RESUMEN
Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/crecimiento & desarrollo , Ácidos Hidroxámicos/farmacología , Latencia del Virus/efectos de los fármacos , Acetilación/efectos de los fármacos , Biomarcadores/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Regulación Viral de la Expresión Génica/efectos de los fármacos , Infecciones por VIH/sangre , VIH-1/genética , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/farmacología , Histonas/efectos de los fármacos , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Provirus/efectos de los fármacos , Provirus/genética , Provirus/crecimiento & desarrollo , ARN Viral/biosíntesis , ARN Viral/sangre , Medición de Riesgo , Regulación hacia Arriba/efectos de los fármacos , Viremia/tratamiento farmacológico , Viremia/virología , VorinostatRESUMEN
The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.
Asunto(s)
Restricción Calórica , Metilación de ADN , Humanos , Adulto , Restricción Calórica/métodos , Ingestión de Energía , Envejecimiento/genética , LongevidadRESUMEN
We have investigated the ability of resting B cells, acting as antigen-presenting cells, to induce tolerance to soluble protein antigens in mice, using an antigen targeted specifically to B cells. We inject mice intravenously with ultracentrifuged Fab fragments of rabbit anti-mouse immunoglobulin D (IgD) (Fab anti-delta). Treatment with Fab anti-delta results in profound tolerance to challenge with 100 micrograms Fab nonimmune rabbit Ig (Fab NRG), precipitated in alum, as measured by antibody production. Tolerance to rabbit Fab is antigen specific, since the treated mice make normal antibody responses to a control antigen, chicken Ig. Tolerance is dependent on antigen presentation by B cells, since intravenous injection of soluble Fab NRG, which is not targeted to B cells, results in a much lower frequency and degree of tolerance, especially at lower doses. T cell help in this system is affected, since T cells from Fab anti-delta-treated mice fail to provide help for an adoptive primary antibody response to Fab NRG when transferred together with normal B cells into severe combined immunodeficient (SCID) mice. The antigen-specific B cell compartment is also affected during tolerance induction, since B cells from treated animals make less antibody than normal B cells when transferred into SCID mice with normal T cells. Although the mechanism of nonresponsiveness in the helper T cell compartment remains to be determined, we think it is likely that the precursors of helper T cells are inactivated or deleted by encountering antigen presented by small, resting B cells, which lack accessory signals necessary to induce helper T cell proliferation and differentiation to effector function.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos B/inmunología , Tolerancia Inmunológica , Inmunoglobulina D/inmunología , Fragmentos Fab de Inmunoglobulinas/inmunología , Animales , Pollos , Femenino , Globulinas/inmunología , Inmunosupresores/inmunología , Inmunoterapia Adoptiva , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , Compuestos Orgánicos , Conejos/inmunologíaRESUMEN
Anti-Ig has been widely used as a model for antigen receptor-mediated B cell activation. B cells activated with mitogenic concentrations of anti-Ig (approximately 10 micrograms/ml) become responsive to a set of T cell-derived, antigen-nonspecific helper factors that enable the B cells to proliferate, and, in some cases, mature to Ig secretion. In the present experiments, we show that anti-Ig can also be used as a model for major histocompatibility complex (MHC)-restricted, antigen-specific T-B cell collaboration. We used murine helper T cell lines and T cell hybridomas specific for a protein antigen, the F(ab')2 fragment of normal rabbit IgG. Small B cells are very efficient at presenting rabbit anti-IgM or rabbit anti-IgD to these rabbit Ig-specific T cell lines and hybridomas, and the responding (initially) small B cells, appear to be the only antigen-presenting cells required. Efficient presentation depends upon binding of rabbit antibody to mIg on the B cell surface. MHC-restricted recognition of rabbit Ig determinants on the B cell surface results in a polyclonal B cell response. This response is qualitatively different from the well-studied response to blastogenic concentrations of anti-Ig plus stable, T cell-derived helper factors, since it (a) requires 1,000-fold lower concentrations of anti-Ig, (b) involves helper T cell functions other than, or in addition to, the local production of the same stable helper factors, and (c) is largely MHC-restricted at the T-B cell level.