RESUMO
Improving equity in women's health requires gender-specific and empowering approaches. However, health programs often disempower women by adopting a 'one-size-fits-all' approach that emphasizes diet, exercise and weight loss over other important aspects like sleep and mental wellbeing. This article reports on the design of Next Level Health (NLH), a program that aims to empower women through developing a wide range of health behaviors to support their holistic wellbeing. NLH is grounded by ethics, theory and evidence to support women to make achievable, sustainable changes that are relevant to their everyday lives. Women utilized the NLH framework to develop an integrative health routine across six domains: physical activity, sleep, nutrition, eating behavior, self-care and stress management. The framework guided them to set small, incremental goals that were adaptive to their needs and built from their existing circumstances. Participants reflected on their progress with a facilitator during monthly meetings, accessed a social media support page and received monthly text messages. Health programs remain an essential approach to improving women's health alongside community- and policy-level strategies. The development of NLH exemplifies how evidence may partner with modern health promotion values to inform relevant and ethical program design for women.
In western societies, health programs often focus on weight loss through exercise and diet to promote women's health. Such approaches disempower women by undervaluing important factors affecting their health like stress and sleep and narrow their scope for 'health success'. This article reports on the development of Next Level Health (NLH) that aims to help women gain greater health-related control by broadening their approach to health. The program is designed to support women to set small, achievable goals across six domains (physical activity, sleep, nutrition, eating behavior, self-care, and stress management) toward developing positive and sustainable health behaviors. Although women work with a facilitator each month to set goals, they are ultimately in control of formulating their health plans and their progression through NLH. Women can support each other by joining a community of other NLH participants through a social media group. NLH offers a novel program that is responsive to women's individual health needs and broadens their potential for health success.
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Nível de Saúde , Saúde Holística , Feminino , Humanos , Nova Zelândia , Saúde da Mulher , Promoção da SaúdeRESUMO
PURPOSE OF REVIEW: Precocious puberty continues to elicit great interest and concern among medical practitioners, as well as the public. RECENT FINDINGS: Studies have elucidated neural regulation of puberty by kisspeptin, neurokinin B, and other factors. Cohort studies from the North America and Europe suggest that the age of thelarche may be earlier than determined 2 decades ago, and menarche may be slightly earlier, but the causes are unclear. Long-term outcomes of gonadotropin-releasing hormone analog therapy demonstrate increases in final height in the youngest treated patients, with no apparent adverse bone or reproductive consequences. SUMMARY: Although the appropriate threshold age of onset of central puberty remains uncertain, gonadotropin-releasing hormone analog therapy is well tolerated and effective in suppressing luteinizing hormone pulses and ovarian activity.
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Estatura/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/administração & dosagem , Puberdade Precoce/diagnóstico , Peso Corporal/efeitos dos fármacos , Criança , Feminino , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Incidência , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/fisiopatologia , Maturidade SexualRESUMO
Although gonadotropin-releasing hormone agonists (GnRHa) have been the standard of care of central precocious puberty (CPP) management for many years, there are still questions about the long-term consequences of treatment. With increased utilization of GnRHa treatment, it is now possible to assess posttreatment outcomes in the immediate posttreatment period and into adulthood. This literature review reports on the long-term effects of GnRHa therapy in girls with CPP after therapy has been discontinued. Published reports confirm the reversibility of hypothalamic-pituitary-ovarian axis suppression in females after cessation of GnRHa therapy, with the majority of patients achieving ovulatory menstrual cycles of normal timing and duration. GnRHa therapy does not appear to induce polycystic ovary syndrome or have long-term negative repercussions on either bone mineral density or body composition. Evidence is currently insufficient to identify agent-specific differences in outcomes, reproductive function, and health of offspring.
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Hormônio Liberador de Gonadotropina/agonistas , Puberdade Precoce/tratamento farmacológico , Resultado do Tratamento , Adolescente , Composição Corporal/efeitos dos fármacos , Índice de Massa Corporal , Densidade Óssea/efeitos dos fármacos , Criança , Feminino , Hormônio Liberador de Gonadotropina/efeitos adversos , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Menarca , Ciclo Menstrual , Ovário/efeitos dos fármacos , Ovulação , Síndrome do Ovário PolicísticoRESUMO
We assessed the pharmacodynamics of a 3-hour leuprolide stimulation test in 11 girls with precocious puberty to determine an optimal single sampling time. Luteinizing hormone level following leuprolide stimulation was near maximum by 30 minutes in girls with central precocious puberty, whereas it continued to rise slowly in girls with nonprogressive puberty.
