Air or oxygen as driving gas for nebulised salbutamol.
The effects of nebulised salbutamol driven by compressed air or oxygen were compared in a randomised crossover study during 27 attacks of acute asthma. Arterial oxygen saturation fell by 2-6% during or after treatment in 10 cases: seven with compressed air, two with oxygen, and one with both driving gases. Hypoxaemia occurred in younger children and in those who fell asleep, but was not related to the level of arterial oxygen saturation before treatment or the size of the response to bronchodilator therapy. More children fell asleep with compressed air nebulisation. Arterial oxygen saturation improved and heart rates remained stable during treatment when oxygen was the driving gas. After treatment, however, arterial oxygen saturation fell and heart rates rose to values that were similar to those after treatment with compressed air. The falls in arterial oxygen saturation we observed, though comparatively small, would be clinically important on the steep part of the oxygen dissociation curve, and our results emphasise that families with home nebulisers should seek medical advice early when their children develop severe asthma. The benefits of using oxygen as the driving gas during nebulisation were transient, and in severe asthma treatment with oxygen needs to be continued after the nebulised salbutamol has been given.


Cancer immunotherapy-associated hypophysitis.
The advances in cancer therapy have included the development of drugs that inhibit immune checkpoint ligands. Two types of immune checkpoint inhibitors, both antibodies that target CTLA-4 and PD-1, have been approved for its use in NSCLC and melanoma as first-line or second-line therapy. Sadly, not desirable consequences of immunotherapy are immune-related adverse events. immune-related hypophysitis is the most common endocrine adverse event after thyroid disfunction. The particularity of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if this form of therapy is used in the future for earlier stages of cancer. Therefore, hypophysitis represents a challenge for the physician, sometimes occurring without specific symptomatology and which should be considered for clinical management. In this review, we describe the current data regarding the pathophysiology and management for immune-related hypophysitis.


Category labels induce boundary-dependent perceptual warping in learned speech categories.
Adults tend to perceive speech sounds from their native language as members of distinct and stable categories; however, they fail to perceive differences between many non-native speech sounds without a great deal of training. The present study investigates the effects of categorization training on adults' ability to discriminate non-native phonetic contrasts. It was hypothesized that only individuals who successfully learned the appropriate categories would show selective improvements in discriminating between-category contrasts. Participants were trained to categorize progressively narrow phonetic contrasts across one of two non-native boundaries, with discrimination pre- and post-tests completed to measure the effects of training on participants' perceptual sensitivity. Results suggest that changes in adults' ability to discriminate a non-native contrast depend on their successful learning of the relevant category structure. Furthermore, post-training identification functions show that changes in perceptual categories specifically correspond to their relative placement of the category boundary. Taken together, these results indicate that learning to assign category labels to a non-native speech continuum is sufficient to induce discontinuous perception of between- versus within-category contrasts.


The Presence of Renal IgG Deposits in Necrotizing Crescentic Glomerulonephritis Associated with ANCA Is Not Related to Worse Renal Clinical Outcomes.
Classical pauci-immune necrotizing crescentic glomerulonephritis (CGN) associated with antineutrophil cytoplasmic autoantibodies (ANCA) is characterized by the absence of renal immunoglobulin (Ig) deposits. However, IgG deposits can sometimes be present. We wanted to assess whether necrotizing CGN with IgG deposits is associated with a more severe presentation and outcome than necrotizing CGN without IgG deposits. Between November 2008 and August 2013, we retrospectively identified 158 patients from four centers who had necrotizing CGN due to primary ANCA-associated systemic vasculitis. Glomerular IgG deposits were found in 18 (11%) patients (group 1). For each patient in group 1, we selected 2 patients with classical pauci-immune necrotizing CGN with the nearest date of diagnosis in the same center (group 2, n = 36). We assessed clinical, biological, and pathological characteristics in both groups. Baseline characteristics were similar in both groups, and most patients had ANCA-associated vasculitis with antibodies to myeloperoxidase (74%). Deposits displayed moderate to strong staining in 9 patients. As compared with group 2, group 1 exhibited a higher frequency of interstitial fibrosis/tubular atrophy lesions (p = 0.024) and lower frequency of acute tubular necrosis (p = 0.046). Nevertheless, after a mean follow-up of 30 and 26 months for group 1 and group 2, respectively, IgG deposits did not affect the renal prognosis or probability of relapse. Finally, the groups did not differ in renal or patient survival. IgG deposits, detected in 11% of patients with ANCA-associated necrotizing CGN, did not affect renal or patient outcomes.


A mass of less than 15 solar masses for the black hole in an ultraluminous X-ray source.
Most ultraluminous X-ray sources have a typical set of properties not seen in Galactic stellar-mass black holes. They have luminosities of more than 3 × 10(39) ergs per second, unusually soft X-ray components (with a typical temperature of less than about 0.3 kiloelectronvolts) and a characteristic downturn in their spectra above about 5 kiloelectronvolts. Such puzzling properties have been interpreted either as evidence of intermediate-mass black holes or as emission from stellar-mass black holes accreting above their Eddington limit, analogous to some Galactic black holes at peak luminosity. Recently, a very soft X-ray spectrum was observed in a rare and transient stellar-mass black hole. Here we report that the X-ray source P13 in the galaxy NGC 7793 is in a binary system with a period of about 64 days and exhibits all three canonical properties of ultraluminous sources. By modelling the strong optical and ultraviolet modulations arising from X-ray heating of the B9Ia donor star, we constrain the black hole mass to be less than 15 solar masses. Our results demonstrate that in P13, soft thermal emission and spectral curvature are indeed signatures of supercritical accretion. By analogy, ultraluminous X-ray sources with similar X-ray spectra and luminosities of up to a few times 10(40) ergs per second can be explained by supercritical accretion onto massive stellar-mass black holes.


Radionuclide brain perfusion studies in suspected brain death.
The radionuclide brain perfusion study (RPS) has been suggested as a method of confirming suspected brain death. The hospital records and RPSs of 34 patients referred were reviewed because brain death was suspected. In every case but one the RPS showed absent or drastically reduced cerebral blood flow. No patient survived more than five days, and 25 survived less than 24 hours. These findings are consistent with the results of previous reports of a total of 248 patients; only one of 248 survived and was discharged from the hospital after having had a positive RPS. The RPS is highly accurate in confirming brain death.


The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol.
The role of specific cytochrome P450 (P450) isoforms in the metabolism of ethinylestradiol (EE) was evaluated. The recombinant human P450 isozymes CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP3A4 were found to be capable of catalyzing the metabolism of EE (1 microM). Without exception, the major metabolite was 2-hydroxy-EE. The highest catalytic efficiency (Vmax/Km) was observed with rCYP1A1, followed by rCYP3A4, rCYP2C9, and rCYP1A2. The P450 isoforms 3A4 and 2C9 were shown to play a significant role in the formation of 2-hydroxy-EE in a pool of human liver microsomes by using isoform-specific monoclonal antibodies, in which the inhibition of formation was approximately 54 and 24%, respectively. The involvement of CYP3A4 and CYP2C9 was further confirmed by using selective chemical inhibitors (i.e., ketoconazole and sulfaphenazole). The relative contribution of each P450 isoform to the 2-hydroxylation pathway was obtained from the catalytic efficiency of each isoform normalized by its relative abundance in the same pool of human liver microsomes, as determined by quantitative Western blot analysis. Collectively, these results suggested that multiple P450 isoforms were involved in the oxidative metabolism of EE in human liver microsomes, with CYP3A4 and CYP2C9 as the major contributing enzymes.


Clostridium difficile Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes.
Clostridium difficile is the largest single cause of hospital-acquired infection in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they disrupt the gut bacterial community which protects from C. difficile colonization. Multiple antibiotic classes have been associated with CDI susceptibility, many leading to distinct community structures stemming from variation in bacterial targets of action. These community structures present separate metabolic challenges to C. difficile. Therefore, we hypothesized that the pathogen adapts its physiology to the nutrients within different gut environments. Utilizing an in vivo CDI model, we demonstrated that C. difficile highly colonized ceca of mice pretreated with any of three antibiotics from distinct classes. Levels of C. difficile spore formation and toxin activity varied between animals based on the antibiotic pretreatment. These physiologic processes in C. difficile are partially regulated by environmental nutrient concentrations. To investigate metabolic responses of the bacterium in vivo, we performed transcriptomic analysis of C. difficile from ceca of infected mice across pretreatments. This revealed heterogeneous expression in numerous catabolic pathways for diverse growth substrates. To assess which resources C. difficile exploited, we developed a genome-scale metabolic model with a transcriptome-enabled metabolite scoring algorithm integrating network architecture. This platform identified nutrients that C. difficile used preferentially between pretreatments, which were validated through untargeted mass spectrometry of each microbiome. Our results supported the hypothesis that C. difficile inhabits alternative nutrient niches across cecal microbiomes with increased preference for nitrogen-containing carbon sources, particularly Stickland fermentation substrates and host-derived glycans. IMPORTANCE Infection by the bacterium Clostridium difficile causes an inflammatory diarrheal disease which can become life threatening and has grown to be the most prevalent nosocomial infection. Susceptibility to C. difficile infection is strongly associated with previous antibiotic treatment, which disrupts the gut microbiota and reduces its ability to prevent colonization. In this study, we demonstrated that C. difficile altered pathogenesis between hosts pretreated with antibiotics from separate classes and exploited different nutrient sources across these environments. Our metabolite score calculation also provides a platform to study nutrient requirements of pathogens during an infection. Our results suggest that C. difficile colonization resistance is mediated by multiple groups of bacteria competing for several subsets of nutrients and could explain why total reintroduction of competitors through fecal microbial transplant currently is the most effective treatment for recurrent CDI. This work could ultimately contribute to the identification of targeted, context-dependent measures that prevent or reduce C. difficile colonization, including pre- and probiotic therapies.