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos B/inmunología , Cooperación Linfocítica , Complejo Mayor de Histocompatibilidad , Animales , Anticuerpos Antiidiotipos/inmunología , Especificidad de Anticuerpos , Células Presentadoras de Antígenos/citología , Linfocitos B/citología , Línea Celular , Antígenos H-2/genética , Hibridomas/inmunología , Interfase , Activación de Linfocitos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Conejos , Linfocitos T/inmunologíaRESUMEN
Cultures of isolated mouse splenic B lymphocytes activated by the divalent F(ab')2 fragment of purified rabbit anti-mouse Fab or class-specific anti-mouse IgM antibodies can be driven on to high rate Ig secretion by the addition of the supernatant fluid of a 24-h culture of concanavalin A-activated spleen cells (SN). The polyclonal antibody response to anti-Ig pus SN is comparable in magnitude with the lipopolysaccharide response as measured in a reverse plaque assay. The addition of SN can be delayed for 24 h after addition of anti-Ig without changing the kinetics of the response. Addition at 48 h delays the response by 24 h. The response to F(ab')2 anti-Fab plus SN is sensitive to Fc-dependent inhibition because intact anti-Fab antibodies inhibit strongly at relatively low concentrations. The monovalent Fab' fragment fails to induce Ig secretion, indicating that cross-linkage of surface immunoglobulin is required. Although the production of active SN is T cell dependent, the response to anti-Ig plus SN is T independent. These findings are interpreted as a polyclonal model of a thymus-dependent antibody response. X
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Anticuerpos Antiidiotipos/inmunología , Linfocitos B/inmunología , Inmunoglobulinas/metabolismo , Activación de Linfocitos , Animales , Especificidad de Anticuerpos , Linfocitos B/ultraestructura , Células Cultivadas , Femenino , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunoglobulinas/inmunología , Lipopolisacáridos/inmunología , Masculino , Ratones , Microscopía Electrónica , Conejos , Bazo/inmunología , Linfocitos T/inmunología , Factores de TiempoRESUMEN
Resting murine B lymphocytes can present rabbit anti-Ig to T cell lines specific for normal rabbit globulin. The T cell-B cell interaction is major histocompatibility complex (MHC)-restricted, and leads to activation, proliferation, and differentiation of the resting B cell into an antibody-secreting cell. Efficient antigen presentation and B cell activation depends upon binding of rabbit globulin to (membrane) mIg. To investigate the role of mIg in this polyclonal model for a T cell-dependent primary antibody response, we determined whether crosslinking of mIg is required either for efficient antigen presentation, as measured by helper T cell activation, or for the B cell response to T cell help, since all the direct effects of anti-Ig on B cells require crosslinking of mIg. We found that monovalent Fab' fragments of anti-IgM or anti-IgD work as efficiently as their divalent counterparts. Therefore, a signal transduced through the antigen receptor seems not to be required when T cell help is provided by an MHC-restricted T helper cell recognizing antigen on the B cell surface. Moreover, rabbit globulin bound to class I MHC molecules in the form of anti-H-2K also results in efficient antigen presentation and T cell-dependent B cell activation. However, mIg still appears to be specialized for antigen presentation, since anti-Ig is presented about three- to fivefold more efficiently than anti-H-2K.
