Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders.

Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here, we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12(GRCh38):g.21452130A>G;NM_024854.5:c.464A>G;p.(N155S) and Chr12(GRCh38):g.21462019_21462022del;NM_024854.5:c.892_895del;p.(V298Mfs*4) and proband BII:1 is compound heterozygous for Chr12(GRCh38):g.21468739-21468741del;NM_024854.5:c.1488_1490del;p.(E496del) and Chr12(GRCh38):g.21467619del;NM_024854.5:c.1254+1del. RNA studies demonstrate c.892_895del;p.(V298Mfs*4) is targeted by nonsense mediated decay and c.1254+1delG elicits in-frame skipping of exon-11. Western blot from cultured fibroblasts shows reduced PYROXD1 protein levels in both probands. Testing urine from BII:1 and six individuals with PYROXD1 myopathy showed elevated levels of deoxypyridinoline, a mature collagen crosslink, correlating with PYROXD1-disorder severity. Urine and serum amino acid testing of the same individuals revealed no reportable changes. In contrast to PYROXD1 knock-out, we find no evidence for disrupted tRNA ligase activity, as measured via XBP1 splicing, in fibroblasts expressing PYROXD1 variants. In summary, we expand the clinical spectrum of PYROXD1-related disorders to include an overlapping connective tissue and myopathy presentation, identify three novel, pathogenic PYROXD1 variants, and provide preliminary evidence that elevated urine DPD crosslinks may provide a clinical biomarker for PYROXD1 disorders. Our results advocate consideration of PYROXD1 variants in the differential diagnosis for undiagnosed individuals presenting with a connective tissue disorder and myopathy.

The top 10 research priorities in psoriatic arthritis: a James Lind Alliance Priority Setting Partnership.

OBJECTIVES: To identify and prioritize the top 10 research questions for PsA. METHODS: The British Psoriatic Arthritis Consortium (BritPACT) formed a Priority Setting Partnership (PSP) comprising of people living with PsA, carers and clinicians, supported by the James Lind Alliance (JLA). This PSP followed the established three-stage JLA process: first, an online survey of people living with PsA, carers and clinicians to identify PsA questions, asking, 'What do you think are the most important unanswered questions in psoriatic arthritis research?' The questions were checked against existing evidence to establish 'true uncertainties' and grouped as 'indicative questions' reflecting the overarching themes. Then a second online survey ranked the 'true uncertainties' by importance. Finally, a workshop including people living with PsA and clinician stakeholders finalized the top 10 research priorities. RESULTS: The initial survey attracted 317 respondents (69% people living with PsA, 15% carers), with 988 questions. This generated 46 indicative questions. In the second survey, 422 respondents (78% people living with PsA, 4% carers) prioritized these. Eighteen questions were taken forward to the final online workshop. The top unanswered PsA research question was 'What is the best strategy for managing patients with psoriatic arthritis including non-drug and drug treatments?' Other top 10 priorities covered diagnosis, prognosis, outcome assessment, flares, comorbidities and other aspects of treatment (https://www.jla.nihr.ac.uk). CONCLUSION: The top 10 priorities will guide PsA research and enable PsA researchers and those who fund research to know the most important questions for people living with PsA.

Developing an aerobic exercise intervention for patients with psoriasis to support lifestyle behaviour change and improve health outcomes.

BACKGROUND: Patients with psoriasis do not exercise to the extent recommended for cardiovascular health, which may contribute to the increased risk of cardiovascular disease (CVD) and metabolic syndrome observed in this patient group. We previously identified that patients with psoriasis have significant disease-specific barriers to exercise. Others have reported that individuals with psoriasis develop higher heart rates and systolic blood pressure during bouts of exercise, followed by a slower recovery than healthy control subjects. AIMS: We hypothesized that a bespoke, evidenced-based, exercise programme could be developed for patients with psoriasis. METHODS: We convened a multidisciplinary Working Group comprising key stakeholders, including patients with psoriasis, along with sports scientists and clinicians, to develop the programme. RESULTS: To allow for different levels of fitness, lifestyle and motivation a 10-week intervention comprising two group walking sessions per week each of 1 h duration [led by a sports scientist (RS)] was designed using the Mapometer website. Walking distance was validated by a Walkmeter application, which uses global positioning system technology. The volume of exercise per session was calculated so that participants could incrementally progress to heart-healthy levels of exercise over the course of the programme. Maps of 20 unique walking routes were developed. A GENEactiv Original accelerometer and Newfeel Onwalk 900 pedometer were selected as wearable devices. CONCLUSION: We developed an exercise programme which specifically removed barriers to exercise for those with psoriasis, in partnership with patients. Regular exercise may offer significant health benefits for patients with psoriasis, including reduced CVD risk and increased psychosocial functioning, and this programme merits further investigation.