FcgammaRIIB inhibits the development of atherosclerosis in low-density lipoprotein receptor-deficient mice.
The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcgammaR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcgammaRIIB in atherosclerosis has not been defined. Bone marrow cells from FcgammaRIIB-deficient mice and C57BL/6 control mice were transplanted to low-density lipoprotein receptor-deficient mice. Atherosclerosis was induced by feeding the recipient mice a high-fat diet for 8 wk and evaluated using Oil Red O staining of the descending aorta at sacrifice. The molecular mechanisms triggering atherosclerosis was studied by examining splenic B and T cells, as well as Th1 and Th2 immune responses using flow cytometry and ELISA. The atherosclerotic lesion area in the descending aorta was ~5-fold larger in mice lacking FcgammaRIIB than in control mice (2.75 +/- 2.57 versus 0.44 +/- 0.42%; p < 0.01). Moreover, the FcgammaRIIB deficiency resulted in an amplified splenocyte proliferative response to Con A stimulation (proliferation index 30.26 +/- 8.81 versus 2.96 +/- 0.81%, p < 0.0001) and an enhanced expression of MHC class II on the B cells (6.65 +/- 0.64 versus 2.33 +/- 0.25%; p < 0.001). In accordance, an enlarged amount of CD25-positive CD4 T cells was found in the spleen (42.74 +/- 4.05 versus 2.45 +/- 0.31%; p < 0.0001). The plasma Ab and cytokine pattern suggested increased Th1 and Th2 immune responses, respectively. These results show that FcgammaRIIB inhibits the development of atherosclerosis in mice. In addition, they indicate that absence of the inhibiting IgG receptor cause disease, depending on an imbalance of activating and inhibiting immune cells.


Subluminal Focal Lesions in Peyer's Patches in the Terminal Ileum of Pigs Fed With Different Physical Forms of One Same Diet.
Retrograde backflow of cecum chyme and consequent ascendent colonization of the foregut may occur via the ileocecal valve (IV) under predisposing circumstances. The Peyer's patches (PPs) in the terminal ileum (TI) play a crucial role in targeting antigens and act as a first line of blockage of pathogens in the small intestine. In view of the established impact of the physical form of the diet (grinding and compaction of ingredients) on the physicochemical and microbiological composition of digesta throughout the different gastrointestinal tracts, special attention was paid to PP reaction following different dietary treatments. The aim of this study was to explore the effect of different physical forms of one diet (identical for botanical and chemical composition) administered to growing pigs on macro- and microscopic morphology of PPs in the last 3 cm of the TI, as a region of interest immediately close to the IV involved in the prevention of retrograde contamination of the small intestine. The diet effect was tested after 4 weeks of experimental feeding on PPs of 32 growing pigs, fed with four dietary treatments differing for the physical form: FP-finely ground pelleted diet (dMEAN, 0.463 mm); CM-coarsely ground meal diet (dMEAN, 0.880 mm); CP-coarsely ground pelleted diet (dMEAN, 0.836); and CE-coarsely ground extruded diet (dMEAN, 0.659). A higher prevalence of subluminal focal liquefactive necrosis (FLN) in the last 3 cm of the TI was observed in pigs fed with the CE and the FP diet (n. 3/8 or 37.5% and n. = 1/8 or 12.5%, respectively) (p = 0.076). FLN negatively and significantly correlated with the pH value of digesta of the last part of the small intestine (ρ = -0.361; p = 0.026). All animals enrolled appeared clinically healthy throughout the trial. Growth performance were not affected by the different dietary treatments, but fecal dry matter and pH values were affected in a significant way. Results about the morphology of PPs assessed in this trial can be suggestive of the physical form of the diet as a contributing factor to the onset of different antigenic potentials of the intestinal chyme.


Enhancement of macrophage superoxide anion production by amphotericin B.
Amphotericin B (AmB) appears to have some important immunomodulatory effects, but its mechanism of action has not been explained. We investigated the effects of AmB on activation of human monocyte-derived macrophages. Macrophages cultured in the presence of AmB had an enhanced capacity to produce superoxide anion after stimulation with phorbol myristate acetate. This enhancement was dose dependent within a therapeutic range of AmB levels (0.1 to 3.0 mg/liter). Macrophages cultured in the presence of AmB had enhanced surface expression of Ia antigen; phagocytosis of unopsonized zymosan, opsonized Staphylococcus aureus, or erythrocytes opsonized with C3bi or immunoglobulin G paradoxically appeared to be reduced, but results did not achieve statistical significance. AmB appears to activate macrophages and may do so via direct effects on the plasma membrane.


Starvation of low-density lipoprotein-derived cholesterol induces bradyzoite conversion in Toxoplasma gondii.
Lacking enzymes for sterol synthesis, the intracellular protozoan Toxoplasma gondii scavenges cholesterol from host cells to multiply. T. gondii has a complex life cycle consisting of two asexual stages; the proliferative stage (tachyzoite), and the latent stage characterized by tissue cysts (bradyzoite). In vitro, bradyzoite development can be induced by mimicking host immune response stressors through treatment with IFN-γ, heat shock, nitric oxide, and high pH. However, the extent to which host nutrients contribute to stage conversion in T. gondii is unknown. In this study, we examined the impact of host cholesterol levels on stage conversion in this parasite. Growth of T. gondii tachyzoites (ME49 strain) was investigated in Chinese hamster ovary (CHO) cells using various concentrations of low-density lipoprotein (LDL), oleic acid, or glucose. Squalestatin, which is an inhibitor of squalene synthase and is, therefore, an inhibitor of sterol synthesis, was used to treat the CHO cells. Tachyzoite to bradyzoite conversion rates were analyzed by indirect fluorescent antibody tests. Parasite growth was significantly enhanced by addition of exogenous LDL, whereas no such enhancement occurred with oleic acids or glucose. In ME49, growth inhibition from squalestatin treatment was not obvious. Although growth of the RH strain was unaffected by squalestatin in the presence of lipoprotein, in its absence growth of this strain was suppressed. The frequency of BAG1-positive vacuoles in ME49 increased under lipoprotein-free conditions. However, addition of exogenous LDL did not increase tachyzoite to bradyzoite conversion in this strain. Furthermore, treatment with squalestatin did not enhance stage conversion. Our results suggest that LDL-derived cholesterol levels play a crucial role in bradyzoite conversion in T. gondii.


The Garrett Lee Smith memorial suicide prevention program.
In response to calls for greater efforts to reduce youth suicide, the Garrett Lee Smith (GLS) Memorial Act has provided funding for 68 state, territory, and tribal community grants, and 74 college campus grants for suicide prevention efforts. Suicide prevention activities supported by GLS grantees have included education, training programs (including gatekeeper training), screening activities, infrastructure for improved linkages to services, crisis hotlines, and community partnerships. Through participation in both local- and cross-site evaluations, GLS grantees are generating data regarding the local context, proximal outcomes, and implementation of programs, as well as opportunities for improvement of suicide prevention efforts.


Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival.
The identification of pathways necessary for photoreceptor and retinal pigment epithelium (RPE) function is critical to uncover therapies for blindness. Here we report the discovery of adiponectin receptor 1 (AdipoR1) as a regulator of these cells' functions. Docosahexaenoic acid (DHA) is avidly retained in photoreceptors, while mechanisms controlling DHA uptake and retention are unknown. Thus, we demonstrate that AdipoR1 ablation results in DHA reduction. In situ hybridization reveals photoreceptor and RPE cell AdipoR1 expression, blunted in AdipoR1(-/-) mice. We also find decreased photoreceptor-specific phosphatidylcholine containing very long-chain polyunsaturated fatty acids and severely attenuated electroretinograms. These changes precede progressive photoreceptor degeneration in AdipoR1(-/-) mice. RPE-rich eyecup cultures from AdipoR1(-/-) reveal impaired DHA uptake. AdipoR1 overexpression in RPE cells enhances DHA uptake, whereas AdipoR1 silencing has the opposite effect. These results establish AdipoR1 as a regulatory switch of DHA uptake, retention, conservation and elongation in photoreceptors and RPE, thus preserving photoreceptor cell integrity.


Policy challenges for the Australian health care system.
In contrast to the regular media reports decrying the so-called crisis in the health system, a number of academic commentators have identified areas in which the Australian health care system could improve. George Palmer has been one of those, and over the years has published a body of work identifying areas for improvement. This paper reviews the performance of the Australian health care system against the criteria of equity, efficiency and acceptability, and explicates the contemporary problem areas associated with each criterion.


Denticity and Mobility of the Carbonate Groups in AMCO3F Fluorocarbonates: A Study on KMnCO3F and High Temperature KCaCO3F Polymorph.
We report on a thorough structural study on two members of layered fluorocarbonates KMCO3F (M = Ca, Mn). The Ca-based member demonstrates a phase transition at ∼320 °C, evidenced for the first time. The crystal structure of the high temperature phase (HT-KCaCO3F) was solved using neutron powder diffraction. A new Mn-based phase KMnCO3F was synthesized, and its crystal structure was solved from electron diffraction tomography data and refined from a combination of X-ray synchrotron and neutron powder diffraction. In contrast to other members of the fluorocarbonate family, the carbonate groups in the KMnCO3F and HT-KCaCO3F structures are not fixed to two distinct orientations corresponding to mono- and bidentate coordinations of the M cation. In KMnCO3F, the carbonate group can be considered as nearly "monodentate", forming one short (2.14 Å) and one long (3.01 Å) Mn-O contact. This topology provides more flexibility to the MCO3 layer and enables diminishing the mismatch between the MCO3 and KF layers. This conclusion is corroborated by the HT-KCaCO3F structure, in which the carbonate groups can additionally be tilted away from the layer plane thus relieving the strain arising from geometrical mismatch between the layers. The correlation between denticity of the carbonate groups, their mobility, and cation size variance is discussed. KMnCO3 orders antiferromagnetically below TN = 40 K.


Surgical management of cerebellopontine angle tumors.
Of the 50 cerebellopontine angle tumors diagnosed during a three and one half year period, 36 were removed (all totally) using one of the three approaches to the cerebellopontine angle. Six patients, all elderly (over age 70) with obstructive hydrocephalus and complicating medical problems, had ventriculoperitoneal shunts inserted. One of these subsequently required tumor excision 10 months later. Of the 35 patients with normal functioning facial nerves pre-operatively, 34 (97 per cent) had the nerve spared surgically. Of 12 patients in whom hearing conservation was attempted, the cochlear nerve was spared in eight. However, useful hearing was preserved in one, with sound appreciated only in another.


Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis.
The metabolic side effects of second-generation antipsychotics (SGA) are serious and have not been compared head to head in a meta-analysis. We conducted a meta-analysis of studies comparing the metabolic side effects of the following SGAs head-to-head: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine. We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE and EMBASE (last search January 2009) for randomized, blinded studies comparing the above mentioned SGA in the treatment of schizophrenia or related disorders. At least three reviewers extracted the data independently. The primary outcome was weight change. We also assessed changes of cholesterol and glucose. The results were combined in a meta-analysis. We included 48 studies with 105 relevant arms. Olanzapine produced more weight gain than all other second-generation antipsychotics except for clozapine where no difference was found. Clozapine produced more weight gain than risperidone, risperidone more than amisulpride, and sertindole more than risperidone. Olanzapine produced more cholesterol increase than aripiprazole, risperidone and ziprasidone. (No differences with amisulpride, clozapine and quetiapine were found). Quetiapine produced more cholesterol increase than risperidone and ziprasidone. Olanzapine produced more increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone; no difference was found with clozapine. Some SGAs lead to substantially more metabolic side effects than other SGAs. When choosing an SGA for an individual patient these side effects with their potential cause of secondary diseases must be weighed against efficacy and characteristics of the individual patient.


Developing an efficient NiCo2S4 cocatalyst for improving the visible light H2 evolution performance of CdS nanoparticles.
Developing efficient alternatives to the widely used Pt cocatalyst in photocatalytic H2O splitting is of great importance in view of large-scale production of clear H2 energy. Herein, we report the facile synthesis of NiCo2S4 and its first use as a highly active and cost-affordable cocatalyst to boost visible light H2 generation with the CdS semiconductor. The synthesized NiCo2S4/CdS composite materials are fully characterized by various techniques including X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, X-ray photoelectron spectroscopy (XPS), UV-Vis diffusion reflectance spectroscopy (DRS), and N2 adsorption measurements. With the optimized NiCo2S4/CdS composite sample, a high H2 generation rate of 137 μmol h-1 is obtained under visible light irradiation, which is more than 17 times higher than that of bare CdS material. The results of photoluminescence (PL) spectroscopy, transient photocurrent response and electrochemical impedance spectroscopy demonstrate the remarkably promoted migration and separation of photogenerated charge carriers over the heterostructured NiCo2S4/CdS material, thus leading to obviously enhanced photocatalytic performance. Moreover, a possible mechanism for the photocatalytic H2 evolution reaction is also proposed based on the observed results of activity evaluation and photoelectrochemical measurements.


What steroid supplementation is required for a patient with primary adrenal insufficiency undergoing a dental procedure?
Patients with primary adrenal insufficiency (Addison's disease) lack the endogenous steroid hormones cortisol and aldosterone and require daily steroid therapy (usually hydrocortisone and fludrocortisone) to replace them. These patients are unable to adapt physiologically to stress and may need supplemental steroid therapy when having dental procedures, to prevent adrenal crisis. This paper provides guidance on dental procedures for which steroid supplementation may be required in patients with primary adrenal insufficiency and gives advice on doses and timing of supplementation. It does not address the management of patients with secondary adrenal insufficiency caused by long-term use of high doses of steroids. This document is for guidance only. Patients with primary adrenal insufficiency should be assessed individually as steroid requirements will vary. Although patients with primary adrenal insufficiency (Addison's disease) are invariably very well informed about their steroid requirements prior to a dental procedure, dental staff should have an understanding of the steroid supplementation that may be required.


Urinary collagen type II C-telopeptide fragments are sensitive markers of matrix metalloproteinase-dependent cartilage degradation in rat adjuvant-induced arthritis.
To assess the relevance of collagen type II C-telopeptide fragments (CTX-II) as markers of cartilage degradation during adjuvant-induced arthritis in rats. Rats were injected with Freund's adjuvant on day 0 and treated orally for 21 days twice a day with vehicle or 10 or 20 mg/kg of a newly designed matrix metalloproteinase inhibitor (MMP-Inh). Urine samples were collected for 24 h between days 19 and 20 and the concentration of the cartilage-derived CTX-II was measured with a 2-site, sandwich-type ELISA. To assess arthritis, inflammatory scores were determined, and changes in paw volumes were measured by plethysmography. On day 21, the inflammation was generalized in rats injected with Freund's adjuvant. The urinary concentration of CTX-II was significantly higher in arthritic rats than in control non-injected rats. Oral treatment of arthritic rats with MMP-Inh dramatically decreased the concentration of CTX-II in urine, with values returning to those of controls. Treatment simultaneously reduced the clinical variables of the disease. These results demonstrate that fragments of type II collagen in urine can be used as a measure of cartilage degradation in arthritic rats as well as potent non-invasive markers of the efficacy of chondroprotective treatments.


[On the importance of a comprehensive study for diagnostics of death from acute ethanol poisoning and coronary heart disease].
Over 30 000 cases of acute poisoning with ethyl alcohol and its surrogates are recorded annually in this country. Differential diagnostics between fatal poisoning and death from coronary heart disease encounters serious difficulties. The authors report a comprehensive forensic chemical, morphometric, and pathomorphological study of the activity of ethanol-oxidizing enzyme systems in the internal organs. The results of histochemical examination provide a basis for the extension of diagnostic potential of the available methods and the enhancement of the objective value of expert reports.


Browning of Abdominal Aorta Perivascular Adipose Tissue Inhibits Adipose Tissue Inflammation.
Perivascular adipose tissue (PVAT) can regulate vascular homeostasis by secreting various adipokines. This study investigated the effects of PVAT browning on its endocrine function. In the first section of our study, male Sprague-Dawley rats were randomly divided into cold exposure (8°C) and 24°C acclimation groups. After cold exposure for 7 days, interscapular brown adipose tissue (iBAT), subcutaneous white adipose tissue, thoracic aortic PVAT, and abdominal aortic PVAT (aPVAT) were harvested for histological and brown marker gene expression analysis. In the second part, male rats were fed a high fat diet (HFD) for 10 weeks. In the 11th week, the rats were treated with or without cold exposure. After 14-day cold exposure, aPVAT was collected for histological, gene, and protein expression analysis. Cold exposure had a browning effect on aPVAT by increasing UCP-1 and PGC-1α expression levels. After HFD feeding for 10 weeks, 14-day cold exposure was still able to induce aPVAT browning. Compared with thermoneutrality acclimation rats, TNF-α, IL-6, and p-p65 expression levels were significantly lower in aPVAT from HFD-fed rats with cold exposure. In contrast, p-AMPK expression levels were increased in aPVAT from HFD-fed rats with cold exposure. Our study demonstrated that browning of aPVAT in HFD-fed rats lowered the pro-inflammatory adipokine expression levels and activated AMPK.


[German Translation and Validation of the Patient-Oriented Questionnaire "Thumb Disability Examination" (TDX) for Specific Diagnosis and Follow-Up of Thumb Carpometacarpal Joint Osteoarthritis].
Patient-reported outcome measures (PROMs) are becoming increasingly important in today's patient care. Unfortunately, the most common PROMs in hand surgery are very time-consuming and usually do not cover the actual, diagnosis-specific complaints of the patients. For diagnosis and follow-up of thumb carpometacarpal joint osteoarthritis, Noback et al. developed and validated the Thumb Disability Examination (TDX) questionnaire. This 20-item questionnaire specifically assesses daily living limitations and pain as well as patient-reported satisfaction of thumb function. The aim of this study is to validate the German translation of the TDX, the Thumb Disability Examination - German (TDX-G), and to compare it with the German-language versions of the MHQ and qDASH, which are currently used as gold standard. Translation and back-translation were performed in accordance with accepted guidelines. For statistical validation of the TDX-G, 30 consecutive patients with thumb carpometacarpal joint osteoarthritis were interviewed under standardised conditions. Internal consistency was calculated using Cronbach's alpha. Test-retest reliability was determined in 10 patients who completed the TDX-G twice at an interval of 2 weeks. The validity of the TDX-G was determined by calculating the correlation coefficients of the TDX-G with the MHQ and qDASH, subjective pain sensation (NRS), and hand strength levels (coarse and pinch strength). In addition, the time to collect each questionnaire was compared. The TDX-G has high internal consistency (Cronbach's alpha 0.932) and test-retest reliability (intraclass correlation coefficient 0.963 [0.850-0.991]). There is a significant correlation between TDX-G and MHQ (- 0.782; p<0.001) and qDASH (0.833; p<0.001). All questionnaires correlate significantly with pain on exertion and pinch force, with the TDX-G having the highest correlation in each case. Significantly less time is needed to record the TDX-G (110±28 s) than to record the MHQ (413±98 s). The TDX-G is a reliable tool for diagnosing and monitoring the progression of thumb carpometacarpal joint osteoarthritis. It can be used in both patient care and clinical research and accurately mirrors the symptoms.


A lymphoma plasma membrane-associated protein with ankyrin-like properties.
In this study we have used several complementary techniques to isolate and characterize a 72-kD polypeptide that is tightly associated with a major mouse T-lymphoma membrane glycoprotein, gp 85 (a wheat germ agglutinin-binding protein), in a 16 S complex. These two proteins do not separate in the presence of high salt but can be dissociated by treatment with 2 M urea. Further analysis indicates that the 72-kD protein has ankyrin-like properties based on the following criteria: (a) it cross-reacts with specific antibodies raised against erythrocyte and brain ankyrin; (b) it displays a peptide mapping pattern and a pI (between 6.5 and 6.8) similar to that of the 72-kD proteolytic fragment of erythrocyte ankyrin; (c) it competes with erythrocyte ghost membranes (spectrin-depleted preparations) for spectrin binding; and (d) it binds to purified spectrin and fodrin molecules. Most importantly, in intact lymphoma cells this ankyrin-like protein is localized directly underneath the plasma membrane and is found to be preferentially accumulated beneath receptor cap structures as well as associated with a membrane-cytoskeleton complex preparation. It is proposed that the ankyrin-like 72-kD protein may play an important role in linking certain surface glycoprotein(s) to fodrin which, in turn, binds to actin filaments required for lymphocyte cap formation.


