Ruxolitinib for pediatric patients with treatment-naïve and steroid-refractory acute graft-versus-host disease (REACH4).

In REACH4 (NCT03491215), a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade II-IV acute graft-versus-host disease (aGVHD; n=45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (≥6 to <12 years) and 3 (≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. Phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients <12 years of age. Phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in ruxolitinib-treated patients with aGvHD (anemia, decreased neutrophil and leukocyte count). In pediatric patients with aGvHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals.

Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia.

Acquired severe aplastic anaemia (SAA) has an immune pathogenesis, and immunosuppressive therapy (IST) with anti-thymocyte globulin and cyclosporine is effective therapy. Eltrombopag (EPAG) added to standard IST was associated with higher overall and complete response rates in patients with treatment-naïve SAA compared to a historical IST cohort. We performed a paediatric subgroup analysis of this trial including all patients aged <18 years who received EPAG plus standard IST (n = 40 patients) compared to a historical cohort (n = 87) who received IST alone. Response, relapse, clonal evolution, event-free survival (EFS), and overall survival were assessed. There was no significant difference in either the overall response rate (ORR) or complete response rate at 6 months (ORR 70% in EPAG group, 72% in historical group, P = 0·78). Adults (≥18 years) had a significantly improved ORR of 82% with EPAG compared to 58% historically (P < 0·001). Younger children had lower response rates than did adolescents. The trend towards relapse was higher and EFS significantly lower in children who received EPAG compared to IST alone. Addition of EPAG added to standard IST did not improve outcomes in children with treatment-naïve SAA. EPAG in the paediatric population should not automatically be considered standard of care. Registration: clinicaltrials.gov (NCT01623167).

Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours.

AIMS: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS: Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. RESULTS: Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, -1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg Cmax and AUC(0-∞) were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC(0-τ) with 300 mg BID was ≈ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was <5 msec (upper 90% CI, <10 msec). No unexpected toxicities occurred with supratherapeutic dosing. CONCLUSION: Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen.

MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study.

BACKGROUND: Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma. METHODS: In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment). FINDINGS: Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. INTERPRETATION: To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments. FUNDING: Novartis Pharmaceuticals.

Ruxolitinib in treatment-naive or corticosteroid-refractory paediatric patients with chronic graft-versus-host disease (REACH5): interim analysis of a single-arm, multicentre, phase 2 study.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is a debilitating, and sometimes life threatening, complication of allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in paediatric patients (ie, <18 years) with moderate-to-severe chronic GVHD. METHODS: In this single-arm, phase 2 study, patients were recruited at 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada. Eligible patients were aged 28 days to younger than 18 years, had undergone allogenic HSCT, and had been diagnosed with treatment-naive or corticosteroid-refractory moderate-to-severe chronic GVHD, per 2014 National Institutes of Health consensus criteria. Patients received oral ruxolitinib dosing on the basis of their age at the start of treatment: those aged 12 years to younger than 18 years received 10 mg twice daily (age ≥12 to <18 years group), those aged 6 years to younger than 12 years (age ≥6 to <12 years group) received 5 mg twice daily, and those aged 2 years to younger than 6 years received 4 mg/m2 twice daily (age ≥2 to <6 years group). Treatment was to be administered in 28-day cycles for approximately 36 months, alongside supportive treatment per institutional guidelines. The primary activity endpoint was overall response rate at cycle 7 day 1. Activity and safety analyses are reported in the full analysis set, which included all patients who received at least one dose of ruxolitinib. Here we report the prespecified interim analysis, scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment, and the results for the primary endpoint evaluation reported here is to be considered final. This study is registered with ClinicalTrials.gov, NCT03774082, enrolment is complete, and the study is ongoing. FINDINGS: Between May 20, 2020, and Sept 17, 2021, 48 patients were screened, of whom 45 were enrolled and received at least one dose of study drug (median age was 11·0 years [IQR 7·2-14·3], 16 [36%] were female, 29 [64%] were male, 21 [47%] were White, one [2%] was Black or African American, 23 [51%] were Asian, 17 [38%] were treatment-naive, 28 [62%] were corticosteroid-refractory). As of data cutoff (Oct 19, 2022), after a median ruxolitinib exposure of 55·1 weeks (IQR 13·1-75·3), the overall response rate at cycle 7 day 1 was 40·0% (18 of 45; 90% CI 27·7-53·3), with responses seen in seven (41%) of 17 treatment-naive patients and 11 (39%) of 28 corticosteroid-refractory patients. The most common treatment-related adverse events of grade 3 or worse were neutropenia (eight [18%] of 45) and thrombocytopenia (six [13%]). Seven (16%) patients had grade 3 or worse serious treatment-related adverse events; the most common was hyponatraemia (two [4%] of 45). Three (7%) patients died while on-treatment (within 30 days of treatment discontinuation), one due to Aspergillus infection, one due to septic shock, and one due to acute respiratory distress syndrome; none were considered to be related to study drug. INTERPRETATION: Pending final analysis, this study suggests that ruxolitinib is active and well tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population. The safety profile of ruxolitinib in this patient population is consistent with that of adults. Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD. FUNDING: Novartis.

Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases.

Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation. Peptide aggregation could also be modulated post-liposome assembly by the addition of distinct small molecule ß-sheet breakers. Immunization of both mice and monkeys with a model liposomal vaccine containing ß-sheet aggregated lipopeptide (Palm1-15) induced polyclonal IgG antibodies that specifically recognized ß-sheet multimers over monomer or non-pathological native protein. The rational design of liposome-bound peptide immunogens with defined conformation opens up the possibility to generate vaccines against a range of protein misfolding diseases, such as Alzheimer disease.

Identification of Predictors of Abnormal Calcium, Magnesium and Phosphorus Blood Levels in the Emergency Department: A Retrospective Cohort Study.

PURPOSE: With rising healthcare costs limiting access to care, the judicious use of diagnostic tests has become a critical issue for many jurisdictions. Calcium, magnesium and phosphorus serum levels are regularly performed tests in the emergency department, but their clinical relevance have come into question. Authors sought to determine risk factors that could predict abnormal calcium, magnesium and phosphorus serum levels, as well as identify patients who may need corrective interventions. METHODS: A retrospective cohort study was conducted in two academic hospitals in Québec City. Demographic and clinical characteristics of 1008 patients who had serum calcium and/or magnesium and/or phosphorus levels drawn by an emergency physician were collected. Multivariate logistic regression models were fitted to obtain adjusted odds ratios for each risk factor for abnormal calcium or magnesium or phosphorus blood levels, and for a required intervention. RESULTS: Among patients for whom calcium, magnesium and phosphorus were tested in the Emergency Department, the most significant risk factors (OR>2) for electrolytic abnormality were as follows: hypocalcemia - respiratory distress, diuretics (excluding loop and thiazide), anti-neoplastic medication, long QTc, chronic kidney disease (CKD); hypercalcemia - bone pain, vitamin D, hallucinations; hypomagnesemia - diabetes, corticosteroids; hypermagnesemia - poor extremity perfusion, CKD, furosemide; hypophosphatemia - seizure; hyperphosphatemia - phosphate-binders, CKD, peripheral vascular atherosclerotic disease. Of all patients tested, 3.4% received a corrective intervention initiated by the emergency physician. Predictors of intervention on an electrolyte abnormality include poor peripheral perfusion, nausea and chronic obstructive pulmonary disease (COPD). CONCLUSION: Emergency physicians can potentially reduce the unnecessary testing of calcium, magnesium and phosphorus blood levels by targeting patients with high-acuity conditions or chronic comorbidities such as CKD, diabetes and COPD.

Comparison of prognosis for men with type 2 diabetes mellitus and men with cardiovascular disease.

