RESUMEN
BACKGROUND: Offspring of parents with major mood disorders (MDDs) are at increased risk for early psychopathology. We aim to compare the rates of neurodevelopmental disorders in offspring of parents with bipolar disorder, major depressive disorder, and controls. METHOD: We established a lifetime diagnosis of neurodevelopmental disorders [attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disabilities, specific learning disorders, and motor disorders] using the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version in 400 participants (mean age 11.3 + s.d. 3.9 years), including 93 offspring of parents with bipolar disorder, 182 offspring of parents with major depressive disorder, and 125 control offspring of parents with no mood disorder. RESULTS: Neurodevelopmental disorders were elevated in offspring of parents with bipolar disorder [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.23-4.47, p = 0.010] and major depressive disorder (OR 1.87, 95% CI 1.03-3.39, p = 0.035) compared to controls. This difference was driven by the rates of ADHD, which were highest among offspring of parents with bipolar disorder (30.1%), intermediate in offspring of parents with major depressive disorder (24.2%), and lowest in controls (14.4%). There were no significant differences in frequencies of other neurodevelopmental disorders between the three groups. Chronic course of mood disorder in parents was associated with higher rates of any neurodevelopmental disorder and higher rates of ADHD in offspring. CONCLUSIONS: Our findings suggest monitoring for ADHD and other neurodevelopmental disorders in offspring of parents with MDDs may be indicated to improve early diagnosis and treatment.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastorno Bipolar , Hijo de Padres Discapacitados , Trastorno Depresivo Mayor , Humanos , Niño , Trastorno Bipolar/epidemiología , Trastorno Bipolar/psicología , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Trastorno Depresivo Mayor/epidemiología , Depresión , Hijo de Padres Discapacitados/psicología , Padres/psicologíaRESUMEN
BACKGROUND: Children of parents with mood and psychotic disorders are at elevated risk for a range of behavioral and emotional problems. However, as the usual reporter of psychopathology in children is the parent, reports of early problems in children of parents with mood and psychotic disorders may be biased by the parents' own experience of mental illness and their mental state. METHODS: Independent observers rated psychopathology using the Test Observation Form in 378 children and youth between the ages of 4 and 24 (mean = 11.01, s.d. = 4.40) who had a parent with major depressive disorder, bipolar disorder, schizophrenia, or no history of mood and psychotic disorders. RESULTS: Observed attentional problems were elevated in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia (effect sizes ranging between 0.31 and 0.56). Oppositional behavior and language/thought problems showed variable degrees of elevation (effect sizes 0.17 to 0.57) across the three high-risk groups, with the greatest difficulties observed in offspring of parents with bipolar disorder. Observed anxiety was increased in offspring of parents with major depressive disorder and bipolar disorder (effect sizes 0.19 and 0.25 respectively) but not in offspring of parents with schizophrenia. CONCLUSIONS: Our results suggest that externalizing problems and cognitive and language difficulties may represent a general manifestation of familial risk for mood and psychotic disorders, while anxiety may be a specific marker of liability for mood disorders. Observer assessment may improve early identification of risk and selection of youth who may benefit from targeted prevention.
Asunto(s)
Trastorno Bipolar/psicología , Hijo de Padres Discapacitados/psicología , Trastorno Depresivo Mayor/psicología , Psicología del Esquizofrénico , Adolescente , Ansiedad/psicología , Niño , Preescolar , Femenino , Humanos , Masculino , Padres , Escalas de Valoración Psiquiátrica , Psicopatología , Factores de Riesgo , Esquizofrenia , Adulto JovenRESUMEN
BACKGROUND: Anxiety disorders are highly prevalent in people with bipolar disorder, but it is not clear how many have anxiety disorders even at times when they are free of major mood episodes. We aimed to establish what proportion of euthymic individuals with bipolar disorder meet diagnostic criteria for anxiety disorders. METHOD: We performed a random-effects meta-analysis of prevalence rates of current DSM-III- and DSM-IV-defined anxiety disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and anxiety disorder not otherwise specified) in euthymic adults with bipolar disorder in studies published by 31 December 2015. RESULTS: Across 10 samples with 2120 individuals with bipolar disorder, 34.7% met diagnostic criteria for one or more anxiety disorders during euthymia [95% confidence interval (CI) 23.9-45.5%]. Direct comparison of 189 euthymic individuals with bipolar disorder and 17 109 population controls across three studies showed a 4.6-fold increase (risk ratio 4.60, 95% CI 2.37-8.92, p < 0.001) in prevalence of anxiety disorders in those with bipolar disorder. CONCLUSIONS: These findings suggest that anxiety disorders are common in people with bipolar disorder even when their mood is adequately controlled. Euthymic people with bipolar disorder should be routinely assessed for anxiety disorders and anxiety-focused treatment should be initiated if indicated.
