Enduring language deficits in children of women with epilepsy and the potential role of intrauterine exposure to antiepileptic drugs.
Exposure to certain intrauterine antiepileptic drugs (AEDs) can negatively influence the language skills and intelligence of young children. It remains unanswered whether these deficits are transient or persist as children grow up. This study aims to evaluate the language function of children of women with epilepsy (CWE) aged 9-13 years in comparison with their peers, and its relationship with intrauterine AED exposure. We included 191 CWE in our study from the Kerala Registry of Epilepsy and Pregnancy. Children in the same age group (n = 144) and without maternal epilepsy or antenatal AED exposure served as controls. We used Clinical Examination for Language Function version IV to assess language in both groups. Relevant data related to maternal epilepsy and AED use were obtained from the registry records. The average Core Language Scaled Score (CLSS) was significantly lower in CWE as compared to controls (83.19 vs 90.18, P = .001). Similarly, the mean scaled scores in other language parameters were also significantly lower in CWE. In the multivariate analysis, compared to control children, the average CLSS in CWE was 4.5 units lower (95% confidence interval [CI] = -8.8 to -0.2, P = .04) with AED monotherapy exposure and 7.3 units lower with exposure to AED polytherapy (95% CI = -13.8 to -0.8, P = .03). Intrauterine exposure to phenobarbitone (n = 61) and valproate (n = 55) as either monotherapy or polytherapy showed a negative effect on CLSS in CWE as compared to control children. However, carbamazepine (n = 75) and phenytoin (n = 37) use was not associated with significant variation of CLSS. In head-to-head comparisons between AED monotherapies in CWE, phenobarbitone showed a negative effect on CLSS (-14.7, 95% CI = -23.1 to -6.4, P = .001) as compared to carbamazepine. Intrauterine exposure to phenobarbitone and valproate impairs language development in CWE, with effects persisting into the second decade.


Thiohydrazide complexes of molybdenum and their relevance to reduction of dinitrogen to ammonia.
Aqueous solution of sodium molybdate reacts with aromatic thiohydrazides like thiobenzhydrazide, 2-hydroxythiobenzhydrazide, furan-2-thiohydrazide and thiophen-2-thiohydrazide to form green, neutral diamagnetic 1 : 3 chelates. They were characterized by elemental analysis and spectroscopic methods. Tris(2-hydroxythiobenzhydrazido)molybdenum(vi) was crystallized from benzene and the crystal structure shows that molybdenum(vi) is hexacoordinated to three sulfur and three nitrogen atoms from three identical ligands in facile trigonal prismatic geometry. The OH group is involved in intramolecular and intermolecular hydrogen bonding. The bound ligands of tris(thiohydrazido)molybdenum(vi) undergo a redox reaction differently depending on the solvents. Two complexes of molybdenum bound to those oxidized ligands were isolated and characterized and their structures were also solved. Of them a binuclear complex, containing two MoO2(2+) ions, of the ligand N-2-hydroxybenzoyl-N'-2-hydroxythiobenzoylhydrazine showed some capability to catalyze the reduction of dinitrogen to ammonia by sodium borohydride.


Factors associated with phantom limb pain: a 31/2-year prospective study.
To analyse the prevalence of phantom (limb) pain over time and to analyse factors associated with phantom (limb) pain in a prospective cohort of amputees. A multicentre longitudinal study. One hundred and thirty-four patients scheduled for amputation were included. Patients filled in questionnaires before amputation, and postal questionnaires six months, 1(1/2) years and 2(1/2) years to a maximum of 3(1/2) years after amputation. Preoperative assessment included patients' characteristics, date, side and level of, and reason for amputation. The follow-up questionnaires assessed the frequencies of the experienced phantom pain, prosthetic use and walking distance. The occurrence of phantom pain was defined as phantom pain a few times a day or more frequently. Pre- and postoperative questionnaires were available filled in by 85 amputees (33 females and 52 males). The percentage of lower limb amputees with phantom pain was the highest at six months after amputation, and of upper limb amputees at 1(1/2) years. In general, more women than men experienced phantom pain. One and a half years and 2(1/2) years after amputation the highest percentages of the lower limb amputees used their prosthesis more than 4 hours a day (66%), after that time this percentage decreased to 60%. The results of the two-level logistic regression analysis to predict phantom pain show that phantom pain was less frequently present in men (odds ratio (OR) = 0.12), in lower limb amputees (OR = 0.14) and that it decreased in due course (OR = 0.53 for 1 year). Protective factors for phantom pain are: being male, having a lower limb amputation and the time elapsed since amputation.


Pharmacokinetics of acetaminophen sulfate after oral administration in rats: analysis of plasma profiles exhibiting a non-linear second peak.
The pharmacokinetics of the two-peak plasma profiles of orally administered acetaminophen sulfate (APAPS), a major conjugated metabolite of acetaminophen (APAP), in rats was examined by a two-compartment model having two delivery routes with individual time lags: a direct delivery route of APAPS absorbed in an unchanged form and an indirect one where APAPS was absorbed as APAP after deconjugation in the lower intestine. Pharmacokinetic parameters were estimated by a non-linear least squares program, MULTI(FILT), based on the fast inverse Laplace transform algorithm. Plasma APAPS concentration profiles after oral doses were simulated satisfactorily. In a dose escalation study, the peroral availability of APAPS derived from the direct route was not changed significantly with the doses. However, that from the indirect route was decreased with the dose escalation, suggesting the contribution of a capacity-limited deconjugation of APAPS to APAP by the intestinal microflora to the non-linear pharmacokinetics of orally administered APAPS. The absorption of peroral APAPS in rats at a dose range of 30 to 120 mg APAP eq/kg could be summarized as follows: (1) approximately 25% (22 to 32%) of orally administered APAPS are absorbed from the gastrointestinal tract in an unchanged form; (2) more than 50% (50 to 98%) are deconjugated to APAP in the lower intestinal tract; and (3) the latter plays a significant role as an indirect and non-linear APAPS delivery system because considerable amounts of APAP thus absorbed are rapidly reconjugated to APAPS in the systemic circulation, which gives the second plasma APAPS peak.


Clinicians' and public acceptability of universal risk-of-death screening for older people in routine clinical practice in Australia: cross-sectional surveys.
Clinicians' delays to identify risk of death and communicate it to patients nearing the end of life contribute to health-related harm in health services worldwide. This study sought to ascertain doctors, nurses and senior members of the public's perceptions of the routine use of a screening tool to predict risk of death for older people. Cross-sectional online, face-to-face and postal survey of 360 clinicians and 497 members of the public. Most (65.9%) of the members of the public welcomed (and 12.3% were indifferent to) the use of a screening tool as a decision guide to minimise overtreatment and errors from clinician assumptions. Supporters of the use of a prognostic tool were likely to be males with high social capital, chronically ill and who did not have an advance health directive. The majority of clinicians (75.6%) reported they were likely or very likely to use the tool, or might consider using it if convinced of its accuracy. A minority (13.3%) stated they preferred to rely on their clinical judgement and would be unlikely to use it. Differentials in support for tools by seniority were observed, with more support expressed by nurses, interns and registrars than medical specialists (χ2 = 12.95, p = 0.044) and by younger (< 40 years) clinicians (81.2% vs. 71.2%, p = 0.0058). The concept of integrating prognostication of death in routine practice was not resisted by either target group. Findings indicate that screening for risk of death is seen as potentially useful and suggests the readiness for a culture change. Future research on implementation strategies could be a step in the right direction.


Eliciting risk preferences that predict risky health behavior: A comparison of two approaches.
Information on attitudes to risk could increase understanding of and explain risky health behaviors. We investigate two approaches to eliciting risk preferences in the health domain, a novel "indirect" lottery elicitation approach with health states as outcomes and a "direct" approach where respondents are asked directly about their willingness to take risks. We compare the ability of the two approaches to predict health-related risky behaviors in a general adult population. We also investigate a potential framing effect in the indirect lottery elicitation approach. We find that risk preferences elicited using the direct approach can better predict health-related risky behavior than those elicited using the indirect approach. Moreover, a seemingly innocuous change to the framing of the lottery question results in significantly different risk preference estimates, and conflicting conclusions about the ability of the indicators to predict risky health behaviors.


Silencing JARID1B suppresses oncogenicity, stemness and increases radiation sensitivity in human oral carcinoma.
Oral squamous cell carcinoma (OSCC) is a major cause of human mortality globally and radiotherapy is one of the main treatment modalities, however its therapeutic effect is often limited by radioresistance. JARID1B is an epigenetic factor with reported oncogenic potential in various cancer types. We investigated the effect of JARID1B inhibition on migration and invasion of human OSCC cell lines, as well as on clinical patients' outcome. Wound healing, matrigel invasion, Sulforhodamine B, and spheroid formation assays were used to characterize the signaling pathways of shJARID1B in response to radiation treatment. We evaluated the prognostic relevance of Jarid1b expression in a cohort of 81 OSCC patients. Human OSCC cell lines, including SAS, HSC3, Cal27, TW2.6 and SCC4 cells, were used. shJARID1B cells significantly inhibited migration and invasion ability compared to their vector or wild type counterparts. Silencing shJARID1B significantly inhibited oral cancer stem cell activity and potentiated the tumor-inhibitory activity of radiation therapy in OSCC. Radiotherapy coupled with shJARID1B knockdown reduced mRNA levels of NQO1, KEAP1, NRF2, FOXO1, FOXO3, KLF4, OCT4, CD133, and Nanog in malignant OSCC cells. OSCC spheroid formation ability was markedly reduced in the shJARID1B cells. JARID1B overexpression is a dependent prognostic factor in OSCC patients. Silencing shJARID1B inhibits migration and invasion of human OSCC, reduces cancer stem cell activities and potentiates tumor-inhibiting radiotherapeutic effects. JARID1B knockdown prior to radiotherapy is a potential effective therapeutic strategy for the treatment of OSCC.


