Real-life management of psoriasis with biological agents during pregnancy.

BACKGROUND: French guidelines recommend stopping biologic treatment of psoriasis between 3 and 24 weeks before conception in accordance with the relevant Summary of Product Characteristics (SmPC). The aim of this study was to evaluate the real-life practice of dermatologists in the management of pregnant women with psoriasis previously treated with biologic agents. We wished to assess the level of practitioner adherence to the relevant SmPCs. MATERIAL AND METHODS: We conducted a study in collaboration with GRPso and Resopso. A computerized questionnaire was completed by the practitioners. We performed descriptive statistics and studied the profile of the practitioners, their level of confidence with continuation of biological agents during pregnancy, and their reported practices on the use of biological agents in pregnancy. Statistical analyses were performed using XLSTAT. A p-value of less than 0.05 was considered significant. RESULTS: A total of 63 dermatologists (women: 71%; mean age 43.8 years) participated in this study, the majority of whom were hospital-based (87%). Recommendations were followed by 36.5% of practitioners, while 44% reported discontinuing biologic agents on diagnosis of pregnancy, and 20.5% reported using these agents during pregnancy. Among dermatologists with more than ten years of experience, 19% reported following the SmPC. Among dermatologists with a patient base >200 (patients treated with biologic agents for psoriasis), 19% reported following the SmPC compared to 54% of practitioners with less than 50 patients. The mean age of dermatologists following the SmPC was 41 years vs. 47 years for those not following the SmPC. DISCUSSION: The majority of practitioners do not follow recommendations on discontinuation of biologic agents before the planning of pregnancy by patients.

Long-term occupational exposures on disability-free survival and mortality in older adults.

BACKGROUND: The impact of long-term occupational exposures on health in older adults is increasingly relevant as populations age. To date, no studies have reported their impact on survival free of disability in older adults. AIMS: We aimed to investigate the association between long-term occupational exposure and disability-free survival (DFS), all-cause mortality and cause-specific mortality in initially healthy older adults. METHODS: We analysed data from 12 215 healthy participants in the ASPirin in Reducing Events in the Elderly (ASPREE) study whose mean age was 75 years. Their work history was collated with the 'ALOHA-plus JEM' (Job Exposure Matrix) to assign occupational exposures. The primary endpoint, DFS, was a composite measure of death, dementia or persistent physical disability. The secondary endpoint, mortality, was classified according to the underlying cause. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals, adjusted for confounders. RESULTS: A total of 1835 individuals reached the DFS endpoint during the median 4.7 years follow-up period. Both ever-high and cumulative exposure to all dusts and all pesticides during a person's working years were associated with reduced DFS. Compared to no exposure, men with high exposure to dusts and pesticides had a reduced DFS. Neither of these exposures were significantly associated with all-cause mortality. Men with high occupational exposure to solvents and women exposed to dusts experienced higher all-cause and cancer-related mortality. CONCLUSIONS: Long-term occupational exposure to all dusts and pesticides was associated with a reduced DFS and increased mortality in community-dwelling healthy older adults.

ASO Author Reflections: Indolent Growth and Small Bowel Neuroendocrine Tumor Management.

Surgical treatment is central to management of small bowel neuroendocrine tumors (SBNETs). Current controversies include whether to resect asymptomatic primary tumors in the setting of unresectable metastases, the role of minimally invasive surgery, and how best to incorporate/sequence medical treatments. Low SBNET incidence, long event-times, and variability in disease burden, surgical technique, and institutional treatment preferences remain obstacles to conducting randomized surgical trials for SBNETs. With increasing referral of these patients to high-volume centers, cooperation between experienced SBNET clinicians should allow design of high-quality randomized trials to test new treatments and answer key questions.

Dental public health in action: foundation dentists' delivery of an oral health promotion outreach project for people experiencing homelessness in London.

Dental public health in action: foundation dentists' delivery of an oral health promotion outreach project for people experiencing homelessness in London.Within a decade, the UK has seen a dramatic increase in homelessness. This is defined as being without an available home that could reasonably be occupied. The increase has been driven by increasing poverty, welfare reform, cuts to public services and lack of affordable housing (Bramley et al., 2015; Fitzpatrick et al., 2013; Fitzpatrick et al., 2018). Rough sleeping in England alone has increased by 2,909 people or 165% since 2010 (Ministry of Housing, Communities and Local Government, 2018). This increase has been particularly visible in London (National Audit Office, 2018), where approximately a quarter of the country's rough sleepers reside (Ministry of Housing, Communities and Local Government, 2018).

