Memory loss caused by beta-amyloid protein is rescued by a beta(3)-adrenoceptor agonist

Accumulation of the neurotoxic beta-amyloid protein (Abeta) in the brain is a key step in the pathogenesis of Alzheimer's disease (AD). Although transgenic mouse models of AD have been developed, there is a clear need for a validated animal model of Abeta-induced amnesia which can be used for toxicity testing and drug development. Intracranial injections of Abeta(1-42) impaired memory in a single trial discriminative avoidance learning task in chicks. Memory inhibition was closely associated with the state of aggregation of the Abeta peptide, and a scrambled-sequence of Abeta(1-42) peptide failed to impair memory. Abeta had little effect on labile (short-term and intermediate) memory, but blocked consolidation of memory into long-term storage mimicking the type of anterograde amnesia that occurs in early AD. Since noradrenaline exerts a modulatory influence on labile memory in the chick, we examined the effects of two beta-adrenoceptor (AR) agonists on Abeta-induced amnesia. A beta(3)-AR agonist (CL316243), but not a beta(2)-AR agonist, rescued Abeta-induced memory loss, suggesting the need for further studies on the role of beta(3)-ARs in AD.     

Defective hepatic regeneration after partial hepatectomy in leptin-deficient mice is not rescued by exogenous leptin

Liver regeneration after partial hepatectomy (PH) is impaired in leptin-deficient ob/ob mice. Here, we tested whether exogenous leptin and/or correction of the obese phenotype (by food restriction or long-term leptin administration) would rescue hepatocyte proliferation and whether the hepatic progenitor cell compartment was activated in leptin-deficient ob/ob livers after PH. Because of the high mortality following 70% PH to ob/ob mice, we performed a less extensive (55%) resection. Compared to lean mice, liver regeneration after 55% PH was deeply impaired and delayed in ob/ob mice. Administration of exogenous leptin to ob/ob mice at doses that restored circulating leptin levels during the surgery and postsurgery period or for 3 weeks prior to the surgical procedure did not rescue defective liver regeneration. Moreover, correction of obesity, metabolic syndrome and hepatic steatosis by prolonged administration of leptin or food restriction (with or without leptin replacement at the time of PH) did not improve liver regeneration in ob/ob mice. The hepatic progenitor cell compartment was increased in ob/ob mice. However, after PH, the number of progenitor cells decreased and signs of proliferation were absent from this cell compartment. In this study, we have conclusively shown that neither leptin replacement nor amelioration of the metabolic syndrome, obese phenotype and hepatic steatosis, with or without restitution of normal circulating levels of leptin, was able to restore replicative competence to ob/ob livers after PH. Thus, leptin does not directly signal to liver cells to promote hepatocyte proliferation, and the obese phenotype is not solely responsible for impaired regeneration.     

Preaxial polydactyly of feet in infants of diabetic mothers: epidemiological test of a clinical hypothesis.

Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we tested the hypothesis of Carey et al. (Proc Greenwood Genet Cent 9:95, (1990) on maternal diabetes and preaxial polydactyly of feet in infants born to diabetic mothers. Our results seem to confirm their suggestion, although the hallucal type of preaxial polydactyly that they described seems to be much less frequent. Nevertheless, a high risk exists (OR = 24.60, P = 0.0004) for preaxial polydactyly of the feet in relation with other types of birth defects or postaxial polydactyly. This analysis shows the importance of clinical observations for epidemiologists, because such observations constitute hypotheses and provide actual issues for study, and clinicians will get epidemiological confirmation for their individual observations and hypotheses.     

DMRT1单倍体不足导致性发育异常

目的增加对DMRT1基因单倍体不足导致性发育异常的认识,提高性发育异常疾病的诊断水平。方法描述1例染色体为46XY性发育异常患者的临床特点;对患者及其父母的静脉血进行淋巴细胞培养和染色体核型分析;抽取患者外周血,提取基因组DNA,进行微阵列比较基因组杂交技术(a CGH)扫描。结果 1)患者表现为女性外阴,超声未见子宫和卵巢组织;伴随发育延迟和运动迟缓;临床表现符合9p缺失综合征;2)染色体结果:患者母亲46XX,t(7;9)(q35,p24);父亲46XY;患儿46XY,der(9)t(7;9)(q35,p24);3)a CGH扫描结果:患儿第7号染色体长臂部分(144741153-159098761)重复,长约14.37 Mb;第9号染色体短臂部分(10001-9733061)缺失,长约9.72 Mb,缺失部分包含EZH2、MNX1、DMRT1、DMRT2、SHH、SMARCA2、GLDC、VLDLR、DOCK8和GLIS3基因。结论 DMRT1在性腺发育过程中发挥重要作用。母亲染色体发生平衡易位,因无遗传物质丢失,故不导致疾病发生。在产生配体过程中,因DMRT1单倍体剂量不足,导致子代睾丸发育障碍。     

A general IGF-I overexpression effectively rescued somatic growth and bone deficiency in mice caused by growth hormone receptor knockout

