Efficacy of trabectedin in platinum-sensitive-relapsed ovarian cancer: new data from the randomized OVA-301 study.
The results of the OVA-301 study show that trabectedin in combination with pegylated liposomal doxorubicin (PLD) results in improved progression-free survival and response rate in patients with advanced ovarian cancer. The trial has also demonstrated a trend toward improvement in overall survival. A subgroup analysis indicates that in the subset of patients with platinum-free interval (PFI) of 6 to 12 months, the combined treatment resulted in a 6-month improvement in overall survival. Furthermore, in the patients who have received third-line treatment with a platinum agent, it was found that the survival was better in those who had received trabectedin and PLD. These results suggest that prolonging the PFI by a nonplatinum-effective regimen improves the outcome with subsequent, third-line platinum treatment. This strategy may also have positive effects in treatment tolerability, as it allows extra time to recover from platinum-induced toxicities. This hypothesis is currently been tested in the INOVATYON (INternational OVArian Cancer Patients Trial With YONdelis) phase III study.


Antibiotic prescribing practices for catheter urine culture results.
The literature suggests that positive results of catheter urine cultures frequently lead to unnecessary antimicrobial prescribing, which therefore represents an important target for stewardship. To assess the appropriateness of antibiotic prescribing in response to the results of urine cultures from patients with indwelling urinary catheters. This retrospective study was conducted at a tertiary care centre and involved adults with indwelling urinary catheters from whom urine specimens were obtained for culture. Patients with positive or negative culture results were identified from microbiology laboratory reports. The medical records of consecutive patients were screened to select a sample of 80 inpatients (40 per group). Abstracted patient histories were independently evaluated by an expert panel of 3 infectious diseases consultants blinded to the decisions of prescribers and of fellow panelists. The primary end point was concordance of each patient's treatment decision (with respect to the indication) between the expert panel (based on majority agreement, i.e., at least 2 of the 3 expert panelists) and the prescriber. The secondary end points were unnecessary days of therapy and selected outcomes over a predefined period after urine was obtained for culture. A total of 591 charts were screened to generate the targeted number of patients. Baseline demographic characteristics were comparable for the 2 groups, except antibiotic exposure before urine collection was significantly more frequent for the group with negative culture results. The treatment decision was concordant in 40% (16/40) of the patients with a positive culture result and 85% (34/40) of those with a negative culture result (p < 0.001). The most common reason for discordance was administration of antibiotics when not indicated (23 of 24 patients with a positive result and 5 of 6 patients with a negative result), which accounted for 165 and 32 unnecessary days of therapy per 1000 inpatient-days, respectively (p < 0.001). Adverse effects occurred in 2 of the 23 patients with a positive result who received antibiotics that were not indicated. Appropriateness of antibiotic prescribing, as measured by concordance of decisions between the expert panel and prescribers, was more common among patients with negative urine culture results than among those with positive results. However, there is an opportunity to improve prescribing for both groups through antimicrobial stewardship initiatives. Unnecessary days of therapy and adverse effects were more common in patients with a positive culture result.


Heat denaturation of soy glycinin: influence of pH and ionic strength on molecular structure.
The 7S/11S glycinin equilibrium as found in Lakemond et al. (J. Agric. Food Chem. 2000, 48, xxxx-xxxx) at ambient temperatures influences heat denaturation. It is found that the 7S form of glycinin denatures at a lower temperature than the 11S form, as demonstrated by a combination of calorimetric (DSC) and circular dichroism (CD) experiments. At pH 7.6, at which glycinin is mainly present in the 11S form, the disulfide bridge linking the acidic and the basic polypeptides is broken during heat denaturation. At pH 3.8, at which glycinin has dissociated partly into the 7S form, and at pH 5.2 this disruption does not take place, as demonstrated by solubility and gel electrophoretic experiments. A larger exposure of the acidic polypeptides (Lakemond et al., 2000) possibly correlates with a higher endothermic transition temperature and with the appearance of an exothermic transition as observed with DSC. Denaturation/aggregation (studied by DSC) and changes in secondary structure (studied by far-UV CD) take place simultaneously. Generally, changes in tertiary structure (studied by near-UV CD) occur at lower temperatures than changes in secondary structure.


Genetic interactions of separase regulatory subunits reveal the diverged Drosophila Cenp-C homolog.
Faithful transmission of genetic information during mitotic divisions depends on bipolar attachment of sister kinetochores to the mitotic spindle and on complete resolution of sister-chromatid cohesion immediately before the metaphase-to-anaphase transition. Separase is thought to be responsible for sister-chromatid separation, but its regulation is not completely understood. Therefore, we have screened for genetic loci that modify the aberrant phenotypes caused by overexpression of the regulatory separase complex subunits Pimples/securin and Three rows in Drosophila. An interacting gene was found to encode a constitutive centromere protein. Characterization of its centromere localization domain revealed the presence of a diverged CENPC motif. While direct evidence for an involvement of this Drosophila Cenp-C homolog in separase activation at centromeres could not be obtained, in vivo imaging clearly demonstrated that it is required for normal attachment of kinetochores to the spindle.


The ethical and policy implications of research on income inequality and child well-being.
Child well-being is important for lifelong health and well-being. Although there is a robust evidence base linking social determinants of health (eg, relative poverty and income inequality) to child well-being, social and public health policy tends to focus on interventions to mitigate their effects, rather than remove the root causes. The goal of this study was to examine associations between child well-being and income inequality. We compared reported rates of childhood well-being in the 2007 and 2013 UNICEF reports on child well-being in wealthy countries. Twenty indicators of child well-being (excluding child poverty) were defined consistently in both the 2007 and 2013 reports. These variables were used to create an indicator of change in child well-being over the approximate decade 2000 to 2010. For our analyses of income inequality, we used the Organization for Economic Cooperation and Development Gini coefficient of income inequality for 2009 and change between 2000 and 2009, respectively. The overall index of child well-being in 2013 was closely and negatively correlated with income inequality (r = -0.60, P = .004) but not with average income (r = -0.3460, P = .12). Adjustment for income inequality, children in relative poverty, and the child poverty gap did not change the lack of association between average income and child well-being in 2013 in wealthy countries. Between 2000 and 2010, child well-being scores improved most in Italy, Norway, Portugal, the United Kingdom, and Germany. The biggest declines were seen in Sweden, Canada, Japan, Switzerland, and France. Countries that experienced the largest increases in income inequality had significantly greater declines in child well-being (r = -0.51, P = .02). Children born into socioeconomically disadvantaged families suffer worse child well-being and its lifelong implications, in all societies, worldwide. Our analyses show, however, that some wealthy societies are able to mitigate these inequalities; these societies have better child well-being, on average. This outcome has less to do with specific welfare policies or targeted interventions for poor children than to a societal commitment to greater equality.


Follow-up of a historic cohort of children treated for severe acute malnutrition between 1988 and 2007 in Eastern Democratic Republic of Congo.
It is well documented that treatment for severe acute malnutrition (SAM) is effective. However, little is known about the long-term outcomes for children treated for SAM. We sought to trace former SAM patients 11 to 30 years after their discharge from hospital, and to describe their longer-term survival and their growth to adulthood. A total of 1,981 records of subjects admitted for SAM between 1988 and 2007 were taken from the archives of Lwiro hospital, in South Kivu, DRC. The median age on admission was 41 months. Between December 2017 and June 2018, we set about identifying these subjects (cases) in the health zones of Miti-Murhesa and Katana. For deceased subjects, the cause and year of death were collected. A Cox proportional hazards multivariate regression analysis was used to identify the death-related factors. For the cases seen, age- and gender-matched community controls were selected for a comparison of anthropometric indicators. A total of 600 subjects were traced, and 201 subjects were deceased. Of the deceased subjects, 65·6% were under 10 years old at the time of their death. Of the deaths, 59·2% occurred within 5 years of discharge from hospital. The main causes of death were malaria (14·9%), kwashiorkor (13·9%), respiratory infections (10·4%), and diarrhoeal diseases (8·9%). The risk of death was higher in subjects with SAM, MAM combined with CM, and in male subjects, with HRs* of 1·83 (p = 0·043), 2.35 (p = 0·030) and 1.44 (p = 0·013) respectively. Compared with their controls, the cases had a low weight (-1·7 kg, p = 0·001), short height [sitting (-1·3 cm, p = 0·006) and standing (-1·7 cm, p = 0·003)], short legs (-1·6 cm, p = 0·002), and a small mid-upper arm circumference (-3·2mm, p = 0·051). There was no difference in terms of BMI, thoracic length, or head and thoracic circumference between the two groups. SAM during childhood has lasting negative effects on growth to adulthood. In addition, these adults have characteristics that may place them at risk of chronic non-communicable diseases later in life.


Panic Disorder Comorbidity with Medical Conditions and Treatment Implications.
Panic disorder (PD) is unique among the anxiety disorders in that panic symptoms are primarily of a physical nature. Consequently, comorbidity with medical illness is significant. This review examines the association between PD and medical illness. We identify shared pathophysiological and psychological correlates and illustrate how physiological activation in panic sufferers underlies their symptom experience in the context of the fight-or-flight response and beyond a situation-specific response pattern. We then review evidence for bodily symptom perception accuracy in PD. Prevalence of comorbidity for PD and medical illness is presented, with a focus on respiratory and cardiovascular illness, irritable bowel syndrome, and diabetes, followed by an outline for potential pathways of a bidirectional association. We conclude by illustrating commonalities in mediating mechanistic pathways and moderating risk factors across medical illnesses, and we discuss implications for diagnosis and treatment of both types of conditions.


