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BACKGROUND: We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation. PROCEDURE: This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive nutritional counseling with supplementation of 1,000 mg/day calcium and 800 International Unit cholecalciferol or placebo for 2 years. The primary outcome was change in LS-BMD assessed by quantitative computerized tomography (QCT) at 24 months. Linear regression models were employed to identify the baseline risk factors for low LS-BMD and to compare LS-BMD outcomes. RESULTS: Pre-randomization LS-BMD below the mean was associated with male gender (P = 0.0024), White race (P = 0.0003), lower body mass index (P < 0.0001), and cumulative glucocorticoid doses of ≥ 5,000 mg (P = 0.0012). One hundred eighty-eight (68%) participants completed the study; 77% adhered to the intervention. Mean LS-BMD change did not differ between survivors randomized to supplements (0.33 ± 0.57) or placebo (0.28 ± 0.56). Participants aged 9-13 years and those 22-35 years had the greatest mean increases in LS-BMD (0.50 ± 0.66 and 0.37 ± 0.23, respectively). Vitamin D insufficiency (serum 25[OH]D <30 ng/ml) found in 296 (75%), was not associated with LS-BMD outcomes (P = 0.78). CONCLUSION: Cholecalciferol and calcium supplementation provides no added benefit to nutritional counseling for improving LS-BMD among adolescent and young adult survivors of ALL (93% of whom had LS-BMD Z-scores above the mean at study entry).
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Densidade Óssea , Cálcio da Dieta/administração & dosagem , Colecalciferol/administração & dosagem , Aconselhamento , Suplementos Nutricionais , Leucemia-Linfoma Linfoblástico de Células Precursoras/dietoterapia , Sobreviventes , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lactente , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Masculino , Terapia Nutricional , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
We have studied the Ce valence as a function of pressure in CeRhIn5 at 300 K and at 22 K using x-ray absorption spectroscopy in partial fluorescent yield mode. At room temperature, we found no detectable change in Ce valence greater than 0.01 up to a pressure of 5.5 GPa. At 22 K, the valence remains robust against pressure below 6 GPa, in contrast to the predicted valence crossover at P = 2.35 GPa. This work yields an upper limit for the change in Ce-valence and suggests that the critical valence fluctuation scenario, in its current form, is unlikely.
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Information on the influence of poor maternal nutrition on the regulation of responses to pregnancy, placental and fetal growth and development is critical to a better understanding of pregnancy physiology and pathophysiology. We determined normal changes and effects of controlled and monitored moderate nutrient restriction (NR) (global nutrient intake reduced to 70% of food consumed by mothers feeding ad libitum from 0.16 to 0.5 of gestation) in the baboon, on important hematological, biochemical, and hormonal indices of fetal growth and placental function. Serum IGF-I:IGFBP-3 ratio was lower in pregnant than control non-pregnant baboons feeding ad libitum. Serum concentrations of total and free IGF-I were decreased in NR mothers compared with controls (p<0.05). The decrease in fetal IGF-I did not reach significance (p=0.057). Serum IGF-I: IGFBP-3 ratio was decreased by NR in both mothers and fetuses. Maternal serum IGF-II was unchanged by NR. Placental IGF-I mRNA and protein abundance were similarly reduced whereas IGF-II mRNA increased in placental tissue of NR compared to control mothers. Systemic (maternal) and local (placental) IGFBP-1 and IGFBP-3 mRNA and protein abundance were unchanged by NR. Type 1 IGF receptor protein in the syncytiotrophoblast increased in NR. Type 2 IGF receptor protein was present in the stem villi core, and decreased after NR. We conclude that moderate NR in this important non-human primate model significantly disrupts the maternal and placental IGF-IGFBP axis and influences placental expression of this key system at the gene and protein level. Changes observed appear to be directed toward preserving placental growth.
