RESUMEN
Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL-receptor pathway through a different mechanisms which remains to be determined.
Asunto(s)
Butanoles/farmacología , Colesterol/sangre , Hidroxibenzoatos/farmacología , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Hipolipemiantes/farmacología , Simvastatina/farmacología , Adolescente , Adulto , Anciano , Anticolesterolemiantes/farmacología , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/orina , Masculino , Ácido Mevalónico/orina , Persona de Mediana Edad , Método Simple Ciego , Triglicéridos/sangreRESUMEN
1. Plasma concentrations of luteinising hormone (LH), comb size and body weight were measured between 46 and 208 d of age in intact and castrated cockerels from lines of selected and control Australorp domestic chickens. The selected line had been selected for increased rate of lay by reducing oviposition intervals within sequences. The cockerels were reared and maintained on 15.25 h light/d. 2. Concentrations of plasma LH in the intact control cockerels were low in the 'immature' phase (less than 100 d old) and increased during the 'mature' phase (older than 175 d) with a peak occurring when the testes are beginning to grow at the onset of the 'mature' phase. In comparison with the control line of cockerels, the selected line had significantly higher plasma LH concentrations at the onset of the 'mature' phase. Selection had no effect on the mean concentration of plasma LH in either the immature phase or a few weeks after the onset of the mature phase. 3. There was no effect of selection in sibling females for higher rates of lay on changes in comb size or body weight during sexual maturation in the intact cockerels. 4. Castration at 45-46 d of age resulted in increased plasma LH concentrations and no comb growth. Plasma LH concentration increased progressively between 40-208 d. There was no difference between the two lines of cockerels in plasma LH concentration or rate of body growth after castration. 5. It is concluded that selection of females for a change in the rate of egg production has resulted in increased plasma LH concentrations in sibling males around the onset of sexual maturation. Selection appears to have caused this effect by altering an unidentified component of the inhibitory feedback mechanism which controls the tonic secretion of LH.
Asunto(s)
Peso Corporal/genética , Cruzamiento , Pollos/genética , Hormona Luteinizante/sangre , Maduración Sexual/genética , Animales , Pollos/sangre , Pollos/crecimiento & desarrollo , Cresta y Barbas/crecimiento & desarrollo , Femenino , Masculino , Ovulación/genéticaRESUMEN
Crossbred ewes exposed to long days for 46 months prior to photoperiod reversal showed no alteration in the duration or amplitude of the circulating melatonin peak between 24 and 46 months of continuous long day exposure. By 3 months after photoreversal to short days, both the amplitude and duration of the peak had adapted to the new scotophase. In short day treated ewes, the melatonin peak was abolished by 46 but not 24 months of short day exposure, and was not fully restored in all ewes 3 months after photoreversal. Mean prolactin levels over 24 h remained high up to 46 months of long day treatment, and declined 3 months after short day exposure. Conversely, mean prolactin levels remained low up to 46 months of short day treatment, increasing 3 months after exposure to long days. Thus: (i) depletion of the melatonin-synthesizing capability of the ovine pineal gland by prolonged exposure to long nights is not completely reversed after 3 months of continuous long day exposure, and (ii) a nocturnal melatonin peak is not essential for maintenance of plasma prolactin levels under these conditions.
Asunto(s)
Luz , Melatonina/sangre , Periodicidad , Prolactina/sangre , Ovinos/sangre , Animales , Femenino , Estaciones del Año , Factores de TiempoRESUMEN
Pineal beta-adrenoceptor density and affinity in ewes are modified in a season-dependent manner by gonadal steroids and by the sympathetic innervation of the gland. The present study was undertaken to relate the steroidal effects on the receptors to post receptor endocrine events, and to investigate the influence of the sympathetic innervation of the pineal gland on these events. Plasma melatonin and prolactin profiles were determined during anestrus and during the normal breeding season in ewes subjected to sympathetic denervation of the pineal and/or a range of steroid-related treatments. Wherever valid comparisons could be drawn between effects of the treatments on beta-adrenoceptor variables and on circulating hormone levels, similar effects were noted. Further, ganglionectomy influenced hormone profiles similarly to estradiol under all conditions tested. It appears that gonadal steroids (estradiol) and the sympathetic neurotransmitter noradrenaline have opposing actions on prolactin levels, just as they have on pineal beta-adrenoceptor binding affinity. These findings suggest that steroid-mediated changes in receptor number and affinity are reflected in post receptor endocrine events. In addition, other factors (e.g. photoperiodic information transmitted via the sympathetic innervation) also play important roles in the regulation of the observed hormonal profiles. A steroid-mediated feedback regulation of pituitary prolactin release, partly direct and partly via pineal melatonin release, is suggested.
