143,267 research outputs found
Survival, growth, and safety findings in patients with rapidly progressive, infantile-onset LAL-D: Results from the international LAL-D registry
No full textIn symptomatic infants, lysosomal acid lipase deficiency (LAL-D; historically Wolman disease) is characterized by a rapidly progressive disease course of hepatosplenomegaly and liver disease. This course includes liver failure, malabsorption and growth failure, and systemic inflammation, such as hemophagocytic lymphohistiocytosis, typically leading to death by 6 months of age if untreated. Sebelipase alfa (KANUMA®; Alexion, AstraZeneca Rare Disease, Boston, MA) is a recombinant human LAL (a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme) approved for the treatment of LAL-D in infants with rapidly progressive disease as well as in children and adults with LAL-D. Previous studies showed that enzyme replacement therapy (ERT) with sebelipase alfa led to survival with improved growth and development, hematologic parameters, and liver parameters and was well tolerated. We report long-term outcomes in 29 patients with rapidly progressive LAL-D who were symptomatic in infancy using patient data from the International LAL-D Registry, an ongoing observational, multicenter, international registry (NCT01633489) that collects data on patients with LAL-D. Among these 29 patients treated with sebelipase alfa, 41 % were male, and 28 % had participated in clinical trials with sebelipase alfa. Median age (Q1, Q3) was 2.3 months (1.8, 3.1) at the start of ERT. Patients received a starting ERT dose of ≤1 mg/kg or ≥ 3 mg/kg per week. In patients who had participated in clinical trials of sebelipase alfa, the starting dose was driven by the clinical trial protocol and was between 0.2 and 1.0 mg/kg per week. Overall, 27 of 29 (93 %) patients survived during the median observation time (Q1, Q3) of 6.2 years (3.5, 8.4). At baseline, 11 patients had abnormally low weight-for-age z scores (<−2); for 5 of these patients, weight stabilized after 6 to 12 months of treatment (z scores between −2 and 2). Adverse events occurred in 23 (79 %) patients. Eleven (38 %) patients experienced adverse events potentially related to sebelipase alfa, which were generally not severe and most resolved. Four patients among 7 tested developed antidrug antibodies, and 3 had positive results for neutralizing antidrug antibodies. These results confirmed the dramatic survival and metabolic benefit associated with sebelipase alfa ERT in patients with symptomatic, rapidly progressive LAL-D.The International LAL-D Registry is sponsored by Alexion, AstraZeneca Rare Disease, and is overseen by a scientific advisory board that includes medical experts with experience in LAL-D research or patient care
GISP2 14-C (radiocarbon) measurements (Table 3)
No full textCalculated accumulation rates from 14C data (Table 3 in Lal and Jull (1997) compared with glaciological flow-model estimates (Cutler et al., 1995)
From LAL-D to MASLD:Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism
No full textMetabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LAL[sbnd]D). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal−/− mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal−/− mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.</p
Lysosomal acid lipase deficiency (LAL-D) : na underdiagnosed cause of dyslipidemia and altered liver function
No full textA lipase ácida lisossômica (LAL) é enzima codificada pelo gene LIPA e a deficiência dessa enzima leva a uma desordem lisossômica genética denominada deficiência da lipase ácida lisossômica (LAL-D). A LAL é essencial para o metabolismo lipídico, pois é responsável pela hidrólise de ésteres de colesterol da lipoproteína de baixa densidade (LDL-c) e triglicerídeos, gerando colesterol e ácidos graxos livres que estão envolvidos na regulação da homeostase do colesterol. A deficiência dessa enzima, leva ao acúmulo maciço de ésteres de colesterol e triglicerídeos pelos lisossomos, mas também acarreta aumento na síntese endógena de colesterol. A LAL-D (OMIM # 278000) é uma doença de origem genética, autossômica recessiva, por mutações no gene LIPA (OMIM 613497), mapeado no braço longo do cromossomo 10 (10q23.2-q23.3) e que possui 10 exons. Classicamente, apresenta dois fenótipos: doença