Cutaneous vascular structure and perfusion in patients with chronic plaque psoriasis.

BACKGROUND: Vascular dysfunction is a significant contributor to the pathophysiology of psoriasis. Some individuals have variation within the gene for vascular endothelial growth factor-A (VEGF-A), which confers an increased risk of developing psoriasis and having a severe disease phenotype, and may determine responsiveness to treatment. AIM: To determine whether patients with psoriasis have alterations in cutaneous microvascular anatomy and physiology due to expression of VEGF and whether laser Doppler imaging has utility in the assessment of this. METHODS: Twelve adult volunteers with Type 1 chronic plaque psoriasis underwent laser Doppler imaging of plaque and uninvolved skin. Skin biopsies were taken from the areas imaged for immunohistochemistry, including blood and lymphatic vessel markers, and VEGF-A isotype analysis (VEGF-A121, VEGF-A165 and VEGF-D). Venous blood was collected for DNA extraction, VEGF-A genotyping and peripheral blood mononuclear cell culture. RESULTS: Mean blood vessel area (P < 0·01), number of blood vessels (P < 0·001), number of lymphatic vessels (P < 0·001) and blood flow (P < 0·001) was significantly increased in psoriasis plaques, as was expression of VEGF-A121 (P < 0·01), VEGF-A165 (P < 0·04) and VEGF-D (P < 0·01). Blood flow within psoriasis plaques was independent of their increased vascularity (P < 0·01) and may be associated with baseline productivity of VEGF. The number of blood vessels within uninvolved skin in patients with psoriasis was associated with the VEGF-A (rs833061) genotype (P = 0·01), in a relationship suggesting an allele dosing effect. CONCLUSION: Noninvasive imaging of blood flow may help determine the cutaneous vascular signature for individual patients. This may be a useful prognostic indicator of psoriasis susceptibility and severity, and thus support selection of treatments.

Evaluation of ferritin and the ferritin index as prognostic biomarkers in septic shock.

BACKGROUND: Ferritin, an acute phase reactant, and the ferritin index (FI = observed ferritin level/upper limit of normal level for age and sex) may be prognostic biomarkers in septic shock and cardiac surgery patients. OBJECTIVE: The purpose of this exploratory study is to assess the outcome associations of ferritin and FI levels in septic shock compared to post-cardiac surgery patients. DESIGN: This was a prospective, double-centre, observational study. SETTING: The study setting involved two adult intensive care units (ICUs) in Victoria, Australia. PARTICIPANTS: Sixty-one septic shock and 30 post-cardiac surgery patients participated in this study. MAIN OUTCOME MEASURES: We measured ferritin and FI on ICU admission (T1) and 24 h later (T2) to assess its correlation with mortality, illness severity, and hospital length of stay (LOS). RESULTS: The baseline characteristics of patients in the septic shock group and cardiac surgery group were similar apart from illness severity scores (APACHE III and modified SOFA score). Septic shock patients had more physiological derangements as well as greater use and higher doses of norepinephrine at both T1 and T2. Septic shock patients had significantly higher median ferritin levels (372 µg/L versus 198 µg/L; p < 0.001 at T1, 457 µg/L versus 264 µg/L; p = 0.001 at T2) than post-cardiac surgery patients. Ferritin levels, however, did not have a linear correlation with illness severity or hospital mortality. Instead, there was an association between high ferritin levels at T2 and longer ICU (p = 0.017) and hospital LOS (p = 0.013). Females with septic shock had significantly higher FI (p < 0.001 at T1, p = 0.004 at T2) than males. CONCLUSION: In septic shock patients, ferritin levels and FI were twice the level compared to post-cardiac surgery patients. Both had no association with mortality, but levels above the median at 24 h were associated with longer ICU and hospital LOS.

Circadian rhythms in psoriasis and the potential of chronotherapy in psoriasis management.

