APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

Acid emulsions stabilized by soy whey concentrates and soluble soybean polysaccharides: Role of biopolymer interaction strategies on stability against environmental stresses.

This article focuses on the evaluation of different interaction strategies between soy whey concentrates (SWC) and soluble soybean polysaccharides (SSPS) at pH 3.0 on the emulsion stability against freeze-thawing and mechanical stirring. Emulsions were prepared from aqueous dispersions of both biopolymers (3.0% w/w SSPS and SWC, 1:1 mass ratio) and sunflower oil (10% w/w) by aqueous phase complexation (APC), interfacial complexation (IC) and interfacial complexation and sonication (ICS). SWC control emulsion was a poor emulsifying ability; SSPS addition, through the APC and ICS strategies, noticeably improved the SWC emulsifying properties. ICS emulsions showed the highest stability to environmental stresses, due a combination of low initial particle size, flocculation degree and steric hindrance promoted by the presence of SSPS chains at the interface. This study provides valuable information forthe utilization of whey soy proteins in acid dispersed systems stable to environmental stresses.

Impact of environmental stresses on the stability of acidic oil-in-water emulsions prepared with tofu whey concentrates.

The emulsifying properties of tofu-whey concentrates (TWCs) at pH 3.0, 4.0, and 5.0, and the stability of the resultant oil-in-water emulsions against freeze-thawing (24 h, -20 °C) and controlled or mechanical stress (orbital stirring at 275 rpm, 40 min) were addressed. TWCs were prepared from tofu-whey by heating at 50 °C (8.0 kPa) or 80 °C (24.0 kPa), dialysis (4 °C, 48 h), and freeze-drying, giving the samples TWC50 and TWC80, respectively. The particle size and interfacial properties at the oil/water interface were measured. Emulsions were prepared by mixing the TWC aqueous dispersions (1.0% protein w/w) and refined sunflower oil (25.0% w/w) by high-speed and ultrasound homogenization. The preparation of TWCs at higher temperatures (80 °C) promoted the formation of species of larger particle size, a slight decrease of interfacial activity, and the adsorption of more rigid biopolymer structures associated with an increase of film viscoelasticity in interfacial rheology measurements. The emulsifying properties of both concentrates were enhanced with decreasing pH (5.0-3.0), through a significant decrease of particle size (D4,3) and flocculation degree (FD), but only those prepared with TWC80 exhibited higher stability to freeze-thawing and mechanical stress at pH 3.0. This could be ascribed to a combination of low initial D4,3 and FD values, high protein load, and the presence of rigid species that impart high viscoelasticity to the oil/water interface. These results would be of great importance for the utilization of TWCs as food emulsifiers in acidic systems to impart high stability to environmental stresses.

Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers.

The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.

The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology.

Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.

Influence of chemical composition and structural properties on the surface behavior and foam properties of tofu-whey concentrates in acid medium.

This article focuses on the impact of chemical composition and structural properties of tofu-whey concentrates on their surface behavior at the air/water interface and foaming properties in acid medium. Liquid tofu-whey (pH 5.6 ±â€¯0.1) was concentrated at three combinations of temperature and pressure (50 °C-8.0 kPa, 65 °C-16.0 kPa and 80 °C-24.0 kPa), with further dialysis (4 °C, 48 h) and freeze-drying, giving the samples TWC50, TWC65 and TWC80, respectively. The increase of temperature during the concentration step promoted the enrichment of the concentrates in crude protein and calcium, without appreciable changes in the yield, the carbohydrate content and the polypeptide composition. For TWC80, the increase the degree of glycosylation and the intensity of the hydrophobic effect promoted the decrease of molecular flexibility and the formation of compact aggregates mediated by disulfide bridges as was evidenced by tricine-SDS-PAGE, TGA and FTIR assays. These structural differences have a pronounced impact of the pH-dependence of turbidity and solubility of protein and polysaccharides. At pH 4.0 all concentrates evidenced a ζ-potential close to zero, which enhanced their foam ability (overrun >1500%). Nevertheless, at this pH, TWC80 showed both the highest carbohydrate-to-protein mass ratio in the soluble fraction (>1.8) and foam stability (FS). Thus, the improvement of FS at pH 4.0 would be associated to the effective adsorption of compact rich-in-protein aggregates at the air/water interface and the higher content of soluble polysaccharides in the bulk phase. These findings are relevant for the application of tofu-whey concentrates in acidic dispersed systems, such as foams and aerated food emulsions.

Presenilin-1-associated abnormalities in regional cerebral perfusion.