Asunto(s)
Trastornos de Ansiedad/epidemiología , Trastorno Bipolar/epidemiología , Comorbilidad , Prevalencia , HumanosRESUMEN
BACKGROUND: Psychotic symptoms are common in children and adolescents and may be early manifestations of liability to severe mental illness (SMI), including schizophrenia. SMI and psychotic symptoms are associated with impairment in executive functions. However, previous studies have not differentiated between 'cold' and 'hot' executive functions. We hypothesized that the propensity for psychotic symptoms is specifically associated with impairment in 'hot' executive functions, such as decision-making in the context of uncertain rewards and losses. METHODS: In a cohort of 156 youth (mean age 12.5, range 7-24 years) enriched for familial risk of SMI, we measured cold and hot executive functions with the spatial working memory (SWM) task (total errors) and the Cambridge Gambling Task (decision-making), respectively. We assessed psychotic symptoms using the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia interview, Structured Interview for Prodromal Syndromes, Funny Feelings, and Schizophrenia Proneness Instrument - Child and Youth version. RESULTS: In total 69 (44.23%) youth reported psychotic symptoms on one or more assessments. Cold executive functioning, indexed with SWM errors, was not significantly related to psychotic symptoms [odds ratio (OR) 1.36, 95% confidence interval (CI) 0.85-2.17, p = 0.204). Poor hot executive functioning, indexed as decision-making score, was associated with psychotic symptoms after adjustment for age, sex and familial clustering (OR 2.37, 95% CI 1.25-4.50, p = 0.008). The association between worse hot executive functions and psychotic symptoms remained significant in sensitivity analyses controlling for general cognitive ability and cold executive functions. CONCLUSIONS: Impaired hot executive functions may be an indicator of risk and a target for pre-emptive early interventions in youth.
Asunto(s)
Hijo de Padres Discapacitados , Disfunción Cognitiva/fisiopatología , Toma de Decisiones/fisiología , Función Ejecutiva/fisiología , Memoria a Corto Plazo/fisiología , Trastornos Psicóticos/fisiopatología , Memoria Espacial/fisiología , Adolescente , Adulto , Niño , Disfunción Cognitiva/etiología , Femenino , Humanos , Masculino , Trastornos Psicóticos/complicaciones , Riesgo , Adulto JovenRESUMEN
INTRODUCTION: BAX 855 is a pegylated full-length recombinant factor VIII (rFVIII) with an extended half-life, built on a licensed rFVIII (ADVATE(®) ). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A. AIM: This phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery. METHODS: Elective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively. RESULTS: A total of 15 male patients (aged 19-52 years) underwent 15 procedures (11 major and four minor). The overall intra- and perioperative haemostatic efficacy of BAX 855 was 'excellent' in all 15 subjects (100%). Postoperatively, evaluated at postoperative Day 1, all treatments were 'excellent' except for one minor (dental) procedure which was rated 'good'. No related adverse events, allergic reactions, thrombotic events, nor signs of immunogenicity in terms of induction of binding antibodies to FVIII, PEG or PEG-VIII, or FVIII inhibitors were observed. CONCLUSION: These results demonstrate that BAX 855 is safe and haemostatically effective in patients with severe haemophilia A undergoing surgery.