The physiology and pathology of the skin are influenced by daily oscillations driven by a master clock located in the brain, and peripheral clocks in individual cells. The pathogenesis of psoriasis is circadian-rhythmic, with flares of disease and symptoms such as itch typically being worse in the evening/night-time. Patients with psoriasis have changes in circadian oscillations of blood pressure and heart rate, supporting wider circadian disruption. In addition, shift work, a circadian misalignment challenge, is associated with psoriasis. These features may be due to underlying circadian control of key effector elements known to be relevant in psoriasis such as cell cycle, proliferation, apoptosis and inflammation. Indeed, peripheral clock pathology may lead to hyperproliferation of keratinocytes in the basal layers, insufficient apoptosis of differentiating keratinocytes in psoriatic epidermis, dysregulation of skin-resident and migratory immune cells and modulation of angiogenesis through circadian oscillation of vascular endothelial growth factor A (VEGF-A) in epidermal keratinocytes. Chronotherapeutic effects of topical steroids and topical vitamin D analogues have been reported, suggesting that knowledge of circadian phase may improve the efficacy, and therapeutic index of treatments for psoriasis. In this viewpoint essay, we review the current literature on circadian disruption in psoriasis. We explore the hypothesis that psoriasis is circadian-driven. We also suggest that investigation of the circadian components specific to psoriasis and that the in vitro investigation of circadian regulation of psoriasis will contribute to the development of a novel chronotherapeutic treatment strategy for personalised psoriasis management. We also propose that circadian oscillations of VEGF-A offer an opportunity to enhance the efficacy and tolerability of a novel anti-VEGF-A therapeutic approach, through the timed delivery of anti-VEGF-A drugs.

Antivascular endothelial growth factor-A therapy: a novel personalized treatment approach for psoriasis.

Chronic plaque psoriasis is an inflammatory skin disease in which genetic predisposition along with environmental factors lead to the development of the disease, which affects 2% of the UK's population and is associated with extracutaneous morbidities and a reduced quality of life. A complex crosstalk between innate and adaptive immunity, the epithelia and the vasculature maintain the inflammatory milieu in psoriasis. Despite the development of promising treatment strategies, mostly targeting the immune system, treatments fail to fulfil every patient's goals. Vascular endothelial growth factor-A (VEGF-A) mediates angiogenesis and is upregulated in the plaques and plasma of patients with psoriasis. Transgenic expression of VEGF-A in experimental models led to the development of skin lesions that share many psoriasis features. Targeting VEGF-A in in vivo models of psoriasis-like inflammation resulted in disease clearance. Anti-angiogenesis treatments are widely used for cancer and eye disease and there are clinical reports of patients treated with VEGF-A inhibitors who have experienced Psoriasis Area and Severity Index improvement. Existing psoriasis treatments downregulate VEGF-A and angiogenesis as part of their therapeutic effect. Pharmacogenetics studies suggest the existence of different genetic signatures within patients with psoriasis that correspond with different treatment responsiveness and disease severity. There is a subset of patients with psoriasis with an increased predisposition to produce high levels of VEGF-A, who may be most likely to benefit from anti-VEGF-A therapy, offering an opportunity to personalize treatment in psoriasis. Anti-VEGF-A therapies may offer an alternative to existing anticytokine strategies or be complementary to standard treatments for the management of psoriasis.

The impact of research intercalation during medical school on post-graduate career progression.

BACKGROUND: Medical students at The University of Manchester have the option of research intercalation on the Master of Research programme. There is a paucity of evidence for the benefits of research intercalation. However, we hypothesised that research intercalation would accelerate post-graduate career progression and aimed to objectively measure the career enhancing impact, quantify the benefits and determine the alumni perception of research intercalation. METHODS: Data was collected retrospectively by electronic questionnaire (in 2018) from those commencing research intercalation between 2005 and 2012. RESULTS: Participants (n=52) returned questionnaires (68% response), demonstrating that the cohort had completed 67 postgraduate qualifications, published 304 manuscripts (median 3 publications per person (PP); range: 0-53) and made 430 presentations (median 7 PP; range: 0-37). Alumni had been awarded 49 research grants; funding disclosed on 43% totalled £823,000. Career progression of 73% of alumni had taken the minimum number of years; 27% took longer due to time spent working abroad or to gain additional experience prior to specialty training. Fifty-five publications and 71 presentations were directly related to MRes projects. CONCLUSION: Research intercalation provides graduates with an opportunity to learn valuable transferrable skills, contribute to translational research, and objectively enhances medical career progression.

