RESUMO
We studied 298 patients with severe aplastic anaemia (SAA) allografted in four Latin American countries. The source of cells was bone marrow (BM) in 94 patients and PBSCs in 204 patients. Engraftment failed in 8.1% of recipients with no difference between BM and PBSCs (P=0.08). Incidence of acute GvHD (aGvHD) for BM and PBSCs was 30% vs 32% (P=0.18), and for grades III-IV was 2.6% vs 11.6% (P=0.01). Chronic GvHD (cGvHD) between BM and PBSCs was 37% vs 59% (P=0.002) and extensive 5% vs 23.6% (P=0.01). OS was 74% vs 76% for BM vs PBSCs (P=0.95). Event-free survival was superior in patients conditioned with anti-thymocyte globulin (ATG)-based regimens compared with other regimens (79% vs 61%, P=0.001) as excessive secondary graft failure was seen with other regimens (10% vs 26%, P=0.005) respectively. In multivariate analysis, aGvHD II-IV (hazard ratio (HR) 2.50, confidence interval (CI) 1.1-5.6, P=0.02) and aGvHD III-IV (HR 8.3 CI 3.4-20.2, P<0.001) proved to be independent negative predictors of survival. In conclusion, BM as a source of cells and ATG-based regimens should be standard because of higher GvHD incidence with PBSCs, although the latter combining with ATG in the conditioning regimen could be an option in selected high-risk patients.
Assuntos
Anemia Aplástica/terapia , Soro Antilinfocitário/administração & dosagem , Antígenos HLA , Irmãos , Transplante de Células-Tronco , Doença Aguda , Adolescente , Adulto , Idoso , Aloenxertos , Anemia Aplástica/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , América Latina , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Predisposition to offspring metabolic dysfunction due to poor maternal nutrition differs with the developmental stage at exposure. Post-weaning nutrition also influences offspring phenotype in either adverse or beneficial ways. We studied a well-established rat maternal protein-restriction model to determine whether post-weaning dietary intervention improves adverse outcomes produced by a deficient maternal nutritional environment in pregnancy. Pregnant rats were fed a controlled diet (C, 20% casein) during pregnancy and lactation (CC) or were fed a restricted diet (R, 10% casein isocaloric diet) during pregnancy and C diet during lactation (RC). After weaning, the offspring were fed the C diet. At postnatal day (PND) 70 (young adulthood), female offspring either continued with the C diet (CCC and RCC) or were fed commercial Chow Purina 5001 (I) to further divide the animals into dietary intervention groups CCI and RCI. Another group of mothers and offspring were fed I throughout (III). Offspring food intake was averaged between PND 95-110 and 235-250 and carcass and liver compositions were measured at PND 25 and 250. Leptin (PND 110 and 250) and serum glucose, triglycerides and cholesterol (PND 250) levels were measured. Statistical analysis was carried out using ANOVA. At PND 25, body and liver weights were similar between groups; however, CCC and RCC carcass protein:fat ratios were lower compared with III diet. At PND 110 and 250, offspring CCC and RCC had higher body weight, food intake and serum leptin compared with CCI and RCI. CCI had lower carcass fat and increased protein compared with CCC and improved fasting glucose and triglycerides. Adult dietary intervention partially overcomes adverse effects of programming. Further studies are needed to determine the mechanisms involved.
Assuntos
Dietoterapia/métodos , Desnutrição/dietoterapia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Animais , Peso Corporal , Dieta , Proteínas Alimentares , Feminino , Lactação , Leptina/sangue , Fígado/metabolismo , Masculino , Desnutrição/etiologia , Gravidez , Distribuição Aleatória , Ratos WistarRESUMO
PURPOSE: Increasing evidence exists that maternal obesity (MO) and overnutrition during pregnancy and lactation have long-lasting consequences for progeny metabolism, cardiovascular and endocrine function. Data on effects of MO on offspring reproduction are limited. We hypothesized that MO during pregnancy and lactation in founder F(0) rat mothers would increase testicular and sperm oxidative stress (OS) and adversely impact male fertility in their F(1) offspring. METHODS: We induced pre-pregnancy MO by feeding F(0) females a high-fat diet from weaning through pregnancy and lactation. After weaning, all F(1) rats ate control (C) diet. We determined serum testosterone, malondialdehyde (MDA), reactive oxygen species (ROS) and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity in F(1) testes and sperm at postnatal days (PNDs) 110, 450 and 650. RESULTS: At PNDs 450 and 650, MO offspring had lower luteinizing hormone while testosterone levels were lower at all ages. Testicular MDA and ROS concentrations and SOD and GPx activity were higher in MO F(1) at all ages. Nitrotyrosine immunostaining was higher at all ages in MO F(1) testes than C F(1). At PNDs 450 and 650, MO F(1) spermatozoa showed higher MDA concentrations and lower SOD and GPx activity with reduced sperm concentration, viability and motility, and more sperm abnormalities. Fertility rate was not affected at PND 110 but was lower in MO F(1) at PNDs 450 and 650. CONCLUSIONS: We conclude that MO during pregnancy and lactation increases F(1) testicular and sperm OS leading to premature aging of reproductive capacity.