A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn's disease.
A distinct clinical phenotype has been demonstrated for ulcerative colitis with concomitant primary sclerosing cholangitis (PSC). The course and behaviour of Crohn's disease (CD) with PSC has, in contrast, never been defined. We aimed to define the characteristics of patients with concomitant PSC and CD. The Oxford PSC and IBD databases were abstracted for: PSC subtype, date of diagnosis, symptom onset, smoking history, Mayo Clinic PSC score and outcomes (hepatic failure, liver transplantation, Montréal CD classification, treatment, cancer and death). Patients with PSC/CD were matched 1:2 to two control groups: one with PSC/UC and one with isolated CD. 240 patients with PSC were identified; 32 (13%) with CD, 129 (54%) with co-existing UC, and 79 had PSC without IBD. For PSC/CD vs. CD controls, isolated ileal CD was less common (6% vs. 31%, p=0.03). Smoking was less common in PSC/CD (13% vs. 34%, p=0.045). No difference in the distribution of CD, or treatment required was observed. For PSC/CD vs. PSC/UC controls, more patients with PSC/CD were female (50% vs. 28%, p=0.021). 22% of PSC/CD patients had small duct PSC compared with 6% with PSC/UC, (p=0.038). Major event-free survival was prolonged in the PSC/CD group compared with PSC/UC, (Cox regression p=0.04). Unlike PSC/UC, patients with PSC/CD were as likely to be female as male, more commonly had small duct PSC and less commonly progressed to cancer, liver transplantation, or death. Compared to patients with isolated CD, patients with PSC/CD were less likely to smoke or have ileal disease.


CX3CL1 promotes MMP-3 production via the CX3CR1, c-Raf, MEK, ERK, and NF-κB signaling pathway in osteoarthritis synovial fibroblasts.
Osteoarthritis (OA) is a degenerative joint disease that affects the cartilage, synovium, and subchondral bone and is the leading cause of disability in older populations. Specific diagnostic biomarkers are lacking; hence, treatment options for OA are limited. Synovial inflammation is very common in OA joints and has been associated with both OA's symptoms and pathogenesis. Confirming the role of the synovium in OA pathogenesis is a promising strategy for mitigating the symptoms and progression of OA. CX3CL1 is the only member of the CX3C class of chemokines that combines the properties of chemoattractants and adhesion molecules. CX3CL1 levels in the synovium and serum were both discovered to be positively associated with OA pathogenesis. CX3CL1 and its receptor CX3CR1 belong to a family of G protein-coupled receptors. Matrix metalloproteinases (MMPs), which are responsible for matrix degradation, play a crucial role in OA progression. The relationship between CX3CL1 and MMPs in the pathophysiology of OA is still unclear. CX3CL1-induced MMP-3 production was assessed with quantitative real-time PCR and ELISA. The mechanisms of action of CX3CL1 in different signaling pathways were studied using western blot analysis, quantitative real-time PCR and ELISA. Neutralization antibodies of integrin were achieved to block the CX3CR1 signaling pathway. Luciferase assays were used to study NF-κB promoter activity. We investigated the signaling pathway involved in CX3CL1-induced MMP-3 production in osteoarthritis synovial fibroblasts (OASFs). CX3CL1 was found to induce MMP-3 production in a concentration-dependent and time-dependent manner. Using pharmacological inhibitors and CX3CR1 small interfering RNA to block CX3CR1 revealed that the CX3CR1 receptor was involved in the CX3CL1-mediated upregulation of MMP-3. CX3CL1-mediated MMP-3 production was attenuated by c-Raf inhibitors (GW5074) and MEK/ERK inhibitors (PD98059 and U0126). The OASFs were stimulated using CX3CL1-activated p65 phosphorylation. Our results demonstrate that CX3CL1 activates c-Raf, MEK, ERK, and NF-κB on the MMP-3 promoter through CX3CR1, thus contributing to cartilage destruction during OA.


The provision of aids and adaptations, risk assessments, and incident reporting and recording procedures in relation to injury prevention for adults with intellectual disabilities: cohort study.
Adults with intellectual disabilities (IDs) experience a higher incidence of injury, compared with the general population. The aim of this study was to investigate the provision of aids and adaptations, residential service providers' individual risk assessments and training in these, and injury incident recording and reporting procedures, in relation to injury prevention. Interviews were conducted with a community-based cohort of adults with IDs (n = 511) who live in Greater Glasgow, Scotland, UK and their key carer (n = 446). They were asked about their aids and adaptations at home, and paid carers (n = 228) were asked about individual risk assessments, their training, and incident recording and reporting procedures. Four hundred and twelve (80.6%) of the adults with IDs had at least one aid or adaptation at home to help prevent injury. However, a proportion who might benefit, were not in receipt of them, and surprisingly few had temperature controlled hot water or a bath thermometer in place to help prevent burns/scalds, or kitchen safety equipment to prevent burns/scalds from electric kettles or irons. Fifty-four (23.7%) of the paid carers were not aware of the adult they supported having had any risk assessments, and only 142 (57.9%) had received any training on risk assessments. Considerable variation in incident recording and reporting procedures was evident. More work is needed to better understand, and more fully incorporate, best practice injury prevention measures into routine support planning for adults with IDs within a positive risk-taking and risk reduction framework.


Multifactorial interventions for preventing falls in older people living in the community: a systematic review and meta-analysis of 41 trials and almost 20 000 participants.
To assess the longer term effects of multifactorial interventions for preventing falls in older people living in the community, and to explore whether prespecific trial-level characteristics are associated with greater fall prevention effects. Systematic review with meta-analysis and meta-regression. MEDLINE, EMBASE, CINHAL, CENTRAL and trial registries were searched up to 25 July 2018. We included randomised controlled trials (≥12 months' follow-up) evaluating the effects of multifactorial interventions on falls in older people aged 65 years and over, living in the community, compared with either usual care or usual care plus advice. Two authors independently verified studies for inclusion, assessed risk of bias and extracted data. Rate ratios (RaR) with 95% CIs were calculated for rate of falls, risk ratios (RR) for dichotomous outcomes and standardised mean difference for continuous outcomes. Data were pooled using a random effects model. The Grading of Recommendations, Assessment, Development and Evaluation was used to assess the quality of the evidence. We included 41 trials totalling 19 369 participants; mean age 72-85 years. Exercise was the most common prespecified component of the multifactorial interventions (85%; n=35/41). Most trials were judged at unclear or high risk of bias in ≥1 domain. Twenty trials provided data on rate of falls and showed multifactorial interventions may reduce the rate at which people fall compared with the comparator (RaR 0.79, 95% CI 0.70 to 0.88; 20 trials; 10 116 participants; I2=90%; low-quality evidence). Multifactorial interventions may also slightly lower the risk of people sustaining one or more falls (RR 0.95, 95% CI 0.90 to 1.00; 30 trials; 13 817 participants; I2=56%; moderate-quality evidence) and recurrent falls (RR 0.88, 95% CI 0.78 to 1.00; 15 trials; 7277 participants; I2=46%; moderate-quality evidence). However, there may be little or no difference in other fall-related outcomes, such as fall-related fractures, falls requiring hospital admission or medical attention and health-related quality of life. Very few trials (n=3) reported on adverse events related to the intervention. Prespecified subgroup analyses showed that the effect on rate of falls may be smaller when compared with usual care plus advice as opposed to usual care only. Overall, heterogeneity remained high and was not explained by the prespecified characteristics included in the meta-regression. Multifactorial interventions (most of which include exercise prescription) may reduce the rate of falls and slightly reduce risk of older people sustaining one or more falls and recurrent falls (defined as two or more falls within a specified time period). CRD42018102549.


Niemann-Pick Type C2 Protein Mediates Hepatic Stellate Cells Activation by Regulating Free Cholesterol Accumulation.
In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and so it is important to identify the molecules that regulate HSCs activation and liver fibrosis. Niemann-Pick type C2 (NPC2) protein plays an important role in the regulation of intracellular cholesterol homeostasis by directly binding with free cholesterol. However, the roles of NPC2 in HSCs activation and liver fibrosis have not been explored in detail. Since a high-cholesterol diet exacerbates liver fibrosis progression in both rodents and humans, we propose that the expression of NPC2 affects free cholesterol metabolism and regulates HSCs activation. In this study, we found that NPC2 is decreased in both thioacetamide- and carbon tetrachloride-induced liver fibrosis tissues. In addition, NPC2 is expressed in quiescent HSCs, but its activation status is down-regulated. Knockdown of NPC2 in HSC-T6 cells resulted in marked increases in transforming growth factor-β1 (TGF-β1)-induced collagen type 1 α1 (Col1a1), α-smooth muscle actin (α-SMA) expression, and Smad2 phosphorylation. In contrast, NPC2 overexpression decreased TGF-β1-induced HSCs activation. We further demonstrated that NPC2 deficiency significantly increased the accumulation of free cholesterol in HSCs, increasing Col1a1 and α-SMA expression and activating Smad2, and leading to sensitization of HSCs to TGF-β1 activation. In contrast, overexpression of NPC2 decreased U18666A-induced free cholesterol accumulation and inhibited the subsequent HSCs activation. In conclusion, our study has demonstrated that NPC2 plays an important role in HSCs activation by regulating the accumulation of free cholesterol. NPC2 overexpression may thus represent a new treatment strategy for liver fibrosis.


Function and distribution of 5-HT2 receptors in the honeybee (Apis mellifera).
Serotonin plays a pivotal role in regulating and modulating physiological and behavioral processes in both vertebrates and invertebrates. In the honeybee (Apis mellifera), serotonin has been implicated in division of labor, visual processing, and learning processes. Here, we present the cloning, heterologous expression, and detailed functional and pharmacological characterization of two honeybee 5-HT2 receptors. Honeybee 5-HT2 receptor cDNAs were amplified from brain cDNA. Recombinant cell lines were established constitutively expressing receptor variants. Pharmacological properties of the receptors were investigated by Ca(2+) imaging experiments. Quantitative PCR was applied to explore the expression patterns of receptor mRNAs. The honeybee 5-HT2 receptor class consists of two subtypes, Am5-HT2α and Am5-HT2β. Each receptor gene also gives rise to alternatively spliced mRNAs that possibly code for truncated receptors. Only activation of the full-length receptors with serotonin caused an increase in the intracellular Ca(2+) concentration. The effect was mimicked by the agonists 5-methoxytryptamine and 8-OH-DPAT at low micromolar concentrations. Receptor activities were blocked by established 5-HT receptor antagonists such as clozapine, methiothepin, or mianserin. High transcript numbers were detected in exocrine glands suggesting that 5-HT2 receptors participate in secretory processes in the honeybee. This study marks the first molecular and pharmacological characterization of two 5-HT2 receptor subtypes in the same insect species. The results presented should facilitate further attempts to unravel central and peripheral effects of serotonin mediated by these receptors.


