RESUMO
OBJECTIVES: Although lifestyle interventions are first-line treatment for individuals living with prediabetes and type 2 diabetes (T2D), they are rarely implemented effectively in routine clinical care. METHODS: We present a retrospective analysis of a 12-month, single-centre, structured multidomain lifestyle intervention clinic offered to individuals living with prediabetes and type 2 diabetes. The intervention consisted of expert-guided educational and nutritional counselling combined with a personalized physical exercise prescription, with the main goal of improving metabolic health and reaching remission. Anthropometric parameters, glucose, basal insulin, glycated hemoglobin (A1C), and lipid levels were measured at baseline and at 3, 6, and 12 months after the lifestyle intervention initiation. Remission of prediabetes and T2D were defined as a return of A1C at 6 months to <6.5% (or <5.7% for prediabetes) and persisting for at least 3 months in the absence of glucose-lowering pharmacotherapy. RESULTS: After a multidomain, expert-guided lifestyle intervention, 117 individuals living with prediabetes and T2D had significantly improved metabolic profiles: Mean weight change at 12 months was -4.9 kg (95% confidence interval [CI], -4.0 to -5.7; p<0.001), and mean change in A1C at 12 months was -0.6% (95% CI, -0.4 to -0.7; p<0.001). A substantial proportion of individuals reached the criteria for remission (20% among participants with prediabetes and 12% among those with T2D). CONCLUSIONS: The results of this study suggest that prioritizing lifestyle changes in a multifaceted, progressive, 12-month intervention in this population improves anthropometric and insulin resistance measures, and has the potential to normalize metabolic values, even to the point of reaching the criteria of remission.
Assuntos
Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Humanos , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas , Estudos Retrospectivos , Glicemia/metabolismo , Estilo de Vida , GlucoseRESUMO
The use of blood-contaminated drug preparation equipment is believed to be associated with the transmission of hepatitis C virus (HCV) among injection drug users (IDUs), but the extent of HCV infection risk is unclear. The objective of this review was to appraise the evidence regarding HCV incidence associated with the use of drug preparation equipment such as drug mixing containers, filters and water. In June 2007, cohort and case-control studies examining the association of HCV incidence with the sharing of drug preparation equipment were identified by searching electronic reference databases as well as the reference lists of published papers. Ten studies (seven cohort and three nested case-control) met the inclusion criteria for the review. The relative risk of HCV infection associated with drug preparation equipment were mainly between 2.0 and 5.9; however, the precision of the estimates from individual studies were marked by wide confidence intervals. Few studies exist to allow an adequate assessment of the individual contributions of containers, filters and water to HCV incidence. The major methodological limitations of reviewed studies were short follow-up times, inadequate control of confounders and lack of exclusion of periods when IDUs were not at risk for HCV infection through drug injection. Current evidence implicating the association of drug preparation equipment with HCV incidence is limited by several methodological concerns.
Assuntos
Infecção Hospitalar/transmissão , Contaminação de Equipamentos , Hepatite C/epidemiologia , Hepatite C/transmissão , Abuso de Substâncias por Via Intravenosa/complicações , Adulto , Humanos , Incidência , Medição de RiscoRESUMO
We used data and leftover samples collected through the SurvUDI network to describe the epidemiology of hepatitis C virus (HCV) infection among injection drug users (IDUs) in Eastern Central Canada. Among the 1380 selected IDUs, having participated twice or more between 1997 and 2003, the overall HCV prevalence rate was 60.4% (95% confidence interval [CI]: 57.7-63.0%). Among the 543 initially uninfected participants, the HCV incidence rate was 27.1 per 100 person-years (95% CI: 23.4-30.9 per 100 person-years). Independent predictors of seroconversion, identified among 359 participants, were age, injecting for a year or less, injecting with a syringe previously used by someone else, injecting most often cocaine, engaging in prostitution, and being recruited in a major urban centre. The HCV epidemic severely affects IDUs in this area. Actions to prevent HCV transmission, such as distribution of sterile injection equipment, have to be reinforced. Special efforts have to be targeted towards starting IDUs.
Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/epidemiologia , Abuso de Substâncias por Via Intravenosa/virologia , Adulto , Canadá/epidemiologia , Feminino , Humanos , Incidência , Masculino , Prevalência , Abuso de Substâncias por Via Intravenosa/epidemiologiaRESUMO
Amyloid deposits characteristic of cerebral amyloid angiopathy lead to vessel rupture and intracerebral hemorrhage. Proteoglycans associate with the amyloid fibril deposits and are thought to play a role in the polymerization of amyloid proteins and the propagation of the deposition process. A series of low molecular weight anionic compounds was developed to mimic the glycosaminoglycan moieties of these proteoglycans. These compounds were tested in different in vitro systems to determine their anti-Abeta amyloid activity. Specific compounds were identified as being anti-fibrillogenic and protective against Abeta-induced cvtotoxicity. Such compounds also did not show intrinsic cellular toxicity could cross the blood-brain barrier (BBB) in vivo, and showed a good safety profile following chronic' exposure. Molecules showing an anti-amyloid profile combined with the ability to cross the BBB represent promising therapeutics for CAA.
