New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Morphological And Intracellular Alterations Induced By Cytotoxin Vt2y Produced By Escherichia Coli Isolated From Chickens With Swollen Head Syndrome

Recently, a novel verocytotoxin named VT2y was described which belongs to the STx family and is produced by Escherichia coli isolated from domestic poultry with swollen head syndrome (SHS). The VT2y toxin induced apoptosis in Vero, HeLa, CHO, CEF (primary chicken embryo fibroblast) and PCK (primary chicken kidney) cell lines. Morphological evidence (nuclear shrinkage, chromatin condensation and blebbing of the plasma membrane) of apoptosis could be distinguished in 15 min and was maximal at 1 h after treatment with VT2y. This was confirmed by the terminal dUTP nick-end-labeling (TUNEL) method. © 2001 Federation of European Microbiological Societies.19717984Borenfreund, E., Puerner, J.A., A simple quantitative procedure using monolayer cultures for cytotoxicity assays (HTD/NR-90) (1984) J. Tissue Cult. Methods, 9, pp. 7-9Bradford, M.M., A rapid method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding (1976) Anal. Biochem., 72, pp. 248-254Gannon, V.P.J., Gyles, C.L., Wilcock, B.P., Effects of Escherichia coli Shiga-like toxins (Verotoxins) in pigs (1989) Can. J. Vet. Res., 53, pp. 306-312Gannon, V.P.J., Gyles, C.L., Characteristics of the Shiga-like toxin produced by Escherichia coli associated with porcine edema disease (1990) Vet. Microbiol., 24, pp. 89-100Inward, C.D., Williams, J., Chant, I., Crocker, J., Milford, D.V., Rose, P.E., Taylor, C.M., Verocytotoxin-1 induces apoptosis in Vero cells (1995) J. Infect., 30, pp. 213-218Karmali, M.A., Petric, M., Lim, C., Fleming, P.C., Arbus, G.S., Lior, H., The association between hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli (1985) J. Infect. Dis., 151, pp. 775-782Kerr, J.F.R., Wyllie, A.H., Currie, A.R., Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics (1972) Br. J. Cancer, 26, pp. 239-257Kodama, T., Nagayama, K., Yamada, K., Ohba, Y., Akeda, Y., Honda, T., Induction of apoptosis in human renal proximal tubular epithelial cells by Escherichia coli verocytotoxin 1 in vitro (1999) Med. Microbiol. Immunol., 188, pp. 73-78Lingwood, C.A., Law, H., Richardson, S., Petric, M., Brunton, J.L., De Grandis, S., Karmali, M., Glycolipid binding of purified and recombinant Escherichia coli produced verotoxin in vitro (1987) J. Biol. Chem., 262, pp. 8834-8839MacLeod, D.L., Gyles, C.L., Purification and characterization of an Escherichia coli Shiga-like toxin II variant (1990) Infect. Immun., 58, pp. 1232-1239Marques, L.R.M., Peiris, J.S.M., Cryz, S.J., O'Brien, A.D., Escherichia coli strains isolated from pigs with edema disease produce a variant of Shiga-like toxin II (1987) FEMS Microbiol. Lett., 44, pp. 33-38McConkey, D.J., Nicotera, P., Orrenius, S., Signaling and chromatin fragmentation in thymocyte apoptosis (1994) Immunol. Rev., 142, pp. 343-363Mello, M.L., Vidal, B., (1980) Práticas em Biologia Celular, p. 71. , Edgard Blucher, R.J., EdMiller, J.H., (1972) Experiments in Molecular Biology, , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NYMitchell, D.B., Santone, K.S., Acosta, D., Evaluation of cytotoxicity in cultured cells by enzyme leakage (1980) J. Tissue Cult. Methods, 6, pp. 113-116Morley, A.J., Thomson, D.K., Swollen head syndrome in broiler chicken (1984) Avian Dis., 28, pp. 238-243Nakamura, K., Mase, M., Tanimura, N., Yamaguchi, S., Yuasa, N., Attempts to reproduce swollen head syndrome in specific pathogen-free chickens by inoculating with Escherichia coli and/or turkey rhinotracheits (1998) Avian Pathol., 27, pp. 21-27O'Brien, A.D., Holmes, R.K., Shiga and Shiga-like toxins (1987) Microbiol. Rev., 51, pp. 206-220Pages Mante, A., Costa Quintana, L., Síndrome de cabeza hinchada (SH). Etiología y profilaxis (1987) Med. Vet., 4, pp. 53-57Parreira, V.R., Yano, T., Cytotoxin produced by Escherichia coli isolated from chickens with swollen head syndrome (SHS) (1998) Vet. Microbiol., 62, pp. 111-119Parreira, V.R.P., Caracterização de uma citotoxina produzida por amostras de Escherichia coli de origem aviária (1998) Tese de Doutorado, pp. 27-29. , ICB, Universidade de São Paulo, São PauloParreira, V.R., Yano, T., Gyles, C., Shiga toxin gene in E. coli from swollen head syndrome in chickens (2000) 4th International Symposium and Workshop on 'Shiga toxin (verocytotoxin)-producing Escherichia coli infections', p. 149. , KyotoPattison, M., Chettle, N., Randall, C.J., Wyeth, P.J., Observations on swollen head syndrome in broiler and broiler breeder chickens (1989) Vet. Rec., 125, pp. 229-231Samuel, J.E., Perera, L.P., Ward, S., O'Brien, A.D., Ginsburg, V., Krivan, H.C., Comparison of the glycolipid receptor specificities of Shiga-like toxin type II and Shiga-like toxin type II variants (1990) Infect. 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Aberrant crypt foci and colon cancer: comparison between a short- and medium-term bioassay for colon carcinogenesis using dimethylhydrazine in Wistar rats