Peripheral CD4 loss of regulatory T cells is associated with persistent viraemia in chronic HIV infection.
Chronic HIV infection is associated with T cell abnormalities and altered effector function. Regulatory T cells (Treg) are CD4+ T cells that play a critical role in regulating the immune system. The impact of regulatory T cells on HIV infection and disease progression may be highly significant. We hypothesize that chronic antigenic stimulation from a persistent, high viraemic state may promote a population of Treg that contributes to HIV-associated immune dysfunction. We evaluated the pattern of Treg in chronically infected, HIV-positive individuals over a course of 6 months. Treg are depleted at a distinct rate from that of absolute CD4 cells and loss of Treg is slower in the presence of viral suppression. In vitro depletion of CD25+ CD4+ cells resulted in increased Gag-specific CD4 and CD8 responses. A significant correlation between ex vivo measurement of Treg and Gag-specific CD4 T cell responses was observed (r=-0 x 41, P=0 x 018) with a trend observed with Gag-specific CD8 T cell responses (P=0 x 07). The impact of HIV infection on the Treg population directly complicates the measured effect of Treg on the immune dysfunction although our data support the important role of Treg on modulating the effector T cell response in chronic infection.


Evaluation of Interleukin-6, Leukotriene B-4, and Nitric Oxide Levels in Exhaled Breath Condensate of Asymptomatic Obese Individuals: Are Obese Patients Under Risk of Developing Asthma?
If systemic inflammation in relation with obesity causes asthma, the detection of increased airway inflammation among obese individuals who do not have any respiratory symptoms can be also beneficial in indentifying obese patients who are at risk of developing asthma. The aim of this study was to evaluate the systemic and airway inflammation of asymptomatic obese and non-obese individuals. Obese and non-obese individuals with no respiratory symptoms were included. Inflammatory biomarkers such as C-reactive protein (CRP), exhaled breath condensate (EBC) interleukin-6 (IL-6), EBC leukotriene B-4 (LTB-4), and EBC nitric oxide (NO) levels of obese and non-obese individuals were determined. Forty-five obese individuals (body mass index [BMI]≥30) and 31 non-obese individuals (BMI≤25) as a control group were included in this study. The mean age of the obese group (38.7±11.4 years) was significantly higher than the one of the non-obese group (29.5±8.6 years; p<0.001). There was no significant relationship between gender and BMI (χ2 =1.471, p=0.225). CRP levels were significantly higher in the obese group (6.94±8.28) than the non-obese group (3.29±0.39; p<0.001). The levels of EBC IL-6 in obese and non-obese group were found as 22.61±12.53 and 21.08±14.39, respectively (p=0.624). There was no significant difference between EBC NO levels of the obese group and non-obese group (24.35±10.9 vs. 21.56±7.83; p=0.226). No significant difference was found between the EBC LTB-4 level in the obese group and the non-obese group (36.39±89.82 vs. 16.64±17.45; p=0.231). Increased systemic inflammation in obese individuals who had no respiratory symptoms might indicate the tendency of asthma. However, airway inflammation was not significantly different between groups. Therefore the relationship between obesity and asthma should be investigated in future large-scale studies determining the direct effects of adipokines on airways.


Endurance exercise training promotes medullary hematopoiesis.
Endurance exercise is a poorly defined yet powerful mediator of hematopoiesis. The purpose of this study was to directly investigate the effects of endurance exercise training on hematopoiesis and to identify potential mechanisms responsible for any observed changes. Four-week-old male C57Bl/6 mice were trained on a treadmill at progressive speeds over a 10-wk period. Tissues were harvested 2 d following the final training session. Flow cytometry, the cobblestone area-forming cell assay, and the methycellulose colony-forming unit assay were used to assess medullary and mobilized hematopoietic stem and progenitor cells. Quantitative real-time PCR and Western blots were used to measure hematopoietic cytokine production. Histochemistry was also used to assess adaptations to exercise in the bone marrow niche. Depending on the cell type, endurance training increased medullary and mobilized hematopoietic stem and progenitor cell content from 50 to 800%. Training also reduced marrow cavity fat by 78%. Skeletal muscle hematopoietic cytokine expression was also increased at least 60% by training. Sedentary mice served as controls for the above experiments. In conclusion, endurance exercise training greatly promotes hematopoiesis and does so through improvements in medullary niche architecture as well as increased skeletal muscle hematopoietic cytokine production.


Ectopic endometrial tissue in mesonephric duct remnants in bitches.
Common congenital embryonic remnants of the canine female genital tract are Gartner cysts originating from mesonephric duct remnants. They can increase in size and lead to adverse effects in fertility and health. In the present study, three cases of mesonephric remnants in bitches were analysed. The mesonephric remnants featured an inner lining endometrium comprising surface epithelium, glands and stroma. This ectopic endometrium was further characterized by immunohistochemistry (oestrogen and progesterone receptors, proliferation activity, cytokeratin, alpha smooth muscle actin, and vimentin) and lectin histochemistry compared with normal uterine endometrium. Furthermore, hypertrophic cells at the serosal site of the uteri were detected and analysed in the same way compared with normal serosa. The ectopic endometrium of case no. 2 mesonephric remnant was comparable with normal endometrium whereas in nos 1 and 3 uteri the ectopic endometrium was reduced in thickness. In all mesonephric remnants, surface and glandular epithelial cells of the ectopic endometrium gave positive immunoreactions for cytokeratin, oestrogen and progesterone receptors and showed lectin-binding patterns comparable with normal endometrium. Some of the stromal cells of the ectopic endometria were smooth muscle actin and vimentin positive. Mitotic activity of the ectopic endometria was comparable with normal endometria. Hypertrophic epithelial cells of the serosal side showed positive reactions to anti-oestrogen receptor and anti-cytokeratin immunohistochemistry as well as lectin binding patterns and mitotic activity comparable with the normal canine serosa. The present study is the first considerable immunohistochemical characterization of canine mesonephric remnants and discusses the appearance of ectopic endometrium in mesonephric remnants.


A one-pot modular assembly strategy for triple-play enhanced cytosolic siRNA delivery.
Robust efficiency for cytosolic small interfering RNA (siRNA) delivery is of great importance for effective gene therapy. To significantly improve the cytosolic siRNA delivery, a "one-pot modular assembly" strategy is developed to assemble a triple-play enhanced cytosolic siRNA delivery system via a facile and innocuous copper-free click reaction. Specifically, three modules are prepared including octreotide for receptor-mediated endocytosis, a cell-penetrating peptide (CPP) for cell penetration, and glutamic acid for the charge-reversal property. All three modules with distinct facilitating endocytosis effects are expediently assembled on the surface of the siRNA/liposome complex to fabricate a multifunctional integrated siRNA delivery system (OCA-CC). OCA-CC has been demonstrated to have enhanced cytosolic delivery and superior gene-silencing efficiency in multiple tumor cells due to the combined effects of all the three modules. High levels of survivin-silencing are also achieved by OCA-CC on orthotopic human breast cancer (MCF-7)-bearing mice accompanied by significant tumor inhibition. This research provides a facile strategy to produce safe and tunable siRNA delivery systems for effective gene therapy and to facilitate the development of multifunctional siRNA vectors.


Effect of real-time ultrasound imaging for biofeedback on trunk muscle contraction in healthy subjects: a preliminary study.
Real-time ultrasound imaging (RUSI) has been increasingly used as a form of biofeedback when instructing and re-training muscle contraction. However, the effectiveness of the RUSI on a single sustained contraction of the lumbar multifidus (LM) and transversus abdominis (TrA) has rarely been reported. This preliminary study aimed to determine if the use of RUSI, as visual biofeedback, could enhance the ability of activation and continuous contraction of the trunk muscles including LM and TrA. Forty healthy individuals were included and randomly assigned into the experimental group and control group. All subjects performed a preferential activation of the LM and/or TrA (maintained the constraction of LM and/or TrA for 30 s and then relaxed for 2 min), while those in the experimental group also received visual feedback provided by RUSI. The thickness of LM and/or TrA at rest and during contraction (Tc-max, T15s, and T30s) were extracted and recorded. The experiment was repeated three times. No significant differences were found in the thickness of LM at rest (P > 0.999), Tc-max (P > 0.999), and T15s (P = 0.414) between the two groups. However, the ability to recruit LM muscle contraction differed between groups at T30s (P = 0.006), with subjects in the experimental group that received visual ultrasound biofeedback maintaining a relative maximum contraction. Besides, no significant differences were found in the TrA muscle thickness at rest (P > 0.999) and Tc-max (P > 0.999) between the two groups. However, significant differences of contraction thickness were found at T15s (P = 0.031) and T30s (P = 0.010) between the two groups during the Abdominal Drawing-in Maneuver (ADIM), with greater TrA muscle contraction thickness in the experimental group. RUSI can be used to provide visual biofeedback, which can promote continuous contraction, and improve the ability to activate the LM and TrA muscles in healthy subjects.