Asunto(s)
Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adulto , Anticuerpos Neutralizantes/sangre , Coagulantes/química , Coagulantes/farmacocinética , Factor VIII/genética , Factor VIII/metabolismo , Semivida , Hemofilia A/sangre , Hemorragia/prevención & control , Hemostasis , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa , Polietilenglicoles/química , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Procedimientos Quirúrgicos Operativos , Resultado del Tratamiento , Adulto JovenRESUMEN
A newly developed recombinant factor IX (BAX326(1) ) was investigated for prophylactic use in paediatric patients aged <12 years with severe (FIX level <1%) or moderately severe (FIX level 1-2%) haemophilia B. The aim of this prospective clinical trial was to assess the safety, haemostatic efficacy and pharmacokinetic profile of BAX326 in previously treated paediatric patients. BAX326 was administered as prophylaxis twice a week for a period of 6 months, and on demand for treatment of bleeds. Safety was assessed by the occurrence of related AEs, thrombotic events and immunologic assessments. Efficacy was evaluated by annualized bleeding rate (ABR), and by treatment response rating (excellent, good, fair, none). PK was assessed over 72 h. None of the 23 treated paediatric subjects had treatment-related SAEs or AEs. There were no thrombotic events, inhibitory or specific binding antibodies against FIX, rFurin or CHO protein. Twenty-six bleeds (19 non-joint vs. 7 joint bleeds) occurred (mean ABR 2.7 ± 3.14, median 2.0), of which 23 were injury-related. Twenty subjects (87%) did not experience any bleeds of spontaneous aetiology. Haemostatic efficacy of BAX326 was excellent or good for >96% of bleeds (100% of minor, 88.9% of moderate and 100% of major bleeds); the majority (88.5%) resolved after 1-2 infusions. Longer T1/2 and lower IR were observed in younger children (<6 years) compared to those aged 6 to 12 years. BAX326 administered as prophylactic treatment as well as for controlling bleeds is efficacious and safe in paediatric patients aged <12 years with haemophilia B.
Asunto(s)
Factor IX/farmacología , Factor IX/uso terapéutico , Hemofilia B/tratamiento farmacológico , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Adolescente , Factores de Edad , Niño , Preescolar , Femenino , Hemofilia B/sangre , Hemofilia B/complicaciones , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Hemorragia/prevención & control , Humanos , Lactante , Masculino , Premedicación , Retratamiento , Factores de Tiempo , Resultado del TratamientoRESUMEN
Haemostatic management of haemophilia B patients undergoing surgery is critical to patient safety. The aim of this ongoing prospective trial was to investigate the haemostatic efficacy and safety of a recombinant factor IX (rFIX) (Bax326) in previously treated subjects (12-65 years, without history of FIX inhibitors) with severe or moderately severe haemophilia B, undergoing surgical, dental or other invasive procedures. Haemostatic efficacy was assessed according to a predefined scale. Blood loss was compared to the average and maximum blood loss predicted preoperatively. Haemostatic FIX levels were achieved peri- and postoperatively in 100% of subjects (n = 14). Haemostasis was 'excellent' intraoperatively in all patients and postoperatively in those without a drain, and 'excellent' or 'good' at the time of drain removal and day of discharge in those with a drain employed. Following the initial dose, the mean FIX activity level rose from 6.55% to 107.58% for major surgeries and from 3.60% to 81.4% for minor surgeries. Actual vs. predicted blood loss matched predicted intraoperative blood loss but was equal to or higher than (but less than 150%) the maximum predicted postoperative blood loss reflecting the severity of procedure and FIX requirements. There were no related adverse events, severe allergic reactions or thrombotic events. There was no evidence that BAX326 increased the risk of inhibitor or binding antibody development to FIX. BAX326 was safe and effective for peri-operative management of 14 subjects with severe and moderately severe haemophilia B.
