Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression.
Although it has been documented that methamphetamine induces astrocyte activation, the mechanism(s) underlying this effect remain poorly understood. We thus sought to examine the molecular mechanisms involved in methamphetamine-mediated activation of astrocytes with a focus on the role of sigma-1 receptor (σ-1R) in this process. The expression of σ-1R and glial fibrillary acidic protein (GFAP) was examined by reverse transcription PCR (RT-PCR), real-time PCR, Western blot, and immunofluorescent staining; phosphorylation of cell signaling pathways was detected by Western blot analysis. Immunoprecipitation was used to determine the interaction between σ-1R and p-Src. Chromatin immunoprecipitation (ChIP) assay was employed to discern the binding of cAMP-response element-binding protein (CREB) with the promoter of σ-1R. The role of σ-1R in astrocyte activation was further validated in σ-1R knockout (KO) mice by Western blot combined with immunofluorescent staining. Exposure of primary rat astrocytes to methamphetamine increased the expression of σ-1R via the activation of Src, ERK mitogen-activated protein kinase, and downstream CREB pathways. Subsequently, CREB translocated into nucleus and interacted with the promoter of σ-1R resulting in increased expression of σ-1R with a concomitant increase in expression of GFAP. This effect was inhibited in cells treated with the σ-1R antagonist-BD1047, thereby implicating the role of σ-1R in the activation of astrocytes. In vivo relevance of these findings was further corroborated in σ-1R KO mice that were administered methamphetamine. In the methamphetamine administered mice, there was a failure of the drug to induce activation of astrocytes, an effect that was evident in wild-type (WT) mice exposed to methamphetamine. The study presented herein demonstrates that methamphetamine-mediated activation of astrocytes involved up-regulation of σ-1R through a positive-feedback mechanism. Understanding the regulation of σ-1R expression could provide insights into the development of potential therapeutic strategies for astrocyte activation induced by methamphetamine.


Two-dimensional infrared spectra of isotopically diluted amyloid fibrils from Abeta40.
The 2D IR spectra of the amide-I vibrations of amyloid fibrils from Abeta40 were obtained. The matured fibrils formed from strands having isotopic substitution by (13)C (18)O at Gly-38, Gly-33, Gly-29, or Ala-21 show vibrational exciton spectra having reduced dimensionality. Indeed, linear chain excitons of amide units are seen, for which the interamide vibrational coupling is measured in fibrils grown from 50% and 5% mixtures of labeled and unlabeled strands. The data prove that the 1D excitons are formed from parallel in-register sheets. The coupling constants show that for each of the indicated residues the amide carbonyls in the chains are separated by 0.5 +/- 0.05 nm. The isotope replacement of Gly-25 does not reveal linear excitons, consistent with the region of the strand having a different structure distribution. The vibrational frequencies of the amide-I modes, freed from effects of amide vibrational excitation exchange by 5% dilution experiments, point to there being a component of an electric field along the fibril axis that increases through the sequence Gly-38, Gly-33, Gly-29. The field is dominated by side chains of neighboring residues.


Evaluation of pediatric bone lesions.
The radiologist is commonly confronted with bone lesions in children. Knowledge of the age of the patient, the lesion location, and various imaging characteristics are all important in making an accurate diagnosis, and determining benign from malignant etiologies should be a primary goal. Various imaging features seen on cross-sectional imaging, including marrow edema, periosteal reaction patterns, and fluid-fluid levels, are discussed. The advantages of different imaging modalities, including CT and MRI, are reviewed.


The association between paralytic side and health-related quality of life in facial palsy: a cross-sectional study of the Korea National Health and Nutrition Examination Survey (2008-2012).
Facial palsy is known to have correlations with low level of quality of life. However, little is known about the association between preference based health-related quality of life (HRQoL) and paralytic side of facial palsy. This study used Korea National Health and Nutrition Examination Survey (KNHANES, 2008-2012) data, only when the facial palsy examination had been included in the survey contents. Hierarchical regression analyses were used to obtain optimal regression coefficients in the association between paralytic side of the facial palsy and HRQoL measured by EuroQoL-5 Dimension (EQ-5D). We also analyzed the association between the deteriorated domains of EQ-5D and facial palsy in both subgroups by using multiple logistic regression models. We included the data of 28,106 participants aged ≥19 years who were examined as facial palsy according to House-Brackmann score and completed EQ-5D questionnaire in KNHANES 2008-2012. The mean EQ-5D score was significantly low and percentages of deteriorated numbers in its domains were significantly high in facial palsy group. These results show that, after adjusting for confounding variables, left facial palsy is associated with impaired HRQoL compared with right-sided palsy. Among the domains of EQ-5D, only 'self-care' domain was directly affected by the disease in left facial palsy patients. These findings could be used in developing model and conducting analyses of economic evaluation about facial palsy interventions.


Combinations of increased thrombin, plasmin and non-specific protease activity in patients with acute leukaemia.
Thrombin generation, plasmin formation and non-specific protease activity, were assessed in a cohort group of 30 patients presenting with acute leukaemia. Abnormalities detected by specific tests of one or more of these three systems were found in 27 (90%) of patients while abnormalities in 'routine' laboratory coagulation tests were seen in only 17 (56%). All patients at presentation had a bleeding tendency which was defined as minor (skin purpura) or major (other bleeding sites). Patients presenting with minor (n = 19) or major haemorrhage (n = 11) could not be differentiated by the degree of thrombocytopenia. Similarly, increased generation of either thrombin or plasmin activity alone was non-discriminatory. However, more complex alterations of haemostasis involving increased activity of more than one of these three systems were seen only in those patients who had major haemorrhage.


The chameleonic reactivity of dilithio bis(alkylamido)cyclodiphosph(iii)azanes with chlorophosphines.
To synthesize a bis(diphosphinylamine) ligand for use in late-metal catalysis dilithio bis(tert-butylamido)cyclodiphosph(iii)azane was treated with two equivalents of (Ph)2PCl. The chlorodiphenylphosphine attacked the dilithium salt kinetically at phosphorus, followed by a rearrangement to an unsymmetrical P, N-di-substituted product. Solid-state structures of both products were determined, and the activation energy for the rearrangement was measured. To gain further insight into the location of chlorophosphine attack (N versus P) on lithium diamides, dilithio bis(cyclohexylamido)cyclodiphosph(iii)azane or dilithio bis(tert-butylamido)cyclodisilazane was treated with two equivalents of PCl3. In each case only the symmetrically N,N'-substituted bis(PCl2) product was obtained and characterized by X-ray analysis. The structures of these latter compounds are unusual, because in both cases a bicyclic compound with a bis(amido) chelated, central P-Cl moiety was expected based on precedent. The two proximal and juxtaposed PCl2 groups may provide a starting point for potentially novel reactivity studies.


Synergistic biosynthesis of biphasic ethylene and reactive oxygen species in response to hemibiotrophic Phytophthora parasitica in tobacco plants.
We observed the biphasic production of ethylene and reactive oxygen species (ROS) in susceptible tobacco (Nicotiana tabacum 'Wisconsin 38') plants after shoot inoculation with Phytophthora parasitica var nicotianae. The initial transient increase in ROS and ethylene at 1 and 3 h (phase I), respectively, was followed by a second massive increase at 48 and 72 h (phase II), respectively, after pathogen inoculation. This biphasic pattern of ROS production significantly differed from the hypersensitive response exhibited by cryptogein-treated wild-type tobacco plants. The biphasic increase in ROS production was mediated by both NADPH oxidase isoforms, respiratory burst oxidase homolog (Rboh) D and RbohF. Conversely, different 1-aminocyclopropane-1-carboxylic acid synthase members were involved in specific phases of ethylene production: NtACS4 in the first phase and NtACS1 in the second phase. Biphasic production of ROS was inhibited in transgenic antisense plant lines expressing 1-aminocyclopropane-1-carboxylic acid synthase/oxidase or ethylene-insensitive3 as well as in transgenic plants impaired in ROS production. All tested transgenic plants were more tolerant against P. parasitica var nicotianae infection as determined based on trypan blue staining and pathogen proliferation. Further, silencing of NtACS4 blocked the second massive increase in ROS production as well as pathogen progression. Pathogen tolerance was due to the inhibition of ROS and ethylene production, which further resulted in lower activation of ROS-detoxifying enzymes. Accordingly, the synergistic inhibition of the second phase of ROS and ethylene production had protective effects against pathogen-induced cell damage. We conclude that the levels of ethylene and ROS correlate with compatible P. parasitica proliferation in susceptible plants.


Associating Peritoneal Metastasis With T2-Weighted MRI Images in Epithelial Ovarian Cancer Using Deep Learning and Radiomics: A Multicenter Study.
The preoperative diagnosis of peritoneal metastasis (PM) in epithelial ovarian cancer (EOC) is challenging and can impact clinical decision-making. To investigate the performance of T2 -weighted (T2W) MRI-based deep learning (DL) and radiomics methods for PM evaluation in EOC patients. Retrospective. Four hundred seventy-nine patients from five centers, including one training set (N = 297 [mean, 54.87 years]), one internal validation set (N = 75 [mean, 56.67 years]), and two external validation sets (N = 53 [mean, 55.58 years] and N = 54 [mean, 58.22 years]). 1.5 or 3 T/fat-suppression T2W fast or turbo spin-echo sequence. ResNet-50 was used as the architecture of DL. The largest orthogonal slices of the tumor area, radiomics features, and clinical characteristics were used to construct the DL, radiomics, and clinical models, respectively. The three models were combined using decision-level fusion to create an ensemble model. Diagnostic performances of radiologists and radiology residents with and without model assistance were evaluated. Receiver operating characteristic analysis was used to assess the performances of models. The McNemar test was used to compare sensitivity and specificity. A two-tailed P < 0.05 was considered significant. The ensemble model had the best AUCs, outperforming the DL model (0.844 vs. 0.743, internal validation set; 0.859 vs. 0.737, external validation set I) and clinical model (0.872 vs. 0.730, external validation set II). After model assistance, all readers had significantly improved sensitivity, especially for those with less experience (junior radiologist1, from 0.639 to 0.820; junior radiologist2, from 0.689 to 0.803; resident1, from 0.623 to 0.803; resident2, from 0.541 to 0.738). One resident also had significantly improved specificity (from 0.633 to 0.789). T2W MRI-based DL and radiomics approaches have the potential to preoperatively predict PM in EOC patients and assist in clinical decision-making. 4 TECHNICAL EFFICACY: Stage 2.