Assuntos
Restrição Calórica , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/fisiologia , Placenta/fisiologia , Prenhez/fisiologia , Somatomedinas/fisiologia , Animais , Peso Corporal , Feminino , Hormônios/sangue , Imuno-Histoquímica , Hibridização In Situ , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Papio , Placenta/citologia , Gravidez , RNA Mensageiro/biossíntese , Valores de Referência , Somatomedinas/análise , Somatomedinas/genéticaRESUMO
Mutations in the high-affinity sulfonylurea receptor (SUR)-1 cause one of the severe recessively inherited diffuse forms of congenital hyperinsulinism or, when associated with loss of heterozygosity, focal adenomatosis. We hypothesized that SUR1 mutations would render the beta-cell insensitive to sulfonylureas and to glucose. Stimulated insulin responses were compared among eight patients with diffuse hyperinsulinism (two mutations), six carrier parents, and ten normal adults. In the patients with diffuse hyperinsulinism, the acute insulin response to intravenous tolbutamide was absent and did not overlap with the responses seen in either adult group. There was positive, albeit significantly blunted, acute insulin response to intravenous dextrose in the patients with diffuse hyperinsulinism. Graded infusions of glucose, to raise and then lower plasma glucose concentrations over 4 h, caused similar rises in blood glucose but lower peak insulin levels in the hyperinsulinemic patients. Loss of acute insulin response to tolbutamide can identify children with diffuse SUR1 defects. The greater response to glucose than to tolbutamide indicates that ATP-sensitive potassium (KATP) channel-independent pathways are involved in glucose-mediated insulin release in patients with diffuse SUR1 defects. The diminished glucose responsiveness suggests that SUR1 mutations and lack of KATP channel activity may contribute to the late development of diabetes in patients with hyperinsulinism independently of subtotal pancreatectomy.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Hiperinsulinismo/congênito , Hiperinsulinismo/genética , Insulina/metabolismo , Mutação/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Receptores de Droga/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Glucose/farmacologia , Heterozigoto , Humanos , Hipoglicemiantes/farmacologia , Injeções Intravenosas , Secreção de Insulina , Masculino , Valores de Referência , Receptores de Sulfonilureias , Tolbutamida/farmacologiaRESUMO
Mutations of glutamate dehydrogenase cause the hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by GTP. Normal allosteric activation of glutamate dehydrogenase by leucine is thus uninhibited, leading us to propose that children with hyperinsulinism/hyperammonemia syndrome will have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases beta-cell GTP, we also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, seven hyperinsulinism/hyperammonemia syndrome patients (aged 9 months to 29 yr) had acute insulin responses to leucine performed using an iv bolus of L-leucine (15 mg/kg) administered over 1 min and plasma insulin measurements obtained at -10, -5, 0, 1, 3, and 5 min. The acute insulin response to leucine was defined as the mean increase in insulin from baseline at 1 and 3 min after an iv leucine bolus. The hyperinsulinism/hyperammonemia syndrome group had excessively increased insulin responses to leucine (mean +/- SEM, 73 +/- 21 microIU/ml) compared with the control children and adults (n = 17) who had no response to leucine (1.9 +/- 2.7 microU/ml; P < 0.05). Four hyperinsulinism/hyperammonemia syndrome patients then had acute insulin responses to leucine repeated at hyperglycemia (blood glucose, 150-180 mg/dl). High blood glucose suppressed their abnormal baseline acute insulin responses to leucine of 180, 98, 47, and 28 microU/ml to 73, 0, 6, and 19 microU/ml, respectively. This suppression suggests that protein-induced hypoglycemia in hyperinsulinism/hyperammonemia syndrome patients may be prevented by carbohydrate loading before protein consumption.
