RESUMEN
Sequencing of the entire exome or genome is increasingly used in clinical practice. Debate continues, however, regarding which incidental findings (IFs) should be returned and who should be involved in those decisions. Previous empirical research regarding stakeholder attitudes to the return of IFs has primarily involved genetics professionals; non-genetics health professionals have not been widely surveyed. Given this, a survey regarding return of IFs was administered at the Best Practices in Pediatrics Conference following an educational presentation on genetics terminology and genetic condition examples. A total of 258 participants completed the survey. Of particular note, respondents who were positively disposed to sequencing did not always report wanting to learn about IFs, even if actionable. This is noteworthy given recent American College of Medical Genetics and Genomics guidelines recommending particular actionable IF be returned 'without reference to patient preference'. This study's findings are important because they provide insight regarding the attitudes to the return of genome sequencing results for an important professional group, primary care providers. Ultimately, as likely gatekeepers to referrals for this technology, their opinions about the test will be key to its successful deployment.
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Actitud del Personal de Salud , Genoma Humano/genética , Hallazgos Incidentales , Médicos de Atención Primaria , Análisis de Secuencia de ADN/métodos , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The introduction of clinical genome-wide sequencing raises complex issues regarding the management of incidental findings. However, there is a lack of empirical studies assessing views of providers involved in potential disclosure of such findings. In an anonymous survey of 279 clinical genetics professionals, we found that the vast majority of participants agreed that they were interested in knowing about clinically actionable incidental findings in themselves (96%) and their child (99%), and they reported that these types of findings should be disclosed in adult (96%) and minor (98%) patients. Approximately three-fourths agreed that they were personally interested in knowing about an adult-onset clinically actionable disease (78%) and a childhood-onset non-clinically actionable disease (75%) in their child. A similar percentage of participants (70%) felt that these two types of findings should be disclosed to patients. Forty-four percent of participants wanted to know about an incidental finding that indicates an adult-onset non-clinically actionable condition in themselves and 31% wanted to know about this type of information in their child. Findings from this study revealed participants' views highly dependent on clinical actionability. Further research is needed with a broader population of geneticists to increase generalizability, and with diverse patients to assess their perspectives about results disclosure from clinical sequencing.
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Genética Médica , Genómica , Conocimientos, Actitudes y Práctica en Salud , Personal de Salud , Secuenciación de Nucleótidos de Alto Rendimiento , Hallazgos Incidentales , Adolescente , Adulto , Anciano , Niño , Femenino , Encuestas de Atención de la Salud , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Arabinosylcytosine, a compound that inhibits DNA synthesis in rapidly dividing cells, stimulates fetal hemoglobin in adult baboons and produces significant perturbations in the pools of erythroid progenitors. It appears that changes in the kinetics of erythroid cell differentiation rather than direct action on the gamma genes underlie stimulation of fetal hemoglobin in the adult animals in vivo. These results also suggest that chemotherapeutic agents selected for their low carcinogenic or mutagenic potential could be used for therapeutic induction of fetal hemoglobin in patients with sickle cell anemia.
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Diferenciación Celular/efectos de los fármacos , Citarabina/farmacología , Eritropoyesis/efectos de los fármacos , Hemoglobina Fetal/biosíntesis , Anemia de Células Falciformes/tratamiento farmacológico , Animales , Citarabina/uso terapéutico , Cinética , Papio , Reticulocitos/efectos de los fármacosRESUMEN
To determine if acute stress activates pancreatic noradrenergic nerves, pancreatic norepinephrine (NE) output (spillover) was measured in halothane-anesthetized dogs. Central neuroglucopenia, induced by intravenous 2-deoxy-D-glucose [( 2-DG] 600 mg/kg + 13.5 mg/kg-1 per min-1) increased pancreatic NE output from a baseline of 380 +/- 100 to 1,490 +/- 340 pg/min (delta = +1,110 +/- 290 pg/min, P less than 0.01). Surgical denervation of the pancreas reduced this response by 90% (delta = +120 +/- 50 pg/min, P less than 0.01 vs. intact innervation), suggesting that 2-DG activated pancreatic nerves by increasing the central sympathetic outflow to the pancreas rather than by acting directly on nerves within the pancreas itself. These experiments provide the first direct evidence of stress-induced activation of pancreatic noradrenergic nerves in vivo. In contrast, neither hemorrhagic hypotension (50 mmHg) nor hypoxia (6-8% O2) increased pancreatic NE output (delta = +80 +/- 110 and -20 +/- 60 pg/min, respectively, P less than 0.01 vs. neuroglucopenia) despite both producing increases of arterial plasma NE and epinephrine similar to glucopenia. The activation of pancreatic noradrenergic nerves is thus stress specific. Furthermore, because both glucopenia and hypotension increased arterial NE, yet only glucopenia activated pancreatic nerves, it is suggested that a regionally selective pattern of sympathetic activation can be elicited by acute stress, a condition in which sympathetic activation has traditionally been thought to be generalized and nondiscrete.