The impact of transfluthrin on the spatial repellency of the primary malaria mosquito vectors in Vietnam: Anopheles dirus and Anopheles minimus.

BACKGROUND: The complexity of mosquito-borne diseases poses a major challenge to global health efforts to mitigate their impact on people residing in sub-tropical and tropical regions, to travellers and deployed military personnel. To supplement drug- and vaccine-based disease control programmes, other strategies are urgently needed, including the direct control of disease vectors. Modern vector control research generally focuses on identifying novel active ingredients and/or innovative methods to reduce human-mosquito interactions. These efforts include the evaluation of spatial repellents, which are compounds capable of altering mosquito feeding behaviour without direct contact with the chemical source. METHODS: This project examined the impact of airborne transfluthrin from impregnated textile materials on two important malaria vectors, Anopheles dirus and Anopheles minimus. Repellency was measured by movement within taxis cages within a semi-field environment at the National Institute of Hygiene and Epidemiology in Hanoi, Vietnam. Knockdown and mortality were measured in adult mosquito bioassay cages. Metered-volume air samples were collected at a sub-set of points in the mosquito exposure trial. RESULTS: Significant differences in knockdown/mortality were observed along a gradient from the exposure source with higher rates of knockdown/mortality at 2 m and 4 m when compared with the furthest distance (16 m). Knockdown/mortality was also greater at floor level and 1.5 m when compared to 3 m above the floor. Repellency was not significantly different except when comparing 2 m and 16 m taxis cages. Importantly, the two species reacted differently to transfluthrin, with An. minimus being more susceptible to knockdown and mortality. The measured concentrations of airborne transfluthrin ranged from below the limit of detection to 1.32 ng/L, however there were a limited number of evaluable samples complicating interpretation of these results. CONCLUSIONS: This study, measuring repellency, knockdown and mortality in two malaria vectors in Vietnam demonstrates that both species are sensitive to airborne transfluthrin. The differences in magnitude of response between the two species requires further study before use in large-scale vector control programmes to delineate how spatial repellency would impact the development of insecticide resistance and the disruption of biting behaviour.

Impurity scattering effects on the validity of Fermi liquid theory in topological crystalline insulator SnTe (001) thin films.

We study the electronic heat capacity (EHC) and the Pauli spin paramagnetic susceptibility (PSPS) of topological crystalline insulator SnTe (001) thin film in the presence of dilute charged impurities in an effective Hamiltonian model for the low-energy regime such as impurity concentration and impurity scattering potential effects. To calculate the EHC and PSPS using the Boltzmann method, we first calculate the electronic density of states by means of the Green's function approach. Also, the impurity effects are considered with the aid of the T-matrix approximation. We demonstrate that the hybridization potential between the front and back surfaces in SnTe (001) thin films leads to the band gap opening and to the zero PSPS at low temperatures obeying the Fermi liquid theory. In particular, we demonstrate two scenarios including the possibilities of the same and different impurity doping. It is shown that in both cases the midgap states emerge, the cation-anion symmetry breaks down and the Fermi liquid theory loses its validity. Moreover, the critical scattering potential with respect to the hybridization potential is found for the validity limit of the Fermi liquid theory. Finally, the Schottky anomaly and the crossover in EHC and PSPS, respectively, are discussed. Our results have strong implications for applications based on SnTe (001) thin films.

Progress towards rabies control and elimination in Vietnam.