Sustained nutrition impact of a multisectoral intervention program two years after completion.

Progress on the nutrition Sustainable Development Goals has been slow. More attention is needed on the 'sustainable' part, focused on impact lasting beyond programme implementation. To determine sustained impact of a multisectoral nutrition intervention that provided water, sanitation, hygiene, livelihood, health and nutrition support (2013-2015) in eastern Chad, we utilize longitudinal household data collected 2 years (2017) after the intervention ended. Between 2013 and 2015, children (6-59 months) in the multisectoral intervention were less likely to be severely wasted, underweight and had a higher weight-for-height z-score (WHZ) compared with the control. To measure sustained programme impact, we use data on six nutrition indicators from 517 children between 2015 and 2017. We ran three models: a generalized linear model on cross-sectional child cohorts; a mixed-effects model on household panel data; and a mixed-effects model on child panel data. For children who were born during the programme, we saw significant improvement in underweight, weight for age z-scores (WAZs) and height-for-age z-scores (HAZs). Boys 6-23 months born after the end of the programme, on the other hand, were significantly more likely to be underweight or wasted and had lower WHZ and WAZ compared with boys born during the programme and girls born during and after the programme. Corresponding to the literature from sub-Saharan Africa, boys appear to be more vulnerable to malnutrition, which might be why they are more sensitive to programme cessation. Future monitoring, evaluations and research need to consider impact sustainability and that it might not be homogeneous across age and gender.

Vascular endothelial growth factor-A as a promising therapeutic target for the management of psoriasis.

Vascular endothelial growth factor-A (VEGF-A), the main angiogenic mediator, plays a critical role in the pathogenesis of several inflammatory immune-mediated diseases, including psoriasis. Even though anti-angiogenic therapies, such as VEGF inhibitors, are licensed for the treatment of various cancers and eye disease, VEGF-targeting interventions are not part of current psoriasis therapy. In this viewpoint essay, we argue that the existing preclinical research evidence on the role of VEGF-A in the pathogenesis of psoriasis as well as clinical observations in patients who have experienced psoriasis remission during oncological anti-VEGF-A therapy strongly suggests to systematically explore angiogenesis targeting also in the management of psoriasis. We also point out that some psoriasis therapies decrease circulating levels of VEGF-A and normalise the psoriasis-associated vascular pathology in the papillary dermis of plaques of psoriasis and that a subset of patients with constitutionally high levels of VEGF-A may benefit most from the anti-angiogenic therapy we advocate here. Given that novel, well-targeted personalised medicine therapies for the development of psoriasis need to be developed, we explore the hypothesis that VEGF-A and signalling through its receptors constitute a promising target for therapeutic intervention in the future management of psoriasis.

Sublethal larval exposure to imidacloprid impacts adult behaviour in Drosophila melanogaster.

Pesticides are now chronically found in numerous ecosystems incurring widespread toxic effects on multiple organisms. For insects, the larvae are very exposed to pesticide pollution and the acute effect of insecticides on larvae has been characterized in a range of species. However, the carry-on effects in adults of sublethal exposure occurring in larvae are not well characterized. Here, we use a collection of strains of Drosophila melanogaster differing in their larval resistance to a commonly used insecticide, imidacloprid, and we test the effect of larval exposure on behavioural traits at the adult stage. Focusing on locomotor activity and on courtship and mating behaviour, we observed a significant carry-on effect of imidacloprid exposure. The heritability of activity traits measured in flies exposed to imidacloprid was higher than measured in controls and in these, courtship traits were genetically less correlated from mating success. Altogether, we did not observe a significant effect of the larval insecticide resistance status on adult behavioural traits, suggesting that selection for resistance in larvae does not involve repeatable behavioural changes in adults. This lack of correlation between larval resistance and adult behaviour also suggests that resistance at the larval stage does not necessarily result in increased behavioural resilience at a later life stage. These findings imply that selection for resistance in larvae as well as for behavioural resilience to sublethal exposure in adult will combine and impose a greater evolutionary constraint. Our conclusions further substantiate the need to encompass multiple trait measures and life stages in toxicological assays to properly assess the environmental impact of pesticides.

The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial.