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Hipoglucemia/fisiopatología , Hipotensión/fisiopatología , Hipoxia/fisiopatología , Norepinefrina/sangre , Páncreas/inervación , Estrés Fisiológico/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adrenalectomía , Animales , Desoxiglucosa/farmacología , Perros , Activación Enzimática , Sistema Nervioso Simpático/irrigación sanguíneaRESUMEN
BACKGROUND: For patients with metastatic prostate cancer, treatment is primarily palliative, relying mainly on the suppression of systemic androgen hormone levels. To help document the achievement of palliation and to characterize positive and negative effects of treatment, we evaluated quality-of-life (QOL) parameters in patients with metastatic prostate cancer who were randomly assigned to two methods of androgen deprivation. METHODS: Patients (n = 739) with stage M1 (bone or soft tissue metastasis) prostate cancer were enrolled in a QOL protocol that was a companion to Southwest Oncology Group INT-0105, a randomized double-blind trial comparing treatment with bilateral orchiectomy (surgical castration) plus either flutamide or placebo. Patients completed a comprehensive battery of QOL questionnaires at random assignment to treatment and at 1, 3, and 6 months later. Data were collected on three treatment-specific symptoms (diarrhea, gas pain, and body image), on physical functioning, and on emotional functioning. All P values are two-sided. RESULTS: Questionnaire return rates for this study never dropped below 80%; only 2% of the patients did not submit baseline QOL assessments. Cross-sectional analyses (corrected for multiple testing) identified statistically significant differences that favored orchiectomy plus placebo for two of the five primary QOL parameters as follows: patients receiving flutamide reported more diarrhea at 3 months (P = .001) and worse emotional functioning at 3 and 6 months (both P<.003). Longitudinal analyses replicated these findings. Other analyzed QOL parameters favored the group receiving placebo but were not statistically significant after adjustment for multiple testing. CONCLUSIONS: We found a consistent pattern of better QOL outcomes at each follow-up assessment during the first 6 months of treatment for orchiectomized patients with metastatic prostate cancer who received placebo versus flutamide. Improvement over time was evident in both treatment groups but more so for patients receiving placebo.
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Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Flutamida/uso terapéutico , Neoplasias de la Próstata/psicología , Neoplasias de la Próstata/terapia , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Estudios Transversales , Diarrea/inducido químicamente , Método Doble Ciego , Flutamida/efectos adversos , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Orquiectomía , Dolor/etiología , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
To determine the role of the autonomic nervous system (ANS) in mediating the glucagon response to marked insulin-induced hypoglycemia in dogs, we measured arterial and pancreatic venous glucagon responses to insulin-induced hypoglycemia during acute, terminal experiments in halothane-anesthetized dogs in which the ANS was intact (control; n = 9), pharmacologically blocked by the nicotinic ganglionic antagonist hexamethonium (n = 6), or surgically ablated by cervical vagotomy and cervical spinal cord section (n = 6). In control dogs, insulin injection caused plasma glucose to fall by 4.4 +/- 0.2 mM to a nadir of 1.7 +/- 0.2 mM. Arterial epinephrine (EPI) levels increased by 13,980 +/- 1860 pM (P less than 0.005), confirming marked activation of the ANS. Pancreatic output of glucagon increased from 0.53 +/- 0.12 to 2.04 +/- 0.38 ng/min during hypoglycemia (change [delta] +1.51 +/- 0.33 ng/min, P less than 0.005). This increased arterial plasma glucagon from 27 +/- 3 to 80 +/- 15 ng/L (delta +52 +/- 14 ng/L, P less than 0.025). Hexamethonium markedly reduced the ANS response to insulin injection (delta EPI +2130 +/- 600 pM, P less than 0.025 vs. control) despite a similar fall of plasma glucose (delta -4.1 +/- 0.2 mM) and a lower nadir (0.6 +/- 0.1 mM). Both the pancreatic glucagon response (delta glucagon output +0.45 +/- 0.2 ng/min) and the arterial immunoreactive glucagon response (delta +5 +/- 4 ng/L) were substantially reduced by hexamethonium (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)
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Sistema Nervioso Autónomo/fisiopatología , Glucemia/metabolismo , Glucagón/metabolismo , Hipoglucemia/fisiopatología , Insulina/farmacología , Islotes Pancreáticos/metabolismo , Animales , Sistema Nervioso Autónomo/fisiología , Perros , Epinefrina/sangre , Glucagón/sangre , Hematócrito , Hexametonio , Compuestos de Hexametonio/farmacología , Hipoglucemia/inducido químicamente , Islotes Pancreáticos/efectos de los fármacos , Cinética , Norepinefrina/sangre , Páncreas/irrigación sanguínea , Flujo Sanguíneo Regional/efectos de los fármacos , Médula Espinal/fisiología , VagotomíaRESUMEN
