High hepatitis C virus prevalence and incidence among Canadian intravenous drug users.

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.

Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus.

Hepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC), mainly through cirrhosis induction, spurring research for a deeper understanding of HCV versus host interactions in cirrhosis. The present study investigated crosstalks between HCV infection and UNC5A, a netrin-1 dependence receptor that is inactivated in cancer. UNC5A and HCV parameters were monitored in patients samples (n=550) as well as in in vitro. In patients, UNC5A mRNA expression is significantly decreased in clinical HCV(+) specimens irrespective of the viral genotype, but not in (HBV)(+) liver biopsies, as compared to uninfected samples. UNC5A mRNA is downregulated in F2 (3-fold; P=0.009), in F3 (10-fold, P=0.0004) and more dramatically so in F4/cirrhosis (44-fold; P<0.0001) histological stages of HCV(+) hepatic lesions compared to histologically matched HCV(-) tissues. UNC5A transcript was found strongly downregulated in HCC samples (33-fold; P<0.0001) as compared with non-HCC samples. In vivo, association of UNC5A transcripts with polyribosomes is decreased by 50% in HCV(+) livers. Consistent results were obtained in vitro showing HCV-dependent depletion of UNC5A in HCV-infected hepatocyte-like cells and in primary human hepatocytes. Using luciferase reporter constructs, HCV cumulatively decreased UNC5A transcription from the UNC5 promoter and translation in a UNC5A 5'UTR-dependent manner. Proximity ligation assays, kinase assays, as well as knockdown and forced expression experiments identified UNC5A as capable of impeding autophagy and promoting HCV restriction through specific impact on virion infectivity, in a cell death-independent and DAPK-related manner. In conclusion, while the UNC5A dependence receptor counteracts HCV persistence through regulation of autophagy in a DAPK-dependent manner, it is dramatically decreased in all instances in HCC samples, and specifically by HCV in cirrhosis. Such data argue for the evaluation of the implication of UNC5A in liver carcinogenesis.

Effect of acrylonitrile on primary Syrian golden hamster embryo cells in culture: transformation and DNA fragmentation.

Application of acrylonitrile to primary Syrian golden hamster embryo cells (HEC) in culture produced foci of morphologically transformed cells. When similar cells were pretreated with simian adenovirus (SA7) and subsequently treated with acrylonitrile, up to an 8.9-fold increase in frequency of virus-transformed foci was noted over frequency noted for cultures treated only with SA7. When [3H]thymidine-labeled primary Syrian golden HEC were treated with acrylonitrile and cellular DNA was subsequently subjected to alkaline sucrose gradients, a shift in the sedimentation pattern reminiscent of that observed for chemical carcinogens was noted. These observations added support to recent studies indicating that acrylonitrile may be carcinogenic.

Complete protection of islets against allorejection and autoimmunity by a simple barium-alginate membrane.

We describe a new technique for microencapsulation with high-mannuronic acid (high-M) alginate crosslinked with BaCl(2) without a traditional permselective component, which allows the production of biocompatible capsules that allow prolonged survival of syngeneic and allogeneic transplanted islets in diabetic BALB/c and NOD mice for >350 days. The normalization of the glycemia in the transplanted mice was associated with normal glucose profiles in response to intravenous glucose tolerance tests. After explantation of the capsules, all mice became hyperglycemic, demonstrating the efficacy of the encapsulated islets. The retrieved capsules were free of cellular overgrowth and islets responded to glucose stimulation with a 5- to 10-fold increase of insulin secretion. Transfer of splenocytes isolated from transplanted NOD mice to NOD/SCID mice adoptively transferred diabetes, indicating that NOD recipients maintained islet-specific autoimmunity. In conclusion, we have developed a simple technique for microencapsulation that prolongs islet survival without immunosuppression, providing complete protection against allorejection and the recurrence of autoimmune diabetes.

Endothelin-dependent effects limit flow-induced dilation of conductance coronary vessels after blockade of nitric oxide formation in conscious dogs.