Specific susceptibility to mucormycosis in murine diabetes and bronchoalveolar macrophage defense against Rhizopus.
To assess the influence of diabetes mellitus in predisposing to pulmonary mucormycosis, a murine model of streptozotocin-induced diabetes was used. Intranasal inoculation of Rhizopus oryzae into diabetic mice resulted in mucormycotic infection with histopathology resembling pulmonary mucormycosis observed in humans. There was no mortality nor infection in inoculated normal mice. Diabetic mice had fatal infections caused by R. oryzae but significantly reduced mortality following inoculation with Aspergillus fumigatus. These findings reflect the specific enhanced susceptibility to mucormycosis observed in human diabetics. Normal bronchoalveolar macrophages formed part of an efficient defense against R. oryzae by inhibiting germination, the critical step in the conversion of R. oryzae to its tissue invasive phase. Bronchoalveolar macrophages inhibited spore germination in vitro and appeared to help prevent germination in vivo. In contrast, spore germination occurred in diabetic mice following intranasal inoculation. Diabetic bronchoalveolar macrophages had a decreased ability to attach to hyphae. In diabetic mice, bronchoalveolar macrophages could damage spores or hyphae of R. oryzae, but serum factors appeared to both promote spore germination and impair attachment of macrophages to spores. This murine model of diabetes mellitus provides an opportunity for evaluation of the relative importance of cell and serum-mediated host factors in the pathogenesis of mucormycosis.


Endoscopic sleeve gastroplasty with argon plasma coagulation: A novel technique.
The endoscopic sleeve gastroplasty (ESG) is a minimally invasive procedure in which the anterior and posterior aspects of the greater curvature are stitched endoscopically, producing a sleeve-like anatomy mimicking that in a sleeve gastrectomy. However, suture dehiscence and enlargement of the stomach within months of the procedure have been observed. Argon plasma coagulation (APC) is widely used in gastrointestinal endoscopy and is able to induce scarring and fibrosis. We coupled ESG with APC to evaluate its potential to improve durability. A 46-year-old woman with obesity presented for ESG. Her pre-procedure weight was 117 kg with a body mass index (BMI) of 41.4 kg/m2 . After each plication was complete, APC (60 W, argon flow rate 1.2 L/min) was used to ablate the mucosal surface of the exposed plicated mucosa. APC was applied until the mucosal color was dark brown, indicating adequate and successful mucosal and submucosal ablation. The procedure was successful, and the patient recovered without peri- or post-operative complications. The procedure time was 47 minutes. A total of seven sutures were used. At 6-month follow-up the patient had lost 17 kg (37.5 lbs), equivalent to 14.5% total weight loss and had a BMI of 35.4 kg/m2 . Endoscopic follow-up at 6 months revealed enhanced fibrosis along the plications, resulting in a superior, sleeve-like lumen. The combination of ESG with APC may act synergistically to reduce weight without adding significant procedure time. Further investigation is needed to determine whether it should be widely recommended.


Multiple Levels of Suffering: Discrimination in Health-Care Settings is Associated With Enhanced Laboratory Pain Sensitivity in Sickle Cell Disease.
People living with sickle cell disease (SCD) experience severe episodic and chronic pain and frequently report poor interpersonal treatment within health-care settings. In this particularly relevant context, we examined the relationship between perceived discrimination and both clinical and laboratory pain. Seventy-one individuals with SCD provided self-reports of experiences with discrimination in health-care settings and clinical pain severity, and completed a psychophysical pain testing battery in the laboratory. Discrimination in health-care settings was correlated with greater clinical pain severity and enhanced sensitivity to multiple laboratory-induced pain measures, as well as stress, depression, and sleep. After controlling for relevant covariates, discrimination remained a significant predictor of mechanical temporal summation (a marker of central pain facilitation), but not clinical pain severity or suprathreshold heat pain response. Furthermore, a significant interaction between experience with discrimination and clinical pain severity was associated with mechanical temporal summation; increased experience with discrimination was associated with an increased correlation between clinical pain severity and temporal summation of pain. Perceived discrimination within health-care settings was associated with pain facilitation. These findings suggest that discrimination may be related to increased central sensitization among SCD patients, and more broadly that health-care social environments may interact with pain pathophysiology.


Cyclic adenosine 3':5'-monophosphate and cytosolic calcium exert opposing effects on biosynthesis of tetrodotoxin-sensitive sodium channels in rat muscle cells.
We have previously presented evidence that electrical activity and increased cytosolic calcium reduce the density of sarcolemmal tetrodotoxin (TTX)-sensitive sodium channels in cultured rat muscle cells (Sherman, S. J., and W. A. Catterall (1984) Proc. Natl. Acad. Sci. U. S. A. 81: 262-266). We show here that growth of cells in ryanodine has a biphasic effect on sodium channel number. At low concentrations (0.3 to 10 microM) where this drug releases calcium from the sarcoplasmic reticulum into the cytoplasm, sodium channel number is reduced 62%; whereas, at higher concentrations where total cellular calcium is depleted, the density of sodium channels is increased 40% above control. These results provide further evidence for modulation of sodium channel number by cytosolic calcium. Growth of muscle cells in the presence of agents that mimic cyclic AMP (cAMP) action or increase intracellular cAMP levels including 8-bromo-cyclic AMP (8-BrcAMP), cyclic nucleotide phosphodiesterase inhibitors, and forskolin increased sodium channel density up to 125%. This action did not involve changes in spontaneous electrical activity. Dibutyryl cGMP had no effect. Measurement of the turnover rate of sodium channels after block of channel accumulation by tunicamycin (1.5 micrograms/ml) gave a half-time of 18 hr for exponential decay of TTX-sensitive sodium channels in cultured rat muscle cells after an initial 6-hr lag period. Treatments which modulate sodium channel number through changes in cytosolic calcium or cAMP had no effect on the rate of channel turnover. The increase of sodium channel number after inhibiton of electrical activity or treatment with 8-BrcAMP was half-maximal at 17 hr, consistent with an increase in the rate of sodium channel biosynthesis and/or incorporation into the sarcolemma without a change in channel turnover time. We conclude that cytosolic calcium decreases and cAMP increases sodium channel number by modulating the rate of biosynthesis and/or processing of channel components. The biochemical mechanisms of these regulatory effects are considered.


MINI REVIEW: Role of Kisspeptin-GPR54 system in regulation of reproductive functions in human and other mammals.
Kisspeptin is a 54- amino acid peptide that acts as a ligand of a receptor called GPR54 which is basically a transmembrane receptor that spins seven times across the cell membrane and coupled with G-protein. Kisspeptin regulates the development of reproductive functions and the onset of puberty in human and other mammals by acting at the brain, hypothalamus, pituitary and gonad levels of reproductive axis. Kisspeptin is also involved in regulation of trophoblastic invasion during pregnancy, ovulation, and sperm hyperactivation. Inactivating mutations in human kisspeptin gene (KISS1) cause idiopathic hypogonadotropic hypogonadism. Some mutations in human kisspeptin receptor gene (KISS1R) make the receptor inactive which result in idiopathic hypogonadotropic hypogonadism. Some mutations in human KISS1R gene make the receptor prematurely activated and result in the development of central precocious puberty. Central precocious puberty is also caused by some mutations in human KISS1 gene that make the kisspeptin resistant to degradation. This leads to an increased basal kisspeptin level and subsequently the development of central precocious puberty. Higher kisspeptin level has been detected in the serum and plasma of central precocious puberty patients, which suggest that serum or plasma kisspeptin level can be used as a marker for diagnosis of central precocious puberty.


Altered allocation to roots and shoots in the endophyte-infected seedlings of Puccinellia distans (Poaceae).
Endophytes play an important role in ecological and evolutionary processes in plants and have marked economic value. Seed-transmitted fungal endophytes are conventionally regarded as mutualistic symbionts, but their fitness consequences for the offspring of the host are not clear. Puccinellia distans infected with the fungus Epichloë typhina (E+) produces seeds that are several times smaller than normal (E-). This observation suggests that the E+ seedlings face a developmental disadvantage. Our growth chamber experiments compared the germination rates of the small E+ and large E- seeds of P. distans and examined the biomass allocation of seedlings to roots and shoots. The E+ seedlings germinated more slowly and maintained shorter shoots and a smaller root biomass for 30-50 days after sowing. Despite this disadvantage, the E+ plants more quickly increased their total size, attaining a larger shoot and whole-plant biomass. The shoot:root biomass ratio increased more rapidly through time in the E+ seedlings, attaining a value nine times higher in the E+ than the E- group 50 days after sowing. Such differences between the E+ and E- seedlings were not explained by the growth allometry between shoots and roots. The seedlings of P. distans infected with the Epichloë endophyte were initially handicapped by their postponed emergence, but this disadvantage was quickly overcome by their superior growth capacity. The decrease in the relative allocation to roots may indicate that endophytes increase the performance of roots as resource-acquiring organs and/or reduce the role of roots in protection against herbivores.


Task-specific gross motor skills training for ambulant school-aged children with cerebral palsy: a systematic review.
The primary objective is to systematically evaluate the evidence for the effectiveness of task-specific training (TST) of gross motor skills for improving activity and/or participation outcomes in ambulant school-aged children with cerebral palsy (CP). The secondary objective is to identify motor learning strategies reported within TST and assess relationship to outcome. Systematic review. Relevant databases were searched for studies including: children with CP (mean age >4 years and >60% of the sample ambulant); TST targeting gross motor skills and activity (skill performance, gross motor function and functional skills) and/or participation-related outcomes. Quality of included studies was assessed using standardised tools for risk of bias, study design and quality of evidence across outcomes. Continuous data were summarised for each study using standardised mean difference (SMD) and 95% CIs. Thirteen studies met inclusion criteria: eight randomised controlled trials (RCTs), three comparative studies, one repeated-measures study and one single-subject design study. Risk of bias was moderate across studies. Components of TST varied and were often poorly reported. Within-group effects of TST were positive across all outcomes of interest in 11 studies. In RCTs, between-group effects were conflicting for skill performance and functional skills, positive for participation-related outcomes (one study: Life-HABITS performance SMD=1.19, 95% CI 0.3 to 2.07, p<0.001; Life-HABITS satisfaction SMD=1.29, 95% CI 0.40 to 2.18, p=0.001), while no difference or negative effects were found for gross motor function. The quality of evidence was low-to-moderate overall. Variability and poor reporting of motor learning strategies limited assessment of relationship to outcome. Limited evidence for TST for gross motor skills in ambulant children with CP exists for improving activity and participation-related outcomes and recommendations for use over other interventions are limited by poor study methodology and heterogeneous interventions. PROSPERO ID42016036727.