Asunto(s)
Pérdida de Sangre Quirúrgica/prevención & control , Coagulantes/uso terapéutico , Factor IX/uso terapéutico , Hemofilia B/tratamiento farmacológico , Hemostasis Quirúrgica/métodos , Procedimientos Quirúrgicos Operativos/métodos , Adolescente , Adulto , Anciano , Inhibidores de Factor de Coagulación Sanguínea/inmunología , Estudios de Casos y Controles , Niño , Coagulantes/efectos adversos , Factor IX/efectos adversos , Femenino , Hemofilia B/inmunología , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa , Cuidados Posoperatorios , Estudios Prospectivos , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Adulto JovenRESUMEN
The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma-derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12-65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti-FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine®) to a newly developed rFIX (Bax326(1) ) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.
Asunto(s)
Coagulantes/uso terapéutico , Sustitución de Medicamentos/normas , Factor IX/uso terapéutico , Hemofilia B/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adolescente , Adulto , Coagulación Sanguínea/efectos de los fármacos , Inhibidores de Factor de Coagulación Sanguínea/sangre , Niño , Coagulantes/efectos adversos , Coagulantes/farmacocinética , Estudios Cruzados , Factor IX/efectos adversos , Femenino , Hemofilia B/inmunología , Hemorragia/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Adulto JovenRESUMEN
BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC(0-72) h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg(-1) per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.
Asunto(s)
Factor IX/uso terapéutico , Hemofilia B/tratamiento farmacológico , Proteínas Recombinantes , Adolescente , Adulto , Anciano , Coagulación Sanguínea/efectos de los fármacos , Niño , Factor IX/farmacocinética , Femenino , Hemofilia B/sangre , Humanos , Masculino , Persona de Mediana Edad , Premedicación , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
Children of parents with major mood and psychotic disorders are at increased risk of psychopathology, including psychotic symptoms. It has been suggested that the risk of psychosis may be more often transmitted from parent to opposite-sex offspring (e.g., from father to daughter) than to same-sex offspring (e.g., from father to son). To test whether sex-specific transmission extends to early manifestations of psychosis, we examined sex-specific contributions to psychotic symptoms among offspring of mothers and fathers with depression, bipolar disorder and schizophrenia. We assessed psychotic symptoms in 309 offspring (160 daughters and 149 sons) aged 8-24 years (mean=13.1, s.d.=4.3), of whom 113 had a mother with schizophrenia, bipolar disorder or major depression and 43 had a father with schizophrenia, bipolar disorder or major depression. In semi-structured interviews, 130 (42%) offspring had definite psychotic symptoms established and confirmed by psychiatrists on one or more assessments. We tested the effects of mental illness in parents on same-sex and opposite-sex offspring psychotic symptoms in mixed-effect logistic regression models. Psychotic symptoms were more prevalent among daughters of affected fathers and sons of affected mothers than among offspring of the same sex as their affected parent. Mental illness in the opposite-sex parent increased the odds of psychotic symptoms (odds ratio (OR)=2.65, 95% confidence interval (CI) 1.43-4.91, P=0.002), but mental illness in the same-sex parent did not have a significant effect on psychotic symptoms in offspring (OR=1.13, 95% CI 0.61-2.07, P=0.697). The opposite-sex-specific parent-of-origin effects may suggest X chromosome-linked genetic transmission or inherited chromosomal modifications in the etiology of psychotic symptoms.
Asunto(s)
Trastornos Mentales/genética , Adolescente , Adulto , Niño , Estudios de Cohortes , Padre , Femenino , Humanos , Modelos Logísticos , Masculino , Madres , Núcleo Familiar , Factores SexualesRESUMEN
BACKGROUND: IMMUNATE Solvent/Detergent (S/D) is a plasma-derived, human factor VIII (FVIII)/von Willebrand factor (VWF) complex subjected to S/D and vapor heat treatment. METHODS: This prospective clinical study evaluated the pharmacokinetics (PK) (compared to IMMUNATE), efficacy and safety of IMMUNATE S/D in 56 previously treated patients with severe hemophilia A. Subjects received IMMUNATE S/D either on-demand (47/56), as a prophylactic regimen (49/56), or both (40/56). RESULTS: IMMUNATE and IMMUNATES/D were equivalent with respect to the FVIII and VWF PK parameters assessed. Bleeding episodes (623) were reported in 47/56 subjects. For 89% of episodes, subjects required only 1 infusion with a mean dose of 29.6 IU/kg and 96% of episodes had an excellent or good response. The duration of prophylaxis ranged from 0.1 to 5.2 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). No FVIII inhibitory antibodies were observed in 56 subjects after 2,646 treatment exposure days. No related serious adverse events were reported. CONCLUSION: The introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules in IMMUNATE S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures and prophylaxis.
