The effect of the ageing of crime scene objects on the results of scent identification line-ups using trained dogs.
In a scent identification line-up, a trained dog matches the scent trace left by a perpetrator at the crime scene to the odour of a suspect in a line-up of different odours. The procedures are strictly defined and the results are routinely used by the police and as evidence in court in a number of European countries. This paper describes the effect of ageing of the odour trace collected at the crime scene on the performance of the dogs in recognising the perpetrator in a line-up. The results show that whilst the dogs perform faultlessly in matching odours collected on the same day, the results drop to a lower level and become more variable in the period studied (2 weeks to 6 months). However, the results do not show a systematic decrease in performance. A possible explanation is the development of a steady state in the glass jars containing the perpetrator odour trace after initial differential evaporation of components of the residue or break down of unsaturated components into saturated ones. Prevention of this initial change may prevent the drop in performance observed in this study, thus increasing the reliability of these scent identifications.


Is rTMS an effective therapeutic strategy that can be used to treat anxiety disorders?
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive procedure whereby a pulsed magnetic field stimulates electrical activity in the brain. Anxiety disorders are the most common of all mental health problems for which effective, mechanism-based treatments remain elusive. Consequently, more advanced non-invasive therapeutic methods are required. A possible method to modulate brain activity and potentially viable for use in clinical practice is rTMS. Here, we focus on the main findings of rTMS from animal models of anxiety and the experimental advances of rTMS that may become a viable clinical application to treat anxiety disorders, one of the most common causes of disability in the workplace in the world. Key advances in combining rTMS with neuroimaging technology may aid such future developments. This article is part of a Special Issue entitled 'Anxiety and Depression'.


Clues to the aetiology and pathogenesis of herpes gestationis.
In a study of twenty-five patients with herpes gestationis we found that 80% possessed the HLA antigen DR3, which confers increased immune responsiveness and a predisposition to 'auto-immune disease'. In five patients the development of herpes gestationis coincided with a change in sexual partner, suggesting that the development of herpes gestationis may depend on exposure to an antigen derived from the father. This might share determinants with a component of the basement membrane zone of skin. Although anti-basement membrane zone antibodies are present in HG it is not clear whether they play a pathogenic role. The infrequency of neonatal involvement and the lack of correlation between immunofluorescence findings and clinical activity in our patients suggested that the antibodies might be a result of tissue damage rather than its cause. Two patients in our study were exceptional in that episodes of herpes gestationis were followed by normal pregnancies. In these patients the relationship of their DR antigens to those of the fetus may have been important in determining whether or not the pregnancy would be affected by herpes gestationis.


Specificity studies on Kallikrein-related peptidase 7 (KLK7) and effects of osmolytes and glycosaminoglycans on its peptidase activity.
KLK7 substrate specificity was evaluated by families of fluorescence resonance energy transfer (FRET) peptides derived from Abz-KLFSSK-Q-EDDnp (Abz=ortho-aminobenzoic acid and Q-EDDnp=glutaminyl-N-[2,4-dinitrophenyl] ethylenediamine), by one bead-one peptide FRET peptide library in PEGA resin, and by the FRET peptide libraries Abz-GXX-Z-XX-Q-EDDnp (Z and X are fixed and random natural amino acids, respectively). KLK7 hydrolyzed preferentially F, Y or M, and its S1' and S2' subsites showed selectivity for hydrophilic amino acids, particularly R and K. This set of specificities was confirmed by the efficient kininogenase activity of KLK7 on Abz-MISLM(↓)KRPPGFSPF(↓)RSSRI-NH2 ((↓)indicates cleavage), hydrolysis of somatostatin and substance P and inhibition by kallistatin. The peptide Abz-NLY(↓)RVE-Q-EDDnp is the best synthetic substrate so far described for KLK7 [kcat/Km=455 (mMs)(-1)] that was designed from the KLK7 substrate specificity analysis. It is noteworthy that the NLYRVE sequence is present in human semaphorin 6B. KLK7 is activated by GAGs, inhibited by neutral salts, and activated by high concentration of kosmotropic salt. Pyroglutamic acid inhibited KLK7 (Ki=33mM) and is present in skin moisturizing factor (124mM). The KLK7 specificity described here and elsewhere reflects its participation in patho-physiological events in skin, the gastrointestinal tract and central nervous system, where KLK7 is significantly expressed.


Effect of growth hormone deficiency and recombinant hGH (rhGH) replacement on the hypothalamic-pituitary-adrenal axis in children with idiopathic isolated GH deficiency.
Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11beta-hydroxysteroid dehydrogenase type 1 isoenzyme (11betaHSD1) activity and reducing cortisone to cortisol conversion. The aim of the present study was to evaluate the hypothalamic-pituitary-adrenal (HPA) axis in children with idiopathic isolated GHD and normal pituitary magnetic resonance imaging (MRI) both before and during rhGH therapy. This was a single-centre study of 10 consecutive children [five males and five females, mean age: 12.2 +/- 1.0 year]. Evaluation was performed at baseline and on rhGH (mean duration: 10.9 +/- 2.9 months, mean dose: 0.030 +/- 0.002 mg/kg bw/day). HPA function was assessed by serum cortisol levels before and after appropriate provocative stimuli, that is, 1 microg ACTH test (N = 5 patients) or insulin tolerance test (ITT, N = 5 patients), evaluating all children with the same stimulation test both before and during rhGH therapy. Central hypoadrenalism was excluded by the presence of either a peak of > 500 nmol/l or a rise in cortisol levels of > 200 nmol/l, after both tests. On rhGH therapy, serum IGF-I levels normalized, while serum cortisol and ACTH levels did not significantly differ from those recorded at baseline. The mean serum cortisol peak after both provocative tests was not significantly different on rhGH therapy and at baseline (498 +/- 41 vs. 580 +/- 35 nmol/l, respectively, P = 0.06), the mean cortisol rise being 280 +/- 45 and 270 +/- 36 nmol/l on rhGH and at baseline, respectively. According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism.


Effect of graphene oxide flakes size and number of layers on photocatalytic hydrogen production.
The present study explored the correlation between the photocatalytic activity toward hydrogen production of the graphene-based materials and graphene oxide (GO) morphology. In this work we applied the technique based on the combination of time-dependent sonication and iterative centrifugation cascades, which were designed to achieve nanosheets size and the number of layers selection. First such obtained GO dispersions were characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM) and optical spectroscopy. Those combined measurements showed that the intensity of the π-π peak at 230 nm seems to be very sensitive to the number of layers of nanosheets. Next, GO dispersions were used to establish influence of the size and the number of layers of GO flakes on the photocatalytic hydrogen production in the photocatalytic system, containing eosin Y as a sensitizer, triethanolamine as a sacrificial electron donor, and CoSO4 as precatalyst. The H2 production efficiency varied by a factor of 3.7 for GO dispersions sonicated for various amount of time. Interestingly it was found that too long ultrasound treatment had negative impact on the GO enhancement of hydrogen production which was related to the fragmentation of GO flakes. The photocatalytic system produced the highest amount of H2 when graphene oxide occurs as monolayers and efficiency becomes lower with the decrease of GO sheets size. Our results demonstrate the importance of optimizing the size and the number of layers of the GO flakes prior to preparation of GO-based materials.


Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.
The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.


Alcohol and simple reaction time in a vigilance setting: a placebo control study.
The present study tested whether earlier reported effects of alcohol on simple auditory and visual reaction time in a vigilance setting should be attributed to the pharmacological properties of alcohol or to subjects' expectancies as to the acute effects of alcohol. Results indicated that an expectancy interpretation can be excluded.


Development of Gene Expression-Based Random Forest Model for Predicting Neoadjuvant Chemotherapy Response in Triple-Negative Breast Cancer.
Neoadjuvant chemotherapy (NAC) response is an important indicator of patient survival in triple negative breast cancer (TNBC), but predicting chemosensitivity remains a challenge in clinical practice. We developed an 86-gene-based random forest (RF) classifier capable of predicting neoadjuvant chemotherapy response (pathological Complete Response (pCR) or Residual Disease (RD)) in TNBC patients. The performance of pCR classification of the proposed model was evaluated by Receiver Operating Characteristic (ROC) curve and Precision Recall (PR) curve. The AUROC and AUPRC of the proposed model on the test set were 0.891 and 0.829, respectively. At a predefined specificity (>90%), the proposed model shows a superior sensitivity compared to the best performing reported NAC response prediction model (69.2% vs. 36.9%). Moreover, the predicted pCR status by the model well explains the distance recurrence free survival (DRFS) of TNBC patients. In addition, the pCR probabilities of the proposed model using the expression profiles of the CCLE TNBC cell lines show a high Spearman rank correlation with cyclophosphamide sensitivity in the TNBC cell lines (SRCC =0.697, p-value =0.031). Associations between the 86 genes and DNA repair/cell cycle mechanisms were provided through function enrichment analysis. Our study suggests that the random forest-based prediction model provides a reliable prediction of the clinical response to neoadjuvant chemotherapy and may explain chemosensitivity in TNBC.


A comparative study on the use of selective media for the enumeration of Clostridium perfringens in poultry faeces.
Isolation and fast detection of Clostridium perfringens is essential in veterinary medical diagnostics and veterinary research, as it allows to recommend suitable treatment options after antimicrobial resistance determination, and is essential to study pathogenesis. In this study four selective media were tested for the enumeration of, and selectivity towards C. perfringens in faecal samples from poultry. The routinely used Columbia agar with 5% sheep (CBA), Shahidi-Ferguson-perfringens agar (SFP), tryptose sulphite cycloserine agar (TSC), and a novel chromogenic medium, CHROMagar™ C. perfringens (CHCP), were tested. Overall, no difference in C. perfringens recovery could be observed between the selective media. The limit of quantification was 103 CFU/mL for all agars. CHCP showed the highest specificity, especially when low C. perfringens loads were present in the faeces, with TSC being the second most specific selective medium. Both CBA and SFP allowed considerable growth of other faecal microbiota and were not specific for C. perfringens. On CHCP, differentiation of C. perfringens from other faecal bacteria was straightforward due to the appearance of C. perfringens as orange colonies, with other bacteria being absent or appearing as blue/green colonies. On TSC, C. perfringens appeared as black colonies, but longer incubation periods were sometimes needed for the black colour to develop. Therefore, CHCP can be recommended when timely and easy identification and enumeration of C. perfringens from complex samples, such as faeces, is needed.