BACKGROUND: Septic shock is associated with decreased vasopressor responsiveness. Experimental data suggest that central alpha2-agonists like dexmedetomidine (DEX) increase vasopressor responsiveness and reduce catecholamine requirements in septic shock. However, DEX may also cause hypotension and bradycardia. Thus, it remains unclear whether DEX is hemodynamically safe or helpful in this setting. METHODS: In this post hoc subgroup analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, an international randomized trial comparing early sedation with dexmedetomidine to usual care in critically patients receiving mechanical ventilation, we studied patients with septic shock admitted to two tertiary ICUs in Australia and Switzerland. The primary outcome was vasopressor requirements in the first 48 h after randomization, expressed as noradrenaline equivalent dose (NEq [µg/kg/min] = noradrenaline + adrenaline + vasopressin/0.4). RESULTS: Between November 2013 and February 2018, 417 patients were recruited into the SPICE III trial at both sites. Eighty-three patients with septic shock were included in this subgroup analysis. Of these, 44 (53%) received DEX and 39 (47%) usual care. Vasopressor requirements in the first 48 h were similar between the two groups. Median NEq dose was 0.03 [0.01, 0.07] µg/kg/min in the DEX group and 0.04 [0.01, 0.16] µg/kg/min in the usual care group (p = 0.17). However, patients in the DEX group had a lower NEq/MAP ratio, indicating lower vasopressor requirements to maintain the target MAP. Moreover, on adjusted multivariable analysis, higher dexmedetomidine dose was associated with a lower NEq/MAP ratio. CONCLUSIONS: In critically ill patients with septic shock, patients in the DEX group received similar vasopressor doses in the first 48 h compared to the usual care group. On multivariable adjusted analysis, dexmedetomidine appeared to be associated with lower vasopressor requirements to maintain the target MAP. TRIAL REGISTRATION: The SPICE III trial was registered at ClinicalTrials.gov ( NCT01728558 ).

Continuous Magnesium Infusion to Prevent Atrial Fibrillation After Cardiac Surgery: A Sequential Matched Case-Controlled Pilot Study.

OBJECTIVE: The authors aimed to test whether a bolus of magnesium followed by continuous intravenous infusion might prevent the development of atrial fibrillation (AF) after cardiac surgery. DESIGN: Sequential, matched, case-controlled pilot study. SETTING: Tertiary university hospital. PARTICIPANTS: Matched cohort of 99 patients before and intervention cohort of 99 consecutive patients after the introduction of a continuous magnesium infusion protocol. INTERVENTIONS: The magnesium infusion protocol consisted of a 10 mmol loading dose of magnesium sulphate followed by a continuous infusion of 3 mmol/h over a maximum duration of 96 hours or until intensive care unit discharge. MEASUREMENTS AND MAIN RESULTS: The study groups were balanced except for a lower cardiac index in the intervention cohort. The mean duration of magnesium infusion was 27.93 hours (95% confidence interval [CI]: 24.10-31.76 hours). The intervention group had greater serum peak magnesium levels: 1.72 mmol/L ± 0.34 on day 1, 1.32 ± 0.36 on day 2 versus 1.01 ± 1.14 and 0.97 ± 0.13, respectively, in the control group (p < 0.01). Atrial fibrillation occurred in 25 patients (25.3%) in the intervention group and 40 patients (40.4%) in the control group (odds ratio 0.49, 95% CI, 0.27-0.92; p = 0.023). On a multivariate Cox proportional hazards model, the hazard ratio for the development of AF was significantly less in the intervention group (hazard ratio 0.45, 95% CI, 0.26-0.77; p = 0.004). CONCLUSION: The magnesium delivery strategy was associated with a decreased incidence of postoperative AF in cardiac surgery patients. These findings provide a rationale and preliminary data for the design of future randomized controlled trials.

Vascular Endothelial Growth Factor Blockade Induces Dermal Endothelial Cell Apoptosis in a Clinically Relevant Skin Organ Culture Model.