Bilayers of Janus WSSe: monitoring the stacking type via the vibrational spectrum.
Motivated by the recent successful synthesis of Janus type single layers of transition metal dichalcogenides, we investigate the stability, vibrational and electronic properties of the Janus single layer structure of WSSe and its bilayers by means of density functional theory. The structural and vibrational analysis show that the Janus single layer of WSSe forms a dynamically stable structure in the 2H phase. Owing to its non-centrosymmetric structure, the Janus WSSe single layer has two in-plane (E) and two out-of-plane (A) Raman active phonon modes. The eigen-frequencies of the prominent Raman active modes are calculated to be 277 (A) and 322 (E) cm-1. Similar to single layer WS2 and WSe2, Janus WSSe is a direct band gap semiconductor that has two electronically different faces. In addition, the possible bilayer stacking orders of the Janus WSSe single layers are investigated. It is found that there are 3 stacking types of bilayer Janus WSSe and each stacking type has distinctive Raman characteristics in its vibrational spectrum. Our results show that thanks to the vibrational characteristics, which stem from the distinctive interlayer interactions at different sides, the stability and stacking types of the bilayer of WSSe Janus structure can be monitored.


Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis.
A single set of conditions consisting of a palladium catalyst, a commercially available ligand, and a base, allow for several types of C-N bond constructions to be conducted in water with the aid of a commercially available "designer" surfactant (TPGS-750-M). Products containing a protected NH2 group in the form of a carbamate, sulfonamide, or urea can be fashioned starting with aryl or heteroaryl bromides, iodides, and in some cases, chlorides, as substrates. Reaction temperatures are in the range of room temperature to, at most, 50 °C, and result in essentially full conversion and good isolated yields.


In situ Stiffness Adjustment of AFM Probes by Two Orders of Magnitude.
The choice on which type of cantilever to use for Atomic Force Microscopy (AFM) depends on the type of the experiment being done. Typically, the cantilever has to be exchanged when a different stiffness is required and the entire alignment has to be repeated. In the present work, a method to adjust the stiffness in situ of a commercial AFM cantilever is developed. The adjustment is achieved by changing the effective length of the cantilever by electrostatic pull-in. By applying a voltage between the cantilever and an electrode (with an insulating layer at the point of contact), the cantilever snaps to the electrode, reducing the cantilever's effective length. An analytical model was developed to find the pull-in voltage of the system. Subsequently, a finite element model was developed to study the pull-in behavior. The working principle of this concept is demonstrated with a proof-of-concept experiment. The electrode was positioned close to the cantilever by using a robotic nanomanipulator. To confirm the change in stiffness, the fundamental resonance frequency of the cantilever was measured for varying electrode positions. The results match with the theoretical expectations. The stiffness was adjusted in situ in the range of 0.2 N/m to 27 N/m, covering two orders of magnitude in one single cantilever. This proof-of-concept is the first step towards a micro fabricated prototype, that integrates the electrode positioning system and cantilever that can be used for actual AFM experiments.


Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae.
If not properly processed and repaired, DNA double-strand breaks (DSBs) can give rise to deleterious chromosome rearrangements, which could ultimately lead to the tumour phenotype. DSB ends are resected in a 5' to 3' fashion in cells, to yield single-stranded DNA (ssDNA) for the recruitment of factors critical for DNA damage checkpoint activation and repair by homologous recombination. The resection process involves redundant pathways consisting of nucleases, DNA helicases and associated proteins. Being guided by recent genetic studies, we have reconstituted the first eukaryotic ATP-dependent DNA end-resection machinery comprising the Saccharomyces cerevisiae Mre11-Rad50-Xrs2 (MRX) complex, the Sgs1-Top3-Rmi1 complex, Dna2 protein and the heterotrimeric ssDNA-binding protein RPA. Here we show that DNA strand separation during end resection is mediated by the Sgs1 helicase function, in a manner that is enhanced by Top3-Rmi1 and MRX. In congruence with genetic observations, although the Dna2 nuclease activity is critical for resection, the Mre11 nuclease activity is dispensable. By examining the top3 Y356F allele and its encoded protein, we provide evidence that the topoisomerase activity of Top3, although critical for the suppression of crossover recombination, is not needed for resection either in cells or in the reconstituted system. Our results also unveil a multifaceted role of RPA, in the sequestration of ssDNA generated by DNA unwinding, enhancement of 5' strand incision, and protection of the 3' strand. Our reconstituted system should serve as a useful model for delineating the mechanistic intricacy of the DNA break resection process in eukaryotes.


The survivin:fas ratio in pediatric renal tumors.
Apoptosis factors inducing or preventing cell death may govern the behavior of certain tumors. Fas is a pro-apoptotic receptor that induces cell death when bound by its ligand and is expressed at greater levels in pediatric renal tumors of good prognosis. Survivin is a novel inhibitor of apoptosis that is expressed in a cell cycle-dependent manner and is abundantly expressed in several tumors of unfavorable histology. This study evaluates the expression of survivin, as well as the prognostic value of the survivin:fas ratio in various types and stages of pediatric renal tumors. Multiple apoptosis mRNA species were quantified by Rnase protection assay (RPA) in 32 pediatric renal tumors and adjacent normal kidney specimens before chemotherapy: Wilms' tumor (WT), n = 9; clear cell sarcoma (CCS), n = 4; rhabdoid tumor of the kidney (RTK), n = 5; mesoblastic nephroma (MN), n = 3 and normal kidney, n = 11. Western Blot and immunocytochemistry were used to confirm survivin protein expression in a selective specimen survey. Follow-up data were obtained on patient outcomes, and antiapoptotic to proapoptotic ratios were calculated and correlated with clinical recurrence of disease. Pediatric renal tumors express greater levels of both pro- and antiapoptotic factors than normal kidney. Survivin and fas appeared to be expressed differentially in the tumor specimens sampled. Five of 10 (50%) tumors that went on to recur expressed survivin, whereas survivin was present in only 2 of 11 (18%) nonrecurrent tumors. Conversely, only 2 of 10 (20%) tumors that recurred were fas positive, whereas 5 of 11 (45%) tumors that did not recur expressed fas. The mean survivin:fas ratio was significantly greater in the 10 tumors that went on to recur after treatment (4 RTK, 3 CCS, 3 WT), than in tumors not recurring (2.16+/-1.4 v 1.0+/-1.07; P =.01, Kruskal-Wallis test). The positive predictive value of tumor recurrence was 85.7% (CI: 42.1%, 99.6%) and the negative predictive value was 71.4% (CI: 41.9%, 91.6%) when a cutoff ratio of 1.6 was considered. The survivin:fas mRNA ratio is of prognostic value in its ability to predict recurrent disease in children undergoing treatment for pediatric renal tumors. In this series, a ratio of greater than 1.6 predicted recurrent disease with a high probability irrespective of clinical stage or pathologic type. Determining the survivin:fas ratio may guide treatment, follow-up and counseling of patients with pediatric renal tumors.


Hospital outbreak of Middle East respiratory syndrome coronavirus.
In September 2012, the World Health Organization reported the first cases of pneumonia caused by the novel Middle East respiratory syndrome coronavirus (MERS-CoV). We describe a cluster of health care-acquired MERS-CoV infections. Medical records were reviewed for clinical and demographic information and determination of potential contacts and exposures. Case patients and contacts were interviewed. The incubation period and serial interval (the time between the successive onset of symptoms in a chain of transmission) were estimated. Viral RNA was sequenced. Between April 1 and May 23, 2013, a total of 23 cases of MERS-CoV infection were reported in the eastern province of Saudi Arabia. Symptoms included fever in 20 patients (87%), cough in 20 (87%), shortness of breath in 11 (48%), and gastrointestinal symptoms in 8 (35%); 20 patients (87%) presented with abnormal chest radiographs. As of June 12, a total of 15 patients (65%) had died, 6 (26%) had recovered, and 2 (9%) remained hospitalized. The median incubation period was 5.2 days (95% confidence interval [CI], 1.9 to 14.7), and the serial interval was 7.6 days (95% CI, 2.5 to 23.1). A total of 21 of the 23 cases were acquired by person-to-person transmission in hemodialysis units, intensive care units, or in-patient units in three different health care facilities. Sequencing data from four isolates revealed a single monophyletic clade. Among 217 household contacts and more than 200 health care worker contacts whom we identified, MERS-CoV infection developed in 5 family members (3 with laboratory-confirmed cases) and in 2 health care workers (both with laboratory-confirmed cases). Person-to-person transmission of MERS-CoV can occur in health care settings and may be associated with considerable morbidity. Surveillance and infection-control measures are critical to a global public health response.


Effects of remediation on the bacterial community of an acid mine drainage impacted stream.
Acid mine drainage (AMD) represents a global threat to water resources, and as such, remediation of AMD-impacted streams is a common practice. During this study, we examined bacterial community structure and environmental conditions in a low-order AMD-impacted stream before, during, and after remediation. Bacterial community structure was examined via polymerase chain reaction amplification of 16S rRNA genes followed by denaturing gradient gel electrophoresis. Also, bacterial abundance and physicochemical data (including metal concentrations) were collected and relationships to bacterial community structure were determined using BIO-ENV analysis. Remediation of the study stream altered environmental conditions, including pH and concentrations of some metals, and consequently, the bacterial community changed. However, remediation did not necessarily restore the stream to conditions found in the unimpacted reference stream; for example, bacterial abundances and concentrations of some elements, such as sulfur, magnesium, and manganese, were different in the remediated stream than in the reference stream. BIO-ENV analysis revealed that changes in pH and iron concentration, associated with remediation, primarily explained temporal alterations in bacterial community structure. Although the sites sampled in the remediated stream were in relatively close proximity to each other, spatial variation in community composition suggests that differences in local environmental conditions may have large impacts on the microbial assemblage.


