Barth syndrome Clarke, Sarah L N; Bowron, Ann; Gonzalez, Iris L ...
Orphanet journal of rare diseases,
02/2013, Letnik:
8, Številka:
1
Journal Article
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First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased ...urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.
Controlled perturbation of protein activity is essential to study protein function in cells and living organisms. Small molecules that hijack the cellular protein ubiquitination machinery to ...selectively degrade proteins of interest, so-called degraders, have recently emerged as alternatives to selective chemical inhibitors, both as therapeutic modalities and as powerful research tools. These systems offer unprecedented temporal and spatial control over protein function. Here, we review recent developments in this field, with a particular focus on the use of degraders as research tools to interrogate complex biological problems.
North America continues to face an opioid overdose epidemic, driven by persistent increases in illicit fentanyls and fluctuations in potency leading to uncertainty for consumers. This qualitative ...study was conducted to better understand how people who inject drugs (PWID) came to recognize fentanyl as a growing adulterant of heroin and the subsequent sensory discernment strategies they employed to continue injecting. Our main objective was to investigate how observations and knowledge are combined as homegrown techniques for detecting fentanyl and minimizing risk. Secondary objectives were to examine the impact of growing fentanyl adulteration on individual drug use behavior.
Between April and May 2019, 28 PWID (18 men, 10 women; average age = 38.43 years, SD = 9.26) were purposely recruited from a needle services program in Greensboro, North Carolina. Study participants were interviewed in-person using a qualitative, semi-structured instrument. Interviews were analyzed with a general inductive approach using NVivo12.
Participants described methods for detecting fentanyl in illicit opioids. Sudden increases in the potency of the ‘rush’ and sharp decreases in the length of the ‘high’ were chief indicators along with changes in drug color and texture. Heavy sedation was associated with fentanyl use and histamine-releasing effects characterized as ‘pins and needles’ were ascribed to injecting fentanyl as a component of the rush. Fentanyl's short high helped explain higher injection frequency and heavy sedation was the leading reason for co-using fentanyl with cocaine/crack or methamphetamine.
PWID have the capacity to recognize changes to the illicit opioid supply. Study participants navigated unpredictable fluctuations in the illicit opioid market by employing homegrown discernment techniques, modifying drug use behavior, and co-using non-opioid drugs. Researchers and policymakers should involve PWID as subject matter experts to help modernize harm reduction for the fentanyl age with practical strategies to boost resiliency and save lives.
Juvenile idiopathic arthritis-associated uveitis Clarke, Sarah L N; Sen, Ethan S; Ramanan, Athimalaipet V
Pediatric rheumatology online journal,
04/2016, Letnik:
14, Številka:
1
Journal Article
Recenzirano
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Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a ...potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management.
The Getting It Right First Time (GIRFT) process is designed to improve the care of patients in the National Health Service (NHS) in England through in-depth review of services, benchmarking and ...presenting a data-driven evidence base to support change. Although it started as a pilot project targeting unwarranted variation in elective orthopaedic surgery, it rapidly became apparent that the approach of clinically led deep dives to review the activity in individual orthopaedic units was effective in improving standards of care and resulted in substantial cost savings that could be reinvested in the clinical service. GIRFT has now expanded to encompass 40 clinical specialties and is funded nationally by the NHS in England. The purpose of this article is to describe its application and benefit to cardiology.
Tobacco smoking causes lung cancer
, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA
. The profound effects of tobacco on the genome of ...lung cancer cells are well-documented
, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0-6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.
...their use does pose challenges in paediatric practice as they are exclusively injectable formulations. ...an urgent unmet need for efficacious oral treatments for children with JIA who do not ...respond adequately to methotrexate remains. The trial met its primary endpoint of lower JIA flare rate by week 44 with tofacitinib (21 29% of 72 patients) versus placebo (37 53% of 70 patients) in patients with polyarticular course JIA (hazard ratio 0·46, 95% CI 0·27–0·79) and reported improvements in secondary endpoints related to disease activity and physical function. ...evidence of the effect of tofacitinib on uveitis incidence or activity is not available and would be important in informing real-world treatment choices, both in polyarticular course JIA and more broadly.
There is a paucity of data on the ocular outcomes in paediatric non-infectious uveitis since the introduction of the biologic agents. The purpose of this study was to outline the clinical ...characteristics of children with non-infectious uveitis and determine the visual outcomes and ocular complication rates in the modern era.
Children with non-infectious uveitis from January 2011 to December 2015 were identified. Data was collected at baseline, 1, 3, 5, and 10 years post diagnosis. The incidence rates of visual impairment, structural ocular complications and surgical intervention were calculated. Using logistic regression the association between various baseline characteristics and later visual impairment was investigated.
Of the 166 children, 60.2% (n = 100) had a systemic disease association. 72.9% (n = 121) children received methotrexate, 58 children progressed to a biologic. The incidence rates of visual acuity loss to > 0.3 LogMAR (6/12) and to ≥1.0 LogMAR (6/60) were 0.05/Eye Year (EY) and 0.01/EY, respectively. Visual outcomes in the Juvenile Idiopathic Arthritis associated Uveitis (JIA-U) and Idiopathic Uveitis cohorts were not statistically significant. Of the 293 affected eyes, posterior synechiae was the predominant complication on presentation, while cataract had the highest incidence rate (0.05/EY). On direct comparison, children with JIA-U were statistically significantly more likely to develop glaucoma while children with Idiopathic Uveitis were statistically significantly more likely to develop macular oedema.
One third of children received a biological therapy, reflecting increasing utilisation and importance of biological agents in the management of inflammatory conditions. Rates of visual impairment and ocular complications are an improvement on previously published data.
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