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Assessing minimal residual disease (MRD) in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is essential for adjusting therapeutic strategies and predicting relapse. Quantitative polymerase chain reaction (qPCR) is the gold standard for MRD. Alternatively, flow cytometry is a quicker and cost-effective method that typically uses leukaemia-associated immunophenotype (LAIP) or different-from-normal (DFN) approaches for MRD assessment. This study describes an optimized 12-colour flow cytometry antibody panel designed for BCP-ALL diagnosis and MRD monitoring in a single tube. This method robustly differentiated hematogones and BCP-ALL cells using two specific markers: CD43 and CD81. These and other markers (e.g. CD73, CD66c and CD49f) enhanced the specificity of BCP-ALL cell detection. This innovative approach, based on a dual DFN/LAIP strategy with a principal component analysis method, can be used for all patients and enables MRD analysis even in the absence of a diagnostic sample. The robustness of our method for MRD monitoring was confirmed by the strong correlation (r = 0.87) with the qPCR results. Moreover, it simplifies and accelerates the preanalytical process through the use of a stain/lysis/wash method within a single tube (<2 h). Our flow cytometry-based methodology improves the BCP-ALL diagnosis efficiency and MRD management, offering a complementary method with considerable benefits for clinical laboratories.
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Citometría de Flujo , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Neoplasia Residual/diagnóstico , Citometría de Flujo/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Inmunofenotipificación/métodos , Masculino , Estudios de Seguimiento , Femenino , Niño , Toma de Decisiones Clínicas , Antígenos CD/análisis , PreescolarRESUMEN
BACKGROUND AND PURPOSE: Late onset Pompe disease (LOPD) is a rare neuromuscular disorder caused by a deficit in acid alpha-glucosidase. Macroglossia and swallowing disorders have already been reported, but no study has focused yet on its frequency and functional impact on patients' daily life. METHODS: We reviewed 100 adult LOPD patients followed in 17 hospitals in France included in the French national Pompe disease registry. The Swallowing Quality of Life Questionnaire and the Sydney Swallow Questionnaire were completed by patients, and a specialist carried out a medical examination focused on swallowing and assigned a Salassa score to each patient. Respiratory and motor functions were also recorded. Subgroup analysis compared patients with and without swallowing difficulties based on Salassa score. RESULTS: Thirty-two percent of patients presented with swallowing difficulties, often mild but sometimes severe enough to require percutaneous endoscopic gastrostomy (1%). Daily dysphagia was reported for 20% of our patients and aspirations for 18%; 9.5% were unable to eat away from home. Macroglossia was described in 18% of our patients, and 11% had lingual atrophy. Only 15% of patients presenting with swallowing disorders were followed by a speech therapist. Swallowing difficulties were significantly associated with macroglossia (p = 0.015), longer duration of illness (p = 0.032), and a lower body mass index (p = 0.047). CONCLUSIONS: Swallowing difficulties in LOPD are common and have significant functional impact. Increased awareness by physicians of these symptoms with systematic examination of the tongue and questions about swallowing can lead to appropriate multidisciplinary care with a speech therapist and dietitian if needed.
