analyzed. Diagnosis of the mycosis was assessed by culture, complement fixation, and immunodiffusion tests; 310 patients (79.5%) were male, and 184 patients (47.1%) were infected with human immunodeficiency virus (HIV). Positivity value for cultures was 35.7% (74/207), reactivity of serological tests was 95.2% (160/168), and a combination of both methodologies was 16.9% (35/207) for non-HIV patients. Positivity value for cultures was 75.0% (138/184), reactivity of serological tests was 92.4% (85/92), and a combination of both methodologies was 26.0% (48/184) for HIV/acquired immunodeficiency syndrome (AIDS) patients; 48.1% (102/212) of extrapulmonary samples from HIV/AIDS patients yielded positive cultures compared with 23.1% (49/212) in non-HIV patients. Lymphocyte counts made for 33.1% (61/184) of HIV/AIDS patients showed a trend to low CD4+ numbers and higher proportion of positive cultures. These results indicate that culture is the most reliable fungal diagnostic method for HIV/AIDS patients, and contrary to what is generally believed, serological assays are useful for diagnosing histoplasmosis in these patients.


[Evaluation of the public health service law of the Saxony-Anhalt region--community affairs, transfer of power and loss of control].
In the state of Saxony-Anhalt, a new Public Health Service law came into force in 1998. Our study investigated whether this new legislation has led to an extension of duties performed by regional health departments and to a subsequent increase in expenditure. Guided interviews at all administrative levels of the public health system were conducted. The catalogue of duties was systematized and a questionnaire was developed and distributed to all regional health departments (response rate: 17 out of 24). Data concerning revenues and expenditures of the regional health departments were analysed on the basis of the administrative districts' budget data. Regional health departments stated that there had been practically no change in their activities over the last few years. When questioned about the coverage of 58 specific duties, a considerable disparity was evident between departments. A core group of "classical" duties comprising environmental health and hygiene, child health protection, individual health appraisal, and public health supervision are carried out on an established basis. Some duties were handled by external institutions, others, mostly community health duties, were not performed on an extensive scale. When asked about the desired model for their health department, most departments preferred the model of being an executor of sovereign duties, however a corporate model was deemed to be almost as acceptable. The following fields will gain increasing significance in the future: environmental medicine, health reporting, preventive medicine, co-ordination of regional health care, and health promotion. Since 1995, staff has been reduced in all regional health departments (-10.4%; 1999: 2.92 employees per 10,000 inhabitants). In 1999, expenditures amounted to an average of 24.64 German Marks per capita (range 14.20-44.58 DM). The number of inhabitants and the revenue of the regional districts were determinants of their health budgets. Our results showed that no uncompensated additional expenditure by regional authorities resulted from this law. So far, most districts have not perceived regional health as a community affair offering possible competitive advantages. The federal state lost considerable influence at the regional level. Recommended are regional health priorities, conjoint staff development, and state guidance by a head agency providing leadership and support, while leaving responsibility with the districts.


Transdermal estradiol in castrate and chemotherapy resistant prostate cancer.
Given prior studies demonstrating the marked clinical activity of oral estrogens in prostate cancer, more recent data demonstrating the safety of transdermal estradiol, and the renewed interest in targeting testosterone metabolism and androgen receptor pathways, we report the results of a trial of transdermal estradiol in advanced heavily pre-treated castrate and chemotherapy refractory patients. Patients with prostate cancer progressing after androgen ablation therapy and chemotherapy were treated with transdermal estradiol patches (0.4 mg per 24 hours total) applied weekly and assessed for tolerability and biochemical activity. Twenty-two patients were treated on study with all patients evaluable for safety and 20 patients evaluable for response. All patients had aggressive and resistant disease, as demonstrated by a median PSA of 170 ng/mL (range 14 to 5030 ng/mL), with more than 60% having been treated with two or more prior chemotherapy regimens, and 20% with visceral disease. Nine patients had a decrease in PSA, of which two patients had a PSA response defined as a decline in PSA by 50%. Therapy was well tolerated and no thrombotic events were observed. In heavily pre-treated patients with advanced castrate and chemotherapy refractory metastatic prostate cancer, transdermal estradiol was safe and had biochemical activity. These data support further studies to understand if transdermal estradiol can be useful following multiple standard therapies.


Diagnosing X-linked Myotubular Myopathy - A German 20-year Follow Up Experience.
X-linked myotubular myopathy (XLMTM) is a life-threatening rare neuromuscular disease, which is caused by pathogenic variants in the MTM1 gene. It has a large phenotypic heterogeneity, ranging from patients, who are able to walk independently to immobile patients who are only able to bring hand to mouth and depend on a respirator 24 hours a day every day. This suggests that ventilator requirements may not illustrate the full clinical picture of patients with XLMTM. At present, there is no curative therapy available, despite first promising results from ongoing gene therapy studies.In this study, we evaluated in detail the data from 13 German XLMTM patients, which was collected over a period of up to 20 years in our university hospital. We compared it to the international prospective longitudinal natural history study (NHS) data from 45 patients (containing 11 German patients). To highlight the broad phenotypic spectrum of the disease, we additionally focused on the clinical presentation of three cases at a glance.Comparing our data with the above mentioned natural history study, it appears the patients of the present German cohort seem to be more often severely affected, with higher frequency of non-ambulatory patients and patients on ventilation (and for longer time) and a higher proportion of patients needing a percutaneous endoscopic gastrostomy. Another key finding is a potential gap in time between first clinical presentation and final diagnosis, showing a need for patients to be treated in a specialized center for neuromuscular diseases.