High knee abduction moments are common risk factors for patellofemoral pain (PFP) and anterior cruciate ligament (ACL) injury in girls: is PFP itself a predictor for subsequent ACL injury?
Identifying risk factors for knee pain and anterior cruciate ligament (ACL) injury can be an important step in the injury prevention cycle. We evaluated two unique prospective cohorts with similar populations and methodologies to compare the incidence rates and risk factors associated with patellofemoral pain (PFP) and ACL injury. The 'PFP cohort' consisted of 240 middle and high school female athletes. They were evaluated by a physician and underwent anthropometric assessment, strength testing and three-dimensional landing biomechanical analyses prior to their basketball season. 145 of these athletes met inclusion for surveillance of incident (new) PFP by certified athletic trainers during their competitive season. The 'ACL cohort' included 205 high school female volleyball, soccer and basketball athletes who underwent the same anthropometric, strength and biomechanical assessment prior to their competitive season and were subsequently followed up for incidence of ACL injury. A one-way analysis of variance was used to evaluate potential group (incident PFP vs ACL injured) differences in anthropometrics, strength and landing biomechanics. Knee abduction moment (KAM) cut-scores that provided the maximal sensitivity and specificity for prediction of PFP or ACL injury risk were also compared between the cohorts. KAM during landing above 15.4 Nm was associated with a 6.8% risk to develop PFP compared to a 2.9% risk if below the PFP risk threshold in our sample. Likewise, a KAM above 25.3 Nm was associated with a 6.8% risk for subsequent ACL injury compared to a 0.4% risk if below the established ACL risk threshold. The ACL-injured athletes initiated landing with a greater knee abduction angle and a reduced hamstrings-to-quadriceps strength ratio relative to the incident PFP group. Also, when comparing across cohorts, the athletes who suffered ACL injury also had lower hamstring/quadriceps ratio than the players in the PFP sample (p<0.05). In adolescent girls aged 13.3 years, >15 Nm of knee abduction load during landing is associated with greater likelihood of developing PFP. Also, in girls aged 16.1 years who land with >25 Nm of knee abduction load during landing are at increased risk for both PFP and ACL injury.


Limited nucleotide changes in the Rev response element (RRE) during HIV-1 infection alter overall Rev-RRE activity and Rev multimerization.
HIV-1 Rev and the Rev response element (RRE) enable a critical step in the viral replication cycle by facilitating the nuclear export of intron-containing mRNAs, yet their activities have rarely been analyzed in natural infections. This study characterized their genetic and functional variation in a small cohort of HIV-infected individuals. Multiple Rev and RRE sequences were obtained using single-genome sequencing (SGS) of plasma samples collected within 6 months after seroconversion and at a later time. This allowed the identification of cognate sequences that were linked in vivo in the same viral genome and acted together as a functional unit. Phylogenetic analyses of these sequences indicated that 4/5 infections were founded by a single transmission event. Rev and RRE variants from each time point were subjected to functional analysis as both cognate pairs and as individual components. While a range of Rev-RRE activities were seen, the activity of cognate pairs from a single time point clustered to a discrete level, which was termed the set point. In 3/5 patients, this set point changed significantly over the time period studied. In all patients, RRE activity was more sensitive to sequence variation than Rev activity and acted as the primary driver of the cognate set point. Selected patient RREs were also shown to have differences in Rev multimerization using gel shift binding assays. Thus, rather than acting as a simple on-off switch or maintaining a constant level of activity throughout infection, the Rev-RRE system can fluctuate, presumably to control replication.


Delta-tocotrienol supplementation improves biochemical markers of hepatocellular injury and steatosis in patients with nonalcoholic fatty liver disease: A randomized, placebo-controlled trial.
The aim of this study was to examine the effects of delta-tocotrienol (δ-tocotrienol) supplementation on biochemical markers of hepatocellular injury and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). The study design was a two-group, randomized, double-blind, placebo-controlled trial. The patients with NAFLD were randomly assigned to receive δ-tocotrienol 300 mg twice daily or placebo for 24 weeks. The primary endpoints were change from baseline in fatty liver index (FLI) and homeostasis model of insulin resistance (HOMA-IR) after 24 weeks. Secondary endpoints included change from baseline in high sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), alanine transaminase (ALT), aspartate transaminase (AST) and grading of hepatic steatosis on ultrasound. Between-group differences were tested for significance using ANCOVA. Mean differences (MD) with 95 % CIs are reported. A total of 71 patients (tocotrienol=35, placebo=36) were randomized and included in the intention to treat analysis. Compared with placebo, δ-tocotrienol significantly reduced (MD [95 % CI]) FLI (-8.52 [-10.7, -6.3]; p < 0.001); HOMA-IR (-0.37 [-0.53, -0.21]; p < 0.001), hs-CRP (-0.61[-0.81, -0.42]; p < 0.001), MDA (-0.91 [-1.20, -0.63]; p < 0.001), ALT (-8.86 [-11.5, -6.2]; p < 0.001) and AST (-6.6 [-10.0, -3.08]; p < 0.001). Hepatic steatosis was also reduced by a significantly greater extent with tocotrienol than with placebo (p =0.047). No adverse events were reported. δ-tocotrienol effectively improved biochemical markers of hepatocellular injury and steatosis in patients with NAFLD. δ-tocotrienol supplementation might be considered as a therapeutic option in the management of patients with NAFLD. Sri Lankan Clinical Trials Registry (SLCTR/2015/023, 2015-10-03).


Dependence of delayed afterdepolarizations on diastolic potentials in ischemic Purkinje fibers.
The mechanism of focal rhythms 1 day after myocardial infarction has been ascribed to both abnormal automaticity and triggered activity arising from delayed after-depolarizations (DADs). During the course of superfusion in vitro, diastolic potentials repolarize to more negative resting potentials. The dependence of DADs and triggered activity on diastolic potentials was studied using extrinsic currents. During sustained activity (maximum diastolic potential = -61 +/- 7 mV), hyperpolarizing current decreased the DADs, rendered them subthreshold, and terminated triggered activity. During the quiescence caused by constant hyperpolarizing current, a stimulated train of action potentials produced DADs. Decreasing the current permitted augmented DADs. In quiescent preparations (resting potential = -68 +/- 7 mV), a train of stimulated action potentials was followed by subthreshold DADs. Depolarizing current increased the DAD amplitude. To exclude depolarization-induced automaticity, constant currents were applied without a previous train of stimuli. Neither DADs nor triggered activity were evoked. Therefore, DADs and triggered activity, postinfarction, depend on the diastolic potential. There is a continuity between subthreshold DADs and sustained activity. DADs may reach a magnitude in which extrinsic interventions may not adequately terminate sustained triggered activity.


Normal human variation: refocussing the enhancement debate.
This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range.


Relativistic correction of atomic scattering factors for high-energy electron diffraction.
Relativistic electron diffraction depends on linear and quadratic terms in the electric potential, the latter being neglected in the frequently used relativistically corrected Schrödinger equation. The quadratic electric potential term modifies atomic scattering amplitudes in particular for large-angle scattering and backscattering. The respective correction increases with increasing scattering angle, increasing atomic number and increasing kinetic energy. Conventional tabulations for electron scattering and its large-angle extrapolations can be amended in closed form by a universal correction based on the screened Coulomb potential squared.


Thermometric sensing of nitrofurantoin by noncovalently imprinted polymers containing two complementary functional monomers.
Molecularly imprinted polymers (MIPs) for nitrofurantoin (NFT) recognition addressing in parallel of two complementary functional groups were created using a noncovalent imprinting approach. Specific tailor-made functional monomers were synthesized: a diaminopyridine derivative as the receptor for the imide residue and three (thio)urea derivatives for the interaction with the nitro group of NFT. A significantly improved binding of NFT to the new MIPs was revealed from the imprinting factor, efficiency of binding, affinity constants and maximum binding number as compared to previously reported MIPs, which addressed either the imide or the nitro residue. Substances possessing only one functionality (either the imide group or nitro group) showed significantly weaker binding to the new imprinted polymers than NFT. However, the compounds lacking both functionalities binds extremely weak to all imprinted polymers. The new imprinted polymers were applied in a flow-through thermistor in organic solvent for the first time. The MIP-thermistor allows the detection of NFT down to a concentration of 5 μM in acetonitrile + 0.2% dimethyl sulfoxide (DMSO). The imprinting factor of 3.91 at 0.1 mM of NFT as obtained by thermistor measurements is well comparable to the value obtained by batch binding experiments.


Decreased lymphocyte responses in free-ranging bottlenose dolphins (Tursiops truncatus) are associated with increased concentrations of PCBs and DDT in peripheral blood.
Since 1987, large-scale mortalities of dolphins have been reported along the Atlantic coast of North America, in the Gulf of Mexico, and in the Mediterranean Sea. Autopsied bottlenose dolphins, Tursiops truncatus, which were collected from the large-scale mortality along the Atlantic coast in 1987 to 1988, exhibited opportunistic infections indicative of immune dysfunction. Further, these animals had high levels of chlorinated hydrocarbons, such as PCBs and DDT, that can suppress immune functions. The purpose of this study was to determine whether there is a relationship between chemical contaminant exposure and immune response in free-ranging dolphins. In June of 1991, peripheral blood was obtained from members of a bottlenose dolphin population that resides along the west coast of Florida. Peripheral blood lymphocyte responses to Concanavalin A (Con A) and phytohemagglutinin (PHA) were determined in vitro and compared by regression analysis with contaminant concentrations in whole blood from a small subset of these animals (n = 5). These data indicate that a reduced immune response in these bottlenose dolphins was correlated with increasing whole blood concentrations of several contaminants. Specifically, inverse correlations were found between Con A-induced lymphocyte proliferation and tetrachlorinated to octachlorinated biphenyls (r2 values ranged from 0.70 to 0.87). Con A-induced lymphocyte responses also correlated inversely with p,p'DDT (r2 values of 0.73 and 0.79); o.p'-DDE (r2 values of 0.93 and 0.96); and p,p'-DDE (r2 values of 0.73 and 0.81).