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Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , alfa-Glucosidasas/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Terapia de Reemplazo Enzimático , Femenino , Francia , Enfermedad del Almacenamiento de Glucógeno Tipo II/mortalidad , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Pruebas de Función Respiratoria , Resultado del Tratamiento , Prueba de Paso , Adulto JovenRESUMEN
Objectives: Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM. The aim of our study was to explore without a priori hypotheses whether MSAs are associated with distinct clinical-pathological changes and severity in a monocentric JDM cohort. Methods: Clinical, biological and histological findings from 23 JDM patients were assessed. Twenty-six histopathological parameters were subjected to multivariate analysis. Results: Autoantibodies included anti-NXP2 (9/23), anti-TIF1γ (4/23), anti-MDA5 (2/23), no MSAs (8/23). Multivariate analysis yielded two histopathological clusters. Cluster 1 (n = 11) showed a more severe and ischaemic pattern than cluster 2 (n = 12) assessed by: total score severity ⩾ 20 (100.0% vs 25.0%); visual analogic score ⩾6 (100.0% vs 25.0%); the vascular domain score >1 (100.0% vs 41.7%); microinfarcts (100% vs 58.3%); ischaemic myofibrillary loss (focal punched-out vacuoles) (90.9 vs 25%); and obvious capillary loss (81.8% vs 16.7). Compared with cluster 2, patients in cluster 1 had strikingly more often anti-NXP2 antibodies (7/11 vs 2/12), more pronounced muscle weakness, more gastrointestinal involvement and required more aggressive treatment. Furthermore, patients with anti-NXP2 antibodies, mostly assigned in the first cluster, also displayed more severe muscular disease, requiring more aggressive treatment and having a lower remission rate during the follow-up period. Conclusion: Marked muscle ischaemic involvement and the presence of anti-NXP2 autoantibodies are associated with more severe forms of JDM.
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Adenosina Trifosfatasas/inmunología , Autoanticuerpos/inmunología , Proteínas de Unión al ADN/inmunología , Dermatomiositis/complicaciones , Isquemia/etiología , Músculo Esquelético/irrigación sanguínea , Adenosina Trifosfatasas/metabolismo , Biomarcadores/metabolismo , Biopsia , Proteínas de Unión al ADN/metabolismo , Dermatomiositis/inmunología , Dermatomiositis/metabolismo , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Isquemia/diagnóstico , Isquemia/inmunología , Masculino , Músculo Esquelético/diagnóstico por imagen , Índice de Severidad de la EnfermedadRESUMEN
Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.
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Predisposición Genética a la Enfermedad/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Mutación , alfa-Glucosidasas/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Estudios de Cohortes , Diagnóstico Tardío , Femenino , Francia/epidemiología , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: The aim of this study was to analyze the adjustable gastric banding (AGB) natural history on a national basis. BACKGROUND: Adjustable gastric banding represented the most common bariatric procedure in France until 2010. Since then, the number of AGBs has decreased and the rate of band removal and revisional surgeries has progressively increased. METHODS: For analysis, we included all adult patients operated on with AGB in France between 2007 and 2013. Data were extracted from a national administrative database ("Programme De Médicalisation des Systèmes d'Information," PMSI), which is an exhaustive source of all surgical procedures performed in France. The Cox proportional hazard model was used to test univariate and multivariate associations with band survival and revisional rate. To control for center-specific effects, we performed a frailty analysis, in which each center was assumed to have a random effect indicating the possibility of different baseline risks for patients at different centers. RESULTS: During the study period, 52,868 patients underwent AGB, and 10,815 bands were removed. The removal rate at 5, 6, and 7 years was 28%, 34%, and 40%, respectively. Female sex, body mass index >50âkg/m, type 2 diabetes, hypertension, dyslipidemia, and sleep apnea were found to be significantly associated with band removal by multivariate analysis. A significant center effect was also found, but this did not change the impact of the highly significant factors already identified. After band removal, the median time to revisional surgery was 1 year (95% confidence interval 1.0-1.1) and the conversion rate at 7 years was 71%. CONCLUSIONS: With a removal rate of about 6% annually and the need for revisional surgery for more than two-thirds of patients after removal, AGB does not appear to provide a long-term solution for obesity.
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Gastroplastia/efectos adversos , Gastroplastia/métodos , Obesidad Mórbida/cirugía , Reoperación/estadística & datos numéricos , Pérdida de Peso , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Francia , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Obesidad Mórbida/diagnóstico , Satisfacción del Paciente/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/fisiopatología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease. METHODS: We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared. RESULTS: Twelve patients (7 males) were identified. Median age at symptom onset was 24years [IQR=15.5; 36.0]. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24h [IQR=21.88; 24.00] (min 20; max 24). ERT was initiated at a median age of 52.5years [IQR=35.75; 66.50]. Median treatment duration was 55months [IQR=39.5; 81.0]. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90min and two increased their assisted walking distance, by 80 and 20m. CONCLUSION: Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities.