Racial and ethnic disparities in end-of-life care for patients with oesophageal cancer: death trends over time.
Given significant morbidity and mortality associated with oesophageal cancer, supportive, high-quality end-of-life care is critical. Most patients with advanced cancer prefer to die at home, but incongruence between preferred and actual place of death is common. Here, we examined trends and disparities in location of death among patients with oesophageal cancer. Using the Centers for Disease Control and Prevention Wide-Range Online Data for Epidemiologic Research database, we utilized multinomial logistic regression to assess associations between sociodemographic characteristics and location of death for patients with oesophageal cancer (n = 237,063). Additionally, we utilized linear regression models to evaluate the significance of changes in location of death trends over time and disparities in the relative change in location of death trends across sociodemographic groups. From 2003 to 2019, there was a decrease of deaths in hospitals, nursing homes, and outpatient medical facilities/emergency departments and an increase of deaths at home and in hospice. Relative to White decedents, Black and Asian decedents were less likely to die at home (relative risk ratio (RRR): 0.58 [95% confidence interval (CI): 0.56-0.60], RRR: 0.57 [95% CI: 0.53-0.61]) and in hospice (RRR: 0.67 [95% CI: 0.64-0.71], RRR: 0.49 [95% CI: 0.43-0.55]) when compared to the hospital. Similar disparities were noted for American Indian and Alaska Native (AIAN) decedents. These disparities persisted even upon stratifying by the number of listed causes of death, a proxy for severity of illness. Time trend analysis indicated that increases in deaths in hospice over time occurred at a slower rate for AIAN and Asian decedents relative to White decedents. 2 in 5 patients with oesophageal cancer die at home, with an increasing proportion dying at home and in hospice-in line with general patient preferences. However, location of death disparities have largely persisted over time among racial and ethnic minority groups. Our findings suggest the importance of improving access to advance care planning and delivering tailored, person-centred interventions. None.


False recognitions in short-term memory - Age-differences in neural activity.
While the knowledge on age-related differences in susceptibility to episodic false memories is extensive, little is known about this phenomenon in visual short-term memory (STM). Our previous behavioural research indicated that older adults are more confident of their erroneous STM recognitions than young adults. However, unlike in episodic memory, we did not find support for older adults' higher rate of false alarms. To further understand this specific age-difference, here we investigated its neural correlates. First, the pattern of behavioural results replicated the one from our previous experiment. Second, younger adults, when compared to older adults, exhibited higher false recognition-related activity of the visual cortex, the anterior cingulate cortex, the frontal operculum/insular cortex as well as regions within the anterior and dorsolateral prefrontal cortex. No age-differences were observed in hippocampal activity. Third, younger but not older adults presented higher activity in the anterior cingulate cortex and the frontal operculum/insular cortex for false recognitions when compared to highly confident correct rejections. Finally, frontal activity was influenced by both the individuals' performance and their metacognitive abilities. The results suggest that age-related differences in confidence of STM false recognitions may arise from age-differences in performance monitoring and uncertainty processing rather than in hippocampal-mediated binding.


Antidiabetic potential of Caralluma europaea against alloxan-induced diabetes in mice.
Medicinal plants play an important role in the management of diabetes mellitus especially in developing countries where resources are lacking. Herbal of natural origin, unlike the synthetic compounds, are more effective, safer and have less side effects. For continuing research on biological properties of Moroccan medicinal plants, the present work was undertaken to evaluate the potential and mechanism of the antidiabetic activity of the Caralluma europaea methanolic extract in alloxan-induced diabetic mice. A high-performance liquid chromatography technique (HPLC) was used to identify and quantify the major phenolic compounds in the methanolic extract. The in vitro antioxidant property was evaluated using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging method, reducing power and ß-carotene-linoleic acid assays. The acute toxicity of the extract was evaluated by giving it orally to mice at single doses of 200, 500, 1000, 2000 mg/kg body weight. The antidiabetic effect was conducted on Swiss albino mice. Diabetes was induced with single intraperitonial injection of alloxan monohydrate (200 mg/kg body weight) and animals were treated with methanol extract at a dose of 250 mg/kg and 500 mg/kg body weight. The blood glucose levels were measured and histopathological analysis of pancreas was performed to evaluate alloxan-induced tissue injuries. The main phenols identified and quantified in the extract were ferulic acid, quercetine, 3,4 dihydroxybenzoic acid, rutin, epigallocatechin, and catechin. Ferulic acid was found to be the main phenolic compound ant its proportion was up to 52% of total phenolic compounds, followed by quercetin (36%). The result showed that methanol extract exhibited an antioxidant effect. Acute toxicity studies revealed that C. europaea extract was safe up 2000 mg/kg body weight and approximate LD50 is more than 2000 mg/kg. Moreover, the methanol extract prevented the diabetogenic effect of alloxan and decreased significantly the blood glucose level (P < 0.001) in treated mice. Morphometric study of pancreas revealed that C. europaea extract protected significantly the islets of Langerhans against alloxan-induced tissue alterations.


Lumetra QIO helps capitated groups redesign offices, implement EMR.
Capitated physician practices are far ahead of their fee-for-service cousins when it comes to using information technology to track patient care and finances. Read about how Lumetra and other quality improvement organizations are helping small capitated practices assess and install IT systems.


The effects of administration of lithium salts and magnesium sulfate on the serum anion gap.
Whether or not an increased serum level of an unmeasured cation will reduce the anion gap (AG) depends on concomitant changes (or lack thereof) in serum unmeasured anions. In the present retrospective study, we sought to determine the effect of lithium carbonate or citrate and magnesium sulfate on the AG. Two groups of psychiatric patients whose average serum lithium levels were 0.6 and 1.0 mEq/L were studied. The AG in each group (10.2 +/- 0.3 [SE] and 9.0 +/- 0.4 mEq/L, respectively) was significantly (P less than 0.05) lower than that of a control group (11.1 +/- 0.3 mEq/L). Separately, we collected 87 pairs of AG and serum magnesium data of patients with toxemia of pregnancy. These included those of 15 patients evaluated both before and during magnesium sulfate infusion. Despite an average serum magnesium level of 4.1 +/- 0.2 mEq/L, the AG of the latter subjects tended to increase slightly from 10.8 +/- 0.5 to 11.7 +/- 0.7 mEq/L during magnesium infusion, instead of decreasing. The other data (72 determinations in the 55 patients without preinfusion values) revealed a mean AG of 11.0 +/- 0.3 mEq/L, coexisting with an elevated serum magnesium of 4.1 +/- 0.1 mEq/L. None of the above-mentioned three mean AG values differed significantly from that of the control group. We conclude that hypermagnesemia resulting from the administration of magnesium sulfate does not reduce the AG, probably because of a concomitant and proportional increase in serum sulfate. The present data reemphasize the need to assess the anion gap as the result of concomitant changes in both unmeasured anions and cations.


Everyday perceptions of safety and racial disparities in hair cortisol concentration.
Black-White disparities in physiological stress during adolescence are increasingly evident but remain incompletely understood. We examine the role of real-time perceptions of safety in the context of everyday routines to gain insight into the sources of observed adolescent racial differences in chronic stress as measured by hair cortisol concentration (HCC). We combined social survey, ecological momentary assessment (EMA), and hair cortisol data on 690 Black and White youth ages 11-17 from wave 1 of the Adolescent Health and Development in Context (AHDC) study to investigate racial differences in physiological stress. Individual-level, reliability-adjusted measures of perceived unsafety outside the home were drawn from a week-long smartphone-based EMA and tested for association with hair cortisol concentration. We observed a statistically significant interaction (p < .05) between race and perceptions of unsafety. For Black youth, perceived unsafety was associated with higher HCC (p < .05). We observed no evidence of an association between perceptions of safety and expected HCC for White youth. For youth who perceive their out-of-home activity locations to be consistently safe, the racial difference in expected HCC was not statistically significant. At the high end of perceived unsafety, however, Black-White differences in HCC were pronounced (0.75 standard deviations at the 95th percentile on perceived unsafety; p < .001). These findings call attention to the role of everyday perceptions of safety across non-home routine activity contexts in explaining race differences in chronic stress as assessed by hair cortisol concentrations. Future research may benefit from data on in situ experiences to capture disparities in psychological and physiological stress.


There is an urgent need for a global rural health research agenda.
People living in rural areas generally experience adverse health outcomes compared to their urban counterparts. They experience a greater burden of non-communicable diseases including: diabetes, hypertension, stroke, kidney disease, and chronic obstructive pulmonary disease (COPD), have limited access to healthcare services, and experience scarcity in specialized healthcare services. The disproportionately high all-cause mortality experienced by rural residents has been termed "the rural mortality penalty". With over 90% of the world's rural population living in Africa and Asia, we argue that the lack of an authoritative and respected global rural health research agenda contributes to increasing health inequalities, given that many of these people are receiving substandard care. There are differences in how rural and urban resident's experience healthcare. Living in rural settings might not be systematically connected to adverse health outcomes. It is important to clearly articulate the positive health outcomes associated with living in rural settings (e.g., the positive relationship between mental health and strong social ties/green spaces). Indeed, health policies stand the chance of unconsciously excluding the positive outcomes associated with rurality, as well as the rural experiences of health. Defining rural health remains an issue of controversy with a persistent reality regarding the lack of consensus as to what it means for a region or area to be considered as "rural". We outline the most common definitions of "rural areas" in the literature, as well as the shortcomings of these definitions. By unpacking the meaning of "rural health", we aim to foster communication among rural health professionals and researchers locally and internationally, as well as highlight the key research and policy implications that could emanate from a "good" definition of rural health. We agree that context remains key when it comes conceptualizing complex subjects like rurality. However, developing minimum criteria to foster communication among rural health researchers is needed. Systematically providing operational definitions of what authors describe as "rural" in the rural health research and policy literature is of utmost relevance.


