APOE3 Christchurch modulates tau phosphorylation and ß-catenin/Wnt/Cadherin signaling in induced pluripotent stem cell-derived cerebral organoids from Alzheimer's cases.

Alzheimer's disease (AD) is the most common cause of dementia among older adults. APOE3 Christchurch (R136S, APOE3Ch ) variant homozygosity was reported in an individual with extreme resistance to autosomal dominant AD due to the PSEN1 E280A mutation. This subject had a delayed clinical age at onset and resistance to tauopathy and neurodegeneration despite extremely high amyloid plaque burden. We established induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and from a non-protected kindred control (with PSEN1 E280A and APOE3/3 ). We used CRISPR/Cas9 gene editing to successfully remove the APOE3Ch to wild type in iPS cells from the protected case and to introduce the APOE3Ch as homozygote in iPS cells from the non-protected case to examine causality. We found significant reduction of tau phosphorylation (pTau 202/205 and pTau396) in cerebral organoids with the APOE3Ch variant, consistent with the strikingly reduced tau pathology found in the resistant case. We identified Cadherin and Wnt pathways as signaling mechanisms regulated by the APOE3Ch variant through single cell RNA sequencing in cerebral organoids. We also identified elevated ß-catenin protein, a regulator of tau phosphorylation, as a candidate mediator of APOE3Ch resistance to tauopathy. Our findings show that APOE3Ch is necessary and sufficient to confer resistance to tauopathy in an experimental ex-vivo model establishing a foundation for the development of novel, protected case-inspired therapeutics for tauopathies, including Alzheimer's.

Nutritional Assessment in Patients with Early-Onset Autosomal Dominant Alzheimer's Disease Due to PSEN1- E280A Genetic Variant: A Cross-Sectional Study.

Background: Weight loss and malnutrition are frequent findings in late-onset and sporadic presentations of Alzheimer's Disease (AD). However, less is known about nutritional status in Early-Onset Autosomal Dominant AD (EO-ADAD). Objective: To analyze the association between nutritional status and other clinical and sociodemographic characteristics in individuals with a genetic form of EO-ADAD. Design settings and participants: Cross-sectional study with 75 non-institutionalized participants from a cohort of Autosomal Dominant AD (13 with mild cognitive impairment and 61 with dementia, ages from 38 to 67 years) underwent a structured clinical assessment with emphasis on nutritional status. Measurements: Primary outcome was nutritional status and it was measured using the Mini Nutritional Assessment (MNA). Patients were categorized according to MNA total score, as undernourished (MNA ≤23.5) and well-nourished (MNA ≥ 24). Sociodemographic and clinical variables identified as potential predictors or confounders of nutritional status were also collected. Results: Undernourishment by MNA was present in 57.3% of the sample. Forty-two percent of participants had abnormal BMI values considered lower than 18.5 or higher than 24.9 kg/m2. Total BMI values were similar in well and undernourished patients (median 24.2 IQR 3.59 and median 23.9 IQR 4.42, respectively, p=0.476). When comparing well and undernourished groups, we found statistically significant differences for variables: severity of dementia (p=0.034), frailty (p=0.001), multimorbidity (p=0.035) and, polymedication (p=0.045). Neither adjusted logistic regression nor the Poisson regression showed that any clinical or sociodemographic variables explained undernourishment. Conclusions: Undernourishment was a frequent finding in our sample of EO-ADAD, especially in later stages of the disease. Patients with polymedication, multimorbidity, frailty and severe dementia show differences in their nutritional status with a tendency to be more frequently undernourished. Further studies with larger sample sizes are needed to establish this association.

[Testing nasogastric tube placement: evaluation of three different methods in intensive care unit]. / Evaluation prospective de trois méthodes de positionnement de la sonde nasogastrique en réanimation.

OBJECTIVE: Evaluation of three methods (aspiration of gastric fluid, pH measurement of gastric fluid, and insufflation of air) in order to determine the right position of the nasogastric (NG) tube. STUDY DESIGN: Prospective, observational study in an intensive care unit. PATIENTS AND METHODS: All patients requiring a NG tube were included. Since the NG tube was inserted three tests were successively performed: aspiration of gastric fluid, pH measurement of the gastric fluid, and auscultation over the epigastrium of air injected through the NG tube. The feasibility and the results obtained for each test were noted and compared to chest X-ray, considered as the reference. Chest X-ray classified the complications as major or minor. RESULTS: A total of 419 NG tube (202 decompressive NG tube and 217 gastric feeding tube) were analysed in 280 patients. Malpositions of the NG tube were observed in 10% (majors, n=11 and minors, n=31). Aspiration of gastric fluid and pH measurement were not sensible (77% and 49%, respectively) and not specific (38% and 74%, respectively). Insufflation of air was sensible (96%) but not specific (17%). The combination of the three methods did not improve the sensibility and specificity. Two complications were only detected by chest X-ray (one insertion in the intrapleural space, and one pneumothorax). CONCLUSION: None of the test evaluated, alone or associated, was sufficient to avoid chest X-ray. Moreover the occurrence of two potential and serious complications only detected by chest X-ray increase this assertion.