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, plays a key role in physiological processes and is a major contributor to several diseases including cancer and psoriasis. Anti-VEGF therapies are widely used as cancer and ophthalmological treatments. There is some evidence that VEGF blockade may have utility in the management of psoriasis, although their potential has been largely unexplored. We hypothesized that a human skin organ culture could provide a stable ex vivo model in which the cutaneous microvascular network could be studied and experimentally manipulated. METHODS: Punch biopsies (3 mm) of skin, donated by healthy individuals (39-72 years old, n = 5), were incubated with monoclonal antibody (mAb) to human VEGF (bevacizumab) at doses based on data from animal and clinical studies. After 3-day culture, cell death and proliferation as well as vascular endothelial cell changes were assessed using quantitative immunohistomorphometry. RESULTS: Anti-VEGF mAb at 0.8 mg/mL induced a significant increase in cleaved caspase-3 expression in CD31+ cells (p < 0.05). None of the doses tested increased TUNEL or decreased Ki-67 expression in the basal layer of the epidermis, confirming the model's viability. In addition, the lactate dehydrogenase (LDH) assay showed no increase in LDH activity in treated samples compared to untreated control. The highest anti-VEGF mAb dose (0.8 mg/mL) induced an increase in TUNEL expression in the upper epidermis, which did not correlate with caspase-3 immunoreactivity. Further investigation revealed that anti-VEGF mAb did not change the expression of markers of terminal differentiation such as keratin 10, filaggrin, and involucrin, suggesting that VEGF depletion does not affect keratinocyte terminal differentiation. In contrast to the control group, levels of VEGF protein were undetectable in the culture supernatant of samples treated with 0.8 mg/mL of anti-VEGF mAb, suggesting sufficient dose. CONCLUSION: Our pilot study provides the first evidence that anti-VEGF therapy promotes endothelial cell apoptosis in human skin ex vivo. Our pragmatic human skin organ culture assay offers a valuable tool for future preclinical endothelial cell and translational microvascular network/anti-angiogenesis research in human skin.

Cannabinoids for the treatment of spasticity.

This review summarizes studies that examined the effectiveness of cannabinoids in treating spasticity, with a focus on understanding the relevance of the existing evidence to paediatric populations. MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched to identify studies that examined the use of cannabinoids in spasticity. We identified 32 studies in adult and paediatric populations. Results were summarized by condition, with adult and paediatric studies considered separately. There is evidence from randomized controlled clinical trials that cannabinoids are more effective than placebo in reducing symptoms of spasticity in adults with multiple sclerosis. Most positive effects were based on patient-rated rather than clinician-rated measures, were modest in size, and should be considered in the context of the narrow therapeutic index of cannabinoids for spasticity and adverse effects. There were comparatively few, and no large studies, of spasticity in conditions other than multiple sclerosis. Few studies have been conducted in paediatric populations. Paediatric studies of spasticity provide low quality evidence and are inadequate to inform clinical practice. Cannabinoids have modest efficacy in reducing muscle spasticity in adults with multiple sclerosis. There is limited evidence of efficacy for cannabinoid use in other conditions, particularly in paediatric populations. Studies in paediatric populations have been of low quality and are insufficient to inform clinical practice.

CANNABINOIDES PARA EL TRATAMIENTO DE LA ESPASTICIDAD: Esta revisión resume los estudios que examinaron la efectividad de los cannabinoides en el tratamiento de la espasticidad, con un enfoque en la comprensión de la relevancia de la evidencia existente para las poblaciones pediátricas. Se realizaron búsquedas en Medline, Embase, PsycINFO y la Biblioteca Cochrane para identificar estudios que examinaron el uso de cannabinoides en la espasticidad. Se identificaron 32 estudios en poblaciones adultas y pediátricas. Los resultados se resumieron por condición, con estudios en adultos y pediátricos considerados por separado. Existe evidencia de ensayos clínicos controlados aleatorios de que los cannabinoides son más efectivos que el placebo para reducir los síntomas de la espasticidad en adultos con esclerosis múltiple. La mayoría de los efectos positivos se basaron en las medidas clasificadas por el paciente en lugar de las clasificadas por el médico, fueron de tamaño modesto y deben considerarse en el contexto del estrecho índice terapéutico de los cannabinoides para la espasticidad y los efectos adversos. Hubo comparativamente pocos, y no hay estudios grandes, de espasticidad en afecciones distintas a la esclerosis múltiple. Se han realizado pocos estudios en poblaciones pediátricas. Los estudios pediátricos de espasticidad proporcionan evidencia de baja calidad y son inadecuados para informar la práctica clínica.