Assuntos
Fármacos para a Fertilidade Feminina , Leuprolida , Hormônio Luteinizante/farmacocinética , Puberdade Precoce/sangue , Criança , Pré-Escolar , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Lactente , Medições Luminescentes , Hormônio Luteinizante/sangue , RadioimunoensaioRESUMO
Bioremediation is an important approach to waste reduction that relies on biological processes to break down a variety of pollutants. This is made possible by the vast metabolic diversity of the microbial world. To explore this diversity for the breakdown of plastic, we screened several dozen endophytic fungi for their ability to degrade the synthetic polymer polyester polyurethane (PUR). Several organisms demonstrated the ability to efficiently degrade PUR in both solid and liquid suspensions. Particularly robust activity was observed among several isolates in the genus Pestalotiopsis, although it was not a universal feature of this genus. Two Pestalotiopsis microspora isolates were uniquely able to grow on PUR as the sole carbon source under both aerobic and anaerobic conditions. Molecular characterization of this activity suggests that a serine hydrolase is responsible for degradation of PUR. The broad distribution of activity observed and the unprecedented case of anaerobic growth using PUR as the sole carbon source suggest that endophytes are a promising source of biodiversity from which to screen for metabolic properties useful for bioremediation.
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Fungos/metabolismo , Poliuretanos/metabolismo , Aerobiose , Anaerobiose , Biotransformação , Carbono/metabolismo , DNA Fúngico/química , DNA Fúngico/genética , DNA Ribossômico/química , DNA Ribossômico/genética , DNA Espaçador Ribossômico/química , DNA Espaçador Ribossômico/genética , Fungos/classificação , Fungos/genética , Fungos/crescimento & desenvolvimento , Genes de RNAr , RNA Fúngico/genética , RNA Ribossômico/genética , Análise de Sequência de DNA , Serina Endopeptidases/metabolismoRESUMO
OBJECTIVE: To compare 1-month and 3-month depot formulations of leuprolide acetate (DL), a gonadotropin-releasing hormone analog, in the treatment of central precocious puberty (CPP). STUDY DESIGN: Subjects with CPP naïve to therapy were randomized to 7.5 mg of 1-month DL, 11.25 mg of 3-month DL, or 22.5 mg of 3-month DL. Stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and estradiol levels, growth velocity, and bone age progression were examined in a 2-year period. RESULTS: Forty-nine female and 5 male subjects with CPP were randomized. Mean stimulated LH and FSH levels during treatment were higher in the low-dose 11.25-mg 3-month DL group, and more LH levels >4 IU/L were observed, in comparison with the other two dose groups. Mean LH and FSH levels in the 22.5-mg 3-month group were not different from the monthly DL. No differences in estradiol levels, growth velocity, or bone age progression were observed in dosing groups. CONCLUSIONS: All DL doses resulted in prompt and effective suppression of puberty, but higher LH and FSH levels were seen with the 11.25-mg 3-month DL dose. Multi-monthly DL is effective in treating CPP, but higher dosing may be required in some circumstances.
Assuntos
Leuprolida/administração & dosagem , Puberdade Precoce/tratamento farmacológico , Criança , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Humanos , Masculino , Fatores de TempoRESUMO
OBJECTIVE: To determine clinical and biochemical factors influencing cerebral edema formation during diabetic ketoacidosis (DKA) in children. STUDY DESIGN: We used magnetic resonance diffusion-weighted imaging to quantify edema formation. We measured the apparent diffusion coefficient (ADC) of brain water during and after DKA treatment in 26 children and correlated ADC changes with clinical and biochemical variables. RESULTS: Mean ADC values were elevated during DKA treatment compared with baseline (8.13 +/- 0.47 vs 7.74 +/- 0.49 x 10(-4) mm(2)/sec, difference in means 0.40, 95% CI: 0.25 to 0.55, P < .001). Children with altered mental status during DKA had greater elevation in ADC. ADC elevation during DKA was positively correlated with initial serum urea nitrogen concentration (correlation coefficient 0.41, P = .03) and initial respiratory rate (correlation coefficient 0.61, P < .001). ADC elevation was not significantly correlated with initial serum glucose, sodium or effective osmolality, nor with changes in glucose, sodium or osmolality during treatment. Multivariable analyses identified the initial urea nitrogen concentration and respiratory rate as independently associated with ADC elevation. CONCLUSIONS: The degree of edema formation during DKA in children is correlated with the degree of dehydration and hyperventilation at presentation, but not with factors related to initial osmolality or osmotic changes during treatment. These data support the hypothesis that CE is related to cerebral hypoperfusion during DKA, and that osmotic fluctuations during DKA treatment do not play a primary causal role.