BACKGROUND: People with type 2 diabetes mellitus are at high risk for cardiovascular disease. In some studies, the mortality rate among people with this condition has been equivalent to that among people with cardiovascular disease. We compared cardiovascular mortality between incident cases of diabetes and cardiovascular disease. METHODS: The study population was part of a random sample of 4376 men from Quebec, Canada, aged 35 to 64 years, who did not have cardiovascular disease in 1974 and who were followed until 1998. Three groups of incident cases were identified: diabetes without cardiovascular disease, first cardiovascular event (myocardial infarction, unstable angina or stroke) without diabetes, and both cardiovascular disease and diabetes. These cases were age-matched to a control group without diabetes or cardiovascular disease. RESULTS: During the 24-year follow-up period, new diabetes without cardiovascular disease was documented in 137 men. A first cardiovascular event without diabetes was documented in 527 men. Relative to the 627 controls, men with 1 of the 2 diseases of interest had higher cardiovascular mortality (age-adjusted relative risk [RR] 3.11, 95% confidence interval [CI] 1.96-4.92) for those with diabetes and 4.46 (95% CI 3.15-6.30) for those with cardiovascular disease). However, within the first 5 years after diagnosis, men with cardiovascular disease had higher cardiovascular mortality than men with diabetes (age-adjusted RR 2.03, 95% CI 1.01-4.08). INTERPRETATION: Men with isolated type 2 diabetes and men with isolated cardiovascular disease had similar cardiovascular mortality rates several years after initial diagnosis of either condition. These findings reinforce the need to prevent and optimally manage diabetes and cardiovascular disease.

Supporting early academic family medicine careers with the clinician scholar enhanced-skills program.

CONTEXT: The Clinician Scholar Program (CSP) is an enhanced-skills (R3) residency program to train clinician researchers/educators/leaders for academic family practice. This article intends to share Laval University's CSP development and evaluation strategy, and provide recommendations for similar innovations in other disciplines/settings. METHODS: This article uses Kern's model to present the program development, and a program-oriented approach for program evaluation, carried from 2011 to 2017 using descriptive data. Questionnaires, reflexive texts and an Objective Structured Teaching Exam supported data collection. RESULTS: Seven CSP graduates and 14 controls participated in the program evaluation. Residents were highly satisfied with the program, nevertheless they suggested to allow physicians to come back for training later in career. The CSP enriched knowledge, skills and attitudes about academic practice. CSP increased residents' entrustment level about academic competencies. All graduates joined an academic practice within five years of program completion. CONCLUSION: Key recommendations to implement similar programs include academic medicine core training, project- based learning with learner-centered objectives, relevant and authentic learning and assessment, and multi-level program evaluation approach. Programs should consider concomitant graduate studies and opportunity to offer such training after a few years of clinical practice to meet other needs at a timely stage of career.

CONTEXTE: Le programme clinicien érudit (PCÉ) est un programme de résidence de compétences avancées (R3) destiné à former des cliniciens chercheurs / éducateurs / leaders en vue d'une pratique de médecine familiale universitaire. Cet article a pour but de faire connaître la stratégie de développement et d'évaluation du PCÉ de l'Université Laval et de formuler des recommandations pour des innovations similaires dans d'autres disciplines/contextes. MÉTHODES: Cet article utilise le modèle de Kern pour présenter le développement du programme et une approche d'évaluation orientée sur le programme, réalisée de 2011 à 2017 à l'aide de données descriptives. Des questionnaires, des textes réflexifs et un examen d'enseignement objectif structuré ont permis de recueillir des données. RÉSULTATS: Sept diplômés du PCÉ et 14 témoins ont participé à l'évaluation du programme. Les résidents étaient très satisfaits du programme, suggérant néanmoins de permettre une formation plus tard dans la carrière. Le PCÉ a enrichi les connaissances, les habiletés et les attitudes relatives à la pratique universitaire. Le PCÉ a augmenté le niveau de confiance des résidents en ce qui concerne les compétences académiques. Tous les diplômés se sont engagés dans une pratique universitaire dans les cinq années suivant leur graduation du programme. CONCLUSIONS: Les principales recommandations pour la mise en œuvre de programmes similaires incluent la réalisation d'un tronc commun en médecine universitaire, l'apprentissage par projet avec des objectifs centrés sur l'apprenant, des stratégies d'apprentissage et d'évaluation pertinentes et authentiques, et une approche d'évaluation de programme à plusieurs niveaux. Les programmes doivent envisager offrir des études supérieures en parallèle et la possibilité d'offrir cette formation après quelques années de pratique clinique afin de répondre à d'autres besoins à un stade opportun de leur carrière.

A physician-physiotherapist collaborative model in a family medicine teaching clinic.

Persons with musculoskeletal disorders frequently seek care in family medicine clinics. However, musculoskeletal education provided in medical schools is often considered insufficient. The implementation of a collaborative model that integrates physiotherapists into teaching clinics may benefit the musculoskeletal training of medical residents. This paper describes a model developed in a family medicine teaching clinic by examining the interprofessional educational and collaborative activities implemented in this model. The model allowed to provide physiotherapy services, involve the physiotherapist in the training of family medicine residents and enhance interprofessional collaboration, particularly for the management of persons with musculoskeletal disorders.