Dynamic Balance and Chest Mobility of Older Adults after Speleotherapy Combined with Pulmonary Rehabilitation, Endurance and Strength Training-A Prospective Study in Chronic Respiratory Diseases.
As people age, they are more likely to experience balance disturbances. Pulmonary rehabilitation is recognized as a core component in the management of older adults with chronic respiratory diseases. The aim of the study was to assess the dynamic balance and chest mobility of older adults participating in speleotherapy combined with pulmonary rehabilitation, endurance and strength training. The study group consisted of 51 older adults with chronic respiratory disorders who participated in a 3-week pulmonary rehabilitation programme in underground salt chambers in the 'Wieliczka' Salt Mine Health Resort. These individuals underwent the Four Square Step Test (FSST) and circumferential chest mobility measurement before and after the outpatient rehabilitation programme conducted 135 m underground. Before rehabilitation in the underground salt chambers, half of the results (50%, 22 patients) were below the norm in the assessment of chest mobility between maximal inhale and exhale. The average time needed to perform FSST decreased significantly (p ≤ 0.05) from 10.2 ± 1.9 s before the stay to 9.1 ± 1.7 s after the stay and the average increase in chest mobility increased significantly (p ≤ 0.05) from 4.5 ± 5.5 cm to 5.4 ± 2.8 cm. Speleotherapy combined with pulmonary rehabilitation, endurance and strength training increased the dynamic balance and chest mobility of older adults with chronic respiratory diseases, as measured by the FSST and circumferential chest expansion assessment.


Effects of chlortetracycline amended feed on anaerobic sequencing batch reactor performance of swine manure digestion.
The effects of antimicrobial chlortetracycline (CTC) on the anaerobic digestion (AD) of swine manure slurry using anaerobic sequencing batch reactors (ASBRs) was investigated. Reactors were loaded with manure collected from pigs receiving CTC and no-antimicrobial amended diets at 2.5 g/L/d. The slurry was intermittently fed to four 9.5L lab-scale anaerobic sequencing batch reactors, two with no-antimicrobial manure, and two with CTC-amended manure, and four 28 day ASBR cycles were completed. The CTC concentration within the manure was 2 8 mg/L immediately after collection and 1.02 mg/L after dilution and 250 days of storage. CTC did not inhibit ASBR biogas production extent, however the volumetric composition of methane was significantly less (approximately 13% and 15% for cycles 1 and 2, respectively) than the no-antimicrobial through 56 d. CTC decreased soluble chemical oxygen demand and acetic acid utilization through 56 d, after which acclimation to CTC was apparent for the duration of the experiment.


Sudden unexpected death in epilepsy: some approaches for its prevention and medico-legal consideration.
Worldwide, mortality associated with epilepsy is a matter of grave concern. The mortality rate in epileptic population is two to three times more than that of the general population. Sudden unexplained death in epilepsy, better known as sudden unexpected death in epilepsy (SUDEP), is a mysterious and rare condition, in which typically young or middle-aged people with epilepsy die without a clearly defined cause. At times, this may raise a strong suspicion of foul play and raise several medico-legal issues. There may be several different underlying mechanisms but most research has focused on seizure-related cerebral and respiratory depression, cardiac arrhythmia and autonomic dysfunction. In recent years, some significant risk factors have been recognized and strategies have been suggested that could be useful in prevention of SUDEP. Present communication provides some of the updates on new advances in prevention of SUDEP as well as highlights related medico-legal issues.


The 'positive-inside rule' applies to thylakoid membrane proteins.
In integral membrane proteins, regions that span the lipid bilayer alternate with regions that are exposed on either side of the membrane. For proteins from the plasma membrane of both prokaryotic and eukaryotic cells it has been shown that the exposed parts follow a 'positive-inside rule': on average, segments that are translocated across the membrane have a 2-4-fold lower frequency of positively charged residues than non-translocated segments. We now present an analysis of proteins from the thylakoid membrane of chloroplasts. It is shown that these proteins have the same charge asymmetry as has been reported for proteins from other membrane systems, with their more highly charged regions facing the stromal compartment.


Epidemiology of human rotaviruses in a maternity unit as studied by electrophoresis of genomic RNA.
An epidemiological survey of Rotavirus infections in a maternity unit was carried out between May 1983 and August 1984. Rotaviruses have been detected throughout the survey in 184 of 528 fecal samples obtained from 3 and 6 day-old newborns. Rotavirus excretion could be detected neither from the mothers nor from the medical attendants. Rotavirus RNA was analyzed by polyacrylamide gel electrophoresis. All the strains isolated exhibited the same electropherotype. This result contrasts with the genomic variability amongst Rotavirus strains usually observed in pediatric wards, and is in agreement with some other studies conducted in maternity wards; in these locations Rotavirus infection seems to have a special epidemic status as compared with other communities.


Human Endometrial Stromal Cells Are Highly Permissive To Productive Infection by Zika Virus.
Zika virus (ZIKV) is a recently re-emerged flavivirus transmitted to humans by mosquito bites but also from mother to fetus and by sexual intercourse. We here show that primary human endometrial stromal cells (HESC) are highly permissive to ZIKV infection and support its in vitro replication. ZIKV envelope expression was detected in the endoplasmic reticulum whereas double-stranded viral RNA colocalized with vimentin filaments to the perinuclear region. ZIKV productive infection also occurred in the human T-HESC cell line together with the induction of interferon-β (IFN-β) and of IFN-stimulated genes. Notably, in vitro decidualization of T-HESC with cyclic AMP and progesterone upregulated the cell surface expression of the ZIKV entry co-receptor AXL and boosted ZIKV replication by ca. 100-fold. Thus, endometrial stromal cells, particularly if decidualized, likely represent a crucial cell target of ZIKV reaching them, either via the uterine vasculature in the viremic phase of the infection or by sexual viral transmission, and a potential source of virus spreading to placental trophoblasts during pregnancy.


Clinicopathological features and outcome of antibody-negative anti-glomerular basement membrane disease.
To explore the clinicopathological characteristics of patients with anti-GBM antibody-negative anti-GBM disease. The clinical and renal pathological findings were retrospectively studied in 19 patients. All patients met the following inclusion criteria: linear GBM IgG deposition on immunofluorescence(IF); and lack of serum anti-GBM antibodies by ELISA and indirect immunofluorescence assay. There were 17 male and two female patients, with a median age of 36 years (range 15-61 years). Hypertension was present in 68% of cases, nephrotic-range proteinuria (> 3.5 g/24 hours) in 42%, nephrotic syndrome in 37%, microhaematuria in 95%, renal insufficiency in 63% and lung involvement in 16%. On biopsy all patients had linear GBM staining for polyclonal IgG by IF. The dominant IgG subtype was IgG4 or IgG1. By light microscopy, mesangial proliferative GN without crescents was seen in four patients; proliferative GN (mesangial proliferative GN in eight; endocapillary proliferative GN in two; and membranoproliferative GN in two) with crescents (focal in 11; diffuse in one) in 12 patients; and crescentic GN without mesangial or endocapillary proliferative or membranoproliferative changes in three patients. By electron microscopy, six patients showed scarce electron dense deposits in glomeruli and 11 patients had global podocyte effacement. Totally, 10 (53%) patients received immunosuppressive therapy. The median follow-up was 15 months and six (32%) patients progressed to end-stage renal disease. Anti-GBM antibody-negative anti-GBM disease was different from classic anti-GBM disease clinically and pathologically. The pathogenesis of the renal injury in these patients has not been elucidated until now and it should be studied and identified further.


Plasmodium Iron-Sulfur [Fe-S] cluster assembly protein Dre2 as a plausible target of Artemisinin: Mechanistic insights derived in a prokaryotic heterologous system.
Iron-sulfur (Fe-S) cluster containing proteins have been assigned roles in various essential cellular processes, such as regulation of gene expression, electron transfer, sensing of oxygen and balancing free radical chemistry. However, their role as the drug target remains sparse. Recently the screening of protein alkylation targets for artemisinin in Plasmodium falciparum led to identification of Dre2, a protein involved in redox mechanism for the cytoplasmic Fe-S cluster assembly in different organisms. In the present study, to further explore the interaction between artemisinin and Dre2, we have expressed the Dre2 protein of both P. falciparum and P. vivax in E. coli. The opaque brown colour of the IPTG induced recombinant Plasmodium Dre2 bacterial pellet, suggested iron accumulation as confirmed by the ICP-OES analysis. In addition, overexpression of rPvDre2 in E. coli reduced its viability, growth and increased the ROS levels of bacterial cells, which in turn led to an increase in expression of stress response genes of E. coli such as recA, soxS, mazF. Moreover, the overexpression of rDre2 induced cell death could be rescued by treatment with Artemisinin derivatives suggesting their interaction. The interaction between DHA and PfDre2 was later demonstrated by CETSA and microscale thermophoresis. Overall, this study suggests that Dre2 is the probable target of Artemisinin and the antimalarial activity of DHA/Artemether could also be due to yet unidentified molecular mechanism altering the Dre2 activity in addition to inducing DNA and protein damage.


Expression Screening of cDNA Libraries in pEX.
Most methods for screening libraries of cDNA clones rely on the selective binding of either nucleic acid probes to cDNA molecules or antibodies to the polypeptide gene product encoded by the cDNA. Although screening of cDNA libraries with synthetic oligonucleotide probes is undoubtedly a powerful procedure, it is not always the easiest way to clone a cDNA, especially if the equipment for amino acid sequencing and oligonucleotide synthesis is not readily available. The oligonucleotide probe synthesized from the back-translated amino acid sequence of the protein must accommodate the degeneracy of the genetic code either by being a mixture of several sequences, or by being sufficiently long to give hybridization at moderate stringency from a single sequence (1). It cannot always be guaranteed that an easy-to-sequence area of a protein (e.g., the amino terminus) will be present in a cDNA library (where the 5'-end is frequently missing), and simply obtaining sufficient pure protein to perform amino acid sequencing can be a problem. On the other hand, polyclonal and monoclonal antibodies are relatively easy reagents to obtain and, in the latter case, have a built-in purity, being themselves derived from a cloning procedure.