To determine whether exercise-induced increases in tissue plasminogen activator (t-PA) were related to plasma epinephrine concentration during exercise, 14 healthy men (aged 24 to 62 years) were studied during epinephrine infusions (10, 25 and 50 ng/kg per min) and graded supine bicycle exercise, beginning at 33 W and increasing in 33-W increments until exhaustion. Plasma epinephrine, active and total t-PA, active plasminogen activator inhibitor type 1 (PAI-1) and t-PA/PAI-1 complex concentrations were measured at each exercise and infusion level. During epinephrine infusion, active and total t-PA levels increased linearly with the plasma epinephrine concentration (respective slopes [+/- SEM] of 0.062 +/- 0.003 and 0.076 +/- 0.003 pmol/ng epinephrine). During exercise, t-PA levels did not increase until plasma epinephrine levels increased, after which both active and total t-PA levels again increased linearly with the plasma epinephrine concentration, but at twice the rate observed with epinephrine infusion (0.131 +/- 0.005 and 0.147 +/- 0.005 pmol/ng, respectively). The t-PA level in blood was directly proportional to the plasma epinephrine concentration during both exercise and epinephrine infusion, suggesting that epinephrine release during exercise stimulates t-PA secretion. In these healthy subjects, active plasminogen activator inhibitor type 1 and t-PA/PAI-1 complex levels were low (41 +/- 11 and 21 +/- 5 pmol/liter, respectively) and did not change significantly during exercise or epinephrine infusion. It is concluded that approximately 50% of the increase in t-PA during exercise is due to stimulated release of t-PA by epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
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Epinefrina/farmacología , Ejercicio Físico/fisiología , Fibrinólisis/fisiología , Activador de Tejido Plasminógeno/sangre , Adulto , Epinefrina/sangre , Prueba de Esfuerzo , Humanos , Masculino , Inactivadores Plasminogénicos/sangreRESUMEN
To assess central nervous system cholinergic neuroendocrine regulation in Alzheimer's disease (AD), we measured plasma arginine vasopressin, beta-endorphin, and epinephrine responses to a cholinergic challenge elicited by intravenous administration of the acetylcholinesterase inhibitor physostigmine (0.0125 mg/kg) in male patients with AD (n = 12) and compared their responses with those of age-matched normal control subjects (n = 12). Physostigmine promptly increased plasma arginine vasopressin (tenfold), beta-endorphin (twofold to threefold) and epinephrine (threefold) levels in elderly control subjects. In contrast, patients with AD showed attenuated responses to physostigmine. When controls and patients with AD who experienced nausea (n = 2 and n = 6, respectively) were excluded, the arginine vasopressin, beta-endorphin, and epinephrine responses of patients with AD were significantly less than those of control subjects. These data suggest that the central nervous system cholinergic deterioration of AD results in decreased responsiveness of neuroendocrine systems that are regulated by central cholinergic mechanisms.
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Enfermedad de Alzheimer/sangre , Arginina Vasopresina/sangre , Epinefrina/sangre , Fisostigmina/farmacología , betaendorfina/sangre , Anciano , Enfermedad de Alzheimer/fisiopatología , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Humanos , Infusiones Intravenosas , Masculino , Sistema Nervioso Parasimpático/efectos de los fármacos , Sistema Nervioso Parasimpático/fisiopatología , Fisostigmina/administración & dosificaciónRESUMEN
BACKGROUND: The resting cerebrospinal fluid (CSF) norepinephrine concentration is unchanged or even increased in patients with Alzheimer's disease (AD). These in vivo findings appear to be inconsistent with the post-mortem locus ceruleus neuronal loss that is reported in patients with AD. METHODS: The effects of AD and advanced age on central nervous system noradrenergic status were estimated by comparing CSF norepinephrine concentrations following the administration of yohimbine hydrochloride, clonidine hydrochloride, and placebo in outpatients with AD and older and young normal subjects. Levels of yohimbine, its metabolite 11-hydroxy-yohimbine, and clonidine were measured in CSF and plasma samples. Behavioral responses were quantified by rating the Tension, Excitement, and Anxiety items on the Brief Psychiatric Rating Scale. RESULTS: Yohimbine-induced increases of CSF norepinephrine concentrations were greater in both patients with AD and normal older subjects than in normal young subjects. Clonidine-induced decreases of CSF norepinephrine concentrations did not differ among groups. Behavioral arousal following the administration of yohimbine was greater in patients with AD than in the other groups. CONCLUSIONS: Central nervous system noradrenergic responsiveness is enhanced in normal older subjects, and this age effect is retained in patients with AD. Behavioral sensitivity to increased central nervous system noradrenergic activity is enhanced in patients with AD.
