Are there gender-specific differences in pregnancy outcome and placental abnormalities of pregnancies complicated with small for gestational age?

Archives of Gynecology and Obstetrics - Adaptations to pathological intrauterine environment might differ in relation to fetal gender. We aimed to study sex-specific differences in placental...     

Memory deficits of British dementia knock-in mice are prevented by Aβ-precursor protein haploinsufficiency

Familial British Dementia (FBD) is caused by an autosomal dominant mutation in the BRI2/ITM2B gene (Vidal et al., 1999). FBD(KI) mice are a model of FBD that is genetically congruous to the human disease, because they carry one mutant and one wild-type Bri2/Itm2b allele. Analysis of these mice has shown that the British mutation causes memory impairments due to loss of Bri2 function (Tamayev et al., 2010b). BRI2 is a physiologic inhibitor of processing of the Aβ-precursor protein (APP; Matsuda et al., 2008), a gene associated with Alzheimer's disease (Bertram et al., 2010). Here we show that APP haploinsufficiency prevents memory dysfunctions seen in FBD(KI) mice. This genetic suppression is consistent with a role for APP in the pathogenesis of memory deficits. Moreover, it provides compelling evidence that the memory dysfunctions caused by the British BRI2 mutant are dependent on endogenous APP and that BRI2 and APP functionally interact. This evidence establishes a mechanistic connection between Familial British and Alzheimer's dementias.     

Increased AβPP processing in familial Danish dementia patients

An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI, genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-β protein precursor (AβPP), a gene associated with Alzheimer's disease, which inhibits processing of AβPP. AβPP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, AβPP metabolites derived from processing of AβPP by β-, α-, and γ-secretases are increased in Danish dementia mice. AβPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AβPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AβPP and BRI2 functionally interact. Here, we have investigated whether AβPP processing is altered in FDD patients' brain samples. We find that the levels of several AβPP metabolites, including Aβ, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AβPP metabolites, suggesting that Familial Danish and Alzheimer's dementias share common pathogenic mechanisms.     

Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

According to the prevailing "amyloid cascade hypothesis," genetic dementias such as Alzheimer's disease and familial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD (FDD(KI/+)) genetically congruous with human cases. FDD(KI/+) mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. Bri2(+/-) mice exhibit synaptic and memory deficits similar to FDD(KI/+) mice, and memory loss of FDD(KI/+) mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy.     

Early versus delayed follow-up after misoprostol treatment for early pregnancy loss

Research questionDoes extending the follow-up after misoprostol treatment for early pregnancy loss increase the success rate?DesignPatients who had experienced early pregnancy loss (<12 weeks) and were treated with misoprostol in a single university-affiliated medical centre were prospectively followed before and after the implementation of a new treatment protocol extending the follow-up from 1 to 2 weeks. All patients received misoprostol 800 μg vaginally on day 1 and a second dose, when needed, on day 4 or 8. Patients underwent surgical aspiration after 1 week in the early follow-up group (n = 84) or 2 weeks in the delayed follow-up group (n = 85) if complete expulsion was not achieved (defined as endometrial thickness ≤15 mm and absence of gestational sac on transvaginal sonography). The primary outcome was treatment success, defined as no need for surgical aspiration.ResultsWomen in the delayed follow-up group had a higher rate of successful treatment compared with women in the early follow-up group (88.2% versus 76.2%, respectively; P = 0.040), and a lower rate of second dose administration (32.9% versus 51.2%, respectively; P = 0.016). The incidence of non-expulsion of the gestational sac was also lower in the delayed follow-up group (1.2% versus 10.7%; P = 0.009). Treatment acceptability did not differ between the study groups.ConclusionIn women with early pregnancy loss treated with misoprostol, extending the follow-up protocol from 1 to 2 weeks resulted in an increase in treatment success.