Outbreak of tuberculosis among substance users and homeless people in Greater Montréal, Canada, 2003-2016.

BACKGROUND: In Canada, active tuberculosis (TB) is found mainly among migrants from endemic countries and Indigenous populations. However, cases of active tuberculosis in substance users and homeless persons have been reported in Greater Montréal since 2003. OBJECTIVE: To describe the Montréal TB outbreak in terms of the sociodemographic characteristics, risk factors and clinical characteristics of cases, as well as the intensity of public health interventions, the follow-up and identification of locations of potential transmission. METHODS: All cases of active tuberculosis with the same genotype of interest residing in Quebec and epidemiologically linked cases were included in the analysis. Data were retrospectively extracted from routine public health investigations. Characteristics of cases were summarized using Excel. Spatial analysis of locations frequented during cases' infectiousness periods was performed. RESULTS: Between January 2003 and February 2016 a total of 35 cases were identified. Most (86%) were non-Indigenous people born in Canada. Of these, 28 had several risk factors, including substance use (93%), alcohol abuse (64%), homelessness (46%), comorbidities such as HIV coinfection (36%) and advanced stage of the disease. Seven cases without risk factors were all close contacts of cases. Intensity of case management by public health authorities was high. Locations frequented by cases with risk factors included crack houses, shelters and rehabilitation centers in Montréal's downtown core and a residential setting in a suburban area. CONCLUSION: TB outbreaks can occur in marginalized Canadian-born urban populations, especially those with substance use. Tailored interventions in this population may be needed for screening, and earlier identification of both latent and active TB and better linkage to care.

Regulation of lipid metabolism and gene expression by fenofibrate in hamsters.

Fenofibrate is a potent hypolipidemic agent that lowers plasma lipid levels and may thus decrease the incidence of atherosclerosis. Here we investigated the molecular mechanism of fenofibrate's hypolipidemic action by characterizing its in vivo effects on the expression of mRNAs and the activities of pivotal enzymes in cholesterol and triglyceride metabolism in the hamster. Treatment of hamsters with fenofibrate led to a dose-dependent reduction in serum cholesterol concentrations. Studies on the incorporation of [(14)C]acetate and [(14)C]mevalonate into cholesterol suggested that this effect occurs primarily through inhibition of cholesterol biosynthesis at steps prior to mevalonate. Fenofibrate decreased levels of hepatic enzyme activities and mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase. A potential mechanism for transcriptional regulation of these enzymes is via SREBP-2 that we found to be suppressed 2-fold by fenofibrate. Fenofibrate also lowered circulatory triglyceride levels. In keeping with the effect, we observed strong suppression of fatty acid synthase, acetyl-CoA carboxylase and apolipoprotein C-III mRNA and stimulation of lipoprotein lipase and acyl-CoA oxidase mRNA in the liver of fenofibrate-treated hamsters. These observations suggest that the effect of fenofibrate on triglyceride metabolism is likely to be a result of both decreased fatty acid synthesis and increased lipoprotein lipase and acyl-CoA oxidase gene expression in the liver. Surprisingly, alterations in lipoprotein lipase, acyl-CoA oxidase, acetyl-CoA carboxylase, and apolipoprotein C-III could not be observed in hamster hepatocytes incubated with fenofibric acid in vitro. These observations raise the possibility that changes in these genes may be secondary to the metabolic alterations occurring in animals but not in cultured cells and thus that the effect of fenofibrate on these genes may be indirect.

High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists.

Dyslipidemia, a major risk factor for cardiovascular disease, may be directly linked to diabetic hyperglycemia and insulin resistance. An appropriate dyslipidemic animal model that has diabetes would provide an important tool for research on the treatment of diabetic dyslipidemia. Ten days of high fat feeding in golden Syrian hamsters resulted in a significant increase in insulin resistance and baseline serum lipid levels accompanied by a pronounced dyslipidemia. Thirteen days of treatment with fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) selective agonist, produced a dose-dependent decrease in serum lipid levels. The pattern observed was characterized by lowered very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) and raised high-density lipoprotein (HDL) cholesterol in a fashion similar to that seen in man. Diabetic conditions were also significantly improved by fenofibrate with a normalization of impaired glucose tolerance and an improvement of insulin sensitivity during an oral glucose tolerance test. These data suggest that fenofibrate may correct not only the dyslipidemia but also the insulin resistance caused by a high fat diet, and the high fat fed hamster may be a good animal model for research on the treatment of diabetic dyslipidemia with PPARalpha selective agonists.

PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver.

11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol-cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11betaHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11betaHSD1 expression and activity after chronic treatment of wild-type mice with PPARalpha agonists, while 11betaHSD1 in the livers of PPARalpha knockout mice, or in mice treated for only 7 h with PPARalpha agonists, was unaltered. Our results are the first to show PPARalpha agonists can affect glucocorticoid metabolism in the liver by altering 11betaHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARalpha agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.

Immunoregulatory activity of peptides related to platelet factor 4.

Platelet factor 4 (PF4), a secreted platelet protein, alleviates concanavalin A-induced immunosuppression in mice. We now find that activity also resides in (i) the C-terminal tridecapeptide of PF4 (P13S), (ii) an analog of this in which arginine replaces the lysine residues and in which the last two amino acids are absent, (iii) the C-terminal 18 amino acids of low-affinity platelet factor 4, which is very similar to P13S, and (iv) peptide fragments of P13S that contain only 5-9 amino acids. P13S treated with fluorescamine to derivatize the free amino groups retained immunoregulatory activity but did not bind to heparin-agarose. The N-terminal and middle portions of PF4, polylysine, protamine, and three unrelated peptides were inactive in this assay.

Effect of the thiol group inhibitor monobromobimane and other inhibitors on the composition of the platelet cytoskeletal core and its association with glycoprotein IIIa.

SDS-polyacrylamide gel electrophoresis was used to study the effects of the thiol inhibitor monobromobimane (MB), EDTA, and prostaglandin E1 (PGE1) on the formation and composition of the platelet cytoskeletal core (Triton-insoluble residue) and its association with glycoprotein (GP) IIIa. Stimulation or aggregation of platelets in response to ADP or thrombin increased the amount of Triton-insoluble myosin. Aggregation resulted in incorporation of [125I]GP IIIa and a new band at about 210 kDa into the cytoskeletal core. EDTA and PGE1 caused little disaggregation of platelets that were aggregated in PRP with ADP and that had secreted the contents of their granules. In contrast to EDTA, PGE1 decreased the amount of Triton-insoluble residue and its association with GP IIIa. MB added after ADP-induced aggregation caused an increase in the amount of cytoskeletal core despite marked disaggregation and a substantial decrease in core-associated GP IIIa. With aspirin-treated platelets that had not secreted, EDTA, PGE1, and MB all caused disaggregation and loss of cytoskeletal GP IIIa. MB diminished, but did not reverse, thrombin-induced aggregation of washed platelets and arrested GP IIIa incorporation into the cytoskeletal core. Concanavalin A (Con A) cross-links glycoproteins on a single platelet and induces incorporation of GP IIIa into the Triton-insoluble residue in the absence of platelet aggregation. This induction was not inhibited by MB, although this reagent, as well as aspirin, inhibited Con A-induced secretion. Since GP IIIa incorporation caused by ADP-induced aggregation differs from that caused by Con A in its susceptibility to MB, it seems unlikely that thiol groups are directly involved in the association of GP IIIa with the cytoskeletal core.