Les personnes ayant des troubles musculosquelettiques consultent fréquemment en cliniques de médecine de famille. Cependant, l'enseignement musculosquelettique dispensé dans les programmes de médecine est souvent considéré comme insuffisant. L'implantation d'un modèle de collaboration qui intègre les physiothérapeutes aux cliniques d'enseignement pourrait améliorer la formation des médecins résidents. Cet article décrit un modèle développé dans une clinique d'enseignement en médecine familiale en examinant les activités interprofessionnelles d'éducation et de collaboration implantées dans ce modèle. Le modèle a permis d'offrir des services de physiothérapie, d'impliquer le physiothérapeute dans la formation des médecins résidents et d'améliorer la collaboration interprofessionnelle, particulièrement pour la prise en charge des personnes ayant des troubles musculosquelettiques.

Apolipoprotein-B, low-density lipoprotein cholesterol, and the long-term risk of coronary heart disease in men.

We examined whether plasma apolipoprotein-B (apo-B) levels add further information on the risk of coronary heart disease (CHD) after taking into account low-density lipoprotein (LDL) cholesterol concentrations and other traditional risk factors. Among 2,072 CHD-free men from the Québec Cardiovascular Study at entry and followed for 13 years, 230 had a first CHD event (CHD death or nonfatal myocardial infarction). Increased apo-B (tertile 1 vs 3) levels were associated with a significant increased risk of CHD after adjustment for nonlipid and lipid risk factors other than LDL cholesterol levels (relative risk 1.89, 95% confidence interval 1.31 to 2.73). High plasma LDL cholesterol concentrations (tertile 1 vs 3) were also associated with an increased risk of CHD independently of nonlipid and lipid risk factors (relative risk 2.02, 95% confidence interval 1.44 to 2.84). However, apo-B levels modulated to a significant extent the risk of CHD associated with increased concentrations of LDL cholesterol (>/=4.3 mmol/L). For instance, among men with high LDL cholesterol levels, those with an apo-B level <128 mg/dl were not at increased risk for CHD (relative risk 1.53, 95% confidence interval 0.89 to 2.62). In contrast, high levels of apo-B and LDL cholesterol were associated with a significant twofold increased risk of CHD (p <0.001). Receiver-operating curve analysis also indicated that plasma apo-B levels improved the ability to discriminate incident CHD cases among patients with high LDL cholesterol levels compared with a model based on LDL cholesterol levels (p = 0.04). In conclusion, plasma apo-B levels modulated the risk of CHD associated with LDL cholesterol over a 13-year follow-up.

Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Québec Cardiovascular Study.

OBJECTIVE: The objective of the present study was to investigate the association between large and small low-density lipoprotein (LDL) and long-term ischemic heart disease (IHD) risk in men of the Quebec Cardiovascular Study. METHODS AND RESULTS: Cholesterol levels in the large and small LDL subfractions (termed LDL-C> or =260A and LDL-C<255A, respectively) were estimated from polyacrylamide gradient gel electrophoresis of whole plasma in the cohort of 2072 men of the population-based Quebec Cardiovascular Study. All men were free of IHD at the baseline examination and followed-up for a period of 13 years, during which 262 first IHD events (coronary death, nonfatal myocardial infarction, and unstable angina pectoris) were recorded. Our study confirmed the strong and independent association between LDL-C<255A levels as a proxy of the small dense LDL phenotype and the risk of IHD in men, particularly over the first 7 years of follow-up. However, elevated LDL-C> or =260A levels (third versus first tertile) were not associated with an increased risk of IHD over the 13-year follow-up (RR=0.76; P=0.07). CONCLUSIONS: These results indicated that estimated cholesterol levels in the large LDL subfraction were not associated with an increased risk of IHD in men and that the cardiovascular risk attributable to variations in the LDL size phenotype was largely related to markers of a preferential accumulation of small dense LDL particles.

Inflammatory markers and long-term risk of ischemic heart disease in men A 13-year follow-up of the Quebec Cardiovascular Study.