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Envejecimiento/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Clonidina/farmacología , Norepinefrina/líquido cefalorraquídeo , Yohimbina/farmacología , Adulto , Anciano , Envejecimiento/sangre , Envejecimiento/psicología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/psicología , Atención Ambulatoria , Análisis de Varianza , Presión Sanguínea/efectos de los fármacos , Clonidina/sangre , Clonidina/líquido cefalorraquídeo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Norepinefrina/sangre , Escalas de Valoración Psiquiátrica , Estimulación Química , Yohimbina/sangre , Yohimbina/líquido cefalorraquídeoRESUMEN
BACKGROUND: To determine whether elevations of plasma norepinephrine (NE) in major depression represent increased sympathetic nervous system (SNS) activity and to assess the effects of desipramine hydrochloride on sympathetic function. METHODS: SNS activity was assessed in depressed patients and controls by an isotope-dilution, plasma NE kinetic technique using mathematical modeling and compartmental analysis. This approach provided estimates of the rate of NE appearance into an extravascular compartment, which is the site of endogenous NE release from SNS nerves, the corresponding rate of NE appearance into plasma, and the rate of NE clearance from plasma. RESULTS: Norepinephrine appearance into the extravascular and vascular compartments was significantly elevated in 17 depressed patients compared with that in 36 controls. The rate of NE clearance from plasma was similar in both groups. This is compatible with increased SNS activity in major depression. Desipramine, given for 2 days, significantly reduced the concentration of NE in plasma of patients and controls by markedly suppressing the rates of extravascular and vascular NE appearance, compatible with a short-term reduction in SNS activity. Desipramine prolonged the rate of NE clearance from plasma, consistent with a blockade of NE re-uptake into SNS nerve terminals. The initial suppression of SNS activity by desipramine was reversed by long-term (28 days) treatment of patients, with extravascular and vascular NE appearance rates returning to approximately basal levels. An associated rise in plasma NE concentrations compared with the baseline was attributable to a progressive reduction in plasma NE clearance. CONCLUSION: Sympathetic nervous system activity is elevated in major depression and is suppressed by short-term desipramine administration. The demonstration of SNS reactivation occurring with prolonged desipramine treatment is compatible with the theory that long-term treatment desensitizes CNS alpha 2-adrenergic receptors and emphasizes the value of examining the temporal course of responses to pharmacological challenges of neuroendocrine systems. Previously reported elevations of plasma NE during prolonged administration of tricyclic antidepressants are probably the result of a reduction in plasma NE clearance, not an increase in SNS activity.
