Body weight impact on puberty: effects of high-calorie diet on puberty onset in female rhesus monkeys

Secular trends toward a declining age at puberty onset with correlated changes in body weight have been reported in economically advanced countries. This has been attributed to excess calorie intake along with reduced physical activity in children. However, because the timing of puberty in humans is also influenced by other factors, such as genetic traits, living conditions, geographical location, and environmental chemicals, it is difficult to distinguish the effect of diet and body size from other factors in a human population. Here we report that feeding juvenile female rhesus monkeys born and raised at the Wisconsin National Primate Research Center with a high-calorie diet results in acceleration of body growth and precocious menarche. The monkeys fed a high-calorie diet also had an elevated body mass index. The most significant treatment effects on circulating hormones were increased leptin and IGF-I levels throughout the experiment. The findings of this study suggest the importance of close monitoring of juvenile feeding behaviors as an important intervention to reduce the prevalence of precocious development and metabolic diseases in adulthood.     

Molecular analysis of afibrinogenemic mutations caused by a homozygous FGA1238?bp deletion, and a compound heterozygous FGA1238?bp deletion and novel FGA c.54+3A>C substitution

We identified two afibrinogenemic girls in two Japanese families and performed molecular analysis to clarify the mechanisms of fibrinogen defects. Genetic analyses were performed by PCR amplification of the fibrinogen gene and DNA sequence analysis. To analyze the mechanisms of mature fibrinogen defects in plasma, we cloned minigenes from the proposita's PCR-amplified DNA, transfected them into CHO cells, and sequenced the cDNA amplified with the RT reaction followed by PCR. Sequence analyses indicated that one was caused by a homozygous 1238?bp deletion of the fibrinogen Aα-chain gene (FGAΔ1238) and the other was a compound heterozygous FGAΔ1238 and novel FGA c.54+3A>C substitution. The minigene corresponding to FGAΔ1238 generates two aberrant mRNAs, both of which may induce a frameshift and terminate prematurely. In contrast, the minigene corresponding to FGA c.54+3A>C generates two aberrant mRNAs, one of which may induce a frameshift and terminate prematurely, and the other uses a cryptic 5' splice site in exon 1, resulting in the deletion of six amino acids in signal peptides. Molecular analyses of both genetic variants suggest that the lack of a mature Aα-chain, impaired assembly, and/or secretion of the fibrinogen molecule may lead to afibrinogenemia.     

Efficacy of prophylactic treatment with montelukast and montelukast plus add-on loratadine for seasonal allergic rhinitis

Cysteinyl leukotriene and leukotriene receptor occupancy have been linked to several processes in seasonal allergic rhinitis (SAR), including nasal congestion, rhinorrhea, and recruitment of inflammatory cells. We investigated whether add-on loratadine, an antihistamine, might be effective for SAR patients showing unsatisfactory control of symptoms with the leukotriene receptor antagonist (LTRA) montelukast alone. Patients with SAR caused by Japanese cedar pollen (SAR-JCP; mean age, 29.4 years) were given prophylactic montelukast for 1 month before peak JCP dispersal. Patients recorded the severity of the symptoms (sneezing, rhinorrhea, nasal congestion, and ocular symptoms) daily on visual analog scale (VAS). We selected patients with VAS scores of >50 for any of the symptoms just before the peak pollen season (March 2 to March 8) and designated them as "poorly controlled" patients. Then, in the peak JCP season (from March 9), we conducted a randomized, double-blind, placebo-controlled study to determine whether add-on loratadine might be effective for these "poorly controlled" patients. Montelukast alone was effective, as evaluated by improvement of the VAS scores, in 95 of the 137 patients (69.3%). Add-on loratadine significantly decreased the total scores for nasal symptoms (p < 0.05), sneezing (p < 0.05), and rhinorrhea (p < 0.05) when compared with placebo. The symptoms of SAR in two of three SAR-JP patients could be controlled (VAS score[s] under 50) by prophylactic treatment with montelukast alone under the condition of mild JCP dispersal. Furthermore, the effect of add-on antihistamine on sneezing and rhinorrhea was found in selected SAR-JCP patients.     