Study protocol of physical activity and sedentary behaviour measurement among schoolchildren by accelerometry--cross-sectional survey as part of the ENERGY-project.
Physical activity and sedentary behaviour among children should be measured accurately in order to investigate their relationship with health. Accelerometry provides objective and accurate measurement of body movement, which can be converted to meaningful behavioural outcomes. The aim of this study was to evaluate the best evidence for the decisions on data collection and data processing with accelerometers among children resulting in a standardized protocol for use in the participating countries. This cross-sectional accelerometer study was conducted as part of the European ENERGY-project that aimed to produce an obesity prevention intervention among schoolchildren. Five countries, namely Belgium, Greece, Hungary, Switzerland and the Netherlands participated in the accelerometer study. We used three different Actigraph models--Actitrainers (triaxial), GT3Xs and GT1Ms. Children wore the device for six consecutive days including two weekend days. We selected an epoch length of 15 seconds. Accelerometers were placed at children's waist at the right side of the body in an elastic belt. In total, 1082 children participated in the study (mean age = 11.7 ± 0.75 y, 51% girls). Non-wearing time was calculated as periods of more than 20 minutes of consecutive zero counts. The minimum daily wearing time was set to 10 hours for weekdays and 8 hours for weekend days. The inclusion criterion for further analysis was having at least three valid weekdays and one valid weekend day. We selected a cut-point (count per minute (cpm)) of <100 cpm for sedentary behaviour, <3000 cpm for light, <5200 cpm for moderate, and >5200 cpm for vigorous physical activity. We also created time filters for school-time during data cleaning in order to explore school-time physical activity and sedentary behaviour patterns in particular. This paper describes the decisions for data collection and processing. Use of standardized protocols would ease future use of accelerometry and the comparability of results between studies.


A slowly inactivating potassium current truncates spike activity in ganglion cells of the tiger salamander retina.
Voltage-gated ganglion cell membrane currents were studied under whole-cell patch clamp in isolation and in retinal slices. The cells were identified by (1) backfilling their axons with rhodamine and later identifying them by their fluorescence in the slice or the mix of isolated cells or (2) by filling them with Lucifer yellow during recording in retinal slices. Both methods yielded cells with similar currents. In some cases, isolated cells lacked processes yet showed currents similar to other cells, suggesting that voltage-gated currents in all cells were located primarily at the soma. Both a conventional inactivating sodium current and a sustained calcium current were found. We describe 3 inactivating outward currents, ordered in their rate of inactivation. The fastest current resembled IA reported by Connor and Stevens (1971a, b). A slower current labeled IB inactivated with a time constant of 339 msec at 0 mV. The current with slowest inactivation is labeled IC here, inactivating with a time constant of 4.03 sec at 0 mV. An additional outward current was sustained and calcium dependent labeled IK(Ca). IB was the largest of these currents. It was slower than IA, was not blocked by 4AP, and inactivated over a much more positive potential range. IB appears to play an important role in spike generation, different from that of IA: Its inactivation leads to a slow depolarizing shift of the membrane during a current step, truncating spike activity after about 300-700 msec as the membrane potential enters the region of sodium inactivation. We analyze how the inactivating outward current acts to ensure a graded spiking response and to truncate the spiking output in the presence of large excitatory inputs.


In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.
Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.


Immigrant reproductive dysfunction facilitates ecological speciation.
The distributions of species are not only determined by where they can survive - they must also be able to reproduce. Although immigrant inviability is a well-established concept, the fact that immigrants also need to be able to effectively reproduce in foreign environments has not been fully appreciated in the study of adaptive divergence and speciation. Fertilization and reproduction are sensitive life-history stages that could be detrimentally affected for immigrants in non-native habitats. We propose that "immigrant reproductive dysfunction" is a hitherto overlooked aspect of reproductive isolation caused by natural selection on immigrants. This idea is supported by results from experiments on an externally fertilizing fish (sand goby, Pomatoschistus minutus). Growth and condition of adults were not affected by non-native salinity whereas males spawning as immigrants had lower sperm motility and hatching success than residents. We interpret these results as evidence for local adaptation or acclimation of sperm, and possibly also components of paternal care. The resulting loss in fitness, which we call "immigrant reproductive dysfunction," has the potential to reduce gene flow between populations with locally adapted reproduction, and it may play a role in species distributions and speciation.


A magnetometer-based approach for studying human movements.
This paper investigates the use of body-mounted magnetic field sensors for the analysis of certain human movements. We demonstrate that, in several usual dynamic situations, magnetometers allow to estimate accurately a body inclination while being insensitive to its acceleration. Doing this, it is then possible to combine this information together with the one provided by an accelerometer to separate in a very accurate way the gravitational and kinematical components of acceleration. The proposed method is illustrated by the study of the sit-to-stand movement, estimating trunk inclination and absolute acceleration.


The comments of voices on the appearance of patients with psychosis: 'the voices tell me that I am ugly'.
There are high rates of obesity and low self-esteem in patients with psychosis. The occurrence of negative voice content directly about appearance is therefore plausible. Derogatory comments about appearance are likely to be distressing, increase depression and contribute to social withdrawal. To systematically assess the occurrence of voice content regarding appearance and identify correlates. Sixty patients experiencing verbal auditory hallucinations at least once a week in the context of non-affective psychosis completed a measure assessing positive and negative voice content about appearance. They also completed assessments about body image, self-esteem, psychiatric symptoms and well-being. Fifty-five (91.7%) participants reported hearing voices comment on their appearance. A total of 54 (90%) patients reported negative voice content about their appearance with 30 (50%) patients experienced negative appearance comments on a daily basis. The most common negative comment was 'the voices tell me that I am ugly' (n = 48, 80%). There were 39 (65%) patients who reported positive voice content on appearance. The most frequent positive comment was 'I look as nice as other people' (n = 26, 43.3%). Negative voice content about appearance was associated with body image concerns, paranoia, voice hearing severity, depression, worry, negative self-beliefs and safety-seeking behaviours. Positive appearance voice content was associated with greater body esteem and well-being and lower levels of depression and insomnia. Voice content about appearance is very common for patients seen in clinical services. Negative voice content may reflect - and subsequently reinforce - negative beliefs about one's appearance, low self-esteem, worry and paranoia. None.


Functional changes of the SCN in spontaneous hypertension but not after the induction of hypertension.
The present study investigates the circadian behavior of spontaneously hypertensive rats (SHRs) during the pre-hypertensive and hypertensive stage, with the aim to gain insight into whether observed changes in the functionality of suprachiasmatic nucleus (SCN) in the hypertensive state are cause or consequence of hypertension. Four types of animals were used in this study: (1) SHRs which develop hypertension genetically; (2) their normotensive controls, Wistar Kyoto rats (WKYs); (3) Wistar rats whereby hypertension was surgically induced (2 Kidney 1 Clamp (2K1C) method); and (4) sham-operated control Wistar rats. Period length and activity levels and amplitude changes of locomotor and wheel running activity were determined, in constant conditions, as a measure of the functionality of the SCN. Hereto two conditions were used, constant darkness (0 lux) and constant dim (5 lux) light. SHRs showed a shortened period of their locomotor and running wheel activity rhythms in constant darkness during both pre-hypertensive and hypertensive stages and exhibited period lengthening in constant dim light conditions, only during hypertensive stages. Total amount as well as the amplitude of daily running wheel rhythms showed an inverse correlation with the period length, and this relation was significantly different in SHRs compared to WKYs. None of the aforementioned changes in circadian rhythms were observed after the surgical induction of hypertension. The present findings suggest early functional changes of the SCN in the etiology of spontaneous hypertension.