Asunto(s)
Melatonina/sangre , Glándula Pineal/fisiología , Prolactina/sangre , Estaciones del Año , Ovinos/fisiología , Anestro/sangre , Animales , Ritmo Circadiano , Estradiol/farmacología , Femenino , Ganglios Simpáticos/fisiología , Ganglionectomía , Ovariectomía , Receptores Adrenérgicos beta/fisiología , Sistema Nervioso Simpático/fisiologíaRESUMEN
The results of a seasonal study of the regulation by steroids of ovine pineal beta-adrenoceptors are reported. The effects of ovariectomy, steroid implants and superior cervical ganglionectomy were investigated in Merino ewes. The results confirm earlier observations showing a seasonal variation in the sensitivity of the receptors to modification by gonadal steroids. A marked difference in receptor density and affinity between the follicular and luteal phases of the estrous cycle is shown for the first time, a difference which can be modified by appropriate steroid-related treatments. A season-dependent antagonism between the sympathetic innervation of the gland (presumably acting via the neurotransmitter noradrenaline) and gonadal steroids in the regulation of ovine pineal beta-adrenoceptor function is also shown.
Asunto(s)
Glándula Pineal/fisiología , Receptores Adrenérgicos beta/fisiología , Animales , Estradiol/fisiología , Estro/fisiología , Femenino , Ganglionectomía , Ovariectomía , Progesterona/sangre , Estaciones del Año , OvinosRESUMEN
1. Haemodynamic parameters and tissue blood flow rates were measured in two groups of five sheep infused I.V. for 24 h with either saline or 128.6 micrograms mouse epidermal growth factor (mEGF) kg-1 body weight. Measurements were made preinfusion and at +3, +12, +24, +27 and +48 h. We wished to assess relationships between blood flow rates and known functional changes in various organs during EGF treatment, especially any relationship between skin blood flow rate and the known depilatory effects of the protein in sheep. 2. Cardiac output increased and total peripheral resistance and mean arterial pressure decreased during and after infusion in the mEGF-treated group relative to the control group. 3. The greatest increase in blood flow rates occurred in woolled skin (+500%) during mEGF infusion, a result which in itself may have been disparate with the known depilatory effects of EGF. The mucosas of the alimentary tract (except abomasum) and the submaxillary and sublingual salivary glands also showed vasodilatation. 4. There were short-term increases in pituitary and adrenal gland blood flow that may have been associated with the corticotrophin-releasing factor properties of EGF. Flow in the thyroids showed the greatest increase post-infusion when thyroid hormone metabolism may have been reverting to normal. Blood flow rates decreased in the pancreas and perirenal fat. 5. Our general conclusion was that mEGF had specific vasodilator effects in the skin, the thyroid, submaxillary and sublingual glands and the mucosas of most of the alimentary tract.
Asunto(s)
Factor de Crecimiento Epidérmico/farmacología , Hemodinámica/efectos de los fármacos , Animales , Glándulas Endocrinas/irrigación sanguínea , Remoción del Cabello , Masculino , Ratones , Flujo Sanguíneo Regional/efectos de los fármacos , Ovinos , Piel/irrigación sanguínea , Vísceras/irrigación sanguíneaRESUMEN
In the present study, two raters, a psychologist and a nurse, each made five independent ratings of 30 different video-recorded patient-examinations. Having thus excluded patient fluctuation, individual-rater consistency and between-rater agreement over the 6 weeks of the study are examined. While between-rater agreement was apparently being maintained, mean AIMS scores steadily increased. In the hands of these raters, AIMS items 2 and 4 emerged as very reliable, while items 1, 6, and 7 showed high variability. Some patients appeared to be hard to rate. Differences between the study raters and the author JB highlight the issue: how reproducible is an AIMS rating?
Asunto(s)
Discinesia Inducida por Medicamentos/diagnóstico , Examen Físico , Discinesia Inducida por Medicamentos/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , MovimientoRESUMEN
The possibility that egg production in broiler breeder hens may be increased by selection for reduced oviposition interval under continuous light was investigated by comparing the pattern of pre-ovulatory releases of plasma luteinising hormone (LH) and the associated ovipositions in the same broiler hens maintained under normal cycles (15.25 h light/d) or continuous light. The lighting conditions had no effect on plasma concentrations of LH before and at the pre-ovulatory LH peak in first, mid-sequence or terminal ovulatory cycles. Plasma LH concentrations were similar during first, mid-sequence and terminal ovulatory cycles. Mid-sequence oviposition intervals and the interval between a mid-sequence LH peak and its associated oviposition were longer under continuous light than under normal lighting. Pre-ovulatory releases of LH occurred during a restricted period of day in both lighting conditions. Under continuous lighting they were probably entrained by the daily pattern of restricted feeding. Any selection programme for reduced oviposition interval under continuous lighting in broiler breeder hens should take into account the entraining effects of the daily pattern of feeding.