OBJECTIVE: To determine whether endothelin (ET)-dependent effects limit shear stress-induced dilation of large epicardial coronary arteries after blockade of nitric oxide (NO) formation. METHODS: In conscious dogs instrumented for measuring coronary blood flow (CBF) and external diameter (CD) of the circumflex coronary artery, flow-dependent CD dilation was elicited by intracoronary (i.c.) adenosine (500 ng kg-1 min-1). RESULTS: I.c. adenosine increased CBF by 28 +/- 4 from 38 +/- 5 ml min-1 and CD by 0.25 +/- 0.03 from 3.53 +/- 0.07 mm without other hemodynamic effects. After N omega-nitro-L-arginine methyl ester (L-NAME), baseline CD fell (P < 0.01) to 3.35 +/- 0.08 mm but CBF was not significantly altered (36 +/- 5 ml min-1). CBF increases caused by adenosine were smaller (17 +/- 2 ml min-1, P < 0.05) and CD responses were nearly abolished (0.02 +/- 0.01 mm, P < 0.01). I.c. Ro 61-1790, an ETA receptor blocker, given after L-NAME did not significantly influence baseline CBF (36 +/- 5 ml min-1) but increased (P < 0.01) CD to 3.45 +/- 0.09 mm. CBF responses to adenosine were not significantly altered by Ro 61-1790 but CD responses (0.10 +/- 0.01 mm) were partially restored (P < 0.01). In contrast, blockade of ETB receptors with Ro 46-8443 after L-NAME had no further effects on CD and CBF responses to adenosine. CONCLUSION: ETA receptor-mediated effects limit flow-dependent dilation of large epicardial coronary arteries in conscious dogs. Suppression of the L-arginine/NO-dependent pathway with L-NAME reveals significant ET-dependent effects.

Contrasting effects of blockade of nitric oxide formation on resistance and conductance coronary vessels in conscious dogs.

OBJECTIVES: To determine the differential effects of blockade of nitric oxide (NO) formation by an arginine analogue on basal and stimulated NO release in conductance and resistance coronary vessels. METHODS: In conscious dogs, instrumented for measuring coronary blood flow (CBF) and external epicardial coronary artery diameter (CD), intracoronary (ic) acetylcholine (ACH, 3.0 ng/kg), adenosine (ADENO 100.0 ng/kg) and nitroglycerin (NTG, 10.0 ng/kg) were injected before and after ic N omega-nitro-L-arginine methyl ester (L-NAME, 50.0 micrograms.kg-1 min-1 for 12 min) to block NO synthesis. RESULTS: Before L-NAME, ACH increased CBF by 65.3 +/- 9.0 from 42.4 +/- 2.9 ml/min and CD by 0.199 +/- 0.035 from 3.374 +/- 0.193 mm. L-NAME failed to alter baseline CBF but reduced (P < 0.01) CD to 3.220 +/- 0.199 mm. CBF responses to ACH were smaller (P < 0.01) (32.8 +/- 5.3 ml/min) after L-NAME. In contrast, ACH-induced increases in CD (0.184 +/- 0.053 mm) were not altered. L-NAME did not change CBF responses to NTG but increased CD responses (0.345 +/- 0.062 vs 0.217 +/- 0.043 mm, P < 0.01). ADENO-induced increases in CBF were smaller after L-NAME (46.5 +/- 5.6 vs 79.8 +/- 10.9 ml/min, P < 0.01). Increases in CD created by ADENO, a flow-dependent phenomenon, were nearly abolished after L-NAME (0.043 +/- 0.018 vs 0.195 +/- 0.026 mm, P < 0.01) and partially restored by ic L-arginine. The effects of L-NAME on CBF and CD responses to ACH and ADENO continuously delivered into the coronary artery were similar to those of boluses. CONCLUSIONS: L-NAME selectively reduced ACH-induced dilation in resistance coronary vessels but failed to prevent responses of conductance coronary vessels in spite of reducing baseline CD and blocking flow-dependent effects of ADENO. Therefore, blockade of NO formation resulted in disparate effects on receptor-operated dilation of resistance and conductance coronary vessels.

Endothelin-dependent tone limits acetylcholine-induced dilation of resistance coronary vessels after blockade of NO formation in conscious dogs.