Asunto(s)
Linfocitos B/inmunología , Comunicación Celular , Complejo Mayor de Histocompatibilidad , Receptores de Antígenos de Linfocitos B/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos , Complejo Antígeno-Anticuerpo , Membrana Celular/inmunología , Inmunoglobulina D/análisis , Inmunoglobulina M/análisis , Ratones , Ratones EndogámicosRESUMEN
Crosslinking of surface immunoglobulins (sIg) in B cells led to the accumulation of submembranal phosphotyrosine, which was followed morphologically with the PY20 antiphosphotyrosine monoclonal antibody. Phosphotyrosine was not detected before sIg crosslinking. After sIg crosslinking, phosphotyrosine-containing proteins were redistributed from scattered small clusters near the plasma membrane to a juxtanuclear region, where immunofluorescent staining decreased with time. Double immunofluorescent staining of individual cells showed accumulation of phosphotyrosine beneath crosslinked sIg molecules at the cell surface. The sIg molecules were subsequently internalized more rapidly than the phosphotyrosine-containing molecules were redistributed. Genistein, a protein tyrosine kinase (PTK) inhibitor, blocked intracellular tyrosine phosphorylations but not cell surface patching of crosslinked sIg. When polyacrylamide beads coated with anti-Ig antibodies were added to the cells, intracellular tyrosine phosphorylation occurred beneath the regions of contact with the beads. This study provides an independent line of evidence confirming recent biochemical experiments that show that crosslinking of the antigen receptor induces PTK activity in B cells, and that components of the newly described sIg complex are among the PTK substrates. The surprising finding that the bulk of the induced phosphotyrosine remains associated with crosslinked sIg for many minutes suggests a role for complex local protein interactions in phosphotyrosine-mediated signal transduction through the antigen receptor of B cells.
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Antígenos de Superficie/inmunología , Linfocitos B/inmunología , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal , Tirosina/metabolismo , Anticuerpos Monoclonales/inmunología , Linfocitos B/enzimología , Línea Celular , Reactivos de Enlaces Cruzados , Citoplasma/metabolismo , Técnica del Anticuerpo Fluorescente , Genisteína , Humanos , Inmunoglobulina G/inmunología , Isoflavonas/farmacología , Fosforilación , Fosfotirosina , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos B/metabolismo , Tirosina/análogos & derivadosRESUMEN
In comparison to B cell stimulation mediated by surface immunoglobulin (Ig) antigen receptor ligation, little is known about the intracellular events associated with T cell-dependent B cell responses. A model for the efferent phase of T cell-B cell interaction was used to examine the capacity of activated T cells to trigger nuclear expression of the trans-acting transcription factor, NF-kappa B, in B cells. Fixed, activated, but not fixed, resting Th2 cells were found to induce increased binding activity for a kappa B site-containing oligonucleotide in a time-dependent manner. This induction of NF-kappa B was eliminated by an antibody directed against a 39-kD cell interaction protein on activated T cells as well as by a soluble form of B cell CD40. Of particular relevance to intracellular signaling, NF-kappa B induction was not diminished by prior depletion of B cell protein kinase C (PKC) with phorbol myristate acetate. These results strongly suggest that T cell-dependent B cell stimulation is associated with NF-kappa B induction via p39-CD40 interaction and that this is brought about by non-PKC dependent signaling, in marked contrast to the previously documented requirement for PKC in sIg receptor-mediated stimulation. This suggest that NF-kappa B responds to more than one receptor-mediated intracellular signaling pathway in B cells and may be part of a "final common pathway" for B cell stimulation.
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Linfocitos B/metabolismo , FN-kappa B/biosíntesis , Linfocitos T/fisiología , Animales , Linfocitos B/inmunología , Secuencia de Bases , Línea Celular , ADN , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia MolecularRESUMEN
Release of human growth hormone during sleep is significantly related to slow, synchronized stages of sleep and therefore would seem to be controlled by related neural mechanisms. When sleep-waking cycles are reversed by 12 hours, the release of growth hormone with sleep is reversed; thus release does not follow an inherent circadian rhythm independent of sleep.
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Hormona del Crecimiento/sangre , Periodicidad , Sueño , Adulto , Electroencefalografía , Electromiografía , Frecuencia Cardíaca , Humanos , Masculino , Fases del Sueño , Sueño REMRESUMEN
Prolactin concentrations of 30 unmedicated psychiatric inpatients and 11 normal controls were measured at baseline and at 30 and 60 minutes after the administration of 10 mg of intramuscular methadone hydrochloride. Methadone raised the prolactin level at 60 minutes to more than twice the mean baseline level for the full subject sample. Patients with depressive disorders had lower mean basal prolactin levels than did the other subjects, and also manifested attenuated prolactin responses to methadone. Eight of 16 depressives had markedly blunted prolactin responses, a finding consistent with other studies reporting deficient responses in depression. These data are consistent with the hypothesis that the pathophysiology of depressive disorders involves dysfunctions in the anterior pituitary itself or in the hypothalamic neurotransmitter and neuromodulator systems (eg, endorphins) that regulate the secretion of prolactin and other neurohormones.