de Wolman (DW) e doença de depósito de ésteres de colesterol (CESD). A DW é um subtipo fulminante com ausência ou menos de 1% da atividade da LAL, manifestando-se no período neonatal, que pode levar ao óbito no primeiro ano de vida. Já a CESD tem apresentação mais tardia, mas pode estar presente na infância, idade adulta, dependendo da atividade residual da LAL, que pode variar de 1% a 12% do normal. Dislipidemia, disfunção hepática, hepatomegalia, hepatoesplenomegalia são as principais características dessa desordem lisossômica. Existe terapêutica específica com reposição enzimática, que reverte parcialmente, ou retarda as complicações da doença. Objetivo: Investigar a prevalência da deficiência da lipase ácida lisossômica em uma população de risco atendida nos ambulatórios do Setor de Lípides, Aterosclerose e Biologia Vascular de Disciplina de Cardiologia da Universidade Federal d e São Paulo (UNIFESP) a partir de critérios clínicos e laboratoriais. Métodos : Estudo retrospectivo avaliou 2000 prontuários médicos consecutivos, de pacientes adultos e pediátricos de ambos os sexos, atendidos nos ambulatório s de um único centro por dislipidemia. Os critérios de triagem seletiva para LAL-D incluíram LDL-C ≥160 mg/dL, HDL-C 1,5 x o limite superior da normalidade, presença de esteatose hepática, por ultrassom ou biópsia, e mutação no gene LIPA . Para os pacientes em uso de hipolipemiantes, o valor de LDL-C foi corrigido de acordo com a intensidade do tratamento. Os pacientes que preencheram os critérios de LAL-D foram submetidos a teste de atividade da LAL por método enzimático fluorescente para análise da atividade da lipase ácida lisossômica utilizando um inibidor específico da enzima, o que permite sua avaliação em gota de sangue seco em papel filtro. Resultados : Entre os 2000 participantes rastreados, foram encontrados 21 pacientes que preencheram os critérios de suspeição para LAL-D, sendo 9 homens, 12 mulheres, com idades entre 23 e 82. Os critérios de triagem mais prevalentes foram ALT > 1,5 x o limite superior em 100% dos pacientes, enquanto que, o HDL e a enzima hepática AST > 1,5 x o limite superior foram observados em 36,36 % dos pacientes. Não se encontrou deficiência de LAL pelo teste de atividade da LAL, sugerindo que essa condição seja muito rara, mesmo em serviços que atendem pacientes com critérios clínicos e laboratoriais para LAL-D. Conclusões: Embora utilizando-se critérios clínicos e laboratoriais, a condição é muito rara, mesmo em serviços que atendem populações de risco para LAL-D. O diagnóstico precoce da LAL-D é fundamental para permitir orientação nutricional, de estilo de vida e terapêutica específica, visando atenuar ou retardar a evolução e as complicações da doença.Lysosomal acid lipase (LAL) is the enzyme encoded by the LIPA gene; deficiency of this enzyme leads to a congenital lysosomal disorder called Lysosomal Acid Lipase Deficiency (LAL-D). LAL is essential for lipid metabolism as it is responsible for the hydrolysis of the esters of cholesterol of low-density lipoprotein (low-density lipoprotein, LDL-c) and triglycerides, generating cholesterol and free fatty acids that are involved in the regulation of homeostasis of the cholesterol. The deficiency of this enzyme leads to the accumulation of lysosomal esters of cholesterol and triglyceride and eventually failure of the LDL-c receptor pathway. Despite the massive accumulation of cholesterol esters by lysosomes, there is an increase in cellular cholesterol synthesis. LAL-D (OMIM # 278000) is a disease of genetic origin, autosomal recessive, caused by mutations in the LIPA gene (OMIM 613497), mapped on the long arm of chromosome 10 (10q23.2-q23.3) and containing 10 exons. Classically, it has two phenotypes, Wolman Disease (WD) and Cholesterol Ester Storage Disease (CESD). WD is a fulminant subtype with absence or less than 1% of LAL activity manifesting in the neonatal period, which can lead to death in the first year of life. CESD has a later presentation, but may be present in childhood and adulthood, depending on the residual activity of LAL, which may vary from 1% to 12% of normal. Dyslipidemia, liver dysfunction, hepatomegaly, hepatosplenomegaly are the main features of this lysosomal disorder. There is specific therapy with enzyme replacement that partially reverses or