Asunto(s)
Factor VIII/uso terapéutico , Hemofilia A/terapia , Anticuerpos/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Factor VIII/administración & dosificación , Factor VIII/efectos adversos , Factor VIII/inmunología , Factor VIII/farmacocinética , Hemorragia/prevención & control , Humanos , Farmacocinética , Resultado del Tratamiento , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/farmacocinéticaRESUMEN
In addition to a few disorders such as acute T-cell leukemia that are typically associated with the human T-cell leukemia virus (HTLV) 1 in endemic regions, this virus may also play a role in some other hematological diseases. Here, we examine the incidence of HTLV in hematological diseases from a nonendemic region in central Europe. Data obtained by PCR and/or serological techniques from a total of 730 cases showed that besides the expected presence of HTLV-1 in T-lymphoid diseases (2 of 27 cases), HTLV-1 was only detected in myelodysplastic syndrome (MDS), in which an incidence of 17% (11 of 65 cases) was found. A correlation with a history of multiple transfusions or treatment with blood products in the HTLV-1-positive MDS could not be ascertained. Cytogenetics detected the presence of del(5)(q) in six HTLV-positive cases (five MDS and one T-cell acute lymphocytic leukemia) but in only one HTLV-negative case. These data indicate that allelic deletions of a series of 5q-located genes that typically occur in MDS may be associated with HTLV infections in central Europe.
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Síndromes Mielodisplásicos/virología , Adulto , Anciano , Anciano de 80 o más Años , Transfusión Sanguínea , Europa (Continente)/epidemiología , Femenino , Eliminación de Gen , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/etnología , Síndromes Mielodisplásicos/genética , Reacción en Cadena de la Polimerasa/métodosRESUMEN
G-proteins are essential in signal transduction pathways. A G-protein alpha subunit termed G alpha 16 was found to be exclusively expressed in hematopoietic cell lines. In cells derived from patients, G alpha 16 expression has been detected in progenitor- and pre-B ALL cells and also in peripheral blood stem cells (PBSC). In this study, we analyzed G alpha 16 expression using a RT-PCR technique by testing elutriated blood cells from normal donors, PBSC from breast cancer patients and bone marrow or peripheral blood cells from acute leukemia patients. Both of two ALL patients and 15/16 AML patients expressed G alpha 16. In elutriation experiments, G alpha 16 expression was found in fractions containing the highest number of precursor cells but was absent in mature T and B cell fractions. In addition, CD34-enriched PBSC were positive for G alpha 16 expression. Further in vitro experiments using the cell line KG1 showed that G alpha 16 expression was not affected by the growth inhibiting hemoregulatory peptide pEEDCK which has a sequence homology present within G alpha 16. Taken together, these data demonstrate that G alpha 16 is expressed in various normal and malignant hematopietic progenitors but not in their differentiated counterparts. G alpha 16 could play a vital role in signal transduction pathways controlling proliferation in early normal and malignant hematopoiesis.