Categorization influences detection: A perceptual advantage for representative exemplars of natural scene categories.
Traditional models of recognition and categorization proceed from registering low-level features, perceptually organizing that input, and linking it with stored representations. Recent evidence, however, suggests that this serial model may not be accurate, with object and category knowledge affecting rather than following early visual processing. Here, we show that the degree to which an image exemplifies its category influences how easily it is detected. Participants performed a two-alternative forced-choice task in which they indicated whether a briefly presented image was an intact or phase-scrambled scene photograph. Critically, the category of the scene is irrelevant to the detection task. We nonetheless found that participants "see" good images better, more accurately discriminating them from phase-scrambled images than bad scenes, and this advantage is apparent regardless of whether participants are asked to consider category during the experiment or not. We then demonstrate that good exemplars are more similar to same-category images than bad exemplars, influencing behavior in two ways: First, prototypical images are easier to detect, and second, intact good scenes are more likely than bad to have been primed by a previous trial.


[Endothelial protection in patients with apparent cardiac failure in long-term therapy by carvedilol].
We studied effects of beta-adrenoblocker carvedilol vs placebo in 60 patients with chronic cardiac failure (CCF) of functional classes III-IV in a 6-month open randomized trial. We examined clinical course, exercise tolerance (a 6 min walk test), endothelial state markers (endothelium-dependent vasodilation, number of circulating endotheliocytes) and activity of systems affecting endothelium (triglycerides, malonic dialdehyde, IL-8, uric acid). The drug was added to conventional therapy (ACE inhibitors, diuretics, cardiac glycosides) in a stable CCF course. Carvedilol group of patients demonstrated a marked trend to reduction of the number of hospitalizations, attenuation of CCF, better tolerance to exercise, lower levels of uric acid (p < 0.05), malonic dialdehyde (p < 0.05) and IL-8 (p = 0.09). There was also wider basal diameter of the brachial artery, and in the diameter at the peak of reactive hyperemia (p = 0.07). The effect was dose-dependent: in patients given 25-50 mg/day of carvedilol there was a trend to a lower circulation of endotheliocytes, triglyceridemia, lipid peroxidation and chronic inflammation. Thus, long-term treatment of CCF with inclusion of standard doses of carvedilol not only improves clinical status of the patients but produces a noticeable endothelioprotective effect.


Development of Subdermal Implants Using Direct Powder Extrusion 3D Printing and Hot-Melt Extrusion Technologies.
Implants are drug delivery platforms that consist of a drug-polymer matrix with the ability of providing a localized and efficient controlled release of the drug with minimal side effects and achievement of the desired therapeutic outcomes with low drug loadings. Direct powder extrusion (DPE) 3D printing technology involves the extrusion of material through a nozzle of the printer in the form of pellets or powder. The present study aimed at investigating the use of the CELLINK BIO X™ bioprinter using DPE 3D printing technique to fabricate and evaluate the impact of different shapes (cuboid, cylinder, and tube) of raloxifene hydrochloride (RFH)-loaded subdermal implants on the release of RFH from the implants. This study further evaluated the impact of different processing techniques, viz., hot-melt extrusion (HME) technology vs. DPE 3D printing technique, on the release of RFH from the implants fabricated by each processing technique. All the fabricated implants were characterized by XRD, DSC, SEM, and FTIR, and evaluated for their water uptake, mass loss, and in vitro RFH release. The current study successfully demonstrated a great opportunity of controlling and/or tuning the release of RFH from the subdermal implants by altering the implant shape, and hence surface area, and could be a great contribution and/or addition to the personalization of medicines and improvement of patient compliance.


Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites.
Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.


Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in Medulloblastoma Cells: Involvement of HDACs and EGFR.
Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognoses. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients' quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50 = 168 μM) and D283 (IC50 = 334 μM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.


Social and clinical predictors of short- and long-term readmission after a severe exacerbation of copd.
The aim of this study was to evaluate the predictive ability of multiple social, and clinical factors for readmission after a severe acute exacerbation of COPD (AECOPD) during various time periods. We performed a prospective cohort study in which recruited patients with AECOPD. We systematically collected numerous clinical (symptoms, pulmonary function, comorbidities, and treatment) and social (financial situation, housing situation, family support, caregiver overload, ability to perform activities, and risk of social exclusion) variables using several questionnaires and indices. The patients were followed closely for one year and readmissions at 30, 60, and 365 days were analysed. 253 patients were included, aged 68.9±9.8years, FEV1 = 42.1%±14.2%, and a Charlson's index = 1.8±0.9. Of these patients, 20.2%, 39.6%, and 63.7% were readmitted within the first 30, 90, and 365 days after discharge, respectively. In the multivariate model applied, the variables that were independently associated with readmission over all three periods of the analysis were dependence to perform basic activities of daily living (BADLs) (odds ratio [OR] = 2.10-4.10) and a history of two or more admissions within the previous year (OR = 2.78-3.78). At 90 days, a history of bacterial isolates in a previous sputum culture (OR = 2.39) and at 365 days, a high grade of dyspnoea (OR = 2.51) and obesity (OR = 2.38) were also identified as predictors of hospital readmission. The patients' limitation to perform BADLs and their history of admissions for AECOPD were the best predictive variables for the likelihood of readmission when adjusted for many other social and clinical variables, regardless of the time period considered for such prediction.


On the determination of a generalized Darcy equation for yield-stress fluid in porous media using a Lattice-Boltzmann TRT scheme.
Simulating flow of a Bingham fluid in porous media still remains a challenging task as the yield stress may significantly alter the numerical stability and precision. We present a Lattice-Boltzmann TRT scheme that allows the resolution of this type of flow in stochastically reconstructed porous media. LB methods have an intrinsic error associated to the boundary conditions. Depending on the schemes this error might be directly linked to the effective viscosity. As for non-Newtonian fluids viscosity varies in space the error becomes inhomogeneous and very important. In contrast to that, the TRT scheme does not present this deficiency and is therefore adequate to be used for simulations of non-Newtonian fluid flow. We simulated Bingham fluid flow in porous media and determined a generalized Darcy equation depending on the yield stress, the effective viscosity, the pressure drop and a characteristic length of the porous medium. By evaluating the flow in the porous structure, we distinguished three different scaling regimes. Regime I corresponds to the situation where fluid is flowing in only one channel. Here, the relation between flow rate and pressure drop is given by the non-Newtonian Poiseuille law. During Regime II an increase in pressure triggers the opening of new paths and the relation between flow rate and the difference in pressure to the critical yield pressure becomes quadratic: [Formula: see text]. Finally, Regime III corresponds to the situation where all the fluid is flowing. In this case, [Formula: see text].


Bessel function output from an optical correlator.
We introduce a new filter for an optical correlator that produces a Bessel function correlation output. The advantage of this type of output is that the width of the central dark spot at the center of the correlator output is narrower than the width of the usual correlation spot. In addition, the dark spot is insensitive to changes in illumination intensity. We present experimental results with which we write the new filter onto a programmable magneto-optic spatial light modulator.


Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice.
Accumulation of beta-amyloid (Abeta) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's disease (AD). Presenilin 1 (PS1) plays an essential role in the gamma-secretase cleavage of the amyloid precursor protein (APP) and the generation of Abeta peptides. Reduction of Abeta generation via the inhibition of gamma-secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out (PS1 cKO) mice can prevent the accumulation of Abeta peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively prevented the accumulation of Abeta peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of Abeta via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.


Genome duplication in soybean (Glycine subgenus soja).
Restriction fragment length polymorphism mapping data from nine populations (Glycine max x G. soja and G. max x G. max) of the Glycine subgenus soja genome led to the identification of many duplicated segments of the genome. Linkage groups contained up to 33 markers that were duplicated on other linkage groups. The size of homoeologous regions ranged from 1.5 to 106.4 cM, with an average size of 45.3 cM. We observed segments in the soybean genome that were present in as many as six copies with an average of 2.55 duplications per segment. The presence of nested duplications suggests that at least one of the original genomes may have undergone an additional round of tetraploidization. Tetraploidization, along with large internal duplications, accounts for the highly duplicated nature of the genome of the subgenus. Quantitative trait loci for seed protein and oil showed correspondence across homoeologous regions, suggesting that the genes or gene families contributing to seed composition have retained similar functions throughout the evolution of the chromosomes.


Potentiation of short-latency cortical responses by high-frequency repetitive transcranial magnetic stimulation.
It is generally accepted that low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability, but there is only indirect evidence of its effects despite a large number of studies employing different stimulation parameters. Typically the cortical modulations are inferred through indirect measurements, such as recording the change in electromyographic responses. Recently it has become possible to directly evaluate rTMS-induced changes at the cortical level using electronencephalography (EEG). The present study investigates the modulation induced by high-frequency rTMS via EEG by evaluating changes in the latency and amplitude of TMS-evoked responses. In this study, rTMS was applied to the left primary motor cortex (MI) in 16 participants while an EEG was simultaneously acquired from 29 scalp electrodes. The rTMS consisted of 40 trains at 20 Hz with 10 stimuli each (a total of 400 stimuli) that were delivered at the individual resting motor threshold. The on-line modulation induced by the high-frequency TMS was characterized by a sequence of EEG responses. Two of the rTMS-induced responses, P5 and N8, were specifically modulated according to the protocol. Their latency decreased from the first to the last TMS stimuli, while the amplitude values increased. These results provide the first direct, on-line evaluation of the effects of high-frequency TMS on EEG activity. In addition, the results provide a direct demonstration of cortical potentiation induced by rTMS in humans.