Ovarian Regulation of Kisspeptin Neurones in the Arcuate Nucleus of the Rhesus Monkey (Macaca mulatta)

Tonic gonadotrophin secretion throughout the menstrual cycle is regulated by the negative‐feedback actions of ovarian oestradiol (E₂) and progesterone. Although kisspeptin neurones in the arcuate nucleus (ARC) of the hypothalamus appear to play a major role in mediating these feedback actions of the steroids in nonprimate species, this issue has been less well studied in the monkey. In the present study, we used immunohistochemistry and in situ hybridisation to examine kisspeptin and KISS1 expression, respectively, in the mediobasal hypothalamus (MBH) of adult ovariectomised (OVX) rhesus monkeys. We also examined kisspeptin expression in the MBH of ovarian intact females, and the effect of E₂, progesterone and E₂ + progesterone replacement on KISS1 expression in OVX animals. Kisspeptin or KISS1 expressing neurones and pronounced kisspeptin fibres were readily identified throughout the ARC of ovariectomised monkeys but, on the other hand, in intact animals, kisspeptin cell bodies were small in size and number and only fine fibres were observed. Replacement of OVX monkeys with physiological levels of E₂, either alone or with luteal phase levels of progesterone, abolished KISS1 expression in the ARC. Interestingly, progesterone replacement alone for 14 days also resulted in a significant down‐regulation of KISS1 expression. These findings support the view that, in primates, as in rodents and sheep, kisspeptin signalling in ARC neurones appears to play an important role in mediating the negative‐feedback action of E₂ on gonadotrophin secretion, and also indicate the need to study further their regulation by progesterone.     

Ouabain-induced isoform-specific localization change of the Na+, K+-ATPase alpha subunit in the synaptic plasma membrane of rat brain

Na+, K+-ATPase is one of major membrane proteins that has two subunits, alpha and beta. The alpha subunit has the ATPase activity and the ouabain binding site. Among four isoforms of the alpha subunit, expression of alpha1, alpha2, and alpha3, but not alpha4, is observed in matured rat brain. Ouabain is one of cardiac glycosides, and endogenous ouabain-like compounds have been recognized as a new class of steroid hormone. The alpha subunit is considered as their endogenous receptor. Recent studies envisaged the importance of membrane microdomains (MDs) as signaling platforms, which are recovered as a detergent-resistant membrane microdomain fraction (DRM). Although this ATPase has been considered as a non-DRM protein, some amount of the alpha subunit was found to be a component of the DRM prepared from the synaptic plasma membrane fraction (SPM) of rat brain. Ouabain treatment increased the amount of alpha3 isoform, but not alpha1, in the DRM derived from synaptosome fraction and SPM. These results suggest that the localization of the alpha subunit of Na+, K+-ATPase is regulated with isoform-specific mechanisms and the physiological importance of DRM in the signal transduction of the endogenous ouabain-like steroid hormone in neurons.     

Heterogenous expression of decay accelerating factor and CD59/membrane attack complex inhibition factor on paroxysmal nocturnal haemoglobinuria (PNH) erythrocytes

In order to clarify the characterization of phenotypes of paroxysmal nocturnal haemoglobinuria (PNH) erythrocytes (E), we analysed the expression of decay accelerating factor (DAF) and CD59/membrane attack complex inhibition factor (MACIF) on the membrane surface of PNH-E by means of the flow cytometric method using anti-DAF and/or CD59/MACIF monoclonal antibodies in nine PNH-patients. In two-colour analysis, this expression of PNH-E was classified into three fractions; negative, intermediate and positive according to intensity. The negative fraction was classified into two groups; one group an exclusively negative population, and the other a negative population having slightly DAF-positive E. The intermediate fraction was recognized on PNH-E of cases with PNH II-E and extremely heterogenous. In the positive fraction, this expression was almost the same as on normal E except for case 8. In single-colour analysis for DAF or CD59/MACIF, three fractions were classified as well as the definition in two-colour analysis. In single-colour analysis, the expression on PNH-E was also heterogenous in each fraction and among PNH-patients. However, the intermediate fraction for CD59/MACIF was not found on PNH-E of cases without PNH II-E, although intermediate fraction for DAF was recognized on PNH-E of some cases with PNH III-E in addition to those with PNH II-E. The results suggest that expression of CD59/MACIF and DAF on the membrane surface of PNH-E phenotypes is heterogenous and varies among PNH patients.     

Identification of an Anti–Integrin αvβ6 Autoantibody in Patients With Ulcerative Colitis

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