A structural equation model of the relation between socioeconomic status, physical activity level, independence and health status in older Iranian people.
Health status is an independent predictor of mortality, morbidity and functioning in older people. The present study was designed to evaluate the link between socioeconomic status (SES), physical activity (PA), independence (I) and the health status (HS) of older people in Iran, using structural equation modelling. Using computerized randomly selection, a representative sample of 851 75-year-olds living in Tehran (2007-2008), Iran, was included. Participants answered questions regarding indicators of HS, SES and also PA and I through interviews. Both measurement and conceptual models of our hypotheses were tested using Mplus 5. Maximum-likelihood estimation with robust standard errors (MLR estimator), chi-square tests, the goodness of fit index (and degrees of freedom), as well as the Comparative Fit Index (CFI), and the Root Mean Square Error of Approximation (RSMEA) were used to evaluate the model fit. The measurement model yielded a reasonable fit to the data, χ2=110.93, df=38; CFI=0.97; RMSEA=0.047, with 90% C.I.=0.037-0.058. The model fit for the conceptual model was acceptable; χ2=271.64, df=39; CFI=0.91; RMSEA=0.084, with 90% C.I.=0.074-0.093. SES itself was not a direct predictor of HS (β=0.13, p=0.059) but it was a predictor of HS either through affecting PA (β=0.31, p<0.001) or I (β=0.57, p<0.001). Socioeconomic status appeared to influence health status, not directly but through mediating some behavioral and self-confidence aspects including physical activity and independence in ADL.


The comprehensive osteoarthritis test: a simple index for measurement of treatment effects in clinical trials.
To assess the measurement properties of a simple index of symptom severity in osteoarthritis (OA) of the hips and knees. Both the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the proposed new Comprehensive Osteoarthritis Test (COAT) instrument were completed weekly by 125 subjects in the context of a randomized, 12-week, 3 parallel-arm clinical trial. The reliabilities of the various scales were assessed on a weekly basis by use of Cronbach's alpha coefficients. The validity of the COAT total scale was assessed by correlation with the WOMAC total scale on a weekly basis with correlation coefficients, and in terms of the correlations between subject-level intercepts and slopes over time. The relative responsiveness of the WOMAC and COAT total scales was assessed using a multilevel (longitudinal) multivariate (WOMAC, COAT) linear model. The WOMAC and COAT total scales were highly reliable (mean over weeks: WOMAC alpha = 0.98; COAT alpha = 0.97). The correlations between the WOMAC and COAT scales were very high (mean over weeks = 0.92; subject-level intercepts = 0.91, slopes = 0.88). The COAT total scale was significantly more responsive than the WOMAC total scale in the active treatment (34.8% improvement vs 26.8%; p = 0.002). The COAT total scale is simple to administer, reliable, valid, and responsive to treatment effects.


A benefit-finding intervention for family caregivers of persons with Alzheimer disease: study protocol of a randomized controlled trial.
Caregivers of relatives with Alzheimer's disease are highly stressed and at risk for physical and psychiatric conditions. Interventions are usually focused on providing caregivers with knowledge of dementia, skills, and/or support, to help them cope with the stress. This model, though true to a certain extent, ignores how caregiver stress is construed in the first place. Besides burden, caregivers also report rewards, uplifts, and gains, such as a sense of purpose and personal growth. Finding benefits through positive reappraisal may offset the effect of caregiving on caregiver outcomes. Two randomized controlled trials are planned. They are essentially the same except that Trial 1 is a cluster trial (that is, randomization based on groups of participants) whereas in Trial 2, randomization is based on individuals. Participants are randomized into three groups - benefit finding, psychoeducation, and simplified psychoeducation. Participants in each group receive a total of approximately 12 hours of training either in group or individually at home. Booster sessions are provided at around 14 months after the initial treatment. The primary outcomes are caregiver stress (subjective burden, role overload, and cortisol), perceived benefits, subjective health, psychological well-being, and depression. The secondary outcomes are caregiver coping, and behavioral problems and functional impairment of the care-recipient. Outcome measures are obtained at baseline, post-treatment (2 months), and 6, 12, 18 and 30 months. The emphasis on benefits, rather than losses and difficulties, provides a new dimension to the way interventions for caregivers can be conceptualized and delivered. By focusing on the positive, caregivers may be empowered to sustain caregiving efforts in the long term despite the day-to-day challenges. The two parallel trials will provide an assessment of whether the effectiveness of the intervention depends on the mode of delivery. Chinese Clinical Trial Registry (http://www.chictr.org/en/) identifier number ChiCTR-TRC-10000881.


Image storage based on circular-polarization holography in an azobenzene side-chain liquid-crystalline polymer.
Image storage was investigated in a liquid-crystalline azobenzene polymer film based on circular-polarization holographic recording. An image was stored in pure polarization holograms using two orthogonal circularly polarized 532 nm beams and was reconstructed with a 633 nm beam. The polarization holograms showed high stability and a high diffraction efficiency of 31.8%. Moreover, the polarization holograms could convert arbitrary probe polarization state into circular polarization, and the diffraction efficiency was dependent on the probe polarization state, which was favorable for controlling the reconstructed images.