Rabies is a fatal viral disease that causes an estimated 59,000 human deaths each year. The majority of these deaths occur in developing countries in Asia. Canine rabies is endemic to Vietnam, which is, however, moving towards the disease's elimination. Many countries, such as Vietnam, have invested tremendous resources in controlling rabies, highlighting the goal of regional and global elimination of this neglected disease. In Vietnam, rabies is recognised as one of five high-priority, zoonotic diseases by the Ministry of Health and the Ministry of Agriculture and Rural Development. Investment by the government and by international partners for rabies prevention and control has played a substantial role in reducing human rabies deaths from 404 cases in 1992 to 74 cases in 2017. The catalyst for this effort was the Prime Minister's creation of the National Rabies Program in 1996, which led to increased support and resources for rabies prevention and control. Interventions carried out since then include the expansion of post-exposure prophylaxis centres throughout the country, the introduction or revision of key legislation and guidelines, and improved multisectoral One Health collaboration. In addition, support from international partners, such as the World Organisation for Animal Health (OIE), the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), and the Centers for Disease Control and Prevention (CDC), has helped to increase awareness, manage dog populations more effectively, and improve Vietnam's surveillance and diagnostic capabilities. To pursue the goal of eliminating dog-mediated rabies in Vietnam, political commitment is crucial. Resources must be made available to enforce the regulations and guidelines that will enable Vietnam to achieve greater canine rabies vaccination coverage. In this paper, the authors provide an overview of the animal and human health systems in Vietnam, as well as past, current and future directions of rabies prevention and control.

La rage est une maladie virale à l'issue mortelle faisant chaque année un nombre estimé de 59 000 victimes humaines. La plupart de ces décès surviennent dans les pays en développement d'Asie. Au Vietnam, la rage canine est endémique mais le pays poursuit activement l'objectif d'éliminer la rage de son territoire. À l'instar du Vietnam, plusieurs pays ont investi des ressources colossales pour contrôler la rage, renforçant ainsi la dimension régionale et mondiale de l'objectif d'élimination de cette maladie négligée. Au Vietnam, la rage figure parmi les cinq zoonoses hautement prioritaires prises en compte par le ministère de la Santé et le ministère de l'Agriculture et du développement rural. Les investissements consacrés à la prévention et au contrôle de la rage par le gouvernement et ses partenaires internationaux ont joué un rôle déterminant dans la réduction du nombre de décès humains dus à la rage, qui est passé de 404 cas en 1992 à 74 cas en 2017. L'élément catalyseur de cet effort a été la création en 1996 du Programme national de lutte contre la rage par le premier ministre de l'époque, ce qui a permis de renforcer les ressources et le soutien dédiés à la prévention et à la lutte contre la rage. Depuis lors, les interventions ont porté sur la création de centres de prophylaxie post-exposition sur tout le territoire, l'introduction ou la révision de la législation et des lignes directrices applicables et l'amélioration de la collaboration Une seule santé. En outre, le soutien de partenaires internationaux tels que l'Organisation mondiale de la santé animale (OIE), l'Organisation mondiale de la santé (OMS), l'Organisation des Nations Unies pour l'alimentation et l'agriculture (FAO) et les Centres pour le contrôle et la prévention des maladies (CDC, États-Unis d'Amérique) a abouti à une meilleure sensibilisation, à une gestion plus efficace des populations de chiens et à un renforcement des capacités de surveillance et de diagnostic au Vietnam. Un engagement politique fort est indispensable pour réussir à éliminer totalement la rage transmise par les chiens au Vietnam. Des ressources doivent être rendues disponibles afin de mettre en oeuvre la réglementation et les lignes directrices pertinentes et d'augmenter ainsi la couverture vaccinale de la population canine du pays. Les auteurs décrivent les systèmes de santé animale et publique du Vietnam ainsi que les orientations passées, actuelles et futures de la prévention et du contrôle de la rage dans le pays.