Assuntos
Edema Encefálico/etiologia , Edema Encefálico/fisiopatologia , Cetoacidose Diabética/complicações , Imageamento por Ressonância Magnética/métodos , Edema Encefálico/metabolismo , Criança , Desidratação , Humanos , Concentração de Íons de Hidrogênio , Hiperventilação , Análise Multivariada , Concentração Osmolar , RespiraçãoRESUMO
OBJECTIVES: Pancreatic enzyme concentrations are frequently elevated in children with diabetic ketoacidosis (DKA). We sought to determine the clinical and biochemical characteristics associated with patients with these elevations. Our hypothesis was that pancreatic enzyme elevations would be associated with biochemical markers of hypoperfusion. DESIGN: Prospective cohort study. SETTING: Three university-affiliated children's hospitals. PATIENTS: We collected data on consecutive children <18 yrs of age hospitalized with the diagnosis of DKA. INTERVENTIONS: Serum electrolyte and lactate concentrations and venous pH and Pco2 were measured every 3 hrs from hours 0 to 12 and then every 6 hrs until hour 24. Serum calcium, phosphate, and magnesium concentrations were measured every 6 hrs from hours 0 to 24. Serum amylase, lipase, and triglyceride concentrations were measured at hour 0 and then 12, 24, and 48 hrs after the initiation of therapy. MEASUREMENTS AND MAIN RESULTS: We performed multivariable analyses to test for associations between clinical variables and pancreatic enzyme elevation in 67 children with DKA. Lipase was elevated in 21 (31%) and amylase in 16 (24%) of the children. Pancreatic enzyme values peaked 12-24 hrs after admission. There was no significant correlation between pancreatic enzyme elevation and abdominal pain. In multivariable analyses, an elevated blood urea nitrogen (BUN) concentration was associated with elevated serum amylase (odds ratio 1.04 per unit increase; 95% confidence interval, 1.01-1.09; p = .02), and elevated BUN concentrations and hypophosphatemia were associated with elevated serum lipase (odds ratio 1.04 per unit increase; 95% confidence interval, 1.00-1.08; p = .04; and odds ratio 0.35 per unit increase; 95% confidence interval, 0.15-0.81; p = .01, respectively). CONCLUSIONS: Elevation of pancreatic enzymes is common in children with DKA, but clinical pancreatitis is rare. Pancreatic enzyme levels reach a peak 12-24 hrs after initiation of treatment for DKA. Pancreatic enzyme elevation is associated with increased BUN concentrations at presentation but is not associated with abdominal pain.
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Amilases/sangue , Cetoacidose Diabética/sangue , Lipase/sangue , Nitrogênio da Ureia Sanguínea , Criança , Eletrólitos/sangue , Feminino , Hospitais Universitários , Humanos , Concentração de Íons de Hidrogênio , Magnésio/sangue , Masculino , Fosfatos/sangue , Estudos Prospectivos , Triglicerídeos/sangueRESUMO
CONTEXT: GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin. OBJECTIVE: The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children. DESIGN: This was a phase III, open-label, prospective study of 1-yr duration. SETTING: The study was conducted at nine U.S. medical centers. PATIENTS: Girls ages 2-8 yr (naive) or 2-10 yr (previously treated) and boys 2-9 yr (naive) or 2-11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible. INTERVENTION: A 50-mg histrelin implant was inserted sc in the inner upper arm. MAIN OUTCOME MEASURES: Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures. RESULTS: Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 +/- 19.97 (naive) to 0.8 +/- 0.39 mIU/ml (P < 0.0001) and from 2.1 +/- 2.15 (previously treated) to 0.5 +/- 0.32 mIU/ml (P < 0.0056). Estradiol suppressed from 24.5 +/- 22.27 (naive) to 5.9 +/- 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred. CONCLUSIONS: The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Puberdade Precoce/tratamento farmacológico , Determinação da Idade pelo Esqueleto , Índice de Massa Corporal , Osso e Ossos/diagnóstico por imagem , Mama/crescimento & desenvolvimento , Criança , Pré-Escolar , Implantes de Medicamento , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/efeitos adversos , Hormônio Liberador de Gonadotropina/uso terapêutico , Crescimento/efeitos dos fármacos , Humanos , Hormônio Luteinizante/sangue , Masculino , Estudos Prospectivos , Testosterona/sangueRESUMO