[Activated protein C treatment: experience about 23 patients in the operative period]. / Traitement par la protéine C activée: expérience à propos de 23 patients dans un contexte périopératoire.

OBJECTIVE: To evaluate the use of activated C protein (ACP) in a Surgical Intensive Care Unit. STUDY DESIGN: A prospective observational study. PATIENTS AND METHODS: All patients receiving ACP during 20 months in the operative period. RESULTS: Twenty-three patients were treated by ACP. The origin of sepsis was peritonitis (n = 14), infected pancreatitis (n = 3), mediastinitis (n = 2), one urologic sepsis, one facial cellulitis, one catheter related infection, and one postoperative pneumonia. In two cases, the peritonitis was associated with a pleuretic infection, and in two other cases with parietal cellulites. Mean age was 69+/-13 years. Severities evaluated by SAPS II, LODS were 59+/-13 and 7+/-3, respectively. Mean number organ dysfunction was 3.3+/-1.0. Septic shock was present in 91% with concomitant use of catecholamines for a mean period of 87+/-64 hours. Bacteraemia was present in 43% of the patients. A treatment with hydrocortisone was associated in 52% of the patients. The ICU and hospital lengths of stay were 15+/-16 days, and 34+/-38 days, respectively. Mortality at day 28 was 35%. Two significant bleeding were observed, one requiring red blood cell transfusion and the other one a surgical control of the bleeding associated with red blood cell transfusion. CONCLUSION: With global management of severe sepsis, including the use of activated C Protein, this prospective observational study showed a 30% reduction of the predicted mortality by SAPS II scoring without significant increase of bleeding episodes in a surgical context.

[Hepatorenal syndrome: from physiopathology to treatment]. / Syndrome hépatorénal: de la physiopathologie au traitement.

OBJECTIVES: Data synthesis on physiopathology and treatment of hepatorenal syndrome (HRS). DATA SOURCES: Data were searched in the Medline database from 1975 to 2002 using the following key-words: hepatorenal syndrome, ascite, cirrhosis and portal hypertension. DATA EXTRACTION: Publications from 1986 to 2002 were selected depending on the quality of their methodology and their pertinence. One publication from 1975 was kept. DATA SYNTHESIS: Hepatorenal syndrome is a common and severe complication of patients with advanced liver cirrhosis with ascites. It is a functional renal failure due to intense vasoconstriction of the renal circulation secondary to an intense splanchnic vasodilatation. Two types of HRS are differentiated mainly by the speed and the magnitude of the renal failure. Liver transplantation remains the best treatment but is rarely applicable because of the short survival after diagnosis. In the last few years, new therapy have been developed, vasoconstrictor drugs which mainly elicit their effects on the splanchnic circulation as vasopressin and principally its analogues ornipressine and terlipressine are effective in improving renal function and could act as bridge for liver transplantation. The place of the transjugular intrahepatic portosystemic shunt remain to be evaluated. CONCLUSION: Prognosis of patients with HRS remains poor but the pharmacologic treatment by terlipressine has improved the prognosis particularly in order to wait liver transplantation.

Multilocus approach to cardiovascular risk.

Until now, our familial studies have showed that shared genetic and environmental factors are involved on lipid parameters variability. More precisely, being working on 119 families we have showed that: a) The apolipoprotein E (apo E) common polymorphism is involved in the total cholesterol, low density lipoprotein cholesterol (LDL-Chol), apo E, apo B levels variability, b) the apolipoprotein A-IV gene had no effect on lipid metabolism parameters variability, apo A-IV levels included, c) the apolipoprotein B gene was associated with total cholesterol, high density lipoprotein cholesterol, LDL-Chol, triglycerides and apo B levels genetic variability, d) the lipoproteine lipase (LPL) gene was responsible for 6.5% of the triglycerides variability, e) the apo E and LPL 447 polymorphisms influence in conjunction lipid parameters. These preliminary results on effects and combination effects of polymorphic genes show the interest of a multilocus approach. We have used in a subgroup of 416 individuals of a familial cohort (Stanislas Cohort) a prototype assay that genotypes a panel of 35 polymorphic sites on 15 candidate genes of Cardiovascular diseases. Each sample is amplified by two multiplex polymerase chain reactions, then hybridized to an array of immobilized, oligonucleotide probes. The frequencies of the rare alleles were in agreement with those reported by others in caucasian populations. The realisation of this multiplex assay in the 1,006 families of the Stanislas Cohort, which is underway, will allow us a better understanding of the inter-individual variability of lipids and will contribute to the determination of the genetic susceptibility of one's individual to cardiovascular risk.

Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry.

We measured the levels of two beta-amyloid (Abeta)-sequestering proteins, apolipoprotein (Apo) E and transthyretin (TTR), in ventricular human cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients and controls in relation to brain histological findings. We also studied actin levels in CSF as a marker of the biochemical role of these two proteins in the cytoskeleton. We show that TTR levels in CSF were significantly decreased in AD patients compared to controls and negatively correlated with the senile plaque (SP) abundance. Moreover, actin levels were positively linked to TTR levels and increased in CSF samples of patients homozygous for the ApoE epsilon4-allele. We propose that TTR and ApoE4 may have competition in the aggregation of Abeta and its deposition in the SP of AD brain. The relationships between ApoE, TTR and actin could suggest a metabolic implication of ApoE genetics and TTR levels in cytoskeletal biochemistry which may be relevant to the pathogenesis of AD.

High sensitivity of laser-induced fluorescence detection in capillary gel electrophoresis for accurate apolipoprotein E genotyping.

Human apolipoprotein E (apoE) is a product of a polymorphic gene. In the general population, it shows two major mutations, which lead to the appearance of three common alleles encoding for three protein isoforms. This polymorphism is important in the regulation of lipid metabolism. Accurate apoE phenotyping or genotyping has become essential in clinical laboratories, since the epsilon 4 allele has been associated with cardiovascular and Alzheimer's diseases. Endonuclease restriction isotyping, followed by slab gel electrophoresis, is a rapid and convenient method for the investigation of common apoE genotypes. However, during the large-scale apoE genotyping of the STANISLAS cohort, we were confronted with a partial lack of sensitivity and resolution power of this traditional method, which sometimes leads to the misclassification of the genotypes epsilon 2/2 and epsilon 3/2. We have overcome this difficulty by separating the restriction fragments with capillary gel electrophoresis linked to laser-induced fluorescence detection. The baseline resolution was 2 bp, and the sensitivity limit attainable was similar to that by radioactive detection. The distinction between the epsilon 3/2 and the epsilon 2/2 genotypes became unequivocal, even when only low amounts of DNA were available for amplification.

Association of apolipoprotein E allele epsilon 4 with late-onset sporadic Alzheimer's disease.

Apolipoprotein E, type epsilon 4 allele (ApoE epsilon 4), is associated with late-onset sporadic Alzheimer's disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for epsilon 4 allele frequencies). These data support the involvement of ApoE epsilon 4 allele as a very important risk factor for the clinical expression of AD.

Apolipoprotein B signal peptide polymorphism in patients with myocardial infarction and controls. "The ECTIM study".

We report the allele frequencies of the apolipoprotein B (Apo B) signal peptide polymorphism in patients with myocardial infarction and compare them with controls. The first sample consists of 197 myocardial infarction patients and 168 controls from Belfast (UK). The second sample consists of 167 myocardial infarction patients and 205 controls from Strasbourg (France), and the third consists of 71 patients and 146 controls from Haute-Garonne (Toulouse, France). No significant differences were observed in the frequency distribution of genotypes among cases and controls or between populations. However, there were more rare homozygotes in the Belfast cases. Significant associations were observed between the Apo B signal peptide polymorphism and mean levels of total cholesterol, low density lipoprotein cholesterol, Apo B and lipoprotein particles containing Apo (a) [Lp(a)] in the Strasbourg control population. Individuals homozygous for the rare allele had higher levels of these lipid parameters. In Belfast, although not statistically significant, the Apo B signal peptide polymorphism had a similar effect on Apo-B-related parameters as seen in Strasbourg. No significant associations were observed in the Haute-Garonne population where the risk of myocardial infarction is three times lower than in Belfast. In all three populations, the average Lp(a) levels were consistently different among Apo B signal peptide genotypes. These data implicate the Apo B signal peptide in determining some of the risks of myocardial infarction in these populations. Regardless of the exact mechanism, the Apo B signal peptide is an important candidate locus for the study of potentially atherogenic lipid variants.

Utilization of family characteristics in nutritional classification of preschool children.

Methodologies useful in classifying preschool children into nutritional categories are presented and evaluated with respect to classification accuracy. The methodologies are illustrated with data from a study conducted by the National Nutrition Council of the Philippines on the relationships of family characteristics and preschool children's nutritional levels. We have demonstrated that reasonably good classification ability can be achieved with rather simple statistical methodologies.