Asunto(s)
Proteínas de Unión al GTP/metabolismo , Hematopoyesis , Leucemia/metabolismo , Enfermedad Aguda , Antígenos CD34/metabolismo , Secuencia de Bases , Inhibidores de Crecimiento/farmacología , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia/genética , Leucemia/inmunología , Leucemia Mieloide Aguda/metabolismo , Datos de Secuencia Molecular , Oligopéptidos/farmacología , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Ácido Pirrolidona Carboxílico/análogos & derivados , Transducción de SeñalRESUMEN
Detection of minimal residual disease (MRD) by analysis of the PML-RAR alpha fusion transcript using the RT-PCR method is routinely carried out on peripheral blood and bone marrow of patients with APL (AML, FAB:M3). Therapy aims to achieve repeated negative results in these patients thus confirming clinical complete remission. We report a case of APL in second complete remission in which no leukemic cells had been detected in BM and PB for 20 months, and in which PBPC-pheresis was carried out for future transplantation. In two of five pheresis PML-RAR alpha fusion transcripts were detected. This shows that the residual leukemic population may only reach detection level after enrichment by PBPC-pheresis.
Asunto(s)
Biomarcadores de Tumor/sangre , Células Madre Hematopoyéticas/química , Leucemia Promielocítica Aguda/diagnóstico , Proteínas de Neoplasias/sangre , Células Madre Neoplásicas/química , Proteínas de Fusión Oncogénica/sangre , Adulto , Secuencia de Bases , Médula Ósea/patología , Humanos , Inmunofenotipificación , Leucemia Promielocítica Aguda/sangre , Leucemia Promielocítica Aguda/patología , Datos de Secuencia Molecular , Neoplasia Residual , Reacción en Cadena de la Polimerasa , Inducción de RemisiónRESUMEN
A simple method for short-term recharge of SV40-immortalized marrow stromal cell (MSC) lines based on their specific interaction with the appropriate haemopoietic cells is described. During the first week after the recharge the production of polymorphonuclear and mononuclear blood cells is an order of magnitude higher than in the recharged primary MSC cultures. Progenitor-derived granulopoiesis is predominant. The long-term repopulating potential of the haemopoietic stem cells (HSC) in the recharged cultures is demonstrated when they are cultured in tissue culture wells (Sutherland et al., 1990). The blood cells produced in the later passages show signs of malignancy.
Asunto(s)
Médula Ósea/fisiología , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/fisiología , Virus 40 de los Simios/crecimiento & desarrollo , Animales , Médula Ósea/microbiología , Células Cultivadas , Recuento de Leucocitos , Leucocitos Mononucleares/fisiología , Estudios Longitudinales , Ratones , Ratones Endogámicos BALB C , Neutrófilos/fisiologíaAsunto(s)
Biomarcadores de Tumor/análisis , Médula Ósea/patología , Inversión Cromosómica , Cromosomas Humanos Par 16/ultraestructura , Leucemia Mielomonocítica Aguda/genética , ARN Mensajero/análisis , ARN Neoplásico/análisis , Secuencia de Bases , Médula Ósea/química , Humanos , Leucemia Mielomonocítica Aguda/patología , Datos de Secuencia Molecular , Neoplasia Residual , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Juego de Reactivos para Diagnóstico , Estudios RetrospectivosRESUMEN
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterium which can infect and colonize pigs. After contact with enterocytes and macrophages, S. Typhimurium induces production of cytokines thus triggering the innate immune response. In this study we evaluated the cytokine response of two porcine cell lines, IPI-2I and 3D4/31, of epithelial or macrophage origins, respectively, to the wild-type S. Typhimurium and its hilA and ssrA mutants. We observed that the 3D4/31 cell line essentially did not respond to S. Typhimurium infection when a medium with foetal calf serum was used. However when the 3D4 cell line was incubated overnight in the presence of porcine serum, it efficiently responded to the wild-type strain and the ssrA mutant but not to the noninvasive hilA mutant as measured by mRNA quantification of TNF-alpha, IL-8 and GM-CSF by the real-time RT-PCR. In IPI-2I, all the cytokines were also induced by the wild-type S. Typhimurium and the ssrA mutant although the induction of TNF-alpha was lower than that induced by the wild-type strain. The hilA mutant was unable to induce any of the cytokines tested. The ssrA mutant can therefore be considered as more suitable for further vaccine development as the stimulation of innate immune response is important for animal protection against a challenge with virulent strains.