Disparities in postpartum depression screening participation between immigrant and Danish-born women.
Qualitative studies suggest that immigrant women experience barriers for postpartum depression (PPD) screening. This study examines the prevalence of participation in PPD screening in the universal home-visiting programme in Denmark, in relation to migrant status and its association with acculturation factors, such as length of residence and age at migration. The sample consists of 77 694 births from 72 292 mothers (2015-18) that participated in the programme and were registered in the National Child Health Database. Lack of PPD screening using the Edinburgh Postpartum Depression Scale (EPDS) was examined in relation to migrant group and acculturation factors. We used Poisson regression with cluster robust standard errors to estimate crude and adjusted relative risk. In total, 27.8% of Danish-born women and 54.7% of immigrant women lacked screening. Compared with Danish-born women, immigrant women in all groups were more likely to lack PPD screening (aRR ranging from 1.81 to 1.90). Women with low acculturation were more likely to lack screening. Women who migrated as adults [aRR = 1.27 (95% CI 1.16, 1.38)] and women who had resided in Demark for <5 years [aRR = 1.37 (95% CI 1.28, 1.46)] were more likely to lack screening. Immigrant women in Denmark, particularly recent immigrants, are at increased risk of not being screened for PPD using the EPDS. This can lead to under-recognition of PPD among immigrant women. More work is needed to understand how health visitors recognize the mental health needs of immigrant women who are not screened, and whether this gap results in reduced use of mental health services.


Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor.
In vitro the mineralocorticoid receptor is non-specific and does not distinguish between aldosterone and cortisol. In vivo certain tissues with this receptor are aldosterone selective (eg, kidney and parotid) whereas others with the same receptor are not (eg, hippocampus and heart). Experiments in rats showed that 11 beta-hydroxysteroid dehydrogenase (which converts cortisol to cortisone in man and corticosterone to 11-dehydrocorticosterone in the rat) was much more highly concentrated in aldosterone-selective tissues than in non-selective tissues. The localisation in the selective tissues was such that the enzyme could act as a paracrine or possibly an autocrine mechanism protecting the receptor from exposure to corticosterone. Autoradiographic studies showed that protection is lost when the enzyme is inhibited; 3H-corticosterone and 3H-aldosterone were bound to similar sites. These findings seem to explain why sodium retention, hypokalaemia, and hypertension develop in subjects with congenital deficiency of 11 beta-OHSD and those in whom the enzyme has been inhibited by liquorice.


[Investigation of the perception of incomplete contour figures of the various size].
The purpose of the current research was to estimate the range of angular sizes of incomplete images across which the perception of the given images does not depend on scale. We have measured thresholds of recognition of the identities of objects across a wide range of angular sizes from 0.19 to 50 degrees of visual angle. The methodology derived from the Gollin-test which has been used as a method for studying the perception of objects presented as incomplete contour and pattern recognition. Results demonstrated that there is a wide range of angular sizes (from 1 .0 up to 50 degrees of visual angle) across which thresholds perception of incomplete images does not depend on object size. However, there was found a narrow range of small sizes of stimulus (0.19-1.0 degrees of visual angle) at which there was found dependence of performance on object size. We assume that increase of thresholds and occurrence of undistinguished images (when they have small size) depends on increase of the contribution of sampling noise at the observer's eye retina.


Assessment of the Mobile Mental Health Units' effectiveness in Cyclades islands.
In Greece, the provision of mental health shows inefficiencies in remote and inaccessible areas due to the lack of appropriate structures and access to healthcare. The purpose of this study was to assess the effectiveness of the Mobile Mental Health Units (MMHUs) in Cyclades with and without MMHUs' operation based on Real-World Evidence (RWE). The study population consisted of 724 people who visited the MMHUs of the western and northeastern Cyclades in 2015. The data derived from the patients' medical records of EPAPSY classified by International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) and the Global Assessment of Functioning (GAF) scale. The analysis revealed that 60.9% of the participants were women and the average age was 50.1. 50.4% of the people who visited MMHUs without referral from primary health care professionals and 18.8% with referral. The calculation of effectiveness was based on DALYs (Disability-Adjusted Life Years) and was performed according to the World Health Organization methodology. In the specific population, there are no recorded deaths caused by mental disorders and thus DALYs are equal to Years Lost due to Disability (YLDs) with MMHUs' operation. 18% of the population was diagnosed with mood disorders (F30-F39) and morbidity burden 9.49 (YLDs), while 17.5% of the patients were diagnosed with neurotic, stress-related and somatoform disorders (F40-F48) and corresponding morbidity burden 4.53 (YLDs). Our results revealed that the effectiveness of MMHUs corresponds to 17.98 Disability-Adjusted Life Years (DALYs) averted in 2015. The mood disorders and the neurotic, stress-related disorders have shown a high morbidity burden. Advanced age, non-permanent employment, existence of psychopathology in the family and referral on patients' own will were found to significantly affect the mental health status of the participants. The implementation and expansion of flexible and alternative community-based interventions, such as MMHUs, constitute a best practice both for obtaining higher clinical outcomes and for facing regional inefficiencies related to population's access to healthcare.


Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer.
Cell surface antigens of transformed cells are the traditional targets for antibody-guided detection and therapy of solid neoplasms. Alternative targets may be found in the tumor stroma, which contains newly formed blood vessels, reactive fibroblasts, and extracellular matrix proteins. The F19 cell surface glycoprotein of reactive fibroblasts is a prototypic stromal antigen since it is found in the stroma of > 90% of common epithelial cancers but is absent or expressed at low levels in normal tissues and benign epithelial tumors. In the present study, we define an additional tumor stromal antigen, FB5, that is selectively expressed in vascular endothelial cells of malignant tumors. Immunohistochemical analysis of 128 tumors identified FB5 in endothelial cells in 67% of the samples (including 41 of 61 sarcomas, 26 of 37 carcinomas, and 18 of 25 neuroectodermal tumors) whereas normal blood vessels and other adult tissues tested lacked FB5 expression. In vitro studies showed that FB5 is a M(r) 165,000 cell surface glycoprotein, comprised of a M(r) 95,000 core polypeptide and highly sialyated O-linked oligosaccharides but few if any N-linked sugars, and that the FB5 gene is located on chromosome 11q13-qter. The restricted tissue distribution of the FB5 protein, which we refer to as endosialin, suggests strategies for tumor imaging and therapy that are aimed primarily at the tumor vasculature.


Development of Biodegradable Flame-Retardant Bamboo Charcoal Composites, Part I: Thermal and Elemental Analyses.
In this study, bamboo charcoal (BC) was used as a substitute filler for bamboo powder (BP) in a lignocellulose-plastic composite made from polylactic acid (PLA), with aluminum hypophosphite (AHP) added as a fire retardant. A set of BC/PLA/AHP composites were successfully prepared and tested for flame-retardancy properties. Objectives were to (a) assess compatibility and dispersibility of BC and AHP fillers in PLA matrix, and (b) improve flame-retardant properties of PLA composite. BC reduced flexural properties while co-addition of AHP enhanced bonding between PLA and BC, improving strength and ductility properties. Adding AHP drastically reduced the heat release rate and total heat release of the composites by 72.2% compared with pure PLA. The formation of carbonized surface layers in the BC/PLA/AHP composites effectively improved the fire performance index (FPI) and reduced the fire growth index (FGI). Flame-retardant performance was significantly improved with limiting oxygen index (LOI) of BC/PLA/AHP composite increased to 31 vol%, providing a V-0 rating in UL-94 vertical flame test. Adding AHP promoted earlier initial thermal degradation of the surface of BC/PLA/AHP composites with a carbon residue rate up to 40.3%, providing a protective layer of char. Further raw material and char residue analysis are presented in Part II of this series.


Simple method for quantifying viable bacterial numbers in sputum.
To establish a simple method of quantitative culture for determining the viable bacterial numbers present in expectorated sputum samples. Sputum samples were homogenised with dithiothreitol, sterile saline or glass beads to determine which method recovered the greatest number of viable bacteria. Culture broths were also incubated with dithiothreitol and sampled over time to determine its effect on bacterial viability. Sputum samples homogenised with dithiothreitol were diluted in sterile saline and sampled using either standard bacteriological loops or a precision pipette to determine which method resulted in the least variation. Homogenisation of sputum using dithiothreitol increased the recovery of viable bacteria compared with sterile glass beads and/or saline, with no apparent effect on bacterial viability when incubated with culture broths. By inoculating agar plates with 10(-3), 10(-4) and 10(-5) dilutions of the homogenised sputum sample, all potential pathogens could easily be identified. A 10 microliter sample volume dispensed by precision pipette and spread with a "hockey stick" resulted in the least variation between plates (less than 16%) and an even distribution of bacterial colonies. Numbers of viable bacteria recovered from different aliquots of individual sputum samples were generally of the same order of magnitude. This method represents a relatively quick and simple technique for accurately quantifying viable bacteria present in sputum samples. The use of a small portion appears to be representative of the sample as a whole.


Investigation of the p-coronene series in the context of the 'annulene-within-an-annulene' model by means of ipso-centric ab initio calculations of π-electron currents.
The graph-theoretical Hückel-London-Pople-McWeeny (HLPM) approach to π-electron ring-currents and bond-currents was recently applied to a newly defined series of hypothetical conjugated hydrocarbons called the p-coronenes (with p odd and p > 3) and that investigation ostensibly indicated that the first four of these structures conform to the annulene-within-an-annulene model [Dickens et al., Phys. Chem. Chem. Phys., 2013, 12, 8245]. However, more-refined calculations reported here, which are based on a more-realistic geometry and the ipso-centric ab initio formalism, contradict this finding and indicate that, so far, the only member of the p-coronene series that definitely obeys the AWA rule is its very first member, 5-coronene (also known as [10,5] coronene).