Assignment of orthologous genes via genome rearrangement.
The assignment of orthologous genes between a pair of genomes is a fundamental and challenging problem in comparative genomics. Existing methods that assign orthologs based on the similarity between DNA or protein sequences may make erroneous assignments when sequence similarity does not clearly delineate the evolutionary relationship among genes of the same families. In this paper, we present a new approach to ortholog assignment that takes into account both sequence similarity and evolutionary events at a genome level, where orthologous genes are assumed to correspond to each other in the most parsimonious evolving scenario under genome rearrangement. First, the problem is formulated as that of computing the signed reversal distance with duplicates between the two genomes of interest. Then, the problem is decomposed into two new optimization problems, called minimum common partition and maximum cycle decomposition, for which efficient heuristic algorithms are given. Following this approach, we have implemented a high-throughput system for assigning orthologs on a genome scale, called SOAR, and tested it on both simulated data and real genome sequence data. Compared to a recent ortholog assignment method based entirely on homology search (called INPARANOID), SOAR shows a marginally better performance in terms of sensitivity on the real data set because it is able to identify several correct orthologous pairs that are missed by INPARANOID. The simulation results demonstrate that SOAR, in general, performs better than the iterated exemplar algorithm in terms of computing the reversal distance and assigning correct orthologs.


Diurnal salivary cortisol in relation to perceived stress at home and at work in healthy men and women.
This study investigated the association between diurnal salivary cortisol profile and perceived stress at work and at home. Healthy participants (N=180, 52% women) collected saliva cortisol samples immediately after waking up, 15 min later, 30 min later, and at 9:00, 12:00, 15:00, 18:00 and 21:00. The area under the cortisol awakening curve with respect to ground (AUCgCAR) and increase (AUCiCAR), and diurnal slope between 9:00 and 21:00 were analyzed. Perceived stress at work and at home was measured with the Stress-Energy Questionnaire. Participants reporting stress at home had significantly lower AUCgCAR and a flatter diurnal slope. When performing separate analyses for men and women, this association was only significant among women. Perceived stress at work was not associated with any cortisol measure. This study highlights the importance of stress outside the workplace. The sex differences may indicate an increased vulnerability to non-work stress in women.


Predictors of mortality in insulin dependent diabetes: 10 year observational follow up study.
To evaluate the prognostic significance of microalbuminuria and overt diabetic nephropathy and other putative risk factors for cardiovascular and all cause mortality in insulin dependent diabetes. Ten year observational follow up study. Outpatient diabetic clinic in a tertiary referral centre. All 939 adults with insulin dependent diabetes (duration of diabetes five years or more) attending the clinic in 1984; 593 had normal urinary albumin excretion (< or = 30 mg/24 h), 181 persistent microalbuminuria (31-299 mg/24 h), and 165 overt nephropathy (> or = 300 mg/24 h). All cause and cardiovascular mortality. Fifteen per cent of patients (90/593) with normoalbuminuria, 25% (45/181) with microalbuminuria, and 44% (72/165) with overt nephropathy at baseline died during follow up. Cox multiple regression analysis identified the following significant predictors of all cause mortality: male sex (relative risk 2.03; 95% confidence interval 1.37 to 3.02), age (1.07; 1.06 to 1.08), height (0.96; 0.94 to 0.98), smoking (1.51; 1.09 to 2.08), social class V versus social class IV (1.70; 1.25 to 2.31), log10 urinary albumin excretion (1.45; 1.18 to 1.77), hypertension (1.63; 1.18 to 2.25), log10 serum creatinine concentration (8.96; 3.34 to 24.08), and haemoglobin A1c concentration (1.11; 1.03 to 1.20). Age, smoking, microalbuminuria, overt nephropathy, and hypertension were significant predictors of cardiovascular mortality. Mortality in patients with microalbuminuria was only slightly increased compared with that in patients with normoalbuminuria. Median survival time after the onset of overt diabetic nephropathy was 13.9 years (95% confidence interval 11.8 to 17.2 years). Abnormally increased urinary albumin excretion and other potentially modifiable risk factors such as hypertension, smoking, poor glycaemic control, and social class predict increased mortality in insulin dependent diabetes. Microalbuminuria by itself confers only a small increase in mortality. The prognosis of patients with overt diabetic nephropathy has improved, probably owing to effective antihypertensive treatment.


Coherency and differential Mueller matrices for polarizing media.
The elements of the coherency matrix give the strength of the components of a Mueller matrix in the coherency basis. The Z-matrix (called the polarization-coupling matrix or state-generating matrix) represents a partial sum of the coherency expansion. For transmission through a deterministic medium, the coherency elements can be used directly as generators to calculate the development of polarization upon propagation. The commutation properties of the coherency elements are investigated. New matrices that we call the W-matrix and the X-matrix, both different representations of the Z-matrix in a Jones basis, are introduced. The W-matrix controls the transformation of the Jones vector and also the covariance matrix. The product of the X-matrix with its complex conjugate gives the matrix representation of the Mueller matrix in the Jones basis. The development of Mueller matrix and coherency matrix elements upon propagation through some examples of a uniform medium is investigated. It is shown that the coherency matrix is more easily interpreted than the Mueller matrix. Analytic expressions are presented to calculate the elementary polarization properties from coherency matrix elements or Mueller matrix parameters.


The actor-critic learning is behind the matching law: matching versus optimal behaviors.
The ability to make a correct choice of behavior from various options is crucial for animals' survival. The neural basis for the choice of behavior has been attracting growing attention in research on biological and artificial neural systems. Alternative choice tasks with variable ratio (VR) and variable interval (VI) schedules of reinforcement have often been employed in studying decision making by animals and humans. In the VR schedule task, alternative choices are reinforced with different probabilities, and subjects learn to select the behavioral response rewarded more frequently. In the VI schedule task, alternative choices are reinforced at different average intervals independent of the choice frequencies, and the choice behavior follows the so-called matching law. The two policies appear robustly in subjects' choice of behavior, but the underlying neural mechanisms remain unknown. Here, we show that these seemingly different policies can appear from a common computational algorithm known as actor-critic learning. We present experimentally testable variations of the VI schedule in which the matching behavior gives only a suboptimal solution to decision making and show that the actor-critic system exhibits the matching behavior in the steady state of the learning even when the matching behavior is suboptimal. However, it is found that the matching behavior can earn approximately the same reward as the optimal one in many practical situations.


