Pubertal development of estradiol-induced hypothalamic progesterone synthesis.

In females, a hallmark of puberty is the luteinizing hormone (LH) surge that triggers ovulation. Puberty initiates estrogen positive feedback onto hypothalamic circuits, which underlie the stimulation of gonadotropin releasing hormone (GnRH) neurons. In reproductively mature female rodents, both estradiol (E2) and progesterone (P4) signaling are necessary to stimulate the surge release of GnRH and LH. Estradiol membrane-initiated signaling facilitates progesterone (neuroP) synthesis in hypothalamic astrocytes, which act on E2-induced progesterone receptors (PGR) to stimulate kisspeptin release, thereby activating GnRH release. How the brain changes during puberty to allow estrogen positive feedback remains unknown. In the current study, we hypothesized that a critical step in estrogen positive feedback was the ability for estradiol-induced neuroP synthesis. To test this idea, hypothalamic neuroP levels were measured in groups of prepubertal, pubertal and young adult female Long Evans rats. Steroids were measured with liquid chromatography tandem mass spectrometry (LC-MS/MS). Hypothalamic neuroP increases from pre-puberty to young adulthood in both gonad-intact females and ovariectomized rats treated with E2. The pubertal development of hypothalamic E2-facilitated progesterone synthesis appears to be one of the neural switches facilitating reproductive maturation.

Carnitine levels in skeletal muscle, blood, and urine in patients with primary carnitine deficiency during intermission of L-carnitine supplementation.

BACKGROUND: Primary carnitine deficiency (PCD) is a disorder of fatty acid oxidation with a high prevalence in the Faroe Islands. Only patients homozygous for the c.95A>G (p.N32S) mutation have displayed severe symptoms in the Faroese patient cohort. In this study, we investigated carnitine levels in skeletal muscle, plasma, and urine as well as renal elimination kinetics before and after intermission with L-carnitine in patients homozygous for c.95A>G. METHODS: Five male patients homozygous for c.95A>G were included. Regular L-carnitine supplementation was stopped and the patients were observed during five days. Blood and urine were collected throughout the study. Skeletal muscle biopsies were obtained at 0, 48, and 96 h. RESULTS: Mean skeletal muscle free carnitine before discontinuation of L-carnitine was low, 158 nmol/g (SD 47.4) or 5.4% of normal. Mean free carnitine in plasma (fC0) dropped from 38.7 (SD 20.4) to 6.3 (SD 1.7) µmol/L within 96 h (p < 0.05). Mean T 1/2 following oral supplementation was approximately 9 h. Renal reabsorption of filtered carnitine following oral supplementation was 23%. The level of mean free carnitine excreted in urine correlated (R (2) = 0.78, p < 0.01) with fC0 in plasma. CONCLUSION: Patients homozygous for the c.95A>G mutation demonstrated limited skeletal muscle carnitine stores despite long-term high-dosage L-carnitine supplementation. Exacerbated renal excretion resulted in a short T 1/2 in plasma carnitine following the last oral dose of L-carnitine. Thus a treatment strategy of minimum three daily separate doses of L-carnitine is recommended, while intermission with L-carnitine treatment might prove detrimental.

Hypothalamic galanin-like peptide rescues the onset of puberty in food-restricted weanling rats.

Galanin-like peptide (GALP) is a known mediator of metabolism and reproduction; however, the role that GALP plays in the onset of puberty is unknown. First, we tested the hypothesis that central GALP administration could rescue puberty in food-restricted weanling rats. GALP treatment in food-restricted rats of both sexes rescued the timing of the onset of puberty to that seen in ad lib. fed controls. Second, we tested whether GALP translation knocked-down in ad lib. fed, prepubertal rats would alter the timing of puberty. Knock-down females, but not males, showed a significant (P < 0.01) delay in the onset of puberty compared to controls. Third, we sought evidence that the role of GALP in pubertal onset is mediated by the kisspeptin system. In situ hybridisation analyses showed a significant (P < 0.01) reduction in Kiss1 mRNA within the hypothalamic arcuate nucleus in food-restricted rats compared to ad lib. fed controls and this reduction was prevented with i.c.v. GALP administration. Furthermore, analyses of Fos-immunoreactivity (-IR) after i.c.v. GALP treatment did not elicit Fos-IR within any kisspeptin neurones, nor are GALP and kisspeptin peptides or mRNA colocalised. These data demonstrate that hypothalamic GALP infusion maintained the onset of puberty in food-restricted weanling rats, although probably not via direct innervation of kisspeptin neurones.

Heat shock factor activation in human muscles following a demanding intermittent exercise protocol is attenuated with hyperthermia.

AIM: The present study investigated whether increased activation of heat shock factors (HSF) following exercise relates primarily to the increased muscle temperature or to exercise in general. METHODS: Six subjects completed 40 min of intermittent cycling (15s:15s exercise:recovery at 300 +/- 22 W) at an ambient temperature of either 20.0 +/- 1.3 or 40.3 +/- 0.7 degrees C. Muscle biopsies were taken prior to and immediately following the exercise protocol with samples analysed for HSF DNA binding by electrophoretic mobility shift assay. RESULTS: Exercise at 40 degrees C resulted in significantly increased oesophageal (39.3 +/- 0.2 degrees C) and muscle temperature (40.0 +/- 0.2 degrees C) at the end of the exercise protocol compared with 20 degrees C (oesophageal, 38.1 +/- 0.1 degrees C; muscle, 38.9 +/- 0.2 degrees C). However, an increased DNA binding of HSF was not evident following exercise at 40 degrees C (reduced by 21 +/- 22%) whereas it increased by 29 +/- 51% following exercise at 20 degrees C. CONCLUSION: It appears that increased temperature is not the major factor responsible for activation of HSF DNA binding.

Pallido-Luysio-Nigral atrophy revealed by rapidly progressive hemidystonia: a clinical, radiologic, functional, and neuropathologic study.

Pallido-luysio-nigral atrophy (PLNA) is a rare neurodegenerative disease in which the clinical and radiologic correlates have not yet been clearly established. A 62-year-old man insidiously developed dystonic postures, choreoathetoid movements, slowness, and stiffness, which initially affected the right hand and foot and progressively spread to the entire right side. T2-weighted magnetic resonance imaging showed increased signal intensity in both left and right medial pallida and in the left substantia nigra. Tests using HMPAO-SPECT and FDG-PET demonstrated left cortical hyperperfusion and hypermetabolism, whereas the left lenticular nucleus was slightly hypometabolic. At age 65, abnormal movements and postures involved all four limbs and the axis causing major gait disturbances, and facial and bulbar muscles atrophied resulting in dysarthria, dysphagia, and impaired breathing. Diffuse amyotrophy and fasciculations also appeared. Death occurred at age 66, 4 years after onset. At autopsy, severe bilateral neuronal loss and gliosis restricted to the pallidum, the subthalamic nucleus, the substantia nigra, and the hypoglossal nucleus were noted, accounting for the diagnosis of PLNA with lower motor neuron involvement. Progressive hemidystonia with adult onset represents an unusual clinical presentation for this disorder. Moreover, this observation indicates that a diagnosis of PLNA should be considered for specific magnetic resonance imaging, SPECT, and/or PET data, and suggests that in PLNA, pallidal dysfunction might play a key role in the dystonic presentation.