Dynamical Transitions at Low Temperatures in the Nearest Hydration Shell of Phospholipid Bilayers.
For the so-called dynamical transition from harmonic to anharmonic (or diffusive) motions in biological systems, the presence of hydration water is important. To explain the molecular mechanism of this transition, the information on molecular motions in the nearest hydration shell would be helpful. In this work, to study molecular motions in the nearest hydration shell of spin-labeled model biological membranes, a pulsed version of electron paramagnetic resonance, electron spin echo envelope modulation (ESEEM) spectroscopy, is used. For hydration by deuterium water, the 2H ESEEM frequency spectra resemble the solid-state 2H NMR line shape that is widely used for structural and dynamical studies. Two types of model membranes were investigated and compared: bilayers consisting of unsaturated lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and bilayers consisting of fully saturated lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). The lipid chain packing for the POPC bilayer is known to be more defective than that for the DPPC bilayer. For both the POPC and the DPPC bilayers, the 2H ESEEM NMR-like spectra showed a sharp narrowing between 180 and 190 K. From the other side, in both bilayers at 188 K, an inflection was observed for the temperature dependence of molecular motions detected by the spin relaxation of spin labels in the bilayer interior. It was concluded that dynamical transition in the bilayer interior is accompanied by an onset of isotropic water molecular dynamics in the nearest hydration shell of the bilayer with a rate of ∼105 s-1. Also, the 2H ESEEM NMR-like spectra in the POPC bilayer showed slight changes above 100 K that could be ascribed to another dynamical transition resulting in the appearance of restricted orientational motion of water molecules. These data also are interrelated with spin relaxation of spin labels in the POPC bilayer interior and support the hypothesis ascribing the transition at 100 K to excessive lipid chain flexibility.


Impairment of Tomato WAT1 Enhances Resistance to Vascular Wilt Fungi Despite Severe Growth Defects.
Verticillium dahliae is a particularly notorious vascular wilt pathogen of tomato and poses a reoccurring challenge to crop protection as limited qualitative resistance is available. Therefore, alternative approaches for crop protection are pursued. One such strategy is the impairment of disease susceptibility (S) genes, which are plant genes targeted by pathogens to promote disease development. In Arabidopsis and cotton, the Walls Are Thin 1 (WAT1) gene has shown to be a S gene for V. dahliae. In this study, we identified the tomato WAT1 homolog Solyc04g080940 (SlWAT1). Transient and stable silencing of SlWAT1, based on virus-induced gene silencing (VIGS) and RNAi, respectively, did not consistently lead to reduced V. dahliae susceptibility in tomato. However, CRISPR-Cas9 tomato mutant lines carrying targeted deletions in SlWAT1 showed significantly enhanced resistance to V. dahliae, and furthermore also to Verticillium albo-atrum and Fusarium oxysporum f. sp. lycopersici (Fol). Thus, disabling the tomato WAT1 gene resulted in broad-spectrum resistance to various vascular pathogens in tomato. Unfortunately these tomato CRISPR mutant lines suffered from severe growth defects. In order to overcome the pleiotropic effect caused by the impairment of the tomato WAT1 gene, future efforts should be devoted to identifying tomato SlWAT1 mutant alleles that do not negatively impact tomato growth and development.


On the dual-cone nature of the conical refraction phenomenon.
In conical refraction (CR), a focused Gaussian input beam passing through a biaxial crystal and parallel to one of the optic axes is transformed into a pair of concentric bright rings split by a dark (Poggendorff) ring at the focal plane. Here, we show the generation of a CR transverse pattern that does not present the Poggendorff fine splitting at the focal plane, i.e., it forms a single light ring. This light ring is generated from a nonhomogeneously polarized input light beam obtained by using a spatially inhomogeneous polarizer that mimics the characteristic CR polarization distribution. This polarizer allows modulating the relative intensity between the two CR light cones in accordance with the recently proposed dual-cone model of the CR phenomenon. We show that the absence of interfering rings at the focal plane is caused by the selection of one of the two CR cones.


Chondritic meteorites and the lunar surface.
The landing dynamics of and soil penetration by Surveyor I indicated that the lunar soil has a porosity in the range 0.35 to 0.45. Experiments with Surveyor III's surface sampler for soil mechanics show that the lunar soil is approximately incompressible (as the word is used in soil mechanics) and that it has an angle of internal friction of 35 to 37 degrees; these results likewise point to a porosity of 0.35 to 0.45 for the lunar soil. Combination of these porosity measurements with the already-determined radar reflectivity fixes limits to the dielectric constant of the grains of the lunar soil. The highest possible value is about 5.9, relative to vacuum; a more plausible value is near 4.3. Either figure is inconsistent with the idea that the lunar surface is covered by chondritic meteorites or other ultrabasic rocks. The data point to acid rocks, or possibly vesicular basalts; carbonaceous chondrites are not excluded.


[The amino acid composition of blood serum of harp seal pups in the period of adaptation to captivity].
It is cited results of investigation of amino acid composition of blood serum of harp seal pups in the first days after catch adaptation in conditions of oceanarium. It is shown that changes of amino acid composition are most expressed in the first ten-day period of observation and manifest itself by increase of free amino acid concentration at the expense of their endogenous entrance in blood. At the same time it was detected amino acid imbalance which is conditioned by stress of animals. Results of investigation witness intensification of protein catabolism under conditions of stress. Because of it it is necessary to correlate protein metabolism for prophylaxis of hypotrophy seal pups.


Modulation of alpha 1 beta 1, alpha 2 beta 1 and alpha 3 beta 1 integrin heterodimers during human neuroblastoma cell differentiation.
Two human neuroblastoma cell lines, LAN-5 and GI-CA-N, have been analyzed for their capability to adhere to different extracellular matrix (ECM) components. The GI-CA-N cells adhered to all the tested substrates: laminin (LN), type I and type IV collagen (Coll I, Coll IV), vitronectin (VN), and fibronectin (FN). Conversely LAN-5 cells weakly attached to FN and VN, whilst adhesion on LN and Coll I and IV was strong and induced a rapid elongation of cell processes. By means of RT-PCR and immunoprecipitation we showed that the integrin pattern of these two lines was different and could explain their diversity in adhesion capability. Both cell lines express a large amount of the beta 1 integrin subunit, associated with different alpha chains, probably responsible for their adhesion to some ECM proteins. After treatment of LAN-5 cells with biological differentiating agents, such as gamma-interferon, alone or in combination with tumour necrosis factor-alpha (TNF-alpha), or retinoic acid, the levels of alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 integrin expression were enhanced, while the amount of alpha v remained constant. In contrast, treatment of LAN-5 cells with TNF-alpha, that did not induce any maturation, or starvation in 2% foetal calf serum, that inhibited cell proliferation without affecting neural differentiation, did not induce any change in the integrin assessment. Messenger-RNAs for the two alpha 6 isoforms, A and B, were present in both cell lines. However, in LAN-5 cells, the protein product was neither detectable nor inducible by differentiation. Our results confirm the specific modulation of the alpha 1 beta 1 integrin expression in human neuronal development, and show, for the first time, the involvement of alpha 2 beta 1 and alpha 3 beta 1 heterodimers in this maturational process.


Changes in skeletal dysplasia nosology.
Skeletal dysplasia (SD), also called osteochondrodysplasia (OCD), is a large group of skeletal disorders (over 400 distinct entities) caused by abnormalities in bone development and growth. SDs varies according to different natural histories, prognoses, hereditary patterns to etiopathogenetic mechanisms. At birth, the incidence is low, reported at the level of each entity, but taken collectively; the incidence is estimated at 1:5000 births. Nosology is a branch of medical science. It deals with the systematic classification of diseases and disorders. Thus, combining information about the catalogue of clinically distinct disorders, pending molecular explanations, and genotype-phenotype correlations, the classification of SDs will be more accurate. This is extremely useful for diagnosing patients with genetic skeletal diseases, especially given the expected flow of information with new sequencing technologies. Over the years, various terms and classifications of SD have been used and have attempted to order and classify this group of genetic diseases according to clinical, radiological, and molecular criteria. In 2019, the Nosology Committee of the International Skeletal Dysplasia Society (ISDS) updated the classification of SD. This new classification divides SD into 42 large groups that include 461 entities. Advances in next-generation sequencing techniques have revolutionized the entire field of genetics, with 437 different genes are currently identified in 426 (92.4%) of SDs. Nosology is a real help for the clinician in establishing a diagnosis as accurately as possible, for the recognition of new diseases while serving as a guide for the interpretation of new genetic variants.


The socio-demographic legacy of the Khmer Rouge period in Cambodia.
The study presented in this paper is an examination of the long-term impact of genocide during the period of the Khmer Rouge regime (1975-79) in Cambodia. The very high and selective mortality of the period had a major impact on the population structure of Cambodia. Fertility and marriage rates were both very low under the Khmer Rouge, but recovered immediately after the regime's collapse. Because of the shortage of eligible men, the age and education differences between partners tended to decline. The period also had a lasting impact on the educational attainment of the population. The school system collapsed during the period and therefore individuals -- especially men -- who were of school age at the time have a lower educational attainment than those from the preceding and subsequent birth cohorts.


A successful case of deceased donor liver transplantation for a patient with intrahepatic arterioportal fistula.
Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension that is often difficult to treat with interventional radiology or surgery. Liver transplantation for IAPF is extremely rare. We report a case of bilateral diffuse IAPF with severe portal hypertension requiring deceased donor liver transplantation (DDLT). A 51-year-old woman with no past medical history was admitted to another hospital complaining of abdominal distension and marasmus. A computed tomography scan and digital subtraction angiography indicated a massive pleural effusion, ascites, and a very large IAPF. Several attempts of interventional embolization of the feeding artery failed to ameliorate arterioportal shunt flow. As ruptures of the esophageal varices became more frequent, hepatic encephalopathy worsened. After repeated, uncontrollable attacks of hepatic coma, the patient was referred to our facility for further treatment. Surgical approaches to IAPF other than liver transplantation were challenging because of diffuse collateralization; therefore, we placed the patient on the national waiting list for DDLT. Although her Model for End-Stage Liver Disease score was relatively low, she received a DDLT 2 months after the waiting period. The postoperative course was uneventful, and the patient was discharged 44 days after her transplant. Liver transplantation may be a valid treatment option for uncontrollable IAPF with severe portal hypertension.


Magnetic resonance imaging (MRI) contrast agents for tumor diagnosis.
This review focuses on MRI contrast agents for tumor diagnosis. Several types of low molecular weight Gd3+-based complexes and dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles have been used for clinical tumor diagnosis as longitudinal relaxation time (T1) and transverse relaxation time (T2) MRI contrast agents, respectively. To further improve the sensitivity of MRI, new types of chelates for T1 MRI contrast agents and combination of low molecular weight T1 MRI contrast agents with different types of carriers have been investigated. Different types of materials for forming secure coating layers of SPIO and novel superparamagnetic particles with higher relaxivity values have been explored. Various types of ligands were applied to improve the capability to target tumor for both T1 and T2 contrast agents. Furthermore, MRI contrast agents for detection of tumor metabolism were also pursued.


