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The KIT D816V mutation is found in >80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. Therefore, KIT D816V represents a prime therapeutic target for SM. Here, we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM and mast cell leukemia to develop a patient-specific SM disease model for mechanistic and drug-discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor, and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, a US Food and Drug Administration-approved angiokinase inhibitor that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the adenosine triphosphate binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V-targeted therapy of advanced SM.
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Antineoplásicos/farmacología , Indoles/farmacología , Mastocitosis Sistémica/tratamiento farmacológico , Mutación Puntual/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Células Tumorales CultivadasRESUMEN
Prevention of fatal side effects during cancer therapy of cancer patients with high-dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug-mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation." In the present work we re-analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib-resistant, KIT V560G, D816V-expressing human mast cell (MC) leukemia (MCL) cell line HMC-1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF-CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient-derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT-driven Imatinib resistance and possible TKI-induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co-treatment, potentially reducing the negative side effects associated with MCL therapy.
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Leucemia de Mastocitos , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia de Mastocitos/metabolismo , Leucemia de Mastocitos/patología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/farmacología , Mastocitos/metabolismo , Mastocitos/patología , Proteínas Proto-Oncogénicas c-kit/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , MutaciónRESUMEN
Mast cells (MCs) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MCs occur in low abundance, which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells in the body and established a novel and robust protocol for human iPS cell differentiation toward MCs. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MCs that recapitulate SM disease features: increased number of MCs, abnormal maturation kinetics and activated phenotype, CD25 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MCs are a reliable, inexhaustible, and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics.
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Células Madre Pluripotentes Inducidas , Mastocitosis Sistémica , Humanos , Mastocitosis Sistémica/diagnóstico , Mastocitos/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , MutaciónRESUMEN
Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response.
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Movimiento Celular , Proteína Ligando Fas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Mieloides/metabolismo , Peritonitis/inmunología , Proteínas Tirosina Quinasas/metabolismo , Animales , Células Cultivadas , Proteína Ligando Fas/genética , Proteína Ligando Fas/inmunología , Humanos , Inflamación , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/inmunología , Células Mieloides/patología , Peritoneo/inmunología , Peritoneo/patología , Peritonitis/inducido químicamente , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Médula Espinal/inmunología , Médula Espinal/patología , Quinasa Syk , Tioglicolatos/administración & dosificaciónRESUMEN
BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Anomalías Dentarias/genética , Amelogénesis Imperfecta/genética , Autoantígenos/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 11/genética , Estudios de Cohortes , Coloboma/genética , Displasia de la Dentina/genética , Francia , Pérdida Auditiva Sensorineural/genética , Humanos , Colágenos no Fibrilares/genética , Reproducibilidad de los Resultados , Colágeno Tipo XVIIRESUMEN
The strategies for the timing of fracture fixation in polytrauma patients have changed with improvements in resuscitation and patient assessment. Specifically, the criteria for damage control have been formulated, and more precise parameters have been found to determine those patients who can safely undergo primary definitive fixation of major fractures. Our current recommendations are supported by objective and data-based criteria and development groups. Those were validated and compared to existing scores. This review article introduces the concept of "safe definitive surgery" and provides an update on the parameters used to clear patients for timely fixation of major fractures.