Cloning and expression of genes responsible for altered penicillin-binding proteins 3a and 3b in Haemophilus influenzae.
A Haemophilus influenzae strain (T-1,3) possessing clinical beta-lactam resistance due to altered penicillin-binding protein 3 was used to construct a recombinant cosmid gene bank in Escherichia coli. Three of the recombinant cosmids were capable of transforming a susceptible H. influenzae strain (Rdnov) simultaneously to moxalactam resistance and altered the binding of penicillin-binding proteins 3a and 3b to [35S]penicillin G. Restriction endonuclease mapping of one of the recombinant cosmids, pLB100, was performed to facilitate subsequent subcloning of the gene(s) responsible for the altered penicillin-binding protein 3 (a and b) binding phenotype. Subcloning of individual fragments derived from pLB100 indicated that two adjacent fragments of DNA were both capable of transforming a susceptible Haemophilus strain to moxalactam resistance and altered penicillin-binding protein 3 binding. Expression of plasmid-coded proteins in minicells indicated that one fragment coded for a major 55,000-molecular-weight polypeptide and that the second contained a C-terminal coding region that expressed a 28,000-molecular-weight polypeptide when fused to the N-terminal region of the tetracycline resistance gene. Initial attempts at labeling the plasmid-coded proteins expressed in minicells with [35S]penicillin G were unsuccessful.


Deep Learning Prediction of Ovarian Malignancy at US Compared with O-RADS and Expert Assessment.
Background Deep learning (DL) algorithms could improve the classification of ovarian tumors assessed with multimodal US. Purpose To develop DL algorithms for the automated classification of benign versus malignant ovarian tumors assessed with US and to compare algorithm performance to Ovarian-Adnexal Reporting and Data System (O-RADS) and subjective expert assessment for malignancy. Materials and Methods This retrospective study included consecutive women with ovarian tumors undergoing gray scale and color Doppler US from January 2019 to November 2019. Histopathologic analysis was the reference standard. The data set was divided into training (70%), validation (10%), and test (20%) sets. Algorithms modified from residual network (ResNet) with two fusion strategies (feature fusion [hereafter, DLfeature] or decision fusion [hereafter, DLdecision]) were developed. DL prediction of malignancy was compared with O-RADS risk categorization and expert assessment by area under the receiver operating characteristic curve (AUC) analysis in the test set. Results A total of 422 women (mean age, 46.4 years ± 14.8 [SD]) with 304 benign and 118 malignant tumors were included; there were 337 women in the training and validation data set and 85 women in the test data set. DLfeature had an AUC of 0.93 (95% CI: 0.85, 0.97) for classifying malignant from benign ovarian tumors, comparable with O-RADS (AUC, 0.92; 95% CI: 0.85, 0.97; P = .88) and expert assessment (AUC, 0.97; 95% CI: 0.91, 0.99; P = .07), and similar to DLdecision (AUC, 0.90; 95% CI: 0.82, 0.96; P = .29). DLdecision, DLfeature, O-RADS, and expert assessment achieved sensitivities of 92%, 92%, 92%, and 96%, respectively, and specificities of 80%, 85%, 89%, and 87%, respectively, for malignancy. Conclusion Deep learning algorithms developed by using multimodal US images may distinguish malignant from benign ovarian tumors with diagnostic performance comparable to expert subjective and Ovarian-Adnexal Reporting and Data System assessment. © RSNA, 2022 Online supplemental material is available for this article.


Feasibility of a Neural Network-Based Virtual Sensor for Vehicle Unsprung Mass Relative Velocity Estimation.
With the automotive industry moving towards automated driving, sensing is increasingly important in enabling technology. The virtual sensors allow data fusion from various vehicle sensors and provide a prediction for measurement that is hard or too expensive to measure in another way or in the case of demand on continuous detection. In this paper, virtual sensing is discussed for the case of vehicle suspension control, where information about the relative velocity of the unsprung mass for each vehicle corner is required. The corresponding goal can be identified as a regression task with multi-input sequence input. The hypothesis is that the state-of-art method of Bidirectional Long-Short Term Memory (BiLSTM) can solve it. In this paper, a virtual sensor has been proposed and developed by training a neural network model. The simulations have been performed using an experimentally validated full vehicle model in IPG Carmaker. Simulations provided the reference data which were used for Neural Network (NN) training. The extensive dataset covering 26 scenarios has been used to obtain training, validation and testing data. The Bayesian Search was used to select the best neural network structure using root mean square error as a metric. The best network is made of 167 BiLSTM, 256 fully connected hidden units and 4 output units. Error histograms and spectral analysis of the predicted signal compared to the reference signal are presented. The results demonstrate the good applicability of neural network-based virtual sensors to estimate vehicle unsprung mass relative velocity.


Survey of preventable disaster death at medical institutions in areas affected by the Great East Japan Earthquake: a retrospective preliminary investigation of medical institutions in Miyagi Prefecture.
The 2011, magnitude (M) 9, Great East Japan Earthquake and massive tsunami caused widespread devastation and left approximately 18,500 people dead or missing. The incidence of preventable disaster death (PDD) during the Great East Japan Earthquake remains to be clarified; the present study investigated PDD at medical institutions in areas affected by the Great East Japan Earthquake in order to improve disaster medical systems. A total of 25 hospitals in Miyagi Prefecture (Japan) that were disaster base hospitals (DBHs), or had at least 20 patient deaths between March 11, 2011 and April 1, 2011, were selected to participate based on the results of a previous study. A database was created using the medical records of all patient deaths (n=868), and PDD was determined from discussion with 10 disaster health care professionals. A total of 102 cases of PDD were identified at the participating hospitals. The rate of PDD was higher at coastal hospitals compared to inland hospitals (62/327, 19.0% vs 40/541, 7.4%; P<.01). No difference was observed in overall PDD rates between DBHs and general hospitals (GHs); however, when analysis was limited to cases with an in-hospital cause of PDD, the PDD rate was higher at GHs compared to DBHs (24/316, 7.6% vs 21/552, 3.8%; P<.05). The most common causes of PDD were: insufficient medical resources, delayed medical intervention, disrupted lifelines, deteriorated environmental conditions in homes and emergency shelters at coastal hospitals, and delayed medical intervention at inland hospitals. Meanwhile, investigation of PDD causes based on type of medical institution demonstrated that, while delayed medical intervention and deteriorated environmental conditions in homes and emergency shelters were the most common causes at DBHs, insufficient medical resources and disrupted lifelines were prevalent causes at GHs. Preventable disaster death at medical institutions in areas affected by the Great East Japan Earthquake occurred mainly at coastal hospitals. Insufficient resources (at GHs), environmental factors (at coastal hospitals), and delayed medical intervention (at all hospitals) constituted the major potential contributing factors. Further investigation of all medical institutions in Miyagi Prefecture, including those with fewer than 20 patient deaths, is required in order to obtain a complete picture of the details of PDD at medical institutions in the disaster area.


Effects of Counselling and Sole Reflexology on Fatigue in Pregnant Women: A Randomized Clinical Trial.
Increase of fatigue may lead to problems during pregnancy, delivery and post delivery. Sole reflexology is the application of pressure to areas on the feet. Reflexology is generally relaxing and may be an effective way to alleviate fatigue and stress. To investigate the effect of counselling and sole reflexology on fatigue in pregnant women, referred to the medical centers of Hamadan city, Iran. This study was a randomized clinical trial with three groups - Group A (counselling and reflexology), Group B (reflexology) and Group C (control) with pre and post intervention. A total of forty two pregnant women were selected for each group. Measurement tool was a 30 question standard checklist for fatigue assessment. For all three groups, an explanatory session was held to get their written consents and conduct a pretest. The intervention included five education sessions, twice a week about reflexology in the form of counselling and sole reflexology. The groups were assessed immediately after intervention. Data were analysed using IBM SPSS Statistics 20.0. To analyse the data, descriptive statistics, t test and ANOVA with repeated measures were used. In group A and group B, the mean score of fatigue severity after the intervention demonstrated a significant decrease (p<0.05); furthermore, after intervention, a significant difference was observed between the control and experimental groups in terms of fatigue severity (p<0.01). Based on the results of this study, counselling and sole reflexology significantly decreased fatigue in pregnant women. It is hoped that the results of this study can be used by all treatment groups and midwives for controlling and providing midwifery cares for pregnant women.


Potential role of hands in the spread of respiratory viral infections: studies with human parainfluenza virus 3 and rhinovirus 14.
Hands often become contaminated with respiratory viruses, either directly or through contact with contaminated surfaces. Spread of such viruses could then occur by touching the nasal mucosa or the conjunctivae. In this quantitative study, we compared the survival of mucin-suspended human parainfluenza virus 3 (HPIV-3) and rhinovirus 14 (RV-14) and the transfer of the viruses to and from the fingers of adult volunteers. When each finger pad was contaminated with 10 microliters of either HPIV-3 (1.3 x 10(5) to 5.5 x 10(5) PFU) or RV-14 (2.1 x 10(4) to 1.1 x 10(5) PFU), less than 1.0% of HPIV-3 and 37.8% of RV-14 remained viable after 1 h; after 3 h, nearly 16% of RV-14 could still be detected, whereas HPIV-3 became undetectable. Tests on the potential spread of viruses from contaminated hands or surfaces were conducted 20 min after contamination of the donor surface by pressing together donor and recipient surfaces for 5 s. Transfer of HPIV-3 from finger to finger or finger to metal disk could not be detected, but 1.5% of infectious HPIV-3 was transferred from disk to finger. Irrespective of the type of donor or recipient surface, 0.7 to 0.9% of RV-14 was transferred. The relatively rapid loss of HPIV-3 infectivity on hands suggests that their role in the direct spread of parainfluenza viruses is limited. However, the findings of this study further reinforce the view that hands can be vehicles for rhinovirus colds. These results also suggest a role for nonporous environmental surfaces in the contamination of hands with respiratory viruses.