OBJECTIVE: To investigate the influence of the presenilin-1 gene (PS-1) mutation on regional cerebral perfusion, SPECT was evaluated in 57 individuals. The subjects were members of a large pedigree from Colombia, South America, many of whom carry a PS-1 mutation for early-onset AD. METHODS: Members of this large kindred who were cognitively normal and did not carry the PS-1 mutation (n = 23) were compared with subjects who were carriers of the mutation but were asymptomatic (n = 18) and with individuals with the mutation and a clinical diagnosis of AD (n = 16). Cerebral perfusion was measured in each subject using hexamethylpropyleneamine oxime SPECT. The data were analyzed in two ways: 1) Mean cerebral perfusion in each of 4320 voxels in the brain was compared among the groups using t-tests (t-maps); and 2) each individual received a weighted score on 20 vectors (factors), based on a large normative sample (n = 200), using a method known as singular value decomposition (SVD). RESULTS: Based on t-maps, subjects with the PS-1 mutation who were asymptomatic demonstrated reduced perfusion in comparison with the normal control subjects in the hippocampal complex, anterior and posterior cingulate, posterior parietal lobe, and anterior frontal lobe. The AD patients demonstrated decreased perfusion in the posterior parietal and superior frontal cortex in comparison with the normal control subjects. Discriminant function analysis of the vector scores derived from SVD (adjusted for age and gender) accurately discriminated 86% of the subjects in the three groups (p < 0.0005). CONCLUSION: Regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of AD in carriers of the PS-1 mutation.

Neuropsychological profile of a large kindred with familial Alzheimer's disease caused by the E280A single presenilin-1 mutation.

It was hypothesized that subjective memory complaints represent the earliest sign of dementia in carriers of the presenilin-1 (PS1) mutation. A total of 122 subjects (44 males, 78 females) were included in this study. Forty of them were positive for the mutation in the PS1 gene (mutation positive, MP) whereas 82 showed negative results (mutation negative, MN). Subjects were active, functionally normal, even though some of them complained of memory difficulties. Two groups of neuropsychological instruments were administered: (a) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery (Morris et al., 1989), and (b) some additional neuropsychological tests (Raven Test, Wechsler Memory Scale, Rey-Osterrieth Complex Figure, Boston Naming Test, Naming of Categories, Boston Diagnostic Aphasia Examination, Memory of Three Phrases, Knopman Test, Digit Symbol, and Visual "A" Cancellation Test). Performance in both groups was quite similar. In a secondary analysis, the MP group was subdivided into two subgroups: without and with memory complaints. When comparing both subgroups, a better performance in the first subgroup was found throughout the different subtests. Statistically significant differences were observed in the following test scores: Mini-Mental State Examination, Naming Test (Low Frequency), Memory of Words Test, Recall of Drawings, Wechsler Memory Scale (Logical Memory, Associative Learning, and Total Score), Rey-Osterrieth Complex Figure (Immediate Recall Condition), Boston Diagnostic Aphasia Examination (Complex Ideational Material Subtest), Memory of Three Phrases Test, Serial Verbal Learning (maximum score and Delayed Recall), Knopman Test (First Trial, Second Trial, and Recall after 5 Minutes), Digit Symbol, and Visual "A" Cancellation Test (Additions). Results supported the hypothesis that memory complaints represent the earliest symptom of familial Alzheimer's disease. In addition to the memory difficulties, other minor cognitive impairments were also found, particularly, mild anomia, concentration difficulties and defects in the understanding of complex verbal material.

Role of splenectomy in prevention of hemorrhagic enteritis and death from hemorrhagic enteritis virus in turkeys.

Hemorrhagic diarrhea, gross hemorrhagic enteritis, and death caused by intravenous virus injection of hemorrhagic enteritis virus (HEV) were prevented in otherwise susceptible turkey poults by surgical splenectomy. The splenectomized poults produced anti-HEV antibodies, which indicated that splenectomy did not completely prevent replication of the virus. These results indicate that the spleen is necessary for the development of the intestinal lesions of this disease. The role of a toxic factor in this disease is discussed.

Duck plague: a carrier state in waterfowl.

Healthy waterfowl were found to be carriers of duck plague (DP) virus. Black ducks (Anas rubripes) and Canada geese (Branta canadensis) surviving a natural outbreak of DP at Coloma, Wisconsin, in 1973 yielded DP virus in cloacal swabs taken four years postinfection. Experimental infection of previously unexposed mallard ducks (Anas platyrhynochos) with the Coloma strain of DP virus CO-WI (73) also produced cloacal virus shedding for up to four years after infection. A second DP virus strain, LA-SD (73) from the Lake Andes, South Dakota, epornitic, was detected from cloacal swabs of pintail ducks (Anas acuta), gadwall ducks (Anas strepera), wood ducks (Aix sponsa), and Canada geese infected experimentally one year before. The frequency of swabs positive for DP virus varied between individuals within each of the tested species. The amount of detectable DP virus shed was about 100 plaqueforming units of virus percloacal swab. Oral erosions were present in all species tested except Canada geese and gadwall ducks. Erosions occurred at the openings of the sublingual salivary gland ducts. DP virus was isolated from erosions. All ducks with lesions proved to shed DP virus, although not necessarily at the time they had the lesion.