Assuntos
Glutamato Desidrogenase/genética , Hiperamonemia/fisiopatologia , Hiperinsulinismo/fisiopatologia , Insulina/metabolismo , Leucina , Mutação Puntual , Adolescente , Adulto , Substituição de Aminoácidos , Amônia/sangue , Glicemia/metabolismo , Criança , Pré-Escolar , Diazóxido , Feminino , Glutamato Desidrogenase/química , Humanos , Hiperamonemia/sangue , Hiperamonemia/genética , Hiperinsulinismo/sangue , Hiperinsulinismo/genética , Lactente , Insulina/sangue , Secreção de Insulina , Masculino , SíndromeRESUMO
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age. HI is most often due to defective glucose-insulin coupling by the beta-cell sulfonylurea receptor (SUR1) or glutamate dehydrogenase. HI-induced hypoglycemia carries significant morbidity, and current therapies are suboptimal. Insulin-like growth factor I (IGF-I) decreases insulin secretion in vitro and in healthy adults in vivo. We postulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tolerance. We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1. All had suboptimal glycemic control and served as their own controls. Subjects underwent 24-h glucose monitoring under their home regimens, followed by a supervised fasting study. The controlled fast was terminated when the subject became hypoglycemic (blood glucose, <50 mg/dL) or developed symptoms consistent with hypoglycemia. The fast was repeated 2 days later with administration of rhIGF-I at 40 microg/kg, s.c., every 12 h. At the start of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 +/- 11.1 vs. 6.3 +/- 2.2 microIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 +/- 0.7 vs. 1.2 +/- 0.6 ng/mL; P < 0.04). rhIGF-I suppression of insulin and C peptide persisted throughout the fast. The duration of fasting did not change significantly with rhIGF-I treatment. We have directly demonstrated that rhIGF-I inhibits insulin oversecretion in children with HI due to defective SUR1. Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.
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Transportadores de Cassetes de Ligação de ATP , Hiperinsulinismo/genética , Fator de Crescimento Insulin-Like I/uso terapêutico , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Mutação , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Receptores de Droga/genética , Adulto , Glicemia/metabolismo , Peptídeo C/sangue , Criança , Pré-Escolar , Jejum , Feminino , Humanos , Hiperinsulinismo/congênito , Hiperinsulinismo/tratamento farmacológico , Lactente , Insulina/sangue , Secreção de Insulina , Masculino , Proteínas Recombinantes/uso terapêutico , Receptores de SulfonilureiasRESUMO
P11 cells were used as an in vitro model system to explore effects of exposure to 5-HT on levels of mRNA encoding 5-HT2A receptors. Exposure of cells to the agonist 5-HT resulted in a doubling of receptor mRNA levels. mRNA levels returned to control levels within 8-16 h. The stability of receptor mRNA transcripts was transiently increased, suggesting that a post-transcriptional process was responsible for the up-regulation of receptor mRNA. The 5-HT-induced increase in Levels on 5-HT2A receptor mRNA did not require de novo protein synthesis since the increase was not affected by prior treatment with the protein synthesis inhibitor cycloheximide. Results of studies in which the activity of protein kinase C was either increased with PMA or antagonized with bisindolylmaleimide indicated that protein phosphorylation was essential for increasing levels of 5-HT2A receptor mRNA. These findings suggest that PKC-dependent post-transcriptional and post-translational processes participate in regulating 5-HT2A receptor mRNA expression.
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RNA Mensageiro/biossíntese , Receptores de Serotonina/biossíntese , Agonistas do Receptor de Serotonina/farmacologia , Animais , Cricetinae , Processamento Pós-Transcricional do RNA , Receptores de Serotonina/efeitos dos fármacos , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacosRESUMO
STUDY OBJECTIVE: To quantify the short term respiratory health effects of ambient air pollution in the Paris area. DESIGN: Time series analysis of daily pollution levels using Poisson regression. SETTING: Paris, 1987-92. MEASUREMENTS AND MAIN RESULTS: Air pollution was monitored by measurement of black smoke (BS) (15 monitoring stations), sulphur dioxide (SO2), nitrogen dioxide (NO2), particulate matter less than 13 microns in diameter (PM13), and ozone (O3) (4 stations). Daily mortality and general admissions to public hospitals due to respiratory causes were considered. The statistical analysis was based on a time series procedure using linear regression modelling followed by a Poisson regression. Meterological variables, epidemics of influenza A and B, and strikes of medical staff were included in the models. The mean daily concentration of PM13 and daily 1 hour maximum of SO2 significantly affected daily mortality from respiratory causes. An increase in the concentration of PM13 of 100 micrograms/m3 above its 5th centile value increased the risk of respiratory death by 17%. PM13 and BS were also associated with hospital admissions due to all respiratory diseases (4.1% increased risk when the BS level exceeded its 5th centile value by 100 micrograms/m3). SO2 levels consistently influenced hospital admissions for all respiratory diseases, chronic obstructive pulmonary disease, and asthma. Asthma was also correlated with NO2 levels. CONCLUSIONS: These results indicate that even though the relative risk is weak in areas with low levels of pollution, ambient air pollution, and especially particulate matter and SO2, nonetheless require attention because of the number of people exposed and the existence of high risk groups.