Asunto(s)
Trastorno Depresivo/sangre , Metadona/farmacología , Prolactina/sangre , Adulto , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/fisiopatología , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Persona de Mediana Edad , Prolactina/metabolismoRESUMEN
Levels of c-myc mRNA have been assayed in mouse B cells cultured for 8 hr with Fab'2 anti-Ig or IgG anti-Ig. Fab'2 anti-Ig induces DNA synthesis in B cells, whereas the whole molecule inhibits anti-Ig-induced DNA synthesis by crosslinking the B cell Fc gamma R to mIg. Both the Fab'2 fragment and the IgG anti-Ig induce an increase in c-myc mRNA by 1 hr. Thereafter, levels in cells stimulated with submitogenic doses of Fab'2 anti-Ig or any dose of IgG anti-Ig returned to background, while levels in cultures containing a mitogenic dose of Fab'2 anti-Ig remained elevated.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Linfocitos B/inmunología , Proto-Oncogenes , ARN Mensajero/análisis , Receptores Fc/inmunología , Animales , Femenino , Fragmentos Fab de Inmunoglobulinas/inmunología , Inmunoglobulina G/inmunología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos DBA , Receptores de IgGRESUMEN
Egr-1 is an immediate early gene that is rapidly upregulated in response to mitogenic signals induced by antigen receptor crosslinking on murine B lymphocytes. It has been shown that levels of Egr-1 expression are closely correlated with B cell proliferation in several models of B cell activation and tolerance. We compared the expression of Egr-1 during B cell stimulation with Fab'2 and IgG anti-immunoglobulin (anti-Ig), since it is known that Fab'2 anti-Ig is mitogenic while IgG anti-Ig is not, owing to a dominant inhibitory effect of crosslinking the B cell Fc gamma RII to membrane Ig. While mitogenic doses of Fab'2 anti-Ig induce large and rapid increases in Egr-1 expression, IgG anti-Ig results in smaller increases in Egr-1 mRNA, comparable to that seen with submitogenic concentrations of Fab'2 anti-Ig. However, the correlation between Egr-1 expression and B cell proliferation breaks down when IL-4 is added as a co-mitogen to induce B cell proliferation with IgG anti-Ig or submitogenic concentrations of Fab'2 anti-Ig. No corresponding increases in Egr-1 mRNA levels are observed when IL-4 is added. Therefore, IL-4 overcomes Fc receptor-mediated inhibition of B cell proliferation without affecting inhibition of Egr-1 mRNA induction, as demonstrated earlier for c-myc mRNA in this system.