Organic Livestock Production: A Bibliometric Review.
Due to the increasing interest in organic farming, an overview of this research area is provided through a bibliometric analysis conducted between April and May 2019. A total of 320 documents were published up until 2018 on organic livestock farming, with an annual growth rate of 9.33% and a clear increase since 2005; 268 documents have been published in 111 journals. Germany is the country with the largest number of published papers (56 documents). Authors' top keywords (excluding keywords used for running the search) included: animal welfare (29 times), animal health (22 times), cattle (15 times), grazing (10 times), and sheep (10 times). This could indicate that more research has been done on cattle because of the importance of this species in Germany. Moreover, the prevalence of the terms 'animal welfare' and 'animal health' may indicate that the research on organic livestock production has been focused on these two areas. The bibliometric analysis indicates that: i) countries focused the organic livestock production research on their main production, and ii) more research in species other than cattle and sheep is needed.


Simplified sample processing combined with a sensitive one-tube nested PCR assay for detection of Pneumocystis carinii in respiratory specimens.
Early diagnosis of Pneumocystis carinii pneumonia, a life-threatening complication in immunosuppressed patients, may lower morbidity and mortality. We have developed a one-tube nested PCR assay for the detection of P. carinii in respiratory specimens. Four primers were selected from the sequence of the small-subunit rRNA gene of P. carinii to amplify a 265-bp fragment, and their specificities for P. carinii were confirmed by both theoretical evaluations (by computer-assisted comparison with the sequences in GenBank) and empirical evaluations (with DNA from medically important fungi and diagnostic samples). The assay was optimized for routine diagnostic use. Processing of the clinical samples is rapid and simple (digestion with proteinase K directly in PCR buffer at room temperature in the presence of 10% Chelex 100 and no further purification steps). Bovine serum albumin (1 mg/ml) and glycerol (10%) in the amplification buffer reduced the number of samples inhibitory to the PCR, as assessed by control reactions containing a size-modified target. A total of 749 clinical specimens (312 bronchoalveolar lavage, 403 sputum or induced sputum, and 34 other specimens) from 507 patients (295 human immunodeficiency virus [HIV]-infected and 164 non-HIV-infected patients and 48 patients whose HIV status was unknown) were tested by PCR, and the results were compared with those of an indirect immunofluorescence assay (IFA). Concordant results were obtained for 732 samples (646 negative and 86 positive). There were 17 discrepant results: 12 were PCR positive and IFA negative, and 5 were PCR negative and IFA positive. After resolution of the discrepant results by review of the patients' clinical data, the sensitivity and specificity were 94.8 and 99.1%, respectively, for PCR and 93.8 and 100%, respectively, for IFA. In conclusion, the short procedure time and the technical ease of this PCR assay render it suitable for implementation in routine diagnostic laboratories.


Platelet Consumption and Filter Clotting Using Two Different Membrane Sizes during Continuous Venovenous Haemodiafiltration in the Intensive Care Unit.
Background. The aim of this study was to investigate whether different haemofilter surface areas affect clotting and platelet consumption in critically ill patients undergoing continuous venovenous haemodiafiltration (CVVHDF). Methods. CVVHDF was performed in postdilution technique using a capillary haemofilter with two different membrane sizes, Ultraflux AV 1000S (n = 17, surface 1.8 m(2), volume 130 mL), and the smaller AV 600S (n = 16, surface 1.4 m(2), volume 100 mL), respectively. Anticoagulation was performed with heparin. Results. No significant differences were found when the two filters were compared. CVVHDF was performed for 33 (7-128) hours with the filter AV 1000S and 39 (7-97) hours with AV 600S (P = 0.68). Two (1-4) filters were utilised in both groups over this observation period (P = 0.94). Platelets dropped by 52,000 (0-212,000) in AV 1000S group and by 89,500 (0-258,000) in AV 600S group (P = 0.64). Haemoglobin decreased by 1.2 (0-2.8) g/dL in AV 1000S group and by 1.65 (0-3.9) g/dL in AV 600S group (P = 0.51), leading to the transfusion of 1 (0-4) unit of blood in 19 patients (10 patients with AV 1000S and 9 with AV 600S). Filter observation was abandoned due to death (12.1%), need for systemic anticoagulation (12.1%), repeated clotting (36.4%), and recovery of renal function (39.4%). Conclusion. Our study showed that a larger filter surface area did neither reduce the severity of thrombocytopenia and anaemia, nor decrease the frequency of clotting events.


Reproduction dynamics in copepods following exposure to chemically and mechanically dispersed crude oil.
Conflicting reports on the contribution of chemical dispersants on crude oil dispersion toxicity have been published. This can partly be ascribed to the influence of dispersants on the physical properties of the oil in different experimental conditions. In the present study the potential contribution of dispersants to the reproductive effects of dispersed crude oil in the marine copepod Calanus finmarchicus (Gunnerus) was isolated by keeping the oil concentrations and oil droplet size distributions comparable between parallel chemically dispersed (CD, dispersant:oil ratio 1:25) and mechanically dispersed oil (MD, no dispersant) exposures. Female copepods were exposed for 96 h to CD or MD in oil concentration range of 0.2-5.5 mg·L(-1) (THC, C5-C36) after which they were subjected to a 25-day recovery period where production of eggs and nauplii were compared between treatments. The two highest concentrations, both in the upper range of dispersed oil concentrations reported during spills, caused a lower initial production of eggs/nauplii for both MD and CD exposures. However, copepods exposed to mechanically dispersed oil exhibited compensatory reproduction during the last 10 days of the recovery period, reaching control level of cumulative egg and nauplii production whereas females exposed to a mixture of oil and dispersant did not.


[Genogeographic analysis of a subdivided population. II. Geography of random inbreeding (from frequency of surnames in Adygs)].
An important characteristic of the genetic structure of populations, random inbreeding (interpopulation variation), was evaluated on the basis of quasi-genetic markers (surnames). The following methodological issues are considered: estimation of random inbreeding using the coefficient of isonymy fr in a subdivided population; a comparison of inbreeding levels calculated on the basis of surname frequencies using fr and Wright's FST; a comparison of inbreeding estimates obtained on the basis of surnames and genetic markers; inbreeding variation in populations of the same hierarchical rank; and planning of genetic studies of a subdivided population. The population of Adygs (an indigenous ethnic group of Northern Caucasus) was examined as a model subdivided population. The population system of Adygs is hierarchical. Parameters of random inbreeding were examined at each level of the system "ethnic group==>tribe==>geographic group of auls==>aul." Frequencies of surnames were collected subtotally. Data on frequencies of 1340 surnames in 61 auls representing all Adyg tribes were analyzed. In total, 60,000 people were examined. The inbreeding estimates obtained on the basis of Wright's FST and the coefficient of isonymy fr virtually coincided: for Adygs in general, FST x 10(2) = 2.13 and fr x 10(2) = 2.09. At the same time, the inbreeding level exhibited marked differences among tribes: in Shapsugs, these differences were an order of magnitude higher than in Kabardins (fr x 10(2) = 2.53 and 0.25, respectively). The inbreeding estimates for auls differed by two orders of magnitudes: fr x 10(2) = 0.07 and fr x 10(2) = 7.88. An analysis of ten auls yielded fully coinciding inbreeding estimates based on quasi-genetic (fr x 10(2) = 0.60) and classical (FST x 10(2) = 0.69) gene markers. Computer maps of surname distributions in Adygs (1340 maps) were constructed for the first time ever. Based on these maps, the map of random inbreeding in the Adyg population was obtained.


The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson's disease: effects of L-DOPA and the D1 agonist SKF 82958.
The aim of this study was twofold: (1) to study the predictive validity of the drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD), and (2) to investigate the therapeutic and undesired effects of the D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA pretreated monkeys. A detailed ethogram was used, allowing the separation of therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased the parameters used classically to evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia. However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, induced additional undesired effects; including epileptoid behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA-unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as undesired effects. Although the effects of SKF 82958 on fore-limb movements, rotational behaviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated group from day one. It is concluded that the bilaterally MPTP-treated monkey is an animal model with predictive validity for PD: it adequately predicts the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD, because it did not induce therapeutic effects, but instead elicited several undesired effects.


Host responses during experimental infection with Fasciola gigantica and Fasciola hepatica in Merino sheep II. Development of a predictive index for Fasciola gigantica worm burden.
This study reports on the predictive relationship between serological, immunological and pathological responses following experimental inoculation with incremental doses of Fasciola gigantica in sheep. Fifty, 6-month-old, naive Merino wethers were allocated to one of 5 experimental groups, four of which received 50, 125, 225 and 400 metacercariae, respectively, whilst a 5th group acted as non-inoculated control. Strong individual correlations were observed between liver score, GLDH (glutamate dehydrogenase), GGT (gamma glutamyl transferase), CatL5 (cathepsin L5) antibody titre (IgG1, IgA), eosinophilia, and the total worm count or worm biomass. A combination of multiple indicator traits performed significantly better than any single indicator trait alone. The best predictive index accounted for up to 88% of observed worm burden (Wb) if information on inoculation dose was available. Without knowledge of inoculation dose, such as under field conditions, up to 67% of variation in worm burden could be predicted. In contrast, the best single predictor variable (liver damage score) accounted for up to 50% of worm burden, and in the absence of post-slaughter information, serum levels of anti-cathepsin IgA antibody titres accounted for 35% of predicted variation in worm burden. The utility of a predictive index under both field and experimental inoculation conditions is discussed.