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Trastorno Depresivo/fisiopatología , Norepinefrina/sangre , Sistema Nervioso Simpático/fisiopatología , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Depresión Química , Trastorno Depresivo/sangre , Trastorno Depresivo/tratamiento farmacológico , Desipramina/farmacología , Desipramina/uso terapéutico , Regulación hacia Abajo/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/farmacocinética , Norepinefrina/fisiología , Placebos , Receptores Adrenérgicos alfa/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , TritioRESUMEN
BACKGROUND: Increasing plasma glucose levels improves memory in patients with Alzheimer disease (AD). Increasing plasma glucose levels also increases endogenous insulin levels, raising the question of whether memory improvement is due to changes in insulin, independent of hyperglycemia. We address this question by examining memory and counterregulatory hormone response during hyperglycemia when endogenous insulin was suppressed by concomitant infusion of the somatostatin analogue octreotide (Sandostatin). METHODS: Twenty-three patients with AD and 14 similarly aged healthy adults participated in 4 metabolic conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57 pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h); (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting insulin and glucose); and (4) an active control condition in which somatostatin alone was infused (150 mg/h). Declarative memory (story recall) and selective attention (Stroop interference test) were measured during steady metabolic states. RESULTS: Patients with AD showed improved memory during hyperinsulinemia relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory for patients with AD (P<.05). Hyperinsulinemia increased cortisol levels in subjects with AD, whereas somatostatin alone lowered cortisol concentrations. CONCLUSIONS: These results confirm that elevated insulin without hyperglycemia enhances memory in adults with AD, and indicate that insulin is essential for hyperglycemic memory facilitation. These results also suggest a potential therapeutic role for somatostatin in AD.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/psicología , Glucemia/fisiología , Insulina/sangre , Memoria/fisiología , Somatostatina/sangre , Adulto , Anciano , Enfermedad de Alzheimer/diagnóstico , Atención/fisiología , Glucemia/análisis , Femenino , Glucosa/administración & dosificación , Humanos , Hiperglucemia/inducido químicamente , Hiperinsulinismo/inducido químicamente , Insulina/fisiología , Masculino , Pruebas Neuropsicológicas , Octreótido/sangre , Octreótido/farmacología , Octreótido/uso terapéutico , Placebos , Cloruro de Sodio/administración & dosificación , Cloruro de Sodio/sangre , Somatostatina/fisiologíaRESUMEN
The effectiveness of intensive post-remission chemotherapy regimens for adult patients with acute lymphoblastic leukemia (ALL) is limited by both a high rate of disease recurrence and a substantial incidence of treatment toxicity. To evaluate a potentially more effective and less toxic approach, we conducted a multicenter phase III trial of consolidation therapies comparing the standard L10M regimen with one combining the brief, intensive L17M regimen and escalating methotrexate (MTX) and L-asparaginase (L-asp). Patients over age 15 with previously untreated ALL were eligible. Induction therapy included vincristine, prednisone, doxorubicin, cyclophosphamide and intrathecal methotrexate administered over 36 days. Patients who achieved complete remission (CR) were randomized to receive consolidation with either the L10M regimen or with DAT (daunomycin, cytosine arabinoside, 6-thioguanine) and escalating MTX and L-asp. The randomization was stratified by age, WBC and Ph chromosome status. Maintenance therapy was the same in both arms. Of 353 eligible patients, 218 (62%) achieved CR and 195 were randomized. The treatment arms did not differ significantly with respect to disease-free survival (DFS; P= 0.46) or overall survival (P= 0.39). Estimated DFS at 5 years was 32% (95% confidence interval (CI) 23-42%) in the L10M arm and 25% (95% CI 16-33%) in the DAT/MTX/L-asp arm. In each arm, 4% of patients died of toxicities (infection in all but one case). Infections and nausea/vomiting were somewhat more common in the L10M arm (occurring in 68% and 53% of patients respectively) than the DAT/MTX/L-asp arm (56% and 33%). The DAT/MTX/L-asp consolidation regimen was associated with some reduction in nonfatal toxicities, but no significant improvement in DFS, overall survival or non-relapse mortality when compared to the standard L10M regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Metotrexato/administración & dosificación , Inducción de Remisión , Análisis de SupervivenciaRESUMEN
Carboplatin (CBDCA) is an active agent in the treatment of acute leukemia and is associated with limited extramedullary toxicity. Simultaneous phase II trials were conducted by the Southwest Oncology Group in adult patients with relapsed or refractory acute myeloid leukemia (AML). CBDCA was given as a continuous infusion at a dose of 300 mg/m2 daily for 5 days. Three (8%) of the 37 eligible patients in the relapsed group achieved complete remissions (CRs) lasting 3, 4, and 26 months. Entry of patients was stopped early in the refractory group due to slow accrual and in the relapsed group due to low CR rate. For both groups combined, the CR rate was 3/45 or 7% (95% confidence interval 3-18%). There were 12 fatal toxicities. Four patients died of intracerebral hemorrhage, three of infection, and five of hepatic and/or renal failure. Nonhematologic grade 4 toxicity included diarrhea in three patients, hyperbilirubinemia in four, and mucositis and renal toxicity in one each. These results suggest that CBDCA should not be considered for treatment of relapsed or refractory AML patients with prior high-dose therapy.