BACKGROUND AND PURPOSE: Subclinical cerebral edema occurs in many, if not most, children with diabetic ketoacidosis (DKA) and may be an indicator of subtle brain injury. Brain ratios of N-acetylaspartate (NAA) to creatine (Cr), measured by proton MR spectroscopy, decrease with neuronal injury or dysfunction. We hypothesized that brain NAA/Cr ratios may be decreased in children in DKA, indicating subtle neuronal injury. MATERIALS AND METHODS: Twenty-nine children with DKA underwent cerebral proton MR spectroscopy during DKA treatment (2-12 hours after initiating therapy) and after recovery from the episode (72 hours or more after the initiation of therapy). We measured peak heights of NAA, Cr, and choline (Cho) in 3 locations within the brain: the occipital gray matter, the basal ganglia, and periaqueductal gray matter. These regions were identified in previous studies as areas at greater risk for neurologic injury in DKA-related cerebral edema. We calculated the ratios of NAA/Cr and Cho/Cr and compared these ratios during the acute illness and recovery periods. RESULTS: In the basal ganglia, the ratio of NAA/Cr was significantly lower during DKA treatment compared with that after recovery (1.68 +/- 0.24 versus 1.86 +/- 0.28, P<.005). There was a trend toward lower NAA/Cr ratios during DKA treatment in the periaqueductal gray matter (1.66 +/- 0.38 versus 1.91 +/- 0.50, P=.06) and the occipital gray matter (1.97 +/- 0.28 versus 2.13 +/- 0.18, P=.08). In contrast, there were no significant changes in Cho/Cr ratios in any region. CONCLUSIONS: NAA/Cr ratios are decreased in children during DKA and improve after recovery. This finding suggests that during DKA neuronal function or viability or both are compromised and improve after treatment and recovery.
Assuntos
Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Encéfalo/metabolismo , Cetoacidose Diabética/complicações , Espectroscopia de Ressonância Magnética , Adolescente , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Edema Encefálico/metabolismo , Criança , Colina/metabolismo , Transtornos da Consciência/diagnóstico , Transtornos da Consciência/etiologia , Transtornos da Consciência/metabolismo , Creatina/metabolismo , Cetoacidose Diabética/metabolismo , Escala de Coma de Glasgow , Humanos , PrótonsRESUMO
BACKGROUND: Dosing of monthly depot leuprolide (DL) in central precocious puberty (CPP) varies considerably. U.S. practitioners use 7.5-15 mg, in contrast with the international standard of 3.75 mg. Pubertal suppression using the newer 3-month DL also has been reported from Europe. To date there have been no direct comparisons of these different DL doses. OBJECTIVES: In an open 12-month protocol, we tested the efficacy of three DL doses (7.5 mg- and 3.75 mg-1 month and 11.25 mg-3 month) given sequentially to subjects treated for CPP. Primary outcome measures were stimulated gonadotropin (Gn) levels at 12-wk intervals. The null hypothesis was no difference among doses. METHODS: Both existing and new patients with CPP received our standard therapy (DL 7.5 mg every 4 wk) for a minimum of 24 wk. In subjects with DL-stimulated LH 2 IU/liter or less, the dose was changed to 3.75 mg every 4 wk and evaluated 12 wk later. Subjects who met LH criteria (<4.5 IU/liter) on 3.75 mg then received a single dose of 11.25 mg-3 month and were reevaluated 12 wk later. Serum LH/FSH and sex steroids were obtained 40 min after DL injection. RESULTS: Thirty subjects were enrolled (20 naive; 24 girls, 6 boys), and 21 were evaluated on all three DL doses. DL-stimulated LH levels (mean +/- sd) were 1.30 +/- 0.74, 1.73 +/- 0.99, and 2.13 +/- 1.41 on 7.5 mg, 3.75 mg, and 11.25 mg-3 month, respectively (7.5 vs. 3.75 mg, P = 0.019; 7.5 mg vs. 11.25 mg-3 month, P = 0.004, Wilcoxon ranked sign test). Mean FSH levels were 2.86 +/- 1.91, 3.91 +/- 1.98, and 3.96 +/- 1.34, respectively (7.5 vs. 3.75 mg, P = 0.017; 7.5 mg vs. 11.25 mg-3 month, P = 0.020). No differences were detected in mean sex steroid levels. CONCLUSIONS: Stimulated LH and FSH levels were significantly higher during therapy with both the 3.75 mg and 11.25 mg-3 month depot leuprolide doses, compared with 7.5 mg, contradicting the null hypothesis of no difference. These data suggest that low-dose 1- and 3-month DL preparations are associated with persistently greater gonadal stimulation in most CPP patients, but the LH/FSH results were not corroborated by differences in sex steroid levels. Whether various DL doses lead to long-term therapeutic differences remains to be determined.