Reticulocyte parameters of delta beta thalassaemia trait, beta thalassaemia trait and iron deficiency anaemia.
To analyse the differences in reticulocyte indices between delta beta thalassaemia trait (δβ-TT), beta thalassaemia trait (β-TT) and iron deficiency anaemia (IDA), and to correlate those differences with the physiopathological features of these three types of microcytoses. We performed a descriptive study of 428 samples (43 δβ-TT, 179 β-TT and 206 IDA) that were run on Advia 2120 analyser (Siemens). The following reticulocyte indices were assessed: absolute reticulocyte count (ARC), percentage of reticulocytes, mean corpuscular volume of reticulocytes (MCVr), haemoglobin content of reticulocytes (CHr), mean corpuscular haemoglobin concentration of reticulocytes, red blood cell distribution width of reticulocytes (RDWr), haemoglobin distribution width of reticulocytes (HDWr) and reticulocyte subpopulations based on their fluorescence according to mRNA (low (L-R), medium (M-R) and high (H-R)), MCV ratio and MCHC ratio. Correlation between fetal haemoglobin (HbF) and RDWr in patients with thalassaemia was evaluated. RDWr was significantly higher in δβ-TT compared with β-TT (15.03% vs 13.82%, p<0.001), and so were HDWr (3.65% vs 3.27%, p<0.001), CHr (23.68 vs 22.66 pg, p<0.001) and MCVr (88.3 vs 85.5 fL, p<0.001). A good correlation was observed between HbF and RDWr (r=0.551, p<0.001). IDA subjects have more immature reticulocytes, but less ARC than β-TT, suggesting a certain degree of inefficient erythropoiesis in IDA in comparison with β-TT. Previously described differences between δβ-TT, β-TT and IDA in the corpuscular indices of mature red blood cell can also be observed in reticulocytes. The degree of anisocytosis in reticulocytes from patients with thalassaemia is correlated with HbF.


A study of the water molecule using frequency control over nuclear dynamics in resonant X-ray scattering.
In this combined theoretical and experimental study we report a full analysis of the resonant inelastic X-ray scattering (RIXS) spectra of H2O, D2O and HDO. We demonstrate that electronically-elastic RIXS has an inherent capability to map the potential energy surface and to perform vibrational analysis of the electronic ground state in multimode systems. We show that the control and selection of vibrational excitation can be performed by tuning the X-ray frequency across core-excited molecular bands and that this is clearly reflected in the RIXS spectra. Using high level ab initio electronic structure and quantum nuclear wave packet calculations together with high resolution RIXS measurements, we discuss in detail the mode coupling, mode localization and anharmonicity in the studied systems.


The variability of standard artificial soils: behaviour, extractability and bioavailability of organic pollutants.
Artificial soil is an important standard medium and reference material for soil ecotoxicity bioassays. Recent studies have documented the significant variability of their basic properties among different laboratories. Our study investigated (i) the variability of ten artificial soils from different laboratories by means of the fate, extractability and bioavailability of phenanthrene and lindane, and (ii) the relationships of these results to soil properties and ageing. Soils were spiked with (14)C-phenanthrene and (14)C-lindane, and the total residues, fractions extractable by hydroxypropyl-β-cyclodextrin, and the fractions of phenanthrene mineralizable by bacteria were determined after 1, 14, 28 and 56 days. Significant temporal changes in total residues and extractable and mineralizable fractions were observed for phenanthrene, resulting in large differences between soils after 56 days. Phenanthrene mineralization by indigenous peat microorganisms was suggested as the main driver of that, outweighing the effects of organic matter. Lindane total residues and extractability displayed much smaller changes over time and smaller differences between soils related to organic matter. Roughly estimated, the variability between the artificial soils was comparable to natural soils. The implications of such variability for the results of toxicity tests and risk assessment decisions should be identified. We also suggested that the sterilization of artificial soils might reduce unwanted variability.


Small pipes: preliminary experience with 3-mm or smaller pipeline flow-diverting stents for aneurysm repair prior to regulatory approval.
Flow diversion has become an established treatment option for challenging intracranial aneurysms. The use of small devices of ≤3-mm diameter remains unapproved by major regulatory bodies. A retrospective review of patients treated with Pipeline Embolization Devices of ≤3-mm diameter at 3 Canadian institutions was conducted. Clinical and radiologic follow-up data were collected and reported. Twelve cases were treated with ≥1 Pipeline Embolization Device of ≤3-mm diameter, including 2 with adjunctive coiling, with a median follow-up of 18 months (range, 4-42 months). One patient experienced a posttreatment minor complication (8%) due to an embolic infarct. No posttreatment hemorrhage or delayed complications such as in-stent stenosis/thrombosis were observed. Radiologic occlusion was seen in 9/12 cases (75%) and near-occlusion in 2/12 cases (17%). Intracranial aneurysm treatment with small-diameter flow-diverting stents provided safe and effective aneurysm closure in this small selected sample. These devices should be further studied and considered for regulatory approval.


Birth characteristics and subsequent risks of maternal cardiovascular disease: effects of gestational age and fetal growth.
Prior studies showing an inverse relationship between low birth weight in offspring and maternal risks of cardiovascular diseases (CVD) are limited by lack of information on gestational age and/or insufficient adjustment for confounders. In a nationwide Swedish study, we included information on 923 686 women and their first singleton births between 1983 and 2005. Cox proportional hazards models were used to study associations between gestational length, fetal growth, and maternal incident hospitalization or death from CVD (coronary heart disease, cerebrovascular events, and heart failure). Multivariable adjusted models accounted for birth year, income, education, country of birth, smoking, diabetes mellitus, hypertension, and preeclampsia. The risk of maternal CVD increased with decreasing gestational age whereas the risk increase related to fetal growth appeared to be restricted to very small-for-gestational-age (SGA) infants. Compared with mothers of non-SGA infants born at term, the hazard ratio of CVD ranged from 1.39 (95% confidence interval 1.22-1.58) to 2.57 (95% confidence interval 1.97-3.34) among mothers to moderately and very preterm infants, respectively. There was a significant interaction between preterm birth and fetal growth with respect to mothers' risk of CVD (P<0.001). Among mothers to very SGA infants, the hazard ratio of CVD ranged from 1.38 (95% confidence interval 1.15-1.65) to 3.40 (95% confidence interval 2.26-5.11) in mothers to term and very preterm infants, respectively. Delivery of a preterm or SGA infant is associated with later life maternal hospitalization or death from CVD even after accounting for socioeconomic factors, smoking, and pregnancy-related complications.


Analysis and design of a concave diffraction grating with total-internal-reflection facets by a hybrid diffraction method.
A novel hybrid diffraction method is introduced to simulate the diffraction and imaging of a planar-integrated concave grating that has total internal reflection (TIR) facets. The Kirchhoff-Huygens diffraction formula is adopted to simulate the propagation of the lightwave field in the free-propagation region, and a rigorous coupled-wave analysis is used to calculate the polarization-dependent diffraction by the grating. The hybrid diffraction method can be used to analyze accurately the imaging properties as well as the polarization-dependent diffraction characteristics of a concave grating. The dependence of several merit parameters of a concave grating with TIR facets on its basic geometric parameters is studied. Compared with one with metallic echelle facets, a concave grating with TIR facets shows a much lower polarization-dependent loss. Since more performance specifications can be considered in the design of a concave grating than with the conventional scalar method, design error can be reduced greatly with the present hybrid diffraction method.


Union Rates With the Use of Structural Allograft in Lapidus Arthrodesis: A Comparison Between Two Fixation Constructs.
Although structural allograft has been previously described as acceptable practice for reconstructive foot and ankle surgery, results for an allograft bone wedge in Lapidus arthrodesis are unknown. Additionally, there is no consensus on the superiority of a single fixation construct in Lapidus cases. Our objective was (1) to report union rates for Lapidus arthrodesis with and without the use of an allograft bone wedge and (2) to determine if fixation construct impacts rates of union when using structural allograft. A review was performed for Lapidus cases with fixation constructs of 2 crossed compression screws (CS) and a medial locking plate with single transarticular screw (MPS), both with and without use of an allograft bone wedge. Inclusion required a CT scan to evaluate bony union. There was no significant difference in union rates (p = .41) between the use (90%) and the nonuse (97%) of an allograft bone wedge. Union rates were significantly different (p = .04) when comparing CS fixation (85%) and MPS fixation (98%). The comparative results between the fixation constructs highlight the importance of compression across the arthrodesis site as part of a robust fixation construct. Our findings demonstrate that the use of an allograft bone wedge in Lapidus arthrodesis may mitigate complications due to metatarsal shortening while providing satisfactory rates of union.


Recommendations for administering hepatitis A vaccine to contacts of international adoptees.
The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention and the American Academy of Pediatrics (AAP) recommend routine administration of hepatitis A vaccine for household members and close contacts, including baby-sitters, when children are adopted from countries with high or intermediate rates of hepatitis A infection. This policy expands previous AAP recommendations to immunize travelers to countries who are seeking to adopt a child in countries with high or medium hepatitis A endemicity. All previously nonimmune unvaccinated people who anticipate close exposure to international adoptees during the 60 days after their arrival should receive hepatitis A immunization, ideally 2 or more weeks before the arrival of the adopted child.


Fission Damage in Calcite and the Dating of Carbonates.
Fission damage induced in calcite is shown by etch pits developed with weak acid at the damage sites. The damage can be differentiated from dislocations by annealing. By this method we have observed fossil fission damage in natural samples. Thus, some etch pits previously attributed to dislocations actually result from such damage. Annealing studies indicate that the damage should persist for about 4 x 10(7) years at 50 degrees C, and direct evidence suggests that the fission damage has persisted for at least 10(4) years in one specimen.