Primary flexible implant arthroplasty of the metacarpophalangeal joints during digital replantation.
Primary silicone rubber arthroplasty in a total of four metacarpophalangeal joints during digital replantation or revascularisation in two patients is reported. The results appear preferable to present alternatives and allow good function without prejudicing further management.


Interactive detection and visualization of breast lesions from dynamic contrast enhanced MRI volumes.
Mammography is currently regarded as the most effective and widely used method for early detection of breast cancer, but recently its sensitivity in certain high risk cases has been less than desired. The use of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) has gained considerable attention in the past 10 years, especially for high risk cases, for smaller multi-focal lesions, or very sparsely distributed lesions. In this work, we present an interactive visualization system to identify, process, visualize and quantify lesions from DCE-MRI volumes. Our approach has the following key features: (1) we determine a confidence measure for each voxel, representing the probability that the voxel is part of the tumor, using a rough goodness-of-fit for the shape of the intensity-time curves, (2) our system takes advantage of low-cost, readily available 3D texture mapping hardware to produce both 2D and 3D visualizations of the segmented MRI volume in near real-time, enabling improved spatial perception of the tumor location, shape, size, distribution, and other characteristics useful in staging and treatment courses, and (3) our system permits interactive manipulation of the signal-time curves, adapts to different tumor types and morphology, thus making it a powerful tool for radiologists/physicians to rapidly assess probable malignant volumes. We illustrate the application of our system with four case studies: invasive ductal cancer, benign fibroadenoma, ductal carcinoma in situ and lobular carcinoma.


Identification of Active Sites for CO2 Reduction on Graphene-Supported Single-Atom Catalysts.
Transition metal- and nitrogen-codoped graphene (referred to as M-N-G, where M is a transition metal) has emerged as an important type of single-atom catalysts with high selectivities and activities for electrochemical CO2 reduction (CO2 R) to CO. However, despite extensive previous studies on the catalytic origin, the active site in M-N-G catalysts remains puzzling. In this study, density functional theory calculations and computational hydrogen electrode model is used to investigate CO2 R reaction energies on Zn-N-G, which exhibits outstanding catalytic performance, and to examine kinetic barriers of reduction reactions by using the climbing image nudged elastic band method. We find that single Zn atoms binding to N and C atoms in divacancy sites of graphene cannot serve as active sites to enable CO production, owing to *OCHO formation (* denotes an adsorbate) at an initial protonation process. This contradicts the widely accepted CO2 R mechanism whereby single metal atoms are considered catalytic sites. In contrast, the C atom that is the nearest neighbor of the single Zn atom (CNN ) is found to be highly active and the Zn atom plays a role as an enhancer of the catalytic activity of the CNN . Detailed analysis of the CO2 R pathway to CO on the CNN site reveals that *COOH is favorably formed at an initial electrochemical step, and every reaction step becomes downhill in energy at small applied potentials of about -0.3 V with respect to reversible hydrogen electrode. Electronic structure analysis is also used to elucidate the origin of the CO2 R activity of the CNN site.


Crystallin αB acts as a molecular guard in mouse decidualization: regulation and function during early pregnancy.
Although decidualization is crucial for the establishment of successful pregnancy, the molecular mechanism underlying decidualization remains poorly understood. Crystallin αB (CryAB), a small heat shock protein (sHSP), is up-regulated and phosphorylated in mouse decidua. In mouse primary endometrial stromal cells, CryAB is induced upon progesterone treatment via HIF1α. In addition, CryAB is strongly phosphorylated through the p38-MAPK pathway under stress or during in vitro decidualization. Knockdown of CryAB results in the increase of apoptosis of stromal cells and inhibits decidualization under oxidative or inflammatory stress. Our data indicate that CryAB protects decidualization against stress conditions.


A universal split spinach aptamer (USSA) for nucleic acid analysis and DNA computation.
We demonstrate how a single universal spinach aptamer (USSA) probe can be used to detect multiple (potentially any) nucleic acid sequences. USSA can be used for cost-efficient and highly selective analysis of even folded DNA and RNA analytes, as well as for the readout of outputs of DNA logic circuits.


Benign and Malignant Skin Lesions: Dielectric Characterization, Modelling and Analysis in Frequency Band 1 to 14 GHz.
This paper aims to characterize Non-Melanoma malignancies and their corresponding benign conditions in ex-vivo/in-vivo tissue environments to study the feasibility of microwave techniques for skin cancer detection. The dielectric dataset is developed across the frequency band 1 to 14 GHz using Keysight slim-form and RG405 probe characterization systems. The acquired reflection data captured by the systems is converted to dielectric values using the Open-Water-Short and Open-Water-Liquid calibration methods, respectively. Furthermore, the impact of anaesthesia application during skin excision procedure on ex-vivo dielectric data is investigated. The observations suggest that the dielectric properties (DPs) of excised skin lesions may not accurately represent actual tissue properties as they vary significantly (Dielectric Constant Contrast = 30.7%, Loss-Factor Contrast = 66.6%) compared to pre-excision conditions. In-vivo dielectric data analysis indicates that when compared to healthy skin, malignant Basal Cell Carcinoma presents increased DPs (dielectric constant & loss factor) of (24.8 & 38.6 %), respectively. On the other hand, for malignant Squamous Cell Carcinoma and pre-malignant Actinic Keratosis, the measured results show decreased DPs (dielectric constant & loss factor) accordingly by (19.4 & 18.2 %) and (19.2 & 27.9 %). The corresponding benign lesions have less than 13 % dielectric contrast compared to healthy skin across the tested band. The significant contrasts between in-vivo healthy and cancerous skin DPs strongly suggest the viability of the microwave band for skin cancer detection. The research finding of this study would be critical in developing a portable electromagnetic system for skin cancer detection.


Cathelicidin bovine myeloid antimicrobial peptide (BMAP) 28 is involved in the inflammatory response against alpha-herpesviruses in the bovine nervous system.
The role of the local innate immune response in the neuropathogenesis of bovine herpesvirus (BoHV) type 1 and 5 remains largely unknown. This study determined the gene transcriptional expression of relevant bovine cathelicidins, TNFα and IFNβ in the nervous system of experimentally-infected cattle during the different stages of BoHV-1 and BoHV-5 infectious cycle. We studied the modulation of bovine myeloid antimicrobial peptide (BMAP) 27 and 28 by alpha-herpesviruses during acute infection of the central nervous system (CNS). However, BMAP28 was the main cathelicidin modulated. BoHV-5 supressed BMAP28 expression mainly in frontal cortex and cervical medulla whereas BoHV-1 slightly induced the expression of cathelicidins in the olfactory and posterior cortex. The differences in the regulation of the innate response are likely related to distinct replication rates of both alpha-herpesviruses in the CNS. During latency and reactivation, BoHV-1 and -5 decreased BMAP28 and BMAP27 expression, accompanied by high levels of TNFα and IFNβ transcripts in the posterior brain region and medulla during BoHV reactivation. In terms of cytokines, a remarkably overexpression of IFNβ was induced by BoHV-5 (133.8-fold). In trigeminal ganglion (TG) both alpha-herpesviruses induced cathelidicins gene expression at all stages of the infection cycle, while only acute BoHV-5 infection increased TNFα (129-fold) mRNA levels. This study suggests that the pronounced downregulation of BMAP28 in BoHV-5-acutely-infected CNS is due to a decreased immune stimulation during viral infection, favouring its establishment in the CNS with a low replication rate until latency. Thus, cathelicidins, together with IFNβ and TNFα, are differentially regulated by BoHV-5 and BoHV-1 infections and this regulation is dependent on the stage of virus infection in the bovine nervous system.


Effect of treatment with estrogen conjugates on endogenous plasma steroids.
Plasma dehydroenpiandrosterone sulfate (DS), androstenedione (A2), estrone plus estradiol (E1+2) and estriol (E3) were measured in women treated with conjugated estrogens and controls. Plasma DS, A2, and E1+2 levels were higher in the premenopausal controls than in the untreated postmenopausal women; E3 levels were below the sensitivity of the assay. Estrogen conjugates, 1.25 mg or 2.5 mg daily, increased plasma E1+2 to levels similar to those in premenopausal untreated women, and E3 became readily assayable. A 0.625-mg dose increased the level of E3 without affecting E1+2; consequently, the plasma E3/E1+2 ratio was elevated. It is concluded that at the lowest dose 16 alpha-hydroxylase activity, perhaps by substrate induction, is sufficient for the exogenous esogenous estrogens to be largely metabolized to E3. Estrogen conjugates had no detectable effect on plasma DS or A2.


All units are equal in humpback whale songs, but some are more equal than others.
Flexible production and perception of vocalizations is linked to an impressive array of cognitive capacities including language acquisition by humans, song learning by birds, biosonar in bats, and vocal imitation by cetaceans. Here, we characterize a portion of the repertoire of one of the most impressive vocalizers in nature: the humpback whale. Qualitative and quantitative analyses of sounds (units) produced by humpback whales revealed that singers gradually morphed streams of units along multiple acoustic dimensions within songs, maintaining the continuity of spectral content across subjectively dissimilar unit "types." Singers consistently produced some unit forms more frequently and intensely than others, suggesting that units are functionally heterogeneous. The precision with which singing humpback whales continuously adjusted the acoustic characteristics of units shows that they possess exquisite vocal control mechanisms and vocal flexibility beyond what is seen in most animals other than humans. The gradual morphing of units within songs that we observed is inconsistent with past claims that humpback whales construct songs from a fixed repertoire of discrete unit types. These findings challenge the results of past studies based on fixed-unit classification methods and argue for the development of new metrics for characterizing the graded structure of units. The specific vocal variations that singers produced suggest that humpback whale songs are unlikely to provide detailed information about a singer's reproductive fitness, but can reveal the precise locations and movements of singers from long distances and may enhance the effectiveness of units as sonar signals.


