Serum prolactin levels in the prepubertal period in male and female rats. Control by photoperiod and gonadal status and relationship to puberty onset

In female rats there is a temporary afternoon rise in prolactin during the transition from the weaning period to the period just preceding puberty. The purpose of this study was to determine whether a similar tempopary prolactin peak occurs in males at the same age and to assess the dependence of this elevation upon gonadal status and light cycle cues. Blood samples were collected at 08.00, 20.00 and 02.00 h colony time during the prepubertal period. A prolactin peak occurred only at 28 days of age in males. This peak did not occur in either males or females gonadectomized at 22 days of age Animals reared in constant light from weaning (21 days of age) failed to shoow an afternoon prolactin peak at 28 or 32 days of age. Animals in constant light from weaning age showed maximum prolactin at 08.00 h on days 28, 30, and 32 with minimum levels at 20.00 h. It can be concluded that both males and females exhibit a transient peak of prolactin during the prepubertal period. This peak was abolished by gonadectomy and by constant light, suggesting that it is an expression of a clock mechanism sensitive to photoperiod and gonadal steroids. The prolactin peak does not appear to correlate with pubertal onset per se since both vaginal opening and balanopreputial separation are precocious in constant light despite the fact that the prolactin peak is abolished in the population as a whole.     

Serum vitamin D metabolites are not related to growth rate,bone mineral content,or serum alkaline phosphatase in male puberty

Summary Twenty boys were followed during their puberty for about 2 years with examinations every third month. At each examination we determined serum concentrations of 25OHD₃, 1,25(OH)₂D₃, 24,25(OH)₂D₃, 25.26(OH)₂D₃,alkaline phosphatase (AP) and testosterone together with bone mineral content (BMC) at the distal forearm. Highly significant increases in both BMC (P<0.001), serum AP (P<0.001), and peak height velocity (PHV) followed the increase in serum testosterone. The boys were grouped according to time of maximal increase in BMC, AP, and PHV. The serum levels of the vitamin D metabolites were related to these points. No significant changes in any of the serum vitamin D metabolites were found. Thus vitamin D metabolism does not seem to be significantly influenced during the period of life when both the linear growth and bone mineralization is maximal.     

Delay‐dependent guaranteed cost gain‐scheduling control of LPV state‐delayed systems

Delay‐dependent gain‐scheduling controller design problem is addressed for the linear parameter‐varying state‐delayed systems with time‐varying delays. By choosing a Lyapunov–Krakovskii functional, delay‐dependent conditions for the existence of guaranteed cost gain‐scheduling controller are obtained. Besides, an algorithm is also presented to solve resultant nonconvex matrix inequalities in terms of linear matrix inequalities. Finally, three numerical examples with simulations are illustrated in order to demonstrate the validity of the proposed method. Copyright © 2007 John Wiley & Sons, Ltd.     

Hypobaric hypoxia causes impairment of spermatogenesis in developing rats at pre‐puberty

The effect of hypoxia on the spermatogenesis of male Wistar rats (n = 32) at pre‐puberty was studied using a hypobaric chamber simulating an altitude of 5,000 metres above sea level. Persistent hypoxic exposure with brief interruption for 3 weeks caused significant decreases in body and testis weights and testosterone level compared to the normobaric controls. Histologically, spermatogenic development was arrested; arrays of spermatids were misshaped; numbers of spermatogonia, Sertoli and Leydig cells were reduced; and apoptotic spermatocytes were increased substantially in the germinal epithelium of testis in the hypoxic‐exposed group. These hormonal and histopathological changes did not improve remarkably after 3 weeks of normobaric conditions. There was a significant decrease in sperm production when the rats in the hypoxia/oxygen‐resuming group were examined at 63 days of post‐natal age. Exposing rats to hypoxic conditions at pre‐puberty induced damages on spermatogenesis, which could affect sperm production after sex mature.     

Effects of long‐term paroxetine or bupropion treatment on puberty onset,reproductive and feeding parameters in adolescent male rats

Antidepressant use in adolescents has become more common in recent years. We have found several studies stating that prenatal antidepressant exposure can lead to delayed or earlier puberty onset but there was no study on postnatal paroxetine or bupropion. The main aim of this study was to investigate the effect of postnatal exposure to bupropion or paroxetine on puberty onset, reproductive and feeding results. The male rats (n = 8/group) aged 21 days were exposed to paroxetine (3.6 mg/kg) or bupropion (17 mg/kg) orally by gastric gavage every day from postnatal day 21–90. Also, control group received only saline orally as a vehicle. Postnatal exposure to bupropion or paroxetine delayed puberty onset compared to control group, but it was not significant. Sperm counts were significantly lower in the paroxetine and bupropion groups compared to control group. Sperm motility was significantly lower in only bupropion group. In addition, sperm motility was lower in paroxetine group, but it was not significant. In the histopathological examination, there was damage to the testicular structure in both treatments. Taken together, our result indicates that postnatal paroxetine or bupropion exposure may affect puberty onset and contribute to the impairment in fertility in male rats.     