Clinical Determinants of Dual Tasking in People With Premanifest Huntington Disease.
Dual-tasking deficiencies are common in people with Huntington disease (HD) and contribute to reduced functional independence. To date, few studies have investigated the determinants of dual-tasking deficiencies in this population. The reliability of dual-tasking measures has also been poorly investigated in HD. The purpose of this study was to investigate the influence of clinical determinants on dual-tasking performance and to determine the association of disease burden outcomes on dual-tasking performance in individuals with premanifest HD. Thirty-six individuals with premanifest HD and 28 age- and sex-matched healthy controls were recruited for this study. Participants performed 3 single-task (2 cognitive and 1 motor) and 2 dual-task assessments, comprising motor (postural stability) and cognitive (simple or complex mental arithmetic) components. In addition, participants performed a comprehensive clinical battery comprising motor, cognitive, mood, and sleep assessments as well as lifestyle and disease burden measures. Poorer sleep quality was associated with greater cognitive dual-task cost in individuals with premanifest HD. Compared with healthy controls, people with premanifest HD demonstrated an impaired capacity to dual task. Dual-task measures exhibited acceptable test-retest reliability in premanifest HD and healthy control groups. These results show that dual-tasking measures are sensitive and reliable in individuals with premanifest HD. Furthermore, poor sleep quality is associated with worse cognitive performance on dual tasks, which should be considered by rehabilitation specialists when examining and therapeutically managing dual-tasking problems in individuals with HD and other neurodegenerative populations in the future. This study adds important knowledge to the sparse literature on dual-tasking deficiencies in people with HD. When examining and therapeutically managing dual-tasking problems in this and other neurodegenerative populations, rehabilitation specialists should consider that people with premanifest HD may have an impaired capacity to dual task. Clinicians also should assess sleep quality, as poorer sleep quality is associated with worse cognitive performance on dual tasks in these individuals. If you have premanifest HD and poor quality of sleep, you may pay more attention to maintaining postural stability rather than performing arithmetic calculations to reduce the risk of falling.


Progression of geographic atrophy and genotype in age-related macular degeneration.
We sought to determine whether genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). Prospective analysis of participants in a randomized controlled clinical trial. We included 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS). Fundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed. Genotype frequencies and change in cumulative area of GA. The mean growth rate of GA for the 114 eyes was 1.79 mm(2)/year (range, 0.17-4.76). No association between growth rate and genotype was present for variants in the CFH, C2, C3, APOE, and TLR3 genes. For the single nucleotide polymorphism rs10490924 in LOC387715/ARMS2, there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared with the homozygous nonrisk genotype (unadjusted P = 0.002; Bonferroni-corrected P = 0.014) and for allelic association (Bonferroni-corrected P value = 0.011). Analyses of other measures of GA progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype. Growth rates of GA calculated from digitized serial fundus photographs showed no association with variants in the CFH, C2, C3, APOE, or TLR3 genes. There was a nominally significant association with the LOC387715/ARMS2/HTRA1 genotype, although this finding was not supported by analyses of secondary measures of GA progression. Replication in other populations is needed to establish the existence of an association.


Neurofeedback and brain-computer interface clinical applications.
Most of the research devoted to BMI development consists of methodological studies comparing different online mathematical algorithms, ranging from simple linear discriminant analysis (LDA) (Dornhege et al., 2007) to nonlinear artificial neural networks (ANNs) or support vector machine (SVM) classification. Single cell spiking for the reconstruction of hand movements requires different statistical solutions than electroencephalography (EEG)-rhythm classification for communication. In general, the algorithm for BMI applications is computationally simple and differences in classification accuracy between algorithms used for a particular purpose are small. Only a very limited number of clinical studies with neurological patients are available, most of them single case studies. The clinical target populations for BMI-treatment consist primarily of patients with amyotrophic lateral sclerosis (ALS) and severe CNS damage including spinal cord injuries and stroke resulting in substantial deficits in communication and motor function. However, an extensive body of literature started in the 1970s using neurofeedback training. Such training implemented to control various EEG-measures provided solid evidence of positive effects in patients with otherwise pharmacologically intractable epilepsy, attention deficit disorder, and hyperactivity ADHD. More recently, the successful introduction and testing of real-time fMRI and a NIRS-BMI opened an exciting field of interest in patients with psychopathological conditions.


Community case management of fever due to malaria and pneumonia in children under five in Zambia: a cluster randomized controlled trial.
Pneumonia and malaria, two of the leading causes of morbidity and mortality among children under five in Zambia, often have overlapping clinical manifestations. Zambia is piloting the use of artemether-lumefantrine (AL) by community health workers (CHWs) to treat uncomplicated malaria. Valid concerns about potential overuse of AL could be addressed by the use of malaria rapid diagnostics employed at the community level. Currently, CHWs in Zambia evaluate and treat children with suspected malaria in rural areas, but they refer children with suspected pneumonia to the nearest health facility. This study was designed to assess the effectiveness and feasibility of using CHWs to manage nonsevere pneumonia and uncomplicated malaria with the aid of rapid diagnostic tests (RDTs). Community health posts staffed by CHWs were matched and randomly allocated to intervention and control arms. Children between the ages of 6 months and 5 years were managed according to the study protocol, as follows. Intervention CHWs performed RDTs, treated test-positive children with AL, and treated those with nonsevere pneumonia (increased respiratory rate) with amoxicillin. Control CHWs did not perform RDTs, treated all febrile children with AL, and referred those with signs of pneumonia to the health facility, as per Ministry of Health policy. The primary outcomes were the use of AL in children with fever and early and appropriate treatment with antibiotics for nonsevere pneumonia. A total of 3,125 children with fever and/or difficult/fast breathing were managed over a 12-month period. In the intervention arm, 27.5% (265/963) of children with fever received AL compared to 99.1% (2066/2084) of control children (risk ratio 0.23, 95% confidence interval 0.14-0.38). For children classified with nonsevere pneumonia, 68.2% (247/362) in the intervention arm and 13.3% (22/203) in the control arm received early and appropriate treatment (risk ratio 5.32, 95% confidence interval 2.19-8.94). There were two deaths in the intervention and one in the control arm. The potential for CHWs to use RDTs, AL, and amoxicillin to manage both malaria and pneumonia at the community level is promising and might reduce overuse of AL, as well as provide early and appropriate treatment to children with nonsevere pneumonia. ClinicalTrials.govNCT00513500


Little evidence supports gabapentinoid use in bipolar disorder or insomnia.
The studyHong JSW, Atkinson LZ, Al-Juffali N, et al. Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: systematic review, meta-analysis, and rationale. Mol Psychiatry 2022;27:1339-49.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/review-finds-little-evidence-support-gabapentinoid-use-bipolar-disorder-or-insomnia/.


Cannabidiol: Recent advances and new insights for neuropsychiatric disorders treatment.
The pharmacological research on the Cannabis sativa-derived compounds has never terminated. Among the phytocannabinoids without psychotropic effects, the prevalent one in Cannabis is cannabidiol (CBD). Although CBD was initially considered a type 2 cannabinoid receptor (CB2R) antagonist, it did not show a good cannabinoidergic activity. Furthermore, heterogeneous results were obtained in experimental animal models of anxiety disorders, psychotic stages and neurodegenerative diseases. Recently, CBD has been authorized by the FDA to treat some rare forms of epilepsy and many trials have begun for the treatment of autism spectrum disorders. This review aims to clarify the pharmacological activity of CBD and its multiple therapeutic applications. Furthermore, critical and conflicting results of the research on CBD are discussed with a focus on promising future prospects.


Personal characteristics and experiences of long-term allied health professionals in rural and northern British Columbia.
Health sciences programs are being designed to attract students who are likely to stay and practice in rural and northern Canada. Consequently, student recruitment and screening are increasingly including assessment of suitability for rural practice. Although retention factors among rural physicians and nurses have been investigated, little is known about factors that contribute to the retention of other healthcare professionals who work in rural areas. The primary objective of this project was to identify the personal characteristics and experiences of allied health professionals who have worked long term in northern British Columbia (BC), Canada. The study used a qualitative descriptive approach. Six speech language pathologists, four psychologists, four occupational therapists, eight social workers, and four physiotherapists practicing long term in northern BC were recruited, using a convenience sample and the snowball technique, to participate in semi-structured telephone interviews. The interviews were audiotaped and transcribed verbatim. A thematic content analysis identified the motivations for their decision to begin or stay working in northern communities, the reasons for choosing rural or northern education and key themes concerning personal characteristics and experiences. A process of member checking and an external audit validated the analysis and findings. There were two major themes for choosing rural and northern education. For some, selection of rural or northern training was based on accessibility to health education programs; all participants who chose rural and northern education had already decided that they were going to practice rurally. Generally, participants identified past positive experiences and rural background as influencing their practice location decision. Participants named the community's need for healthcare professionals, career advancement opportunities, welcoming employers, peer support, as well as promises of continuing education and interprofessional teamwork as key to their decision. Professional preferences for variety, challenges, and trying new aspects of the job such as teaching also impacted their decision. Also identified were individual factors and personal preferences such as the need for adventure, wilderness, and outdoor recreation, and community factors (eg people's friendliness and the slow pace). Such factors also influenced retention; however, retention was also affected by factors such as job satisfaction, and some community factors were only associated with retention. The analysis revealed a number of personal characteristics and experiences shared by long-term healthcare professionals, and that there is not one particular factor that determines duration of practice in rural and northern communities. The findings imply a combination of varying personal values impact the decision to come or stay in rural and northern communities. Personal characteristics and experiences help to shape these personal values. Over time and depending on stage of life, personal values change. Age and stage of life, rural background, and location of family members also have bearing on personal values, which in turn impact recruitment and retention. An explicit identification of values that have emerged out of personal characteristics and experiences may be useful in the selection of students for rural health education programs, as well as the recruitment and retention of healthcare professionals in rural and northern areas.