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Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , alfa-Glucosidasas/uso terapéutico , Adulto , Estudios de Cohortes , Terapia de Reemplazo Enzimático/efectos adversos , Femenino , Francia , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Enfermedades de Inicio Tardío/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Respiración , Caminata , alfa-Glucosidasas/administración & dosificación , alfa-Glucosidasas/efectos adversosRESUMEN
Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required. In this study we present preliminary longitudinal data of Motor Function Measure (MFM), timed tests, Purdue pegboard test, and handgrip strength collected over 5 to 9years of follow-up in 13 patients with GSDIII aged between 13 and 56years old. Follow-up for nine of the 13 patients was up to 9years. Similarly to our previous cross-sectional retrospective study, handgrip strength significantly decreased with age in patients older than 37years. MFM scores started to decline after the age of 35. The Purdue pegboard score also significantly reduced with increasing age (from 13years of age) but with large inter-visit variations. The time to stand up from a chair or to climb 4 stairs increased dramatically in some but not all patients older than 30years old. In conclusion, this preliminary longitudinal study suggests that MFM and handgrip strength are the most sensitive muscle function outcome measures in GSDIII patients from the end of their third decade. Sensitive muscle outcome measures remain to be identified in younger GSDIII patients but is challenging as muscle symptoms remain discrete and often present as accumulated fatigue.
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Enfermedad del Almacenamiento de Glucógeno Tipo III/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo III/fisiopatología , Enfermedades Musculares/etiología , Adolescente , Adulto , Estudios Transversales , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo III/genética , Fuerza de la Mano , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades Musculares/complicaciones , Enfermedades Musculares/fisiopatología , Evaluación de Procesos y Resultados en Atención de Salud , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVE: Outcome of JDM is highly heterogeneous. Our objective was to determine clinical and muscle biopsy features associated with poor outcome and response to treatment. METHODS: Clinical data and muscle biopsy were obtained from a monocentric cohort of 29 patients. Clinical subgroups were defined by latent class model analysis of initial and follow-up parameters. Myopathological features were analysed using validated scores. Capillary loss was determined on reconstructions of transversal sections and assessed in the different age groups to take into account variations of muscle capillarization during post-natal development. Regression models were used to identify initial predictors of therapeutic response. RESULTS: Two distinct homogeneous subgroups of patients were identified according to clinical severity and pathological findings. The smallest group of patients (7/29) presented with severe JDM. Compared with the other group (22/29), patients had more severe muscle weakness at disease onset, low remission rate at 12 months, frequent subcutaneous limb oedema or gastrointestinal (GI) involvement and higher myopathological scores (capillary dropout, perifascicular necrosis/regeneration, fibres with internal myonuclei and fibrosis subscores). Relevance of capillary dropout to JDM severity was substantiated by age-based analysis, confirming its major role in JDM pathophysiology. Most of these manifestations could be related to vasculopathy (limb oedema, GI involvement, capillary dropout). Furthermore, Childhood Myositis Assessment Scale <34 with either GI involvement or muscle endomysial fibrosis at disease onset were the best predictors of poor response to treatment. CONCLUSION: Vasculopathy is prominent in severe JDM. Simple criteria can be used at initial evaluation to identify patients requiring a more intensive therapy.