Modulating role of pheromonal cues from oestrus‐specific urine on 3‐methylcholanthrene‐induced male reproductive toxicity

Polyaromatic hydrocarbons (PAHs) are persistent organic pollutants that contribute to endocrine/gonadal disruption. This study was designed to investigate the endocrine modulating role of pheromones in alleviating the reproductive toxic effects of 3‐MC (3‐methylcholanthrene), one of the common PAHs, in rat model. The rats were injected intraperitoneally with 3‐MC at a dose of 25 mg kg^?1 BW. The serum levels of testosterone and other biochemical parameters were altered to significant levels in 3‐MC‐treated rats and oestrus‐specific urine exposure restored all these effects to near normal. Although testis weight did not indicate any significant change, sperm and spermatid counts were significantly reduced in 3‐MC‐treated rats, which became normal in oestrus‐urine‐exposed rats. Hence, this study suggests that oestrus‐specific urinary pheromones have the potential to modulate the endocrine system and alleviate the male reproductive toxic effects produced by 3‐MC.     

Perioperative administration of high‐dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta‐analysis

Delayed graft function (DGF) due to ischemia–reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta‐analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high‐dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I² = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47–1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25–11.68, P = 0.02). Perioperative, high‐dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development.     

Effect of diethylstilbestrol and estramustine phosphate (estracyt®) on delayed hypersensitivity response to oxazolone in male mice

The effects of diethylstilbestrol (DES) and estramustine phosphate (EMP) on delayed hypersensitivity response (DTH) to oxazolone in male mice were investigated using a radioisotopic ear method. DES significantly inhibited the ability to express a DTH response and was most effective when given during the effector phase of the reaction. EMP had no effects when the animals were exposed to the drug during the effector phase, while it resulted in a strong and dose-dependent depression of the DTH response when applied in the sensitization phase. Possible involvement of suppressor cells was investigated by pretreatment of animals with cyclophosphamide or by adoptive transfer of tentative suppressor cells from spleen, lymph nodes, or peritoneal cavity. However, no evidence of cellular or humoral suppressor factors induced by drug treatment was found.     

Numerical solution of time‐delayed optimal control problems by iterative dynamic programming

This work presents a numerical method to solve the optimal control problem with time‐delayed arguments and a fixed terminal time. A series of auxiliary states obtained from the linearly truncated Taylor series expansion are used to represent the status of a time‐delayed state at different time intervals. The backward iterative dynamic programming (IDP) technique can thus be directly employed to solve the delay‐free optimal control problem with augmented states. Five numerical examples are provided, demonstrating the proposed method's effectiveness in solving the time‐delayed optimal control problems. Copyright © 2000 John Wiley & Sons, Ltd.     

Improved approach for passive stability of discrete‐time Markovian jump linear systems via mode‐dependent time‐delayed controllers

In this paper, we investigate the problem of passive stability for discrete‐time Markovian jump linear systems via mode‐dependent time‐delayed controllers by employing an improved free‐weighting matrix approach. A Markov process as discrete‐time, discrete‐state Markov process is considered. First, a new result of mode‐dependent stability analysis is first established for error systems without ignoring any terms in the derivative of Lyapunov–Krasovskii function by considering the relationship between the time‐varying delay and its upper bound. Then, the delay‐dependent passivity criterion is provided and a mode‐dependent time‐delayed controller is designed in terms of linear matrix inequalities. Finally, two numerical examples are given to illustrate the effectiveness and less conservativeness of our proposed method. Copyright © 2011 John Wiley & Sons, Ltd.     

Mutations in the Insulin‐Like Factor 3 Receptor Are Associated With Osteoporosis

Introduction : Insulin‐like factor 3 (INSL3) is produced primarily by testicular Leydig cells. It acts by binding to its specific G protein–coupled receptor RXFP2 (relaxin family peptide 2) and is involved in testicular descent during fetal development. The physiological role of INSL3 in adults is not known, although substantial INSL3 circulating levels are present. The aim of this study was to verify whether reduced INSL3 activity could cause or contribute to some signs of hypogonadism, such as reduced BMD, currently attributed to testosterone deficiency. Materials and Methods : Extensive clinical, biochemical, and hormonal study, including bone densitometry by DXA, was performed on 25 young men (age, 27–41 yr) with the well‐characterized T222P mutation in the RXFP2 gene. Expression analysis of INSL3 and RXFP2 on human bone biopsy and human and mouse osteoblast cell cultures was performed by RT‐PCR, quantitative RT‐PCR, and immunohistochemistry. Real‐time cAMP imaging analysis and proliferation assay under the stimulus of INSL3 was performed on these cells. Lumbar spine and femoral bone of Rxfp2‐deficient mice were studied by static and dynamic histomorphometry and μCT, respectively. Results : Sixteen of 25 (64%) young men with RXFP2 mutations had significantly reduced BMD. No other apparent cause of osteoporosis was evident in these subjects, whose testosterone levels and gonadal function were normal. Expression analyses showed the presence of RXFP2 in human and mouse osteoblasts. Stimulation of these cells with INSL3 produced a dose‐ and time‐dependent increase in cAMP and cell proliferation, confirming the functionality of the RXFP2/INSL3 receptor–ligand complex. Consistent with the human phenotype, bone histomorphometric and μCT analyses of Rxfp2^?/? mice showed decreased bone mass, mineralizing surface, bone formation, and osteoclast surface compared with wildtype littermates. Conclusions : This study suggests for the first time a role for INSL3/RXFP2 signaling in bone metabolism and links RXFP2 gene mutations with human osteoporosis.     