La rabia es una enfermedad vírica fatal, que según las estimaciones mata a 59 000 personas al año, mayoritariamente en países en desarrollo asiáticos. La rabia canina es endémica en el Vietnam, país que no obstante avanza ahora hacia la eliminación de la enfermedad. Como el Vietnam, muchos países han invertido cantidades colosales de recursos en la lucha antirrábica, subrayando con ello su compromiso con el objetivo de eliminar esta enfermedad desatendida a escala regional y mundial. El Ministerio de Salud y el Ministerio de Agricultura y Desarrollo Rural del Vietnam tienen catalogada la rabia como una de las cinco enfermedades zoonóticas que revisten máxima prioridad. Las inversiones en prevención y control de la rabia realizadas por el gobierno y por asociados internacionales han ayudado sensiblemente a reducir el número de personas muertas por la rabia, que ha pasado de 404 casos en 1992 a 74 en 2017. El catalizador de este esfuerzo fue la creación en 1996, por iniciativa del Primer Ministro, del Programa Nacional contra la Rabia, que se tradujo en un aumento del apoyo y los recursos destinados a prevenir y combatir la enfermedad. Entre otras intervenciones, desde entonces se ha multiplicado en todo el país el número de centros donde se dispensa profilaxis tras la exposición, se han promulgado o revisado leyes, decretos y directrices fundamentales y se ha mejorado la colaboración multisectorial en clave de Una sola salud. Además, el respaldo de asociados internacionales como la Organización Mundial de Sanidad Animal (OIE), la Organización Mundial de la Salud (OMS), la Organización de las Naciones Unidas para la Alimentación y la Agricultura (FAO) o los Centros para el Control y la Prevención de Enfermedades (CDC) de los Estados Unidos ha ayudado a generar una mayor conciencia del problema, a gestionar más eficazmente las poblaciones de perros y a dotar al país de mejores medios de vigilancia y diagnóstico. Para hacer realidad el objetivo de eliminar del Vietnam la rabia transmitida por perros, la voluntad política es un factor clave, pues hay que poner sobre la mesa los recursos necesarios para aplicar los reglamentos y normas que permitirán al país ampliar la cobertura de vacunación canina antirrábica. Tras trazar una panorámica de los sistemas sanitario y zoosanitario del Vietnam, los autores describen el rumbo pasado, presente y futuro de las labores de prevención y control de la rabia en el país.

Potentially beneficial effects of rhamnose on skin ageing: an in vitro and in vivo study.

OBJECTIVE: Recent findings showed that skin ageing preferentially affects human papillary dermal fibroblasts suggesting that the papillary dermis represents a critical zone altered by skin ageing. Based on these findings, we investigated the potential anti-ageing effect of rhamnose. METHODS: We investigated the potential anti-ageing effect of rhamnose using in vitro reconstructed skin containing fibroblasts obtained either from young or old donors, and in vivo clinical investigation. RESULTS: We detected positive effects of rhamnose in both epidermal and dermal compartments of in vitro reconstructed skin. Moreover, we were able to show that such in vitro findings were also obtained in vivo including an effect on collagen IV and procollagen I production. CONCLUSION: We provide evidence that rhamnose has a potentially beneficial effect on papillary dermis and dermal-epidermal junction, both of the areas which are affected by skin ageing.

OBJECTIF: Le vieillissement de la peau humaine affecte particulièrement les fibroblastes du derme papillaire suggérant que le derme papillaire représente une zone importante altérée par le vieillissement. A partir de ces résultats, nous avons étudié le potentiel effet anti-âge du rhamnose. METHODES: Le potentiel effet anti-âge du rhamnose a été étudié in vitro en utilisant un modèle de peau reconstruite contenant des fibroblastes isolés à partir d'un donneur jeune et d'un donneur âgé et dans une étude clinique in vivo. RÉSULTATS: Nous avons observé un effet positif du rhamnose dans le compartiment épidermique et dermique de la peau reconstruite in vitro. En outre, nous avons pu montrer in vivo comme in vitro, un effet sur la production du collagène IV et du procollagène I. CONCLUSION: Le rhamnose a un effet bénéfique potentiel sur deux zones touchées par le vieillissement cutané, le derme papillaire et la jonction dermo-épidermique.

Expression profiles of host immune response-related genes against HEV genotype 3 and genotype 1 infections in rhesus macaques.

Hepatitis E virus (HEV) genotype (gt) 3 infection is food-borne causing sporadic infections in older individuals and gt1 infection is waterborne, often causing epidemics affecting primarily young adults. Although HEV infection causes self-limited disease, gt3 induces chronic infection in immunocompromised individuals. Hepatic host gene expression against gt3 infection remains unknown. Host gene expression profiles for HEV gt1 (n = 3) and gt3 (n = 7) infections were analysed in the livers of experimentally infected rhesus macaques. HEV RNA was detected from 2 to 24 days after inoculation (DAI) in stool and serum, elevated alanine aminotransferase (ALT) activity was detected from 7 to 31 DAI, and anti-HEV antibody became detectable between 12 and 42 DAI. All 10 animals cleared the infection between 34 and 68 DAI. We found that 24%, 48% and 41% of hepatic immune response genes against gt3 infection were upregulated during the early, peak and decline phases of HEV RNA replication. For gt1 infection, 25% of hepatic immune response-related genes were downregulated during early viremia, but 6%, 34% and 37% of genes were upregulated at the early, peak and during decline of HEV RNA replication, respectively. Our study demonstrated distinct differences in the expression profiles of host immune response-related genes of HEV gt3 and gt1 infections in experimentally infected rhesus macaques.