Asunto(s)
Proteínas Bacterianas/genética , Citocinas/biosíntesis , Salmonelosis Animal/microbiología , Salmonella enterica/inmunología , Enfermedades de los Porcinos/microbiología , Animales , Adhesión Bacteriana , Células Cultivadas , Células Epiteliales/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Interleucina-8/biosíntesis , Macrófagos/metabolismo , Mutación , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Salmonella enterica/genética , Salmonella enterica/patogenicidad , Porcinos , Transactivadores/genética , Factor de Necrosis Tumoral alfa/biosíntesis , VirulenciaRESUMEN
Immunate Solvent Detergent (S/D) is a plasma derived, purified, human factor VIII (FVIII) - von Willebrand factor (VWF) complex subjected to two virus inactivation/removal processes: S/D and vapor heat treatment. This prospective, multicentre, three-part clinical study evaluated the pharmacokinetics (in comparison to the predecessor product Immunate), efficacy and safety of Immunate S/D in 56 previously treated patients with severe haemophilia A. Subjects received Immunate S/D on-demand, as a prophylactic regimen or both. The results of the pharmacokinetic population demonstrate that Immunate and Immunate S/D were equivalent with respect to the FVIII - and to the retrospectively VWF - parameters assessed. A total of 623 bleeding episodes were reported in 47/56 subjects. The duration of prophylaxis ranged from 0.1-5.2 months with a total of 175.6 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). Ninety-six percent of bleeding episodes were rated as having an excellent or good response. For most bleeding episodes (89%), subjects required only one infusion with a mean dose of 29.6 IU kg(-1). No FVIII inhibitory antibodies were observed in any subject. No related serious adverse events were reported. Thus, the introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules of Immunate S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures, and prophylaxis.
Asunto(s)
Detergentes/farmacocinética , Factor VIII/farmacocinética , Hemofilia A/tratamiento farmacológico , Solventes/farmacocinética , Detergentes/efectos adversos , Hemofilia A/sangre , Hemofilia A/virología , Hemorragia/tratamiento farmacológico , Hemorragia/prevención & control , Humanos , Dolor/tratamiento farmacológico , Dolor/prevención & control , Estudios Prospectivos , Seguridad , Solventes/efectos adversos , Resultado del Tratamiento , Inactivación de VirusRESUMEN
A prospective, randomised, multicentre, single-blind phase 3 study was performed to assess the safety of a vaccination schedule consisting of two vaccinations (21-35 days apart) with the tick-borne encephalitis (TBE) vaccine FSME-IMMUN "adults" (five consecutive lots) in comparison to another licensed TBE vaccine (Encepur), with polygeline) (two lots) in healthy volunteers (n=3966) aged 16-65 years. The safety of the third vaccination with FSME-IMMUN "adults" (6 months after the first vaccination) was investigated in a follow-up study on the same population (n=3705) and TBE antibody titres were analysed pre- and post-vaccination in a subgroup of volunteers (n=564). Following the first vaccination, the overall incidence of fever (> or =38.0 degrees C) was 0.8% in the FSME-IMMUN "adults" study group and 5.6% in the comparator study group; fever was mainly mild. The fever rate after the second vaccination was 0.6% and 0.5% in the two study groups, respectively. Local and systemic reactions after the first vaccination occurred with a lower frequency in the FSME-IMMUN "adults" study group than in the comparator group. Upon analysing the tolerability of the third vaccination with FSME-IMMUN "adults", similar results were determined in both study groups of volunteers previously vaccinated with FSME-IMMUN "adults" or with the comparator vaccine. The immunogenicity results demonstrated similar seroconversion rates (as determined by ELISA or neutralization test) before and after the third vaccination in the FSME-IMMUN "adults" group and in the comparator group respectively. The results of both studies demonstrate that: (1) FSME-IMMUN "adults" is safe and highly immunogenic, (2) all five production lots of FSME-IMMUN "adults" were consistent with respect to a low rate of adverse events, (3) FSME-IMMUN "adults" induces considerably lower adverse reaction rates than the comparator vaccine after the first vaccination, and (4) two vaccinations with the comparator vaccine can be successfully followed by a third vaccination with FSME-IMMUN "adults".