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Dermatomiositis/patología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/patología , Enfermedades Vasculares/patología , Adolescente , Biopsia con Aguja , Capilares/patología , Niño , Preescolar , Estudios de Cohortes , Dermatomiositis/complicaciones , Dermatomiositis/fisiopatología , Progresión de la Enfermedad , Femenino , Francia , Humanos , Inmunohistoquímica , Masculino , Pronóstico , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Enfermedades Vasculares/complicaciones , Enfermedades Vasculares/fisiopatologíaRESUMEN
Background: Measurement of muscle strength and motor function is recommended in clinical trials of neuromuscular diseases, but the loss of hand strength at which motor function is impacted is not documented. Objectives: To establish the relationship between hand strength and function, and to determine the strength threshold that differentiates normal and abnormal hand function in individuals with Duchenne Muscular Dystrophy (DMD) or Spinal Muscular Atrophy (SMA). Methods: Maximal handgrip and key pinch strength were measured with the MyoGrip and MyoPinch dynamometers, respectively. Hand function was assessed using the MoviPlate, the Motor Function Measure items for distal upper limb (MFM-D3-UL) and the Cochin Hand Function Scale (CHFS). Results: Data from 168 participants (91 DMD and 77 SMA, age 6-31 years) were analyzed. Relationships between strength and function were significant (Pâ<â0.001). Hand function was generally preserved when strength was above the strength threshold determined by Receiver-Operating Characteristic (ROC) analysis: For MFM-D3-UL, the calculated handgrip strength thresholds were 41 and 13% of the predicted strength for a healthy subject (% pred) and the key pinch strength thresholds were 42 and 26% pred for DMD and SMA, respectively. For the MoviPlate, handgrip strength thresholds were 11 and 8% pred and key pinch strength thresholds were 21 and 11% pred for DMD and SMA, respectively. For participants with sub-threshold strength, hand function scores decreased with decreasing strength. At equal % pred strength, individuals with SMA had better functional scores than those with DMD. Conclusions: Hand function is strength-dependent for most motor tasks. It declines only when strength falls below a disease-specific threshold. Therefore, therapies capable of maintaining strength above this threshold should preserve hand function.
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Fuerza de la Mano , Atrofia Muscular Espinal , Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/fisiopatología , Fuerza de la Mano/fisiología , Masculino , Adolescente , Niño , Atrofia Muscular Espinal/fisiopatología , Adulto , Adulto Joven , Femenino , Ensayos Clínicos como Asunto , Dinamómetro de Fuerza MuscularRESUMEN
Importance: Sarcopenia and obesity are 2 global concerns associated with adverse health outcomes in older people. Evidence on the population-based prevalence of the combination of sarcopenia with obesity (sarcopenic obesity [SO]) and its association with mortality are still limited. Objective: To investigate the prevalence of sarcopenia and SO and their association with all-cause mortality. Design, Setting, and Participants: This large-scale, population-based cohort study assessed participants from the Rotterdam Study from March 1, 2009, to June 1, 2014. Associations of sarcopenia and SO with all-cause mortality were studied using Kaplan-Meier curves, Cox proportional hazards regression, and accelerated failure time models fitted for sex, age, and body mass index (BMI). Data analysis was performed from January 1 to April 1, 2023. Exposures: The prevalence of sarcopenia and SO, measured based on handgrip strength and body composition (BC) (dual-energy x-ray absorptiometry) as recommended by current consensus criteria, with probable sarcopenia defined as having low handgrip strength and confirmed sarcopenia and SO defined as altered BC (high fat percentage and/or low appendicular skeletal muscle index) in addition to low handgrip strength. Main Outcome and Measure: The primary outcome was all-cause mortality, collected using linked mortality data from general practitioners and the central municipal records, until October 2022. Results: In the total population of 5888 participants (mean [SD] age, 69.5 [9.1] years; mean [SD] BMI, 27.5 [4.3]; 3343 [56.8%] female), 653 (11.1%; 95% CI, 10.3%-11.9%) had probable sarcopenia and 127 (2.2%; 95% CI, 1.8%-2.6%) had confirmed sarcopenia. Sarcopenic obesity with 1 altered component of BC was present in 295 participants (5.0%; 95% CI, 4.4%-5.6%) and with 2 altered components in 44 participants (0.8%; 95% CI, 0.6%-1.0%). An increased risk of all-cause mortality was observed in participants with probable sarcopenia (hazard ratio [HR], 1.29; 95% CI, 1.14-1.47) and confirmed sarcopenia (HR, 1.93; 95% CI, 1.53-2.43). Participants with SO plus 1 altered component of BC (HR, 1.94; 95% CI, 1.60-2.33]) or 2 altered components of BC (HR, 2.84; 95% CI, 1.97-4.11) had a higher risk of mortality than those without SO. Similar results for SO were obtained for participants with a BMI of 27 or greater. Conclusions and Relevance: In this study, sarcopenia and SO were found to be prevalent phenotypes in older people and were associated with all-cause mortality. Additional alterations of BC amplified this risk independently of age, sex, and BMI. The use of low muscle strength as a first step of both diagnoses may allow for early identification of individuals at risk for premature mortality.