Assuntos
Leuprolida/administração & dosagem , Leuprolida/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Criança , Preparações de Ação Retardada , Feminino , Hormônio Foliculoestimulante/sangue , Hormônios Esteroides Gonadais/antagonistas & inibidores , Gonadotropinas/antagonistas & inibidores , Humanos , Hormônio Luteinizante/sangue , Masculino , Reprodutibilidade dos TestesRESUMO
BACKGROUND AND PURPOSE: Ketone bodies provide important alternate fuel for brain metabolism, and their transport into the brain increases with prolonged fasting. During diabetic ketoacidosis (DKA), serum ketone concentrations markedly increase; however, little is known about whether ketone bodies accumulate in cerebral tissues during DKA. We used proton MR spectroscopy (MRS) to detect cerebral beta-hydroxy butyrate (betaOHB) and acetone/acetocaetate (AcAc) in children with DKA. METHODS: Twenty-five children underwent brain MRS: nine within 4 hours of the start of treatment for DKA; 11, at 4-8 hours; and five, at 8-12 hours. MRS was repeated after their recovery from the DKA episode at > or =72 hours after the start of treatment. MRS was evaluated for peaks corresponding to betaOHB (doublet centered on 1.20 ppm) and lactate (doublet centered on 1.33 ppm). Difference spectroscopy was used to identify the AcAc peak at 2.22-2.26 ppm. RESULTS: betaOHB was detected in 13 children (52%), more frequently within 4 hours (eight children, 89%) than after 4 hours (five children, 31%). AcAc was detected in 15 children (60%), more frequently at >4 hours after the start of treatment (12 patients, 75%) than in the first 4 hours (three patients, 33%). Lactate was detected in five children (18%), all within the first 8 hours of treatment. CONCLUSION: In children, betaOHB and AcAc accumulate in the brain during DKA, and they can be detected on MRS. Care should be taken in interpreting MRS results in patients with DKA to avoid erroneously attributing betaOHB peaks to lactate.
Assuntos
Ácido 3-Hidroxibutírico/análise , Acetoacetatos/análise , Cetoacidose Diabética/metabolismo , Ácido Láctico/análise , Espectroscopia de Ressonância Magnética , Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Criança , Feminino , Humanos , Ácido Láctico/metabolismo , MasculinoRESUMO
Insulin and the insulin-like growth factors (IGF-I, IGF-II) constitute a family of peptides capable of stimulating diverse cellular responses, including cell proliferation. In order to determine the effects of these peptides on malignant cells, we analyzed the expression and function of insulin, IGF-I, and IGF-II receptors on B-cell precursor acute lymphoblastic leukemia (BCP ALL) cell lines, utilizing competitive binding, affinity crosslinking, and cell proliferation assays. The BCP ALL cells bound to each peptide with mean specific binding for 125I-insulin, 125I-IGF-I, and 125I-IGF-II of 19.6%, 7.1%, and 4.3% of radioligand added, respectively. Competitive binding to intact cells demonstrated that 125I-IGF-I was displaced by IGF-I = IGF-II >> insulin, 125I-IGF-II was displaced by IGF-II > insulin = IGF-I, and 125I-insulin was displaced by insulin >> IGF-II > IGF-I. These data were remarkable for the potency of IGF-II displacement of 125I-IGF-I and 125I-insulin. Affinity crosslinking of radioligands to SUP-B2 cell membranes demonstrated the high affinity insulin and IGF-I (type 1 IGF) receptors. IGF binding proteins were also present in BCP ALL cell membrane preparations. In the cell proliferation studies, insulin stimulated a 50-130% increase in leukemic cell growth with a half-maximal concentration of 0.1-3.0 ng/ml in three BCP ALL cell lines. The proliferative response to insulin was blocked by the addition of an insulin receptor antibody. However, no response was observed with IGF-I, and IGF-II was only weakly mitogenic with a proliferative response noted at 100 ng/ml. Thus, while BCP ALL cells possess receptors for insulin and IGF-I, only the insulin receptor mediated a proliferative response.