CANABINÓIDES PARA O TRATAMENTO DA ESPASTICIDADE: Esta revisão sintetiza estudos que examinaram a efetividade de canabinóides no tratamento da espasticidade, com foco na compreensão da relevância da evidência existente para populações pediátricas. Medline, Embase, PsycINFO, e Cochrane Library foram pesquisados para identificar estudos que examinaram o uso de canabinóides na espasticidade. Identificamos 32 estudos em populações adultas e pediátricas. Os resultados foram sintetizados por condição com estudos em adultos e pediátricos considerados separadamente. Há evidência de ensaios clínicos randomizados controlados de que os canabinóides são mais efetivos do que placebos na redução de sintomas de espasticidade em adultos com esclerose múltipla. A maioria dos efeitos positivos foram baseados em medidas fornecidas por pacientes e não por clínicos, eram de tamanho modesto, e devem ser considerados no contexto do estreito índice terapêutico dos canabinóides para espasticidade e efeitos adversos. Houve comparativamente menos, e nenhum grande estudo, da espasticidade em condições diferentes da esclerose múltipla. Poucos estudos foram conduzidos em populações pediátricas. Estudos pediátricos da espasticidade fornecem baixa evidência de qualidade e são inadequados para informar a prática clínica.

Hospital-acquired complications in intensive care unit patients with diabetes: A before-and-after study of a conventional versus liberal glucose control protocol.

BACKGROUND: Critically ill patients with diabetes mellitus (DM) are at increased risk of in-hospital complications and the optimal glycemic target for such patients remains unclear. A more liberal approach to glucose control has recently been suggested for patients with DM, but uncertainty remains regarding its impact on complications. METHODS: We aimed to test the hypothesis that complications would be more common with a liberal glycemic target in ICU patients with DM. Thus, we compared hospital-acquired complications in the first 400 critically ill patients with DM included in a sequential before-and-after trial of liberal (glucose target: 10-14 mmol/L) vs conventional (glucose target: 6-10 mmol/L) glucose control. RESULTS: Of the 400 patients studied, 165 (82.5%) patients in the liberal and 177 (88.5%) in the conventional-control group were coded for at least one hospital-acquired complication (P = 0.09). When comparing clinically relevant complications diagnosed between ICU admission and hospital discharge, we found no difference in the odds for infectious (adjusted odds ratio [aOR] for liberal-control: 1.15 [95% CI: 0.68-1.96], P = 0.60), cardiovascular (aOR 1.40 [95% CI: 0.63-3.12], P = 0.41) or neurological complications (aOR: 1.07 [95% CI: 0.61-1.86], P = 0.81), acute kidney injury (aOR 0.83 [95% CI: 0.43-1.58], P = 0.56) or hospital mortality (aOR: 1.09 [95% CI: 0.59-2.02], P = 0.77) between the liberal and the conventional-control group. CONCLUSION: In this prospective before-and-after study, liberal glucose control was not associated with an increased risk of hospital-acquired infectious, cardiovascular, renal or neurological complications in critically ill patients with diabetes.

Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3.

With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when studying unsolved inherited peripheral neuropathy cases with no pathogenic coding mutations.

Complexity, continuity and change: livelihood resilience in the Darfur region of Sudan.

Darfur farming and pastoralist livelihoods are both adaptations to the environmental variability that characterises the region. This article describes this adaptation and the longer-term transformation of these specialised livelihoods from the perspective of local communities. Over several decades farmers and herders have experienced a continuous stream of climate, conflict and other shocks, which, combined with wider processes of change, have transformed livelihoods and undermined livelihood institutions. Their well-rehearsed specialist strategies are now combined with new strategies to cope. These responses help people get by in the short term but risk antagonising not only their specialist strategies but also those of others. A combination of factors has undermined the former integration between farming and pastoralism and their livelihood institutions. Efforts to build resilience in similar contexts must take a long-term view of livelihood adaptation as a specialisation, and consider the implications of new strategies for the continuity and integration of livelihood specialisations.

Excessive angiogenesis associated with psoriasis as a cause for cardiovascular ischaemia.

Psoriasis, a common disease affecting 2%-3% of the UK population, produces significant impairment of quality of life and is an immense burden on sufferers and their families. Psoriasis is associated with significant cardiovascular comorbidity and the metabolic syndrome. Angiogenesis, a relatively under-researched component of psoriasis, is a key factor in pathogenesis of psoriasis and also contributes to the development of atherosclerosis. Vascular endothelial growth factor (VEGF) is a well-established mediator of pathological angiogenesis which is upregulated in psoriasis. It is possible that, in patients with psoriasis, cutaneous angiogenesis may be both a marker for systemic vascular pathology and a novel therapeutic target. In this viewpoint study, the role of VEGF-mediated angiogenesis as a cause for cardiovascular events in patients with psoriasis is explored.

Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan.

Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.