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Carboplatino/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Adulto , Anciano , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Hemorragia Cerebral/inducido químicamente , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Leucemia Mieloide Aguda/mortalidad , Fallo Hepático/inducido químicamente , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Tasa de Supervivencia , Estados UnidosRESUMEN
Overexpression of the heat shock protein HSP72 provides thermotolerance. We asked if two consecutive endurance runs 1 week apart (CR1, CR2) and additional environmental heat stress affect HSP72-expression in leukocytes of nonheat-acclimated endurance athletes. Twelve subjects were allocated randomly into two groups. Group HH completed both runs at 28 degrees C ambient temperature, and group NH performed CR1 at 18 degrees C and CR2 at 28 degrees C. HSP72-expression was determined by flow cytometry and RT-PCR before and 0, 24, and 48 h after exercise. Additionally, post-exercise cells were exposed to in vitro heat shock (HS; 2 h, 42 degrees C). The prolonged, high HSP72 protein level after CR1 in HH compared with NH may reflect thermotolerance induced by endurance exercise at high ambient temperature. Adaptation of cardiocirculatory/thermoregulatory capacity after CR2 in HH went along with a more rapid down-regulation of HSP72 compared with CR1. HSP72 mRNA demonstrated temperature-related changes after exercise. The reduced HS response in vitro after CR2 may represent exercise-related adaptation mechanisms. HSP72 concentrations in leukocytes may indicate previous exercise- and temperature-related stress conditions and adaptation in immunocompetent cells.
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Adaptación Fisiológica/fisiología , Proteínas de Choque Térmico/biosíntesis , Leucocitos Mononucleares/metabolismo , Carrera , Temperatura Corporal , Células Cultivadas , Ambiente , Expresión Génica , Proteínas del Choque Térmico HSP72 , Frecuencia Cardíaca , Proteínas de Choque Térmico/genética , Respuesta al Choque Térmico , Calefacción , Humanos , Ácido Láctico/sangre , Masculino , Consumo de OxígenoRESUMEN
We investigated whether pancreatic norepinephrine (NE) infusions could reproduce the inhibition of insulin secretion and the stimulation of glucagon secretion observed during sympathetic nerve stimulation in halothane-anesthetized dogs. Three minutes of stimulating the sympathetic nerves (8 Hz, 1 msec, 10 mA, n = 6) surrounding the pancreatic artery decreased both the blood flow in the superior pancreatic vein (SPV) (delta = -1.7 +/- 0.6 ml/min, P less than 0.05) and the basal pancreatic output of immunoreactive insulin (IRI) (delta = -79 +/- 5%, P less than 0.001). SPV levels of NE increased by 683 +/- 177 pg/ml (P less than 0.02). Infusion of NE into the superior pancreatic artery at the low dose of 12 ng/min (n = 6) reproduced this increase of SPV levels of NE (delta = +740 +/- 130 pg/ml; P less than 0.01) and caused a small reduction of SPV blood flow (delta = -1.0 +/- 0.4 ml/min, P less than 0.05), but did not change pancreatic IRI (delta = -26 +/- 16%, NS). The medium dose of NE (120 ng/min, n = 6) reproduced the nerve stimulation-induced decrease of SPV blood flow (delta = -1.5 +/- 0.2 ml/min; P less than 0.01) and increased the SPV NE levels by 6,306 +/- 1,839 pg/ml (P less than 0.02), yet did not decrease pancreatic IRI output (delta = +62 +/- 49%, NS). The high dose of NE (1,200 ng/min, n = 6) produced an extreme increment of SPV NE levels (delta = +180,000 +/- 44,000 pg/ml, P less than 0.001) and a much larger reduction of SPV blood flow (delta = -3.7 +/- 0.7 ml/min, P less than 0.01) than did nerve stimulation, yet still did not inhibit insulin output (delta = -13 +/- 46%, NS). Ten minutes of sympathetic nerve stimulation increased the pancreatic output of immunoreactive glucagon (IRG) by 1435 +/- 419 pg/min (P less than 0.02). Pancreatic IRG output increased as well during infusion of NE for 10 min at both 12 ng/min (by 575 +/- 205 pg/min, P less than 0.05) and 120 ng/min (by 718 +/- 231 pg/min, P less than 0.05). In marked contrast, during infusion of NE at 1200 ng/min, pancreatic IRG output decreased (by 400 +/- 190 pg/min, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Glucagón/metabolismo , Insulina/metabolismo , Norepinefrina/farmacología , Páncreas/metabolismo , Sistema Nervioso Simpático/fisiología , Animales , Arterias/fisiología , Perros , Estimulación Eléctrica , Secreción de Insulina , Norepinefrina/sangre , Páncreas/irrigación sanguínea , Páncreas/inervación , Flujo Sanguíneo Regional/efectos de los fármacos , VenasRESUMEN