Steady state oxygen reduction and cyclic voltammetry.
The catalytic activity of Pt and Pt3Ni for the oxygen reduction reaction is investigated by applying a Sabatier model based on density functional calculations. We investigate the role of adsorbed OH on the activity, by comparing cyclic voltammetry obtained from theory with previously published experimental results with and without molecular oxygen present. We find that the simple Sabatier model predicts both the potential dependence of the OH coverage and the measured current densities seen in experiments, and that it offers an understanding of the oxygen reduction reaction (ORR) at the atomic level. To investigate kinetic effects we develop a simple kinetic model for ORR. Whereas kinetic corrections only matter close to the volcano top, an interesting outcome of the kinetic model is a first order dependence on the oxygen pressure. Importantly, the conclusion obtained from the simple Sabatier model still persists: an intermediate binding of OH corresponds to the highest catalytic activity, i.e. Pt is limited by a too strong OH binding and Pt3Ni is limited by a too weak OH binding.


Angiographic signs in specific vasculitides.
Vasculitis, defined by inflammation in the blood vessel wall and reactive mural damage, may present with various clinical signs, depending on the organs involved. Infection, collagen vascular disease, and granulomatous disease or idiopathic inflammation of the vessels may result in various degrees of stenosis, obstruction, aneurysmal dilatation, or rupture. The definitive pathologic diagnosis is established by biopsy; however, the biopsy may pose significant risk to the patient; and the biopsy sample may not be adequate. Knowledge of the angiographic signs of various vasculitides should help in interpreting the clinical picture and reducing the need for biopsy. In this article, we describe the angiographic signs of the most common vasculitides, and review their clinical signs.


Formation of α-SF5-Enolate Enables Preparation of 3-SF5-Quinolin-2-ones, 3-SF5-Quinolines, and 3-SF5-Pyridin-2-ones: Evaluation of their Physicochemical Properties.
This study describes, for the first time, the generation of a SF5 -substituted ester enolate from benzyl SF5 -acetate under soft enolization conditions, which in turn participates in aldol addition reactions in high yield. The reaction was applied in the synthesis of 3-SF5 -quinolin-2-ones, 3-SF5 -quinolines, and 3-SF5 -pyridin-2-ones, none of which have previously been reported. To provide guidelines for their use in drug discovery, the physicochemical properties of these building blocks were determined and compared with those of their CF3 - and t-Bu-analogues.


Structural analysis of the L-methionine gamma-lyase gene from Pseudomonas putida.
The gene encoding L-methionine gamma-lyase from Pseudomonas putida was cloned and the primary structure of the enzyme was deduced from its nucleotide sequence. The L-methionine gamma-lyase gene was expressed in Escherichia coli. The amino acid sequences of BrCN-digested peptides agreed with the corresponding parts of the L-methionine gamma-lyase sequence determined from the gene structure. The polypeptide is composed of 398 amino acid residues with a calculated molecular weight of 42,626, corresponding to the subunit of the homotetrameric enzyme. The deduced amino acid sequence of L-methionine gamma-lyase only showed extensive homology with other well known alpha,gamma-elimination and/or gamma-replacement pyridoxal 5'-phosphate-dependent enzymes, such as cystathionine gamma-lyase, cystathionine gamma-synthase, and O-acetylhomoserine O-acetylserine sulfhydrylase, that participate in the biosynthesis of sulfur amino acids. However, the deduced essential cysteine residue of L-methionine gamma-lyase was not conserved in these enzymes. We confirmed the presence of a part of an open reading frame in the 3'-flanking region of the L-methionine gamma-lyase gene, which showed high homology with the N-terminal region of pyruvate dehydrogenase (lipoamide) from E. coli, suggesting that it participates in the degradative pathway for L-methionine together with L-methionine gamma-lyase.


Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation.
Successful stem cell transplantation (SCT) across HLA barriers can be performed with cord blood, megadoses of stem cells, or with nonmyeloablative conditioning strategies. Because the HLA-mismatched transplants are often T-cell depleted, leukemia relapse rates are high. Treatment of relapsed leukemia after HLA-mismatched SCT is difficult. A novel potential strategy to treat relapsed leukemia after HLA-mismatched SCT is the use of patients' mismatched HLA molecules as antigen-presenting molecules to generate hematopoietic system-specific cytotoxic T cells (CTLs) from the stem cell donor. Adoptive transfer of these hematopoietic system-specific CTLs that are restricted by nonself HLA molecules may eliminate leukemia without affecting the patient's nonhematopoietic cells or donor hematopoietic cells. We investigated the feasibility of this strategy using the hematopoietic system-specific minor histocompatibility antigen HA-1, which is known to induce HLA-A2-restricted CTLs. HLA-A2(-) peripheral blood mononuclear cells were stimulated with HLA-A2(+) T2 cells pulsed with synthetic HA-1 peptide or with dendritic cells transduced with the HA-1 cDNA. Tetrameric HLA-A2/HA-1 peptide complexes were used to monitor and enrich HA-1-specific CTLs. In the alloreactive cultures, HA-1-specific CTLs were enriched up to 7% by 3 rounds of antigen-specific stimulations and up to 87% by fluorescence-activated cell sorting of tetramer-positive T cells. The HA-1-specific CTLs showed specific lysis of the relevant target cells, including leukemic cells. Because the polyclonal CTL cultures also contained natural killer cells and allo-HLA-A2-specific CTLs, CTL clones were generated that showed the expected HA-1 specificity only. Thus, HA-1-specific CTLs restricted by nonself HLA-A2 molecules can be generated in an HLA-A2-mismatched setting.


Increased eligibility for treatment of chronic hepatitis C infection with shortened duration of therapy: Implications for access to care and elimination strategies in Canada.
All oral, highly effective direct-acting antiviral combinations, such as sofosbuvir-ledipasvir, have recently been licensed in Canada but cost as much as $67,000 for a 12-week course of therapy, representing a major economic barrier to predominately single-payer health care systems such as that found in Ontario. In hepatitis C virus (HCV) genotype 1 noncirrhotic patients with a baseline viral load of <6 × 10(6) IU⁄mL, treatment with sofosbuvir-ledipasvir can be shortened to eight weeks without compromising ≥95% efficacy. The number of HCV-infected patients in Ontario eligible for shortened therapy, and the associated cost savings, are unknown. The authors propose that treating every patient with shortened therapy, regardless of baseline viral load, would lead to significant public cost savings and collateral efficiencies, enabling increased HCV treatment capacity and cure. The present study designed a three-part model to investigate the cost of cure per patient and cost savings per patient under three eligibility pathways: conservative, permissive and ideal. In the conservative model, every patient is treated for 12 weeks regardless of baseline viral load, whereas in the permissive model, patients with a baseline viral load <6 × 10(6) IU/mL are treated for eight weeks. In the ideal model, every patient receives eight weeks of therapy regardless of baseline viral load. Relapsed patients are retreated for 12 weeks. Data obtained from the Ontario Public Health Laboratory were used to validate the model and generate the outcomes. In Ontario, 75.34% of HCV genotype 1 patients had a baseline viral load of <6 × 10(6) IU/mL and were eligible for shortened therapy. The cost of cure per patient in the ideal model was $47,328.44, representing a 29% reduction in the cost of curative therapy and 3.5 weeks of shortened treatment duration compared with the conservative model. The ideal model generated a cost savings per patient of $3,855.17 (8% reduction in treatment cost) and 0.7 weeks of shorter therapy compared with the permissive model, and was the shortest and most efficient while maintaining a cure rate ≥95%. These results demonstrate that recommendations for a shortened treatment course of eight weeks using all-oral direct-acting antivirals in HCV genotype 1 noncirrhotic patients, regardless of baseline viral load, affords significant public cost savings and, on a population level, offers opportunities for expanded HCV treatment and cure.


Effect of a large managed care program on emergency department use: results from the CHAMPUS reform initiative evaluation.
To determine the effect of the CHAMPUS Reform Initiative (CRI) on emergency department use and charges, and to ascertain whether any reductions were concentrated among repeat users of the ED, those with less serious ED diagnoses, or those with selected chronic medical conditions. Participants were approximately 1.2 million beneficiaries of the Civilian Health and Medical Program of Uniformed Services (CHAMPUS) residing within either 11 military hospital catchment areas in California and Hawaii ("demonstration areas") or 11 matched control areas in other parts of the United States. Under CRI, participants were offered a choice of the standard CHAMPUS indemnity plan, a Preferred Provider Organization-type plan, or a network-model Health Maintenance Organization plan. Beneficiaries were encouraged to use alternatives to the ED for nonemergency conditions. Visits to civilian EDs during two 12-month periods, before and after institution of CRI, were compared. Under CRI, the number of CHAMPUS ED visits decreased by approximately 40% relative to the control, and allowed charges fell by almost 50%. Relative reductions in ED use under CRI were seen among both frequent and infrequent users of the ED. ED case-mix severity increased modestly relative to control (+3.5% versus +.9%). ED use among patients with diabetes, hypertension, and asthma fell sharply in the demonstration areas (by 14% to 41%) but rose in control areas (by 4% to 9%). In one of the largest managed care demonstrations ever conducted, a nonintrusive use management program and improved access to outpatient care appeared to reduce ED use, allowed charges, and costs to the government. Reductions in ED use were concentrated to some extent among repeat users and patients with less severe illnesses and were effected without capitation of provider groups or strict gatekeeping requirements.