Rapid screening platform for stabilization of scFvs in Escherichia coli.
The poor biophysical properties of antibody fragments such as scFvs and diabodies can preclude their use as therapeutic agents. The non-ideal biophysical properties and insufficient thermal stability of antibody fragments often leads to poor expression, poor solubility, and a predisposition of the proteins to aggregate. We have developed a general platform for engineering stability into antibody fragments. By promoting Escherichia coli cultures to secrete scFvs directly into growth media, automated screening methods can be applied to empirically evaluate multiple stability design strategies including rational, sequence-based, and structure-based designs. Once stabilized, these antibody fragments demonstrate improved expression and durability during purification, handling, and storage. Stabilized antibody fragments can also be used as building blocks for multivalent or bispecific antibody-like molecules.


GPR56 and its related diseases.
GPR56, an orphan G protein-coupled receptor (GPCR), was identified one decade ago by two independent groups through a degenerate PCR-based approach for secretin-like GPCRs and by differential display of melanoma cell lines with different metastatic potentials. The finding that GPR56 was significantly downregulated in high metastatic melanoma cell lines suggests its possible role in cancer metastasis. However, the function of GPR56 remained unclear until 2004 when mutations in the human GPR56 gene were found to cause a specific brain malformation called bilateral frontoparietal polymicrogyria. Although GPR56 is expressed in a wide range of tissues, the consequences of loss-of-function mutations in the GPR56 gene have only been observed in the central nervous system. Studies from knockout mouse model indicate that GPR56 regulates brain development by affecting the integrity of the pial basement membrane in the developing brain.


Compact silicon multimode waveguide spectrometer with enhanced bandwidth.
Compact, broadband, and high-resolution spectrometers are appealing for sensing applications, but difficult to fabricate. Here we show using calibration data a spectrometer based on a multimode waveguide with 2 GHz resolution, 250 GHz bandwidth, and a 1.6 mm × 2.1 mm footprint. Typically, such spectrometers have a bandwidth limited by the number of modes supported by the waveguide. In this case, an on-chip mode-exciting element is used to repeatably excite distinct collections of waveguide modes. This increases the number of independent spectral channels from the number of modes to this number squared, resulting in an extension of the usable range.


Antibodies reactive with surface membranes of cellular elements in the blood.
Autoreactive antibodies or immune complexes may accelerate clearance of mature erythrocytes, leukocytes, and platelets from the circulation in patients with rheumatologic and immunologic disorders. The most compelling evidence for immune injury to hematopoietic cells exists in patients with systemic lupus erythematosus and patients with Felty's syndrome and its variants. These disorders may also cause tissue inflammation, which in turn commonly results in underproduction of erythrocytes and development of thrombocytosis. However, recent evidence indicates that underproduction of hematopoietic cells may also result from immune injury to cellular elements in the bone marrow. In many laboratories, sensitive techniques are now clinically available for the detection of cell-associated immunoglobulin and complement. These assays have helped confirm the role of antibody in the pathogenesis of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura. However, recent data indicate that there is probably a continuum between the amount of immunoglobulin and complement found on normal cells and that found in a variety of disease states. In several of these disorders, additional evidence will be required to establish that the increase in cell-bound immunoglobulin leads to a decrease in the life-span of the cell. In order to provide significant help to the clinician managing an individual patient, these serologic tests must be capable of identifying the portion of the cell-associated protein actually involved in the destructive process. The availability of monoclonal reagents capable of identifying restricted regions on cell-bound immunoglobulin may help identify molecules bound specifically as antibody and may help identify the antigens involved in autoimmune disorders.


Paternal indifference and neglect in early life and creativity: Exploring the moderating role of TPH1 genotype and offspring gender.
For further understanding the joint contribution of environment, heredity and gender to creativity, the present research examined the prospective impact of paternal indifference & neglect in early life, TPH1 rs623580, offspring gender, and the interaction effects thereof on creativity in five hundred and thirty-nine unrelated healthy Chinese undergraduate students. Paternal indifference & neglect in early life was assessed on the Parental Bonding Instrument (PBI) and creativity on the Runco Creativity Assessment Battery (rCAB). Two primary findings emerged. Firstly, significant paternal indifference & neglect × TPH1 genotype interaction effects were identified in predicting all three dimensions of creativity (fluency, originality, and flexibility). Paternal indifference & neglect in early life negatively predicted fluency, originality, and flexibility when individuals carry A allele of TPH1 (rs623580). Secondly, there was a significant interaction effect of TPH1 genotype by offspring gender on flexibility. Only in males, individuals who carry A allele were linked with lower level of flexibility compared to TT homozygote individuals. No significant three-way interaction was found. In conclusion, the current findings provided the first preliminary evidence for the moderation effect of TPH1 on the relationship between parenting and creativity, and TPH1- offspring gender interaction on creativity; future studies are needed to validate these findings.


A pre-trained BERT for Korean medical natural language processing.
With advances in deep learning and natural language processing (NLP), the analysis of medical texts is becoming increasingly important. Nonetheless, despite the importance of processing medical texts, no research on Korean medical-specific language models has been conducted. The Korean medical text is highly difficult to analyze because of the agglutinative characteristics of the language, as well as the complex terminologies in the medical domain. To solve this problem, we collected a Korean medical corpus and used it to train the language models. In this paper, we present a Korean medical language model based on deep learning NLP. The model was trained using the pre-training framework of BERT for the medical context based on a state-of-the-art Korean language model. The pre-trained model showed increased accuracies of 0.147 and 0.148 for the masked language model with next sentence prediction. In the intrinsic evaluation, the next sentence prediction accuracy improved by 0.258, which is a remarkable enhancement. In addition, the extrinsic evaluation of Korean medical semantic textual similarity data showed a 0.046 increase in the Pearson correlation, and the evaluation for the Korean medical named entity recognition showed a 0.053 increase in the F1-score.


A novel fluorescence sensor based on covalent immobilization of 3-amino-9-ethylcarbazole by using silver nanoparticles as bridges and carriers.
A novel technique of covalent immobilization of indicator dyes in the preparation of fluorescence sensors is developed. Silver nanoparticles are used as bridges and carriers for anchoring indicator dyes. 3-amino-9-ethylcarbazole (AEC) was employed as an example of indicator dyes with terminal amino groups and covalently immobilized onto the outmost surface of a quartz glass slide. First, the glass slide was functionalized by (3-mercaptopropyl) trimethoxysilane (MPS) to form a thiol-terminated self-assembled monolayer, where silver nanoparticles were strongly bound to the surface through covalent bonding. Then, 16-mercaptohexadecanoic acid (MHDA) was self-assembled to bring carboxylic groups onto the surface of silver nanoparticles. A further activation by using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) converted the carboxylic groups into succinimide esters. Finally, the active succinimide esters on the surface of silver nanoparticles were reacted with AEC. Thus, AEC was covalently bound to the glass slide and an AEC-immobilized sensor was obtained. The sensor exhibited very satisfactory reproducibility and reversibility, rapid response and no dye-leaching. Rutin can quench the fluorescence intensity of the sensor and be measured by using the sensor. The linear response of the sensor to rutin covers the range from 2.0 x 10(-6) to 1.5 x 10(-4) molL(-1) with a detection limit of 8.0 x 10(-7) molL(-1). The proposed technique may be feasible to the covalent immobilization of other dyes with primary amino groups.


Serum 25-hydroxyvitamin D concentration among users of a referral outpatient unit for vascular diseases and associated factors.
Assess serum 25-hydroxyvitamin D (25OHD) concentration and associated factors among users of a referral outpatient unit for vascular diseases in Southern Brazil. Cross-sectional study conducted for almost one year, from March 2016 to January 2017. The serum vitamin D level was determined biochemically and classified as: sufficient (>50 nmol/L), insufficient (30-50 nmol/L) and deficient (<30 nmol/L). Associations were tested through multiple linear regression. At a reference outpatient clinic specialized in vascular diseases located in a southern Brazilian medium-sized city (latitude 29°S). Consecutive sample of 133 individuals of both sexes, aged at least 40 years. The mean serum 25OHD concentration was 54.9 ± 25.9 nmol/L (57.7 ± 27.9 nmol/L for men; 52.2 ± 24.2 nmol/L for women, p = 0.267). A total of 12.8% of the participants had vitamin D deficiency and 32.3% had insufficiency. Regarding the total sample, variables associated to the serum 25OHD concentration were: age (β = -0.55; CI95% -0.95; -0.17), sun exposure (β = 1.22; CI95% 0.32; 2.10) and vitamin D intake (β = 7.29; CI95% 2.10; 12.48). Among men, a significant association was observed for age (β = -0.82; CI95% -1.47; -0.17, p = 0.015) and borderline for sun exposure (β = 1.22; CI95% 0.32; 2.10, p = 0.053). Among women, only vitamin D intake was significantly associated with serum concentration of this vitamin (β = 8.74; CI95% 1.32; 16.17, p = 0.022). Although the mean 25OHD concentration was greater than 50 nmol/L, about 45% of this consecutive sample presented poor vitamin D nutritional status. Unadjusted for seasonality, factors associated with serum 25OHD concentration were age and sun exposure among men and vitamin D intake among women.


Toxicogenomics; transcript profiling and potential application to chemical allergy.
Novel transcript profiling technologies allow simultaneous measurement of the changes in expression of many hundreds or many thousands of genes. The availability of these methods has brought about revolutionary changes in many areas of investigative biology, where analyses of patterns of gene expression, rather than of individual genes, are being employed. The application of these technologies to toxicology (toxicogenomics) offers new opportunities for both mechanistic toxicity research and predictive toxicology. Here we provide an overview of the basic approaches used in this field. The development of a series of toxicology-specific microarrays in our own laboratory is discussed, together with an example of one area of mechanistic research, chemical allergy, where we believe judicious application of toxicogenomics will make an important contribution.