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Introduction: In 2020, during France's COVID-19 response, healthcare professionals from a hospital and an association initiated health mediation interventions in Marseille's vulnerable neighbourhoods, funded by the regional health authorities. This mixed method research evaluates the CORHESAN program that lasted until June 2022. Methods: We examined CORHESAN documents and reports, conducted interviews, and analysed activity data, comparing it to the COVID-19 hotspots identified on a weekly basis at the neighbourhood level, using generalised linear mixed models (GLMMs). Results: CORHESAN was implemented by a team of up to nine health mediators, six private nurses hired on an ad hoc basis, supervised by a general coordinator and two part-time medical and nursing coordinators. Multiple partnerships were established with shelters, associations, social-housing landlords and local institutions. The team accompanied 6,253 people affected by COVID-19 or contact in the practical implementation of their isolation and contact tracing. Of the 5,180 nasopharyngeal samples for RT-PCR and 1,875 for antigenic testing: 12% were taken at home and 27% in partner facilities in the targeted neighbourhoods; 32% were taken from symptomatic patients and 30% in the context of contact tracing; and 40% were positive. Multiple awareness sessions on prevention methods and distributions of personal protection kits and self-diagnostic tests were conducted in the streets, in shelters, in associations or at home. A total of 5,929 doses of COVID-19 vaccine were administered in a walk-in vaccination centre, at temporary street vaccination posts, during operations at partner facilities, or during home-visits to patients with limited autonomy. GLMMs showed that the intervention significantly targeted its testing interventions in neighbourhoods with socioeconomic disadvantage and/or past under-testing (adjusted odds ratio (aOR), 2.75 [1.50-5.00]) and those with high hotspot level (aOR for level-3 versus level-0, 1.83 [1.24-2.71]). Discussion: The pandemic emphasised the potential of health mediation interventions to address health disparities. Building on this, a new program began in July 2022, aiming at enhancing cancer screening and vaccinations in deprived areas of Marseille. Evaluations are ongoing to assess its activities and impact, and provide evidence to future implementation initiatives.
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COVID-19 , Características de la Residencia , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Francia , SARS-CoV-2 , Femenino , Masculino , Áreas de Pobreza , Adulto , Persona de Mediana EdadRESUMEN
We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999-2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2-0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1-0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2-6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8-10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.
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Trasplante de Células Madre Hematopoyéticas , Leucemia de Mastocitos , Leucemia Mieloide Aguda , Mastocitosis Sistémica , Humanos , Mastocitosis Sistémica/genética , Estudios RetrospectivosRESUMEN
Pulmonary macrophage transplantation (PMT) is a gene and cell transplantation approach in development as therapy for hereditary pulmonary alveolar proteinosis (hPAP), a surfactant accumulation disorder caused by mutations in CSF2RA/B (and murine homologs). We conducted a toxicology study of PMT of Csf2ra gene-corrected macrophages (mGM-Rα+MÏs) or saline-control intervention in Csf2raKO or wild-type (WT) mice including single ascending dose and repeat ascending dose studies evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. Lentiviral-mediated Csf2ra cDNA transfer restored GM-CSF signaling in mGM-Rα+MÏs. Following PMT, mGM-Rα+MÏs engrafted, remained within the lungs, and did not undergo uncontrolled proliferation or result in bronchospasm, pulmonary function abnormalities, pulmonary or systemic inflammation, anti-transgene product antibodies, or pulmonary fibrosis. Aggressive male fighting caused a similarly low rate of serious adverse events in saline- and PMT-treated mice. Transient, minor pulmonary neutrophilia and exacerbation of pre-existing hPAP-related lymphocytosis were observed 14 days after PMT of the safety margin dose but not the target dose (5,000,000 or 500,000 mGM-Rα+MÏs, respectively) and only in Csf2raKO mice but not in WT mice. PMT reduced lung disease severity in Csf2raKO mice. Results indicate PMT of mGM-Rα+MÏs was safe, well tolerated, and therapeutically efficacious in Csf2raKO mice, and established a no adverse effect level and 10-fold safety margin.
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Coverage for recommended COVID-19 and diphtheria-tetanus-poliomyelitis (DTP) booster shots is often inadequate, especially among disadvantaged populations. To help health mediators (HMs) involved in outreach programs deal with the problems of vaccine hesitancy (VH) in these groups, we trained them in motivational interviewing (MI). We evaluated the effectiveness of this training among HMs on their MI knowledge and skills (objective 1) and among the interviewees on their vaccination readiness (VR) and intention to get vaccinated or accept a booster against COVID-19 and/or DTP (objective 2). Two MI specialists trained 16 HMs in a two-day workshop in May 2022. The validated MISI questionnaire evaluated HMs' acquisition of MI knowledge and skills (objective 1). Trained HMs offered an MI-based intervention on vaccination to people in disadvantaged neighborhoods of Marseille (France). Those who consented completed a questionnaire before and after the interview to measure VR with the 7C scale and intentions regarding vaccination/booster against COVID-19 and DTP (objective 2). The training resulted in HMs acquiring good MI skills (knowledge, application, self-confidence in using it). HMs enrolled 324 interviewees, 96% of whom completed both questionnaires. VR increased by 6%, and intentions to get vaccinated or update COVID-19 and DTP vaccination increased by 74% and 52% respectively. Nearly all interviewees were very satisfied with the interview, although 21% still had questions about vaccination. HMs assimilated MI principles well. MI use in outreach programs appears to show promise in improving vaccine confidence and intentions among disadvantaged people.