We compared the effects of sympathetic nerve stimulation to that of pancreatic norepinephrine (NE) infusion on pancreatic somatostatin-like immunoreactivity (SLI) and pancreatic polypeptide (PP) secretion in the halothane-anesthetized dog. During electrical stimulation (8 Hz, 1 msc, 10 mA, n = 6) of the sympathetic nerves surrounding the pancreatic artery, the pancreatic SLI output decreased from 827 +/- 340 fmol/min to 231 +/- 47 fmol/min (delta = -596 +/- 217 fmol/min, P less than 0.05) after 5 min, and PP output decreased from 11,972 +/- 374 pg/min to 5,518 +/- 774 pg/min (delta = -6,454 +/- 1,932 pg/min, P less than 0.02) after 3 min of stimulation. Arterial SLI or PP levels did not change. Sympathetic nerve stimulation also decreased pancreatic blood flow and increased pancreatic venous NE levels. To determine whether the NE, released locally during sympathetic nerve stimulation, is responsible for this inhibition of pancreatic SLI and PP outputs, exogenous NE was infused into the pancreatic artery at three different dose levels. The low dose of 12 ng/min (n = 6) increased pancreatic venous NE levels like sympathetic nerve stimulation. The medium dose of 120 ng/min (n = 6) reproduced the nerve stimulation-induced decrease of pancreatic blood flow. The high dose of 1,200 ng/min (n = 6) markedly exceeded both. It was found that neither the low nor the medium infusion rates of NE significantly affected pancreatic SLI or PP output. In contrast, infusion of NE at the very high dose level of 1,200 ng/min decreased pancreatic SLI output from 850 +/- 165 fmol/min to 318 +/- 59 fmol/min after 5 min of infusion (delta = -532 +/- 143 fmol/min, P less than 0.01) and decreased PP secretion from 22,777 +/- 7,082 pg/min to 12,764 +/- 6,100 pg/min after 3 min of infusion (delta = -10,013 +/- 2,399 pg/min, P less than 0.01). During this high dose rate NE infusion, both the increment of pancreatic venous SPV levels of NE and the decrement of pancreatic blood flow markedly exceeded the effects produced by sympathetic nerve stimulation. We conclude from this study in dogs: that selective electrical stimulation of the sympathetic nerves entering the pancreas decreases blood flow and inhibits pancreatic SLI and PP secretion, that NE infused into the pancreatic artery at moderate rates reproduces the decrease in blood flow yet does not reproduce the inhibition of pancreatic SLI and PP secretion, and that extremely high concentrations of NE, which markedly restrict pancreatic blood flow, decrease both pancreatic SLI and PP outputs.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Norepinefrina/farmacología , Páncreas/metabolismo , Polipéptido Pancreático/metabolismo , Somatostatina/metabolismo , Sistema Nervioso Simpático/fisiología , Animales , Arterias , Perros , Estimulación Eléctrica , Cinética , Norepinefrina/sangre , Páncreas/irrigación sanguínea , Páncreas/inervación , Flujo Sanguíneo Regional/efectos de los fármacos , VenasRESUMEN
Clonidine is an alpha 2-receptor agonist which lowers both blood pressure and plasma norepinephrine (NE) levels in man. To determine whether the clonidine-induced fall in plasma NE is due to decreased NE appearance into plasma or increased NE clearance from plasma, NE infusions [( 3H]NE; 15 microCi/m2 bolus and 0.35 microCi/m2 X min infusion) were performed in 10 normal subjects, aged 25-56 yr. Arterialized plasma samples were obtained for measurements of steady state [3H]NE specific activity and plasma NE to allow calculation of plasma NE appearance rate and NE clearance before and 120-140 min after 1.5 and 5.0 micrograms/kg oral clonidine. Using an identical protocol, responses were compared in 4 subjects after placebo administration. Clonidine produced a dose-related reduction in mean arterial blood pressure, but no significant change in heart rate. The basal supine plasma NE concentration of 204 +/- 21 pg/ml (mean +/- SEM) fell by 27% (P less than 0.02) after low dose clonidine and by 51% (P less than 0.001) after high dose clonidine. There was no change in plasma epinephrine levels. The basal plasma NE appearance rate of 0.25 +/- 0.03 microgram/m2 X min was reduced by 32% (P less than 0.01) after low dose clonidine and by 52% (P less than 0.001) after high dose clonidine. The basal plasma NE clearance of 1.2 +/- 0.08 liters/m2 X min was unchanged after clonidine treatment. There was no change in mean plasma NE levels, plasma NE appearance rate, or mean arterial pressure after placebo administration. These findings demonstrate that the clonidine-induced fall in plasma NE levels is due to a dose-dependent suppression of plasma NE appearance rate and provide evidence for alpha 2-adrenergic inhibition of sympathetic nervous system activity in normotensive subjects.