Reduced fasting periods increase intestinal permeability in chickens.

Fasting of up to 24 hr has been shown to increase intestinal permeability (IP) in chickens. The aim of this study was to determine whether fasting duration of 4.5 and 9 hr increased IP and whether l-glutamine (a non-essential amino acid) supplementation before fasting provided some protection of barrier function as shown in other species. Ross 308 male broilers (n = 96) were fed either a control diet or the same diet supplemented with 1% glutamine from d0 to d38 post-hatch. On d37, the birds were assigned to single-bird metabolism cages and were fasted for either 0, 4.5, 9 or 19.5 hr. This study design was 2 × 4 factorial with two levels of glutamine and four levels of fasting. Birds in the 0-hr fasting group had free access to feed. All birds had ad libitum access to water. To measure IP on day 38, following their respective fasting periods, birds were administered two separate oral gavages of fluorescein isothiocyanate dextran (FITC-d) followed by lactulose, mannitol and rhamnose (LMR) sugars, 60 min apart. Whole blood was collected from the jugular vein 90 min post-LMR sugar gavage. FITC-d and L/M/R ratios were measured by spectrophotometry and high-performance ionic chromatography respectively. Lipopolysaccharide (LPS) endotoxins in plasma of the birds fed the control diet were also measured using chicken-specific LPS antibody ELISA. Serum FITC-d and plasma L/M and L/R ratios for 4.5, 9 and 19.5 hr were significantly (p < .05) higher compared to the non-fasting group. However, IP was not different in the glutamine-supplemented group (p > .05) compared to the control group. LPS concentrations measured by the ELISA were below the detectable range. We conclude that fasting periods of 4.5 and 9 hr increased IP compared to non-fasted birds and dietary glutamine supplementation did not ameliorate changes in IP.

Gene expression and morphological changes in the intestinal mucosa associated with increased permeability induced by short-term fasting in chickens.

Short-term fasting for 4.5 and 9 hr has been demonstrated to increase intestinal permeability (IP) in chickens. This study aimed to investigate the effects of 0, 4.5, 9 and 19.5 hr fasting on intestinal gene expression and villus-crypt architecture of enterocytes in jejunal and ileal samples. On day 38, Ross-308 male birds were fasted according to their group and then euthanised. Two separate intestinal sections (each 2 cm long, jejunum and ileum) were collected. One section was utilised for villus height and crypt depth measurements. The second section was snap-frozen in liquid nitrogen for quantitative polymerase chain reaction (qPCR) analysis of tight junction proteins (TJP) including claudin-1, claudin-3, occludin, zonula occludens (ZO-1, ZO-2), junctional adhesion molecules (JAM) and E-cadherin. Additionally genes involved in enterocyte protection including glucagon-like peptide (GLP-2), heat-shock protein (HSP-70), intestinal alkaline phosphatase (IAP), mammalian target of rapamycin (mTOR), toll-like receptors (TLR-4), mucin (MUC-2), cluster differentiation (CD-36) and fatty acid-binding protein (FABP-6) were also analysed. Normally distributed data were analysed using one-way analysis of variance ANOVA. Other data were analysed by non-parametric one-way ANOVA. Villus height and crypt depth were increased (p < .05) only in the ileum after fasting for 4.5 and 9 hr compared with non-fasting group. mRNA expression of claudin-3 was significantly reduced in the ileum of birds fasted for 9 and 19.5 hr, suggesting a role in IP modulation. However, all other TJP genes examined were not statistically different from control. Nevertheless, ileal FABP-6 of all fasted groups was significantly reduced, which could possibly be due to reduced bile acid production during fasting.

Caretakers' barriers to pediatric antiretroviral therapy adherence in Vietnam - A qualitative and quantitative study.