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COVID-19 , Entrevista Motivacional , Humanos , Intención , Poblaciones Vulnerables , COVID-19/prevención & control , Vacunación , Vacuna contra Difteria y TétanosRESUMEN
OBJECTIVE: As a follow-up to a previous study on the incidence, history and clinical findings of tibial neuropathy (TN), the present work aimed at describing the treatment and prognosis of this disease. MATERIALS AND METHODS: Of 88â German Holstein dairy cows with unilateral (UTN, nâ =â 71) or bilateral (BTN, nâ =â 17) TN, 68 (56 UTN, 12 BTN) with a complete data set were analyzed. They were retrospectively assigned to one of four groups: no treatment - spontaneous healing within 48â h (Spontaneous, 5 UTN), no bandage (0Cast, 8 UTN, 3 BTN) or treatment with anti-inflammatory drugs and support bandage (StV, 3 UTN) or fiberglass cast (Cast, 40 UTN, 9 BTN). Treated cows were re-examined five times (14, 21, 28, 42 and 56â days after the first presentation). The plasma activity of creatine kinase was measured at the last re-examination in 29 cows similar to measurement at day 0. RESULTS: The observed overall success rate of treatment of cows with UTN was considerably higher compared with untreated cows (Cast 98â % and StV 100â % vs. 0Cast 62â %). By comparison, the observed difference between treated and untreated cows with BTN was not so clear (78â % vs. 67â %). Recovering cows exhibited a calculated longer median survival time than cows that did not recover (545â d vs. 100â d). Plasma creatine kinase activities were increased initially and returned within the reference interval (434â U/l and 152â U/L) following treatment. CONCLUSIONS: Cows with ETN have an excellent prognosis provided that treatment with anti-inflammatory drugs and stabilizing bandage is administered. In cows with BTN, the prognosis depended on the type and degree of the primary injury. Loss of skin sensitivity indicated a poor prognosis. From an economic standpoint, treatment of TN is indicated provided that the prognosis is good. In cows that had healed clinically, the average survival time extended into the following lactation. CLINICAL RELEVANCE: This study highlights the advantages of a support bandage for the treatment of cows with TN. Compared with other peripheral neuropathies, muscle damage appears to be of particular importance in TN.
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Enfermedades del Sistema Nervioso Periférico , Neuropatía Tibial , Animales , Bovinos , Creatina Quinasa , Femenino , Lactancia/fisiología , Enfermedades del Sistema Nervioso Periférico/veterinaria , Estudios Retrospectivos , Neuropatía Tibial/veterinariaRESUMEN
OBJECTIVE: The aim of this study was to document the occurrence, history, and clinical findings of tibial neuropathy in German Holstein dairy cows in order to yield information regarding the importance and etiology of this disorder in dairy herds in Central Germany. MATERIALS AND METHODS: This prospective study was undertaken between January 2013 and October 2017 and included 88â German Holstein dairy cows with unilateral (UTN, nâ =â 71) or bilateral (nâ =â 17, BTN) tibial neuropathy. Data were collected from the history as well as the clinical and laboratory examinations. Three grades of paresis were defined. RESULTS: The percentage of cows with tibial neuropathy among all German Holstein dairy cows presented with disorders of the locomotor system in the study period amounted to 2.2â %. UTN was seen predominantly following dystocia or as a result of prolonged lateral recumbency in consequence to a primary disease. The majority of cases of BTN occurred in association with the resumption of cyclicity following calving. These were accompanied by clinical signs of a cauda equina syndrome. Increased plasma activities of creatine kinase (UTN 98â %; BTN 100â %) and aspartate aminotransferase (UTN 89â %; BTN 100â %) were observed in nearly all affected cows. CONCLUSIONS: Tibial neuropathy is a regularly occurring disorder in dairy herds in Central Germany. The condition results in pain and locomotor impairment and therefore constitutes a welfare concern. UTN and BTN have different causes, and the history combined with clinical signs (severity of paresis) provides etiological information. Increased enzymatic activities suggest a muscular involvement in the disease process.
