RESUMEN
PURPOSE: There is a need for early quantitative markers of potential treatment response in patients with hereditary transthyretin (ATTRv) amyloidosis to guide therapy. This study aims to evaluate changes in cardiac tracer uptake on bone scintigraphy in ATTRv amyloidosis patients on different treatments. METHODS: In this retrospective cohort study, outcomes of 20 patients treated with the transthyretin (TTR) gene silencer patisiran were compared to 12 patients treated with a TTR-stabilizer. Changes in NYHA class, cardiac biomarkers in serum, wall thickness, and diastolic parameters on echocardiography and NYHA class during treatment were evaluated. RESULTS: Median heart/whole-body (H/WB) ratio on bone scintigraphy decreased from 4.84 [4.00 to 5.31] to 4.16 [3.66 to 4.81] (p < .001) in patients treated with patisiran for 29 [15-34] months. No changes in the other follow-up parameters were observed. In patients treated with a TTR-stabilizer for 24 [20 to 30] months, H/WB ratio increased from 4.46 [3.24 to 5.13] to 4.96 [ 3.39 to 5.80] (p = .010), and troponin T increased from 19.5 [9.3 to 34.0] ng/L to 20.0 [11.8 to 47.8] ng/L (p = .025). All other parameters did not change during treatment with a TTR-stabilizer. CONCLUSION: A change in cardiac tracer uptake on bone scintigraphy may be an early marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.
Asunto(s)
Neuropatías Amiloides Familiares , Cardiomiopatías , Humanos , Prealbúmina/genética , Estudios Retrospectivos , Estudios de Seguimiento , Neuropatías Amiloides Familiares/diagnóstico por imagen , Cintigrafía , Cardiomiopatías/diagnóstico por imagenAsunto(s)
Edema/diagnóstico , Herpesvirus Humano 4/aislamiento & purificación , Mononucleosis Infecciosa/diagnóstico , Enfermedades Orbitales/diagnóstico , Adolescente , Diagnóstico Diferencial , Edema/virología , Femenino , Humanos , Mononucleosis Infecciosa/virología , Enfermedades Orbitales/virologíaRESUMEN
Recent studies in erythroid cells have shown that autophagy is an important process for the physiological clearance of mitochondria during terminal differentiation. However, autophagy also plays an important role in removing damaged and dysfunctional mitochondria. Defective mitochondria and impaired erythroid maturation are important characteristics of low-risk myelodysplasia. In this study we therefore questioned whether the autophagic clearance of mitochondria might be altered in erythroblasts from patients with refractory anemia (RA, n=3) and RA with ringed sideroblasts (RARS, n=6). Ultrastructurally, abnormal and iron-laden mitochondria were abundant, especially in RARS patients. A large proportion (52+/-16%) of immature and mature myelodysplastic syndrome (MDS) erythroblasts contained cytoplasmic vacuoles, partly double membraned and positive for lysosomal marker LAMP-2 and mitochondrial markers, findings compatible with autophagic removal of dysfunctional mitochondria. In healthy controls only mature erythroblasts comprised these vacuoles (12+/-3%). These findings were confirmed morphometrically showing an increased vacuolar surface in MDS erythroblasts compared to controls (P<0.0001). In summary, these data indicate that MDS erythroblasts show features of enhanced autophagy at an earlier stage of erythroid differentiation than in normal controls. The enhanced autophagy might be a cell protective mechanism to remove defective iron-laden mitochondria.
Asunto(s)
Anemia Refractaria/patología , Anemia Sideroblástica/patología , Autofagia , Eritroblastos/ultraestructura , Células Precursoras Eritroides/ultraestructura , Mitocondrias/ultraestructura , Anciano , Anciano de 80 o más Años , Anemia Refractaria/metabolismo , Anemia Sideroblástica/metabolismo , Estudios de Casos y Controles , Caspasa 3 , Diferenciación Celular , Activación Enzimática , Eritroblastos/metabolismo , Células Precursoras Eritroides/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Proteína 2 de la Membrana Asociada a los Lisosomas , Proteínas de Membrana de los Lisosomas/metabolismo , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Platelet production requires compartmentalized caspase activation within megakaryocytes. This eventually results in platelet release in conjunction with apoptosis of the remaining megakaryocyte. Recent studies have indicated that in low-risk myelodysplastic syndromes (MDS) and idiopathic thrombocytopenic purpura (ITP), premature cell death of megakaryocytes may contribute to thrombocytopenia. Different cell death patterns have been identified in megakaryocytes in these disorders. Growing evidence suggests that, besides apoptosis, necrosis and autophagic cell death, may also be programmed. Therefore, programmed cell death (PCD) can be classified in apoptosis, a caspase-dependent process, apoptosis-like, autophagic and necrosis-like PCD, which are predominantly caspase-independent processes. In MDS, megakaryocytes show features of necrosis-like PCD, whereas ITP megakaryocytes demonstrate predominantly characteristics of apoptosis-like PCD (para-apoptosis). Triggers for these death pathways are largely unknown. In MDS, the interaction of Fas/Fas-ligand might be of importance, whereas in ITP antiplatelet autoantibodies recognizing common antigens on megakaryocytes and platelets might be involved. These findings illustrate that cellular death pathways in megakaryocytes are recruited in both physiological and pathological settings, and that different forms of cell death can occur in the same cell depending on the stimulus and the cellular context. Elucidation of the underlying mechanisms might lead to novel therapeutic interventions.