Assuntos
Fertilidade , Obesidade/metabolismo , Hipernutrição/metabolismo , Estresse Oxidativo , Complicações na Gravidez/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Animal , Animais , Animais Recém-Nascidos , Dieta Hiperlipídica , Feminino , Infertilidade/etiologia , Lactação , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/complicações , Obesidade/etiologia , Hipernutrição/complicações , Gravidez , Ratos , Ratos Wistar , Fatores SexuaisRESUMO
Maternal low protein (MLP) diets in pregnancy and lactation impair offspring brain development and modify offspring behavior. We hypothesized multigenerational passage of altered behavioral outcomes as has been demonstrated following other developmental programming challenges. We investigated potential multigenerational effects of MLP in rat pregnancy and/or lactation on offspring risk assessment behavior. Founder generation mothers (F0) ate 20% casein (C) or restricted (R) 10% casein diet, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second letter lactation diet) to evaluate offspring (F1) effects influenced by MLP in F0. On postnatal day (PND 250), F1 males were mated to non-colony siblings producing F2. On PND 90, F2 females (in diestrous) and F2 males were tested in the elevated plus maze (EPM) and open field. Corticosterone was measured at PND 110. Female but not male CR and RC F2 made more entries and spent more time in EPM open arms than CC females. Overall activity was unchanged as observed in male F1 fathers. There were no open field differences in F2 of either sex, indicating that multigenerational MLP effects are due to altered risk assessment, not locomotion. MLP in pregnancy reduced F1 male and F2 female corticosterone. We conclude that MLP in pregnancy and/or lactation increases the innate tendency to explore novel environments in F2 females via the paternal linage, suggesting lower levels of caution and/or higher impulsiveness to explore unknown spaces. Further studies will be necessary to identify the epigenetic modifications in the germ line through the paternal linage.
Assuntos
Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Dieta com Restrição de Proteínas/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Caracteres Sexuais , Fatores Etários , Análise de Variância , Animais , Corticosterona , Comportamento Exploratório/fisiologia , Feminino , Lactação , Masculino , Aprendizagem em Labirinto/fisiologia , Gravidez , Ratos , Medição de Risco , Assunção de RiscosRESUMO
Maternal protein restriction (MPR) during pregnancy impaired the reproduction of male offspring. We investigated, during the first wave of spermatogenesis, whether MPR exerts deleterious effects on germ cell proliferation and differentiation, as well as androgen receptor (AR) protein expression, which was used as a marker for Sertoli cell (SC) maturation. At the beginning of pregnancy (day 0), dams were fed a control diet (C: 20% casein) or a restricted isocaloric diet (R: 10% casein). After birth, four groups were established: CC, RR, CR and RC (first letter diet during pregnancy and second during lactation). Male offspring were studied at postnatal days 14, 21 and 36. At birth, pup body weight was unchanged. Body weight and testis weight were reduced in RR and CR groups at all ages evaluated. MPR delayed the germinal epithelium development at all ages evaluated. On performing Western blot and immunohistochemistry, AR expression was found to be lower in the three restricted groups. The results suggest that MPR during pregnancy and/or lactation delays SC maturation and germ cell differentiation, and affects intratubular organization. These changes might be responsible for the lower fertility rate at older ages.
Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Desenvolvimento Fetal , Túbulos Seminíferos/embriologia , Animais , Feminino , Lactação , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Túbulos Seminíferos/patologia , Testículo/embriologia , Testículo/patologiaRESUMO
Developmental programming resulting from a suboptimal intrauterine environment can predispose offspring to a wide-range of lifelong health complications. Little is known about the effects maternal protein restriction during pregnancy and/or lactation has on offspring neurodevelopment. We hypothesized that maternal isocaloric low protein diet during pregnancy and/or lactation would negatively influence male offspring affect and risk assessment behaviors as measured by elevated plus maze and open field tests. Control mothers received 20% casein (C) and restricted mothers (R) 10% casein to provide four groups: CC, RR, CR, and RC (first letter pregnancy diet and second letter lactation diet) to evaluate effects of maternal diet on offspring risk assessment, anxiety and exploratory behaviors. Elevated plus maze results showed an effect of pre- and/or postnatal diet manipulation in open arm time (p<0.05) with increases seen in the RR (157±22.7s), CR (137±23.2s) and RC (146.8±10.8s) offspring relative to CC (52±8.6s) offspring. This behavior indicates decreased avoidance (less anxiety) and increased exploration by experimental groups. However, in the open field test the RR (17±4.2 entries) offspring entered the center zone less than the CC (35±6.6 entries) offspring thus exhibiting increased anxiety with no other groups showing effects. Elevated levels of corticosterone were measured before, during and after immobilization in the RR compared to CC offspring. These findings show protein restriction during critical periods of development negatively program offspring behavior. The underlying anatomical structures affected remain to be elucidated.
Assuntos
Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Dieta com Restrição de Proteínas , Comportamento Exploratório/fisiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Atividade Motora/fisiologia , Gravidez , RatosRESUMO
Suboptimal developmental environments program offspring to lifelong health complications including affective and cognitive disorders. Little is known about the effects of suboptimal intra-uterine environments on associative learning and motivational behavior. We hypothesized that maternal isocaloric low protein diet during pregnancy and lactation would impair offspring associative learning and motivation as measured by operant conditioning and the progressive ratio task, respectively. Control mothers were fed 20% casein (C) and restricted mothers (R) 10% casein to provide four groups: CC, RR, CR, and RC (first letter pregnancy diet and second letter lactation diet), to evaluate effects of maternal diet on male offspring behavior. Impaired learning was observed during fixed ratio-1 operant conditioning in RC offspring that required more sessions to learn vs. the CC offspring (9.4±0.8 and 3.8±0.3 sessions, respectively, p<0.05). Performance in fixed ratio-5 conditioning showed the RR (5.4±1.1), CR (4.0±0.8), and RC (5.0±0.8) offspring required more sessions to reach performance criterion than CC offspring (2.5±0.5, p<0.05). Furthermore, motivational effects during the progressive ratio test revealed less responding in the RR (48.1±17), CR (74.7±8.4), and RC (65.9±11.2) for positive reinforcement vs. the CC offspring (131.5±7.5, p<0.05). These findings demonstrate negative developmental programming effects due to perinatal isocaloric low protein diet on learning and motivation behavior with the nutritional challenge in the prenatal period showing more vulnerability in offspring behavior.
Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Aprendizagem/fisiologia , Motivação , Animais , Animais Recém-Nascidos , Condicionamento Operante , Feminino , Humanos , Lactação , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos WistarRESUMO
Obesity involving women of reproductive years is increasing dramatically in both developing and developed nations. Maternal obesity and accompanying high energy obesogenic dietary (MO) intake prior to and throughout pregnancy and lactation program offspring physiological systems predisposing to altered carbohydrate and lipid metabolism. Whether maternal obesity-induced programming outcomes are reversible by altered dietary intake commencing before conception remains an unanswered question of physiological and clinical importance. We induced pre-pregnancy maternal obesity by feeding female rats with a high fat diet from weaning to breeding 90 days later and through pregnancy and lactation. A dietary intervention group (DINT) of MO females was transferred to normal chow 1 month before mating. Controls received normal chow throughout. Male offspring were studied. Offspring birth weights were similar. At postnatal day 21 fat mass, serum triglycerides, leptin and insulin were elevated in MO offspring and were normalized by DINT. At postnatal day 120 serum glucose, insulin and homeostasis model assessment (HOMA) were increased in MO offspring; glucose was restored, and HOMA partially reversed to normal by DINT. At postnatal day 150 fat mass was increased in MO and partially reversed in DINT. At postnatal day 150, fat cell size was increased by MO. DINT partially reversed these differences in fat cell size. We believe this is the first study showing reversibility of adverse metabolic effects of maternal obesity on offspring metabolic phenotype, and that outcomes and reversibility vary by tissue affected.