Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α‐syn co‐pathology

Several degenerative brain disorders such as Alzheimer''s disease (AD), Parkinson''s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid‐β (Aβ) and α‐synuclein (α‐syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α‐syn in Aβ aggregation and the arising characteristic olfactory impairments observed during the progression of these diseases is still not well understood. Therefore, we assessed Aβ load in olfactory bulbs of APP‐transgenic mice expressing APP695 ^KM670/671NL and PSEN1 ^L166P under the control of the neuron‐specific Thy‐1 promoter (referred to here as APPPS1) and APPPS1 mice co‐expressing SNCA ^A30P (referred to here as APPPS1 × [A30P]aSYN). Furthermore, the olfactory capacity of these mice was evaluated in the buried food and olfactory avoidance test. Our results demonstrate an age‐dependent increase in Aβ load in the olfactory bulb of APP‐transgenic mice that go along with exacerbated olfactory performance. Our study provides clear evidence that the presence of α‐syn significantly diminished the endogenous and seed‐induced Aβ deposits and significantly ameliorated olfactory dysfunction in APPPS1 × [A30P]aSYN mice.     

Usefulness of left ventricular diastolic dysfunction assessed by pulsed tissue Doppler imaging as a predictor of atrial fibrillation recurrence after successful electrical cardioversion

The impact of left ventricular (LV) diastolic dysfunction on risk of atrial fibrillation (AF) recurrence is still unknown. The aim of this study was to assess the role of LV diastolic dysfunction in predicting AF recurrence after successful electrical cardioversion in patients with nonvalvular AF. In 51 patients with a first episode of nonvalvular AF undergoing successful electrical cardioversion, tissue Doppler echocardiography was performed to measure peak early diastolic mitral annulus velocity (E(m)) and the ratio of mitral inflow to mitral annulus velocity at end-diastole (E/E(m)). Clinical end points were recurrent persistent AF at 2-week follow-up (early AF recurrence [ERAF]) and at 1-year follow-up (including ERAF and late AF recurrence). Seventeen patients showed evidence of ERAF, whereas late AF recurrence occurred in another 5 patients. In time-independent analysis E/E(m) (odds ratio [OR] 1.746, p = 0.0084) and indexed LV end-systolic volume (OR 1.083, p = 0.040) were independent predictors of ERAF. Based on a logistic model risk of ERAF was 25% for an E/E(m) of 5.6 but increased to 50% for an E/E(m) of 8.1 and to 75% for an E/E(m) of 10.5. In time-dependent analysis E/E(m) emerged as the only predictor of ERAF (OR 1.757, p = 0.0078). E/E(m) also independently predicted risk of recurrence at 1 year in time-independent (OR 1.757, p = 0.0078) and time-dependent (OR 1.319, p = 0.0003) analyses. In conclusion LV diastolic dysfunction independently predicts AF recurrence in patients with nonvalvular AF undergoing successful electrical cardioversion.     

The Pampas fox (Lycalopex gymnocercus) as new definitive host for Spirometra erinacei (Cestoda: Diphyllobothriidae)

Spirometra erinacei, Faust, Campbell and Kellogg, 1929, is a pseudophyllidean cestode of the family Diphyllobothriidae. The genus Spirometra is cosmopolitan and these parasites infect carnivores, specially felids and canids. In Argentina, S. erinacei and S. mansonoides have been reported sporadically only in domestic definitive hosts. The Pampas fox, Lycalopex gymnocercus, is the most abundant native carnivore in southern South America, where it inhabits grasslands and open woodlands and areas highly modified by extensive ranching and agricultural activities. This report describes the first finding of S. erinacei infecting Pampas fox, and provides an estimate prevalence of this cestode in rural areas of southern Buenos Aires province, Argentina based on 78 complete Pampas fox intestine samples analysis. This study found a 15.4% of prevalence of S. erinacei in small intestine (adult stage) and a 21.8% in fecal samples (egg stage). In the present work, the first case of S. erinacei in a wild definitive host from Argentina was reported expanding the list of definitive hosts of S. erinacei in South America.     

Docosahexaenoic acid induces apoptosis in the human PaCa-44 pancreatic cancer cell line by active reduced glutathione extrusion and lipid peroxidation

We investigated the ability of fatty acids to induce growth inhibition and apoptosis in the human PaCa-44 pancreatic cancer cell line and the mechanism(s) underlying apoptosis. Butyric acid, alpha-linoleic acid, and docosahexaenoic acid (DHA) were supplemented at 200 microM concentration in the medium of cell cultures. Our results showed that all fatty acids inhibited cell growth, whereas only DHA induced cell apoptosis. An oxidative process was implicated in apoptosis induced by DHA because butylated hydroxytoluene and vitamin E prevented lipid peroxidation and reversed apoptosis. Intracellular and extracellular glutathione [reduced glutathione (GSH) and oxidized glutathione (GSSG)] concentrations were measured following DHA treatment in the presence or in the absence of GSH extrusion inhibitors such as cystathionine or methionine. DHA induced intracellular GSH depletion without affecting intracellular GSSG concentration and increased extracellular GSH and GSSG levels. Intracellular GSH depletion and extracellular GSH increase were both reversed by cystathionine. Inhibition of active GSH extrusion from the cell by cystathionine or methionine completely reversed lipid peroxidation and apoptosis. These data document the antiproliferative and apoptotic activities of DHA. The date provide evidence that intracellular GSH depletion represents an active extrusion process rather than a consequence of an oxidative stress, suggesting a causative role of GSH depletion in DHA-induced apoptosis.     