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Poluição do Ar/efeitos adversos , Transtornos Respiratórios/epidemiologia , Adolescente , Adulto , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poeira/efeitos adversos , Poeira/análise , Hospitalização/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Razão de Chances , Paris/epidemiologia , Análise de Regressão , Transtornos Respiratórios/mortalidade , Estações do Ano , Fumaça/efeitos adversos , Fumaça/análise , Dióxido de Enxofre/efeitos adversos , Dióxido de Enxofre/análiseRESUMO
Amodiaquine is used for antimalarial prophylaxis and treatment and has been associated with neutropenia and agranulocytosis in man. The effect of the drug on the in vitro growth of bone marrow human myeloid progenitor cells (GM-CFU) was tested using the soft agar culture technique: 42 haematologically normal subjects were studied and it was found that amodiaquine, at concentrations tested in vitro (0.005, 0.05 and 0.5 micrograms.ml-1), had no quantitative effect on the colony and cluster growth. Our results argue against direct toxicity of the drug on GM-CFU. Therefore, in cases of amodiaquine-associated neutropenia, alternative mechanisms should be considered: a abnormally sensitive GM-CFU; b) toxic effect of metabolites such as desethyl-amodiaquine; c) immune-mediated toxicity.
Assuntos
Amodiaquina/farmacologia , Células da Medula Óssea , Células-Tronco Hematopoéticas/efeitos dos fármacos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Ensaio de Unidades Formadoras de Colônias , Feminino , Granulócitos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-IdadeRESUMO
HPA-23 is a competitive inhibitor of the RNA-dependent DNA polymerase (reverse transcriptase) of the human immunodeficiency virus (HIV). It may therefore potentially benefit patients with HIV infection. This study aimed at defining the haematopoietic toxicity of this drug and particularly its effects on the normal human granulocyte-macrophage progenitor cells (GM-CFU). Our in vitro studies, in semi-solid agar, have shown an inhibitory effect of increasing concentrations of HPA-23 on colony and cluster formation. This effect is probably dose-dependent. An almost complete inhibition of colony formation was observed at doses of more than 20 micrograms/ml. Regarding cluster formation, a similar although much more progressive inhibitory effect was found. Our experimental data should be extrapolated with caution to clinical situations. However, they must be kept in mind for optimal design of HPA-23 therapy in HIV infected patients.
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Antimônio/toxicidade , Antivirais/toxicidade , Granulócitos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos de Tungstênio , Tungstênio/toxicidade , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimônio/uso terapêutico , Antivirais/uso terapêutico , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tungstênio/uso terapêuticoRESUMO
BACKGROUND/PURPOSE: Congenital hyperinsulinism induces severe and unremitting hypoglycemia in newborns and infants. If poorly controlled, seizures and irreversible brain damage may result. Subtotal (<95%) or near-total (95% to 98%) pancreatectomy have been performed for glycemic control in babies who do not respond to aggressive medical therapy. Because hypoglycemia often persists after subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To define the effect of more or less extensive pancreatectomy on the management and outcome of refractory congenital hyperinsulinism, the authors examined our single institutional experience. METHODS: The records of children treated between 1963 and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were reviewed. Outcome parameters included glycemic response to surgery, need for reresection, surgical morbidity, surgical and long-term mortality, and development of diabetes mellitus (DM). A complete response was defined as discharge to home on no glycemic medications, no continuous feedings, and without DM. Histological reports were reviewed and categorized as either diffuse or focal disease. RESULTS: Of 101 children treated for congenital hyperinsulinism during this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed a complete response, occurring in 50% of patients having > or = 95% pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16). The remaining three babies had local excision of a solitary focal lesion, and each showed a complete response. Histopathology showed diffuse islet abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A complete response was observed for 82% of focal but only 33% of diffuse lesions. Eight patients (15%) required reresection for persistent hypoglycemia, seven having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3) occurring before 1975. DM developed in seven children (14%), each having diffuse lesions, and was independent of resection type. CONCLUSION: Because euglycemia is more readily restored, and because the risks for surgical complications and DM do not appear increased, the authors recommend 95% pancreatectomy as the initial procedure of choice for newborns and infants with congenital hyperinsulinism.