Asunto(s)
Apoptosis , Autofagia , Megacariocitos/patología , Síndromes Mielodisplásicos/patología , Púrpura Trombocitopénica Idiopática/patología , Humanos , Megacariocitos/fisiología , Síndromes Mielodisplásicos/fisiopatología , Necrosis , Púrpura Trombocitopénica Idiopática/fisiopatologíaRESUMEN
A 31-year-old woman presented with recurrent transient monocular blindness. As transient ischaemic attacks were suspected further investigations were targeted at evaluation of premature atherosclerotic lesions in the internal carotid artery. Initially laboratory tests were not performed. After referral to a cardiovascular-disease prevention outpatient clinic, laboratory evaluation disclosed a marked isolated polycythaemia that turned out to be secondary to right-left shunting through multiple pulmonary arteriovenous malformations. The ultimate diagnosis was hereditary haemorrhagic telangiectasia. Later on, physical signs such as telangiectasia and central cyanosis were noticed. In the clinical decision-making process, laboratory tests associated with causes of transient monocular visual loss were not carried out and therefore clues important for the ultimate diagnosis were not obtained. In only a minority of young patients with transient monocular visual loss can this be ascribed to premature atherosclerosis. For these reasons, a proper physical examination and laboratory tests directed towards other causes must be part of the initial diagnostic work-up in young patients with visual disturbances and suspected transient ischaemic attacks.
Asunto(s)
Amaurosis Fugax/etiología , Policitemia/etiología , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Adulto , Malformaciones Arteriovenosas/complicaciones , Malformaciones Arteriovenosas/diagnóstico , Malformaciones Arteriovenosas/genética , Diagnóstico Diferencial , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Ataque Isquémico Transitorio/diagnósticoRESUMEN
Idiopathic thrombocytopenic purpura (ITP) is a heterogeneous disease, whereby it is unclear if and in which way prednisone and splenectomy affect the platelet kinetics leading to a complete remission. To determine the effects of prednisone and splenectomy on the mean platelet life (MPL) and platelet production, platelet kinetic studies with Indium-111 tropolonate-labeled autologous platelets were performed in patients with ITP ( n=41). In 17 patients platelet kinetic studies were performed before and during prednisone treatment, and in 24 patients before and after splenectomy. MPL increased after prednisone therapy only in patients ( n=13) with a full recovery (FR, platelets >150 x 10(9)/l) and partial recovery (PR, 50 x 10(9)/l Asunto(s)
Glucocorticoides/uso terapéutico
, Prednisona/uso terapéutico
, Púrpura Trombocitopénica Idiopática/terapia
, Esplenectomía
, Adulto
, Plaquetas/fisiología
, Femenino
, Hematopoyesis
, Humanos
, Radioisótopos de Indio
, Cinética
, Masculino
, Persona de Mediana Edad
, Recuento de Plaquetas
, Inducción de Remisión
RESUMEN
A 52-year-old woman with a medical history of diabetes mellitus type 2, chronic alcoholism and liver function disorders was hospitalized because of complaints of haematemesis, abdominal complaints and dyspnoea. This was due to a severe lactic acidosis caused by acute alcohol intoxication and the use of metformin. With bicarbonate infusion and haemofiltration, the lactic acidosis disappeared, but she developed a distributive shock with multiple organ failure and died 23 days after admission. Lactic acidosis is a rare but serious adverse effect of metformin. Almost all patients described had contraindications to the drug, like renal failure, liver disease, alcohol abuse, and intercurrent conditions causing hypoxia or ischaemia. It is important to be aware of the circumstances in which metformin should not be prescribed.
Asunto(s)
Acidosis Láctica/inducido químicamente , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Cirrosis Hepática Alcohólica/complicaciones , Metformina/efectos adversos , Acidosis Láctica/complicaciones , Intoxicación Alcohólica/complicaciones , Contraindicaciones , Diabetes Mellitus Tipo 2/complicaciones , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiologíaRESUMEN
A man aged 51 for the last 3 months had displayed general malaise, epigastric pain, nausea, vomiting and constipation. Also, he had a pseudo-athletic appearance with symmetrical large accumulations of fat on the front of the trunk, the lower back, the shoulders and the proximal extremities, characteristic of 'benign symmetrical lipomatosis'. He died of embolism of the aortic bifurcation and autopsy revealed an extensive adenocarcinoma in the upper abdomen, probably originating from the pancreas or the stomach. Benign symmetrical lipomatosis mostly occurs in middle-aged men. The pathogenesis is unknown. Association with alcohol abuse, metabolic abnormalities, polyneuropathy and certain malignancies has been described. Treatment is symptomatic by surgery or liposuction.