Parathyroid hormone induction of cyclooxygenase‐2 in murine osteoblasts: Role of the calcium‐calcineurin‐NFAT pathway

Murine MC3T3‐E1 and MC‐4 cells were stably transfected with ?371/+70 bp of the murine cyclooxygenase‐2 (COX‐2) promoter fused to a luciferase reporter (Pluc371) or with Pluc371 carrying site‐directed mutations. Mutations were made in (1) the cAMP response element (CRE) at ?57/?52 bp, (2) the activating protein‐1 (AP‐1)–binding site at ?69/?63 bp, (3) the nuclear factor of activated T‐cells (NFAT)–binding site at ?77/?73 bp, and (4) both the AP‐1 and NFAT sites, which comprise a composite consensus sequence for NFAT/AP‐1. Single mutation of CRE, AP‐1, or NFAT sites decreased parathyroid hormone (PTH)–stimulated COX‐2 promoter activity 40% to 60%, whereas joint mutation of NFAT and AP‐1 abrogated the induction. On electrophoretic mobility shift analysis, PTH stimulated binding of phosphorylated CREB to an oligonucleotide spanning the CRE and binding of NFATc1, c‐Fos, and c‐Jun to an oligonucleotide spanning the NFAT/AP‐1 composite site. Mutation of the NFAT site was less effective than mutation of the AP‐1 site in competing binding to the composite element, suggesting that cooperative interactions of NFATc1 and AP‐1 are more dependent on NFAT than on AP‐1. Both PTH and forskolin, an activator of adenylyl cyclase, stimulated NFATc1 nuclear translocation. PTH‐ and forskolin‐stimulated COX‐2 promoter activity was inhibited 56% to 80% by calcium chelation or calcineurin inhibitors and 60% to 98% by protein kinase A (PKA) inhibitors. These results indicate an important role for the calcium‐calcineurin‐NFAT signaling pathway in the PTH induction of COX‐2 and suggest that cross‐talk between the cAMP/PKA pathway and the calcium‐calcineurin‐NFAT pathway may play a role in other functions of PTH in osteoblasts. © 2010 American Society for Bone and Mineral Research     

Neurological excitation in a 6‐week‐old male infant after morphine overdose

While respiratory depression is a known complication of morphine overdose, the neuro‐excitatory side effect of the morphine metabolite morphine‐3‐glucuronide is less widely known. Here, we report the case of an infant with neurological excitation after morphine overdose. The neuro‐excitation in this infant was probably induced by an elevated morphine‐3‐glucuronide concentration.     

Eight case reports on sex‐hormone profiles in sexually mature male Down syndrome

Down syndrome (DS) is a congenital disorder usually caused by an extra copy of chromosome 21. Although the number of postpubertal patients with DS is increasing, only limited information is available on their gonadal and sexual development. The aim of this case report was to examine sex‐hormone profiles in sexually mature male patients with DS. Eight postpubertal male patients with trisomy 21 (mean age 28 years, range 15–54 years) participated in this study. The serum level of luteinizing hormone and follicle‐stimulating hormone was significantly elevated and testosterone was slightly decreased. The testicular volume was smaller in all eight cases than that observed in healthy male subjects. The elevated luteinizing hormone and follicle‐stimulating hormone levels, the lower testosterone levels and a smaller testicular volume observed in all eight cases suggest a significant degree of germinal cell hypoplasia in mature male patients with DS.     

Anti‐gal antibodies in α1,3‐galactosyltransferase gene‐knockout pigs

Fang J, Walters A, Hara H, Long C, Yeh P, Ayares D, Cooper DKC, Bianchi J. Anti‐gal antibodies in α1,3‐galactosyltransferase gene‐knockout pigs. Xenotransplantation 2012; 19: 305–310. © 2012 John Wiley & Sons A/S. Abstract Serum anti‐galactose‐α1,3‐galactose (Gal) IgM and IgG antibody levels were measured by ELISA in α1,3‐galactosyltransferase gene‐knockout (GTKO) pigs (78 estimations in 47 pigs). A low level of anti‐Gal IgM was present soon after birth, and rose to a peak at 4–6 m, which was maintained thereafter even in the oldest pigs tested (at >2 yr). Anti‐Gal IgG was also present at birth, peaked at 3 m, and after 6 m steadily decreased until almost undetectable at 20 m. No differences in this pattern were seen between pigs of different gender. Total IgM followed a similar pattern as anti‐Gal IgM, but total IgG did not decrease after 6m. The data provide useful baseline data for future experimental studies in GTKO pigs, e.g., relating to the antibody response to WT pig allografts.