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Antígenos CD , Linfocitos B/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas Inmediatas-Precoces/biosíntesis , Interleucina-4/farmacología , Receptores de IgG/inmunología , Factores de Transcripción/biosíntesis , Anticuerpos Antiidiotipos/farmacología , Linfocitos B/inmunología , División Celular , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteína 1 de la Respuesta de Crecimiento Precoz , Expresión Génica , Humanos , Proteínas Inmediatas-Precoces/genética , Fragmentos Fab de Inmunoglobulinas/farmacología , Inmunoglobulina G/farmacología , ARN Mensajero/análisis , ARN Mensajero/aislamiento & purificación , Factores de Transcripción/genéticaRESUMEN
The physiologic relationships of plasma TSH, T4 and T3 levels measured every 20 min in seven healthy young men and one healthy young woman have been investigated. A nocturnal TSH surge was observed in all subjects on both nights of the 36-48 h baseline observation period. In males the maximum plasma TSH value occurred at 2300 h. The mean peak TSH level was 2.0 +/- 0.3 (se) muU/ml compared with a mean of 1.3 +/- 0.9 muU/ml for the entire baseline records of the 8 subjects. The effect of iv infusion of 32-1000 mug of somatostatin (SRIF) for 1 1/2-3 h was investigated in four of the male subjects during 2 or 4 consecutive nights following the control period. Temporal relationships between the hormonal fluctuations observed throughout the control period and during the nights of SRIF infusion were investigated using time series analysis and Student's t test. Rapid fluctuations of plasma T4 and T3 concentration were noted, even when corrected for changes in total protein concentration, with an average coefficient of variation of 10% for T3 and 12% for T4. No increment of plasma T4 or T3 followed the nocturnal TSH surge nor were the rapid fluctuations of the thyroid hormones altered by the TSH surge. SRIF infusion commencing at 2300 h suppressed the elevated TSH levels (P is less than 0.01) while similar infusions begun at 2100 h blocked the expected nocturnal TSH rise observed during control periods in male subjects. Plasma T4 and T3 levels were not significantly affected by the administration of SRIF. The relationship of the rapid plasma T4 and T3 variations to postural changes was investigated in four euthyroid male subjects. Serum levels of TSH, T4 and T3 and total protein were determined at 15 min intervals while postural changes were carefully monitored. The ratios of T4 and T3 to total protein were relatively stable (3-4% coefficient of variation) when the subjects were kept in a supine and motionless position. A 50 mug bolus infusion of T4 raised the basal T4 level by only 1-2 mug/dl. The data suggest that short-term fluctuation of plasma T4 and T3 result from changes in protein concentration due to hemodynamic responses to alteration of posture and physical activity and not to pulsatile secretion of T4 and T3.
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Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangre , Adulto , Ritmo Circadiano , Femenino , Humanos , Masculino , Radioinmunoensayo , Somatostatina/farmacología , Factores de TiempoRESUMEN
The relation of nyctohemeral variation in plasma TSH to sleep-wake cycles was examined in 10 normal young men who had their sleep polygraphically monitored and their blood sampled every 20 min for 24,36, or 48 h periods. Studies of normal sleepwake cycles in which sleep was allowed from the usual bedtime to 0630 h totalled 21 nights (night = 1840-0620 h) and their corresponding 16 days. TSH was measured by a sensitive RIA. On 17 nights, the mean nightly TSH significantly exceeded that of the day's and, on 18 nights, clear nyctohemerally maximal peaks in TSH were seen in the 2100-0100 h interval. Greater amplitude, duration and rhythmic repetition over several nights distinguished 2100-0100 h maxima from a background of persistent briefly episodic release. These nyctohemeral peaks were pre-sleep maxima, as rises uniformly began, and on 15 nights, the peaks occurred prior to the onset of sleep. The peaks clustered within the 30 min just before (12 nights) or after (3 nights) entry into sleep. TSH release then declined across sleep. Other evidence suggestive of an inhibitory influence in sleep upon TSH release was that sleep began early on the 3 nights without clear 2100-0100 h TSH maxima and that the mean 2100-0100 h TSH peak was significantly reduced when sleep began prior to the usual 2300-0000 h interval and significantly increased when the onset of sleep was delayed or postponed. After a 24 h baseline, 4 men underwent phase-reversal of their sleep-wake cycles for 48 h, in which sleep was shifted to the 1100-1830 h interval. On the first wakeful night of reversal, the 2100-0100 h peak began normally, but, in the absence of sleep, the enhanced TSH release then simply continued across this night, delaying achievement of the nyctohemeral maxima. On the second wakeful night of reversal, the maximum in mean TSH lay in the same 0400-0600 h interval as that of first reversal night, and the mean 2100-0100 h peak was no longer evident. The TSH of the second 24 h of reversal also was significantly reduced, suggestive of a negative feedback effect of enhanced release of the first reversal day. No shift of basal pre-sleep TSH peaks to the 0900-1300 h interval or of sleep-enhanced TSH release was seen during reversal. Thus, despite the persistence of TSH's nyctohemeral rhythmicity across acute sleep-wake reversal, its pattern changed significantly in relation to shifts in sleep. We currently view these results as consistent with the origin of TSH's nyctohemeral rhythmicity in a circadian mechanism whose expression is subject to modulation by the inhibitory influences of feedback and sleep.