Internet as a tool to access high-risk men who have sex with men from a resource-constrained setting: a study from Peru.
In Peru, current interventions in high-risk men who have sex with men (MSM) reach a limited number of this population because they rely solely on peer education. The objective of this study was to assess the use of the internet as an alternative tool to access this population. Two nearly identical banner ads-both advertising an online survey but only one offering free HIV/syphilis tests and condoms-were displayed randomly on a Peruvian gay website. The inclusion of the health incentive increased the frequency of completed surveys (5.8% vs 3.4% of delivered impressions; p<0.001), attracting high-risk MSM not previously tested for HIV but interested in a wide variety of preventive Web-based interventions. Eleven per cent (80/713) of participants who said they had completed the survey offering free testing visited our clinic: of those who attended, 6% had already been diagnosed as having HIV, while 5% tested positive for HIV. In addition, 8% tested positive for syphilis. The internet can be used as a tool to access MSM in Peru. The compensation of a free HIV/syphilis test increased the frequency of participation in our online survey, indicating that such incentives may be an effective means of reaching this population. However, as only a small percentage of participants actually reported for testing, future research should develop and assess tailored internet interventions to increase HIV/STI testing and delivery of other prevention services to Peruvian MSM.


Electrocatalytic activity of various types of h-BN for the oxygen reduction reaction.
The electrocatalytic activities of various types of h-BN, i.e., spin coated BN nanotubes (BNNTs) and BN nanosheets (BNNSs) and sputter deposited BN, on Au electrodes as well as those of BNNS modified glassy carbon (GC) and Pt electrodes for the oxygen reduction reaction (ORR) were examined in O2 saturated 0.5 M H2SO4 solution based on the theoretical prediction that monolayered BN on a metal substrate may act as an electrocatalyst for ORR even though bulk BN is an insulator with a wide band gap. The overpotential for ORR at Au electrodes was reduced by ca. 100, ca. 270, and ca. 150 mV by spin coating of the dispersion of BNNT and liquid exfoliated BNNS, and sputter deposition of BN, respectively, proving the theoretical prediction. On the other hand, no change in the overpotential was observed at the glassy carbon electrode with BNNS modification and the overpotential even increased at the Pt electrode, suggesting that the interaction between BN and Au plays an important role in BN becoming ORR active.


Retinal light damage in rats with altered levels of rod outer segment docosahexaenoate.
To compare retinal light damage in rats with either normal or reduced levels of rod outer segment (ROS) docosahexaenoic acid. Weanling male albino rats were maintained in a weak cyclic light environment and fed either a nonpurified control diet or a purified diet deficient in the linolenic acid precursor of docosahexaenoic acid (DHA). Half the rats on the deficient diet were given linseed oil, containing more than 50 mol% linolenic acid, once a week to maintain ROS DHA at near normal levels. Diets and linseed oil supplementation were continued for 7 to 12 weeks. To replenish DHA in their ROS, some 10-week-old rats on the deficient diet were given linseed oil three times a week for up to 3 additional weeks. Groups of animals were killed at various times for ROS fatty acid determinations or were exposed to intense green light using intermittent or hyperthermic light treatments. The extent of retinal light damage was determined biochemically by rhodopsin or photoreceptor cell DNA measurements 2 weeks after exposure and morphologically by light and electron microscopy at various times after light treatment. Rats maintained for 7 to 12 weeks on the linolenic acid-deficient diet had significantly lower levels of DHA and significantly higher levels of n-6 docosapentaenoic acid (22:5n-6) in their ROS than deficient-diet animals supplemented once a week with linseed oil or those fed the nonpurified control diet. As determined by rhodopsin levels and photoreceptor cell DNA measurements, deficient diet rats exhibited protection against retinal damage from either intermittent or hyperthermic light exposure. However, the unsaturated fatty acid content of ROS from all three dietary groups was the same and greater than 60 mol%. In 10 week-old deficient-diet rats given linseed oil three times a week, ROS DHA was unchanged for the first 10 days, whereas 22:5n-6 levels declined by 50%. After 3 weeks of treatment with linseed oil, ROS DHA and 22:5n-6 were nearly the same as in rats supplemented with linseed oil from weaning. The time course of susceptibility to retinal light damage, however, was different. Hyperthermic light damage in rats given linseed oil for only 2 days was the same as for rats always fed the deficient diet. Six days after the start of linseed oil treatment, retinal light damage was the same as in rats given the linseed oil supplement from weaning. Morphologic alterations in ROS of linseed oil-supplemented rats immediately after intermittent light exposure were more extensive than in either the deficient-diet animals or those fed the control diet. The deficient-diet rats also exhibited better preservation of photoreceptor cell nuclei and structure 2 weeks after exposure. Rats fed a diet deficient in the linolenic acid precursor of DHA are protected against experimental retinal light damage. The relationship between retinal light damage and ROS lipids does not depend on the total unsaturated fatty acid content of ROS; the damage appears to be related to the relative levels of DHA and 22:5n-6.


Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs.
Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials.


Species-specific alternative splicing leads to unique expression of sno-lncRNAs.
Intron-derived long noncoding RNAs with snoRNA ends (sno-lncRNAs) are highly expressed from the imprinted Prader-Willi syndrome (PWS) region on human chromosome 15. However, sno-lncRNAs from other regions of the human genome or from other genomes have not yet been documented. By exploring non-polyadenylated transcriptomes from human, rhesus and mouse, we have systematically annotated sno-lncRNAs expressed in all three species. In total, using available data from a limited set of cell lines, 19 sno-lncRNAs have been identified with tissue- and species-specific expression patterns. Although primary sequence analysis revealed that snoRNAs themselves are conserved from human to mouse, sno-lncRNAs are not. PWS region sno-lncRNAs are highly expressed in human and rhesus monkey, but are undetectable in mouse. Importantly, the absence of PWS region sno-lncRNAs in mouse suggested a possible reason why current mouse models fail to fully recapitulate pathological features of human PWS. In addition, a RPL13A region sno-lncRNA was specifically revealed in mouse embryonic stem cells, and its snoRNA ends were reported to influence lipid metabolism. Interestingly, the RPL13A region sno-lncRNA is barely detectable in human. We further demonstrated that the formation of sno-lncRNAs is often associated with alternative splicing of exons within their parent genes, and species-specific alternative splicing leads to unique expression pattern of sno-lncRNAs in different animals. Comparative transcriptomes of non-polyadenylated RNAs among human, rhesus and mouse revealed that the expression of sno-lncRNAs is species-specific and that their processing is closely linked to alternative splicing of their parent genes. This study thus further demonstrates a complex regulatory network of coding and noncoding parts of the mammalian genome.