Primary capillary hemangioblastoma of peripheral soft tissues.
A case of capillary hemangioblastoma located in the peripheral soft tissue of the inner ankle in a 74-year-old woman is presented. The tumor was an unencapsulated but sharply circumscribed nodule 2.5 cm in size, of a yellow-white color. It showed reddish-brown spots with small cysts up to 2 mm filled with blood. Grossly the tumor was not attached to any peripheral nerve. Signs of von Hippel-Lindau's disease were excluded by thorough clinical evaluation. No additional tumor or erythrocytosis was found in the patient clinically. Immunohistochemically, the tumor stromal cell reacted strongly with antibodies to S-100 protein, NSE, and calponin and they were negative with antibodies to GFAP, CD34, CD31, cytokeratins, actin, desmin, EMA, and HMB-45. Endothelium of the capillaries reacted positively with antibodies to CD31, CD34, and Factor VIII-related protein. Capillary pericytes were actin-positive. All cells of the tumor stained positively with antibody to vimentin. MIB1 antibody reacted only in very few cells (<1%). Ultrastructurally, the stromal cells contained electron-lucent cytoplasm with lipid droplets, a small amount of rough endoplasmic reticulum, and glycogen particles. No electron-dense structures typical of secretory granules were seen in the stromal cells. No mutation of coding sequence of VHL gene was found.


Xyloside-induced disruption of interphotoreceptor matrix proteoglycans results in retinal detachment.
Unique domains of the retinal interphotoreceptor matrix (IPM), termed cone matrix sheaths, are composed largely of chondroitin 6-sulfate proteoglycan in most higher mammalian species. Recent investigations suggest that cone matrix sheaths participate in the maintenance of normal retinal attachment. To investigate the potential functional roles of IPM proteoglycans further, the synthesis of cone matrix sheath chondroitin 6-sulfate proteoglycan was perturbed in vivo. Intravitreal injections of p-nitrophenyl-beta-D-xylopyranoside (xyloside), a sugar that inhibits chondroitin sulfate proteoglycan synthesis, were administered to Yucatan micropigs. Their eyes were examined funduscopically and electroretinographically. At selected times, the eyes were enucleated and examined histochemically and immunohistochemically with various probes directed against cone photoreceptor cells and cone matrix sheaths. The IPM was affected selectively after xyloside administration; no inner retinal pathology or dysfunction was detected morphologically or electroretinographically. The degree of xyloside-induced perturbation was dependent on the duration of xyloside exposure and dose. It was classified into three stages, based on morphologic and histochemical criteria. Although all three stages could be observed in a given retina, a single stage typically predominated, depending on the particular dosage regimen. The early stage was characterized by IPM disruption, as evidenced by disorganization of chondroitin 6-sulfate and peanut agglutinin (PNA)-binding glycoconjugates. Cone photoreceptor cell outer segment degeneration and markedly decreased chondroitin 6-sulfate immunoreactivity distinguished the middle stage. During the late stage, there was a near complete absence of both immunoreactive chondroitin 6-sulfate and PNA-binding glycoconjugates in the IPM. Shallow retinal detachments that appeared funduscopically as patches of retinal whitening frequently were observed after moderate durations of xyloside exposure; these progressed peripherally with continued xyloside exposure. Histologically, the areas of retinal whitening corresponded to regions in which cone matrix sheaths were split transversely (ie, in a plane perpendicular to the longitudinal axes of the photoreceptor cell outer segments) or were separated completely from cone outer segments. Similar effects were not observed in control eyes. These results suggest that adhesion between the neural retina and retinal pigmented epithelium may be dependent, in part, on continuous synthesis of cone matrix sheath-associated proteoglycans and, potentially, other IPM proteoglycans. In addition, these proteoglycans appear to be necessary for the maintenance of cone photoreceptor cell outer segment integrity.


Application of molecular biological techniques to analyze Salmonella seasonal distribution in stream water.
Salmonella is a leading cause of waterborne diseases. Salmonella can survive for a long time in aquatic environments, and its persistence in the environment is of great concern to public health. Nonetheless, the presence and diversity of Salmonella in the aquatic environments in most areas remain relatively unknown. In this study, we examined three analytical processes for an optimum Salmonella detection method, and the optimized method was used to evaluate seasonal variations of Salmonella in aquatic environments. In addition, Salmonella strains were isolated by selective culture medium to identify the serotypes by biochemical testing and serological assay, and to identify the genotypes by pulsed-field gel electrophoresis based on the genetic patterns. A total of 136 water samples were collected in the study area in 9 months. Forty-one (30.1%) samples were found to contain Salmonella-specific invA gene, and most (24/41) of the detections occurred in summer. The serovars of Salmonella enterica were identified, including Bareilly, Isangi, Newport, Paratyphi B var. Java, Potsdam and Typhimurium.


Interaction of antibodies to sheep urothelial plaque regions with the lumenal plasma membranes of other mammals.
The lumenal plasma membrane of most mammalian urothelia possesses discrete polygonal plaque regions which are characterized by particles projecting through the lumenal leaflet and bridging the membrane interior. Fractions enriched in plaque regions were prepared from sheep urinary bladders and were used as antigen. A 50% saturated ammonium sulphate fraction of immunized rabbit serum showed at least two antibodies to plaque region components in Ouchterlony diffusion test. Intact sheep urothelium was treated with the antibody preparation and labelling was visualized by treatment with peroxidase-conjugated goat anti-rabbit antibody followed by peroxidase reaction. Control tissue treated with non-immune globulin showed no reaction product. The plaque-specific antibody preparation was also shown to stain the lumenal leaflet of isolated sheep membranes. Further, cross reactivity of sheep plaque antibody was demonstrated with rat and rabbit membranes. The possibility that antibodies to specific components in sheep urothelial membranes may be used diagnostically to detect changes in urothelial plasma membranes of other species is discussed.


Another Look at WIC's Breastfeeding Data: State Totals Reveal More Than Regional Averages.
Breastfeeding is known to be the most beneficial way of feeding infants, but 68% of the infants enrolled in the U.S. Department of Agriculture's Special Supplemental Nutrition Program for Women, Infants, and Children are fully formula fed. Mandated annual reports about breastfeeding aggregate data from the states into regions, which obscures important information. The aim of this study is to reexamine the data supplied by the Special Supplemental Nutrition Program for Women, Infants, and Children to identify which areas of the United States have the lowest incidence of breastfeeding infants. A retrospective cross-sectional observational study was conducted. Data from the Breastfeeding Data Local Agency Report were extracted, graphed, and analyzed. Data provided from the Special Supplemental Nutrition Program for Women, Infants, and Children for fiscal year 2016 show that the range of fully formula fed infants at the regional level is 60% to 78%, while at the state level the range is wider, at 51% to 89%. The states with the largest numbers of fully formula fed infants were Mississippi (89%), Louisiana (88%), Alabama (88%), and Arkansas (87%). When examining data from all 90 reporting agencies, the range of fully formula fed infants was 38% to 95%. Aggregating state, Native American nation, and territorial data at the regional level resulted in a loss of important information. WIC's current breastfeeding interventions may be more effective in some areas than others. Future research can examine successful and unsuccessful interventions on a state or local level.


Liver Transplantation for Hemoperitoneum Secondary to Huge Multiple Hemangiomatosis: A Case Report of a Tele-intensive Care Unit in Deceased-Donor Management.
Patients with growing and nonresectable liver hemangiomas should be followed up by a transplant center with extensive experience in complex liver disease. They could be treated on an emergency basis with orthotopic liver transplantation, with an expectation of good long-term results. We describe the case of a 37-year-old woman with liver hemangiomatosis followed up for 8 years, who presented with bleeding requiring transfusions and developed hemodynamic instability. We listed her for emergency transplant before her sister's living donor work-up could be completed. A liver from a cadaveric donor became available at a small local hospital with no experience in organ donation. Tele-intensive care unit (tele-ICU) technology was used for providing clinical data electronically to physicians, nurses, and other critical care specialists, creating medication orders, and communicating with on-site caregivers to implement changes in donor care. The recipient was transplanted on an emergency basis with a specific customization and application of the telemedicine system in the management of the organ procurement by the recipient team. Tele-ICU technology was used for providing an effective intensive care unit service, managing and stabilizing the deceased donor and allowing the procurement to be carried out uneventfully. Tele-ICU technology could be a promising resource for emergency transplantation, reducing the urgent need for a living donation and allowing prompt recipient team management of the deceased donor. Our first tele-ICU case offers early confirmation of the feasibility of the telemedicine system in deceased-donor management.