Asunto(s)
Ritmo Circadiano , Sueño , Tirotropina/sangre , Vigilia , Retroalimentación , Humanos , Masculino , Hipófisis/fisiología , Factores de TiempoRESUMEN
Ten prepubertal boys who ranged in age from 6 11/12 to 14 2/12 years were studied for 2 consecutive nights. The subjects went to sleep at their usual times and sleep patterns were monitered polygraphically. Each night blood samples were drawn every 30 min from 1800 to 0600 h and plasma LH and testosterone (T) levels were measured on each sample. During evening wakefulness the mean LH (range 2.8-5.1 mIU/ml) and T (range 31-116 pg/ml) levels were in the normal prepubertal range for each subject. In the 5 youngest subjects (age 6 11/12 to 10 8/12 years) the mean hormone levels during sleep were significantly higher than the wakeful levels in 2 of 9 and 0 of 9 study nights for LH and T, respectively. In contrast, in the older prepubertal boys (age 13 2/12 to 14 2/12 years) the mean levels during sleep were significantly higher than wakeful values during 8 of 9 and 5 of 9 study nights for the same respective hormones. These data suggest that in young prepubertal subjects the sleep related rises of LH and T are either absent or not discernible in the peripheral blood. The prepubertal pattern of sleep-entrained LH and T release may be seen in prepubertal boys approaching the time of puberty and these hormonal rhythms are antecedent to the physical changes of puberty.
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Hormona Luteinizante/sangre , Pubertad , Sueño/fisiología , Testosterona/sangre , Vigilia/fisiología , Adolescente , Estatura , Peso Corporal , Niño , Ritmo Circadiano , Humanos , MasculinoRESUMEN
Half-hourly sampling of plasma TSH was done across 3 days in four normal young men. Sleep was denied for 64 h from 0700 h on awakening from accommodation sleep until polygraphic sleep was resumed at 7100 h of the third day (D3) such that 2 consecutive nights of usual 2300-0700 h sleep were missed. This protocol allowed examination of any modulatory effects on the daily patterns in TSH concentrations during sleep deprivation on D1-2 (1100-3500, 3500-5900 h) or during resumption of usual nightly sleep on D3 (5900-8300) compared to that of a previously studied group of normal young men. The circadian nature of the daily TSH waveform was evidenced by its daily repetition within a subject both basally and during D1-2 sleep deprivation and by its synchronization within the basal, deprived, or resumed sleep days. The peaks in each subject's daily TSH patterns on D1-2 were consistently longer, and the daily maxima and cosine acrophases on D1-2 were consistently later than those on D3 when basal sleep was resumed. About half the daily TSH concentration maxima and daily cosinor amplitudes on D1-2 were greater than those of the respective sleep-resumed TSH patterns of D3. Both the group mean TSH patterns and the cosinor 95% confidence ellipses also indicated the daily peak in the TSH waveform to be significantly longer, later, and larger during D1-2 sleep deprivation than during the basal or D3 periods. These results indicate that significant alteration of the daily TSH waveform can occur in response to absence of sleep and are compatible with the existence of an inhibitory effect in early nightly sleep on TSH release. The TSH patterns during the 1700-2300 h intervals of rising TSH levels were congruent in the basal, deprived, and resumed sleep periods. Prompt reversion to the basal TSH pattern also occurred when sleep was resumed on D3. Both of these observations suggest the alteration in TSH waveform during sleep deprivation to have arisen from an inhibitory effect in sleep rather than from a change in period or phase of a generating oscillator.