Nitric oxide (NO) impairs endothelin (ET) formation and/or action in isolated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance coronary vessels in conscious dogs. In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of Nomega-nitro-L-arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ETA/ETB receptor blocker. Before L-NAME, ACh (100 ng. kg-1. min-1) increased coronary blood flow (CBF) by 43+/-4% from 47+/-6 mL. min-1. After L-NAME, ACh failed to increase CBF (-3+/-2% from 50+/-7 mL. min-1). CBF responses to ACh were partially restored (+10+/-2% from 50+/-7 mL. min-1, P<0.01) after the addition of bosentan. Bosentan alone (without L-NAME) did not alter CBF responses to ACh. Blockade of ETA (Ro 61-1790) but not ETB (Ro 46-8443) receptors partially restored CBF responses to ACh after L-NAME. Myocardial immunoreactive ET levels in the perfusion territories of the circumflex and left anterior descending coronary arteries did not differ. ETA-dependent tone magnified the inhibitory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO release has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.

Influence of dual ET(A)/ET(B)-receptor blockade on coronary responses to treadmill exercise in dogs.

We hypothesized that endothelin (ET) release during exercise may be triggered by alpha-adrenergic-receptor activation and thereby influence coronary hemodynamics and O(2) metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88+/-0.26 from 1.10+/- 0.12 ml x min(-1) x g(-1)) and in a fall (P<0.01) in coronary sinus O(2) saturation (17.4+/-1.5 to 9.6+/-0.7 vol%), whereas myocardial O(2) consumption (MVO(2)) increased (109+/-13% from 145+/-16 microl O(2) min(-1) x g(-1)). Tezosentan, a dual ET(A)/ET(B)-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O(2) saturation and MVO(2) was shifted upward (P<0.05) after tezosentan administration; i.e., as MVO(2) increased during exercise, coronary sinus O(2) saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases (P<0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As MVO(2) increased during exercise, coronary sinus O(2) saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ET(A)/ET(B) receptors alters coronary hemodynamics and O(2) metabolism during exercise, but ET activity failed to increase beyond baseline levels.

Hemodynamic and endocrine effects of acute and chronic administration of nifedipine.

Although it is well known that calcium channel blockers can influence contraction of vascular smooth muscle, there is less knowledge on its effect on excitation contraction coupling in the endocrine glands and more specifically on insulin and glucagon release. In this study, nifedipine was administered in doses of 40 to 80 mg/day to 14 patients with essential hypertension, and its hemodynamic effects were evaluated by non-invasive methods, and its effect on glucose metabolism by an arginine infusion test. Nifedipine produced a significant reduction in systolic and diastolic blood pressure, both after the first dose (30/12 mm Hg) and after 8 weeks of administration (19/12 mm Hg). There were no significant changes in cardiac output (5.1 to 4.9 L/min), muscle (2.4 to 3.2 mL/sec/min) or cutaneous basal flow (9.8 to 8.6 mL/100 mL) as measured non-invasively by echocardiogram and by plethysmography. Insulin and glucagon release were evaluated by the arginine infusion test. Nifedipine produced a tendency towards an increase in glucagon release and a reduction in insulin release although these changes did not reach statistical significance. In this group of patients, nifedipine produced a significant reduction in systolic and diastolic pressure, but no significant changes in insulin or glucagon plasma levels.

Hemodynamic and endocrine effects of acute and chronic administration of nifedipine.

Although it is well known that calcium channel blockers can influence contraction of vascular smooth muscle, there is less knowledge on its effect on excitation contraction coupling in the endocrine glands and more specifically on insulin and glucagon release. In this study, nifedipine was administered in doses of 40 to 80 mg/day to 14 patients with essential hypertension, and its hemodynamic effects were evaluated by non-invasive methods, and its effect on glucose metabolism by an arginine infusion test. Nifedipine produced a significant reduction in systolic and diastolic blood pressure, both after the first dose (30/12 mm Hg) and after 8 weeks of administration (19/12 mm Hg). There were no significant changes in cardiac output (5.1 to 4.9 L/min), muscle (2.4 to 3.2 mL/sec/min) or cutaneous basal flow (9.8 to 8.6 mL/100 mL) as measured non-invasively by echocardiogram and by plethysmography. Insulin and glucagon release were evaluated by the arginine infusion test. Nifedipine produced a tendency toward an increase in glucagon release and a reduction in insulin release although these changes did not reach statistical significance. In this group of patients, nifedipine produced a significant reduction in systolic and diastolic pressure, but no significant changes in insulin or glucagon plasma levels.