We Matter Too! Addressing the Wellness of Program Coordinators in Graduate Medical Education.
Burnout and stress in medical settings have been associated with despondent staff and decreased productivity. Although Program Coordinators (PCs) play an integral role in residency training programs, there exist few, if any, interventions aimed at addressing their burnout. A longitudinal study design was used to evaluate data from residency/fellowship training PCs who participated in a wellness retreat held at a single institution in August 2016. Subjects completed anonymous, pre- and post-retreat questionnaires in addition to a 3-month follow-up questionnaire, which included questions used to assess aspects of job demand, resiliency, and well-being. The seven-item Physician Well-Being Index and a logistic regression model were used to assess well-being. Mean values and SDs were reported to examine changes in mental health scores and participants' job satisfaction over the course of the intervention. Nineteen of the 45 (43%) invited residency/fellowship training PCs completed data collection. Coordinators ranged in age from 25 to 64 years; all were female. Well-being, sleep, resiliency, and employee satisfaction scores improved over the assessment period. Well-being scores initially decreased by 0.37 at the postassessment, but increased at follow-up (mean: 2.0; SD 1.7). Stress scores increased from baseline to post, but decreased from baseline to follow-up: 0.2 and -0.2, respectively. Residency PCs experienced improvements in mental quality of life, resiliency, stress, and sleep scores on attending the wellness program. Attention to such findings may have important implications, as we address the burnout crisis in the medical education community.


Tailoring Public Health Policies.
In an effort to contain the spread of COVID-19, many states and countries have adopted public health restrictions on activities previously considered commonplace: crossing state borders, eating indoors, gathering together, and even leaving one's home. These policies often focus on specific activities or groups, rather than imposing the same limits across the board. In this Article, I consider the law and ethics of these policies, which I call tailored policies.In Part II, I identify two types of tailored policies: activity-based and group-based. Activity-based restrictions respond to differences in the risks and benefits of specific activities, such as walking outdoors and dining indoors. Group-based restrictions consider differences between groups with respect to risk and benefit. Examples are policies that treat children or senior citizens differently, policies that require travelers to quarantine when traveling to a new destination, and policies that treat individuals differently based on whether they have COVID-19 symptoms, have tested positive for COVID-19, have previous COVID-19 infection, or have been vaccinated against COVID-19. In Part III, I consider the public health law grounding of tailored policies in the principles of "least restrictive means" and "well-targeting." I also examine how courts have analyzed tailored policies that have been challenged on fundamental rights or equal protection grounds. I argue that fundamental rights analyses typically favor tailored policies and that equal protection does not preclude the use of tailored policies even when imperfectly crafted. In Part IV, I consider three critiques of tailored policies, centering on the claims that they produce inequity, cause harm, or unacceptably limit liberty. I argue that we must evaluate restrictions comparatively: the question is not whether tailored policies are perfectly equitable, wholly prevent harm, or completely protect liberty, but whether they are better than untailored ones at realizing these goals in a pandemic. I also argue that evaluation must consider indirect harms and benefits as well as direct and apparent ones.


Low sequence variation among isolates of infectious hypodermal and hematopoietic necrosis virus (IHHNV) originating from Hawaii and the Americas.
A 2.9 kb fragment of the infectious hypodermal and hematopoietic necrosis virus (IHHNV) genome, which contains the coding sequence of putative non-structural and capsid proteins, was amplified and sequenced from each of 14 IHHNV isolates collected from cultured penaeid shrimp stocks in Hawaii and various sites in the Americas between 1982 and 1997. The sequence comparison indicates that the IHHNV genome is very stable, with 99.6 to 100% similarity among these 14 isolates. Only nucleotide substitutions were found. The percentage of substitution was higher in the putative capsid proteins region (1.3%) than in the putative non-structural proteins region (0.6%). Out of 25 substitutions found, 14 resulted in amino acid changes. There is no apparent association between clinical outcomes and particular amino acid substitutions. Based on genetic distances, the isolates were clustered into 3 groups that generally correspond with their geographic origins.


Diabetes insipidus and blindness caused by a suprasellar tumor: Pieter Pauw's observations from the 16th century.
Tumors in the suprasellar region may cause both visual and endocrinologic symptoms. This association, well known to modern physicians, was established during the 19th century. However, we have identified a 16th-century autopsy report, written by the Dutch professor of anatomy Pieter Pauw (1564-1617), which describes an 18-year-old girl who developed marked polyuria and subsequently became totally blind from a cystic tumor compressing the optic chiasm. Based on prevailing theories on the nature of diabetes, Pauw attributed the disease to the kidneys. Undoubtedly, however, his lucid report is the earliest known account of diabetes insipidus caused by an arachnoid cyst, the Rathke cleft cyst, or craniopharyngioma in the region of the pouch of Rathke. The description also gives insights into the role of anatomic dissections in late 16th-century northern Europe.


Risk of Pregnancy Complications and Low Birth Weight Offsprings in Korean Women With Rheumatic Diseases: A Nationwide Population-Based Study.
To determine the risk of pregnancy complications and adverse offspring outcomes in Korean women with rheumatic diseases (RDs). Women aged 20-44 years with pregnancies ending in delivery were identified from the National Health Insurance Service-National Health Information Database (2009-2016). Women with RD including systemic lupus erythematosus (SLE), seropositive rheumatoid arthritis (SPRA), and ankylosing spondylitis (AS) (n = 4,284) were age-matched with controls (n = 26,023). Outcome variables included threatened abortion (TA), preterm birth (PB), preeclampsia/eclampsia (PE/E), intrauterine growth retardation (IGR), urinary tract infection, low birth weight (LBW) offsprings, and offspring death within 1 year of birth. Women with RDs had increased risks for cesarean section delivery (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.4-1.6), TA (OR, 1.4; 95% CI, 1.2-1.5), PB (OR, 2.4; 95% CI, 1.9-3.2), PE/E (OR, 4.4; 95% CI, 3.3-5.9), and IGR (OR, 2.4; 95% CI, 2.0-3.1) than the controls. The risk of pregnancy complications was increased in SLE and SPRA pregnancies but not in AS pregnancies. Offsprings of women with RDs had an increased risk of LBW (OR, 4.0; 95% CI, 3.2-4.9). The offspring mortality rate within 1 year of birth was higher in women with RDs (6.2/10,000 persons) than in the controls (4.9/10,000 persons). Women with RDs are at a risk of developing pregnancy complications, and the risk of LBW offsprings and offspring death within 1 year of birth is increased in these women. Therefore, this population requires special attention during their childbearing years.


A double-blind placebo-controlled study of ketoconazole + desonide gel combination in the treatment of facial seborrheic dermatitis.
The pathobiology of seborrheic dermatitis is rooted in a peculiar inflammatory reaction to Malassezia spp. Both topical corticosteroids and antifungals are routinely used with success, either singly or in combination. To assess the effect of a new combination therapy in this condition. Eighteen patients with facial seborrheic dermatitis were treated in a pilot double-blind trial with an anhydrous gel containing the combination of 2% ketoconazole and 0.05% desonide (n = 9) or the unmedicated gel (n = 9). The products were applied once daily for 3 consecutive weeks. Disease severity was assessed at the start and weekly during treatment, as well as 2, 4 and 8 weeks after the end of treatment or at the time of recurrence. The overall clinical assessments were performed using a visual analogue scale. Objective measurements included squamometry X after harvesting the stratum corneum and the erythema index yielded by narrow-band reflectance spectrophotometry. Data were evaluated in an intent-to-treat analysis. The combination therapy yielded reductions in the overall clinical symptom severity of 49, 84 and 92% after 1, 2 and 3 weeks of treatment, respectively. The corresponding improvements with the placebo gel were significantly smaller (p < 0.01), reaching 23, 29 and 42% at successive 1-week intervals. At the end of the 3-week treatment, the clinical signs had completely subsided in 6/9 patients treated with the medicated gel and in only 1/9 patients using the placebo gel. Thus, the clinical response rate was significantly faster (p < 0.01) with the combination therapy than with the vehicle. Differences between the treatment groups using objective noninvasive assessments were also significantly (p < 0.01) in favor of the combination therapy. The squamometry X measurements showed 47, 67 and 74% improvements with the combination gel after 1, 2 and 3 weeks, respectively. The corresponding values with the placebo gel were 34, 46 and 53%, respectively. The erythema index was almost completely reduced to normal at week 2 of treatment in contrast with about 50% reduction with the unmedicated vehicle. None of the patients reported any side effects. The combination of ketoconazole with desonide in an anhydrous gel is well tolerated and proves to be significantly more effective than the vehicle for treating facial seborrheic dermatitis. The fast response to treatment and the limited additional improvement between weeks 2 and 3 of the treatment suggest that this combination product may be efficacious with once daily applications for 2 weeks. These data call for expanded studies comparing each single compound, the vehicle and the combination therapy.


[Preclinical investigation of Mn(II)-diethylenetriaminepentaacetate (Mangapentetate) as paramagnetic contrast agent for magnetic resonance tomography].
The preclinical evaluation of 0.5 M solution of a manganese(II)-DTPA complex (Mangapentetate, Pentamang) has been carried out in order to test the ability of manganese to be used as substitute for potentially toxic gadolinium in paramagnetic contrast agents in the MRI clinical routines. The toxicologic tests of the Mn(II) - DTPA were carried out in mice, rats, and rabbits. Liquid phantoms served for direct comparison of the ability of Mn(II) - DTPA to increase the intensity of T1-weighted SE-images to the contrast properties of the Gd(III) - DTPA (Magnevist). Normal healthy rabbits (n = 12) were used for quantification of the imaging ability of Mn(II) - DTPA. The value of LD50 in rabbits was above 10 ml/kg, rather close to that one of Gd(III) - DTPA. An increase in intensity of the T1-weighted images induced by addition of Mn(II) - DTPA in phantom tests did not differ significantly from the values obtained with Gadopentetate. Mn(II) - DTPA delivered prominent enhancement of normal kidneys in healthy rabbits as well as chest tumors in dogs.