Asunto(s)
Pollos/fisiología , Luz , Hormona Luteinizante/sangre , Oviposición , Ovulación , Animales , Femenino , Factores de TiempoRESUMEN
Plasma luteinising hormone (LH) concentrations were measured during the ovulatory cycle in lines of Australorps and White Leghorns selected for reduced oviposition interval and maintained under continuous light and noise. Selection significantly increased plasma LH concentrations in mid-sequence ovulatory cycles of Australorps but not in the White Leg-horns. Selection in the Australorps apparently increased the rate of ovarian follicular maturation, resulting in more frequent LH peaks. The effect of selection on plasma LH concentrations is a function of the lighting condition to which the hens are exposed.
Asunto(s)
Pollos/fisiología , Ritmo Circadiano , Hormona Luteinizante/sangre , Oviposición , Ovulación , Animales , Femenino , LuzRESUMEN
The effects of selection under continuous light for reduced oviposition interval within a sequence of eggs on plasma luteinising hormone (LH) concentrations during the ovulatory cycle were investigated in lines of Australorps and White Leghorns maintained on a 24-h light:dark cycle. Selection did not significantly alter LH concentrations during mid-sequence cycles in either breed. In the control lines, concentrations were higher in the Australorps than in the White Leghorns before and at peak in mid-sequence cycles. The increase in egg production resulting from selection was associated with an advance in the mean time of lay of mid-sequence eggs in both breeds and, in the Australorps, with more pre-ovulatory LH peaks being initiated at the beginning of the open period of the ovulatory cycle. Selection reduced the time an egg spends in the oviduct and, in the Australorps, significantly reduced the interval between a pre-ovulatory LH peak and the oviposition of the egg currently in the shell gland. We suggest that selection under continuous light for reduced oviposition interval increased the rate of ovarian follicular maturation by a mechanism which did not involve an increase in pre-ovulatory concentration of plasma LH in a 24-h light-dark cycle.
Asunto(s)
Pollos/fisiología , Luz , Hormona Luteinizante/sangre , Oviposición , Ovulación , Selección Genética , Animales , Pollos/sangre , Pollos/genética , FemeninoRESUMEN
The proliferative activities of germinative cells of the wool follicles and the epidermis have been determined in sheep treated with epidermal growth factor (EGF). Infusions of 0.17-0.72 mg EGF/kg metabolic body weight (MBW) for 28 h resulted in marked declines in the mitotic indices (MI) of the follicle bulb cell populations 24 h after the beginning of treatment, the lowest values being recorded at 48 h. Follicular activity subsequently recovered and the MI returned to preinfusion levels after 3-8 days. The inhibition of fiber production resulting from the decline in bulb cell division caused the development of a break in the fleece. By contrast, the MI of the peripheral cells of the sebaceous gland acini and the basal cells of the epidermis increased after EGF treatment, reaching peaks 48-72 h after the beginning of infusion. The degree to which all of these responses were observed appeared to be approximately correlated with the amount of EGF administered.
Asunto(s)
Factor de Crecimiento Epidérmico/farmacología , Epidermis/efectos de los fármacos , Cabello/efectos de los fármacos , Lana , Animales , Peso Corporal , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Epidérmicas , Epidermis/patología , Cabello/citología , Cabello/patología , Masculino , Índice Mitótico/efectos de los fármacos , Ovinos , Factores de TiempoRESUMEN
The relative activities of endogenous DNA-bound RNA polymerases have been quantified in individual blastocysts of ovariectomized mice during delayed implantation and following oestradiol-induced resumption of development. Incorporation of [3H]UMP into an acid insoluble product was detected in the cell nuclei by autoradiography. Nucleolar polymerase I and the nucleoplasmic polymerase II were present in delayed blastocysts harvested from progesterone- or oil-treated ovariectomized females. However, the activities of these enzymes were considerably reduced in comparison with those of blastocysts of intact mice. A stimulation of transcription appeared to occur 18 h after oestradiol benzoate injection of progesterone-treated females but more rapidly in blastocysts from oil-treated females. The data indicate that progesterone may retard the rate of oestradiol-induced reactivation in delayed blastocysts.