Poly(I:C) and lipopolysaccharide innate sensing functions of circulating human myeloid dendritic cells are affected in vivo in hepatitis C virus-infected patients.
The role of peripheral dendritic cells (DCs) in hepatitis C virus (HCV) infection is unclear. To determine if persistent infection exerts an inhibitory pressure on HCV-specific innate responses, we analyzed DC function in blood through quantification of cell-associated HCV RNA levels in conjunction with multiparametric flow cytometry analysis of pathogen recognition receptor-induced cytokine expression. Independently of the serum viral load, fluorescence-activated cell sorter-purified total DCs had a wide range of cell-associated HCV genomic RNA copy numbers (mean log(10), 5.0 per 10(6) cells; range, 4.3 to 5.8). Here we report that for viremic patients with high viral loads in their total DCs, the myeloid DC (MDC) subset displayed impaired expression of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) but normal IL-6 or chemokine CCL3 expression in response to poly(I:C) and lipopolysaccharide (LPS). IL-6-expressing cells from this subgroup of viremic patients demonstrated a significant increase (sixfold more) in TNF-alpha(-) IL-12(-) cell frequency compared to healthy donors (mean, 38.8% versus 6.5%; P < 0.0001), indicating a functional defect in a subpopulation of cytokine-producing MDCs ( approximately 6% of MDCs). Attenuation of poly(I:C) and LPS innate sensing was HCV RNA density dependent and did not correlate with viremia or deficits in circulating MDC frequencies in HCV-infected patients. Monocytes from these patients were functionally intact, responding normally on a per-cell basis following stimulation, independent of cell-associated HCV RNA levels. Taken together, these data indicate that detection of HCV genomic RNA in DCs and loss of function in the danger signal responsiveness of a small proportion of DCs in vivo are interrelated rather than independent phenomena.


Unsupervised Domain Adaptation by Statistics Alignment for Deep Sleep Staging Networks.
Deep sleep staging networks have reached top performance on large-scale datasets. However, these models perform poorer when training and testing on small sleep cohorts due to data inefficiency. Transferring well-trained models from large-scale datasets (source domain) to small sleep cohorts (target domain) is a promising solution but still remains challenging due to the domain-shift issue. In this work, an unsupervised domain adaptation approach, domain statistics alignment (DSA), is developed to bridge the gap between the data distribution of source and target domains. DSA adapts the source models on the target domain by modulating the domain-specific statistics of deep features stored in the Batch Normalization (BN) layers. Furthermore, we have extended DSA by introducing cross-domain statistics in each BN layer to perform DSA adaptively (AdaDSA). The proposed methods merely need the well-trained source model without access to the source data, which may be proprietary and inaccessible. DSA and AdaDSA are universally applicable to various deep sleep staging networks that have BN layers. We have validated the proposed methods by extensive experiments on two state-of-the-art deep sleep staging networks, DeepSleepNet+ and U-time. The performance was evaluated by conducting various transfer tasks on six sleep databases, including two large-scale databases, MASS and SHHS, as the source domain, four small sleep databases as the target domain. Thereinto, clinical sleep records acquired in Huashan Hospital, Shanghai, were used. The results show that both DSA and AdaDSA could significantly improve the performance of source models on target domains, providing novel insights into the domain generalization problem in sleep staging tasks.


Hypothesis on the mechanism of erythrocyte invasion by malaria merozoites.
Plasmodium knowlesi merozoites invade erythrocytes by a sequence of events: attachment, widespread deformation of the erythrocyte membrane, endocytosis, and resealing of the membrane and vesicle. The possible mechanisms by which these events occur are discussed. In particular, there is a detailed discussion of the role of the Duffy blood group system in invasion.


Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically with BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells.
JAK2-V617F plays a key role in the pathogenesis of myeloproliferative neoplasm. However, its inhibitor ruxolitinib has shown limited clinical efficacies because of the ruxolitinib-persistent proliferation of JAK2-V617F-positive cells. We here demonstrate that the USP9X inhibitor WP1130 or EOAI3402143 (G9) inhibited proliferation and induced apoptosis more efficiently in cells dependent on JAK2-V617F than on cytokine-activated JAK2. WP1130 preferentially downregulated activated and autophosphorylated JAK2-V617F by enhancing its K63-linked polyubiquitination and inducing its aggresomal translocation to block downstream signaling. Furthermore, JAK2-V617F associated physically with USP9X in leukemic HEL cells. Induction of apoptosis by inhibition of USP9X was mediated through the intrinsic mitochondria-mediated pathway, synergistically enhanced by BH3 mimetics, prevented by overexpression of Bcl-xL, and required oxidative stress to activate stress-related MAP kinases p38 and JNK as well as DNA damage responses in HEL cells. Although autophosphorylated JAK2-V617F was resistant to WP1130 in the ruxolitinib-persistent HEL-R cells, these cells expressed Bcl-2 and Bcl-xL at lower levels and showed an increased sensitivity to WP1130 as well as BH3 mimetics as compared with ruxolitinib-naive HEL cells. Thus, USP9X represents a promising target along with anti-apoptotic Bcl-2 family members for novel therapeutic strategies against JAK2-V617F-positive myeloproliferative neoplasms, particularly under the ruxolitinib persistence conditions.


Allelic loss in locally metastatic, multisampled prostate cancer.
In order to determine whether retention or loss of potential tumor suppressor loci that map to 8p, 10q, or 16q reflect genetic relationships among prostatic intraepithelial neoplasias (PINs), multicentric primary prostatic cancers, and regional lymph node metastases or are associated with the metastatic phenotype, we analyzed 19 cases of locally metastatic prostate carcinoma (stage D1) utilizing polymerase chain reaction techniques. In each case, tissue samples from metastatic tumor, the (dominant) primary tumor, and nonneoplastic prostatic tissue were examined. In selected cases, allelic loss in additional tumor foci, separate from the dominant tumor nodule, and areas of PIN were examined. Allelic loss of sequences on 8p, 10q, and 16q were observed in 20-29% of PINs, 18-42% of primary tumors, and 8-25% of metastatic tumors. Discrepancies in sequence dosage between histological components were most pronounced for 8p sequences, especially between the dominant tumor nodule and metastatic deposits in cases in which > or = 3 separate tumor foci/gland were identified. These results suggest that putative premalignant lesions, moderately or poorly differentiated, geographically separate primary tumor foci, and metastases within morphologically "complex" prostates (those with > or = 3 foci/gland) are likely to be more discordant for sequence dosage at 8p than those within "simpler" glands (< 3 foci/gland). Also, our results suggest that lymph node metastases may be genetically related to either the dominant or additional primary tumor foci in more complex prostates and that accumulation of genetic aberration may differ in primary and metastatic lesions.


Infant treatment decisions: ethics and cost.
Though society has been conditioned to believe that cost should not enter into medical care decisions, moral reasons do exist for considering cost in treatment decisions. Ethicists traditionally have distinguished between ordinary, or morally obligatory, means of preserving life and extraordinary, or morally optional, means. Treatment that offers a reasonable hope of benefit to the patient without excessive pain, expense, or other inconvenience would be considered ethically ordinary. Treatment that can not be obtained without excessive expense, which could greatly burden the patient's family and deprive them of other goods, could be legitimately withheld. The principle of proportionality, which requires balancing the probability and extent of potential harm against the probability and extent of good, also has been applied to medical care decisions. It has been used to focus attention on the cost of technologies and policies. Some have argued, however, that the individual patient--not a larger social good--should be the physician's only concern. Society should recognize that doing everything possible to save everyone who might survive leaves fewer resources to meet the needs of the poor and the disadvantaged. One way to limit the costs of intensive care, therefore, would be to limit the availability of neonatal treatment facilities. Infants would thus have to be selected for treatment according to prospects for survival or other medical indicators. Before society cuts back on infant care, however, it must address the question of justice. Since many low-birth weight babies are born to poor families, withholding infant treatment in some cases might increase, rather than reduce, the inequalities that already exist in health care delivery.(ABSTRACT TRUNCATED AT 250 WORDS)


[Regulation of the mitochondrial ATP-sensitive potassium channel in rat uterus cells by ROS].
In previous study we demonstrated the presence of ATP-sensitive potassium current in the inner mitochondrial membrane, which was sensitive to diazoxide and glybenclamide, in mitochondria isolated from the rat uterus. This current was supposed to be operated by mitochondrial ATP-sensitive potassium channel (mitoK(ATP)). Regulation of the mitoK(ATP) in uterus cells is not studied well enough yet. It is well known that the reactive oxygen species (ROS) can play a dual role. They can damage cells in high concentrations, but they can also act as messengers in cellular signaling, mediating survival of cells under stress conditions. ROS are known to activate mitoK(ATP) during the oxidative stress in the brain and heart, conferring the protection of cells. The present study examined whether ROS mediate the mitoK(ATP) activation in myometrium cells. Oxidative stress was induced by rotenone. ROS generation was measured by 2',7'-dichlorofluorescin diacetate. The massive induction of ROS production was demonstrated in the presence of rotenone. Hyperpolarization of the mitochondrial membrane was also detected with the use of the potential-sensitive dye DiOC6 (3,3'-dihexyloxacarbocyanine iodide). Diazoxide, a selective activator of mitoK(ATP), depolarized mitochondrial membrane either under oxidative stress or under normal conditions, while mitoK(ATP) blocker glybenclamide effectively restored mitochondrial potential in rat myocytes. Estimated <K1/2> value for diazoxide to mitoK(ATP) under normoxia was four times higher than under oxidative stress conditions: 5.01 +/- 1.47-10(-6) M and 1.24 +/- 0.21 x 10(-6) M respectively. The ROS scavenger N-acetylcysteine (NAC) successfully eliminates depolarization of mitochondrial membrane by diazoxide under oxidative stress. These results suggest that elimination of ROS by NAC prevents the activation of mitoK(ATP) under oxidative stress. Taking into account the higher affinity of diazoxide to mitoK(ATP) under stress conditions than under normoxia, we conclude that the oxidative stress conditions are more favourable than normoxia for the activation of mitoK(ATP). Thus we hypothesize that the ROS regulate the activity of the mitoK(ATP) in myocytes.