Tool use by wild New Caledonian crows Corvus moneduloides at natural foraging sites.
New Caledonian crows Corvus moneduloides use tools made from sticks or leaf stems to 'fish' woodboring beetle larvae from their burrows in decaying wood. Previous research on this behaviour has been confined to baited sites, leaving its ecological context and significance virtually unexplored. To obtain detailed observations of natural, undisturbed tool use, we deployed motion-triggered video cameras at seven larva-fishing sites. From 1797 camera hours of surveillance over 111 days, we recorded 317 site visits by at least 14 individual crows. Tool use was observed during 150 site visits. Our video footage revealed notable variation in foraging success among identifiable crows. Two nutritionally independent, immature crows spent considerable time using tools, but were much less successful than local adults, highlighting the potential role of individual and social learning in the acquisition of tool-use proficiency. During systematic surveys of larva-fishing sites, we collected 193 tools that crows had left inserted in larva burrows. Comparing these tools with the holes in which they were found, and with raw materials available around logs, provides evidence for tool selectivity by New Caledonian crows under natural conditions. Taken together, these two complementary lines of investigation provide, to our knowledge, the first quantitative description of larva fishing by wild crows in its full ecological context.


Cyclosporine A Treatment Inhibits Abcc6-Dependent Cardiac Necrosis and Calcification following Coxsackievirus B3 Infection in Mice.
Coxsackievirus type B3 (CVB3) is a cardiotropic enterovirus. Infection causes cardiomyocyte necrosis and myocardial inflammation. The damaged tissue that results is replaced with fibrotic or calcified tissue, which can lead to permanently altered cardiac function. The extent of pathogenesis among individuals exposed to CVB3 is dictated by a combination of host genetics, viral virulence, and the environment. Here, we aimed to identify genes that modulate cardiopathology following CVB3 infection. 129S1 mice infected with CVB3 developed increased cardiac pathology compared to 129X1 substrain mice despite no difference in viral burden. Linkage analysis identified a major locus on chromosome 7 (LOD: 8.307, P<0.0001) that controlled the severity of cardiac calcification and necrosis following infection. Sub-phenotyping and genetic complementation assays identified Abcc6 as the underlying gene. Microarray expression profiling identified genotype-dependent regulation of genes associated with mitochondria. Electron microscopy examination showed elevated deposition of hydroxyapatite-like material in the mitochondrial matrices of infected Abcc6 knockout (Abcc6-/-) mice but not in wildtype littermates. Cyclosporine A (CsA) inhibits mitochondrial permeability transition pore opening by inhibiting cyclophilin D (CypD). Treatment of Abcc6 -/- mice with CsA reduced cardiac necrosis and calcification by more than half. Furthermore, CsA had no effect on the CVB3-induced phenotype of doubly deficient CypD-/-Abcc6-/- mice. Altogether, our work demonstrates that mutations in Abcc6 render mice more susceptible to cardiac calcification following CVB3 infection. Moreover, we implicate CypD in the control of cardiac necrosis and calcification in Abcc6-deficient mice, whereby CypD inhibition is required for cardioprotection.


The Impact of a Single Nucleotide Polymorphism in SIGMAR1 on Depressive Symptoms in Major Depressive Disorder and Bipolar Disorder.
Ample evidence suggested a role of sigma-1 receptor in affective disorders since the interaction of numerous antidepressants with sigma receptors was discovered. A recent study on Japanese subjects found a genetic variant within the encoding gene SIGMAR1 (rs1800866A>C) associated with major depressive disorder (MDD). We aimed to evaluate the same polymorphism in both MDD and bipolar disorder (BD) as well as its relationship to response to treatment with antidepressants and mood stabilizers. A total of 238 MDD patients treated for an acute episode of depression, 132 BD patients in treatment with mood stabilizers for a manic or mixed episode, and 324 controls were genotyped for rs1800866. At discharge, response to treatments was evaluated in MDD and BD patients by the Hamilton Rating Scale for Depression (HRSD) and the Young Mania Rating Score (YMRS), respectively. In our Korean sample, allele frequencies were different from those reported in other Asian and non-Asian populations. The CC genotype was associated with BD and, as a trend, with MDD. No significant effect was observed on response to antidepressants in MDD or mood stabilizers in BD, although the CC genotype was more frequent among BD patients experiencing a mixed episode. The present findings are the first to propose the putative role of genetic variants within SIGMAR1 and sigma-1 receptor in BD. Sigma-1 receptor can modulate a number of central neurotransmitter systems as well as some other signaling pathways (e.g., neurotrophin and growth factor signaling) which are seemingly involved in BD and other mood disorders.


A leap forward in iridium-NHC catalysis: new horizons and mechanistic insights.
This review summarises the most recent advances in Ir-NHC catalysis while revisiting all the classical reactions in which this type of catalyst has proved to be active. The influence of the ligand system and, in particular, the impact of the NHC ligand on the activity and selectivity of the reaction have been analysed, accompanied by an examination of the great variety of catalytic cycles hitherto reported. The reaction mechanisms so far proposed are described and commented on for each individual process. Moreover, some general considerations that attempt to explain the influence of the NHC from a mechanistic viewpoint are presented at the end of the review. The first sections are dedicated to the most widely explored reactions that use Ir-NHCs, i.e., hydrogenation and transfer hydrogenation, for which a general overview that tries to compile all the Ir-NHC catalysts hitherto reported for these processes is provided. The next sections deal with hydrogen borrowing, hydrosilylation, water splitting, dehydrogenation (of alcohols, alkanes, aminoboranes and formic acid), hydrogen isotope exchange (HIE), signal amplification by reversible exchange and C-H bond functionalisation (silylation and borylation). The last section compiles a series of reactions somewhat less explored for Ir-NHC catalysts that include the hydroalkynylation of imines, hydroamination, diboration of olefins, hydrolysis and methanolysis of silanes, arylation of aldehydes with boronic acids, addition of aroyl chlorides to alkynes, visible light driven reactions, isomerisation of alkenes, asymmetric intramolecular allylic amination and reactions that employ heterometallic catalysts containing at least one Ir-NHC unit.


XX SRY-negative true hermaphrodism in two dogs: clinical, morphological, genetic and cytogenetic studies.
This work aimed at giving a deeper insight into peculiar cases of intersexuality occurring in dogs and known as XX true hermaphrodism due to the existence of both testicular and ovarian tissue in one or both gonads in the presence of an XX chromosome constitution. Clinical, histological and genetic approaches were used in the study of an 8-month-old Cocker Spaniel dog and a 3-year-old mixed-breed Pitbull, both showing a female phenotype, clitoromegaly and male behavior. A normal female karyotype (2n = 78,XX) was noticed, and polymerase chain reaction failed to detect SRY in genomic DNA obtained from peripheral blood lymphocytes of both dogs. The reproductive tract was removed by standard ovariohysterectomy and processed for histology. Thereafter, a normal female phenotype was reconstructed by vaginoplasty. Histological examination revealed bilateral ovotestis in both cases: the gonads showed immature testicular parenchyma containing seminiferous tubules, Sertoli and Leydig cells, but no signs of spermatogenesis, together with differently developed ovarian follicles containing oocytes. In the ovotestes, steroidogenesis was detected by P450c17-immunoreactivity in Leydig cells as well as in theca cells, whereas no MIS-immunoreactivity was shown by the Sertoli cells. Genital tracts of Wolffian and Müllerian origin co-existed in both subjects. Both dogs belong to the very rare cases in which testicular tissue develops in the absence of the key gene, SRY. Up to date very few genetic events have been associated with this abnormal sexual differentiation: SOX9 over-expression and RSPO1 mutation. Nevertheless, neither of them has been found in these dogs.


Crowdsourcing biomedical research: leveraging communities as innovation engines.
The generation of large-scale biomedical data is creating unprecedented opportunities for basic and translational science. Typically, the data producers perform initial analyses, but it is very likely that the most informative methods may reside with other groups. Crowdsourcing the analysis of complex and massive data has emerged as a framework to find robust methodologies. When the crowdsourcing is done in the form of collaborative scientific competitions, known as Challenges, the validation of the methods is inherently addressed. Challenges also encourage open innovation, create collaborative communities to solve diverse and important biomedical problems, and foster the creation and dissemination of well-curated data repositories.


Synaptic functions in rat sympathetic neurons in microcultures. I. Secretion of norepinephrine and acetylcholine.
This is the first of a series of four papers that describes the use of a sensitive "microculture" procedure for examining the neurotransmitter profile of a neuron by assaying the transmitter(s) it releases. Sympathetic principal neurons isolated from the superior cervical ganglia of neonatal or adult rats were grown for 10 d to several months on small islands of cardiac myocytes (island diameter, ca. 0.5 mm). To assay transmitter status a neuron and a myocyte in the same microculture were impaled with microelectrodes, the neuron was stimulated and the pharmacology of the effect(s) on the group of electrically coupled myocytes, and on the neuron itself, was investigated. Because the growing axonal processes were confined to the island, the innervation of the myocytes became dense; transmission from neuron to myocytes occurred reliably and was often intense. Most experiments were done on islands containing only a single neuron so that the observed effect(s) on the myocytes could be confidently assigned to that neuron. After the physiological assay, the fine structure or cytochemistry of the neuron was often examined. With single-neuron microcultures the physiology and anatomy of the neuron, including the fine structure of its synaptic endings and varicosities, could be correlated unambiguously. During the course of this work, we have observed five pharmacologically distinct effects exerted on the myocytes by either neonate- or adult-derived neurons. Three of these effects, one exerted at least in large part by adenosine and the others by agents still under study (one appears to be 5-HT), are described by Furshpan et al. (1986), Matsumoto et al. (in press), and D. Sah and S. G. Matsumoto (unpublished observations). This paper is concerned with evidence for secretion by these neurons of norepinephrine (NE) and acetylcholine (ACh). The physiological effects of the secretion of these two substances onto the myocytes (excitation and inhibition, respectively) were generally similar to those reported in vivo. The minimal latencies of the responses were short, probably due to the high density of innervation. ACh secreted by a neuron onto itself, at autapses, evoked fast nicotinic EPSPs. We have not detected autaptic effects attributable to the secretion of NE. A minority of the neurons were detectably only adrenergic or only cholinergic. The incidence of these transmitter states was strongly dependent on culture age and culture conditions; in a heterogeneous group of about 300 reasonably well-characterized neurons about 17% (12% of neonate-derived) were apparently purely adrenergic and about 10% (13% of neonate-derived) were apparently purely cholinergic.(ABSTRACT TRUNCATED AT 400 WORDS)


Spectral density matrix description of polarization mode dispersion.
We introduce a power spectral density matrix formalism that incorporates both the pulse shape and the field polarization and can therefore easily describe averages over random fluctuations of the local birefringence vector. We demonstrate that quantities such as the differential time delay, power diffusion, and decoherence effects can be obtained directly from the equations of motion for the power density matrix. This approach can be applied to pulses with arbitrary frequency-dependent polarization and intensity distributions and in particular makes possible the minimization of the eye-opening penalty through the proper choice of the initial pulse profile.