BACKGROUND: Poor antiretroviral therapy (ART) adherence leads to drug resistance and treatment failures. The options for second and third line ART regimens, particularly for pediatric patients, are very limited in low and middle-income countries. HIV-infected children are mostly passive drug-takers, thus caretakers play a very important role in assuring ART adherence. Pediatric ART adherence is still a challenging problem in Vietnam since non-adherence is the major risk factor for treatment failure. Our study explores and measures caretakers' barriers in order to improve pediatric ART adherence in future. METHODS: Exploring caretakers' barriers was conducted through a qualitative study with Focus Group Discussion (FGD) on two topics: 1. Current society - family support and difficulties in taking care children under ART; 2. Stigma experience. Based on the finding from the qualitative study a quantitative study measuring caretakers' barriers was conducted through a designed questionnaire. Study methods strictly followed the consolidated criteria with 32-item checklist for interviews and focus groups. RESULTS: In total eight FGDs with 53 participants were conducted. Common caretakers' barriers to children's ART adherence, were financial burden, lack of ART KP (Knowledge-Practice), stigma, depression, shifting caretaker, drug taste and side effects, lack of family support, fixed health check-up schedule and HIV non-disclosure. In the questionnaire study a total of 209 caretakers participated. The most commonly reported caretakers' barriers were: financial burden (144; 69%), KP burden (143; 68%), depression (85; 41%) and stigma (30; 14.8%). Some caretakers' characteristics that significantly associated with reported barriers (p<0.05). Rural caretakers reported significantly more financial burden (OR=2.26) and stigma (OR=3.53) than urban. Caretakers with under high school level education reported significantly more financial burdens (OR=2.08) and stigma (OR=4.15) compared to caretakers with high school education or over. CONCLUSION: Financial burden, KP burden, depression and stigma were common reported caretakers' barriers to pediatric ART adherence. Family residence, caretaker's education level and job were considered as the key factors determining caretakers' barriers related to financial burden and stigma. These findings may be important for policy makers and researchers in order to develop effective interventions regarding to caretakers' burdens and associated factors. Furthermore, a tool for nurses in monitoring caretakers' barriers to pediatric ART adherence was developed first with FDG, and then interview questionnaire. This tool could be applied and modified easily in any pediatric ART clinic settings in accordance to economic, social and cultural circumstances.

New biomarkers for increased intestinal permeability induced by dextran sodium sulphate and fasting in chickens.

Increased intestinal permeability (IP) can lead to compromised health in chickens. As there is limited literature on in vivo biomarkers to assess increased IP in chickens, the objective of this study was to identify a reliable biomarker of IP using DSS ingestion and fasting models. Male Ross chickens (n = 48) were reared until day 14 on the floor pen in an animal care facility, randomized into the following groups: control, DSS and fasting (each with n = 16), and then placed in metabolism cages. DSS was administered in drinking water at 0.75% from days 16 to 21, while controls and fasted groups received water. All birds had free access to feed and water except the birds in the fasting group that were denied feed for 19.5 h on day 20. On day 21, all chickens were given two separate oral gavages comprising fluorescein isothiocyanate dextran (FITC-d, 2.2 mg in 1 ml/bird) at time zero and lactulose, mannitol and rhamnose (LMR) sugars (0.25 g L, 0.05 g M and 0.05 g R in 2 ml/bird) at 60 min. Whole blood was collected from the brachial vein in a syringe 90 min post-LMR sugar gavage. Serum FITC-d and plasma LMR sugar concentrations were measured by spectrophotometry and high-performance ion chromatography respectively. Plasma concentrations of intestinal fatty acid binding protein, diamine oxidase, tight junction protein (TJP), d-lactate and faecal α-antitrypsin inhibitor concentration were also analysed by ELISA. FITC-d increased significantly (p < 0.05) after fasting compared with control. L/M and L/R ratios for fasting and L/M ratio for DSS increased compared with control chickens (p < 0.05). TJP in plasma was significantly increased due to fasting but not DSS treatment, compared with controls. Other tests did not indicate changes in IP (p > 0.05). We concluded that FITC-d and LMR sugar tests can be used in chickens to assess changes in IP.

Systemic availability of guanidinoacetate affects GABAA receptor function and seizure threshold in GAMT deficient mice.