Rapid-learning system for cancer care.
Compelling public interest is propelling national efforts to advance the evidence base for cancer treatment and control measures and to transform the way in which evidence is aggregated and applied. Substantial investments in health information technology, comparative effectiveness research, health care quality and value, and personalized medicine support these efforts and have resulted in considerable progress to date. An emerging initiative, and one that integrates these converging approaches to improving health care, is "rapid-learning health care." In this framework, routinely collected real-time clinical data drive the process of scientific discovery, which becomes a natural outgrowth of patient care. To better understand the state of the rapid-learning health care model and its potential implications for oncology, the National Cancer Policy Forum of the Institute of Medicine held a workshop entitled "A Foundation for Evidence-Driven Practice: A Rapid-Learning System for Cancer Care" in October 2009. Participants examined the elements of a rapid-learning system for cancer, including registries and databases, emerging information technology, patient-centered and -driven clinical decision support, patient engagement, culture change, clinical practice guidelines, point-of-care needs in clinical oncology, and federal policy issues and implications. This Special Article reviews the activities of the workshop and sets the stage to move from vision to action.


Near-infrared fluorescence image-guidance in anastomotic colorectal cancer surgery and its relation to serum markers of anastomotic leakage: a clinical pilot study.
Near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) might help reduce anastomotic leakage (AL) after colorectal surgery. This pilot study aims to analyze whether a relation exists between measured fluorescence intensity (FI) and postoperative inflammatory markers of AL, C-reactive protein (CRP), Intestinal fatty-acid binding protein (I-FABP), and calprotectin, to AL, in order to evaluate the potential of FI to objectively predict AL. Patients scheduled for anastomotic colorectal cancer surgery were eligible for inclusion in this prospective pilot study. During surgery, at three time points (after bowel devascularization; before actual transection; after completion of anastomosis) a bolus of 0.2 mg/kg ICG was administered intravenously for assessment of bowel perfusion. FI was scored in scale from 1 to 5 based on the operating surgeon's judgment (1 = no fluorescence visible, 5 = maximum fluorescent signal). The complete surgical procedure was digitally recorded. These recordings were used to measure FI postoperatively using OsiriX imaging software. Serum CRP, I-FABP, and calprotectin values were determined before surgery and on day 1, 3, and 5 postoperative; furthermore, the occurrence of AL was recorded. Thirty patients (n = 19 males; mean age 67 years; mean BMI 27.2) undergoing either laparoscopic or robotic anastomotic colorectal surgery were included. Indication for surgery was rectal-(n = 10), rectosigmoid-(n = 2), sigmoid-(n = 10), or more proximal colon carcinomas (n = 8). Five patients (16.7%) developed AL (n = 2 (6.6%) grade C according to the definition of the International Study group of Rectal Cancer). In patients with AL, the maximum fluorescence score was given less often (P = 0.02) and a lower FI compared to background FI was measured at 1st assessment (P = 0.039). However, no relation between FI and postoperative inflammatory parameters could be found. Both subjective and measured FI seem to be related to AL. In this study, no relation between FI and inflammatory serum markers could yet be found.


PKCdelta modulates p21WAF1/CIP1 ability to bind to Cdk2 during TNFalpha-induced apoptosis.
Cyclin-dependent kinase 2 (Cdk2) activity is thought to be involved in cell death-associated chromatin condensation and other manifestations of apoptotic death. Here we show that during TNFalpha-induced apoptosis, PKCdelta is activated in a caspase-3-dependent manner and phosphorylates p21(WAF1/CIP1), a specific cyclin-dependent kinase inhibitor, on (146)Ser. This residue is located near a cyclin-binding motif (Cy2) that plays an important role in the interaction between p21(WAF1/CIP1) and Cdk2, and its phosphorylation modulates the ability of p21(WAF1/CIP1) to associate with Cdk2. The phosphorylation of p21(WAF1/CIP1) is temporally related to the activation kinetics of Cdk2 activity during the apoptosis. We propose that during TNFalpha-induced apoptosis, PKCdelta-mediated phosphorylation of p21(WAF1/CIP1) at (146)Ser attenuates the Cdk2 binding of p21(WAF1/CIP1) and thereby upregulates Cdk2 activity.


Harnessing Event Report Data to Identify Diagnostic Error During the COVID-19 Pandemic.
COVID-19 exposed systemic gaps with increased potential for diagnostic error. This project implemented a new approach leveraging electronic safety reporting to identify and categorize diagnostic errors during the pandemic. All safety event reports from March 1, 2020, to February 28, 2021, at an academic medical center were evaluated using two complementary pathways (Pathway 1: all reports with explicit mention of COVID-19; Pathway 2: all reports without explicit mention of COVID-19 where natural language processing [NLP] plus logic-based stratification was applied to identify potential cases). Cases were evaluated by manual review to identify diagnostic error/delay and categorize error type using a recently proposed classification framework of eight categories of pandemic-related diagnostic errors. A total of 14,230 reports were included, with 95 (0.7%) identified as cases of diagnostic error/delay. Pathway 1 (n = 1,780 eligible reports) yielded 45 reports with diagnostic error/delay (positive predictive value [PPV] = 2.5%), of which 35.6% (16/45) were attributed to pandemic-related strain. In Pathway 2, the NLP-based algorithm flagged 110 safety reports for manual review from 12,450 eligible reports. Of these, 50 reports had diagnostic error/delay (PPV = 45.5%); 94.0% (47/50) were related to strain. Errors from all eight categories of the taxonomy were found on analysis. An event reporting-based strategy including use of simple-NLP-identified COVID-19-related diagnostic errors/delays uncovered several safety concerns related to COVID-19. An NLP-based approach can complement traditional reporting and be used as a just-in-time monitoring system to enable early detection of emerging risks from large volumes of safety reports.


Heart Failure and Pancreas Exocrine Insufficiency: Pathophysiological Mechanisms and Clinical Point of View.
Heart failure is associated with decreased tissue perfusion and increased venous congestion that may result in organ dysfunction. This dysfunction has been investigated extensively for many organs, but data regarding pancreatic (exocrine) dysfunction are scarce. In the present review we will discuss the available data on the mechanisms of pancreatic damage, how heart failure can lead to exocrine dysfunction, and its clinical consequences. We will show that heart failure causes significant impairment of pancreatic exocrine function, particularly in the elderly, which may exacerbate the clinical syndrome of heart failure. In addition, pancreatic exocrine insufficiency may lead to further deterioration of cardiovascular disease and heart failure, thus constituting a true vicious circle. We aim to provide insight into the pathophysiological mechanisms that constitute this reciprocal relation. Finally, novel treatment options for pancreatic dysfunction in heart failure are discussed.


Radical excision of intramedullary cavernous angiomas.
This is a retrospective study of patients with surgically treated, intramedullary cavernous malformations. We conducted the study to elucidate the outcomes of the patients, as well as potential pitfalls in their care. A series of 12 patients underwent radical excision of intramedullary cavernous malformations between 1986 and 1996. All lesions were diagnosed by magnetic resonance imaging. Although seven patients experienced recurrent episodes of pain and sensorimotor disturbances, the histories of the other five patients were relevant for slowly progressing deficits (mostly sensory). All cavernomas were completely resected. No deaths were recorded. In follow-up examinations (5-102 mo after discharge), there was no evidence of recurrence, either clinically or in control magnetic resonance imaging scans. In follow-up examinations, two patients demonstrated sensory deficits that were slightly more pronounced than the preoperative deficits. The postoperative neurological status of 3 of 12 patients was unchanged, compared with the preoperative status. The status of the remaining seven patients had improved. For four patients there was effective functional improvement, and for three others there was complete postoperative relief of pain. Deficits of the long tracts were less prone to recover. The clinical course of cavernous malformations may be difficult to distinguish from that of spinal dural arteriovenous malformations or focal demyelinating disease. In the latter case, even magnetic resonance imaging results could be deceptive. Radical resection of these malformations is feasible, with relatively low surgical morbidity, provided that the preoperative deficits of the patients are limited. Given the generally progressive course of the illness and the few acute catastrophic myelopathies, complete excision is advocated whenever malformations are symptomatic.


Role of extracorporeal shock wave lithotripsy in the treatment of pancreatic stones.
Calcifications in chronic pancreatitis are usually the result of chronic inflammation or altered metabolism. Calcifications can perpetuate the cycle of ductal obstruction and contribute to pain, worsening of pancreatic inflammation, ductal disruption, and deterioration of the exocrine and endocrine function of the gland. Removal of pancreatic duct calculi can reduce pain and improve glandular function. Purely endoscopic stone removal has limited success, because of stone location, burden, and presence of strictures in the pancreatic duct. Extracorporeal shock wave lithotripsy (ESWL) allows fragmentation of stones refractory to endoscopic methods and facilitates spontaneous stone passage or endoscopic removal. Among the various forms of lithotripters, none is clearly superior to the others. Current data suggest that ESWL is effective in complete duct clearance in up to 50% of patients and in duct decompression and symptomatic improvement in up to 70% of patients. ESWL should be considered as a useful adjunctive tool in the treatment of pancreatic duct calculi.


Association of increased pHi with calcium ion release in skeletal muscle.
The pH difference across the cell membrane of frog sartorius muscle cells was measured with the distribution of 5,5-dimethyl-2,4-oxazolidine-dione (DMO) as the marker. Depolarization of the muscles to values at or below the contraction threshold caused by elevating external potassium up to approximately 20 mM resulted in an internal alkalinization. The change was smaller with superthreshold depolarization (20--30 mM [K+]). The alkalinization was blocked by agents that block calcium release from the sarcoplasmic reticulum (procaine and dantrolene sodium). Other agents that cause calcium release (caffeine, theophylline, and quinine) were found to give alkalinization when tested at concentrations just below the contracture threshold. Increased acidification of the extracellular medium was associated with the internal alkalinization. The data were interpreted as indicating the presence of a calcium-stimulated H+ and/or OH- ion transport system in the muscle membrane.