Asunto(s)
Ritmo Circadiano , Privación de Sueño , Tirotropina/sangre , Adulto , Humanos , Masculino , Factores de TiempoRESUMEN
On 2 consecutive nights, plasma LH, FSH and testosterone (T) were measured every20 min for 12 h during evening wakefulness and polygraphic sleep in 5 pairs of male monozygotic twins in pubertal stages 1-4, and in a male dizygotic also studied in 3 twins. During sleep, significant enhancement of episodic LH release was seen on 16 of 18 nights on the stage 1-4 twins. During wakefulness, minimal episodic LH release was observed in the stage 1-3 twins, which then gradually increased in the more mature twins, until finally the significant sleep-wake difference in mean LH was lost in the stage 5 male. Testosterone also rose significantly in sleep on 19 of 20 study nights in the stage 1-5 twins. In the early pubertal twins this nocturnal rise in T was small, but in the midpubertal pairs it was profound, as peaks in T occurred which lay in the normal range for adult males. In these less mature twins the majority of the episodic secretion of T also was limited to sleep. In wakefulness, the T levels gradually increased across puberty until, in the stage 5 twin, wakeful peaks in T finally reached the adult male range. In the midpubertal twins, a close temporal relationship was seen between initiation of sleep-enhanced LH release and the subsequent initial rise in T (mean lag time 29.1 min). In the stage 5 twin, this episodic LH-T relationship persisted into wakefulness where the largest increments in T were seen just prior to sleep onset. Evidence of sleep-enhanced FSH release was more equivocal, and was limited mainly to pubertal stage 1 and 3 pairs. Similarities in hormonal patterns were seen within the monozygotic twin pairs and probably contributed to the parallel progress in puberty of the pair. Thus, sleep-wake rhythmicity in release of gonadotropins, particularly LH and thereby of testosterone, was seen to evolve transiently in twin boys across puberty. The existence of such rhythmicity suggests that a fundamental, sleep-entrained CNS mechanism plays an important, if not a dominant, role in sexual maturation in boys.
Asunto(s)
Hormona Folículo Estimulante/sangre , Hormona Luteinizante/sangre , Pubertad , Testosterona/sangre , Gemelos , Adolescente , Niño , Ritmo Circadiano , Femenino , Humanos , Masculino , Embarazo , Sueño , Gemelos Dicigóticos , Gemelos Monocigóticos , VigiliaRESUMEN
A sensitive RIA for parathyroid hormone (PTH) with specificity for the carboxy-terminal region of the hormone was developed and applied to clinical studies. The assay was useful in identifying patients with chronic hyperparathyroid states, such as primary and secondary hyperparathyroidism. In addition, the assay could detect acute changes in PTH seen during calcium, pentagastrin, and EDTA infusions and after parathyroidectomy. These studies demonstrated that an immunoassay with predominant specificity for the carboxy-terminal fragment of PTH can be used to evaluate acute as well as chronic changes in hormone secretion.
Asunto(s)
Hormona Paratiroidea/metabolismo , Calcitonina/sangre , Calcio/sangre , Humanos , Hiperparatiroidismo/sangre , Cinética , Glándulas Paratiroides/cirugía , Hormona Paratiroidea/sangre , Pentagastrina , Radioinmunoensayo/métodos , Valores de ReferenciaRESUMEN
The long term effects of nightly dexamethasone administration on basal levels and diurnal fluctuations of circulating gonadotropins, androgens, and cortisol were studied by frequent sampling in four women with polycystic ovarian disease and a similar number of normal women. Basal LH, testosterone, and androstenedione levels were elevated in the patients with polycystic ovarian disease. There were significant diurnal variations of all steroids measured in both groups, with the exception of androstenedione and androstenediol in the polycystic ovarian disease and control subjects, respectively. Nightly dexamethasone administration for 1 month resulted in marked suppression of dehydroepiandrosterone, androstenediol, and cortisol. For testosterone the mean percent decreases of the 24-h transverse means were 15% and 46% for the polycystic ovarian disease and normal subjects, respectively. For androstenedione the mean percent decreases were only 7% and 20%, respectively. The diurnal variation of all steroids disappeared with dexamethasone. These results support the concept that in patients with polycystic ovarian disease the majority of delta 5-androgens is adrenal while the preponderance of elevated testosterone and androstenedione is ovarian in origin. These results do not support the use of long term dexamethasone as an effective agent in suppressing the elevated levels of testosterone and androstenedione in patients with this disease.