Metabolism and distribution of [2,3-14C]acrolein in Sprague-Dawley rats. II. Identification of urinary and fecal metabolites.

The metabolites of [2,3-14C]acrolein in the urine and feces of Sprague-Dawley rats were identified after either intravenous administration in saline at 2.5 mg/kg or oral administration by gavage as an aqueous solution as either single or multiple doses at 2.5 mg/kg or as a single dose of 15 mg/kg. Selected urine and feces samples were pooled by sex and collection interval and profiled by combinations of reverse-phase, anion-exchange, cation-exchange, and ion-exclusion high-performance liquid chromatography (HPLC). Feces were also profiled by size-exclusion chromatography. Metabolites were identified by comparison with well-characterized standards by HPLC and by mass spectrometry. The urinary metabolites were identified as oxalic acid, malonic acid, N-acetyl-S-2-carboxy-2-hydroxyethylcysteine, N-acetyl-S-3-hydroxypropylcysteine, N-acetyl-S-2-carboxyethylcysteine, and 3-hydroxypropionic acid. The fecal radioactivity from the oral dose groups was partitioned into methanol-soluble, water-soluble, and insoluble radioactivity, some of which could be liberated by dilute acid hydrolysis. HPLC analysis of these extracts revealed no discrete metabolites. Size-exclusion chromatography indicated a molecular weight range of 2,000 to 20,000 Da for the radioactivity, which was unaffected by hydrolysis at reflux with 6 M acid or base. This radio-activity was thought to be a homopolymer of acrolein, which was apparently formed in the gastrointestinal tract. The pathways of acrolein metabolism were epoxidation followed by conjugation with glutathione, Michael addition of water followed by oxidative degradation, and glutathione addition to the double bond either following or preceding oxidation or reduction of the aldehyde. The glutathione adducts were further metabolized to the mercapturic acids.

Metabolism and distribution of [2,3-(14)C]acrolein in laying hens.

The metabolism and distribution of [2,3-(14)C]-acrolein were studied in 10 laying hens orally administered 1.09 mg/kg of body weight/day for 5 days. Eggs, excreta, and expired air were collected. The hens were killed 12-14 h after the last dose and edible tissues collected. The nature of radioactive residues was determined in tissues and eggs. All of the identified metabolites were the result of the incorporation of acrolein-derived radioactivity into normal natural products of intermediary metabolism in the hen except for 1,3-propanediol, which is a known degradation product of glycerol in bacteria.

Metabolism and distribution of [2,3-(14)C]acrolein in lactating goats.

The metabolism and distribution of [2,3-(14)C]acrolein were studied in a lactating goat orally administered 0.82 mg/kg of body weight/day for 5 days. Milk, urine, feces, and expired air were collected. The goat was killed 12 h after the last dose, and edible tissues were collected. The nature of the radioactive residues was determined in milk and tissues. All of the identified metabolites were the result of the incorporation of acrolein into the normal, natural products of intermediary metabolism. There was evidence that the three-carbon unit of acrolein was incorporated intact into glucose, and subsequently lactose, and into glycerol. In the case of other natural products, the incorporation of radioactivity appeared to result from the metabolism of acrolein to smaller molecules followed by incorporation of these metabolites into the normal biosynthetic pathways.

Reproduction study in rats or ginseng extract G115.

The effect of ginseng extract G115 on reproductive performance was studied in two generations of Sprague-Dawley rats. Animals of both sexes were fed wither control diet or diet supplemented with ginseng extract G115 at dose levels of 1 . 5, 5 or 15 mg/kg body weight/day. Parameters of reproduction and lactation in the treated groups were comparable to those of the controls for two generations of dams and pups. For F1 males and females, no treatment-related effects were seen in weekly body weights and food consumption, haematological and clinical chemical data, and ophthalmic, gross and histopathological examinations. The gross autopsies of F1 and F2 animals also revealed no significant treatment-related findings.