Assuntos
Linfoma de Burkitt/patologia , Insulina/farmacologia , Divisão Celular/efeitos dos fármacos , Reagentes de Ligações Cruzadas , Humanos , Técnicas In Vitro , Insulina/metabolismo , Cariotipagem , Mitógenos/farmacologia , Receptor de Insulina/metabolismo , Receptores de Somatomedina/metabolismo , Proteínas Recombinantes/farmacologia , Somatomedinas/metabolismo , Células Tumorais CultivadasRESUMO
CONTEXT AND OBJECTIVE: The histrelin implant has proven to be an effective method of delivering GnRH analog (GnRHa) therapy to children with central precocious puberty (CPP), yet there are limited data available regarding hormonal suppression and auxological changes during an extended course of therapy. DESIGN: This was a phase 3, prospective, open-label study. SETTING AND PARTICIPANTS: Thirty-six children with CPP who participated in a phase 3, open-label study and required further GnRHa therapy were eligible to continue treatment receiving a new implant upon removal of the prior 12-month histrelin implant during a long-term extension phase. OUTCOME MEASURES: Hormone levels and auxologic parameters were measured periodically for up to 6 years of treatment and up to 1 year of posttreatment follow-up. RESULTS: Hormonal suppression was maintained throughout the study in patients who had prior GnRHa therapy (n = 16) and in treatment-naive patients (n = 20). Bone age to chronological age ratio decreased from 1.417 (n = 20) at baseline to 1.18 (n = 8) at 48 months in treatment-naive children (P < .01). Predicted adult height in girls increased from 151.9 cm at baseline to 166.5 cm at month 60 (n = 6; P < .05), with a 10.7-cm height gain observed among treatment-naive children (n = 5). No adverse effect on growth or recovery of the hypothalamic-pituitary-gonadal axis was observed with hormonal suppression. The histrelin implant was generally well tolerated during long-term therapy. CONCLUSIONS: Long-term histrelin implant therapy provided sustained gonadotropin suppression safely and effectively and improved predicted adult height in children with CPP.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Puberdade Precoce/tratamento farmacológico , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Regulação para Baixo/efeitos dos fármacos , Esquema de Medicação , Implantes de Medicamento , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Gônadas/efeitos dos fármacos , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Injeções Subcutâneas , Masculino , Puberdade/efeitos dos fármacos , Fatores de TempoRESUMO
Normal adult human keratinocytes in monolayer culture and SCL-1, a skin-derived squamous-cell carcinoma cell line, were investigated for the expression of receptors for insulin-like growth factors (IGF) and insulin. As demonstrated by affinity crosslinking, radiolabeled IGF-1, IGF-2, and insulin bound specifically to both cell types. Each cell expressed type I IGF receptors, with affinity for IGF-1 greater than IGF-2 much greater than insulin. Insulin receptors, with highest affinity for insulin, were also present on both cells. However, keratinocytes and SCL-1 cells differed in 125I-IGF-2 binding. 125I-IGF-2-bound to both type I and type II IGF receptors in normal keratinocytes, but bound predominantly to membrane-associated IGF binding proteins in SCL-1. IGF-1 was slightly more potent than IGF-2 in stimulating growth of both keratinocytes and SCL-1 cells. In keratinocytes, concentrations of IGF-1 ranging from 5-100 ng/ml, and of IGF-2 from 50-100 ng/ml, resulted in a significant increase in cell number. At the maximum dose of 100 ng/ml, either IGF-1 or IGF-2 caused a 2.3-times increase in cell number. In SCL-1 cells, IGF-1 was more potent than IGF-2 or insulin at lower concentrations, but either IGF-1 or IGF-2 at the maximal concentration of 333 ng/ml stimulated a 4.7-times increase in thymidine incorporation. The stimulatory effect of insulin in SCL-1 was 10-50 times less potent than that of the IGF. The effect of either IGF on SCL-1 was completely inhibited by the type I IGF receptor antibody alpha IR-3, suggesting that both IGFs are mitogenic through the type I IGF receptor. Insulin action was partially blocked by alpha IR-3, suggesting that insulin can act through both the insulin and type I IGF receptors. It thus appears that IGF-1 and IGF-2 are mitogens for normal and transformed human keratinocytes and that their actions are primarily mediated through the type I IGF receptor, whereas insulin is a mitogen through both the IGF-1 receptor and the insulin receptor.