REPAS, a summary rating scale for resistance to passive movement: item selection, reliability and validity.
To establish: (i) item characteristics and item selection for the REPAS; (ii) internal consistency, inter-rater and test-retest reliability of the final REPAS version and its subtests; (iii) the association between the REPAS and selected other clinical scales of impairment and activity limitation. Thirty-three neurological patients with central paresis. Two REPAS assessments with a one-week interval by two independent raters. Concurrent assessment of the Motricity Index, Box-and-Block test, Functional Ambulation Category, Timed walking, Barthel Index, Disability Rating Scale, Carer Burden Scale, and Hygiene Score. Twenty-six of 52 REPAS items fulfilled the item selection criteria. The final test version showed a high internal consistency, inter-rater and test-retest reliability (correlation coefficients: 0.87-0.97, no significant difference between raters or with test repetition). Reliability of the arm and leg subtests was substantial (correlation coefficients: arm subtest 0.63-0.98, leg subtest 0.56-0.96). REPAS scores were moderately associated with basic ADL competence and a carer's burden with arm or leg adductor spasticity. The REPAS, arm subtest scores, degree of arm paresis and gross manual dexterity showed a moderately high association. The Ashworth scale-based guidelines assured comparability of test administration and scoring. The REPAS is a reliable and valid summary rating scale for resistance to passive movement.


Attenuation corrected-optical coherence tomography for quantitative assessment of skin wound healing and scar morphology.
Imaging the structural modifications of underlying tissues is vital to monitor wound healing. Optical coherence tomography (OCT) images high-resolution sub-surface information, but suffers a loss of intensity with depth, limiting quantification. Hence correcting the attenuation loss is important. We performed swept source-OCT of full-thickness excision wounds for 300 days in mice skin. We used single-scatter attenuation models to determine and correct the attenuation loss in the images. The phantom studies established the correspondence of corrected-OCT intensity (reflectivity) with matrix density and hydration. We histologically validated the corrected-OCT and measured the wound healing rate. We noted two distinct phases of healing-rapid and steady-state. We also detected two compartments in normal scars using corrected OCT that otherwise were not visible in the OCT scans. The OCT reflectivity in the scar compartments corresponded to distinct cell populations, mechanical properties and composition. OCT reflectivity has potential applications in evaluating the therapeutic efficacy of healing and characterizing scars.


Recent advances in lipid-engineered multifunctional nanophytomedicines for cancer targeting.
Cancer is a leading cause of death in many countries around the world. However, the efficacy of current treatments available for variety of cancers is considered to be suboptimal due to the pathophysiological challenges associated with the disease which limits the efficacy of the anticancer drugs. Moreover, the vulnerability towards off-target effects and high toxicity also limits the use of drugs for the treatment of cancers. Besides, the biopharmaceutical challenges like poor water solubility and permeability of the drugs, along with the absence of active targeting capability further decreases the utility of drugs in cancer therapy. As a result of these deficiencies, the current therapeutic strategies face noncompliance to patients for providing meaningful benefits after administration. With the advancements in nanotechnology, there has been a paradigm shift in the modalities for cancer treatment with the help of phytomedicine-based nanosized drug delivery systems coupled with variegated surface-engineering strategies for targeted drug delivery. Among these delivery systems, lipid-based nanoparticles are considered as one of the highly biocompatible, efficient and effective systems extensively explored for anticancer drug delivery. These include diverse range of systems including liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipidic carriers and supramolecular carriers, which alters pharmacokinetic and biodistribution of the drugs for active targeting to the desired site of action by overcoming the biopharmaceutical challenges associated with anticancer drug delivery. The present review endeavours to provide a comprehensive account on the recent advances in the application of lipid-based nanostructured systems for improving the pharmacotherapeutic performance of phytomedicines for cancer targeting application.


Congenital cytomegalovirus is the second most frequent cause of bilateral hearing loss in young French children.
To estimate the prevalence of congenital cytomegalovirus (cCMV) among causes of bilateral hearing loss in young French children. Children <3 years old with hearing loss were prospectively included at their first visit to a referral center. Cytomegalovirus polymerase chain reaction was performed on dried blood spots from Guthrie cards. Medical records were reviewed. One hundred children with bilateral hearing loss were included at a median age of 15 months; the prevalence of cCMV was 8% (8/100) (95% CI, 2.7%-13.3%) in this population and 15.4% (8/52) in the subpopulation of children with profound bilateral hearing loss. Delayed neurodevelopment and brain abnormalities on computed tomography scan were found more often in children with cCMV than in children with hearing loss without cCMV (P = .027, P = .005). In 6 of 8 cCMV cases, cCMV infection had not been diagnosed before the study. In a comprehensive study of the causes of bilateral hearing loss in young French children, cCMV is the second most frequent cause of hearing loss after connexin mutations. It underlines that a majority of French children with hearing loss and cCMV are not diagnosed early and therefore may not benefit from early intervention including the possibility of neonatal antiviral treatment. These results make the case for promoting systematic cytomegalovirus screening in neonates with confirmed hearing loss identified through neonatal hearing screening.


A new c.1621 C > G, p.R541G lamin A/C mutation in a family with DCM and regional wall motion abnormalities (akinesis/dyskinesis): genotype-phenotype correlation.
Mutations in the lamin A/C gene (LMNA) are established causes of familial dilated cardiomyopathy (DCM) with atrio-ventricular block although relatively little is known about genotype-phenotype correlations. We describe a 23-year-old patient who presented with inferolateral wall thinning and akinesis with evidence of mid-myocardial fibrosis on cardiac magnetic resonance. Molecular analysis driven by clinical similarities with a previously described case harboring the p.R541C LMNA mutation revealed a novel c.1621 C > G, p.R541G substitution whose pathogenicity was confirmed by transfection of mouse myoblasts. Our results emphasize the role of LMNA mutations at position R541 in DCM cases with segmental LV wall motion akinesis/dyskinesis.


Peritoneal cell-free DNA as a sensitive biomarker for detection of peritoneal metastasis in colorectal cancer: a prospective diagnostic study: A prospective diagnostic study.
The detection of peritoneal metastasis (PM) is limited by current imaging tools. In this prospective study, we aimed to evaluate the sensitivity and specificity of peritoneal cell-free DNA (cfDNA) for diagnosis of PM. Colorectal cancer (CRC) patients with/without PM were enrolled. The cfDNA experimental personnel and statists were blinded to the diagnosis of PM. Ultradeep sequencing covering large genomic regions (35000X, Next-generation sequencing) of cfDNA in peritoneal lavage fluid (FLD) and matched tumor tissues was performed. A total of 64 cases were recruited prospectively and 51 were enrolled into final analysis. In training cohort, 100% (17/17) PM patients obtained positive FLD cfDNA, comparing to 5/23 (21.7%) in patients without PM. Peritoneal cfDNA had a high sensitivity of 100% and specificity of 77.3% for diagnosis of PM (AUC: 0.95). In validation group of 11, 5/6 (83%) patients with PM obtained positive FLD cfDNA, comparing to 0/5 in non-PM (P = 0.031) with a sensitivity of 83.3% and specificity of 100%. Positive FLD cfDNA was associated with poor recurrence-free survival (P = 0.013) and was preceding radiographic evidence of recurrence. Peritoneal cfDNA is a promising sensitive biomarker for earlier detection of PM in CRC than current radiological tools. It can potentially guide selection for targeted therapies and serve as a surrogate instead of laparoscopic explore in the future. Trial Registration Chinese Clinical Trial Registry at chictr.org.cn (ChiCTR2000035400). URL: http://www.chictr.org.cn/showproj.aspx?proj=57626.


Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction.
Learned associations between drugs and environment play an important role in addiction and are thought to be encoded within specific patterns of sparsely distributed neurons called neuronal ensembles. This hypothesis is supported by correlational data from in vivo electrophysiology and cellular imaging studies in relapse models in rodents. In particular, cellular imaging with the immediate early gene c-fos and its protein product Fos has been used to identify sparsely distributed neurons that were strongly activated during conditioned drug behaviors such as drug self-administration and context- and cue-induced reinstatement of drug seeking. Here we review how Fos and the c-fos promoter have been employed to demonstrate causal roles for Fos-expressing neuronal ensembles in prefrontal cortex and nucleus accumbens in conditioned drug behaviors. This work has allowed identification of unique molecular and electrophysiological alterations within Fos-expressing neuronal ensembles that may contribute to the development and expression of learned associations in addiction.


Butyrate restores motile function and actin cytoskeletal network integrity in apc mutated mouse colon epithelial cells.
Loss of function of the Apc gene product is an early and frequent event in colorectal carcinogenesis. Altered migration of intestinal epithelial cells has been described in vivo in the Min mouse Apc+/Min model. Using cell lines established from this model we show in vitro that Apc+/Min cells are less motile than Apc+/+ cells and exhibit a disordered actin cytoskeletal network. This would increase the probabilities of the initiated cell to acquire additional genetic alterations leading to neoplasia. Butyrate, a product of indigestible carbohydrate fermentation by the colonic flora, is able to restore both motility and actin cytoskeletal organization. This feature may contribute to explain the protective effect exerted by butyrogenic diets on colon carcinogenesis in animal models.


A patient with Takayasu's arteritis treated with corticosteroids who developed primary biliary cirrhosis.
A 40-year-old woman with a history of fever and arthralgia since age 17 had received long-term prednisolone (PSL) therapy. She was diagnosed with Takayasu's arteritis in 1980 and given PSL. The symptoms were well controlled until she developed itching in 1998. Laboratory tests showed elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, total cholesterol, and immunoglobulin M (IgM). She tested positive for anti-mitochondria antibody and for both IgG and IgM anti-pyruvate dehydrogenases. Liver biopsy findings were typical of primary biliary cirrhosis (PBC). Our patient's clinical course suggested that an adequate amount of PSL to control Takayasu's arteritis does not necessarily prevent the development of PBC.


Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma.
Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1-8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.


Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells.
β-Thalassemia pathology is due not only to loss of β-globin (HBB), but also to erythrotoxic accumulation and aggregation of the β-globin-binding partner, α-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in β-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize β-globin:α-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing β-thalassemia.