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Hiperinsulinismo/congênito , Hiperinsulinismo/cirurgia , Pancreatectomia , Feminino , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/patologia , Hipoglicemia/etiologia , Hipoglicemia/patologia , Hipoglicemia/cirurgia , Lactente , Recém-Nascido , Ilhotas Pancreáticas/patologia , Masculino , Estudos RetrospectivosRESUMO
We retrospectively studied 32 patients treated with the m-BACOD regimen in a single institution between January 1988 and December 1991. After four to seven courses, four patients presented severe acute pneumonitis (PaO2 < 55 mmHg in room air), with diffuse bilateral interstitial syndrome. Broncho-alveolar lavage displayed increased lymphocyte count (> 45%) with inversion of CD4/CD8 in two cases and no evidence of parasitic, bacterial or viral infection. All patients received methyl-prednisolone (0.5 to 1 mg/kg/d x 1 week) with both complete clinical and radiological recovery within a week. The m-BACOD regimen was continued without bleomycine for four patients and without bleomycine plus methotrexate for two patients, until the completion of eight courses, without recurrence of pneumonitis. Drug-exclusion decisions were made empirically because the exact nature of the pneumonitis was not recognized at the time of diagnostic. Because of the regular administration in the m-BACOD regimen, methotrexate leads to an increased risk of pneumonitis. We concluded that the use of the m-BACOD regimen should henceforth be discontinued.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfoma não Hodgkin/tratamento farmacológico , Pneumonia/induzido quimicamente , Adulto , Anti-Inflamatórios/uso terapêutico , Bleomicina/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Doxorrubicina/efeitos adversos , Feminino , Humanos , Leucovorina/efeitos adversos , Masculino , Metotrexato/efeitos adversos , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Oxigenoterapia , Pneumonia/terapia , Vincristina/efeitos adversosRESUMO
Since 1990, many epidemiological time series studies have provided evidence that ambient air pollution levels have adverse health effects. The ERPURS study (Evaluation des Risques de la Pollution Urbaine pour la Santé) has permitted to quantify this impact in the Paris region. This study was based on an ecological time series approach. We present, step by step, the method used, illustrated by an example: association between SO2 levels and total mortality (excluding external causes), 1987-1990. Mortality modelling has taken trend into account by a linear term, seasons by trigonometrics functions sum, day of the week effects by 6 dummy variables, temperature peak by a dummy variable, influenza epidemics by appropriate variables, mean temperature by linear and quadratic terms, relative humidity by a linear term. SO2 1 day lag was introduced in the model by a linear term. The central issue is the control of seasonal variations and long term trend. An inadequate control can lead to some spurious results. The relationship between mortality and weather variables is generally nonlinear. The use of statistical and graphical diagnostics, are necessary at each step. Time series analysis are important tools to study short term relationship between air pollutants and health indicators. The method applied in the ERPURS study is only one of the possible approaches. Whatever the method used, it is important to understand the underlying process of the data and to control for confounding factors with the appropriate method for the temporal structure of the data.
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Poluentes Atmosféricos , Dióxido de Enxofre/intoxicação , Poluentes Ocupacionais do Ar , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Modelos Estatísticos , Mortalidade , Paris/epidemiologia , Estações do Ano , População UrbanaRESUMO
This paper analyses 14 epidemiologic investigations (published from January 1980 to September 1991) about the relationship between urban air pollution and mortality. Air pollution indicators and mortality indicators are examined. Methods to analyse the relationships between these two kinds of indicators are classified according as they bring "qualitative information" trying to answer the question: "is there any relationship between air pollution and mortality?" or according as they try to quantify this relationship. Results are presented by author. Confounding factors and means to take them into account are described. This paper ends by a discussion about interest and limits of these studies. It emphasizes the importance of the collaboration between metrologists of urban air pollution and epidemiologists.