We tested the hypothesis that elevated plasma interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen concentrations are independent risk factors and interact in increasing the long-term risk of ischemic heart disease (IHD) in men. A total of 1982 IHD-free men from the Quebec Cardiovascular Study were followed over a period of 13 years during which 210 first fatal IHD events and non-fatal myocardial infarctions were recorded. Increased CRP levels (4th versus 1st quartile) were not associated with an increased risk of IHD after adjustment for non-lipid risk factors (age, body mass index, systolic blood pressure, diabetes, smoking and medication use at baseline), lipid risk factors (LDL and HDL cholesterol and triglyceride levels) and for IL-6 and fibrinogen (RR=0.70, 95% CI=0.43-1.13). High plasma IL-6 levels (4th versus 1st quartile) were associated with a 70% greater risk of IHD independent of confounding risk factors and of the other 2 inflammatory markers (RR=1.71, 95% CI=1.07-2.75). The relationship between high fibrinogen levels (4th versus 1st quartile) and IHD risk was borderline significant in multivariate analyses (RR=1.53, 95% CI=0.97-2.43). An inflammation score based on plasma IL-6 and fibrinogen levels improved the IHD risk predictive value of a multivariate model of traditional risk factors (p=0.03). Including plasma CRP levels into the inflammatory score provided no additional predictive value. In conclusion, elevated plasma IL-6 concentrations are more strongly related to IHD risk than CRP and fibrinogen. An inflammation score based on high plasma IL-6 and fibrinogen levels used in combination with traditional risk factors may improve our ability to adequately identify high risk individuals.

Insulin resistance syndrome, body mass index and the risk of ischemic heart disease.

BACKGROUND: Many people who are not obese according to standard height and weight criteria may still display features of insulin resistance syndrome and thus be at high risk of ischemic heart disease. We sought to investigate the effect of cumulative features of insulin resistance syndrome on the risk of ischemic heart disease associated with variations in body mass index (BMI) among men who participated in the Quebec Cardiovascular Study. METHODS: A cohort of 1824 nondiabetic men free of ischemic heart disease was evaluated at the 1985 baseline evaluation and followed for a period of 13 years, during which 284 first ischemic heart disease events were recorded. Relative hazards (RHs) of ischemic heart disease in 3 BMI groups (normal weight, overweight and obese) were estimated using Cox proportional hazards regression. RESULTS: Although obese men (BMI > or = 30 kg/m2) were the most likely to accumulate features of insulin resistance syndrome, the univariate risk of ischemic heart disease in this group was not significantly increased compared with normal-weight men (BMI < 25 kg/m2) (RH 1.26, 95% confidence interval [CI] 0.88-1.80). However, obese men who accumulated more than 4 features of insulin resistance syndrome were at increased risk of ischemic heart disease (RH 1.81, 95% CI 1.02-3.19) compared with normal-weight men who had fewer than 3 features of the syndrome. Conversely, having more than 4 features of insulin resistance syndrome was associated with a 3-fold increase in the risk of ischemic heart disease among normal-weight men (RH 3.01, 95% CI 1.70-5.32). INTERPRETATION: Although obesity is an important risk factor for ischemic heart disease, variations in BMI alone poorly reflect the risk of ischemic heart disease associated with features of insulin resistance syndrome.

Characterization of the metabolic interaction between trihalomethanes and chloroacetic acids using rat liver microsomes.

The aim of this study was to investigate the in vitro metabolism of trihalomethanes (THMs) in the presence of trichloroacetic acid (TCA), dichloracetic acid (DCA), monochloroacetic acid (MCA), and 4-methylpyrazole (4-MP) using liver microsomes from male Sprague-Dawley rats. Using the vial equilibration technique, initial experiments were carried out with starting concentrations of approximately 40 ppm THMs and 12-22 mM chloroacetic acids. The results indicated a mutual metabolic inhibition between THMs present as binary or quaternary mixtures. Although DCA and MCA had no influence on THMs, TCA produced a marked inhibition of the metabolism of all THMs: chloroform (CHCl3) (55%), bromodichloromethane (BDCM) (34%), dibromochloromethane (DBCM) (30%), and bromoform (TBM) (23%). The presence of 4-MP also reduced THM metabolism, the importance of which decreased in the following order: CHCl3 > BDCM > DBCM = TBM. In further vial equilibration experiments, using 9-140 ppm as starting concentrations of THMs, enzyme kinetic parameters (i.e., Michaelis constant, K(m), and maximum velocity, V(max)) were determined both in the absence and in the presence of TCA (12.2 mM). Results are consistent with a competitive inhibition between TCA and CHCl3, whereas the metabolic inhibition of BDCM and TMB by TCA was non-competitive. As for DBCM, results suggest a more complex pattern of inhibition. These results suggest that CYP2E1 is involved in the metabolism of THMs as well as in the metabolic interaction between THMs and TCA.

Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk.

The objective of the present study was to examine concordance/discordance among 4 atherogenic indexes of cardiovascular risk: plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, and apolipoprotein B-100 (apoB). Analyses were conducted in a cohort of 2,103 men without coronary artery disease (CAD) at the onset of the Quebec Cardiovascular Study. Although there were strong and highly significant correlations among the 4 risk indexes (0.78 < r < 0.97), only 50% of all subjects had concordant apoB and LDL cholesterol levels (i.e., values that fell into the same quintile of the population distribution). Moreover, concordance/discordance was not the same throughout the range of both variables; it was greater at the extremes of their respective distributions (65%), but significantly less in the midpoints (<40%). ApoB appeared to be more concordant with non-HDL cholesterol than with LDL cholesterol, although >1/3 of all subjects had discordant levels. Kappa analysis confirmed that there was only fair agreement between apoB and total or LDL cholesterol (0.38 and 0.36, respectively) and only moderate agreement between non-HDL cholesterol and apoB (0.47). Finally, a significant proportion of subjects (528 of 2,103) who had disproportionately higher apoB levels than would have been predicted based on their LDL cholesterol concentrations was more obese and manifested several features of the metabolic syndrome. They also had a significantly increased cardiovascular risk. In summary, plasma apoB and the various cholesterol indexes are complementary rather than competitive indexes of atherosclerotic risk and provide further evidence as to why measurement of apoB should be part of a standard lipoprotein assessment of CAD risk.

Effect of plasma C-reactive protein levels in modulating the risk of coronary heart disease associated with small, dense, low-density lipoproteins in men (The Quebec Cardiovascular Study).

This purpose of this study was to investigate how plasma C-reactive protein (CRP), a nonspecific acute-phase reactant, modulates the risk of coronary heart disease (CHD) associated with the small, dense, low-density lipoprotein (LDL) phenotype. LDL particle size and plasma CRP were measured in the Quebec Cardiovascular Study cohort of 2,025 men free of CHD at baseline, among whom 103 had a first CHD event during a 5-year follow-up period. Plasma CRP levels were measured using the Behring Latex-Enhanced (highly sensitive) CRP assay. LDL particle size phenotype was characterized using 2% to 16% polyacrylamide gradient gel electrophoresis. There were weak but significant associations between plasma CRP levels and features of LDL size, such as the proportion of LDL with a diameter <255 A (r = 0.09, p <0.001) and LDL peak particle size (r = -0.09, p <0.001). Variations in plasma CRP levels modulated the risk of CHD associated with small LDL peak particle size (relative risk 4.3 vs 2.5 in men with high vs low plasma CRP levels, respectively) and with an elevated proportion of LDL <255 A (relative risk 6.6 vs 3.0). Thus, increased plasma CRP levels further elevate the risk of CHD associated with having small, dense LDL particles.

Manganese distribution in the brain and neurobehavioral changes following inhalation exposure of rats to three chemical forms of manganese.

The central nervous system is an important target for manganese (Mn) intoxication in humans; it may cause neurological symptoms similar to Parkinson's disease. Manganese compounds emitted from the tailpipe of vehicles using methylcyclopentadienyl manganese tricarbonyl (MMT) are primarily Mn phosphate, Mn sulfate, and Mn phosphate/sulfate mixture. The purpose of this study is to compare the patterns of Mn distribution in various brain regions (olfactory bulb, frontal parietal cortex, globus pallidus, striatum and cerebellum) and other tissues (lung, liver, kidney, testis) and the neurobehavioral damage following inhalation exposure of rats to three Mn species. Rats (n=15 rats per Mn species) were exposed 6 h per day, 5 days per week for 13 consecutive weeks to metallic Mn, Mn phosphate or Mn phosphate/sulfate mixture at about 3000 microgm(-3) and compared to controls. At the end of the exposure period, spontaneous motor activity was measured for 36 h using a computerized autotrack system. Mn in tissues was determined by instrumental neutron activation analysis (INAA). The Mn concentrations in the brain were significantly higher in rats exposed to Mn phosphate and Mn phosphate/sulfate mixture than in control rats or rats exposed to metallic Mn. Exposure to Mn phosphate/sulfate mixture caused a decrease in the total ambulatory count related to locomotor activity. Our results confirm that Mn species and solubility have an influence on the brain distribution of Mn in rats.

