Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer’s Disease

Abstract Network hyperexcitability is a feature of Alzheimer’ disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD

Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease

Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta (Aβ) is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how Aβ leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds Aβ and mediates toxicity. While many candidates have been observed in model systems, their relevance to human AD brain remains unknown. This is in part due to methodological limitations preventing visualization of Aβ binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Förster resonance energy transfer (FRET) to image over 1 million individual synaptic terminals in temporal cortex from AD (n = 11) and control cases (n = 9). Within presynapses and post-synaptic densities, oligomeric Aβ generates a FRET signal with transmembrane protein 97. Further, Aβ generates a FRET signal with cellular prion protein, and post-synaptic density 95 within post synapses. Transmembrane protein 97 is also present in a higher proportion of post synapses in Alzheimer’s brain compared to controls. We inhibited Aβ/transmembrane protein 97 interaction in a mouse model of amyloidopathy by treating with the allosteric modulator CT1812. CT1812 drug concentration correlated negatively with synaptic FRET signal between transmembrane protein 97 and Aβ. In human-induced pluripotent stem cell derived neurons, transmembrane protein 97 is present in synapses and colocalizes with Aβ when neurons are challenged with human Alzheimer’s brain homogenate. Transcriptional changes are induced by Aβ including changes in genes involved in neurodegeneration and neuroinflammation. CT1812 treatment of these neurons caused changes in gene sets involved in synaptic function. These data support a role for transmembrane protein 97 in the synaptic binding of Aβ in human Alzheimer’s disease brain where it may mediate synaptotoxicity

Guidelines on Chemotherapy in Advanced Stage Gynecological Malignancies: An Evaluation of 224 Professional Societies and Organizations

BACKGROUND: Clinical practice guidelines are important for guiding practice, but it is unclear if they are commensurate with the available evidence. METHODS: We examined guidelines produced by cancer and gynecological societies and organizations and evaluated their coverage of and stance towards chemotherapy for advanced stage disease among 4 gynecological malignancies (breast, ovarian, cervical, endometrial cancer) where the evidence for the use of chemotherapy is very different (substantial and conclusive for breast and ovarian cancer, limited and suggesting no major benefit for cervical and endometrial cancer). Eligible societies and organizations were identified through systematic internet searches (last update June 2009). Pertinent websites were scrutinized for presence of clinical practice guidelines, and relative guidelines were analyzed. RESULTS: Among 224 identified eligible societies and organizations, 69 (31%) provided any sort of guidelines, while recommendations for chemotherapy on advanced stage gynecological malignancies were available in 20 of them. Only 14 had developed their own guideline, and only 5 had developed guidelines for all 4 malignancies. Use of levels of evidence and grades of recommendations, and aspects of the production, implementation, and timeliness of the guidelines did not differ significantly across malignancies. Guidelines on breast and ovarian cancer utilized significantly more randomized trials and meta-analyses. Guidelines differed across malignancies on their coverage of disease-free survival (p = 0.033), response rates (p = 0.024), symptoms relief (p = 0.005), quality of life (p = 0.001) and toxicity (p = 0.039), with breast and ovarian cancer guidelines typically covering more frequently these outcomes. All guidelines explicitly or implicitly endorsed the use of chemotherapy. CONCLUSIONS: Clinical practice guidelines are provided by the minority of professional societies and organizations. Available guidelines tend to recommend chemotherapy even for diseases where the effect of chemotherapy is controversial and recommendations are based on scant evidence

Effect of periodontal disease treatment during pregnancy on preterm birth incidence : a metaanalysis of randomized trials

We conducted a metaanalysis of randomized controlled trials to determine whether periodontal disease treatment with scaling and/or root planing during pregnancy may reduce preterm birth (PTB) or low birthweight (LBW) infant incidence. Treatment resulted in significantly lower PTB (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.35-0.86; P = .008) and borderline significantly lower LBW (OR, 0.48; 95% CI, 0.23-1.00; P = .049), whereas no difference was found for spontaneous abortion/stillbirth (OR, 0.73; 95% CI, 0.41-1.31; P = .292). Subgroup analysis suggested significant effect of treatment in the absence of history of PTB or LBW (OR, 0.48; 95% CI, 0.29-0.77; P = .003) and less severe periodontal disease as defined by probing depth (OR, 0.49; 95% CI, 0.28-0.87; P = .014) or bleeding on probing site (OR, 0.37; 95% CI, 0.14-0.95; P = .04). If ongoing large and well-designed randomized trials support our results, we might need to reassess current practice or at least be cautious prior to rejecting treatment of periodontal disease with scaling and/or root planing during pregnancy

Treatment of unexplained infertility with aromatase inhibitors or clomiphene citrate : a systematic review and meta-analysis

