A closer look at ARSA activity in a patient with metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease mainly caused by a deficiency of arylsulfatase A activity. The typical clinical course of patients with the late infantile form includes a regression in motor skills with progression to dysphagia, seizures, hypotonia and death. We present a case of a 4-year-old female with rapidly progressive developmental regression with loss of motor milestones, spasticity and dysphagia. MRI showed volume loss and markedly abnormal deep white matter. Enzymatic testing in one laboratory showed arylsulfatase A activity in their normal range. However, extraction of urine showed a large increase in sulfatide excretion in a second laboratory. Measurement of arylsulfatase A in that laboratory showed a partial decrease in arylsulfatase A activity measured under typical conditions (about 37% of the normal mean). When the concentration of substrate in the assay was lowered to one quarter of that normally used, this individual had activity \u3c10% of controls. The patient was found to be homozygous for an unusual missense mutation in the arylsulfatase A gene confirming the diagnosis of MLD. This case illustrates the importance of careful biochemical and molecular testing for MLD if there is suspicion of this diagnosis

Antinociceptív neurotranszmitterek / modulátorok hatásmechanizmusa: homológ és heterológ receptor kölcsönhatások vizsgálata és új, endogén peptid-kötőhelyek azonosítása = Neurochemical studies on neurotransmitters in pain regulation: identification of novel peptide binding sites and investigation of homologous and heterologous receptor interactions

Az antinocicepcióban kulcsszerepet játszó mu opioid receptor endogén ligandumának tekintett endomorfinok (1 és 2) kötőhelyeit karakterizáltuk biokémiai és autoradiográfiás módszerekkel. Megállapítottuk, hogy az endomorfin 1 két kötőhelyet ismer fel, amelyek közül a kis affinitású a klasszikus mu receptortól részben eltérő lokalizációval, ligandspecificitással bír és regulációja nem követi az ismert reakció utakat. Új, konformációsan gátolt endomorfin analógok kifejlesztésével módosítható volt a peptidek affinitása, szelektivitása. Világossá vált, hogy akár kismértékű szerkezeti módosítások is jelentős funkcionális eltéréseket eredményezhetnek. Az opioid és kannabinoid rendszer összefüggéseit vizsgáltuk molekuláris biológiai és biokémiai módszerekkel in vitro és in vivo. A legmarkánsabb változásokat a mu opioid receptorok esetében kaptunk, legfőképpen az előagyi és az agytörzsi területeken. Mind endogén CB1 agonista, mind CB2 antagonista befolyásolta a mu opioid receptor expresszióját és regulációját. A kannabisz és opioid rendszer közötti interakciók pontos mechanizmusainak feltárásával új kapuk nyílhatnak meg a fájdalomcsillapítás terápiás alkalmazásában a távolabbi jvőben | The endomorphins (1 and 2) are putative endogenous ligands for mu opioid receptors, which play a major role in antinociception. It was found, that endomorphin1 labels two distinct sites with partially different localization, ligand selectivity profiles. The regulation of its binding is not identical to that of the classical opioid ligands. The recently developed endomorphin analogs with constrained structure show changes in affinity and selectivy. Relatively small chemical modifications might lead to major changes in functional consequences. We investigated the interaction of the opioid system with several others related to nociception/antinociception. Among them, the occurrence of possible changes in mRNA expression and in functional activity of opioid receptors after acute in vivo and in vitro treatments with cannabinoids were studied. Wild-type, CB1 knockout mice and CB2 receptor deficient animals were among the the subjects of the study. We examined the changes of opioid receptor?s mRNA levels by using real-time PCR, analyzed the capability of mu-, delta and kappa opioid agonists to activate G-proteins and investigated mu-opioid receptors binding properties by using competition assays. Our data show changes in the expression and functional integrity of mu opioid receptors in forebrain, cerebellum and brainstem after different cannabinoid treatments. A better knowledge of the observed interactions may lead to exciting therapeutic possibilities in a long term

Hyperuniform monocrystalline structures by spinodal solid-state dewetting

Materials featuring anomalous suppression of density fluctuations over large length scales are emerging systems known as disordered hyperuniform. The underlying hidden order renders them appealing for several applications, such as light management and topologically protected electronic states. These applications require scalable fabrication, which is hard to achieve with available top-down approaches. Theoretically, it is known that spinodal decomposition can lead to disordered hyperuniform architectures. Spontaneous formation of stable patterns could thus be a viable path for the bottom-up fabrication of these materials. Here we show that mono-crystalline semiconductor-based structures, in particular Si$_{1-x}$Ge$_{x}$ layers deposited on silicon-on-insulator substrates, can undergo spinodal solid-state dewetting featuring correlated disorder with an effective hyperuniform character. Nano- to micro-metric sized structures targeting specific morphologies and hyperuniform character can be obtained, proving the generality of the approach and paving the way for technological applications of disordered hyperuniform metamaterials. Phase-field simulations explain the underlying non-linear dynamics and the physical origin of the emerging patterns.Comment: 6 pages, 3 figures, supplementary information (7 pages) enclose

Feasibility and acceptability of Problem Management Plus (PM+) among Syrian refugees and asylum seekers in Switzerland: a mixed-method pilot randomized controlled trial