Aberrant crypt foci (ACF) in the colon of carcinogen-treated rodents are considered to be the earliest hallmark of colon carcinogenesis. In the present study the relationship between a short-term (4 weeks) and medium-term (30 weeks) assay was assessed in a model of colon carcinogenesis induced by dimethylhydrazine (DMH) in the rat. Six-week-old male Wistar rats were given subcutaneous injections of DMH (40 mg/kg) twice a week for 2 weeks and killed at the end of the 4th or 30th week. ACF were scored for number, distribution pattern along the colon and crypt multiplicity in 0.1% methylene-blue whole-mount preparations. ACF were distinguished from normal crypts by their larger size and elliptical shape. The incidence, distribution and morphology of colon tumors were recorded. The majority of ACF were present in the middle and distal colon of DMH-treated rats and their number increased with time. By the 4th week, 91.5% ACF were composed of one or two crypts and 8.5% had three or more crypts, while by the 30th week 46.9% ACF had three or more crypts. Thus, a progression of ACF consisting of multiple crypts was observed from the 4th to the 30th week. Nine well-differentiated adenocarcinomas were found in 10 rats by the 30th week. Seven tumors were located in the distal colon and two in the middle colon. No tumor was found in the proximal colon. The present data indicate that induction of ACF by DMH in the short-term (4 weeks) assay was correlated with development of well-differentiated adenocarcinomas in the medium-term (30 weeks) assay

Aberrant crypt foci and colon cancer: comparison between a short- and medium-term bioassay for colon carcinogenesis using dimethylhydrazine in Wistar rats

Aberrant crypt foci (ACF) in the colon of carcinogen-treated rodents are considered to be the earliest hallmark of colon carcinogenesis. In the present study the relationship between a short-term (4 weeks) and medium-term (30 weeks) assay was assessed in a model of colon carcinogenesis induced by dimethylhydrazine (DMH) in the rat. Six-week-old male Wistar rats were given subcutaneous injections of DMH (40 mg/kg) twice a week for 2 weeks and killed at the end of the 4th or 30th week. ACF were scored for number, distribution pattern along the colon and crypt multiplicity in 0.1% methylene-blue whole-mount preparations. ACF were distinguished from normal crypts by their larger size and elliptical shape. The incidence, distribution and morphology of colon tumors were recorded. The majority of ACF were present in the middle and distal colon of DMH-treated rats and their number increased with time. By the 4th week, 91.5% ACF were composed of one or two crypts and 8.5% had three or more crypts, while by the 30th week 46.9% ACF had three or more crypts. Thus, a progression of ACF consisting of multiple crypts was observed from the 4th to the 30th week. Nine well-differentiated adenocarcinomas were found in 10 rats by the 30th week. Seven tumors were located in the distal colon and two in the middle colon. No tumor was found in the proximal colon. The present data indicate that induction of ACF by DMH in the short-term (4 weeks) assay was correlated with development of well-differentiated adenocarcinomas in the medium-term (30 weeks) assay

DELTA-OPIOID RECEPTOR MODULATION OF THE HYPOTHALAMIC -PITUITARY-ADRENOCORTICAL AXIS

STUDY ON THE MODULATION OPERATED BY DELTA-OPIOID RECEPTOR ON THE HYPOTHALAMIC -PITUITARY-ADRENOCORTICAL AXI

Effect of deltorphin on pituitary-adrenal response to insulin-induced hypoglycemia and ovine corticotropin-releasing hormone in healthy man

To determine the role of delta-opioid receptors in the modulation of hypothalamic-pituitary-adrenal activity, we studied in normal subjects the effect of the highly selective delta-opioid receptor agonist deltorphin (DT) on the secretion of ACTH, cortisol, and arginine vasopressin in response to insulin-induced hypoglycemia. In an attempt to clarify the site of opiate modulation of ACTH secretion, we also studied in normal subjects the effect of DT on the ACTH response to ovine CRH-41. DT blunted the ACTH, cortisol, and arginine vasopressin responses to insulin-induced hypoglycemia, whereas it had no effect on the ACTH and cortisol responses to CRH. We conclude that DT-induced activation of delta-opioid receptors exerts an inhibitory influence on hypoglycemia-stimulated ACTH secretion. Based on the lack of an effect of DT on the ACTH response to CRH, we postulate that DT may modulate the secretion of ACTH through suprapituitary mechanisms

Stress-induced activation of sympathetic nervous system is attenuated by the delta-opioid receptor agonist deltorphin in healthy man

Stress-induced activation of sympathetic nervous system is attenuated by the delta-opioid receptor agonist deltorphin in healthy ma