Treatment of unexplained infertility is empiric and different regimens or protocols have been used so far. Clomiphene can be used alone or combined with gonadotrophins. Aromatase inhibitors may offer an alternative for first-line treatment. To compare the efficacy of aromatase inhibitors versus climiphene, we conducted a systematic review and meta-analysis for randomized controlled trials comparing the above regimens to estimate live pregnancy rates in women with unexplained infertility. Trials were located through PubMed and Cochrane Library searches. Methodological quality of included trials has been assessed. Then, 2 x 2 tables were constructed, and pooled odds ratios (ORs) were calculated. Ten arms (273 patients) were included in the meta-analysis. ORs were homogeneous between studies (heterogeneity chi2 = 2.33, P = 0.676). No difference was observed for live pregnancies (pooled OR 0.87, 95% CI, 0.46-1.65, P = 0.666) for aromatase inhibitors versus clomiphene citrate; however, the definition of live pregnancy by the authors was clear only in one trial. Data regarding secondary outcomes were omitted, and methodogical quality of eligible trials did not reach high scores. Evidence from randomized data regarding the use of aromatase inhibitors is fragmented and weak. Aromatase inhibitors may have a role in the treatment of women with unexplained infertility desiring pregnancy. However, meticulous reporting and study design should be a priority in this field and large, registered, and properly designed randomized trials are essential to test whether aromatase inhibitors can be introduced as a first-line treatment in carefully selected subgroups of women with unexplained infertility

Combined vitamin C and E supplementation during pregnancy for preeclampsia prevention: a systematic review

The effect of combined vitamin C and E supplementation during pregnancy on the prevention of preeclampsia and major adverse infant outcomes has been reviewed. We searched MEDLINE and the Central Library of Controlled Trials of the Cochrane Library through August 2006 for relevant clinical trials. Interstudy heterogeneity was evaluated using the chi(2) statistic (Q statistic) test. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated with a fixed or random-effects model as appropriate. Four trials that collectively randomized 4680 pregnant women to either the combination of vitamin C and vitamin E or placebo were included in the analysis. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia, 11% versus 11.4%, RR 0.97 (95% CI 0.82-1.13), fetal or neonatal loss, 2.6% versus 2.3%, RR 1.10 (95% CI 0.78-1.57), or small for gestational age (SGA) infant, 20.6% versus 20%, RR 0.94 (95% CI 0.74-1.19). Although there was a higher risk for preterm birth in the vitamin group, 19.5% versus 18%, RR 1.07 (95% CI 0.96-1.20), this finding was not significant. Combined vitamin C and E supplementation during pregnancy does not reduce the risk of preeclampsia, fetal or neonatal loss, small for gestational age infant, or preterm birth. Such supplementation should be discouraged unless solid supporting data from randomized trials become available. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall that many methods have been used to prevent preeclampsia, state that increased oxidative stress has been postulated and many trials have used antioxidants to prevent the disease, and explain that MEDLINE analysis of the literature questions the use of vitamin C and E supplements

Vaginal progesterone gel for luteal phase support in IVF/ICSI cycles: a meta-analysis

Objective: To investigate whether vaginal progesterone gel may result in similar or higher pregnancy rates compared with all other vaginal progesterone forms when used for luteal-phase support. Design: Meta-analysis of randomized controlled trials using odds ratios (OR) and 95% confidence intervals (CI). Patient(s): Infertile women undergoing IVF or ICSI. Intervention(s): Vaginal progesterone gel 90mg once or twice daily versus any other vaginal progesterone form for luteal phase support. Main Outcome Measure(s): Clinical pregnancy rates. Result(s): Seven randomized controlled trials, involving 2,447 patients, were included in the analysis. No difference was observed in the overall clinical pregnancy rate when comparing vaginal progesterone gel with any other vaginal progesterone form. Moreover, clinical pregnancy rates were similar in protocols using only GnRH agonists and when comparing vaginal gel with the traditional treatment of 200 mg x 3 vaginal progesterone capsules. Conclusion(s): This meta-analysis provides solid evidence that no significant difference exists between vaginal gel and all other vaginal progesterone forms in terms of clinical pregnancy rates. (Fertil Steril (R) 2010; 94: 2083-7. (C) 2010 by American Society for Reproductive Medicine.

Immunohistochemical evaluation of cathepsin D in normal, hyperplastic and malignant endometrium: Correlation with hormone receptor status c-erbB-2, p53, Rb proteins and proliferation associated indices

The immunohistochemical expression of cathepsin D was performed in paraffin embedded tissue from 79 endometrial carcinomas, 35 cases of hyperplasia, and 32 normal endometrium using the streptavidin-biotin method to investigate the role of cathepsin D (CD) in these lesions and its possible relationship with other potential and established prognostic markers. The association between CD and the other markers was assessed by univariate analysis. Tumor cell CD expression was lower in the group of carcinomas compared to the normal proliferative (P = 0.022) and secretory endometrium (P = 0.0005). In addition, hyperplastic cell CD expression was lower compared with epithelial cell CD expression in the secretory phase of normal endometrium (P = 0.009). Malignant cell CD expression was inversely correlated with tumor stromal cells (P = 0.007). A positive relationship of stromal cell CD expression with pRb (P = 0.046) and PCNA score (P < 0.0001) was detected in the group of carcinomas. In the proliferative phase of normal endometrium, epithelial CD expression was positively correlated with estrogen status (P = 0.015). The data show that down-regulation of CD expression is an early event in endometrial carcinogenesis. In addition, stromal cell CD expression may be involved in cell growth process in endometrial carcinomas