Deficiency of guanidinoacetate methyltransferase (GAMT) causes creatine depletion and guanidinoacetate accumulation in brain with the latter deemed to be responsible for the severe seizure disorder seen in affected patients. We studied electrical brain activity and GABAA mediated mechanisms of B6J.Cg-Gamt(tm1Isb) mice. Electrocorticographic (ECoG) monitoring of pharmacological treatments with ornithine (5 % in drinking water for 5-18 days) and/or Picrotoxin (PTX) (a GABAA receptor antagonist) (1.5 mg/kg, I.P.) in Gamt(MUT) and Gamt(WT) groups [n = 3, mean age (SEM) = 6.9 (0.2) weeks]. Mice were fitted with two frontal and two parietal epidural electrodes under ketamine/xylazine anesthesia. Baseline and test recordings were performed for determination of seizure activity over a 2 h period. The ECoG baseline of Gamt(MUT) exhibited an abnormal monotonous cortical rhythm (7-8 Hz) with little variability during awake and sleep states compared to wild type recordings. Ornithine treatment and also PTX administration led to a relative normalization of the Gamt(MUT) ECoG phenotype. Gamt(WT) on PTX exhibited electro-behavioral seizures, whereas the Gamt(MUT) did not have PTX induced seizures at the same PTX dose. Gamt(MUT) treated with both ornithine and PTX did not show electro-behavioral seizures while ornithine elevated the PTX seizure threshold of Gamt(MUT) mice even further. These data demonstrate: (1) that there is expression of electrical seizure activity in this Gamt-deficient transgenic mouse strain, and (2) that the systemic availability of guanidinoacetate affects GABAA receptor function and seizure thresholds. These findings are directly and clinically relevant for patients with a creatine-deficiency syndrome due to genetic defects in GAMT and provide a rational basis for a combined ornithine/picrotoxin therapeutic intervention.

A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly.

UNLABELLED: We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. CONCLUSION: Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period. WHAT IS KNOWN: • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.

Bayesian evaluation of a physiologically-based pharmacokinetic (PBPK) model of long-term kinetics of metal nanoparticles in rats.

Biomathematical modeling quantitatively describes the disposition of metal nanoparticles in lungs and other organs of rats. In a preliminary model, adjustable parameters were calibrated to each of three data sets using a deterministic approach, with optimal values varying among the different data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo (MCMC) simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. The previously-developed model structure and some physiological parameter values were modified to improve physiological realism. The data from one of the three previously-identified studies and from two other studies were used for model calibration. The data from the one study that adequately characterized mass balance were used to generate parameter distributions. When data from a second study of the same nanomaterial (iridium) were added, the level of agreement was still acceptable. Addition of another data set (for silver nanoparticles) led to substantially lower precision in parameter estimates and large discrepancies between the model predictions and experimental data for silver nanoparticles. Additional toxicokinetic data are needed to further evaluate the model structure and performance and to reduce uncertainty in the kinetic processes governing in vivo disposition of metal nanoparticles.

[Inborn errors of metabolism: transition from childhood to adulthood]. / Erreurs innées du métabolisme: transition enfant-adulte.

Inborn errors of metabolism (IEM) are due to mutations of genes coding for enzymes of intermediary metabolism and are classified into 3 broad categories: 1) intoxication, 2) energy defect and 3) cellular organelles synthesis or catabolism defect. Improvements of therapy over these last 20 years has improved prognosis of children with IEM. These children grow up and should have their transition to specialized adult care. Adult patients with IEM are a relatively new phenomenon with currently only limited knowledge. Extrapolated pediatric guidelines are applied to the adult population taking into account adult life stages (social independence, pregnancy, aging process and potential long-term complications).

In vitro and in vivo studies with tetra-hydro-jasmonic acid (LR2412) reveal its potential to correct signs of skin ageing.