Evaluation of the influence of chloroacetic acids on the pharmacokinetics of trihalomethanes in the rat.

Chloroacetic acids (monochloroacetic acid [MCA], dichloroacetic acid [DCA], and trichloroacetic acid [TCA]) and trihalomethanes (THMs: chloroform [CHCl(3)], bromodichloromethane [BDCM], dibromochloromethane [DBCM], and bromoform [TBM]) are common by-products of the chlorination of drinking water. The purpose of this study was to evaluate the influence of chloroacetic acids on the pharmacokinetics of trihalomethanes in the male Sprague-Dawley rat. In the first series of studies, groups of 5 animals were given, by intravenous injections, a single dose of 0.125 mmol/kg of one of the four THMs. Additional groups received a binary mixture containing 0.125 mmol/kg of a THM plus 0.125 mmol/kg of a chloroacetic acid. The venous blood concentrations of unchanged THMs were measured by headspace gas chromatography from 5 min to 6 h postadministration. The areas under the blood concentration versus time curves (AUCs) of CHCl(3), BDCM, and DBCM were increased by a factor of 3.5, 1.6, and 2, respectively, by coadministration of TCA. DCA coadministration resulted in an increase in the AUC of DBCM (x2.5) and TBM (x1.3), whereas MCA modified the Cmax (x1.5) and AUC (x1.8) of BDCM and the AUC of DBCM (x2.5). In the second series of experiments, animals received either a single dose of 0.03125 mmol/kg of one of the four THMs, a mixture containing 0.03125 mmol/kg of each of the four THMs (total dose = 0.125 mmol/kg), or a mixture containing 0.03125 mmol/kg of each of the four THMs plus 0.125 mmol/kg of either TCA or DCA. Results indicated that the AUCs of CHCl(3), BDCM, DBCM, and TBM were increased during coadministration compared to single administrations (+2.5-fold). Combined administration of the four THMs with TCA, and not DCA, resulted in an increase of the AUCs of THMs (CHCl(3): x11.7; BDCM, DBCM, and TBM: x3.9) and an increase in the Cmax of CHCl(3) (x1.9). Overall, these results indicate that, at the dose levels tested in this study, TCA alters the blood concentration profiles of THMs.

Moderate alcohol consumption is more cardioprotective in men with the metabolic syndrome.

The aim of the present study was to evaluate the relation among alcohol consumption, the metabolic syndrome, and the risk of ischemic heart disease (IHD). The study was conducted in a cohort of 1966 men from the Quebec Cardiovascular Study. All men were initially free of IHD and, during the follow-up period of 13 y, 219 first cases of IHD were diagnosed. Alcohol consumption was determined by calculating the g/d intake based on standard portions of beer, wine, and spirits. Metabolic syndrome was diagnosed according to a modification of the National Cholesterol Education Program Adult Treatment Panel III definition. Men who consumed >or=15.2 g of alcohol/d (4th quartile of the distribution) were younger (P < 0.001), had elevated plasma HDL-C concentrations (P < 0.001), and lower plasma concentrations of insulin (P = 0.01), CRP (P = 0.01), and fibrinogen (P < 0.001) than men in the 1st quartile (<1.3 g of alcohol/d). After adjustment for a series of coronary risk factors, alcohol consumption >or=15.2 g/d was associated with a 39% reduction in the 13-y risk of IHD [relative risk (RR) of IHD = 0.61, P = 0.02]. Finally, an alcohol consumption <15.2 g/d was associated with an increase of the risk of IHD in men with the metabolic syndrome (RR = 2.24, P < 0.001) but not in men without the metabolic syndrome (RR = 1.31, P = 0.22). These results confirm that moderate daily alcohol consumption has cardioprotective properties and suggest that the effects may be more important in subjects with a deteriorated risk profile, such as those with the metabolic syndrome.