delays the complications of the disease. Objectives: to investigate the prevalence of Lysosomal Acid Lipase Deficiency in a risk population attended at the outpatient clinics of the Lipids, Atherosclerosis and Vascular Biology Section, Cardiology Division of the Federal University of São Paulo (UNIFESP) based on clinical and laboratory criteria. Methods: Retrospective study evaluated two-thousand consecutive medical records of adult and pediatric patients treated at outpatient clinics of a single center for dyslipidemia. Selective screening criteria for LAL-D included LDL-C> 160 mg / dL, HDL-C 1.5 x upper normal limit, presence of liver steatosis by ultrasound or biopsy, and mutation in the LIPA gene. For patients on lipid-lowering therapy, LDL-C was corrected according to the intensity of treatment. Patients who met the LAL-D criteria underwent LAL activity testing by enzymatic fluorescent method to analyze lysosomal acid lipase activity using a specific enzyme inhibitor that enables the evaluation in dry blood spot in filter paper. Results: Among the 2000 screened subjects we found 21 patients who met the LAL-D suspicion criteria, being nine males, 12 females, ages between 23 and 82 years old. The most prevalent screening criteria were ALT > 1.5 x upper normal limit in 100% of patients, while the HDL-C and the liver enzyme AST > 1.5 x upper normal limit was observed in 36.36 % of patients. No LAL deficiency was found by the LAL activity test, suggesting that this condition is very rare, even in services that serve a population at risk. Conclusions: Although clinical and laboratory criteria have been used to screen for LAL-D, the condition is very rare, even in services that serve a population at risk. Early diagnosis of LAL-D is critical to enable nutritional, lifestyle, and specific therapeutic guidance to alleviate or delay disease course and complications.Dados abertos - Sucupira - Teses e dissertações (2020
The LAL compton program
No full textInternational audienceRecently LAL (Laboratoire de l'Accelerateur Lineaire, Orsay France) has launched an R&D program that involves optical Fabry-Perot resonators and high power fibre lasers. This program is part of the global effort aiming at the design of a polarised positron source for the next linear collider (ILC or CLIC). At the same time an important effort is devoted to the possible applications of this technology at lower energy for medical and industrial applications. In this framework a collaboration was started between different French laboratories (RadioThomX project) and industrial partners to study the feasibility of a low energy machine that should provide a high x-ray flux (~ 1012 - 1013 X s-1 at 50 keV in the 10% energy bandwidth). In both the high and the low energy studies the designs are based on the possibility to increase the average flux by a high collision repetition frequency. Different options are explored at present. In the following we will give an overview of the LAL activities, the physics contexts and the possible applications of the high average power Fabry-Perot technology applied to Compton scattering experiments
Measurement of the D+/- production asymmetry in 7 TeV pp collisions
No full textThe asymmetry in the production cross-section \sigma of D+/- mesons, A_P = (\sigma(D+) - \sigma(D-))/(\sigma(D+) + \sigma(D-)), is measured in bins of pseudorapidity \eta and transverse momentum p_T within the acceptance of the LHCb detector. The result is obtained with a sample of D+ -> K_S pi+ decays corresponding to an integrated luminosity of 1.0 fb^-1, collected in pp collisions at a centre of mass energy of 7 TeV at the Large Hadron Collider. When integrated over the kinematic range 2.0 K_S pi+ decay is negligible. No significant dependence on \eta or p_T is observed
Endotoxin signal detected using standard LAL without BG blocking buffer displayed by tertiles of (1–3)-β-D glucan.
No full textEndotoxin signal detected using standard LAL without BG blocking buffer displayed by tertiles of (1–3)-β-D glucan.</p
Clinical correlates of (1–3)-β-D glucan, endotoxin signals detected using LAL[–] and markers of inflammation.
No full textClinical correlates of (1–3)-β-D glucan, endotoxin signals detected using LAL[–] and markers of inflammation.</p
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