SUM M A R YGonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. I t is still unknown how puberty in humans, occurring during the early years of the second decade of life, is initiated. 1 The hallmark of puberty is increased secretion of the gonadotropins, luteinizing hormone (LH) and folliclestimulating hormone (FSH), which act in concert to stimulate the gonads to drive sex-hormone secretion and gametogenesis. The production of gonadotropins from pituitary gonadotropic cells is controlled by the pulsatile delivery of GnRH. Inactivating mutations in the genes encoding GNRH1 2 or the GNRH receptor (GNRHR) 3 give rise to normosmic idiopathic hypogonadotropic hypogonadism in humans. 4 However, GnRH neurons lack sex-steroid receptors. This suggests the existence of GnRH-regulating neurons, which would mediate this effect.A major breakthrough in identifying such candidate neurons was the finding that inactivating mutations in genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), the cognate receptor for a hypothalamic peptide, kisspeptin, resulted in pubertal failure. 4,5 More recently, mutations in TAC3 or TACR3 (encoding neurokinin B and its receptor, respectively) were shown to result in the same phenotype. 6 Kisspeptin and neurokinin B are coexpressed, along with dynorphin, in sex-hormone-responsive neurons in the arcuate nucleus (infundibular nucleus in primates), and their coordinated activity appears to regulate GnRH secretion. 7 Gene defects associated with normosmic idiopathic hypogonadotropic hypogonadism have been described in all the neuropeptides and receptors identified as stimulators of GnRH except for the kisspeptin gene (KISS1).Although Kiss1-and Kiss1r-knockout mouse models largely produce phenocopies (i.e., affected noncarriers) of human normosmic idiopathic hypogonadotropic hypogonadism resulting from inactivating mutations of KISS1R, there is evidence of remarkable residual activity of the hypothalamic-pituitary-gonadal axis.

SUM M A R YGonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. I t is still unknown how puberty in humans, occurring during the early years of the second decade of life, is initiated. 1 The hallmark of puberty is increased secretion of the gonadotropins, luteinizing hormone (LH) and folliclestimulating hormone (FSH), which act in concert to stimulate the gonads to drive sex-hormone secretion and gametogenesis. The production of gonadotropins from pituitary gonadotropic cells is controlled by the pulsatile delivery of GnRH. Inactivating mutations in the genes encoding GNRH1 2 or the GNRH receptor (GNRHR) 3 give rise to normosmic idiopathic hypogonadotropic hypogonadism in humans. 4 However, GnRH neurons lack sex-steroid receptors. This suggests the existence of GnRH-regulating neurons, which would mediate this effect.A major breakthrough in identifying such candidate neurons was the finding that inactivating mutations in genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), the cognate receptor for a hypothalamic peptide, kisspeptin, resulted in pubertal failure. 4,5 More recently, mutations in TAC3 or TACR3 (encoding neurokinin B and its receptor, respectively) were shown to result in the same phenotype. 6 Kisspeptin and neurokinin B are coexpressed, along with dynorphin, in sex-hormone-responsive neurons in the arcuate nucleus (infundibular nucleus in primates), and their coordinated activity appears to regulate GnRH secretion. 7 Gene defects associated with normosmic idiopathic hypogonadotropic hypogonadism have been described in all the neuropeptides and receptors identified as stimulators of GnRH except for the kisspeptin gene (KISS1).Although Kiss1-and Kiss1r-knockout mouse models largely produce phenocopies (i.e., affected noncarriers) of human normosmic idiopathic hypogonadotropic hypogonadism resulting from inactivating mutations of KISS1R, there is evidence of remarkable residual activity of the hypothalamic-pituitary-gonadal axis.

Background and Purpose. Few randomized controlled studies have examined the effects of exercise in patients with ankylosing spondylitis (AS). This study investigated the effects of a 12-week, multimodal exercise program in patients with AS. Subjects. A convenience sample of 30 patients with AS (18 male, 12 female), with a mean age of 34.9 years (SD=6.28), participated in the study. Twenty-six subjects were classified as having stage I AS and 4 subjects were classified as having stage II AS according to the modified New York Criteria. Methods. This study was a randomized controlled trial. Subjects were assigned to either a group that received an exercise program or to a control group. The exercise program consisted of 50 minutes of multimodal exercise, including aerobic, stretching, and pulmonary exercises, 3 times a week for 3 months. Subjects in both groups received medical treatment for AS, but the exercise group received the exercise program in addition to the medical treatment. All subjects received a physical examination at baseline and at 12 weeks. The examinations were conducted under the supervision of a physician who specialized in physical medicine and rehabilitation and included the assessment of spinal mobility using 2 methods: clinical measurements (chin-to-chest distance, Modified Schober Flexion Test, occiput-to-wall distance, finger-to-floor distance, and chest expansion) and inclinometer measurements (gross hip flexion, gross lumbar flexion, and gross thoracic flexion). In addition, vital capacity was measured by a physiologist, and physical work capacity was evaluated by a doctorally prepared exercise instructor. Results. The measurements of the exercise group for chest expansion, chin-to-chest distance, Modified Schober Flexion Test, and occiput-to-wall distance were significantly better than those of the control group after the 3-month exercise period. The spinal movements of the exercise group improved significantly at the end of exercise program, but those of the control group showed no significant change. In addition, the results showed that the posttraining value of gross thoracic flexion of the exercise group was significantly higher than that of the control group. Physical work capacity and vital capacity values improved in the exercise group but decreased in the control group. Discussion and Conclusion. In this study, a multimodal exercise program including aerobic, stretching, and pulmonary exercises provided in conjunction with routine medical management yielded greater improvements in spinal mobility, work capacity, and chest expansion.

Oocytes grow within ovarian follicles, and only gain the ability to complete meiosis when they are nearly fully grown. We have found that both of the major types of intracellular pH regulatory mechanisms in the mammal-the Na+/H+ and HCO3-/Cl- exchangers-were essentially inactive in mouse oocytes over most of the course of their growth. However, as oocytes approached full size, Na+/H+ and HCO3-/Cl- exchangers became simultaneously active, and, at the same time, the intracellular pH of isolated oocytes increased sharply by about 0.25 pH unit. This activation of intracellular pH regulatory mechanisms and increase in pH occurred coincident with the acquisition of meiotic competence. The activation of pH regulatory mechanisms during oocyte growth represents a previously unknown milestone in the development of the capacity of the oocyte to function independently upon ovulation.

The objective of this study was to determine if exposure to divalent cations, Cd(2+), Ni(2+), and Co(2+) would lead to malformations in Xenopus laevis embryos, and whether addition of Mg(2+) and Zn(2+); separately and in combination, would reduce their toxicity and teratogenicity on the embryos of Xenopus laevis as assessed by 96-h FETAX tests. Results indicate that exposure to Cd(2+), Ni(2+) or Co(2+) lead to an increase in toxicity and teratogenicity in embryos, whereas Mg(2+), Zn(2+), or a combination of them reduced the toxic and teratogenic effects of these divalent cations. Modulation of Cd(2+), Ni(2+) or Co(2+) toxicity and teratogenicity by Mg(2+) and Zn(2+), varied with the metal. Zn(2+) was observed to be a better suppressor of Co(2+) toxicity and teratogenicity than Mg(2+). In contrast, Ni(2+), and Cd(2+) teratogenicity was reduced more prominently by Mg(2+). On the other hand, combination of Mg(2+) and Zn(2+) showed potentialization effect on all divalent cation toxicity and teratogenicity. We concluded that Mg(2+) and Zn(2+) reduced the toxicity and teratogenicity of Cd(2+), Ni(2+), Co(2+).