Metabolic, hormonal, oxidative, and inflammatory factors in pediatric obesity-related liver disease

OBJECTIVE: To examine the role of metabolic, hormonal, oxidative, and inflammatory factors in pediatric obesity-related liver disease. STUDY DESIGN: In 50 obese children (age 7 to 14 years) with (n = 20, group 1) or without (n = 30, group 2) hypertransaminasemia and ultrasonographic liver brightness, we studied insulin resistance (fasting glucose/insulin ratio [FGIR]) and serum levels of leptin, iron, transferrin, ferritin, C-reactive protein (CRP), white blood cell (WBC) count, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, C282Y and H63D mutations, and erythrocytic glutathione peroxidase (GPX) activity. RESULTS: FGIR (6.7 +/- 4.1 vs 9.2 +/- 5.2; P = .02), serum ferritin (88.8 +/- 36.0 vs 39.9 +/- 24.0 ng/mL; P = .0001), serum CRP (5.4 +/- 6.0 vs 1.1 +/- 1.6 mg/dL; P = 0.004), and GPX (8.4 +/- 0.9 vs 5.0 +/- 0.5 U/g Hb; P = .05) were significantly higher and more frequently deranged in group 1 than in group 2. FGIR, ferritin, and CRP values were simultaneously deranged in 41% of the group 1 patients and in none of the group 2 patients ( P = .098). Serum leptin, iron, and transferrin, WBC, TNF-alpha, IL-6, and C282Y and H63D mutations were similar in the 2 groups. CONCLUSIONS: Insulin resistance, oxidative stress, and low-grade systemic inflammatory status are implicated in pediatric obesity-related liver disease. These findings may be useful in planning pathophysiologically based therapeutic trials for hepatopathic obese children who are unable to follow hypocaloric diets.     

Alterations of tooth eruption and growth in pups suckling from diabetic dams

Several studies have confirmed a decrease in the quality and quantity of milk of mothers with diabetes during lactation. However, it remains unclear how maternal diabetes affects the offspring specifically during lactation. The aim of this study was to evaluate body and mandibular growth and tooth eruption in pups suckling from diabetic dams. The study was performed on 13 Wistar rat pups that were born to dams that were subjected to experimental diabetes on the day of parturition. Body weight and body size were recorded regularly throughout the study. The experimental pups and a group of eight age-matched pups suckling from nondiabetic dams were killed at weaning. Both hemimandibles were excised and fixed. Right hemimandibles were radiographed to assess mandibular growth and tooth eruption. The left hemimandibles were processed to obtain buccolingually oriented sections at the level of the first mesial root of the first lower molar. Histologic and histomorphometric studies were performed. Results showed that body weight and body size were significantly lower in experimental animals at weaning compared with their age-matched controls. Smaller mandible size and reduced tooth eruption in experimental animals compared with controls were observed. The length, width, and bone volume of the developing alveolus were reduced in experimental animals compared with controls. The results obtained in this study allow the conclusion that suckling from diabetic dams results in reduced body, mandible size, and tooth eruption of the pups at weaning.     

How antipsychotics work: the patients' perspective

BACKGROUND: While much is known about the neuropharmacology and objective efficacy of antipsychotics, little is known about how these drugs act on psychosis from the patients' perspective. Most previous studies of the patient's perspective have focused on drug tolerability and acceptability-rather than their effects on psychosis per se. METHODS: The authors examined how antipsychotics work from a patient's perspective by analyzing their responses to a subjective questionnaire. Ninety-one patients with schizophrenia (cross-sectional component) and eight neuroleptic na?ve patients (before and after treatment, longitudinal component) participated. The patients' responses to the questionnaire were analyzed using Principal Component Analysis (PCA) and general linear models. RESULTS: Analysis of the patients' responses showed that from their perspective the drugs were substantially more effective in: "help deal, help stop thinking, and make the symptoms not bother" rather than "take away" or "change my mind". This differentiation was clear in the raw data and was supported by a formal PCA. Two underlying factors-the first termed detachment and second eradication-explained 71% of the variance in the patients' perspective on how antipsychotics work for them. Neuroleptic na?ve patients, who had no prior exposure, expected drugs to help with both detachment and eradication, but, changed their mind with just 6 weeks of experience with the medications. CONCLUSIONS: From the patients' perspective the action of antipsychotics is best characterized by a detachment from symptoms-rather than an eradication or elimination of symptoms. They have more wide-ranging expectations prior to antipsychotic exposure, but, even 6 weeks of exposure is sufficient to change their mind in favor of detachment. This finding is consistent with some of the very earliest ideas that antipsychotics produced a state of "indifference" and is also consistent with the more recent, neurobiologically informed notions that antipsychotics work by dampening the salience of psychotic symptoms.