Multifarious effects of estrogen on the pituitary gonadotrope with special emphasis on studies in the ovine species.
The gonadotrope is a complex cell that expresses receptors for gonadotropin releasing hormone (GnRH) and estrogen. It has synthetic machinery for the production of 3 gonadotropin subunits which are assembled into two gonadotropins, luteinising hormone (LH) and follicle stimulating hormone (FSH). The production and secretion of LH and FSH are differentially regulated by GnRH and estrogen. Patterns of secretion of LH are dictated by the pulsatile release of GnRH from the median eminence as well as the feedback effects of estrogen. The means by which estrogen plays such an important role in the regulation of LH and FSH is reviewed in this chapter, with emphasis on work that has been done in the sheep. Estrogen regulates the second messenger systems in the gonadotrope as well as the number of GnRH receptors and the function of ion channels in the plasma membrane. Estrogen also regulates gene expression in these cells. Additionally, GnRH appears to regulate the level of estrogen receptor in the ovine gonadotrope, so there is substantial cross-talk between the signalling pathways for GnRH and estrogen. No clear picture has emerged as to how estrogen exerts a positive feedback effect on the gonadotrope and it is suggested that this might be forthcoming from more definitive studies on the way that estrogen regulates the second messenger systems and the trafficking of secretory vesicles.


Fatty acid composition of bovine teat canal keratin.
Keratin from 507 excised teats was pooled, separated into three samples, and analyzed for fatty acid composition of extracellular and intracellular lipids. Mean weight of keratin collected per teat canal was 8.97 mg. Extracellular lipids were recovered in petroleum ether. Intracellular lipids were extracted in chloroform: methanol (2:1, vol/vol) solution. Average keratin wet weight of extracellular and intracellular lipid fractions were 37.1 and 21.9 mg/g, respectively. Polar and nonpolar lipids were present in both fractions. Predominant fatty acids in extracellular and intracellular lipids were C16, C18:1, and C18. Extracellular lipids contained greater concentrations of C4 to C18:1 fatty acids than did intracellular lipids. Percent of total fatty acid weight comprised by each of C4, C10, C12 and C14 was also significantly greater in extracellular than intracellular fractions. Intracellular lipids contained a greater concentration and percent total fatty acid content comprised by C18:2 than extracellular lipids. Data suggest lipids accessible at the keratin interface are in part of milk fat origin.


Functional bladder capacity and urodynamics in males with nocturia.
Previous studies in males with lower urinary tract symptoms (LUTS) have shown that nocturia in some patients is associated with nocturnal polyuria whereas other patients have preserved circadian urine output rhythm. This outpatient study based on 7-dayss frequency/volume (FV) charts showed that patients with nocturnal polyuria and age-matched controls without nocturia had a diurnal variation in functional bladder capacity (FBC) with higher night-time values. In contrast, patients without nocturnal polyuria no diurnal variation was observed in FBC with lower day and night-time values than both controls and nocturnal polyuric patients. Nocturia volumes correlated significantly to daytime FBC in both patient groups. Voided volumes obtained from daytime pressure/flow urodynamic investigations correlated significantly with night-time FBC obtained from the FV chart. In patients with LUTS nocturia was caused by nocturnal polyuria in 10 of 23 patients and by diminished night-time functional bladder capacity in the remaining 13 patients. In conclusion, nocturia in males with LUTS referred for BPH evaluation is caused by a mismatch between nocturnal urine production and night-time FBC analogous with the pathophysiology of nocturnal enuresis. The evaluation of circadian urine production and FBC seems mandatory in the assessment of patients with nocturia and LUTS.


Effect of organic zinc supplementation on hematological, mineral, and metabolic profile in dairy cows in early lactation.
The aim of the current trial was to evaluate the effect of organically chelated zinc - methionin (Zn-Met) supplementation (30 mg Zn /kg DM TMR) on hematological, biochemical, and mineral profile of dairy cows in early lactation (1 - 90 d p.p.). Twenty dairy cows were randomly allocated to one of two dietary treatments in a randomized design. Animals in group C were treated as control (no zinc supplementation); whereas animals in group S were supplemented with organic Zn. Zn-Met supplementation had a significant effect on hematological parameters. White blood cell (WBC) counts 60 days p.p. and red blood cell (RBC) count, hemoglobin concentration (HGB), hematocrit level (HCT) and platelet count (PLT) on calving day, 30th- and 60th- day p.p were significantly higher in cows fed Zn than in the control group. In calves from supplemented mothers, there was a significant increase in RBC (p≤0.001), HCT (p≤0.01) and MCV (p≤0.05). There was no difference in other parameters among the groups, except of the highly significant difference in Zn concentration in blood serum of the S-group during the entire experimental time. The results obtained confirm the beneficial effect on serum zinc level and hematological parameters with no negative effects of 30mg Zn/kg TMR addition on mineral and biochemical parameters.


Clinical manifestations and outcomes of 420 children with Henoch Schönlein Purpura from a single referral center from Turkey: A three-year experience.
Objectives: Henoch Schönlein Purpura (HSP) is the most common systemic vasculitis in childhood. We aimed to evaluate the clinical features, seasonal variation, treatment outcomes and the possible predicting factors related to outcome among a large cohort of pediatric HSP patients.Methods: We conducted a medical record review study between July 2016 and January 2019 and evaluated the clinical manifestations and potential risk factors for severe gastrointestinal (GI) involvement, biopsy-proven nephritis and relapses.Results: The study included 420 HSP patients, of which the mean age at diagnosis was 7.68 ± 3.15 years. Clinical manifestations were arthralgia and/or arthritis (n = 244, 58.1%), abdominal pain (n = 235, 56%), subcutaneous edema (n = 163, 38.8%), and renal involvement (n = 125, 29.8%). Disease recurred for at least once, in 69 (16.4%) patients and colchicine treatment yielded a favorable response in 11 of 12 relapsing patients, who did not respond to ibuprofen or steroids. Frequencies of renal involvement and biopsy-proven nephritis were higher in patients with severe GI involvement. Besides, patients with biopsy-proven nephritis had higher rates of abdominal pain, intussusception, severe GI involvement, and systemic steroid administration.Conclusion: We speculate that renal involvement, biopsy-proven nephritis and severe GI involvement can be related to each other. Colchicine may be effective in patients with relapsing disease.


Silk nanospheres and microspheres from silk/pva blend films for drug delivery.
Silk fibroin protein-based micro- and nanospheres provide new options for drug delivery due to their biocompatibility, biodegradability and their tunable drug loading and release properties. In the present study, we report a new aqueous-based preparation method for silk spheres with controllable sphere size and shape. The preparation was based on phase separation between silk fibroin and polyvinyl alcohol (PVA) at a weight ratio of 1/1 and 1/4. Water-insoluble silk spheres were easily obtained from the blend in a three step process: (1) air-drying the blend solution into a film, (2) film dissolution in water and (3) removal of residual PVA by subsequent centrifugation. In both cases, the spheres had approximately 30% beta-sheet content and less than 5% residual PVA. Spindle-shaped silk particles, as opposed to the spherical particles formed above, were obtained by stretching the blend films before dissolving in water. Compared to the 1/1 ratio sample, the silk spheres prepared from the 1/4 ratio sample showed a more homogeneous size distribution ranging from 300 nm up to 20 microm. Further studies showed that sphere size and polydispersity could be controlled either by changing the concentration of silk and PVA or by applying ultrasonication on the blend solution. Drug loading was achieved by mixing model drugs in the original silk solution. The distribution and loading efficiency of the drug molecules in silk spheres depended on their hydrophobicity and charge, resulting in different drug release profiles. The entire fabrication procedure could be completed within one day. The only chemical used in the preparation except water was PVA, an FDA-approved ingredient in drug formulations. Silk micro- and nanospheres reported have potential as drug delivery carriers in a variety of biomedical applications.


Screening for celiac disease in non-Hodgkin's lymphoma patients: a serum anti-transglutaminase-based approach.
Several studies have shown the existence of an association between celiac disease (CD) and non-Hodgkin's lymphoma (NHL). Our aim was to evaluate the usefulness of the serum anti-tissue transglutaminase (anti-tTG) antibody assay in screening for CD in consecutive NHL patients. In all, 80 consecutive patients (median age 61 years) with a new diagnosis of NHL were included. To compare the frequency of CD and of positive results for the anti-tTG assay, we enrolled 500 blood donors. In all patients serum anti-tTG was determined with two different ELISA: one based on tTG from guinea pig (gp-tTG) and the other based on human recombinant t-TG (h-tTG) as the antigens. Serum anti-endomysial antibodies (EmA) were also assayed. Subjects with positive serum EmA and/or anti-tTG underwent intestinal biopsy for histology study, HLA-DQ phenotype determination, and serum anti-gliadin (AGA) assay. Eight of 80 (10%) NHL patients were positive for anti-tTG ELISA--two of these exclusively for anti-gp-tTG and six for anti-h-tTG (7.5%). None of the 80 NHL patients were positive for serum EmA. The frequency of anti-tTG positivity in the blood donor controls was 2/500 (0.4%), significantly lower than that observed in the NHL patients (P < 0.0001). Both these blood donors were found to have CD. Only in one anti-h-tTG-positive NHL patient was there intestinal mucosa atrophy, and follow-up confirmed a CD diagnosis (CD frequency in NHL patients is 1.2%; versus blood donors: P = 0.4). In all the other seven anti-tTG-positive NHL patients a normal intestinal architecture was found, although, inflammatory infiltration of the lamina propria was observed in four patients. No anti-tTG-positive NHL patients, including the subject diagnosed as having CD, had a family history of CD, and all had normal weight and no signs of malabsorption. Anti-tTG false positive results were associated with a higher frequency of serum autoantibody positivity and T-cell type NHL. In conclusion, NHL patients the anti-tTG assay often gives discordant data with the EmA assay, with a high frequency of anti-tTG false positive results for CD diagnosis.


Detection of copy number variants reveals association of cilia genes with neural tube defects.
Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs. The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined. Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways. Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.