Assuntos
Angiopatia Amiloide Cerebral/tratamento farmacológico , Glicosaminoglicanos/uso terapêutico , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica , Células Cultivadas , Angiopatia Amiloide Cerebral/metabolismo , Dicroísmo Circular , Humanos , Técnicas In Vitro , Cinética , Camundongos , Microscopia Eletrônica , Mimetismo Molecular , RatosRESUMO
We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Amiloidose/genética , Encéfalo/patologia , Transtornos Cognitivos/genética , Envelhecimento , Substituição de Aminoácidos , Amiloide/análise , Amiloide/genética , Precursor de Proteína beta-Amiloide/análise , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/patologia , Amiloidose/psicologia , Animais , Encéfalo/crescimento & desenvolvimento , Transtornos Cognitivos/patologia , Cruzamentos Genéticos , Feminino , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , Regiões Promotoras Genéticas , Mapeamento por RestriçãoRESUMO
Natural resistance of inbred mouse strains to infection with Legionella pneumophila is controlled by the expression of a single dominant gene on chromosome 13, designated Lgn1. The genetic difference at Lgn1 is phenotypically expressed as the presence or absence of intracellular replication of L. pneumophila in host macrophages. In our effort to identify the Lgn1 gene by positional cloning, we have generated a high-resolution linkage map of the Lgn1 chromosomal region. For this, we have carried out extensive segregation analysis in a total of 1270 (A/J x C57BL/6J) x A/J informative backcross mice segregating the resistance allele of C57BL/6J and the susceptibility allele of A/J. Additional segregation analyses were carried out in three preexisting panels of C57BL/6J x Mus spretus interspecific backcross mice. A total of 39 DNA markers were mapped within an interval of approximately 30 cM overlapping the Lgn1 region. Combined pedigree analyses for the 5.4-cM segment overlapping Lgn1 indicated the locus order and the interlocus distances (in cM): D13Mit128-(1.4)-D13Mit194-(0.1)-D13Mit147-(0.9)-D13 Mit36-(0.9)-D13Mit146-(0.2)-Lgn1/D13Mit37-(1.0)- D13Mit70. Additional genetic linkage studies of markers not informative in the A/J x C57BL/6J cross positioned D13Mit30, -72, -195, and -203, D13Gor4, D13Hun35, and Mtap5 in the immediate vicinity of the Lgn1 locus. The marker density and resolution of this genetic linkage map should allow the construction of a physical map of the region and the isolation of YAC clones overlapping the gene.
Assuntos
Mapeamento Cromossômico , Ligação Genética , Doença dos Legionários/imunologia , Animais , Cruzamentos Genéticos , Marcadores Genéticos , Imunidade Inata/genética , Camundongos , Camundongos EndogâmicosRESUMO
The host response to Pseudomonas aeruginosa lung infection varies among inbred mouse strains. Mice of the BALB/c strain are resistant to P. aeruginosa lung infection, whereas mice of the DBA/2 strain are susceptible. This phenotypic variation correlates with a difference in the magnitude of the inflammatory response induced early following infection. In order to determine whether the ability of lung phagocytic cells to kill P. aeruginosa plays a role in the host response to the infection, we measured the in vitro bactericidal activity of resident and inflammatory alveolar and interstitial macrophages, using a temperature-sensitive mutant of P. aeruginosa. Lung macrophages obtained from resistant and susceptible animals displayed similar bactericidal activities, suggesting that the ability of phagocytes to kill P. aeruginosa does not play a crucial role in the outcome of infection. The bactericidal activity of lung phagocytes was also assessed in vivo following endobronchial infection with the temperature-sensitive mutant of P. aeruginosa. Resistant mice showed a rapid influx of polymorphonuclear leukocytes (PMNs) to the bronchoalveolar space which was shortly followed by an efficient clearance of the bacteria. Susceptible mice had a delay in both the inflammatory response to P. aeruginosa and the initiation of bacterial clearance. Susceptible mice have been shown to have a defect in tumor necrosis factor alpha production when infected intratracheally with P. aeruginosa. Intratracheal instillation of tumor necrosis factor alpha to susceptible mice at the time of infection significantly improved the recruitment of PMNs to the site of infection without affecting the process of bacterial clearance. Overall, these results suggest that both recruitment of a high number of PMNs to the lungs and an efficient activation process of the phagocytes are crucial for the prompt clearance of P. aeruginosa.