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Sarcopenia , Humanos , Femenino , Anciano , Masculino , Sarcopenia/complicaciones , Sarcopenia/epidemiología , Estudios de Cohortes , Fuerza de la Mano , Fuerza Muscular , Obesidad/complicaciones , Obesidad/epidemiologíaRESUMEN
Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 µg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT.
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Anticuerpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma de Células B Grandes Difuso , Prednisona , Rituximab , Vincristina , Humanos , Masculino , Femenino , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Persona de Mediana Edad , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Rituximab/efectos adversos , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Anciano , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Prednisona/efectos adversos , Vincristina/uso terapéutico , Vincristina/efectos adversos , Vincristina/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano de 80 o más Años , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Alterations in adipose tissue (AT) metabolism related to inflammation and adipokine's production lead to perturbations in its capacity to store lipids and release fatty acids (FA) during feeding/fasting transition or during exercise. Exercise has a beneficial effect on AT metabolism, but conventional trainings are not always suitable for patients with functional limitations. Dynamic eccentric (ECC) exercise prevents the accumulation of AT and may then overcome those limitations. Consequently, this study aimed at investigating AT's adaptations after ECC training. Nine-week-old male rats were randomly assigned to a control sedentary or three-trained groups for which treadmill slopes modulated exercise oxygen consumption (VO2) and mechanical work (n = 15 per group): (1) + 15% uphill-concentric group (CONC), (2) - 15% downhill group (ECC15, same mechanical work as CONC) and (3) - 30% downhill group (ECC30, same VO2, or oxygen cost as CONC). Body composition and energy expenditure (EE) were measured before and after 8 weeks of training. Subcutaneous AT was collected to study total FA profile and gene expression. Higher total EE was driven by lean mass gain in trained animals. In AT, there was a decrease in arachidonic acid with CONC or ECC15 training. Increased adiponectin, leptin, lipases, Glut4 and Igf1 mRNA levels in ECC15 group suggested major metabolic adaption in AT. In conclusion, ECC could induce beneficial modifications in AT fatty acid profile and the expression of key genes related to metabolism and insulin sensitivity.
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Tejido Adiposo , Condicionamiento Físico Animal , Masculino , Ratas , Animales , Tejido Adiposo/metabolismo , Consumo de Oxígeno , Metabolismo Energético , Biología , Músculo Esquelético/metabolismoRESUMEN
Microbacterium sp. C448, isolated from a soil regularly exposed to sulfamethazine (SMZ), can use various sulphonamide antibiotics as the sole carbon source for growth. The basis for the regulation of genes encoding the sulphonamide metabolism pathway, the dihydropteroate synthase sulphonamide target (folP), and the sulphonamide resistance (sul1) genes is unknown in this organism. In the present study, the response of the transcriptome and proteome of Microbacterium sp. C448 following exposure to subtherapeutic (33 µM) or therapeutic (832 µM) SMZ concentrations was evaluated. Therapeutic concentration induced the highest sad expression and Sad production, consistent with the activity of SMZ degradation observed in cellulo. Following complete SMZ degradation, Sad production tended to return to the basal level observed prior to SMZ exposure. Transcriptomic and proteomic kinetics were concomitant for the resistance genes and proteins. The abundance of Sul1 protein, 100-fold more abundant than FolP protein, did not change in response to SMZ exposure. Moreover, non-targeted analyses highlighted the increase of a deaminase RidA and a putative sulphate exporter expression and production. These two novel factors involved in the 4-aminophenol metabolite degradation and the export of sulphate residues formed during SMZ degradation, respectively, provided new insights into the Microbacterium sp. C448 SMZ detoxification process.