Somatic and autonomic nerve density of the urethra, periurethral tissue, and anterior vaginal wall: an immunohistochemical study in adult female cadavers.
Retropubic procedures may disrupt nerves supplying the pelvic viscera; however, knowledge of pelvic neuroanatomy is limited. We sought to characterize somatic and autonomic nerve density within the urethra, periurethral tissue, and anterior vagina. Axial sections were obtained from pelvic tissue harvested from female cadavers ≤24 h from death at three anatomical levels: the midurethra, proximal urethra, and upper trigone. Periurethral/perivesical tissue was divided into medial and lateral sections, and the anterior vagina into middle, medial, and lateral sections. Double immunofluorescent staining for beta III tubulin (βIIIT), a global axonal marker, and myelin basic protein (MBP), a myelinated nerve marker, was performed. Threshold-based automatic image segmentation distinguished stained areas. Autonomic and somatic density were calculated as percentage of tissue stained with βIIIT alone, and with βIIIT and MBP respectively. Statistical comparisons were made using nonparametric Friedman tests. Six cadavers, aged 22-73, were examined. Overall, autonomic nerve density was highest at the midurethral level in the lateral and middle anterior vagina. Somatic density was highest in the external urethral sphincter (midurethra mean 0.15%, SD ±0.11; proximal urethra 0.19%, SD ±0.19). Comparison of annotated sections revealed significant differences in autonomic density among the lateral, medial, and middle vagina at the midurethra level (0.71%, SD ±0.48 vs 0.60%, SD ±0.48 vs 0.70%, SD ±0.63, p=0.03). Autonomic density was greater than somatic density in all sections. Autonomic and somatic nerves are diffusely distributed throughout the periurethral tissue and anterior vagina, with few significant differences in nerve density among sections analyzed. Minimizing tissue disruption near urethral skeletal muscle critical for urinary continence may prevent adverse postoperative urinary symptoms.


Autoimmune diseases in parents of children with infantile autism: a case-control study.
This register study compared the rates and types of autoimmune disease in the parents of 111 patients (82 males, 29 females; mean age at diagnosis 5y 5mo [SD 2y 6mo]) with infantile autism (IA) with a matched control group of parents of 330 children from the general population. All parents were screened through the nationwide Danish National Hospital Register. We inquired about 35 autoimmune diseases during an observation period of 27 years. At follow-up the case and control mothers were identical in age (65y 7mo [SDs 9y 7mo and 9y respectively]). For case and control fathers the figures were 70 years 2 months (SD 10y 2mo) and 69 years 1 month (SD 10y 1mo) respectively. A similar proportion of case and control mothers had a diagnosis of any autoimmune disease: 10.8% versus 9.1%. For case fathers the proportion was 8.6% versus 4.6%. Two autoimmune conditions were associated with IA: ulcerative colitis in mothers (p=0.05) and type 1 diabetes in fathers (p=0.02). Additional studies are required to determine whether there is a true association between a parental history of autoimmune disease and pervasive developmental disorder in their offspring.


Healthy Eating Index-2015 Is Associated with Grip Strength among the US Adult Population.
The Healthy Eating Index-2015 (HEI-2015) was designed to reflect adherence to the 2015-2020 Dietary Guidelines for Americans (DGA). The study aims to examine the association between HEI-2015 and grip strength in a nationally representative sample of the U.S. adult population. This cross-sectional study used data from the National Health and Nutrition Examination Surveys of 2011-2014. Low grip strength was defined as <35.5 kg for men and <20 kg for women. HEI-2015 was computed from two days of 24-h dietary recalls and comprised 13 components. Each component was scored on the density out of 1000 calories and summed to a total score divided into quartiles. Weighted logistic regressions examined the study aim while controlling for associated covariates. The sample included 9006 eligible participants, of those, 14.4% (aged 20+ years), and 24.8% (aged ≥50 years) had low grip strength. Mean (±SD) HEI-2015 total score was 54.2 ± 13.6 and in the lowest and highest quartiles 37.3 ± 5.1 and 72.0 ± 6.5, respectively. In the multivariable model, participants in the highest vs. lowest HEI-2015 quartile had 24% lower odds of having low grip strength (Odds Ratio (OR) = 0.76; 95% CI: 0.60-0.96). Specifically, participants who met the DGA for protein intakes, whole grains, greens and beans, vegetables, or whole fruits had 20-35% lower odds of having low grip strength than those who did not. Higher compliance to the DGA might reduce the risk for low grip strength as a proxy measure for sarcopenia among U.S. adults, particularly adequate intakes of proteins, whole grains, greens and beans, vegetables, and whole fruits.


[The cross-border hospitals in surgical treatment of soldiers and civilians wounded in local military conflicts].
The gunshot wounds in local military conflicts are the result of unstable flight of bullet with shifted center. The period of maximal transmission of energy is more and more reduced which results in the effect of interstitial explosion causing significant lesions of tissues and organs. Nowadays, the diagnostic opportunities of cross-border hospitals are significantly enlarged due to the introduction of endoscopic ultrasonography, magnetic resonance imaging, computer tomography and other methods of contemporary diagnosis. Health care organizers should take into account that in case of sufficient medical care and experienced personnel in cross-border hospitals it is possible to provide effective surgical aid to the wounded in the local military conflicts even if the hospitals are in transport blockade. Positive results in the treatment of more than 2000 wounded soldiers have been obtained.


Eyes Open on Sleep and Wake: In Vivo to In Silico Neural Networks.
Functional and effective connectivity of cortical areas are essential for normal brain function under different behavioral states. Appropriate cortical activity during sleep and wakefulness is ensured by the balanced activity of excitatory and inhibitory circuits. Ultimately, fast, millisecond cortical rhythmic oscillations shape cortical function in time and space. On a much longer time scale, brain function also depends on prior sleep-wake history and circadian processes. However, much remains to be established on how the brain operates at the neuronal level in humans during sleep and wakefulness. A key limitation of human neuroscience is the difficulty in isolating neuronal excitation/inhibition drive in vivo. Therefore, computational models are noninvasive approaches of choice to indirectly access hidden neuronal states. In this review, we present a physiologically driven in silico approach, Dynamic Causal Modelling (DCM), as a means to comprehend brain function under different experimental paradigms. Importantly, DCM has allowed for the understanding of how brain dynamics underscore brain plasticity, cognition, and different states of consciousness. In a broader perspective, noninvasive computational approaches, such as DCM, may help to puzzle out the spatial and temporal dynamics of human brain function at different behavioural states.


Effect of alpha-tocopherol on the production of malondialdehyde in rat tissue homogenates after hypobaric exposure.
Alpha-tocopherol content and production of malondialdehyde (MDA) was measured in liver, kidney, heart, lung, brain and skeletal muscle homogenates of control and hypoxic rats (following a 2-h-exposure to 200 mm Hg): the samples were incubated at 37 degrees C in air for 1 h. MDA production showed no relation with the content of alpha-tocopherol in control and hypoxic rats. In control animals, the lowest MDA level was found in lungs: it was several fold lower than in other tissues. After hypobaric exposure, a marked increase in MDA level could be observed in lungs only. No marked changes in alpha-tocopherol concentration could be observed in any of the tissues tested. A single i.p. injection of 25 and 50 mg/alpha-tocopherol acetate/kg body mass, 2 hours prior to the exposure produced organ-specific accumulation of alpha-tocopherol. Both doses of alpha-tocopherol resulted in a reduced (by about 40%) production of MDA in lung homogenates. The addition of alpha-tocopherol (750 nmol/g wet tissue mass) to homogenates from control and hypoxic rats prior to the incubation resulted in a marked inhibition of MDA production in all tissues (49-70%).


Self-reported mental health in children ages 6-12 years across eight European countries.
Worldwide, approximately one in eight children or adolescents suffers from a mental disorder. The present study was designed to determine the self-reported prevalence of mental health problems in children aged 6-11 years across eight European countries including Italy, France, Germany, the Netherlands, Lithuania, Bulgaria, Romania, and Turkey. Data were drawn from 6245 children participating in the School Children Mental Health in Europe (SCHME) study and a large cross-sectional survey in France. Self-reported child mental health was assessed using the Dominique Interactive (DI). Overall, 22.0% of children were identified per their own evaluation as having at least one mental disorder, ranging from 16.4% in the Netherlands to 27.9% in Bulgaria. The prevalence of internalizing disorders was 18.4% across countries and ranged from 11.8% in the Netherlands to 24.3% in Turkey. The prevalence of externalizing disorders was lower with an average of 7.8%, ranging from 3.5% in Turkey to 10.5% in Bulgaria. Combining samples across European countries, 1 in 5 children reported internalizing problems and 1 in 12 children externalizing problems. The net completion rates of 4.1-74.3% preclude conclusions about national differences in prevalence rates.


Genetic determinants and molecular pathways in the pathogenesis of Type 2 diabetes.
T2DM (Type 2 diabetes mellitus) has reached epidemic proportions worldwide, exerting major health consequences at an individual and public health level alike. Unfortunately, the molecular pathophysiology of diabetes remains incompletely understood, impairing progress towards more effective prevention and treatment strategies. Although the rapid increase in the prevalence of insulin resistance and T2DM over the past several decades highlights a major environmental contribution related to overnutrition, obesity and inactivity, susceptibility is likely to reflect individual differences in complex gene-environment interactions. In the present review, we focus on mediators of genetic and environmental risk for T2DM at a molecular level.


Hypoglycemic and pancreatic protective effects of Portulaca oleracea extract in alloxan induced diabetic rats.
Diabetes is a major public health concern. In spite of continuous new drug development to treat diabetes, herbal remedies remain a potential adjunct therapy to maintain better glycemic control while also imparting few side-effects. Portulaca oleracea has been traditionally used to manage several diseases due to the anti-oxidant and anti-atherogenic effects it imparts. To better understand the mechanisms associated with potential protective effect of P. oleracea extract against diabetes, alloxan-induced diabetic rats were used in this study. Forty Wistar rats (male, 7-8-wk-old, 140-160 g) were divided into four groups (n = 10/group): Group I (control), Group II (P. oleracea-treated; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks), Group III (diabetic control; daily IP injection of alloxan [at 75 mg/kg] for 5 days) and Group IV (P. oleracea-pre-treated diabetic; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks and then daily IP injection of alloxan [at 75 mg/kg] for 5 days). Body weight, food consumption, blood (serum) levels of glucose, C peptide, Hb A1C, insulin, tumor necrosis factor (TNF)-α and interleukin (IL)-6 were determined for all groups. The results indicated that while Hb A1C, serum levels of glucose, TNF-α and IL-6 were all significantly decreased in the P. oleracea-pre-treated diabetic rats, these hosts also had significant increases in C peptide and insulin compared to levels in the counterpart diabetic rats. These results were confirmed by the histopathological assessments which showed marked improvement of the destructive effect on pancreatic islet cells induced by alloxan. P. oleracea extract is a general tissue protective and regeneartive agent, as evidenced by increasing β-cell mass and therefore improved the glucose metabolism. Thus, stimulation of Portulaca oleracea signaling in β- cells may be a novel therapeutic strategy for diabetes prevention.