[Contribution to the study of cholecystoses. Clinical, radiological and pathological analysis (author's transl)].
Cholecystoses is a generic term introduced by Colesson and Jutras for a group of abnormalities of the gallbladder that appear to be separate from inflammatory diseases. Cholecystoses imply a benign proliferation of normal tissue elements, whereas cholecystosis indicates a pathologic process that is distinct from inflammation. 1 072 cholecystectomies were examined. 180 cholecystoses were diagnosed, 162 were associated with gallstones. There was no difference concerning the clinical symptom between cholecystoses and cholelithiasis. Radiological study confirms and clarifies the nature and character of these gallbladder lesions. In the histological examination 49,4 per cent of the cases were cholesterolosis, 2,9 per cent polyposis and 47,7 per cent adenomatosis. The treatment of cholecystoses is first and foremost medical, exception in case of calcareous and porcelain gallbladders. Surgery is only indicated in cases in which medical treatment is unsuccessful and when a cancerous degeneration is suspected.


Serum Prognostic Factors of Androgen-deprivation Therapy Among Japanese Men With De Novo Metastatic Prostate Cancer.
To date, several serum prognostic factors have been reported in metastatic prostate cancer. In this study, we examined the prognostic value of these serum markers in Japanese men. This study included 104 patients with metastatic prostate cancer who were treated with primary androgen-deprivation therapy from 2001 to 2013. Clinicopathological factors including several serum markers were investigated for association with progression-free (PFS) and overall (OS) survival. During a median follow-up of 48.1 months, median PFS and OS were 24.0 months and 67.4 months, respectively. When adjusted by age, prostate-specific antigen at diagnosis, Gleason score, and clinical stage, serum lactate dehydrogenase value was significantly associated with PFS [hazard ratio (HR)=1.42, 95% confidence interval (CI)=1.15-1.74; p=0.0004] and OS (HR=1.46, 95% CI=1.13-1.82; p=0.0014), in addition to alkaline phosphatase value for OS (HR=1.04; 95% CI=1.00-1.07; p=0.015). This study demonstrates the prognostic significance of alkaline phosphatase and lactate dehydrogenase values in Japanese men with de novo metastatic hormone-sensitive prostate cancer.


Shikonin relieves osteoporosis of ovariectomized mice by inhibiting RANKL-induced NF-κB and NFAT pathways.
Postmenopausal osteoporosis is very common in women. Currently, many kinds of new drugs are being developed for this disease. Postmenopausal osteoporosis is closely related to overactivity of osteoclasts in body. Shikonin is purple red naphthoquinone pigment extracted from lithospermum, which has anti-inflammation, antivirus, anticancer and other bioactivities. At the same time, it has been proved that shikonin can promote the proliferation and differentiation of osteoblasts, but its influence on osteoclasts and molecular mechanism are unknown. Our study showed that shikonin could inhibit the activity and formation of RANKL-mediated osteoclasts depending on dose without affecting the activity of bone marrow macrophages (BMM). In addition, we have also found that shikonin can inhibit the expression of specific marker gene of osteoclasts, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), cathepsin K (Ctsk), tartrate resistant acid phosphatase (TRAcP) and calcitonin receptor. Shikonin also could promote the proliferation of MC3T3-E1, increasing the expression of mRNA related to osteogenesis, like the expression of bone morphogenetic protein-2 (BMP-2), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and osteocalcin (OCN). Luciferase reporter gene assay and Western blot analysis further indicated that shikonin could inhibit the activity of RANKL-induced NF-κB and NFAT receptors. Moreover, shikonin can also slow down bone loss of ovariectomized (OVX) mice by inhibiting the activity of osteoclasts. This work explains the molecular mechanism of shikonin in RANKL-mediated formation of osteoclasts, and reveals the potential of further developing shikonin into a new drug for prevention and treatment of postmenopausal osteoporosis.


New aspects of the theory of microcirculation.
New aspects and details of the mechanism of the microcirculation in the tissues are discussed in the paper. Particular attention is payed to the role of the blood pressure amplitude for the filtration and resorption processes through the capillary wall. A new model of the microcirculation is discribed in which the interstitial space is considered as a functional unit determining the intensity of the transcapillary exchange processes. The components of the hydraulic interstitial pressure are characterized as well as the process of formation and transport of limphatic fluid. The proposed model is a base for the better understanding of the theory of microcirculation.


Radiation Proctitis and Management Strategies.
Radiotherapy (RT) is a treatment modality that uses high-energy rays or radioactive agents to generate ionizing radiation against rapidly dividing cells. The main objective of using radiation in cancer therapy is to impair or halt the division of the tumor cells. Over the past few decades, advancements in technology, the introduction of newer methods of RT, and a better understanding of the pathophysiology of cancers have enabled physicians to deliver doses of radiation that match the exact dimensions of the tumor for greater efficacy, with minimal exposure of the surrounding tissues. However, RT has numerous complications, the most common being radiation proctitis (RP). It is characterized by damage to the rectal epithelium by secondary ionizing radiation. Based on the onset of signs and symptoms, post-radiotherapy RP can be classified as acute or chronic, each with varying levels of severity and complication rates. The treatment options available for RP are limited, with most of the data on treatment available from case reports or small studies. Here, we describe the types of RT used in modern-day medicine and radiation-mediated tissue injury. We have primarily focused on the classification, epidemiology, pathogenesis, clinical features, treatment strategies, complications, and prognosis of RP.


Pb(3)F(5)NO(3), a cationic layered material for anion-exchange.
Our research involves the development of new cationic materials for anion-based applications. We report the solvothermal synthesis and characterization of Pb(3)F(5)NO(3), a new layered lead fluoride material that, unlike the majority of layered and open-framework materials, is cationic in charge. The structure consists of polyhedral lead centers connected by doubly and triply bridging fluoride groups. We quantitatively exchanged the interlamellar nitrate groups of Pb(3)F(5)NO(3) for dichromate, under ambient aqueous conditions. Nuclear magnetic resonance and UV-vis spectroscopy show the reaction proceeds to 61.0% completion in several days. The material is also stable to 450 degrees C, which is vastly superior to organic resins that are still the standard for anion-exchange. The presence of extraframework anions also opens up other potentially unique anion-based properties, such as new catalytic reactions, anion intercalation, or growth of anionic clusters within the void spaces of the cationic material.


Chronic effects of carbamazepine on life-history strategies of Ceriodaphnia dubia in three successive generations.
Trace quantities of pharmaceuticals are continuously being discharged into the environment through domestic and industrial wastewater effluents, causing concern among scientists and regulators regarding potential long-term impacts on aquatic ecosystems. These compounds and their metabolites are constantly interacting with organisms at various life-cycle stages and may differentially influence the development of embryonic, larval, juvenile, and adult stages. To understand the possible cumulative effects of exposure to carbamazepine (CBZ), a multigenerational approach was taken in which survival, reproduction, respiration, growth, brood size, and biomass of Ceriodaphnia dubia were assessed at sublethal concentrations over the course of three successive generations. CBZ exposure significantly decreased fecundity at 196.7 μg/L in the F0 and F1 generations over 2 weeks and acclimatized at 264.6 μg/L in the F2 generation. Similarly, a significant decrease of neonate dry weight was observed at the 196.7 μg/L CBZ treatment in the F1 generation, and it acclimatized at 264.6 μg/L treatment level in the F2 generation. Median time to first brood release was significantly delayed at 264.6 μg/L in the F2 generation, indicating slower maturation. Results over three successive generations are not different than what one would obtain by testing simply the F0 generation. Furthermore, the effects measured were observed at concentrations two orders of magnitude higher than are environmentally relevant, and it is unlikely that CBZ poses a substantial risk to the environment regarding the end points measured in this study. However, additional research through laboratory and field multigenerational studies may be required to understand the overall risk of CBZ to other nontarget organisms.


Properties of stereotyped series of postsynaptic potentials in hypoglossal motoneurons.
A stereotyped series of postsynaptic potentials produced in cat hypoglossal motoneurons by stimulation of the cerebral cortex, the inferior alveolar nerve or the lingual nerve was studied. These include an excitatory postsynaptic potentials (EPSP) and subsequently 3 different types of inhibitory postsynaptic potentials (IPSPs). The first is a short-lasting IPSP which was blocked by strychnine administration. The second is a gamma-aminobutyric acid (GABA) IPSP which was blocked by picrotoxin administration. This IPSP was sensitive to membrane polarization and dependent on a conductance increase. The third is a long-duration hyperpolarizing potential which was enhanced by the injection of picrotoxin and insensitive to membrane polarization. Moreover, we have demonstrated that the amplitude of cortically induced EPSPs decreased greatly with depolarization.


Genome-wide SNPs reveal the drivers of gene flow in an urban population of the Asian Tiger Mosquito, Aedes albopictus.
Aedes albopictus is a highly invasive disease vector with an expanding worldwide distribution. Genetic assays using low to medium resolution markers have found little evidence of spatial genetic structure even at broad geographic scales, suggesting frequent passive movement along human transportation networks. Here we analysed genetic structure of Aedes albopictus collected from 12 sample sites in Guangzhou, China, using thousands of genome-wide single nucleotide polymorphisms (SNPs). We found evidence for passive gene flow, with distance from shipping terminals being the strongest predictor of genetic distance among mosquitoes. As further evidence of passive dispersal, we found multiple pairs of full-siblings distributed between two sample sites 3.7 km apart. After accounting for geographical variability, we also found evidence for isolation by distance, previously undetectable in Ae. albopictus. These findings demonstrate how large SNP datasets and spatially-explicit hypothesis testing can be used to decipher processes at finer geographic scales than formerly possible. Our approach can be used to help predict new invasion pathways of Ae. albopictus and to refine strategies for vector control that involve the transformation or suppression of mosquito populations.


Vertical distribution of flying black-flies (Diptera: Simuliidae) in Central Nigeria.
Flying black-flies were collected using an array of 4 nets mounted on a vehicle at heights between 0.15 and 3.0 m above the ground. The vertical distribution differed amongst the 8 most abundant species, but within a particular species such as S. squamosum, there was no significant difference in the vertical distribution of the males and females, nor between females of different physiological conditions. This infers that the height of the trap on the vehicle will not normally be a source of bias during population studies. However, there was some evidence of circadian changes in the vertical distribution; during the afternoon, black-flies of all species flew higher compared with in the evening.