Assuntos
Divisão Celular/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Queratinócitos/citologia , Mitógenos , Carcinoma de Células Escamosas , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , Humanos , Insulina/farmacologia , Fator de Crescimento Insulin-Like II/metabolismo , Queratinócitos/efeitos dos fármacos , Cinética , Proteínas de Membrana/isolamento & purificação , Proteínas de Membrana/metabolismo , Receptor de Insulina/isolamento & purificação , Receptor de Insulina/metabolismo , Receptores de Superfície Celular/isolamento & purificação , Receptores de Superfície Celular/metabolismo , Receptores de Somatomedina , Proteínas Recombinantes/farmacologia , Neoplasias Cutâneas , Timidina/metabolismoRESUMO
Recent studies have provided a consensus that insulin-like growth factor-I (IGF-I) stimulates IGF-binding protein-3 (IGFBP-3) in vivo and in vitro. While it also appears well established that IGFBP-1 is inversely related to insulin concentrations, evidence regarding regulation of other IGFBP is inconclusive. Using immunoprecipitation and Western ligand blot, we have characterized the IGFBPs released into conditioned medium (CM) by cells from the adult human fibroblast cell line N3652 and the human epidermal squamous cell carcinoma line SCL-1. N3652 cells expressed IGFBP-3, IGFBP-2, a 24-kilodalton (kDa) IGFBP presumed to be IGFBP-4, and IGFBPs at 30 and 28 kDa. SCL-1 expressed IGFBP-3 and a putative IGFBP-4, with intermediate bands at 34 and 30 kDa. As determined by ligand blot of CM from confluent cells 72 h after the addition of peptides to serum-free medium, IGF-I and IGF-II potently stimulated IGFBP-3 in both cell lines, but otherwise IGFBP regulation in the two cells diverged. In N3652 cells, IGFBP-3 concentrations in CM increased to 700% and 800% of basal levels in the presence of IGF-I and IGF-II (at 100 ng/ml; n = 5 experiments), respectively. IGFBP-3 was not affected by insulin up to 10 micrograms/ml. In contrast, IGFBP-4 levels were diminished 54% and 73% by 100 ng/ml IGF-I and IGF-II, respectively, with no response to insulin. In SCL-1 cells, IGF-I and IGF-II were virtually identical in stimulating a mean 200% increase in IGFBP-3 (n = 5 experiments). Insulin was less potent, but caused a significant stimulation of IGFBP-3 levels. IGF-I, IGF-II, and insulin all stimulated an approximately 50% increase in IGFBP-4 concentrations. To test the hypothesis that IGF-induced alterations in IGFBP-3 and IGFBP-4 concentrations were regulated via the type 1 IGF receptor, we attempted to block IGFBP changes with type 1 IGF receptor antibody alpha IR-3 and to induce IGFBP changes with an IGF-II analog, [Leu27]IGF-II, with little affinity for the type 1 receptor. alpha IR-3 failed to block either the IGF-induced rise in IGFBP-3 in each cell line or the decline in IGFBP-4 in N3652 CM. [Leu27]IGF-II was as potent as IGF-II or IGF-I in inducing changes in IGFBP-3 and IGFBP-4 concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Proteínas de Transporte/metabolismo , Fator de Crescimento Insulin-Like II/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Receptores de Superfície Celular/metabolismo , Carcinoma de Células Escamosas , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Insulina/farmacologia , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Cinética , Receptores de Somatomedina , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Neoplasias CutâneasRESUMO
Deficits in bone mineral have been widely reported in Turner syndrome. The bone mineral status of 19 adolescents with Turner syndrome (16 receiving GH therapy) was evaluated by dual photon absorptiometry of the lumbar spine and whole body and compared with a normal female control group (n = 45) with the same mean age (14.3 yr). The conventional measurements of bone mass, bone mineral content (BMC = g), and bone mineral density (BMD = g/cm2), as well as bone mineral apparent density (BMAD = g/cm3), an expression of bone mineral adjusted for bone volume, were determined for both sites. Although mean BMC was decreased in Turner females, mean BMD and BMAD in the two groups were not significantly different. Analyzed in relation to chronologic age, bone age, height, and pubertal status, mean BMD and BMAD values in Turner subjects were equal to or greater than that of controls. BMD and BMAD were elevated in the Turner group vs. controls matched for height. In subjects with bone age less than or equal to 12.5 yr, mean spinal BMAD was unexpectedly greater in Turner patients compared with controls (0.148 +/- 0.011 vs. 0.134 +/- 0.013, P = 0.009). When data were analyzed by pubertal status, mean spinal BMD and BMAD in subjects with Tanner breast stages 1-2 were higher in the Turner group than in the controls (BMAD 0.146 +/- 0.011 vs. 0.132 +/- 0.015, P = 0.015). No differences were seen in mid- to late pubertal females. Bone mineral properties were additionally reassessed after a mean interval of 1.3 yr in 10 of the subjects with Turner syndrome. Percentage increases in mean follow-up spinal BMD and BMAD were greater in 5 subjects begun on estrogen replacement than in 5 untreated patients. We conclude that: 1) bone mineral values in adolescents with Turner syndrome on GH therapy are not abnormal, 2) lumbar bone mineral is greater in younger Turner adolescents matched with controls for bone age or pubertal status, a difference which could relate to GH therapy, and 3) estrogen therapy may augment bone mineral accretion in Turner syndrome, but early estrogen replacement cannot be justified on the basis of bone mineral status.