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Enfermedades de los Bovinos , Distocia , Neuropatía Tibial , Animales , Bovinos , Enfermedades de los Bovinos/epidemiología , Distocia/veterinaria , Femenino , Incidencia , Lactancia , Leche , Embarazo , Estudios Prospectivos , Neuropatía Tibial/veterinariaRESUMEN
OBJECTIVE: Clinical ketosis is common during the dairy cows' transition period and is responsible for considerable economic loss. Early identification of cows with subclinical ketosis is the first step for maintaining the health and productivity of dairy cows. The goals of the study were two-fold: The first was to examine the usefulness of a mobile test device as a cow-side test; and the second was to compare BHB concentrations measured by the ketometer using capillary blood and blood collected from the coccygeal vessels with values determined by a reference method in the laboratory using jugular blood. MATERIAL AND METHODS: Blood samples were collected from a jugular vein or the coccygeal vessels in 81 dairy cows at 7 time points (14 and 7â days pre-partum and 7, 14, 21, 28, and 42â days post-partum) for kinetic enzymatic measurement of BHB concentration in the laboratory. Blood samples were concurrently collected from the coccygeal vessels or by pricking the vulvar lip at the transition of the skin to the mucosa (capillary blood) to determine BHB concentration using the WellionVetâ¯BELUAâ¯ketometer (MED TRUST GmbH, Marz, Austria). RESULTS: Initial errors in operating the ketometer were quickly eliminated with experience. BHB concentrations of jugular blood measured in the laboratory were 0.07â mmol/l lower than those measured in coccygeal blood. The mean BHB concentration measured in coccygeal and capillary blood using the WellionVet BELUA ketometer did not significantly differ but were 0.13 and 0.12â mmol/l respectively, lower than the mean jugular vein concentrations measured in the laboratory. CONCLUSION: The WellionVet BELUA ketometer is useful for determination of BHB concentration in cows provided that the manufacturer's specifications are followed. Capillary blood is best collected at the transition from the vulvar skin to its mucosa. The device generates rapid results that correlate well with BHB concentrations determined in the laboratory and with the results obtained from different blood collection sites. It is ideally suited for monitoring dairy cows for subclinical ketosis using capillary or coccygeal blood.
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Ácido 3-Hidroxibutírico/sangre , Bovinos/sangre , Animales , Capilares , Enfermedades de los Bovinos/sangre , Enfermedades de los Bovinos/diagnóstico , Industria Lechera/métodos , Femenino , Venas Yugulares , Cetosis/sangre , Cetosis/diagnóstico , Cetosis/veterinaria , Región Sacrococcígea/irrigación sanguíneaRESUMEN
This chapter will review the design and execution of release testing requirements for retroviral vectors and gene-modified cells consistent with ensuring the success of the clinical trial on the basis of current US regulatory requirements. It is the ethical and legal responsibility of the clinical trial sponsor(s) to ensure safety of the patients through proper evaluation of the drug products prior to use. Any clinical trial drug product used in human subjects must be produced and evaluated for safety, quality, purity, and effectiveness according to Current Good Manufacturing Practices appropriate for the stage of clinical development.
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Vectores Genéticos , Retroviridae/genética , Técnicas de Transferencia de Gen , Terapia Genética , Humanos , Control de CalidadRESUMEN
Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of < 20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy (n = 97; venlafaxine XR for study days 15-56; in case of sustained non-improvement on day 28, lithium augmentation for days 29-56) or TAU (n = 95; escitalopram continuation; non-responders on day 28 were switched to venlafaxine XR for four weeks, i.e. days 29-56). The primary outcome was remission (HAMD-17 ≤ 7) after 8 weeks of treatment as assessed by blinded raters. Remission rates were 24% for EMC and 16% for TAU, which was not significantly different (p = 0.2056). Sensitivity analyses for the primary and secondary effectiveness endpoints consistently showed favorable results for patients randomized to EMC. The results confirm data from post-hoc analyses of clinical trials showing that early non-improvement identifies patients who likely need alternate interventions. However, the herein used two-step switch/augmentation strategy for this risk group was not more effective than the control intervention. Alternate strategies and other design aspects are discussed in order to support researchers addressing the same research question.