Multi-slice echo-planar spectroscopic MR imaging provides both global and local metabolite measures in multiple sclerosis.
MR spectroscopy (MRS) provides information about neuronal loss or dysfunction by measuring decreases in N-acetyl aspartate (NAA), a metabolite widely believed to be a marker of neuronal viability. In multiple sclerosis (MS), whole-brain NAA (WBNAA) has been suggested as a marker of disease progression and treatment efficacy in treatment trials, and the ability to measure NAA loss in specific brain regions early in the evolution of this disease may have prognostic value. Most spectroscopic studies to date have been limited to single voxels or nonlocalized measurements of WBNAA only, and longitudinal studies have often been hampered by standardization and reproducibility problems. Multi-slice echo-planar spectroscopic imaging (EPSI) is presented as a promising alternative to single-voxel or nonlocalized spectroscopy for obtaining global metabolite estimates in MS. In the same session, measurements of metabolites in specific brain areas chosen after image acquisition (e.g., normal-appearing white matter (NAWM), gray matter (GM), and lesions) can be obtained. The identification and exclusion of regions that are inadequate for spectroscopic evaluation in global assessments can significantly improve quality and reproducibility, as demonstrated by a low within-subject variance in healthy controls. The reproducibility of the technique makes it a promising tool for future longitudinal spectroscopic studies of MS.


Recovery of Fusarium oxysporum Fo47 Mutants Affected in Their Biocontrol Activity After Transposition of the Fot1 Element.
ABSTRACT To investigate the biocontrol mechanisms by which the antagonistic Fusarium oxysporum strain Fo47 is active against Fusarium wilt, a Fot1 transposon-mediated insertional mutagenesis approach was adopted to generate mutants affected in their antagonistic activity. Ninety strains in which an active Fot1 copy had transposed were identified with a phenotypic assay for excision and tested for their biocontrol activity against F. oxysporum f. sp. lini on flax in greenhouse experiments. Sixteen strains were affected in their capacity to protect flax plants, either positively (more antagonistic than Fo47) or negatively (less antagonistic). The molecular characterization of these mutants confirms the excision of Fot1 and its reinsertion in most of the cases. Moreover, we demonstrate that other transposable elements such as Fot2, impala, and Hop have no transposition activity in the mutant genomes. The phenotypic characterization of these mutants shows that they are affected neither in their in vitro growth habit nor in their competitiveness in soil compared with wild-type strain Fo47. These results show that mutants are not impaired in their saprophytic phase and suggest that the altered biocontrol phenotype should likely be expressed during the interaction with the host plant.


Molecular differences between human thyroid follicular adenoma and carcinoma revealed by analysis of a murine model of thyroid cancer.
Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated ± 2-fold in FTC samples. Then the expression of 45 deregulated genes in mouse tumors was investigated by quantitative RT-PCR in a first cohort of human NT, FA, and FTC (discovery group). Five genes were found significantly down-regulated in FA and FTC compared with NT. However, 17 genes were found differentially expressed between FA and FTC: 5 and 12 genes were overexpressed and underexpressed in FTC vs FA, respectively. Finally, 7 gene products, selected from results obtained in the discovery group, were investigated in a second cohort of human tumors (validation group) by immunohistochemistry. Four proteins showed significant differences between FA and FTC (peroxisomal proliferator-activated receptor-γ, serum deprivation response protein, osteoglycin, and dipeptidase 1). Altogether our data indicate that the establishment of an enriched panel of molecular biomarkers using data coming from mouse thyroid tumors and validated in human specimens may help to set up a more valid platform to further improve diagnosis and prognosis of thyroid malignancies.


Validating and comparing stroke prognosis scales.
To compare the prognostic accuracy of various acute stroke prognostic scales using a large, independent, clinical trials dataset. We directly compared 8 stroke prognostic scales, chosen based on focused literature review (Acute Stroke Registry and Analysis of Lausanne [ASTRAL]; iSCORE; iSCORE-revised; preadmission comorbidities, level of consciousness, age, and neurologic deficit [PLAN]; stroke subtype, Oxfordshire Community Stroke Project, age, and prestroke modified Rankin Scale [mRS] [SOAR]; modified SOAR; Stroke Prognosis Instrument 2 [SPI2]; and Totaled Health Risks in Vascular Events [THRIVE]) using individual patient-level data from a clinical trials archive (Virtual International Stroke Trials Archive [VISTA]). We calculated area under receiver operating characteristic curves (AUROC) for each scale against 90-day outcomes of mRS (dichotomized at mRS >2), Barthel Index (>85), and mortality. We performed 2 complementary analyses: the first limited to patients with complete data for all components of all scales (simultaneous) and the second using as many patients as possible for each individual scale (separate). We compared AUROCs and performed sensitivity analyses substituting extreme outcome values for missing data. In total, 10,777 patients contributed to the analyses. Our simultaneous analyses suggested that ASTRAL had greatest prognostic accuracy for mRS, AUROC 0.78 (95% confidence interval [CI] 0.75-0.82), and SPI2 had poorest AUROC, 0.61 (95% CI 0.57-0.66). Our separate analyses confirmed these results: ASTRAL AUROC 0.79 (95% CI 0.78-0.80 and SPI2 AUROC 0.60 (95% CI 0.59-0.61). On formal comparative testing, there was a significant difference in modified Rankin Scale AUROC between ASTRAL and all other scales. Sensitivity analysis identified no evidence of systematic bias from missing data. Our comparative analyses confirm differences in the prognostic accuracy of stroke scales. However, even the best performing scale had prognostic accuracy that may not be sufficient as a basis for clinical decision-making.