[Does the use of fentanyl make Vater's ampulla cannulation difficult? A prospective and comparative study].
Fentanyl is a synthetic opioid with excellent results in perioperative analgesia. It is commonly used for proximal and distal gastrointestinal endoscopic procedures, but its contracting action on the sphincter of Oddi, similar to that of morphine, makes its use for endoscopic cholangiopancreatography (ERCP) controversial. To determinate if intravenous fentanyl as part of deep sedation hinders the cannulation of Vater's papilla during ERCP. Prospective, comparative, randomized and double-blind trial that enrolled patients undergoing ERCP in 2008, > 18 years old, without previous endoscopic or surgical procedures related with Vater s papilla. Patients were randomized into two groups: patients in whom ERCP was performed with intravenous propofol (group A), and patients in whom the procedure was performed with intravenous fentanyl and propofol (group B). Gender, age, comorbid conditions, reasons for referral, difficulty of cannulation, diagnosis, therapeutic procedures, procedure time and endoscopic complications were all documented. 432 were included: 214 in group A and 218 in group B. Both groups were similar in relation with demographic characteristics, time of sedation and endoscopic procedure. Difficulty in cannulation had not a statistical significance (p = 0.163). The administered dose of propofol were less for group B (p < 0.001). No procedure-related mortality was documented. The combination of fentanyl and propofol may be used during ERCP, since it does not hinder the cannulation of Vater's papilla.


A new technology for revascularization of cerebral embolism using liquid jet impact.
Revascularization time is the dominant factor in the treatment of acute cerebral embolism. In this paper we describe a rapid revascularization therapy using liquid jets generated by the interaction of gas bubbles with shock waves, which impact on the thrombi. The interaction of a shock wave with a gas bubble attached to an artificial thrombus which was inserted into a tube model of a cerebral artery was investigated. The shock wave was generated by detonating a microexplosive pellet. The overpressure of the shock wave was 3.0 +/- 0.6 MPa (n = 7) and 12.7 +/- 0.4 MPa (n = 3). The initial air bubble radii were varied from 0.87 mm to 2.18 mm. The subsequent collapse of the bubble was photographed using a high-speed framing camera, and the liquid jet penetrating into the artificial thrombus was visualized using x-ray photography. The penetration depth of the liquid jet increased with increasing bubble size. There was an optimal separation distance between the bubble and the shock wave source to obtain the maximum penetration depth. Liquid jets have the potential to penetrate through thrombi in as little as a few microseconds, and with very efficient ablation.


Renal function in children with beta-thalassemia major and thalassemia intermedia.
In beta-thalassemia, profound anemia and severe hemosiderosis cause functional and physiological abnormalities in various organ systems. In recent years, there have been few published studies demonstrating proteinuria, aminoaciduria, low urine osmolality, and excess secretion of the tubular damage markers, such as urinary N-acetyl-D-glucosaminidase (U(NAG)) and beta2 microglobulin, in patients with thalassemia. The object of this study was to analyze renal tubular and glomerular function in pediatric patients with beta-thalassemia and to correlate the renal findings to iron overload. Thirty-seven patients with beta-thalassemia major and 11 with thalassemia intermedia were studied. Twelve children without iron metabolism disorders or renal diseases served as a control group. No difference in blood urea nitrogen (BUN), serum creatinine, creatinine clearance, electrolytes, fractional excretion of sodium and potassium, and tubular phosphorus reabsorption was found. Serum uric acid was equal in the two groups, but its urine excretion was significantly higher in the thalassemic group. U(NAG) and U(NAG) to creatinine ratio (U(NAG/CR)) were elevated in all patients with thalassemia compared with the control group (p < 0.001) and were directly correlated to the amount of transfused iron but not to actual ferritin level. We found that renal tubular function is impaired in children with beta- thalassemia major and intermedia. It is not known whether these functional abnormalities would have any long-term effects on the patients. Further studies are needed, and means of preventing these disturbances should be sought.


Spatio-temporal Rho GTPase signaling - where are we now?
Rho-family GTPases are molecular switches that transmit extracellular cues to intracellular signaling pathways. Their regulation is likely to be highly regulated in space and in time, but most of what is known about Rho-family GTPase signaling has been derived from techniques that do not resolve these dimensions. New imaging technologies now allow the visualization of Rho GTPase signaling with high spatio-temporal resolution. This has led to insights that significantly extend classic models and call for a novel conceptual framework. These approaches clearly show three things. First, Rho GTPase signaling dynamics occur on micrometer length scales and subminute timescales. Second, multiple subcellular pools of one given Rho GTPase can operate simultaneously in time and space to regulate a wide variety of morphogenetic events (e.g. leading-edge membrane protrusion, tail retraction, membrane ruffling). These different Rho GTPase subcellular pools might be described as 'spatio-temporal signaling modules' and might involve the specific interaction of one GTPase with different guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and effectors. Third, complex spatio-temporal signaling programs that involve precise crosstalk between multiple Rho GTPase signaling modules regulate specific morphogenetic events. The next challenge is to decipher the molecular circuitry underlying this complex spatio-temporal modularity to produce integrated models of Rho GTPase signaling.


The Role of GSK3 in Presynaptic Function.
The past ten years of research have identified a number of key roles for glycogen synthase kinase 3 (GSK3) at the synapse. In terms of presynaptic physiology, critical roles for GSK3 have been revealed in the growth and maturation of the nerve terminal and more recently a key role in the control of activity-dependent bulk endocytosis of synaptic vesicles. This paper will summarise the major roles assigned to GSK3 in both immature and mature nerve terminals, the substrates GSK3 phosphorylates to exert its action, and how GSK3 activity is regulated by different presynaptic signalling cascades. The number of essential roles for GSK3, coupled with the numerous signalling cascades all converging to regulate its activity, suggests that GSK3 is a key integrator of multiple inputs to modulate the strength of neurotransmission. Modulation of these pathways may point to potential mechanisms to overcome synaptic failure in neurodegenerative disorders such as Alzheimer's disease.


Human responses to multiple sources of directional information in virtual crowd evacuations.
The evacuation of crowds from buildings or vehicles is one example that highlights the importance of understanding how individual-level interactions and decision-making combine and lead to the overall behaviour of crowds. In particular, to make evacuations safer, we need to understand how individuals make movement decisions in crowds. Here, we present an evacuation experiment with over 500 participants testing individual behaviour in an interactive virtual environment. Participants had to choose between different exit routes under the influence of three different types of directional information: static information (signs), dynamic information (movement of simulated crowd) and memorized information, as well as the combined effect of these different sources of directional information. In contrast to signs, crowd movement and memorized information did not have a significant effect on human exit route choice in isolation. However, when we combined the latter two treatments with additional directly conflicting sources of directional information, for example signs, they showed a clear effect by reducing the number of participants that followed the opposing directional information. This suggests that the signals participants observe more closely in isolation do not simply overrule alternative sources of directional information. Age and gender did not consistently explain differences in behaviour in our experiments.


B7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct mechanisms.
The molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood. Here we show that B7-CD28 co-stimulation and B7 expression by specific antigen-presenting cell (APC) types are required for clonal deletion and for regulatory T (Treg) cell generation from endogenous tissue-restricted antigen (TRA)-specific thymocytes. While B7-CD28 interaction is required for both clonal deletion and Treg induction, these two processes differ in their CD28 signaling requirements and in their dependence on B7-expressing dendritic cells, B cells, and thymic epithelial cells. Meanwhile, defective thymic clonal deletion due to altered B7-CD28 signaling results in the accumulation of mature, peripheral TRA-specific T cells capable of mediating destructive autoimmunity. Our findings thus reveal a function of B7-CD28 co-stimulation in shaping the T cell repertoire and limiting autoimmunity through both thymic clonal deletion and Treg cell generation.


Loss of the Protein Cystathionine β-Synthase During Kidney Injury Promotes Renal Tubulointerstitial Fibrosis.
Renal tubulointerstitial fibrosis (TIF) is the common pathway of progressive chronic kidney disease. Inflammation has been widely accepted as the major driving force of TIF. Cystathionine β-synthase (CBS) is the first and rate-limiting enzyme in the transsulfuration pathway. CBS is considered to play protective role in liver and pulmonary fibrosis, but its role in TIF remains unknown. The purpose of this study was to investigate the potential role and mechanism of CBS in renal inflammation and TIF. Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of collagen I, collagen III, fibronectin, CD3, CD68, IL-1β, TNF-α were measured in sham operation and unilateral ureteral obstruction (UUO) rats. Proteomics and gene array analysis were performed to screen differentially expressed molecules in the development of renal inflammation and TIF in UUO rats. The expression of CBS was detected in patients with obstructive nephropathy and UUO rats. We confirmed the expression of CBS using western blot and real-time PCR in HK-2 cells. Overexpression plasmid and siRNA were transfected specifically to study the possible function of CBS in HK-2 cells. Abundant expression of CBS, localized in renal tubular epithelial cells, was revealed in human and rat renal tissue, which correlated negatively with the progression of fibrotic disease. Expression of CBS was dramatically decreased in the obstructed kidney from UUO rats as compared with the sham group (SHM). In addition, knocking down CBS exacerbated extracellular matrix (ECM) deposition, whereas CBS overexpression attenuated TGF-β1-induced ECM deposition in vitro. Inflammatory and chemotactic factors were also increased in CBS knockdown HK-2 cells stimulated by IL-1β. These findings establish CBS as a novel inhibitor in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.