Hemorrhagic enteritis in turkeys: purification and quantification of the virus.

Two methods for purifying the virus of hemorrhagic enteritis from infected turkey spleens are described. One procedure utilized precipitation with polyethylene glycol, and the other consisted of trichlorotrifluoroethane extraction. Both procedures included sucrose-cesium chloride gradient centrifugation in the final purification step. The buoyant density of the viral fraction was 1.34 g/cm3, typical for adenoviral particles, and the size and morphologic characteristics of the virions observed by transmission electron microscopy suggested that the purified virus belongs to the family Adenoviridae. The biologic activity of the purified virus was titrated by inoculating 10-fold dilutions of the viral suspension into turkey poults. Mortality and hemorrhagic diarrhea proved to be inconsistent parameters of infection, and the degree of splenomegaly was proportional to the virus dose. The body/spleen ratio was the parameter selected for measuring viral activity, and the body/spleen ratio 50% was adopted as the unit for the titration of the virus. By using the same system it was demonstrated that the infectivity of the virus could be neutralized with antiserum produced in turkeys.

Is the immune system necessary for placental reproduction? A hypothesis on the mechanisms of alloimmunotherapy in recurrent spontaneous abortion.

Recurrent spontaneous abortion is being treated with alloimmunotherapy which consists of the inoculation of allogeneic mononuclear cells. However the mechanisms explaining the benefits of this therapy are not clear yet. Taking the immunotrophic hypothesis as the paradigm of the field of reproductive immunology, hereby we present a hypothesis to propose a role for the immune system in reproduction and at the same time to explain how alloimmunotherapy may work. We base our view on several facts: first, immunodeficient mice reproduce--albeit their progeny may not be as robust and numerous as that from normal individuals. Second, maternal lymphocytes cross the placenta and may induce graft versus host disease. Third, graft versus host disease in newborn F1 mice inoculated with paternal lymphocytes can be prevented by inoculation of the mother with the same paternal lymphocytes before and during pregnancy. We propose that: 1) the immune system by itself is not necessary for placental reproduction; 2) the immune system plays its major role in reproduction by counteracting the allogeneic response generated against the fetus; 3) recurrent spontaneous abortion represents a type of graft versus host disease induced by maternal cells infiltrating the fetus; and 4) alloimmunotherapy induces an antiidiotypic response necessary to counteract the graft versus host reaction in the fetus.

Prion plaques: molecular tumors. A hypothesis on the etiopathogenesis of prion diseases.

In spite of remarkable advances in the etiopathogenesis of spongiform encephalopathies in man and animals and the growing acceptance of the prion hypothesis, there is no explanation for the supposed 'autocatalytic' activity of this protein molecule. Our molecular tumor hypothesis proposes that the prion protein is a genotoxin which interacts directly or indirectly but specifically with its homologous cellular gene introducing mutations which lead to aberrant processing and accumulation of the protein. It is also speculated that this hypothesis would shed some light on other diseases not presently classified as prion diseases and in the process of ageing.

Initial stress differences between sliding and sectional mechanics with an endosseous implant as anchorage: a 3-dimensional finite element analysis.

Endosseous implants have been used as orthodontic anchorage in recent years. A 3-dimensional mathematical model was constructed that uses the finite element method, which simulated an endosseous implant and an upper canine with its periodontal ligament and cortical and cancellous bone. Levels of initial stress were measured during 2 types of canine retraction mechanics (friction and frictionless). The lower magnitude and more uniform stresses in the implant and its cortical bone were found to have a moment-force ratio (M/F) of 6.1:1, whereas the canine and its supporting structures exerted a M/F ratio of 10.3:1. On the basis of these results, when the anchor unit is an endosseous implant, it seems better to use a precalibrated retraction system without friction (T-loop) where a low load-deflection curve would be generated.

[Detection of antibodies to beta-amyloid in carriers of E280A mutation in the presenilin-1 gene]. / Detección de anticuerpos contra el beta-amiloide en individuos portadores de la mutación E280A en el gen de la presenilina-1.