Reproduction and subchronic feeding study of carnauba wax in rats.

The reproductive performance of Wistar rats fed carnauba wax at levels of 0.1, 0.3 or 1% in the diet and the effects of subchronic administration of carnauba wax at these dose levels on the resultant progeny were studied. Reproductive indices, body-weight gain, food consumption, haematological and clinical chemical data, ophthalmic, gross and histopathological examinations were used to study the possible toxic or pathological effects. Serum free fatty acid levels were found to be decreased in male and female rats fed carnauba wax at dietary levels of 0.3 and 1.0%. No other effects of feeding carnauba wax at levels up to 1.0% of the diet were observed.

Subchronic feeding study of carnauba wax in beagle dogs.

Carnauba wax fed at levels of 0.1, 0.3 and 1% in the diet to beagle dogs for 28 wk did not produce evidence of toxicity or pathological effects. Body weight gain, food consumption, clinical chemical, haematological, and urine analysis data, and organ weights of animals fed carnauba wax were comparable with those of control animals. Ophthalmic, gross and histopathological examinations revealed no significant treatment-related findings.

[Drugs, Poverty and HIV: results regarding a provincial needle exchange program in Point de Repères, Quebec]. / Drogues, pauvreté et VIH: données en provenance du programme d'échange de seringues Point de Repères, Québec.

In this study (n = 200), the characteristics of IDUs participating in a provincial needle exchange program (NEP) for more than 2 years (> 2 years) were compared with those of IDUs having participated for less than 2 years (< or = 2 years). Compared to the < or = 2 years, the > 2 years were more often recipients of welfare (RC: 4.7), especially among the HIV-positive (RC: 62.0); tried quitting drugs more frequently (RC: 3.8); more often recommended the NEP to other IDUs (RC: 3.1); and more often requested being given shelter and longer opening hours (RC: 3.6). These results highlight the urgent need to improve and develop transitional and support services for the > 2 years. Preventive interventions that would reach out to the < or = 2 years where they live should also be implemented in close collaboration with organizations involved in mental health and drug use prevention.

Risk behaviours and HIV infection among men having sexual relations with men: baseline characteristics of participants in the Omega Cohort Study, Montreal, Quebec, Canada.

OBJECTIVE: To describe characteristics of men having sex with men (MSM) participating in the Omega Cohort, to describe HIV-positive participants at baseline interview, and to estimate HIV incidence. METHODS: The Omega Cohort is a study on the incidence and psychosocial determinants of HIV infection among MSM living in Montreal. MSM complete a questionnaire and are tested for HIV every six months. RESULTS: During the previous six months, 31% and 12% of 810 participants (mean age = 33 years) reported unprotected anal sex with regular and casual partners, respectively. Eight participants (0.98%) were HIV-infected at baseline. HIV incidence was 0.89 per 100 person-years (7/787 person-years) [95% confidence interval: 0.36-1.83]. CONCLUSION: A significant proportion of participants reported current risk behaviours. Despite this, HIV incidence is relatively low. It is important to target MSM who do not practice safe sex and to encourage those practicing safe sex to sustain these behaviours.

Presence of the canine transmissible venereal tumor in the nasal cavity of dogs in the area of dakar (senegal).

Canine transmissible venereal tumors were observed in the nasal passages of three dogs from Dakar, Senegal. Genital tumors were not present in these dogs. These observations, combined with those of few previous reports, stress the necessity to include this neoplasm in the differential diagnosis of nasal tumors in the dog.

Administration and service delivery in the SSI program: the first 10 years.

This article provides an overview of the administrative structures and processes through which the Social Security Administration delivers its services to Supplemental Security Income (SSI) claimants and recipients. It documents the improvements and adjustments that have been made in the administration of SSI from 1974, when the program began, through 1983, the 10th year of its operation. The first decade of SSI was marked by significant changes that have led to improvements in fiscal responsibility and administrative efficiency for the program. Among the subjects covered are the legislative history of the program, the claims process, posteligibility procedures, underpayments and overpayments, the administrative complexities that have had to be surmounted, and administrative efforts aimed at quality assurance.