BACKGROUND: LR2412, a synthetic derivative of jasmonic acid, improved the reconstruction and homeostasis of our organotypic skin models. OBJECTIVES: The need for efficient 'anti-ageing' treatments, in particular for the management of photoaged skin, prompted us to investigate this new ingredient for its potential to correct signs of skin ageing in vitro and in vivo and to identify its mode of action. RESULTS: In vitro, penetration of LR2412 was evaluated using a Franz diffusion cell on excised human skin. Its exfoliating properties and interactions with the stratum corneum were studied using electron microscopy and X-ray diffraction. Experiments were performed on a human reconstructed skin model. In vivo, the effects of LR2412 on steroid-induced skin atrophy, a clinical skin ageing model, were assessed vs. vehicle. A patch test study evaluated its effect on deposition of fibrillin-rich microfibrils in the papillary dermis in clinically photoaged volunteers. A clinical study on the appearance of crow's feet wrinkles was conducted over 3 months of daily application. Penetration studies revealed that LR2412 reaches viable epidermis and superficial dermis, which are skin targets of anti-ageing actives. Within the upper layers of the stratum corneum LR2412 accelerates desquamation and improves the mechanical properties. At the dermal-epidermal junction of reconstructed skin, collagen IV, laminin-5 and fibrillin were stimulated. In vivo, LR2412 reversed steroid-induced atrophy. The patch test model confirms the deposition of fibrillin-rich microfibrils, then an in use clinical study revealed that it reduced facial wrinkles. CONCLUSIONS: The in vitro and in vivo data demonstrate that based on its multiple interactions within human skin, LR2412 has potential to partially correct the signs of ageing in intrinsically and photoaged skin.

Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches.

WHAT IS KNOWN AND OBJECTIVE: The prevailing theory regarding Alzheimer disease (AD) is that insoluble amyloid ß-peptide (Aß) plays a critical role in the cortical plaques characteristic of the disease. Because Aß is formed from the sequential splicing of amyloid precursor protein (APP) catalysed by 'secretase' enzymes (α, ß and γ), clinical trials of secretase inhibitors will either result in beneficial pharmacotherapy or, if negative, cast doubt on the role of Aß in AD. With recent clinical trial failures, is the Aß theory wrong? METHODS: Literature searches were conducted on the topics of secretases and clinical trials, including PubMed searches, United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected and evaluated for relevance and quality. RESULTS AND DISCUSSION: Several direct-acting (e.g. CTS-21166, LY2811376) and indirect-acting (e.g. ACI-91) ß-secretase inhibitors and several γ-secretase inhibitors (e.g. avagacestat, JNJ-40418677 and semagacestat) have not fared well in early clinical trials due to the lack of efficacy or concerns over possible serious side effects. WHAT IS NEW AND CONCLUSION: The failures of secretase inhibitors in clinical trials appear to bring into question the long-hypothesized association between AD and Aß production. However, the disease might have been too advanced in these patients to benefit from this type of therapy (mainly preventive). Secretase inhibitors are still being studied, along with new diagnostic tools, with the hope of testing patients earlier, that is, with less advanced disease. If these trials also fail, the prevailing view of the role of Aß in AD will truly be in doubt.

Point of care HIV testing in dental settings in high-income countries: A mixed-methods systematic review.

OBJECTIVES: Expanding HIV testing beyond specialized services has been a key strategic approach to eliminating the transmission of HIV. In recent years, dental settings have been identified as offering an opportunity for delivering point of care HIV testing (POCT) interventions. Intervention components and implementation strategies have varied across studies and there is uncertainty about the prevalence of undiagnosed HIV in the dental patient population. Therefore, this systematic review aimed to synthesize the HIV testing outcomes of intervention studies, identify the core components of POCT interventions implemented in dental settings; and understand the barriers and facilitators to intervention implementation. METHODS: A mixed-methods systematic review was undertaken. Two authors reviewed abstracts and full papers for inclusion and appraised the studies using the Mixed Methods Appraisal Tool. A convergent integrated mixed methods study design underpinned the synthesis. Outcomes were presented using descriptive statistics. Intervention components were mapped to the Template for Intervention Description and Replication (TIDieR) checklist. Barriers and facilitators were described using a narrative thematic analysis. RESULTS: POCT was offered to 22 146 dental patients, 62.5% accepted POCT. Intervention studies that reported higher uptake of testing utilized a dedicated dental or researcher staff member to provide testing, integrated testing and provided results within the routine dental appointment and adopted a provider-initiated universal approach to offering testing. Six themes emerged that were pertinent to the barriers and facilitators to HIV testing in dental setting. CONCLUSIONS: POCT uptake in dental settings was comparable with other non-specialized health settings. Key to the operationalization of the intervention were perceptions about its value and relevance to the dental patient population, attitudes toward the intervention, logistical barriers to its implementation, the risk of HIV testing stigma to the patient-practitioner relationship and maximising the fit of the intervention within the constraints of the dental setting.