Both growth hormone and insulin-like growth factor (IGF)-I are essential for postnatal somatic growth, while exerting distinct effects on energy homeostasis. Although growth hormone controls IGF-I production, whether IGF-I was the exclusive mediator of its growth promotion is still debated. In order to further explore their in vivo interactions in somatic growth as well as in energy homeostasis, we have crossed mutant (MT-IGF) transgenic mice onto the GHR ? / ? background. As expected, GHR gene deficiency caused growth retardation, including significant decreases in lumbar, femur and total body lengths, as well as decreased bone area, mineral content and mineral density. IGF-I overexpression alone in MT-IGF mice increased the weight, with no significant change in bone mineralization or longitudinal growth. Compared to GHR ? / ? littermates, overexpressed IGF-I in bitransgenic mice (GHR ? / ? and MT-IGF positive) exhibited fully restored body weight, lumbar (but not femur) and total body lengths, and normalized overall bone area, mineral content and density. On the other hand, there were significant changes in fasting glucose level, glucose tolerance, lean/fat masses and even adipose histology as a result of the transgenic/knockout double-crossing. IGF-I overexpression normalized glucose tolerance in GHR ? / ? mice. Intriguingly, on GHR+/ ? background of partial growth hormone insensitivity, overexpression of IGF-I caused a significant weight gain. Our results thus establish that the growth defect and bone deficiency caused by lack of growth hormone signaling can be effectively restored by increasing IGF-I production in vivo.     

Clinical spectrum of Kabuki‐like syndrome caused by HNRNPK haploinsufficiency

Kabuki syndrome is a genetically heterogeneous disorder characterized by postnatal growth retardation, skeletal abnormalities, intellectual disability, facial dysmorphisms and a variable range of organ malformations. In ~30% of affected individuals, the underlying genetic defect remains unknown. A small number of inactivating heterozygous HNRNPK mutations has recently been reported to be associated with a condition partially overlapping or suggestive of Kabuki syndrome. Here, we report on an 11‐year‐old girl with a complex phenotype in whom the diagnosis of KS was suggested but molecular testing for the known causative disease genes was negative. Whole‐exome sequencing identified a previously undescribed de novo truncating mutation in HNRNPK as the molecular defect underlying the trait. Analysis of available records of patients with HNRNPK haploinsufficiency was performed to delineate the associated clinical phenotype and outline their distinguishing features in comparison with the KS clinical spectrum. The clinical profile associated with inactivating HNRNPK mutations supports the idea that the associated disorder should be considered as a distinct nosologic entity clinically related to KS, and that the condition should be considered in differential diagnosis with KS, in particular in subjects exhibiting brain malformation (nodular heterotopia), craniosynostosis, and polydactyly.     

Sleep is increased by weight gain and decreased by weight loss in mice

OBJECTIVE: To determine whether weight loss could reverse excessive sleep in high-fat diet-induced obesity. DESIGN: Three groups of mice participated in the study. A weight gain/loss group was fed with high-fat food for 6 weeks (weight gain), and regular food again for 4 weeks (weight loss). A control group and a weight gain only group were fed with regular food and high-fat food, respectively, for 10 weeks after the baseline. PARTICIPANTS: Adult male C57BL/6 mice. MEASUREMENTS: The amounts of wake, rapid eye movement sleep (REMS) and non-REM sleep (NREMS) were determined at week 0 (baseline), week 6, and week 10. RESULTS: The weight gain/loss group displayed a significant decrease in wakefulness and increases in NREMS and episodes of NREMS during 6 weeks of weight gain, which were reversed during subsequent 4 weeks of weight loss. The weight gain only group displayed significant decrease in wakefulness and increase of NREMS and REMS at both week 6 and week 10. The control group did not show significant sleep alterations during the experiment. CONCLUSION: These observations indicate that sleep alterations induced by weight gain are reversed by weight loss in obese animals. These data may shed light on the mechanisms underlying the well-established association between obesity and sleepiness in humans and may lead to new therapeutic strategies for these 2 increasingly prevalent problems in the modern societies.     

Wheat-dependent exercise-induced anaphylaxis in mice is caused by gliadin and glutenin treatments

Various foods may be associated with food-dependent exercise-induced anaphylaxis (FDEIAn). However, although the most frequently reported cause of FDEIAn has been wheat, the mechanism of FDEIAn for wheat has remained largely uninvestigated. To investigate the effect of wheat-fractionated proteins on FDEIAn, female B10.A mice (16-20 g) were divided into four groups; i.e. salt-soluble (S-group), gliadin-rich (GLI-group), and glutenin-rich (GLU-group)-sensitized mice, and unsensitized mice. The three sensitized groups were run on a treadmill after oral intake of each wheat-fractionated protein. The mice showed a significant increase in serum IgE, especially in the GLI- and GLU-group. After oral administration of each wheat-fractionated protein, the running time until exhaustion was remarkably shorter for the GLI- and GLU-group than for the S-group and unsensitized mice. The level of intestinal erosion was higher in all the sensitized mice than that in the unsensitized ones after exhaustive running. Furthermore, moderate exercise for 30 min after oral ingestion of each wheat-fractionated protein also induced intestinal erosion in the GLI- and GLU-group. In addition, we observed leaking of gliadin and glutenin proteins out of the intestine into the liver. These results indicated that the main factor involved in wheat-dependent exercise-induced anaphylaxis might be the gliadin and glutenin in wheat proteins.