Role of the regulatory domain of protein kinase D2 in phorbol ester binding, catalytic activity, and nucleocytoplasmic shuttling.
Protein kinase D2 (PKD2) belongs to the PKD family of serine/threonine kinases that is activated by phorbol esters and G protein-coupled receptors (GPCRs). Its C-terminal regulatory domain comprises two cysteine-rich domains (C1a/C1b) followed by a pleckstrin homology (PH) domain. Here, we examined the role of the regulatory domain in PKD2 phorbol ester binding, catalytic activity, and subcellular localization: The PH domain is a negative regulator of kinase activity. C1a/C1b, in particular C1b, is required for phorbol ester binding and gastrin-stimulated PKD2 activation, but it has no inhibitory effect on the catalytic activity. Gastrin triggers nuclear accumulation of PKD2 in living AGS-B cancer cells. C1a/C1b, not the PH domain, plays a complex role in the regulation of nucleocytoplasmic shuttling: We identified a nuclear localization sequence in the linker region between C1a and C1b and a nuclear export signal in the C1a domain. In conclusion, our results define the critical components of the PKD2 regulatory domain controlling phorbol ester binding, catalytic activity, and nucleocytoplasmic shuttling and reveal marked differences to the regulatory properties of this domain in PKD1. These findings could explain functional differences between PKD isoforms and point to a functional role of PKD2 in the nucleus upon activation by GPCRs.


Weather as a risk factor for epileptic seizures: A case-crossover study.
Most epileptic seizures occur unexpectedly and independently of known risk factors. We aimed to evaluate the clinical significance of patients' perception that weather is a risk factor for epileptic seizures. Using a hospital-based, bidirectional case-crossover study, 604 adult patients admitted to a large university hospital in Central Germany for an unprovoked epileptic seizure between 2003 and 2010 were recruited. The effect of atmospheric pressure, relative air humidity, and ambient temperature on the onset of epileptic seizures under temperate climate conditions was estimated. We found a close-to-linear negative correlation between atmospheric pressure and seizure risk. For every 10.7 hPa lower atmospheric pressure, seizure risk increased in the entire study population by 14% (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.01-1.28). In patients with less severe epilepsy treated with one antiepileptic medication, seizure risk increased by 36% (1.36, 1.09-1.67). A high relative air humidity of >80% increased seizure risk in the entire study population by up to 48% (OR 1.48, 95% CI 1.11-1.96) 3 days after exposure in a J-shaped association. High ambient temperatures of >20°C decreased seizure risk by 46% in the overall study population (OR 0.54, 95% CI 0.32-0.90) and in subgroups, with the greatest effects observed in male patients (OR 0.33, 95% CI 0.14-0.74). Low atmospheric pressure and high relative air humidity are associated with an increased risk for epileptic seizures, whereas high ambient temperatures seem to decrease seizure risk. Weather-dependent seizure risk may be accentuated in patients with less severe epilepsy. Our results require further replication across different climate regions and cohorts before reliable clinical recommendations can be made.


Healthcare use of families of injured workers before and after a workplace injury in british columbia, Canada.
To examine the overall healthcare and mental healthcare services use of families of injured workers before and after a workplace injury. We use an administrative database that links individual publicly funded healthcare data and Workers' Compensation Board (WCB) data for the entire population of British Columbia (BC), Canada. The spouses and children of all injured workers who filed a WCB claim in 1994 and missed one or more days of work due to the injury (lost time) were included. We compare their change in use of healthcare services relative to a year before the injury to families of workers who did not require time off for their injuries (no lost time) and families of individuals who were not injured (non-injured comparisons). Differences in healthcare services use among the three groups of spouses were marginal, and differences for increases in mental healthcare services use were non-significant. As well, all three groups of children decreased their use of physician and hospital services and increased their use of mental healthcare services, with very little difference among groups. This was a descriptive study looking at a broad group of injured workers and their families. Even modest increases in healthcare use following a workplace injury have some basis for further study.


Maternal nano-titanium dioxide inhalation alters fetoplacental outcomes in a sexually dimorphic manner.
The placenta plays a critical role in nutrient-waste exchange between the maternal and fetal circulations, thus functioning as an interface that profoundly impacts fetal growth and development. The placenta has long been considered an asexual organ, but, due to its embryonic origin it shares the same sex as the fetus. Exposures to toxicant such as diesel exhaust, have been shown to result in sexually dimorphic outcomes like decreased placental mass in exposed females. Therefore, we hypothesize that maternal nano-TiO2 inhalation exposure during gestation alters placental hemodynamics in a sexually dimorphic manner. Pregnant Sprague-Dawley rats were exposed from gestational day 10-19 to nano-TiO2 aerosols (12.17 ± 1.69 mg/m3) or filtered air (sham-control). Dams were euthanized on GD20, and fetal tissue was collected based on fetal sex: whole placentas, placental junctional zone (JZ), and placental labyrinth zone (LZ). Fetal mass, placental mass, and placental zone percent areas were assessed for sex-based differences. Exposed fetal females were significantly smaller compared to their exposed male counterparts (2.65 ± 0.03 g vs 2.78 ± 0.04 g). Nano-TiO2 exposed fetal females had a significantly decreased percent junctional zone area compared to the sham-control females (24.37 ± 1.30% vs 30.39 ± 1.54%). The percent labyrinth zone area was significantly increased for nano-TiO2 females compared to sham-control females (75.63 ± 1.30% vs 69.61 ± 1.54%). Placental flow and hemodynamics were assessed with a variety of vasoactive substances. It was found that nano-TiO2 exposed fetal females only had a significant decrease in outflow pressure in the presence of the thromboxane (TXA2) mimetic, U46619, compared to sham-control fetal females (3.97 ± 1.30 mm Hg vs 9.10 ± 1.07 mm Hg) and nano-TiO2 fetal males (9.96 ± 0.66 mm Hg). Maternal nano-TiO2 inhalation exposure has a greater effect on fetal female mass, placental zone mass and area, and adversely impacts placental vasoreactivity. This may influence the female growth and development later in life, future studies need to further study the impact of maternal nano-TiO2 inhalation exposure on zone specific mechanisms.


Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis.
A variant of hepatitis B virus has been described recently in HBsAg+ Mediterranean patients who lack HBeAg and who have an unusual and severe form of chronic hepatitis. This variant is unable to produce HBeAg because of the presence of a novel translational stop codon at the end of the precore region of the genome. By direct sequencing of DNA, generated by the polymerase chain reaction, we have evaluated the association between infection with this variant and the fulminant course of hepatitis B. Eighteen patients with fulminant hepatitis B were studied. Of the 15 cases from whose serum viral DNA could be sequenced, the variant was found in the admission sera of 8 of 9 HBeAg- patients but in none of 6 HBeAg+ patients who had fulminant hepatitis B. Patients harboring the variant progressed more rapidly into hepatic encephalopathy, but those infected with the variant strain alone had a greater likelihood of survival than those infected with the normal strain or a mixture. The mutant strain may emerge spontaneously during fulminant hepatitis as occurs in chronic hepatitis B infection during seroconversion from HBeAg to antibody. Alternately, and perhaps less commonly, patients may be infected with the variant ab initio.


The utility of MRCP in preoperative mapping of biliary anatomy in adult-to-adult living related liver transplant donors.
To assess the utility of magnetic resonance cholangiopancreatography (MRCP) in preoperative mapping of biliary anatomy in adult-to-adult living related liver transplant (LRLT) donors. From 57 potential donors with preoperative MRCP, 27 cases (16 men, 11 women, age range 22-51 years, mean 37.2 years) underwent right lobe resection and had intraoperative cholangiography (IOC) for comparison. The MRCP and IOC reports were retrospectively reviewed in all 27 cases. The MRCP was performed on 1.5 Tesla MR magnets using breath-hold heavily T2-weighted sequences in axial/coronal thin sections, and variable-thickness rotating slabs. The accuracy of preoperative MRCP for biliary mapping in potential LRLT donors was analyzed compared to the IOC findings. Of 27 donors, 26 (96.3%) had MRCP which showed adequate information of central intrahepatic biliary anatomy. Of these, 19 had normal bifurcation confirmed by IOC, and single biliary anastomosis was created in the recipient at transplantation. MRCP correctly predicted 17 of 19 normal cases (sensitivity for normals: 89.5%). In seven donors with variant biliary anatomy, two separate biliary anastomoses were performed in the recipient. MRCP correctly predicted five of seven variants (sensitivity for variants: 71.4%). Overall, MRCP had an accuracy 84.6% (22/26). MRCP has potential in the preoperative assessment of nondilated bile ducts in LRLT donors, however further improvements are desired to increase its quality and accuracy.


Clinical supervision in the palliative care team setting: a concrete approach to team wellness.
Clinical supervision is a structured, case-based approach to learning that is used most often in the mental health field. An established palliative care consultation service at a large, academic medical center implemented a modified clinical supervision model in an effort to improve team members' awareness of their own emotions and the way those emotions impact behavior during, primarily, clinical encounters. This report discusses clinical supervision in detail and, by way of a case, illustrates the power of this intervention as a source of self-care and a concrete approach to managing palliative care team well-being.


Evaluation of an experimental Ti-Co alloy for dental restorations.
Precision and surface quality of pure titanium (Ti) castings for dental and biomedical uses are limited because of the high melting temperature and the violent reactivity of Ti with mold materials during casting procedures. This feasibility study evaluates an experimental low-melting Ti-Co alloy in term of its microstructure and physical and mechanical properties. Tensile samples of Ti-12 wt % Co alloy were cast under a protective argon atmosphere. The melting range of the cast samplers was determined. Cast samples were annealed at 1010°C for various time intervals in order to homogenize microstructures. Microstructures were examined by optical and scanning electron microscopy. Tensile strength and microhardness tests were performed and correlated with microstructures resulting from annealing processes. Ti2Co intermetallic compound coexisted with Ti-Co solid solution in all samples. The melting range of the alloy was 1062-1088°C, which is 568°C lower than that of Ti. The thickness of the surface oxide scale on cast samples was dramatically reduced to 1-3 μm because of the low-melting nature of the alloy. Solution treatment at 1010°C for 100 h yields the highest tensile strength. Ultimate tensile strength is measured from 852 to 1240 MPa which is stronger than currently used dental alloys. Microhardness values were ranged from 341 to 488 KHN and elongation was from 1.2 to 1.8%. Both microhardness and percentage elongation are similar to those of dental Co-Cr alloys. One hundred hours of annealing dissolved dendritic boundaries and transformed the alloy to a more microductitle matrix, however, the intermetallic compound of Ti2Co remained.