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Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Citalopram/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Intervención Médica Temprana , Clorhidrato de Venlafaxina/uso terapéutico , Adolescente , Adulto , Anciano , Antidepresivos/efectos adversos , Antidepresivos de Segunda Generación/uso terapéutico , Citalopram/administración & dosificación , Citalopram/efectos adversos , Preparaciones de Acción Retardada/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Litio/uso terapéutico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Clorhidrato de Venlafaxina/administración & dosificación , Clorhidrato de Venlafaxina/efectos adversos , Adulto JovenRESUMEN
AIMS: In patients with stable coronary heart disease (CHD), we aimed to assess 1. the prognostic power of biomarkers reflecting haemodynamics, micronecrosis, inflammation, coagulation, lipids, neurohumoral activity, and renal function; 2. whether changes in concentrations of these biomarkers over 12 months affected subsequent CHD risk; and 3. whether pravastatin modified the change in biomarker concentrations and this influenced the risk of future events. METHODS: In the LIPID study, 9014 patients were randomised to pravastatin 40 mg or placebo 3-36 months after an acute coronary syndrome. Eight biomarkers were measured at baseline (n=7863) and 12 months later (n=6434). RESULTS: During a median of 6.0 (IQR 5.5-6.5) years follow-up, 1100 CHD-related deaths and nonfatal myocardial infarctions occurred, 694 after biomarker measurement at 12 months. Baseline BNP, CRP, cystatin C, D-dimer, midregional pro-adrenomedullin, and sensitive troponin I predicted recurrent CHD events. In a multivariable model, sensitive troponin I, BNP, and cystatin C had the strongest associations with outcome (P<0.001 for trend). The strongest improvement in risk prediction was achieved by including sensitive troponin I (net reclassification improvement (NRI) 5.5%; P=0.003), BNP (4.3%; P=0.02), history of MI (NRI 7.0%; P<0.001). In landmark analyses, among biomarkers, changes to 12 months in sensitive troponin I (HR 1.32 (1.03-1.70) for T3/T1), BNP (HR 1.37 (1.10-1.69) for Q4/Q1) and Lp-PLA2 (HR 1.52 (1.16-1.97)) improved CHD risk prediction. CONCLUSIONS: Baseline levels and changes in sensitive troponin I, and BNP may have the potential to guide the intensity of secondary prevention therapy.
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Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Pravastatina/administración & dosificación , 1-Alquil-2-acetilglicerofosfocolina Esterasa/sangre , Adrenomedulina/sangre , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Cistatina C/sangre , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo , Troponina I/sangre , Troponina I/metabolismo , Troponina T/sangre , Troponina T/metabolismoRESUMEN
INTRODUCTION: To examine whether midregional pro-adrenomedullin (MR-proADM) plasma concentrations predict incident cardiovascular outcomes in the general population. Natriuretic peptides (N-terminal pro-brain natriuretic peptide (NT-proBNP), B-type natriuretic peptide (BNP), and midregional pro-atrial natriuretic peptide (MR-proANP)) were analyzed for comparison. MATERIAL AND METHODS: MR-proADM plasma concentrations and those of the natriuretic peptides were determined in 8444 individuals of the FINRISK 1997 cohort. Patients were followed for 14 years (median). Cox regression analyses, discrimination, and reclassification analyses adjusting for Framingham risk factors were performed to evaluate the additional benefit from MR-proADM. RESULTS: MR-proADM concentrations significantly predicted all-cause death (hazard ratio highest quintile versus lowest 1.18, 95% confidence interval 1.08-1.28), stroke (1.20, 1.05-1.38), major adverse cardiac events (MACE) (1.27, 1.17-1.37), and heart failure (1.67, 1.49-1.87). MR-proADM remained associated with MACE, death, and heart failure even after additional adjustment for NT-proBNP and C-reactive protein. Adding MR-proADM to the Framingham risk factors significantly improved discrimination (P < 0.001 for C-statistics and integrated discrimination improvement) and risk reclassification for heart failure (net reclassification improvement 12.12%, P < 0.001). CONCLUSIONS: In a healthy general population sample of the FINRISK 1997 cohort MR-proADM significantly predicted all-cause death, MACE, and especially heart failure even beyond NT- proBNP. It also improved risk reclassification for heart failure.