Assuntos
Densidade Óssea , Hormônio do Crescimento/uso terapêutico , Síndrome de Turner/tratamento farmacológico , Absorciometria de Fóton , Adolescente , Criança , Feminino , Humanos , Valores de Referência , Coluna Vertebral/metabolismo , Síndrome de Turner/metabolismoRESUMO
Recently, we and others have detected a haplotype of the human progesterone receptor gene (PR). This haplotype consists of a 320-bp insertion in intron G together with point mutations in exons 4 and 5 and was named PROGINS. Whereas the exon 5 mutation is silent, the mutation in exon 4 results in a V660L substitution. Interestingly, this genetic polymorphism was seen to cosegregate with an increased risk of sporadic ovarian cancer in different ethnic groups. Our data provide evidence for the existence of an epidemiological link between a mutated progesterone receptor allele and ovarian cancer (odds ratio, 3.02; 95% confidence interval, 1.86-4.91). Functional characterization of the mutated receptor protein revealed a greater transcriptional activity compared with the wild-type receptor. By contrast, hormone binding and hormone dissociation rates were similar in both receptor proteins. We found that the increased transcriptional activity was due to increased stability resulting in higher expression of the mutant protein. Thus, the long-lasting hyperactivation of progesterone receptor-driven genes secondary to the increased transcriptional activity of the mutated progesterone receptor may participate in ovarian carcinogenesis. This is of special interest, because only a few genetic markers are available for the majority of women diagnosed with sporadic ovarian cancer.
Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Receptores de Progesterona/genética , Animais , Ligação Competitiva , Células COS , Chlorocebus aethiops , Elementos de DNA Transponíveis , Feminino , Hormônios/metabolismo , Humanos , Íntrons , Concentração Osmolar , Receptores de Progesterona/metabolismo , Transcrição Gênica , TransfecçãoRESUMO
Identification of the mechanisms by which a T cell is able to sense ligands of varying strength, such as those that mediate tumor growth, viral evasion, and autoimmunity, is a major goal of T-cell activation studies. In recent years, parameters important for T-cell activation by strong ligands (agonists) are beginning to be characterized. Here, we review our current work on the factors that are critical for T-cell activation by ligands that differ in potency, typified by full agonists, weak agonists, partial agonists, and antagonists. Furthermore, we discuss mechanisms contributing to the lack of a full range of effector functions observed in T cells following their stimulation by suboptimal ligands. Finally, we present strategies for the design of peptide-based therapies to control activation of polyclonal, autoreactive T-cell populations.
Assuntos
Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Peptídeos e Proteínas de Sinalização Intracelular , Ligantes , Complexo Principal de Histocompatibilidade/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6 , Proteínas Tirosina Fosfatases/metabolismoRESUMO
Eighteen patients with chronic progressive multiple sclerosis (MS) were treated in an open preliminary trial of the interferon inducer and immune modulator, poly ICLC. All patients produced substantial interferon levels and experienced acute side effects, including fever and transient worsening of neurologic symptoms. Of nine patients with rapid neurologic deterioration at the time of entry into the study, only three had disease progression during treatment. We conclude that poly ICLC can be administered safely to MS patients, and that a controlled trial will be necessary to determine efficacy.