The specific enhancement of interferon alpha induced growth inhibition by BCR/ABL only occurs in multipotent cells.
The causative oncogene in CML is the BCR/ABL protein tyrosine kinase. This stem cell disease is often treated with interferon alpha (IFN-alpha) which can initiate haematological and cytological remission which is associated with increased survival. There is however no clear indication of why CML cells are more responsive to IFN-alpha. To establish if BCR/ABL increases the sensitivity of multipotent cells to IFN-alpha a temperature sensitive mutant of BCR/ABL was expressed in the multipotent haemopoietic stem cell line FDCP-Mix. The effect of IFN-alpha in terms of proliferation, induction of apoptosis, changes in cell cycle inhibitor proteins, and differentiation was assessed by [3H]thymidine incorporation, Annexin V and Western blot analysis. When the BCR/ABL tyrosine kinase was activated, the IFN-alpha-induced inhibition on the growth rate of the FDCP-Mix cell population was more marked than in control populations. The BCR/ABL-mediated effect was due to decreased rates of DNA synthesis. There was no IFN-alpha-mediated induction of apoptosis. This enhanced BCR/ABL mediated growth inhibition occurred over a range of growth factor concentrations and was independent of changes in p21(Cip1) and p27(Kip) levels. When FDCP-Mix cells were induced to differentiate into mature macrophages and neutrophils in the presence of IFN-alpha, there was increased sensitivity to IFN-alpha that was independent of BCR/ABL activity. BCR/ABL PTK expression in this primitive multipotent haematopoietic cell line results in an enhanced response to IFN-alpha. In contrast, the more mature myeloid progenitor cells are equally responsive to this growth inhibitor. This data may explain some of the clinical effects of IFN-alpha.


On the hot seat. As the recession grows, an IRS report shows enviable salaries and uneven community benefits provided by tax-exempt hospitals.
As they look to collect a share of the billions in stimulus dollars designed to boost the economy, not-for-profit hospitals found the tax breaks they get coming under more scrutiny. An IRS report on executive pay and community benefits found six-figure salaries and uneven aid. "It's going to seem out of synch with today's economy," says healthcare attorney Gerald Griffith, left.


N-Polybenzylated alicyclic 1,2-diamines: cytotoxicity and G1 phase arrest in cancer cell line.
Cytotoxicity in the μM range was observed in cancer cell lines treated with N,N,N',N'-tetrabenzyl-4,5-diamino-2-cyclopentenone. Cell cycle analysis on HeLa cells showed a clear G1 phase arrest. A preliminary SAR on structural analogs was performed in order to identify the pharmacophores.


Synergistic antiproliferative and apoptotic effects induced by epidermal growth factor receptor and protein kinase a inhibitors in human prostatic cancer cell lines.
Our results revealed that the blockade of epidermal growth factor receptor (EGFR) tyrosine kinase and protein kinase A (PKA) signaling pathways by specific inhibitors (PD153035 and Rp-cAMPs) leads to a synergistic inhibition of EGF- and serum-stimulated growth of human prostatic cancer cells (LNCaP, DU145 and PC3) concomitant with an arrest in the G1 phase of cellular cycle. Of particular interest, the combination of PD153035 and Rp-cAMPs also caused a more substantial apoptotic/necrotic death of these prostatic cancer cells as compared to drugs alone. Moreover, we observed that the inhibition of acidic sphingomyelinase and caspase cascades results in a marked reduction of DNA fragmentation and apoptotic death induced by PD153035, alone or in combination with Rp-cAMPs, in EGF stimulated PC3 cells. This suggests that these agents might mediate their cytotoxic effects at least in part via the ceramide generation and activation of caspase signaling pathways. N-oleoylethanolamine (OE), an inhibitor of acidic ceramidase, consistently potentiated the apoptotic effects of PD153035 in all the prostatic cancer cell lines tested. Additionally, the cellular ceramide content estimated for PC3 cells was increased after treatment with PD153035, alone or in combination, at a lower dose with OE and Rp-cAMPs. The synergistic apoptotic effect of PD153035 plus Rp-cAMPs induced in PC3 was also accompanied by a significant rate of mitochondrial membrane depolarization and release of cytochrome c into cytosol as compared to drugs alone. Combined, the results indicated that the simultaneous inhibition of EGFR and PKA signaling cascades might lead to a more massive apoptotic death of metastatic prostatic cancer cells by increasing ceramide accumulation and activating of caspase cascade of a mitochondrial dependent manner.


Aminophenyl chalcones potentiating antibiotic activity and inhibiting bacterial efflux pump.
Chalcones and their derivatives are substances of great interest for medicinal chemistry due to their antibacterial activities. As the bacterial resistance to clinically available antibiotics has become a worldwide public health problem, it is essential to search for compounds capable of reverting the bacterial resistance. As a possibility, the chalcone class could be an interesting answer to this problem. The chalcones (2E)-1-(4'-aminophenyl)-3-(phenyl)‑prop-2-en-1-one (APCHAL), and (2E)-1-(4'-aminophenyl)-3-(4-chlorophenyl)‑prop-2-en-1-one (ACLOPHENYL) were synthesized by the Claisen-Schmidt condensation and characterized by 1H and 13C nuclear magnetic resonance (NMR), Fourier-transform infrared (FT-IR), and mass spectrometry (MS), In addition, microbiological tests were performed to investigate the antibacterial activity, modulatory potential, and efflux pump inhibition against Staphylococcus aureus (S. aureus) multi-resistant strains. Regarding the S. aureus Gram-positive model, the APCHAL presented synergism with gentamicin and antagonism with penicillin. APCHAL reduced the Minimum inhibitory concentration (MIC) of gentamicin by almost 70%. When comparing the effects of the antibiotic modifying activity of ACLOPHENYL and APCHAL, a loss of synergism is noted with gentamicin due to the addition of a chlorine to the substance structure. For Escherichia coli (E. coli) a total lack of effect, synergistic or antagonistic, was observed between ACLOPHENYL and the antibiotics. In the evaluation of inhibition of the efflux pump, both chalcones presented a synergistic effect with norfloxacin and ciprofloxacin against S. aureus, although the effect is much less pronounced with ACLOPHENYL. The effect of APCHAL is particularly notable against the K2068 (MepA overexpresser) strain, with synergistic effects with both ciprofloxacin and ethidium bromide. The docking results also show that both compounds bind to roughly the same region of the binding site of 1199B (NorA overexpresser), and that this region overlaps with the preferred binding region of norfloxacin. The APCHAL chalcone may contribute to the prevention or treatment of infectious diseases caused by multidrug-resistant S. aureus.


Infection Prevention in the Neonatal Intensive Care Unit.
Although many aspects of infection prevention and control (IPC) mirror institutional efforts, optimization of IPC practices in the neonatal intensive care unit requires careful consideration of its unique population and environment, addressed here for key IPC domains. In addition, innovative mitigation efforts to address challenges specific to limited resource settings are discussed.


Central dopaminergic neurons during development of genetic and DOCA-salt hypertension in the rat.
The in vivo binding of [3H]spiroperidol was measured in discrete areas of the brain in 7-, 9- and 16-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) controls. An increase in the [3H]spiroperidol binding in the striatum, tuberculum olfactorium and frontal cortex but not in the cerebellum was detected at all ages in SHR. The increase was more pronounced in 7- than in 9- or 16-week-old SHR. In vitro data indicated an increase in Bmax but no variation in Kd in the striatum of 7-week-old SHR. Moreover no difference was detectable in the dopaminergic cell bodies (A9, A10). This increase was specific to [3H]spiroperidol binding sites since no difference was observed in the in vivo binding of [3H]QNB and [3H]LSD in the same brain regions. No variation in dopamine level or dopamine utilization, as estimated by measuring the disappearance of the amine induced by alpha-methyl-p-tyrosine, was observed. The DOPA accumulation after injection of the DOPA decarboxylase inhibitor NSD 1015 was greater in the tuberculum olfactorium from 7-week-old SHR. An increase in [3H]spiroperidol binding sites was also observed in the striatum and tuberculum olfactorium after 7 weeks of DOCA-salt treatment. These results suggest that dopaminergic neurons might be implicated in the onset of hypertension in the rat.


Influence of type of helmet on facial trauma in motorcycle accidents.
The mandatory use of helmets by motorcyclists has lowered the incidence of facial trauma, but we know little about the effects of different models of helmet on such injuries. We aimed to find out how different types of helmet affect facial injuries. We collected retrospective data from the medical records of 157 patients treated in a trauma centre in metropolitan São Paulo between January and December 2011. Patients wearing open-face helmets were twice as likely to require an operation as those wearing full-face helmets. The type of helmet is strongly associated with the treatment required.


Advanced photocatalytic oxidation processes for micropollutant elimination from municipal and industrial water.
The objective of this study was to develop and validate an innovative technology to ensure efficient elimination of different types of micropollutants and toxic compounds in waste water. The process is a tertiary treatment process, which can be easily integrated into municipal and industrial waste water treatment plants. It is based on oxidation by ozone and subsequent photocatalytic treatment. After development and validation of this system at laboratory scale, the solution was tested at pilot scale. The first part of this work was to develop a TiO2-based film on glass substrate, characterize its physico-chemical properties and optimize its composition at laboratory scale to be photoactive on the degradation of model water containing several pollutants. The model water consisted of a mixture of 22 major micropollutants including pesticides, plasticizers, brominated compounds, and pharmaceuticals. The best photocatalyst for the degradation of the selected micropollutants was a TiO2 coating doped with 2 wt% of Ag and where 10 wt% P25 was added. Then, in order to scale up the process, its deposition on steel substrates was tested with dip and spray coating at laboratory scale. Calcination parameters were optimized to limit steel corrosion while keeping similar photoactive properties regarding the degradation of the model polluted water. The optimized solution was deposited by spray coating in a pilot scale reactor in order to assess its efficiency in a pilot water treatment plant.