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Antiinfecciosos , Biodegradación Ambiental , Microbacterium , Sulfametazina , Microbacterium/genética , Microbacterium/metabolismo , Sulfametazina/metabolismo , Microbiología del Suelo , Cinética , Transcriptoma , Proteoma , Sulfonamidas/metabolismo , Farmacorresistencia Bacteriana , Antiinfecciosos/metabolismo , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Dihidropteroato Sintasa/genética , Dihidropteroato Sintasa/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: The French Pompe disease registry was created in 2004 for study of the natural course of the disease in patients. It rapidly became a major tool for assessing the long-term efficacy of enzyme replacement therapy (ERT) after the market release of alglucosidase-alfa. METHODS: Approximately 10 years after publication of the baseline characteristics of the 126 initial patients of the French Late-Onset Pompe Disease registry, we provide here an update of the clinical and biological features of patients included in this registry. RESULTS: We describe 210 patients followed at 31 hospital-based French neuromuscular or metabolic centers. The median age at inclusion was 48.67 ± 14.91 years. The first symptom was progressive lower limb muscle weakness, either isolated (50%) or associated with respiratory symptoms (18%), at a median age of 38 ± 14.9 years. At inclusion, 64% of the patients were able to walk independently and 14% needed a wheelchair. Positive associations were found between motor function measure, manual motor test, and 6-minute walk test (6MWT) results, and these parameters were inversely associated with the time taken to sit up from a lying position at inclusion. Seventy-two patients had been followed for at least 10 years in the registry. Thirty-three patients remained untreated a median of 12 years after symptom onset. The standard ERT dose was administered for 177 patients. DISCUSSION: This update confirms previous findings for the adult population included in the French Pompe disease registry, but with a lower clinical severity at inclusion, suggesting that this rare disease is now diagnosed earlier; thanks to greater awareness among physicians. The 6MWT remains an important method for assessing motor performance and walking ability. The French Pompe disease registry provides an exhaustive, nationwide overview of Pompe disease and can be used to assess individual and global responses to future treatments.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Adulto , Humanos , Persona de Mediana Edad , Adulto Joven , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , alfa-Glucosidasas/uso terapéutico , Debilidad Muscular/etiología , Francia/epidemiología , Sistema de Registros , Caminata , Terapia de Reemplazo Enzimático/efectos adversos , Terapia de Reemplazo Enzimático/métodosRESUMEN
OBJECTIVE: The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5-29 years. Secondary aims were to test the effect of mutation, ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength. METHODS: The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 ± 1.6 years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age. RESULTS: For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5 years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again. INTERPRETATION: Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.
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Fuerza de la Mano/fisiología , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/fisiopatología , Evaluación de Resultado en la Atención de Salud/normas , Adolescente , Adulto , Niño , Preescolar , Progresión de la Enfermedad , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Humanos , Masculino , Dinamómetro de Fuerza Muscular , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND: The relevance of registries as a key component for developing clinical research for rare diseases (RD) and improving patient care has been acknowledged by most stakeholders. As recent studies pointed to several limitations of RD registries our challenge was (1) to improve standardization and data comparability; (2) to facilitate interoperability between existing RD registries; (3) to limit the amount of incomplete data; (4) to improve data quality. This report describes the innovative concept of the DM-Scope Registry that was developed to achieve these objectives for Myotonic Dystrophy (DM), a prototypical example of highly heterogeneous RD. By the setting up of an integrated platform attractive for practitioners use, we aimed to promote DM epidemiology, clinical research and patients care management simultaneously. RESULTS: The DM-Scope Registry is a result of the collaboration within the French excellence network established by the National plan for RDs. Inclusion criteria is all genetically confirmed DM individuals, independently of disease age of onset. The dataset includes social-demographic data, clinical features, genotype, and biomaterial data, and is adjustable for clinical trial data collection. To date, the registry has a nationwide coverage, composed of 55 neuromuscular centres, encompassing the whole disease clinical and genetic spectrum. This widely used platform gathers almost 3000 DM patients (DM1 n = 2828, DM2 n = 142), both children (n = 322) and adults (n = 2648), which accounts for > 20% of overall registered DM patients internationally. The registry supported 10 research studies of various type i.e. observational, basic science studies and patient recruitment for clinical trials. CONCLUSION: The DM-Scope registry represents the largest collection of standardized data for the DM population. Our concept improved collaboration among health care professionals by providing annual follow-up of quality longitudinal data collection. The combination of clinical features and biomolecular materials provides a comprehensive view of the disease in a given population. DM-Scope registry proves to be a powerful device for promoting both research and medical care that is suitable to other countries. In the context of emerging therapies, such integrated platform contributes to the standardisation of international DM research and for the design of multicentre clinical trials. Finally, this valuable model is applicable to other RDs.
