23 research outputs found

    Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation

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    Sphingosine- 1- phosphate (S1P) lyase is a vitamin B6- dependent enzyme that degrades sphingosine- 1- phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6- dependent enzymes, a finding ascribed largely to the vitamin’s chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6- treated patient- derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162713/2/jimd12238.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162713/1/jimd12238_am.pd

    Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

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    The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

    Corticosteroids in the treatment of acute asthma

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    Abstract: Asthma is a prevalent chronic disease of the respiratory system and acute asthma exacerbations are among the most common causes of presentation to the emergency department (ED) and admission to hospital particularly in children. Bronchial airways infl ammation is the most prominent pathological feature of asthma. Inhaled corticosteroids (ICS), through their anti-infl ammatory effects have been the mainstay of treatment of asthma for many years. Systemic and ICS are also used in the treatment of acute asthma exacerbations. Several international asthma management guidelines recommend the use of systemic corticosteroids in the management of moderate to severe acute asthma early upon presentation to the ED. On the other hand, ICS use in the management acute asthma has been studied in different contexts with encouraging results in some and negative in others. This review sheds some light on the role of systemic and ICS in the management of acute asthma and discusses the current evidence behind their different ways of application particularly in relation to new developments in the fi eld

    Corticosteroids in the treatment of acute asthma

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    Asthma is a prevalent chronic disease of the respiratory system and acute asthma exacerbations are among the most common causes of presentation to the emergency department (ED) and admission to hospital particularly in children. Bronchial airways inflammation is the most prominent pathological feature of asthma. Inhaled corticosteroids (ICS), through their anti-inflammatory effects have been the mainstay of treatment of asthma for many years. Systemic and ICS are also used in the treatment of acute asthma exacerbations. Several international asthma management guidelines recommend the use of systemic corticosteroids in the management of moderate to severe acute asthma early upon presentation to the ED. On the other hand, ICS use in the management acute asthma has been studied in different contexts with encouraging results in some and negative in others. This review sheds some light on the role of systemic and ICS in the management of acute asthma and discusses the current evidence behind their different ways of application particularly in relation to new developments in the field

    Anaphylaxis to lidocaine with tolerance to articaine in a 12year old girl

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    AbstractTrue allergic reactions to local anesthetics are extremely rare and constitute less than 1% of all reactions. In addition, many of those allergic reactions are caused by the preservative constituents of the local anesthetics. Here we report a 12year old girl with anaphylaxis to lidocaine (an amide local anesthetic) on two occasions. The allergy was confirmed by positive skin prick test to the drug. Skin testing and challenge to another amide local anesthetic (articaine) were negative. Subsequently, its use was well tolerated in a dental procedure. Up to our knowledge, this is the first report of a patient who is allergic to lidocaine and tolerant to articaine

    Colonic basidiobolomycosis presenting with intestinal obstruction and a normal eosinophil count

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    Gastrointestinal basidiobolomycosis (GIB), caused by Basidiobolus ranrum, is a rare fungal infection with a limited geographic distribution. The majority of the cases are reported from the warm areas of Arizona in USA, Saudi Arabia and Iran.We report a middle aged patient who was admitted to hospital with suspected metastatic colonic carcinoma. He presented with constipation, anorexia and weight loss. Computed tomography scan disclosed a mass involving the mid and distal sigmoid colon and hypodense lesion in hepatic segment IV. Excised tissue during a Hartmann’s surgery showed an extensive eosinophil-rich transmural inflammation with mural necrotizing granulomas and several broad septated fungal hyphae. He was commenced on voriconazole following surgery. The diagnosis of basidiobolomycosis was established by histopathological examination. Since the diagnosis was not suspected preoperatively tissue culture for fungi was not collected. However molecular testing confirmed the diagnosis of GIB. Therapy involved a combination of surgical resection of the mass and prolonged voriconazole treatment. Increased awareness among physicians is needed for early diagnosis and treatment of GIB. Keywords: Fungal, Gastrointestinal, Basidiobolomycosis, Colon cance

    Understanding Healthcare Providers’ Value Perceptions of Content Creation and Design of a Personalized Asthma Management App: A case study in Saudi Arabia

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    Asthma is a serious global health problem affecting all age groups. Asthma management apps have been designed to increase self-management. However, most of these apps have not involved relevant stakeholders in the design and development phases, thus have not considered some important aspects such as human values and ethical aspects. This paper aims to understand healthcare providers as important stakeholders, their perspectives, values, and requirements for a personalized mHealth asthma management app’s content and design features. Semi-structured interviews were conducted with seven healthcare providers in Saudi Arabia. NVivo 12 software was used to code the interview data into themes and sub-themes for qualitative analysis. Three themes have been revealed from this study: Health Education Content, Asthma Safety, and Asthma App Design and its Features. This qualitative study contributes by identifying valuable perspectives and ideas for content creation and design features of a personalized mHealth asthma management app

    Endovascular Management of Arterial Injuries Related to Venous Access: A Retrospective Review of 10‑Year Single-Center Experience

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    Purpose: Retrospective review of the pattern and management techniques of arterial injuries related to central venous access with long-term outcomes. Materials and Methods: Between January 2007 and November 2017, a total of 20 patients (13 females) were included with the mean age of 63 (28–89 years) and mean body mass index of 25.75 (13.3–36.5). Venous access procedures included central venous catheter (CVC) placement, dialysis line insertion, or endovascular venous procedures. The study excluded patients who had arterial injuries related to arterial access, such as postarterial line placement, postangiography, or percutaneous coronary interventions. Results: Iatrogenic arterial injuries occurred after attempted venous access procedures involving the common femoral vein (n = 18) and subclavian vein (n = 2). Injuries were related to CVC placement (n = 5), temporary dialysis catheter (n = 14), and inferior vena cava filter insertion (n = 1). Nine patients had transarterial venous catheter insertion complicated by active bleeding from pseudoaneurysm and arteriovenous fistula. Other injuries included isolated fistula (n = 3), isolated pseudoaneurysm (n = 4), isolated branch injury (n = 2), and intra-arterial insertion (n = 2). Endovascular management included stent–graft placement (n = 14), embolization of bleeding vessel (n = 2), and thrombin injection for pseudoaneurysm (n = 2). Conservative management with manual compression achieved hemostasis in two patients. Technical success was achieved in 100%. One patient required repeat angiography and embolization of bleeding branch vessel following stent–graft placement to control bleeding fistula and pseudoaneurysm. Clinical success was achieved in all patients. Procedure-related complications included puncture site hematoma (n = 1) and partially occlusive thrombus/spasm of deep femoral artery after stent–graft placement. Six patients (33%) died within 20 days after the procedure (3–20 days) due to other comorbidities. Three additional patients (16%) died during the same hospital admission at the time of the procedure (38–114 days). There were no reported complaints related to possible stent–graft stenosis or occlusion at mean follow-up time of 5 years (50 days–8.64 years) in all seven patients who survived after stent–graft placement procedure. Conclusion: Despite technically successful endovascular management of arterial injuries related to venous access in critically ill patients, the mortality rate remains high due to other comorbidities. Allowing for the small sample size, stent–graft placement for arterial injuries in this cohort of patients appears to be an effective option with high long-term patency rate
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