Asunto(s)
Clonidina/farmacología , Norepinefrina/sangre , Adulto , Presión Sanguínea/efectos de los fármacos , Clonidina/sangre , Relación Dosis-Respuesta a Droga , Epinefrina/sangre , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Cinética , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana EdadRESUMEN
The alpha 2-adrenergic receptor antagonist yohimbine is often used as a neuroendocrine probe in human studies, in which it is assumed to increase plasma norepinephrine (NE) by increasing sympathetic outflow. In this study we have tested that assumption by using a radioisotope dilution technique to measure norepinephrine (NE) kinetics in arterialized plasma after administration of oral yohimbine (20 or 40 mg) or placebo to normal young men. In agreement with previous studies, we found that yohimbine causes dose-dependent increases in blood pressure, heart rate, and plasma NE. We further found that the increase in plasma NE is, in fact, due to an increase in the rate of appearance of NE into plasma and not to reduced NE clearance from plasma. In addition, we found that yohimbine causes a dose-dependent increase in plasma epinephrine, which had not been found in studies measuring catecholamines in venous plasma. We conclude that yohimbine increases plasma NE levels by increasing the rate of NE release from sympathetic nerves, and probably increases epinephrine release from the adrenals.
Asunto(s)
Sistema Nervioso Simpático/fisiología , Yohimbina/farmacología , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Epinefrina/sangre , Humanos , Masculino , Norepinefrina/sangre , Sistema Nervioso Simpático/efectos de los fármacos , Yohimbina/administración & dosificaciónRESUMEN
In the current study we tested the hypothesis that human plasma beta-endorphin (beta E) is derived from at least two subpopulations of beta E-releasing cells: one sensitive to glucocorticoids as well as to dopamine (DA; regulated analogously to the corticotrophs of the rat pituitary), and one insensitive to glucocorticoids but sensitive to DA (regulated analogously to the melanotrophs of the rat pituitary). To test this hypothesis, human plasma levels of ACTH, cortisol, and beta E-like immunoreactivity were measured at baseline and after haloperidol treatment (0.05 mg/kg, i.v.) in two experimental groups, one pretreated with dexamethasone (1.5 mg) and one pretreated with placebo. Plasma PRL levels were also measured in both groups as an indicator of DA receptor blockade. Dexamethasone partially suppressed both baseline and haloperidol-stimulated levels of human plasma beta E-like immunoreactivity, whereas it completely suppressed both basal and haloperidol-stimulated levels of ACTH and cortisol and had no statistically significant effect on either basal or haloperidol-stimulated PRL levels. These data support a negative feedback effect of glucocorticoids on one DA-sensitive cell population that releases both ACTH and beta E (corticotroph like), but not on a second cell population that releases beta E but not ACTH.
Asunto(s)
Hipófisis/metabolismo , betaendorfina/biosíntesis , Administración Oral , Hormona Adrenocorticotrópica/sangre , Adulto , Análisis de Varianza , Dexametasona/administración & dosificación , Dexametasona/farmacología , Dopamina/farmacología , Método Doble Ciego , Haloperidol/farmacología , Humanos , Hidrocortisona/sangre , Masculino , Hipófisis/citología , Hipófisis/efectos de los fármacos , Prolactina/sangre , RadioinmunoensayoRESUMEN
We assessed the effects of age on cholinergic regulation of the hypothalamic-pituitary-adrenal axis and other neuroendocrine systems by measuring the plasma cortisol and beta-endorphin responses to an infusion of the centrally active cholinesterase inhibitor physostigmine (0.0125 mg/kg) in 12 healthy older men (68 +/- 1.7 yr) and 9 healthy young men (25 +/- 1.4 yr). We also measured the responses to physostigmine of plasma GH, arginine vasopressin, epinephrine, and norepinephrine (NE). As estimated by comparing calculated areas under the curve, older subjects had greater cortisol (P = 0.02) and beta-endorphin (P less than 0.01) secretory responses, but a reduced GH (P less than 0.01) secretory response. The arginine vasopressin response did not differ between groups. By analysis of variance, older subjects also had a greater epinephrine response (P = 0.01). Older subjects had higher basal NE concentrations (P less than 0.05), but NE responses to physostigmine did not differ between groups. These findings suggest age-related enhancement of the cholinergic stimulatory regulation of the hypothalamic-pituitary-adrenal axis and adrenal medulla. They also confirm previous reports of reduced GH secretory response with aging in normal men.