Sex and gender differences in myocardial hypertrophy and heart failure.
Cardiovascular disease is the most common cause of death in men and women worldwide. Men develop most, but not all, cardiovascular diseases at an earlier age while the number of affected women significantly increases with higher age. Heart failure (HF) is a common cause of cardiovascular death and carries a poor prognosis in both genders. Risk factors and myocardial adaptations in HF in men and women are different. Female hearts develop a more favorable physiological form of myocardial remodeling than male hearts. This may be related to sex hormones, estrogens and testosterone. A clinical study for gender differences in human aortic stenosis supports the hypotheses. HF management differs between both sexes, with underdiagnosis and undertreatment and less use of invasive therapies in women. Nevertheless, women frequently have better outcomes than men. Gender research will contribute directly to patient-oriented benefit by suggesting clinical protocols.


Mushroom Poisoning in the Northeast of Iran; a Retrospective 6-Year Epidemiologic Study.
Toxic mushrooms are distributed across the globe with over 5000 species. Among them, 100 species are responsible for most of the cases of mushroom poisoning. This study aimed to evaluate the epidemiologic pattern of mushroom poisoning among patients referred to the main toxicology center of Mashhad province located in North-east of Iran. This cross-sectional study was conducted on patients with final diagnosis of mushroom poisoning referred to the toxicology center of Mashhad, Iran, from February 2005 to 2011. Patients' demographic characteristics, clinical presentations, laboratory findings, outcomes, and therapeutic measures were collected using a predesigned checklist and searching patient's profile. 32 cases with the mean age of 24.6 ± 16.7 years were presented to the toxicology center following mushroom poisoning (59% female). Mushroom poisoning accounted for 0.1% of all admitted cases. The mean time elapsed from consumption to referral to poisoning department was 61.9 ± 49.4 hours. 19 (59%) cases were discharged with complete recovery, 7 (22%) expired, and 6 (19%) cases left hospital against medical advice. Mushroom poisoning mortality accounted for 1.5% of deceased cases in the studied center. There was significant relationship between mortality rate and higher values of INR (p = 0.035), PT (p = 0.011) and PTT (p = 0.003). Likewise, there was significant relationship between the need for mechanical ventilation and higher values of INR (p = 0.035), PT (p = 0.006) and PTT (p = 0.014). The relationships between the need for ICU admission, mechanical ventilation, and mortality rate with the rise of hepatic transaminases and serum bilirubin were not significant. Based on the findings, the prevalence of mushroom poisoning among patients referred to Mashhad toxicology center was very low (0.1%), but with a high mortality rate of 22%. Nausea and vomiting were the most common early symptoms of intoxication and higher values of coagulation profile were correlated with poor outcome.


Effect of NT-proBNP testing on diagnostic certainty in patients admitted to the emergency department with possible heart failure.
Difficulty in distinguishing congestive heart failure (HF) from other causes of dyspnoea in the emergency department (ED) may result in delay in appropriate treatment and referral. Although the diagnostic value of serum amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is well documented, the impact on diagnostic certainty of providing these results to ED physicians is not well studied. We sought to determine the effect of providing NT-proBNP results on diagnostic certainty of physicians managing patients presenting to the ED with suspected HF. A randomized controlled study was conducted in 68 patients presenting to the ED with dyspnoea. ED clinicians initially rated the probability of HF as the cause of dyspnoea without the knowledge of the result. A scale of 1-7 was used, with 1 representing a high degree of certainty of a diagnosis other than HF and 7 representing a high degree of certainty of HF being the cause of dyspnoea. In 38 patients, the ED physician then reassessed the probability of HF as the cause of dyspnoea after receiving the NT-proBNP result. A cardiologist blinded to the NT-proBNP result determined the final diagnosis after review of medical records and investigations. Providing the NT-proBNP result reduced diagnostic uncertainty, defined as a test score of 3-5, from 66% of cases to 18% of cases (P < 0.0001) and improved diagnostic accuracy from 53% to 71% (P = 0.016). Measurement of NT-proBNP concentrations reduces diagnostic uncertainty and improves diagnostic accuracy in patients presenting to the ED with dyspnoea and possible HF.


Higgs EFT for 2HDM and beyond.
We discuss the validity of the Standard Model Effective Field Theory (SM EFT) as the low-energy effective theory for the two-Higgs-doublet Model (2HDM). Using the up-to-date Higgs signal strength measurements at the LHC, one can obtain a likelihood function for the Wilson coefficients of dimension-6 operators in the EFT Lagrangian. Given the matching between the 2HDM and the EFT, the constraints on the Wilson coefficients can be translated into constraints on the parameters of the 2HDM Lagrangian. We discuss under which conditions such a procedure correctly reproduces the true limits on the 2HDM. Finally, we employ the SM EFT to identify the pattern of the Higgs boson couplings that are needed to improve the fit to the current Higgs data. To this end, one needs, simultaneously, to increase the top Yukawa coupling, decrease the bottom Yukawa coupling, and induce a new contact interaction of the Higgs boson with gluons. We comment on how these modifications can be realized in the 2HDM extended by new colored particles.


[Summary of the best evidence for the management of endotracheal intubation and extubation in adult mechanically ventilated patients in intensive care unit based on guidelines and randomized controlled trials].
To summarize the best evidence for extubation management of adult patients with mechanical ventilation in the intensive care unit (ICU), which will provide practical guidelines for medical staffs. BMJ best clinical practice, UpToDate clinical consultants, Guidelines International Network (GIN), National Guideline Clearinghouse (NGC), National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), Registered Nurses' Association of Ontario (RNAO), Medlive guide, Cochrane Library, JBI evidence-based Health Care Center Database, Web of Science, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Ebsco, SinoMed, CNKI, Wanfang Database, etc., were systematically searched. Clinical guidelines, systematic reviews, expert consensus, and randomized controlled trial (RCT) studies were searched from the above database unit August 31st, 2020. Literature quality was evaluated using Appraisal of Guidelines for Research and Evaluation II (AGREE II), JBI quality evaluation tools, and Cochrane risk bias assessment. Two researchers evaluated the quality of the included literature respectively, and then the best evidence of endotracheal intubation and extubation management in ICU adult patients with mechanical ventilation was extracted and summarized. A total of 12 articles were collected, including 2 guidelines, 5 systematic reviews, 2 expert consensus, and 3 RCTs. This paper summarizes 17 best evidences on extubation management of adult patients with mechanical ventilation in ICU, including accurate pre-extubation assessment, personnel and equipment, medication, posture, oxygen therapy, airway management, and post-extubation monitoring. Medical staff should choose the best evidence that meets the requirements of the clinical settings and standardize the management of patients after extubation to reduce the incidence of complications and re-intubation rate to ensure the safety of patients, which will be very important for the management of ICU adult patients with mechanical ventilation after extubation.


Interference of BN 52021 (ginkgolide B) with the bronchopulmonary effects of PAF-acether in the guinea-pig.
The interaction between the ginkgolide BN 52021 and the effects of PAF-acether on the bronchopulmonary system of the guinea-pig was studied. In pentobarbitone or ethyl carbamate-anaesthetized animals, BN 52021 (1 mg/kg i.v. or 10 mg/kg p.o.) inhibited bronchoconstriction, the hematocrit increase and the accompanying thrombopenia and leukopenia induced by PAF-acether (33-100 ng/kg) and failed to block the bronchoconstriction produced by collagen, arachidonic acid and the tripeptide formyl-Met-Leu-Phe (FMLP). BN 52021, 3 mg/kg, reduced the bronchoconstriction induced by aerosolized PAF-acether. BN 52021, 300 microM, also inhibited the superoxide production by PAF-acether-stimulated alveolar macrophages and failed to reduce the same effects when triggered by FMLP (0.01-1 microM). BN 52021 blocked the formation of thromboxane-triggered by PAF-acether (100 ng) injected into perfused lung, under conditions where the effects of arachidonic acid where not modified. Finally, pretreatment of parenchyma lung strips with BN 52021 (100 microM) partially inhibited the contraction induced by PAF-acether (0.1 microM) and suppressed the accompanying release of thromboxane. BN 52021 is a selective antagonist of the effects of PAF-acether on the bronchopulmonary system and on circulating blood cells of the guinea-pig.


Self-proteolysis of the cysteine proteinase, cruzipain, from Trypanosoma cruzi gives a major fragment corresponding to its carboxy-terminal domain.
The major cysteine proteinase (cruzipain) purified from Trypanosoma cruzi epimastigotes catalyzes its own degradation in the presence of beta-mercaptoethanol, at 56 degrees C and pH 6. The reaction is affected by the same inhibitors which inhibit the azocaseinase activity, and yields a major 25-kDa fragment, which contains carbohydrate, few, if any, aromatic amino acids, and presents a proline-rich N-terminus (GPGPXPEP...), in addition to a number of small peptides, which can be isolated by reversed-phase HPLC, but are lost during electrophoresis. The results, together with recently published evidence of Mottram et al. and Eakin et al., are compatible with a structure for cruzipain consisting of a conventional cysteine proteinase moiety, linked to a long C-terminal extension including the 25-kDa fragment, which would contain a high proportion of the carbohydrate and the proline residues present in the original 60-kDa molecule.


History of foot ulcers increases mortality among patients with diabetes in Northern Thailand.
Studies within the Caucasian population with diabetes showed an increased mortality in patients with diabetic foot ulcers. However, there were no such studies based on Asian populations. We therefore designed our study on the association of foot ulcer with mortality within the Asian population. Ninety-seven Asian individuals with diabetes who had previously participated in the 'Multidisciplinary Diabetic Foot Protocol' between 2005 and 2007 at our centre were followed up in 2010 to ascertain their mortality rate. Cox proportional-hazard regression analyses were used to estimate hazard ratios. Forty-seven patients had a history of foot ulcer (group 1), while 50 had none (group 2). The mean follow-up was 43.74 months. Twenty-one patients died during this period (21.65%). The mortality rates in group 1 and group 2 were 15 (31.92%) and six (12.00%), respectively. Patients with a history of foot ulcer had higher mortality rates than those without (hazard ratio 3.51, 95% CI 1.03-11.96, P = 0.04). Our study showed that history of foot ulcer increased mortality. This association appeared to be stronger in younger Asian patients than those in the Caucasian populations.