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Enfermedades Raras , Sistema de Registros , Investigación Biomédica , Bases de Datos Factuales , Humanos , Distrofia MiotónicaRESUMEN
OBJECTIVE: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management. METHODS: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed. RESULTS: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce. CONCLUSIONS: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.
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Arritmias Cardíacas/fisiopatología , Debilidad Muscular/fisiopatología , Distrofia Miotónica/fisiopatología , Insuficiencia Respiratoria/fisiopatología , Adolescente , Arritmias Cardíacas/epidemiología , Arritmias Cardíacas/etiología , Niño , Preescolar , Medicina Basada en la Evidencia , Femenino , Deformidades del Pie/epidemiología , Deformidades del Pie/etiología , Francia/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Debilidad Muscular/epidemiología , Debilidad Muscular/etiología , Distrofia Miotónica/complicaciones , Distrofia Miotónica/epidemiología , Distrofia Miotónica/genética , Sistema de Registros , Insuficiencia Respiratoria/epidemiología , Insuficiencia Respiratoria/etiología , Índice de Severidad de la Enfermedad , Expansión de Repetición de TrinucleótidoRESUMEN
BACKGROUND: The interest in bariatric surgery has considerably increased in the scientific community in the last two decades. We present a bibliometric analysis of scientific publications in bariatric surgery focusing on the period 2010-2014. METHODS: We used the Web of Science database as source of data. The main bibliometric indicators were applied in order to assess the increase of scientific production, the productivity of journals, authors, and countries. RESULTS: Bibliographic research retrieved 7860 papers for the period 2010-2014. The scientific production in bariatric surgery has an exponential distribution (r = 97.9 %). A total of 76.8 % (21,893/28,505) of authors signed one paper and 307 (1.1 %) signed ten or more. The two most prolific journals are Obesity Surgery and SOARD, responsible for 22 % of the publication. The largest contributors in absolute number of articles are the USA, the UK, and Italy, while Sweden, Norway, and Switzerland are the most prolific nations after adjustment for the number of inhabitants and prevalence of obesity. CONCLUSION: Bariatric surgery has been a field of intense research in the last 20 years. We observed a growing interest of non-surgical journals and an increasing participation of new countries. Nevertheless, latest trends suggest a saturation of scientific production in this field.
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Cirugía Bariátrica/estadística & datos numéricos , Bibliometría , Obesidad Mórbida/cirugía , Edición/tendencias , Bases de Datos Bibliográficas , Humanos , Edición/estadística & datos numéricosRESUMEN
Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1.49, 1.10 and 0.70% of the predicted values (%pred), respectively. The MFM score and handgrip strength were also age-sensitive but only in patients older than 29 and 37 years old with annual losses of 1.42 and 1.84%pred, respectively. Muscle strength assessed by MMT and elbow extension measured by HHD demonstrated an annual loss of less than 0.50%pred and are thus unlikely to be promising outcome measures for future clinical trials. In conclusion, our results identified age-sensitive outcomes from retrospective data and may serve for future longitudinal studies in which an estimation of the minimal number of subjects is provided.