Background: Syrian refugees in Switzerland face several barriers in accessing mental health care. Cost-effective psychological interventions are urgently needed to meet the mental health needs of refugees. Problem Management Plus (PM+) is an evidence-based, psychological intervention delivered by trained non-specialist ‘helpers’. Objective: To assess the feasibility and acceptability of PM+ among Syrian refugees in Switzerland. Methods: We conducted a single-blind pilot randomized controlled trial (RCT) with Syrian refugees impaired by psychological distress (K10 > 15 and WHODAS 2.0 > 16). Participants were randomized to PM+ or Enhanced Treatment As Usual (ETAU). Participants were assessed at baseline, and 1 week and 3 months after the intervention, and completed measures indexing mental health problems and health care usage. Semi-structured interviews were conducted with different stakeholders. Results: N = 59 individuals were randomized into PM+ (n = 31) or ETAU (n = 28). N = 18 stakeholders were interviewed about facilitators and barriers for the implementation of PM+. Retention rates in the trial (67.8%) and mean intervention attendance (M = 3.94 sessions, SD = 1.97) were high. No severe events related to the study were reported. These findings indicate that the trial procedures and PM+ were feasible, acceptable and safe. Conclusions: The findings support the conduct of a definitive RCT and show that PM+ might have the potential to be scaled-up in Switzerland. The importance, as well as the challenges, of implementing and scaling-up PM+ in high-income countries, such as Switzerland, are discussed

Large age shifts in HIV-1 incidence patterns in KwaZulu-Natal, South Africa

HIV incidence has recently been in decline across some of the most intense epidemics in sub-Saharan Africa due to the scale-up of prevention and transmission-blocking treatments. Understanding whether declines in incidence are being felt equally across age and gender can help prioritize demographic groups where more effort is needed to lower transmission. We found that HIV incidence has declined disproportionately in the youngest men and women in a population with the highest HIV prevalence in the world. Shifts in the age distribution of risk may be the consequence of aging prevalence, prioritized prevention to younger individuals, and delays in age at infection from reduced overall force of infection. Our results highlight the need to expand age targets for HIV prevention

HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa

Background: Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART. Methods and Findings: Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results. Conclusions: Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact

Feasibility study of multidisciplinary oncology rounds by videoconference for surgeons in remote locales

BACKGROUND: This study was undertaken to assess the feasibility of using videoconferencing to involve community-based surgeons in interactive, multidisciplinary oncology rounds so they may benefit from the type of community of practice that is usually only available in academic cancer centres. METHODS: An existing videoconference service provider with sites across Ontario was chosen and the series was accredited. Indirect needs assessment involved examining responses to a previously conducted survey of provincial surgeons; interviewing three cancer surgeons from different regions of Ontario; and by analyzing an online portfolio of self-directed learning projects. Direct needs assessment involved a survey of surgeons at videoconference-enabled sites. A surgical, medical and radiation oncologist plus a facilitator were scheduled to guide discussion for each session. A patient scenario developed by the discussants was distributed to participants one week prior to each session. RESULTS: Direct and indirect needs assessment confirmed that breast cancer and colorectal cancer topics were of greatest importance to community surgeons. Six one-hour sessions were offered (two breast, two colorectal, one gynecologic and one lung cancer). A median of 22 physicians and a median of eight sites participated in each session. The majority of respondents were satisfied with the videoconference format, presenters and content. Many noted that discussion prompted reflection on practice and that current practice would change. CONCLUSIONS: This pilot study demonstrated that it is possible to engage remote surgeons in multidisciplinary oncology rounds by videoconference. Continued assessment of videoconferencing is warranted but further research is required to develop frameworks by which to evaluate the benefits of telehealth initiatives

Socially-augmented argumentation tools: rationale, design and evaluation of a debate dashboard

Collaborative Computer-Supported Argument Visualization (CCSAV) is a technical methodology that offers support for online collective deliberation over complex dilemmas. As compared with more traditional conversational technologies, like wikis and forums, CCSAV is designed to promote more critical thinking and evidence-based reasoning, by using representations that highlight conceptual relationships between contributions, and through computational analytics that assess the structural integrity of the network. However, to date, CCSAV tools have achieved adoption primarily in small-scale educational contexts, and only to a limited degree in real world applications. We hypothesise that by reifying conversations as logical maps to address the shortcomings of chronological streams, CCSAV tools underestimate the importance of participation and interaction in enhancing collaborative knowledge-building. We argue, therefore, that CCSAV platforms should be socially augmented in order to improve their mediation capability. Drawing on Clark and Brennan’s influential Common Ground theory, we designed a Debate Dashboard, which augmented a CCSAV tool with a set of widgets that deliver meta-information about participants and the interaction process. An empirical study simulating a moderately sized collective deliberation scenario provides evidence that this experimental version outperformed the control version on a range of indicators, including usability, mutual understanding, quality of perceived collaboration, and accuracy of individual decisions. No evidence was found that the addition of the Debate Dashboard impeded the quality of the argumentation or the richness of content

Adapting to changes in volcanic behaviour: Formal and informal interactions for enhanced risk management at Tungurahua Volcano, Ecuador

This paper provides an example of how communities can adapt to extreme forms of environmental change and uncertainty over the longer term. We analyse the interactions between scientists, communities and risk managers and examine the interpretation and communication of uncertain scientific information during a long-lived volcanic eruption in Tungurahua, Ecuador. This is complemented with a detailed study of the eruptions of 2006 and 2014, which exemplifies the complexity of interactions during periods of heightened volcanic activity. Our study describes how a ‘shadow network’ has developed outside of, but in interaction with, the formal risk management institutions in Ecuador, improving decision-making in response to heightened volcanic activity. The findings suggest that the interactions have facilitated important adaptations in the scientific advisory response during eruptions (near-real-time interpretation of the volcanic hazards), in hazard communication, and in the evacuation processes. Improved communication between stakeholders and the establishment of thresholds for evacuations have created an effective voluntary evacuation system unique to Tungurahua, allowing people to continue to maintain their livelihoods during heightened volcanic activity and associated periods of uncertainty. Understanding how shadow networks act to minimise the negative consequences of volcanic activity provides valuable insights for increasing societal resilience to other types of hazards