Necroptosis: a crucial pathogenic mediator of human disease.
Necroptosis is a genetically regulated form of necrotic cell death that has emerged as an important pathway in human disease. The necroptosis pathway is induced by a variety of signals, including death receptor ligands, and regulated by receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), which form a regulatory necrosome complex. RIPK3-mediated phosphorylation of MLKL executes necroptosis. Recent studies, using animal models of tissue injury, have revealed that RIPK3 and MLKL are key effectors of injury propagation. This Review explores the functional roles of RIPK3 and MLKL as crucial pathogenic determinants and markers of disease progression and severity in experimental models of human disease, including acute and chronic pulmonary diseases; renal, hepatic, cardiovascular, and neurodegenerative diseases; cancer; and critical illness.


Complete Plasmodium falciparum liver-stage development in liver-chimeric mice.
Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase-deficient mouse (Fah-/-, Rag2-/-, Il2rg-/-, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS-to-blood-stage transition of a human malaria parasite.


Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis.
We hypothesized that modulation of endothelin-converting enzyme-1 (ECE-1) activity would affect phosphorylation of p38-mitogen activated protein kinase (p38-MAPK) and potentiate apoptosis in adult rat ventricular myocytes (ARVMs) during sepsis. The activity of ECE-1 in ARVMs was altered by increasing the substrate availability for ECE-1 by exogenous administration of bigendothelin-1 (bigET-1, 100 nM) and by inhibiting ECE-1 using FR901533 (10 microM) for 24-h. FR901533 significantly decreased the concentration of ET-1 in both sham and sepsis groups. FR901533 decreased p38-MAPK phosphorylation in sepsis but not in sham group. BigET-1 upregulated p38-MAPK phosphorylation, produced hypertrophy, decreased cell viability and reversed FR901533-induced down-regulation of p38-MAPK phosphorylation in both groups. Although, FR901533 did not affect cell cross-sectional area, it significantly reduced the viability of ARVM in both groups. The peak shortening of sham ARVMs was elevated by bigET-1, FR901533 and pretreatment with FR901533 followed by bigET-1. However, the contractility of septic ARVMs was not altered by either bigET-1 or FR901533 treatments per se. Septic ARVM exhibited significantly increased caspase-3 activity at 12 and 24-h. Pretreatment with FR901533 significantly elevated caspase-3 activity in both sham and sepsis group. The data demonstrated that bigET-1-induced hypertrophy in septic ARVM correlates with an ECE-1 dependent-activation of p38-MAPK. The results suggest that non-responsiveness of ARVM to bigET-1 is due to ECE-1 dependent apoptosis. We concluded that ECE-1 may play a crucial role in ARVM dysfunction via increased caspase-3 activity and p38-MAPK phosphorylation during sepsis.


The teaching of medical ethics in the Federal Republic of Germany.
Eduard Seidler sets his discussion of the teaching of medical ethics in the Federal Republic of Germany against an historical background. Immediately after the Second World War the freshness of the memory of the 'Nuremberg Medical Trials' influenced the way in which moral dilemmas were treated in Germany. At the present time no systematic instruction in medical ethics is provided in either undergraduate or postgraduate or continuing medical education. As a result of this, an inquiry was set up in 1977/78. Questionnaires were sent out with a view to collecting information on how subjects referring to medical ethics are treated during medical training. The inquiry showed that no special discipline can claim to be the only competent one for medical ethics, but that everyone has something to contribute. Dr Seidler concludes by stating that basic curricula related to the problems of medical ethics would have to be developed and should be carried on continuously within the training programme.


Antibodies to orthokeratotic keratinocytes in monitoring the drug-induced inhibition of parakeratotic differentiation in adult and infant mice.
Parakeratosis (PK) is a common feature of the abnormal epidermis in several disorders of keratinization. Tar phenols, retinoids and steroids which cause the inhibition of PK and the restoration of orthokeratosis (OK) are used for treating psoriasiform conditions. In this work, we studied two experimental models of the drug-induced inhibition of PK: (1) the suppression of the normal development of PK in the infant mouse tail and (2) the OK conversion of established PK in the adult tail. Two markers of OK were studied: the histological evaluation of the granular layer and the expression of cytoplasmic antigens linked to OK differentiation. It was demonstrated that high-boiling tar phenols cause a more potent inhibition of PK than betamethasone valerate. Most importantly, immunofluorescence showed that the switch to OK differentiation was located in the cells situated in a suprabasal position. The use of these immunological markers to investigate and anti-parakeratotic mechanisms has revealed that these drugs act at stages of keratinocyte differentiation which are distinct from those previously suggested.


Differences in Mental, Cognitive, and Functional Health by Sexual Orientation Among Older Women: Analysis of the 2015 Behavioral Risk Factor Surveillance System.
This study addresses a gap in the knowledge base regarding whether there are differences in mental, cognitive, and functional health between sexual minority women aged 65 and older and their heterosexual counterparts, as well as whether disparities are moderated by age, socioeconomic status, and race/ethnicity. This study analyzes 2015 Behavioral Risk Factor Surveillance System data from 21 states. Multivariate logistic regression is used to test the hypotheses. Compared to heterosexual women, lesbian/gay women aged 65 and older report worse functional health and bisexual women report worse cognitive health and more difficulties with instrumental activities of daily living. Disparities are particularly present for women in their late 60s and those in their 70s. While the likelihood of a depression diagnosis tends to be lower for heterosexual women with higher income, the inverse is true of sexual minority women. Additionally, sexual minority women with less education have lower odds of frequent mental distress and activity limitations than those with some college education. Sexual minority women of color have significantly lower odds of frequent mental distress, activity limitations, and use of special equipment compared to white sexual minority women. Findings indicate a need for gerontological services that provide support to older sexual minority women, particularly in relation to cognitive and functional health. Future research is needed to understand risk and protective factors contributing to these disparities, including forms of resilience that occur among older sexual minority women of color.


Protocol for a qualitative study exploring perspectives on the INternational CLassification of Diseases (11th revision); Using lived experience to improve mental health Diagnosis in NHS England: INCLUDE study.
Developed in dialogue with WHO, this research aims to incorporate lived experience and views in the refinement of the International Classification of Diseases Mental and Behavioural Disorders 11th Revision (ICD-11). The validity and clinical utility of psychiatric diagnostic systems has been questioned by both service users and clinicians, as not all aspects reflect their lived experience or are user friendly. This is critical as evidence suggests that diagnosis can impact service user experience, identity, service use and outcomes. Feedback and recommendations from service users and clinicians should help minimise the potential for unintended negative consequences and improve the accuracy, validity and clinical utility of the ICD-11. The name INCLUDE reflects the value of expertise by experience as all aspects of the proposed study are co-produced. Feedback on the planned criteria for the ICD-11 will be sought through focus groups with service users and clinicians. The data from these groups will be coded and inductively analysed using a thematic analysis approach. Findings from this will be used to form the basis of co-produced recommendations for the ICD-11. Two service user focus groups will be conducted for each of these diagnoses: Personality Disorder, Bipolar I Disorder, Schizophrenia, Depressive Disorder and Generalised Anxiety Disorder. There will be four focus groups with clinicians (psychiatrists, general practitioners and clinical psychologists). This study has received ethical approval from the Coventry and Warwickshire HRA Research Ethics Committee (16/WM/0479). The output for the project will be recommendations that reflect the views and experiences of experts by experience (service users and clinicians). The findings will be disseminated via conferences and peer-reviewed publications. As the ICD is an international tool, the aim is for the methodology to be internationally disseminated for replication by other groups. ClinicalTrials.gov: NCT03131505.


Late onset post transplantation lymphoproliferative disorders: analysis of international data from 5 studies.
Organ transplantation increases the risk of cancer including lymphomas through various and insidious mechanisms. In this study, we aimed to gather and analyze data of 5 international studies on late onset lymphoproliferative disorders after renal and liver transplantation. We conducted a comprehensive search for the available data by Pubmed and Google scholar search engines on post transplant lymphoproliferative disorders. A standard questionnaire was developed to collect data from different published studies. Finally, trustable data of a total of 5 publishes were included in the final analysis. We reviewed all their characteristics and various factors available which may affect outcome. We also compared outcome of patients with very late onset PTLD (>10 years) and late PTLDs. For data analysis we used SPSS v. 13.0. Kaplan-Meier Method was used for survival analysis and Students' t test and chi2 tests were used where appropriate. P<0.05 was defined as significant. overall 55 cases of PTLD from 5 international reports were entered into analysis. There were 32 (58%) males and 23 (42%) female patients. Mean age at diagnosis of PTLD was 39+/-12 years. The mean interval between transplantation and the diagnosis of PTLD was 86+/-54 whereas follow up time after diagnosis of PTLD was 34+/-99 months. Exteranodal involvement was 65%. There were no significant differences in outcomes of patients with late and very late onset PTLDs. Despite discontinuation or reduction of immunosuppressive agents, surgical therapy, chemotherapy, and radiotherapy, 55% of the patients died. Late onset PTLD has its highest relevance within the first year after diagnosis. Controlling infections in PTLD patients during this time period could have beneficial effects on patients' survival. Long post-transplant latency period, aggressive behavior and poor response to treatment necessitate early diagnosis and treatment of late onset post-transplant lymphomas in kidney transplant recipients.