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Poluição Ambiental , Métodos Epidemiológicos , Mortalidade , Poluentes Atmosféricos/análise , Fatores de Confusão Epidemiológicos , França , Humanos , Conceitos Meteorológicos , Saúde da População UrbanaRESUMO
The follow-up of patients treated with sequential chemotherapy in internal medicine departments with special interest in haematology imposes a heavy burden on the entire treating staff. The chances of errors, notably in medical prescriptions and care, are not negligible, and these errors result in iatrogenic complications, readmissions and prolonged stays in hospitals. Designing a medical decision and therapeutic follow-up aid system should be time-saving for the staff and ensure good quality and safe prescriptions as well as reliable therapeutic evaluations and better hospital management. The system described here is developed on 4D Macintosh computer which handles a relational data-base. It includes the data-base, i.e. a knowledge-based system devised by the expert clinician containing "declarative" data and deduced rules which represent the expert's reasoning and determine the action to be taken, and the interface between them. The system easily accepts many parameters, thereby enabling medical knowledge and therapeutic attitudes to be updated.
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Tomada de Decisões Assistida por Computador , Quimioterapia Assistida por Computador , Doenças Hematológicas/tratamento farmacológico , Quimioterapia Combinada , Humanos , Fatores de TempoRESUMO
INTRODUCTION: Maternal obesity (MO) remains a serious obstetric problem with acute and chronic morbidities for both mothers and offspring. The mechanisms underlying these adverse consequences of MO remain unknown. Endocannabinoids (ECB) are neuromodulatory lipids released from adipocytes and other tissues. Metabolic crosstalk between placenta and adipocytes may mediate sequelae of MO. The goal of this study was to elucidate placental and systemic ECB in MO. MATERIAL AND METHODS: Placentas, sera, and subcutaneous fat were collected at Cesarean sections performed near term (0.9 G) in four non-obese (nOB) and four obese (OB) baboons (Papio spp.). Concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled to tandem mass spectrometry. AEA and 2-AG pathways were characterized in placentas by Q-RT-PCR, Western blot and immunohistochemistry. RESULTS: Placental 2-AG levels were lower and maternal fat AEA levels were higher in OB (1254.1 ± 401.3 nmol/kg and 17.3 ± 4 nmol/kg) vs. nOB (3124.2 ± 557.3 nmol/kg and 3.1 ± 0.6 nmol/kg) animals. Concentrations of 2-AG correlated positively between maternal fat and placenta (r = 0.82, p = 0.013), but correlated negatively with maternal leptin concentrations (r = -0.72, p = 0.04 and r = -0.83, p = 0.01, respectively). CONCLUSION: This is the first study to demonstrate differential ECB pathway regulation in maternal fat and placenta in MO. Differential regulation and function exist for AEA and 2-AG as the major ECB pathways in placenta.