Assuntos
Pulmão/imunologia , Pseudomonas aeruginosa , Pseudomonas/imunologia , Animais , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Fagocitose , Especificidade da EspécieRESUMO
STK, a new member of the hepatocyte growth factor receptor family, is the receptor for macrophage-stimulating protein (MSP), which acts on murine resident peritoneal macrophages. We established polyclonal and monoclonal antibodies against STK and characterized the structure of STK protein and STK expression on cells of the mononuclear phagocyte system. Western blotting showed that the STK transcript is translated into a single-chain precursor and then cleaved into a 165-kD disulfide-linked heterodimer composed of a 35-kD alpha-chain and a 144-kD beta-chain. Western blotting detected STK protein on resident peritoneal macrophages, a target of MSP, and showed that it was autophosphorylated in cells stimulated by MSP. By flow cytometric analysis using a monoclonal anti-STK antibody, we showed that STK protein is expressed on restricted macrophage populations such as resident peritoneal macrophages, but not on exudate peritoneal macrophages or mononuclear phagocytes of the bone marrow, peripheral blood, spleen, or alveoli. Resident peritoneal macrophages were classified into two fractions according to their reactivity with an anti-STK antibody and a marker antibody for macrophages: STKhigh-F4/80high cells and STKnegative-F4/80low cells. Acute exudative macrophages were all STKnegative-F4/80low, but they gradually became predominantly STKhigh-F4/80high several days after entrance into the peritoneal cavity. These results showed that after monocytes migrate into the peritoneal cavity, they undergo terminal differentiation in the peritoneal microenvironment. This is the first evidence of tissue-specific terminal differentiation of peritoneal macrophages, and this terminal differentiation can be characterized by the expression of STK receptor tyrosine kinase.
Assuntos
Substâncias de Crescimento/metabolismo , Fator de Crescimento de Hepatócito , Macrófagos Peritoneais/enzimologia , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Biomarcadores/análise , Western Blotting , Diferenciação Celular , Indução Enzimática , Citometria de Fluxo , Macrófagos Peritoneais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Peroxidases/análise , Fagocitose , Fosforilação , Processamento de Proteína Pós-Traducional , Receptores Proteína Tirosina Quinases/imunologia , Receptores de Superfície Celular/imunologiaRESUMO
The early endobronchial inflammation induced by Pseudomonas aeruginosa infection varies in resistant and susceptible strains of mice. Mice of the DBA/2 strain are severely afflicted by the infection, with a high bacterial burden accumulating rapidly following inoculation and a high mortality rate occurring. Mice of the BALB/c strain are resistant to infection and clear the bacteria within 3 to 7 days. Infection of (BALB/c x DBA/2)F1 hybrid mice showed that the resistance to lung P. aeruginosa infection is inherited as a dominant trait. Mice of the A/J and C57BL/6 strains were found to have an intermediate phenotype to Pseudomonas aeruginosa infection when compared with BALB/c and DBA/2 strains. The decrease in the bacterial load seen early after infection coincided with a steady and strong recruitment of inflammatory cells to the bronchoalveolar spaces of mice of the resistant BALB/c strain. On the other hand, the recruitment of inflammatory cells to the lungs of mice of the susceptible DBA/2 strain was deficient, resulting in the failure to control bacterial multiplication. Chemotactic factors, proinflammatory cytokines, and the number and function of recruited inflammatory cells may play major roles in the determination of the genetic resistance to lung infection with P. aeruginosa in a normal immunocompetent host.
Assuntos
Bronquite/genética , Infecções por Pseudomonas/genética , Animais , Bronquite/imunologia , Bronquite/mortalidade , Líquido da Lavagem Broncoalveolar/citologia , Cruzamentos Genéticos , Genes Dominantes , Imunidade Celular , Imunidade Inata/genética , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Fenótipo , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/mortalidade , Especificidade da EspécieRESUMO
A rapid and sensitive screening sandwich enzyme-linked immunosorbent assay (ELISA) was developed for the detection of staphylococcal enterotoxin B (SEB) in cheese by using a highly avid anti-SEB antibody (Ab) as the capture Ab (CAb) and as the biotinylated Ab conjugate. The glutaraldehyde fixation method for the immobilization of CAb on polystyrene dipsticks was superior to the adsorption fixation and the adsorption-glutaraldehyde fixation methods. The glutaraldehyde fixation method resulted in a higher surface-saturating CAb concentration as evaluated by the peroxidase saturation technique and by the ability of the CAb-coated dipstick to discriminate between positive and negative controls (index of discrimination). Of nine blocking agents used alone or in pairs, lysine-human serum albumin, bovine serum albumin, human serum albumin, and gelatin effectively saturated available sites on the CAb-coated dipsticks without causing interference with the antigen-Ab reactions. The addition of 1% polyethylene glycol to the diluent of the biotinylated anti-SEB Ab conjugate improved the detection of SEB. A concentration of 4% polyethylene glycol allowed a 5-min reaction time for the streptavidin-biotin-horseradish peroxidase conjugate. Cheddar cheese homogenate reduced the sensitivity of the SEB assay; however, the sensitivity was restored when 1.6% (wt/vol) of either a nonionic detergent (Mega-9) or two zwitterionic detergents (Zwittergent 3-10 and 3-12 detergent) was added to the diluent. By using the rapid sandwich ELISA, a minimum of 0.5 to 1.0 ng of SEB per ml was detected within 45 min. The whole procedure for the analysis of the cheddar cheese samples was completed within 1 h.(ABSTRACT TRUNCATED AT 250 WORDS)