Efficacy of zinc sulfate on concurrent chemoradiotherapy induced taste alterations in oral cancer patients: A double blind randomized controlled trial.
To observe the efficacy of zinc sulfate on taste alterations in oral cancer patients receiving concurrent chemotherapy with radiotherapy. Seventy patients were randomly assigned to both intervention and control group at Oncology Section of Atomic Energy Medical Centre Karachi from September 2017 to March 2018. One group received zinc sulfate capsules (50 mg TDS daily after meals) and the other group received placebo (thrice after meals). Patients were advised to start taking capsules on the first day of their chemoradiation. Both the groups continued the capsules a month after their CCRT ended. Sweet taste was most effected by cancer and its treatment followed by bitter and salty taste. Sour taste was least effected. When both the groups were compared for four tastes for detection threshold, the differences in observation at 3 stages of median IQR were not significant. For recognition threshold between zinc sulfate and placebo, no significant difference was observed in median IQR for salty taste and bitter taste. However, sweet taste (baseline p-value 0.245, end p-value 0.010, follow-up p-value 0.038) was statistically significant at end of CCRT and follow-up stage and sour taste (baseline p-value 0.24, end p-value 0.006, follow-up p-value 0.898) at end of CCRT only. Zinc sulfate was not found to be beneficial in preventing chemoradiation induced taste alterations. Taste and smell alterations are common in patients with cancer and do not receive sufficient support to manage taste alterations. This area requires more research to develop a comprehensive understanding of the nature and its management.


The lifetime prevalence of hospitalised head injury in Scottish prisons: A population study.
There is mounting evidence that associates brain injury and offending behaviour, and there is a need to understand the epidemiology of head injury in prisoners in order to plan interventions to reduce associated disability and risk of reoffending. This is the first study to determine the lifetime prevalence of hospitalised head injury (HHI) in a national population of current prison inmates. In addition characteristics of prisoners with HHI and were compared to prisoners without HHI to discover whether those with HI differed demographically. Whole life hospital records of everyone aged 35 years or younger and resident in a prison in Scotland on a census date in 2015 were electronically linked via their unique NHS identifier and checked for ICD-9 and 10 codes for head injury. Using a case-control design, these data were compared with a sample from the general population matched 3:1 for age, gender and area-based social deprivation. Comparison of demographic variables was made between prisoners with and without HHI. HHI was found in 24.7% (1,080/4,374) of prisoners and was significantly more prevalent than found in the matched general population sample (18.2%; 2394/13122; OR 2.10; 95%CI 1.87, 2.16). The prevalence of HHI in prisoners and controls was similar with the exception of a higher risk of HHI in prisoners in lower deprivation quintiles. Having three or more HHI was more common in prisoners (OR 3.04; 95%CI 2.33, 3.97) as were HHI with ICD codes for intracranial injuries (OR 1.81; 95% CI 1.54, 2.11), suggesting that more severe HHI is more prevalent in prisoners than the general population. The distributions within demographic variables and the characteristics of HHI admissions in prisoners with and without a history of HHI were similar. Prisoners in Scotland aged 35 years or younger have a higher lifetime prevalence of HHI than the general population and are more likely to have had repeated HI or intracranial injuries. Further work is required to elucidate the correspondence between self-report of HI and hospitalised records and to ascertain persisting effects of HI in prisoners and the need for services to reduce associated disability and risk of reoffending.


Optimizing Communication and Adherence to Iron Chelation Therapy From Diagnosis to Treatment in Patients With Myelodysplastic Syndromes.
Myelodysplastic syndromes (MDS), a heterogeneous group of blood diseases, are usually diagnosed in older individuals, with a median age at diagnosis of more than 70 years. Anemia is a common symptom in patients with MDS and may require frequent red blood cell transfusions, which can lead to iron overload. Iron chelation therapy is recommended to decrease iron concentrations in tissue and minimize organ dysfunction. However, the currently available iron chelation therapies are associated with side effects, financial constraints, and dosing issues, which may affect patient adherence. Moreover, many patients with MDS lack an understanding of the disease and their prognosis and treatments. This review can be used in the advanced practice setting to discuss the importance of communicating with patients about MDS from the time of diagnosis and will explore strategies to enhance adherence to iron chelation therapy. An individualized approach that weighs the risks and benefits of treatment for older patients with MDS will allow advanced practitioners to set expectations while developing adherence strategies to optimize outcomes. This approach provides a platform for advanced practitioners to communicate with patients to ensure they understand the natural history of MDS, their individual prognoses, and the goals of both active treatment and supportive care.


Aligning payment reform and delivery innovation in emergency care.
Current alternative payment models (APMs) that move away from traditional fee-for-service payment often have explicit goals to reduce utilization in episodic settings, such as emergency departments (ED). We apply the new HHS payment reform taxonomy to illustrate a pathway to success for EDs in APMs. Despite the unique challenges faced by EDs, a variety of category 2 and 3 APMs may be applicable to EDs in the short- and long term to improve efficiency and value. Full and partially capitated models create incentives for longitudinal and episodic ED providers and payers to unite to create interventions to reduce costs. However, prospective attribution remains a challenge for EDs because of exogenous demand, which makes it important for EDs to be one of the components of capitated payment along with longitudinal providers who can exert greater control on overall care demands. The goal of payment and delivery reforms in ED care is to improve population health across the continuum of acute and longitudinal care. In order to deliver cost-conscious care, ED providers will need additional resources, expanded information, and new processes and metrics to facilitate cost-conscious decisions. Improved availability of electronic information across settings, evidence generated from developing and testing acute care-specific payment models, and engaging acute care providers directly in reform efforts will help meet these goals.


Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease.
To quantify postural sway in subjects with Parkinson's disease and elderly controls, and determine the effects of Parkinson's disease, deep brain stimulation, levodopa, and their interactions on postural control during quiet stance. Centre of foot pressure (CoP) displacement under each foot was measured during three 60 s trials of quiet stance with eyes open in 11 controls and six patients with Parkinson's disease. Subjects with Parkinson's disease were tested in four treatment conditions: off both deep brain stimulation and levodopa (off condition); on deep brain stimulation; on levodopa; and on both deep brain stimulation and levodopa. The variables extracted from CoP included: root mean square distance (rms), mean velocity, 95% power frequency (f(95%)), area of the 95% confidence ellipse (ellipse area), direction of its major axis (mdir), and postural asymmetry between the feet. rms and area of postural sway were larger than normal in subjects with Parkinson's disease in the off condition, increased further with levodopa, and significantly decreased with deep brain stimulation. Mean velocity and f(95%) were also larger than normal but were restored to normal by all treatments, especially by deep brain stimulation. The combined effect of deep brain stimulation and levodopa resulted in a postural sway that was an average of the effect of each treatment individually. Levodopa increased sway more in the mediolateral than in the anterior-posterior direction. Subjects with Parkinson's disease had asymmetrical mean velocity and f(95%) between the feet, and this asymmetry increased with levodopa but decreased with deep brain stimulation. The f(95%) of the CoP correlated with tremor, posture, and gait subcomponents of the unified Parkinson's disease rating scale. Subjects with Parkinson's disease have abnormal postural sway in stance. Treatment with levodopa increases postural sway abnormalities, whereas treatment with deep brain stimulation improves postural sway. Quantitative evaluation of static posturography may be a useful adjunct to clinical measures in patients with Parkinson's disease.