Assuntos
Modelos Animais de Doenças , Endocanabinoides/metabolismo , Obesidade/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Receptores de Canabinoides/metabolismo , Gordura Subcutânea Abdominal/metabolismo , Animais , Ácidos Araquidônicos/sangue , Ácidos Araquidônicos/metabolismo , Transporte Biológico , Cromatografia Líquida de Alta Pressão , Endocanabinoides/sangue , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Glicerídeos/sangue , Glicerídeos/metabolismo , Leptina/sangue , Obesidade/sangue , Obesidade/patologia , Papio , Placenta/patologia , Alcamidas Poli-Insaturadas/sangue , Alcamidas Poli-Insaturadas/metabolismo , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/patologia , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/biossíntese , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Receptores de Canabinoides/biossíntese , Receptores de Canabinoides/genética , Gordura Subcutânea Abdominal/patologia , Espectrometria de Massas em TandemRESUMO
INTRODUCTION: Placental abruption is a serious condition that increases perinatal morbidity and mortality. Clinical prevention and treatment options are limited, especially in human preterm deliveries. Knowledge of the mechanisms that keep the placenta in place during pregnancy is critical for developing strategies for the prevention of abruption. Failure of physiological transformation of spiral arteries has been described as a major contributing factor of the placental abruption development. Baboons (Papio spp.) share striking similarities with humans in regard to placental structure, utero-placental blood flow, and fetal development; however, the mode of trophoblast invasion is shallow in baboons. This fact prompted the hypothesis that the incidence of placental abruption will be increased in baboons compared to humans. MATERIAL AND METHODS: Baboon placentas were collected between 2002 and 2008. Two independent veterinary pathologists evaluated the slides. A certified physician pathologist performed additional histology. RESULTS: Placental abruption was diagnosed in 22 baboons among 2423 live births during the study period (0.9% prevalence). The most common clinical presentations were fetal demise and vaginal bleeding. The most common pathological findings were intraplacental hemorrhages with or without hematoma formation (86.4%). Other findings consisted of neutrophil infiltration (50%), decidual necrosis (22.7%), decidual vascular congestion and inflammation, villous congestion and retroplacental hemorrhage/hematoma (each 18.2%). These pathologic findings were the same for term and preterm deliveries. CONCLUSION: This is the first systematic study of placental abruption in non-human primates, analyzing a large colony of baboons. Despite differences in trophoblast invasion, the clinical features observed in placental abruption affecting baboons resembled those reported in humans. The cluster of placental pathological findings in baboons also agreed with clinical reports, but the prevalence of these findings differed between baboons and humans. We discuss a mechanism of anti-abruption forces that offset shallow trophoblast invasion observed in baboons.
Assuntos
Descolamento Prematuro da Placenta/patologia , Descolamento Prematuro da Placenta/fisiopatologia , Modelos Animais de Doenças , Doenças dos Macacos/patologia , Doenças dos Macacos/fisiopatologia , Papio , Descolamento Prematuro da Placenta/epidemiologia , Descolamento Prematuro da Placenta/imunologia , Animais , Animais de Laboratório , Feminino , Morte Fetal/etiologia , Hematoma/etiologia , Hemorragia/etiologia , Doenças dos Macacos/epidemiologia , Doenças dos Macacos/imunologia , Infiltração de Neutrófilos , Placenta/irrigação sanguínea , Placenta/imunologia , Placenta/patologia , Placentação , Gravidez , Prevalência , Fatores de Risco , Texas , Hemorragia Uterina/etiologiaRESUMO
INTRODUCTION: More than one-fourth of U.S. women are overweight; more than one-third are obese. Maternal obesity has been linked to an increased incidence of stillbirths, fetal macrosomia, fetal intrauterine growth restriction and pre-eclampsia. The placenta plays a key role in the nutrients and oxygen supply to the fetus. The data about structural changes in the placental villous membrane (VM), a major component of the feto-maternal nutrient and oxygen exchange barrier, during obesity are sparse and inconsistent. Our objective was to evaluate the morphometric changes in the placental exchange barrier in a baboon model of obesity. MATERIALS AND METHODS: The previously described baboon model of maternal obesity was studied. We compared 4 obese to 4 non-obese baboons. Placental stereology with the use of transmission electron microscopy was performed to estimate VM oxygen diffusing capacities and morphometry. RESULTS: The specific placental oxygen diffusing capacities per unit of fetal weight were similar in baboons and humans. Maternal leptin concentrations correlated negatively with placental basement membrane thickness (r = -0.78, p < 0.05), while fetal leptin levels correlated negatively with endothelial thickness of fetal capillaries (r = -0.78, p < 0.05). The total and specific villous membrane oxygen diffusing capacities were not different between the two groups. CONCLUSION: To the best of our knowledge this is the first report of placental oxygen diffusing capacities and placental ultrastructural changes in a baboon model of obesity. Previously reported placental inflammation in maternal obesity is not associated with changes in the VM diffusing capacities and ultrastructure.