A meta-opinion: cannabinoids delivered to oral mucosa by a spray for systemic absorption are rather ingested into gastro-intestinal tract: the influences of fed / fasting states.
Introduction: Sativex® spray is clinically utilized to deliver delta9-tetrahydrocannabinol and cannabidiol to oral mucosa for systemic absorption. We challenge the consensus that the mechanism of absorption following the oro-mucosal application occurs via the buccal tissue. Areas covered: Correctness of the consensus of this absorption pathway arose when reviewing publications regarding the influence fed versus fasting states have on pharmacokinetics of these cannabinoids administered to the oral mucosa. This finding is more suitable for peroral administration, where stomach content affects the absorption profile. We hypothesize that these cannabinoids are ingested and absorbed in the gastrointestinal tract. Expert opinion: Although clinical importance of Sativex® is not disputed, the wide acceptance of its being a successful example of drug delivery through oral mucosa is questionable. Sativex® acts as an example for other drugs delivered to oral mucosa for systemic absorption and unintentionally washed by the saliva flow into the gastrointestinal tract. Delivery of each medicine through oral mucosa should be validated in-vivo to ensure this route to be the predominant one. Revealing the underlying absorption mechanisms would enable predicting the impact of different physiological parameters such as saliva flow and fed/fasting states on the pharmacokinetics of the delivered medication.


Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis.
Cold stimuli and the subsequent activation of β-adrenergic receptor (β-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the β3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the β-AR pathway and triggers Ca2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.


Epidemiology of cystic fibrosis-related diabetes.
Cystic fibrosis-related diabetes (CFRD) has emerged as an important complication of CF. To better understand who is at risk of developing CFRD, to gain insight into the impact of CFRD on pulmonary and nutritional status, and to assess the association of CFRD with various practice patterns and comorbid conditions, we characterized the Epidemiologic Study of Cystic Fibrosis (ESCF) patient population. Analyses were performed on the 8247 adolescents and adults who were evaluated at one of 204 participating sites during 1998. CFRD was defined as the use of insulin or an oral hypoglycemic agent at any time during the year. Previously reported risk factors for CFRD including age, gender (female), and pancreatic insufficiency were confirmed in this study. Patients with CFRD had more severe pulmonary disease, more frequent pulmonary exacerbations, and poorer nutritional status as compared with those without diabetes. CFRD also was associated with liver disease. CFRD is a common complication in adolescents and adults that is associated with more severe disease.


The human glomerular endothelial cells are potent pro-inflammatory contributors in an in vitro model of lupus nephritis.
Juvenile-onset lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus patients (JSLE). As the exact role of human renal glomerular endothelial cells (GEnCs) in LN has not been fully elucidated, the aim of this study was to investigate their involvement in LN. Conditionally immortalised human GEnCs (ciGEnCs) were treated with pro-inflammatory cytokines known to be involved in LN pathogenesis and also with LPS. Secretion and surface expression of pro-inflammatory proteins was quantified via ELISA and flow cytometry. NF-κΒ and STAT-1 activation was investigated via immunofluorescence. Serum samples from JSLE patients and from healthy controls were used to treat ciGEnCs to determine via qRT-PCR potential changes in the mRNA levels of pro-inflammatory genes. Our results identified TNF-α, IL-1β, IL-13, IFN-γ and LPS as robust in vitro stimuli of ciGEnCs. Each of them led to significantly increased production of different pro-inflammatory proteins, including; IL-6, IL-10, MCP-1, sVCAM-1, MIP-1α, IP-10, GM-CSF, M-CSF, TNF-α, IFN-γ, VCAM-1, ICAM-1, PD-L1 and ICOS-L. TNF-α and IL-1β were shown to activate NF-κB, whilst IFN-γ activated STAT-1. JSLE patient serum promoted IL-6 and IL-1β mRNA expression. In conclusion, our in vitro model provides evidence that human GEnCs play a pivotal role in LN-associated inflammatory process.


[Study of the surface of Escherichia coli ribosomes and ribosomal particles by the tritium bombardment method].
A new technique of atomic tritium bombardment has been used to study the surface topography of Escherichia coli ribosomes and ribosomal subunits. The technique provides for the labeling of proteins exposed on the surface of ribosomal particles, the extent of protein labeling being proportional to the degree of exposure. The following proteins were considerably tritiated in the 70S ribosomes: S1, S4, S7, S9 and/or S11, S12 and/or L20, S13, S18, S20, S21, L1, L5, L6, L7/L12, L10, L11, L16, L17, L24, L26 and L27. A conclusion is drawn that these proteins are exposed on the ribosome surface to an essentially greater extent than the others. Dissociation of 70S ribosomes into the ribosomal subunits by decreasing Mg2+ concentration does not lead to the exposure of additional ribosomal proteins. This implies that there are no proteins on the contacting surfaces of the subunits. However, if a mixture of subunits has been subjected to centrifugation in a low Mg2+ concentration at high concentrations of a monovalent cation, proteins S3, S5, S7, S14, S18 and L16 are more exposed on the surface of the isolated 30S and 50S subunits than in the subunit mixture or in the 70S ribosomes. The exposure of additional proteins is explained by distortion of the native quaternary structure of ribosomal subunits as a result of the separation procedure. Reassociation of isolated subunits at high Mg2+ concentration results in shielding of proteins S3, S5, S7 and S18 and can be explained by reconstitution of the intact 30S subunit structure.


Agronomic efficiency of intercropping tomato and lettuce.
Four experiments were carried out at the São Paulo State University, Brazil, with the aim of determining the agronomic viability of intercropping tomato and lettuce, under greenhouse conditions. The studied intercropping systems were established by transplanting lettuce at 0, 10, 20 and 30 days after transplanting (DAT) tomato and by transplanting tomato at 0, 10, 20 and 30 DAT lettuce. Intercropped tomato and lettuce were evaluated during two seasons and compared to their sole cropping. The experimental design was a randomized complete block with nine treatments. The productivity and the classification of the tomato fruits were not influenced by having lettuce intercropped with it, but lettuce production was lowered when tomato was intercropped with it. The longer the delay in lettuce transplanting, the greater the reduction in its productivity. There was an effect of cropping season on the extent of the agronomic advantage of intercropping over sole cropping. In the first cropping season, intercropping established by transplanting lettuce during the interval between 30 days before up to 20 DAT tomato yielded land use efficiency (LUE) indices of 1.63 to 2.22. In the second period, intercropping established with the transplanting of lettuce up to 30 days before tomato yielded LUE indices of 1.57 to 2.05.


Common channels for water and protons at apical and basolateral cell membranes of frog skin and urinary bladder epithelia. Effects of oxytocin, heavy metals, and inhibitors of H(+)-adenosine triphosphatase.
We have compared the response of proton and water transport to oxytocin treatment in isolated frog skin and urinary bladder epithelia to provide further insights into the nature of water flow and H+ flux across individual apical and basolateral cell membranes. In isolated spontaneous sodium-transporting frog skin epithelia, lowering the pH of the apical solution from 7.4 to 6.4, 5.5, or 4.5 produced a fall in pHi in principal cells which was completely blocked by amiloride (50 microM), indicating that apical Na+ channels are permeable to protons. When sodium transport was blocked by amiloride, the H+ permeability of the apical membranes of principal cells was negligible but increased dramatically after treatment with antidiuretic hormone (ADH). In the latter condition, lowering the pH of the apical solution caused a voltage-dependent intracellular acidification, accompanied by membrane depolarization, and an increase in membrane conductance and transepithelial current. These effects were inhibited by adding Hg2+ (100 microM) or dicyclohexylcarbodiimide (DCCD, 10(-5) M) to the apical bath. Net titratable H+ flux across frog skin was increased from 30 +/- 8 to 115 +/- 18 neq.h-1.cm-2 (n = 8) after oxytocin treatment (at apical pH 5.5 and serosal pH 7.4) and was completely inhibited by DCCD (10(-5) M). The basolateral membranes of the principal cells in frog skin epithelium were found to be spontaneously permeable to H+ and passive electrogenic H+ transport across this membrane was not affected by oxytocin. Lowering the pH of the basolateral bathing solution (pHb) produced an intracellular acidification and membrane depolarization (and an increase in conductance when the normal dominant K+ conductance of this membrane was abolished by Ba2+ 1 mM). These effects of low pHb were blocked by micromolar concentrations of heavy metals (Zn2+, Ni2+, Co2+, Cd2+, and Hg2+). Lowering pHb in the presence of oxytocin (50 mU/ml) produced a transepithelial current (3 microA.cm-2 at pHb 5.5) which was blocked by 100 microM of Hg2+, Zn2+, or Ni2+ at the basolateral side, and by DCCD (10(-5) M) or Hg2+ (100 microM) from the apical side. The net hydroosmotic water flux (JH2O) induced by oxytocin in frog bladder sacs was blocked by inhibitors of H(+)-adenosine triphosphatase (ATPase). Diethylstilbestrol (DES 10(-5) M), oligomycin (10(-8) M), and DCCD (10(-5) M) prevented JH2O when present in the lumen. These effects cannot be attributed to inhibition of metabolism since cyanide (10(-4) M), or 2-deoxyglucose (10(-3) M) had no effect on JH2O.(ABSTRACT TRUNCATED AT 400 WORDS)


A novel tdTomato transgenic mouse model to visualize FAP-positive cancer-associated fibroblasts.
Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP-tdTomato transgenic mouse-derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP-tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP-tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato-positive fibroblasts cocultured with mouse cancer cells. These FAP-tdTomato transgenic mice have the potential to be used to investigate real-time FAP dynamics and the importance of FAP expression in tumour development.


The next revolution: percutaneous aortic valve replacement.
Aortic valve replacement (AVR) is a treatment of choice for patients with symptomatic severe aortic stenosis (AS). However, a significant proportion of these patients do not undergo surgical AVR due to high-risk features. Transcatheter aortic valve implantation (TAVI) has emerged as an alternative for patients with severe AS who are not candidates for open-heart surgery. Since the introduction of TAVI to the medical community in 2002, there has been an explosive growth in procedures. The balloon-expandable Edwards SAPIEN valve and the self-expanding CoreValve ReValving(TM) system contribute the largest patient experience with more than 10,000 patients treated with TAVI to date. Clinical outcomes have stabilized in experienced hands, with 30-day mortality less than 10%. Careful patient selection, growing operator experience, and an integrated multidisciplinary team approach contribute to notable improvement in outcomes. In the first randomized pivotal PARTNER trial, in patients with severe AS not suitable candidates for surgical AVR, TAVI compared with standard therapy, significantly improved survival and cardiac symptoms, but was associated with higher incidence of major strokes and major vascular events. The results of randomized comparison of TAVI with AVR among high-risk patients with AS for whom surgery is a viable option are eagerly awaited to provide further evidence on the applicability of TAVI in these patients.