OBJECTIVE: To investigate some immune component that could contribute to the pathogenesis of Alzheimer's disease associated with the E280A mutation of the presenilin-1 gene (PS-1). PATIENTS AND METHODS: Serum antibodies against both cardiolipin and beta-amyloid peptides (beta 1-40 and beta 1-42) were quantitated by means of an indirect ELISA technique in carriers of the mutation, either healthy or with Alzheimer's disease, as well as in normal controls without the mutation. RESULTS: Out of 19 patients with Alzheimer's disease only 2 had increased values of antibodies to cardiolipin, namely: one with 14.58 micrograms/ml of IgM and the other with 36.16 micrograms/ml of IgG. The remaining individuals revealed values under 10 micrograms/ml, considered normal, and there was no significant difference between the groups. Significant serum reactivity (p < 0.001) was detected against both beta-amyloid peptides in the mutation carriers, either with or without Alzheimer's disease, as compared to the control group. No correlation was detected between this antibody response and the mental or functional situation of the patients. CONCLUSION: beta-amyloid antibodies, present in the mutation carriers, may simply represent a marker of immune activation induced by beta-amyloid with no in vivo effect; however, despite the results, the possibility can not be ruled out of a pathogenic role of these antibodies in early onset Alzheimer's disease.

Clients' perceptions of involuntary hospitalization.

Because involuntary hospitalization involves the restricting of an individual's autonomy and choice, the challenge in nursing practice is to listen to the client's perceptions and then to set "limits in a humane and least restrictive manner to assure the safety of the client and others" (American Nurses' Association, 1982). However, the danger is that limits may be used to enforce socially desired behavior beyond what is necessary for safety (Garritson, 1983). Study results indicate that clients can clearly offer many specific ideas about their health care experience and needs. These perceptions offer an experiential grounding in the process of offering sensitive, relevant, quality care. Because nursing is a client-centered process, studies on clients' perceptions of care experiences are an area in which nurses can make a major research contribution. Implementation of care based on these client-centered studies could offer significant administrative and practice contributions. The client wants to be heard; nurses have an opportunity to take an active role.

Immune signalling responses in intestinal epithelial cells exposed to pathogenic Escherichia coli and lactic acid-producing probiotics.

Enterohaemorrhagic Escherichia coli O157:H7 and adherent-invasive Escherichia coli are two groups of enteric bacterial pathogens associated with haemorrhagic colitis and Crohn's Disease, respectively. Bacterial contact with host epithelial cells stimulates an immediate innate immune response designed to combat infection. In this study, immune responses of human epithelial cells to pathogens, either alone or in combination with probiotic bacteria were studied. Industrially prepared Lactobacillus helveticus strain R0052 was first examined by microarray analysis and then compared to broth-grown strains of R0052 and Lactobacillus rhamnosus strain GG using quantitative realt-time polymerase chain reaction. Results showed host immune activation responses increased following pathogen exposure, which were differentially ameliorated using probiotics depending on both the preparation of probiotics employed and conditions of exposure. These findings provide additional support for the concept that specific probiotic strains serve as a promising option for use in preventing the risk of enteric bacterial infections.

PCR activity of CMV in healthy CMV-seropositive individuals: does latency need redefinition?

To demonstrate a possible association between stress factors and the presence of human cytomegalovirus (HCMV) DNA in leukocytes and in cell-free body fluids, at 2-week intervals over a 6-month period, specimens were taken for HCMV DNA testing from 11 healthy CMV-seropositive individuals who were also surveyed for stress-producing events occurring during the previous week. A positive polymerase chain reaction (PCR) signal was given in 104/127 (81.9%) urines, 73/127 (57.3%) throat washings and 68/127 (53.6%) leukocyte samples. An association was found between HCMV DNA in urine and a stress-producing event at work (p < 0.04). An association was also found between detection of HCMV DNA in throat washings and alcohol ingestion (P < 0.006) and between the presence of oral herpes lesions and the detection of HCMV DNA in leukocytes (p < 0.0019). The results suggest that viral reactivation is more common than previously thought and that stress may be a triggering event.

Heparin plus aspirin as a "single" therapy for recurrent spontaneous abortion associated with both allo- and autoimmunity.

PROBLEM: The aim of this study was to contribute to the study of the pathogenesis and the treatment of recurrent spontaneous abortion (RSA) associated with immune alterations. METHOD OF STUDY: This is a prospective clinical trial with 11 patients with RSA associated with allo- and autoimmunity not receiving lymphocyte immunizations but only heparin and aspirin preconceptionally and through pregnancy. A concurrent group of 8 patients receiving a complete therapy (lymphocyte immunizations, heparin, and aspirin) but not receiving heparin and aspirin preconceptionally is also included in this report. RESULTS: The rate of pregnancy success in these patients was 90.9% (10/11), and the rate of success of the concurrent group was 75.0% (6/8). CONCLUSIONS: The results are in agreement with the working hypothesis regarding the possible final common mechanism in the pathogenesis of abortion associated with allo- and autoimmunity. The "single" therapy with heparin and aspirin was effective, less costly, and logistically simpler to provide than a complete therapy including lymphocyte immunizations.