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Adrenomedulina/sangre , Insuficiencia Cardíaca/sangre , Péptidos Natriuréticos/sangre , Precursores de Proteínas/sangre , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Femenino , Finlandia , Insuficiencia Cardíaca/diagnóstico , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Biomarkers may contribute to risk stratification in coronary heart disease (CHD). We examined whether plasma midregional proadrenomedullin (MR-proADM) concentration at baseline and its change over one year predicts long-term outcomes in stable CHD patients. METHODS: The LIPID study randomised patients 3-36 months after an acute coronary syndrome with total cholesterol 4.0-7.0 mmol/L (155-271 mg/dL), to placebo or pravastatin 40 mg. Follow-up was 6.0 years. MR-proADM plasma concentrations at baseline and one year later were determined in 7863 and 6658 patients, respectively. These were categorised into quartiles to perform Cox regression analysis, adjusting for baseline parameters. RESULTS: Baseline MR-proADM concentrations predicted major CHD events (non-fatal myocardial infarction or CHD death; hazard ratio (HR) 1.52, 1.26-1.84 for Q4-Q1), CHD death (HR 2.21, 1.67-2.92), heart failure (HR 2.30, 1.78-2.97) and all-cause mortality (HR 1.82, 1.49-2.23). Associations were still significant after adjustment for baseline B-type natriuretic peptide (BNP) concentration. Increase in MR-proADM after one year was associated with increased risk of subsequent CHD events (HR 1.34, 1.08-1.66), non-fatal myocardial infarction (HR 1.50, 1.12-2.03), heart failure (HR 1.78, 1.37-2.30) and all-cause mortality (HR 1.31, 1.04-1.64). Associations with heart failure and all-cause mortality remained significant after adjusting for baseline and change in BNP concentration. Change in MR-proADM moderately improved risk reclassification for major CHD events (net reclassification improvement (NRI) 3.48%) but strongly improved risk reclassification for heart failure (NRI 5.60%). CONCLUSIONS: Baseline and change in MR-proADM concentrations over one year are associated with risk of major clinical events, even after adjustment for BNP concentrations.
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Adrenomedulina/sangre , Enfermedad Coronaria/sangre , Insuficiencia Cardíaca/sangre , Precursores de Proteínas/sangre , Adulto , Anciano , Biomarcadores/sangre , Enfermedad Coronaria/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Pravastatina/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Recurrencia , Medición de RiesgoRESUMEN
AIMS AND BACKGROUND: Midregional proadrenomedullin (MR-proADM) is a protein, which exerts various effects on the cardiovascular system. Recent studies underscored its prognostic implications in patients with acute dyspnea and cardiovascular diseases. Therefore, we aimed to determine the distribution of MR-proADM in the general population and to reveal potential associations of MR-proADM with cardiovascular risk factors and measures of subclinical cardiovascular disease. METHODS AND RESULTS: MR-proADM plasma concentrations were determined in individuals of the population-based cohort of the Gutenberg Health Study (N = 5000) using a commercially available fluoroimmunoassay. Individuals were enrolled between April 2007 and October 2008. Subclinical cardiovascular disease was assessed using echocardiographic and functional measures of myocardial and vascular function. The mean age of the study population was 55.5 ± 10.9 years. In the overall population we determined a median MR-proADM plasma concentration of 0.44 nmol/L in men and women. MR-proADM concentrations were elevated in individuals with hypertension, diabetes, dyslipidemia, known cardiovascular disease, heart failure, peripheral artery disease, atrial fibrillation, and history of myocardial infarction and stroke. In men, we observed a positive association of MR-proADM with reduced ejection fraction, intraventricular septal diameter, wall thickness, and echocardiographic measures of diastolic dysfunction. CONCLUSIONS: In this study, we present age-dependent reference values for MR-proADM in a representative population sample. Elevated MR-proADM plasma concentrations were strongly associated with classical cardiovascular risk factors and manifest cardiovascular diseases. Furthermore, we revealed a gender-specific association with echocardiographic measures of hypertension. MR-proADM seems to be a promising prognostic biomarker for subclinical and manifest cardiovascular disease.