Molecular dynamics of 1-palmitoyl-2-oleoylphosphatidylcholine membranes containing transmembrane alpha-helical peptides with alternating leucine and alanine residues.
The effects of the transmembrane alpha-helical peptide Ac-K(2)(LA)(12)K(2)-amide [(LA)(12)] on the molecular organization and dynamics of 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) membranes were investigated using conventional and saturation-recovery EPR observations of phosphatidylcholine spin labels, and the results were compared with our earlier, similar study of Ac-K(2)L(24)K(2)-amide (L(24)) [Subczynski, W. K., Lewis, R. N. A. H., McElhaney, R. N., Hodges, R. S., Hyde, J. S., and Kusumi, A. (1998) Biochemistry 37, 3156-3164]. At peptide-to-POPC ratios between 1/10 and 1/40, both methods (covering a time scale of 100 ps-10 micros) detect the presence of a single homogeneous membrane environment for both peptides, suggesting that these peptides are both well dispersed and that POPC is exchanging rapidly between the boundary and the bulk domains. The local diffusion-solubility product of oxygen molecules (oxygen transport parameter) in the membrane, studied by saturation-recovery EPR, decreases by a factor of about 2 by including 10 mol % (LA)(12) whereas incorporating L(24) has practically no effect. (LA)(12) increases the alkyl chain order of POPC more than L(24). L(24) increases hydrophobicity (decreases the degree of water penetration into the hydrophobic region of the membrane) more than does (LA)(12). We ascribe the much stronger effects of (LA)(12) on membrane order and dynamics to the increased roughness of its hydrophobic surface and also to the increased motional freedom of its leucine side chains. In L(24), the leucine side chains are packed tightly, giving a smooth hydrophobic surface. In (LA)(12), they are separated by the small methyl groups of the alanine side chains, giving them additional motional freedom and the ability to protrude between the phospholipid hydrocarbon chains. The frequency of gauche-trans isomerization of hydrocarbon chains and concentration of vacant pockets (voids) in the lipid bilayer are thus reduced, which decreases oxygen transport. This explanation was confirmed by calculating the orientational order of leucine side chains in (LA)(12) and L(24) from molecular dynamics simulation studies.


Concentration and risk of pharmaceuticals in freshwater systems are related to the population density and the livestock units in Iberian Rivers.
Considerable amounts of pharmaceuticals are used in human and veterinary medicine, which are not efficiently removed during wastewater and slurries treatment and subsequently entering continuously into freshwater systems. The intrinsic biological activity of these non-regulated pollutants turns their presence in the aquatic environment into an ecological matter of concern. We present the first quantitative study relating the presence of pharmaceuticals and their predicted ecotoxicological effects with human population and livestock units. Four representative Iberian River basins (Spain) were studied: Llobregat, Ebro, Júcar and Guadalquivir. The levels of pharmaceuticals were determined in surface water and sediment samples collected from 77 locations along their stream networks. Predicted total toxic units to algae, Daphnia and fish were estimated for pharmaceuticals detected in surface waters. The use of chemometrics enabled the study of pharmaceuticals for: their spatial distribution along the rivers in two consecutive years; their potential ecotoxicological risk to aquatic organisms; and the relationships among their occurrence and predicted ecotoxicity with human population and animal farming pressure. The Llobregat and the Ebro River basins were characterized as the most polluted and at highest ecotoxicological risk, followed by Júcar and Guadalquivir. No significant acute risks of pharmaceuticals to aquatic organisms were observed. However potential chronic ecotoxicological effects on algae could be expected at two hot spots of pharmaceuticals pollution identified in the Llobregat and Ebro basins. Analgesics/antiinflammatories, antibiotics and diuretics were the most relevant therapeutic groups across the four river basins. Among them, hydrochlorothiazide and gemfibrozil, as well as azithromycin and ibuprofen were widely spread and concentrated pharmaceuticals in surface waters and sediments, respectively. Regarding their predicted ecotoxicity, sertraline, gemfibrozil and loratidine were identified as the more concerning compounds. Significantly positive relationships were found among levels of pharmaceuticals and toxic units and population density and livestock units in both surface water and sediment matrices.


Neuropsychological functioning in children with and without specific learning disorder.
To investigate neuropsychological functioning in children with and without Specific Learning Disorder. The comparative cross-sectional study was conducted in schools affiliated with Punjab Education Foundation, Gujrat, Pakistan, from January -to June 2019, and comprised children diagnosed with Specific Learning Disorder and age-matched and class matched high achievers as controls. Bender Gestalt Test II with copy test, recall test, perceptual test and motor test subscales was administered on both the groups for the assessment of neuropsychological functioning. Data was analysed using SPSS 21. Of 116 subjects, 64(55.2%) were cases and 52(44.8%) controls. Overall, there were 64(55.2%) girls and 52(44.8%) boys with a mean age of 10.41±1.14. There was significant difference on recall test (p<0.01) between the groups which had 100% predictive power. Memory function was significantly impaired in children with Specific Learning Disorder.


Electrochemically Driven C4-Selective Decyanoalkylation of Cyanopyridines with Unactivated Alkyl Bromides Enabling C(sp3)-C(sp2) Coupling.
With cyanopyridines and alkyl bromides as coupling partners, an electrochemically driven C4-selective decyanoalkylation has been established to access diverse 4-alkylpyridines in one step. The reaction proceeds through the single electron reduction/radical-radical coupling tandem process under mild electrolytic conditions, achieving the cleavage of the C(sp2)-CN bond and the formation of C(sp3)-C(sp2). The practicality of this protocol is illustrated by no sacrificial anodes, a broad substrate scope, and gram-scale synthesis.


Screening of Turkish women for postpartum depression within the first postpartum year: the risk profile of a community sample.
To explore the prevalence of postpartum depression (PPD) and potential risk factors giving rise to PPD among Turkish women. A descriptive design and random survey method were used. Collected from 9 public health centers, the sample consisted of 679 mothers within their first year after delivery. The Edinburgh Postpartum Depression Scale (EPDS) and a risk factor questionnaire were used during home visits. The EPDS results revealed a 25.6% prevalence of higher-level depression (12 or above) and a 16.7% prevalence of lower-level depression. Maximum prevalence occurred at 2, 8, 10, and 12 months postpartum. Seventeen independent variables were found to be associated with the elevated scores on EPDS. Strong predictors of depression were as follows: previous psychiatric illness (odds ratio [OR] 15.95); smoking (OR 4.17); lower economic status (OR 4.10); relationship problems with husband (OR 3.49) or mother-in-law (OR 2.53); dissatisfaction in social relations (OR 1.53); previous loss of a baby (OR 7.49); and giving birth to a baby girl (OR 2.54). PPD is common among Turkish women. There is an increased need to educate public and health care practitioners about PPD. Public health nursing interventions, in particular, need to be developed to provide support to postpartum women.


Central obesity predicts non-Hodgkin's lymphoma mortality and overall obesity predicts leukemia mortality in adult Taiwanese.
Obesity may increase the risk of neoplasia, including that of the lymphohematopoietic system. In a large Taiwanese cohort, we have evaluated whether body fat and its distribution is associated with non-Hodgkin's lymphoma (NHL) and leukemia mortalities. During 1997-2007 in Taiwan, 383,956 subjects aged 19-98 years without any cancer history were obtained through a health screening center and followed up for a median of 7.2 years. Unit records were linked to the national death registry; ICD-9 codes were used to identify 143 NHL and 73 leukemia deaths. Objectively, height, weight, and waist circumference data were measured to calculate body mass index (BMI) and central obesity status. Based on World Health Organization criteria modified for Asia and Taiwan, BMI was classified to <18.5, 18.5-23.9, 24-26.9, and ≥ 27 kg/m(2). Waist circumference ≥ 90 cm in men and ≥ 80 cm in women was defined as central obesity. Cox proportional hazard regression models were adjusted for possible confounders including gender, age, education, smoking status, alcohol consumption, physical activity, and clinic location. BMI was not associated with NHL deaths, although the trend was significant, but central obesity with adjustment was (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.27-2.75) compared with non-centrally obese subjects. BMI, but not central obesity, was associated with leukemia mortality (HR = 1.93, 95% CI = 1.00-3.75). An increased risk for NHL with increased abdominal fatness and more so with lower BMI is apparent in Taiwanese; this may indicate that metabolically localized and proinflammatory fat is important. For leukemia, where most is myeloid leukemia, increased general fatness is evidently a risk with Taiwanese ethnicity.


Hospital accreditation and patient care, a dilemma?
Despite the massive financial and human efforts of hospitals in the Flemish part of Belgium to increase quality through the path of external accreditation, so far this has not convinced the end user, in casu the patient. In this study of 307 hospital patients we conclude that the knowledge about accreditation is very limited to none existent (2%) in a sample of Belgian patients not working in medical practice and that patients do not choose their hospital care in accordance to the accreditation status of the hospital. We remain convinced that improving quality is a continuous concern for medical professionals and hospital management. However, we believe that patients, medical professionals and hospital managers might define quality care in a somewhat different way and we question the methodology of imposing a 2 vast amount of strict protocols as a way to improve quality in patient care. There is no conclusive evidence to support that these uniformly imposed "quality programs" improve patient care, except on safety issues.


[Prognostic importance of the tumor receptor status in patients with ovarian cancer].
Estrogen (ER), progesterone (PR), androgen (AR) and glucocorticoid (GR) receptor levels were assayed in 70 malignant epithelial ovarian tumors from untreated patients and in 23 malignancies from those receiving preoperative chemotherapy. Both PR+ and AR+ frequency and their mean levels in tumor were found to be relatively lower after preoperative chemotherapy. The prognostic significance of receptor status in tumor was identified: the efficacy of combined chemotherapy in PR- and RA- tumor patients was much lower as compared with PR+ and RA+ tumors; a 2-year recurrence-free survival of 12.5% and median duration of remission of 6 months were observed in the former group, while in the latter the disease-free survival rate was as high as 66.7%, and a median duration of remission had not been reached at 24 months of follow-up.