Effects of ten years organic and conventional farming on early seedling traits of evolving winter wheat composite cross populations.
Early vigour traits of wheat composite cross populations (CCPs) based on high yielding (Y) or high quality (Q) or Y*Q varietal intercross evolving under organic or conventional conditions in parallel populations were studied hydroponically. To eliminate storage and year effects, frozen F6, F10, F11 and F15 seeds were multiplied in one field, resulting in the respective Fx.1 generations. This eliminated generation and growing system effects on seed size for the F6.1 F10.1 and F15.1. Due to a severe winter kill affecting the F11, the generation effect persisted, leading to larger seeds and markedly different seedling traits in the F11.1 compared to the F10.1 and F15.1. Seedling traits were similar among parallel populations. Shoot length and weight increased in both systems until the F11.1 across farming systems and remained constant thereafter. Over time, seminal root length and root weight of organic CCPs increased and total- and specific- root length decreased significantly compared to the conventional CCPs. Rooting patterns under organic conditions suggests better ability to reach deeper soil nutrients. In both systems, Q and YQ CCPs were more vigorous than Y CCPs, confirming genetic differences among populations. Overall, heterogeneous populations appear very plastic and selection pressure was stronger in organic systems.


Phylogenomic evidence for ancient hybridization in the genomes of living cats (Felidae).
Inter-species hybridization has been recently recognized as potentially common in wild animals, but the extent to which it shapes modern genomes is still poorly understood. Distinguishing historical hybridization events from other processes leading to phylogenetic discordance among different markers requires a well-resolved species tree that considers all modes of inheritance and overcomes systematic problems due to rapid lineage diversification by sampling large genomic character sets. Here, we assessed genome-wide phylogenetic variation across a diverse mammalian family, Felidae (cats). We combined genotypes from a genome-wide SNP array with additional autosomal, X- and Y-linked variants to sample ∼150 kb of nuclear sequence, in addition to complete mitochondrial genomes generated using light-coverage Illumina sequencing. We present the first robust felid time tree that accounts for unique maternal, paternal, and biparental evolutionary histories. Signatures of phylogenetic discordance were abundant in the genomes of modern cats, in many cases indicating hybridization as the most likely cause. Comparison of big cat whole-genome sequences revealed a substantial reduction of X-linked divergence times across several large recombination cold spots, which were highly enriched for signatures of selection-driven post-divergence hybridization between the ancestors of the snow leopard and lion lineages. These results highlight the mosaic origin of modern felid genomes and the influence of sex chromosomes and sex-biased dispersal in post-speciation gene flow. A complete resolution of the tree of life will require comprehensive genomic sampling of biparental and sex-limited genetic variation to identify and control for phylogenetic conflict caused by ancient admixture and sex-biased differences in genomic transmission.


Symptoms of frontotemporal dementia provide insights into orbitofrontal cortex function and social behavior.
Recent investigations into the brain substrates of behavioral changes in frontotemporal dementia (FTD) demonstrate that the orbitofrontal cortex (OFC) plays a crucial role in normal social and emotional behavior. The initial symptoms of FTD reflect the early involvement of OFC as well as the disruption of an associated network involving the insula, striatum, and medial frontal lobes. As predicted by patients with other types of OFC lesions, FTD patients show impairments involving stimulus-reward reversal learning, response inhibition, and ability to judge the appropriateness of their behavior in the social context. While the natural reward system remains intact in these patients, that is, patients will seek out directly rewarding stimuli, such as food and sex, with progressive OFC dysfunction they lose the ability to process complex stimulus-reward contingencies. These abnormalities are apparent in their social interactions, which break down early in the disease. Also, deficits in emotion recognition and empathy have been directly linked to OFC atrophy in these patients. In contrast, some patients with early FTD show intact cognitive skills, including memory and executive functioning. Here, we review the behavioral and neuropsychological changes that accompany OFC atrophy in FTD and argue that phylogenetically new neurons found in this region, called von Economo neurons, are selectively vulnerable in FTD.


Characterization of fasted human gastric fluid for relevant rheological parameters and gastric lipase activities.
To characterize human gastric fluid with regard to rheological properties and gastric lipase activity. In addition, traditional physicochemical properties were determined. Fasted HGA were collected from 19 healthy volunteers during a gastroscopic examination. Rheological characterization of the aspirates was conducted on a TA AR-G2 rheometer, using cone and plate geometry. Lipase activity was measured by continuous titration of released free fatty acid from tributyrate. Further, pH, osmolality, buffer capacity, and surface tension were measured and the total protein content and bile salt level were determined using assay kits. Rheological examination of HGA showed non-Newtonian shear-thinning behavior with predominant elastic behavior in the linear range. The apparent viscosity was measured to be in the range of 1.7-9.3 mPas at a shear rate of 50s(-1). The FaSSGF and HCl pH 1.2 have no shear-thinning properties and showed lower viscosity (1.1 mPas at 50 s(-1)). The observed viscosity of the HGA will decrease the intrinsic dissolution rate of drugs. The activity of the gastric lipase was 7.4 ± 4.0 U/mL (N = 6, n = 3) and 99.0 ± 45.3 U/mL (N = 19, n = 3) at pH 2.8 and 5.4, respectively. pH, surface tension, buffer capacity, bile salt concentration, and osmolality were measured and compared with literature data. The rheological behavior and the mean apparent viscosity of HGA are significantly different from that of water and should therefore be considered important during development of gastric simulated media. Further, the activity of the HGL is active even under fasted gastric conditions and might contribute to the digestion and emulsification of lipid-based drug delivery systems in the entire gastrointestinal tract. HGL should therefore be considered in gastric evaluation of lipid-based drug delivery systems.