Intermittent claudication: From its risk factors to its long-term prognosis in men. The Quebec Cardiovascular Study.

BACKGROUND: The natural history of intermittent claudication, from its risk factors to its cardiovascular prognosis, has been reported in few prospective studies. OBJECTIVE: To assess incident intermittent claudication, as well as its risk factors and long-term prognosis in men. METHODS: A random sample of 4376 men 35 to 64 years of age from Quebec City (Quebec), who were free of cardiovascular disease (CVD), was evaluated in 1974 for CVD risk factors and followed until 1998. To assess the prognosis, the event rates between 1985 and 1998 were computed among men with incident claudication without other CVD, incident survivors of a first myocardial infarction (MI) without other CVD and men free of CVD between 1974 and 1985. RESULTS: From 1974 to 1998, 300 men developed intermittent claudication. Tobacco consumption, high systolic blood pressure and diabetes at least doubled the adjusted RR (aRR) of intermittent claudication. In 1985, there were 80 claudicants, 2868 men free of CVD and 68 survivors of a first MI. During the 13-year follow-up, a new CVD occurred in 48.8% of the claudicants, in 18.9% of men without CVD (aRR 2.08; 95% CI 1.48 to 2.90) and in 45.6% of MI survivors (aRR compared with claudicants 1.12; 95% CI 0.69 to 1.79). There was also no significant difference between claudicants and MI survivors for fatal CVD, nonfatal CVD and total mortality. CONCLUSIONS: Men with intermittent claudication are at high risk for CVD that may be equivalent to men with previous MI.

Effect of increased plasma osmolality on cold-induced thirst attenuation.

The effects of elevating plasma osmolality (P (osm)) on thirst ratings was studied in eight dehydrated males during exposure to 4 degrees C. On two occasions, subjects were dehydrated (DH; 3-4% body mass) via 90 min exercise-heat exposure and overnight fluid restriction (day 1). On a third occasion, subjects were exposed to heat but were given fluid (EU). On day 2, subjects consumed NaCl (NaCl; 0.1 g NaCl kg(-1) body mass in 500 ml H(2)O; DH only) or Placebo (P; 500 ml H(2)O; DH and EU). Subjects stood for 30 min at 24 degrees C and for 45 min at 4 degrees C (75 min post-dose). P (osm) was elevated (P < 0.05) 30 and 75 min after NaCl administration in DH + NaCl versus DH + P and EU + P treatments. Thirst ratings remained elevated (P < 0.05) in the DH + NaCl treatment 30 min after dosing and 45 min at 4 degrees C versus DH + P and EU + P. Attenuation of thirst when dehydrated in the cold can be over-ridden by increasing P (osm).

Effect of plant sterols and endurance training on LDL particle size and distribution in previously sedentary hypercholesterolemic adults.

BACKGROUND: Plant sterols and exercise favourably alter lipid profiles in a way that protect against future coronary heart disease (CHD). However, their effects on other indicators of CHD risk, such as LDL particle size, still need further clarification. OBJECTIVE: This study examined the effect of plant sterols, exercise, and the combination of plant sterols and exercise, on LDL particle size and distribution in previously sedentary, hypercholesterolemic adults. DESIGN: In an 8-week, placebo-controlled, parallel-arm clinical trial, 84 subjects were randomized to one of four intervention groups: (1) combination of sterols and exercise, (2) exercise, (3) sterol, or (4) control. RESULTS: Exercise significantly (P < 0.05) reduced post-treatment LDL peak particle size from 255 to 253 A. Additionally, exercise significantly (P < 0.05) decreased the proportion of large LDL particles within plasma. Sterol supplementation significantly (P < 0.05) decreased the estimated cholesterol concentrations within small, medium, and large LDL particles by 13.4, 13.5, and 14.4%, respectively, yet had no effect on the distribution of cholesterol among various LDL particle sizes. Furthermore, decreased body weight post-training was associated with increased cholesterol in small LDL particles (r = -0.52, P < 0.0001). Decrease in body fat percent (BF%) post-training was associated with increased cholesterol concentrations in small LDL particles (r = -0.29, P < 0.01). CONCLUSION: On the basis of modulating LDL electrophoretic characteristics, the present study demonstrates that plant sterols have no effect on CHD risk, while short-term exercise may potentially increase CHD risk by decreasing LDL peak particle size. SPONSORSHIP: This study was sponsored by The Heart and Stroke Foundation of Canada.

Comparison of various electrophoretic characteristics of LDL particles and their relationship to the risk of ischemic heart disease.

BACKGROUND: Several cross-sectional studies and 3 prospective, nested, case-control studies have indicated that individuals with small, dense low density lipoprotein (LDL) particles are at increased risk for ischemic heart disease (IHD). However, whether LDL particle size is an independent risk factor for future IHD events remains controversial. The objective of the present study was to further analyze the cardiovascular risk associated with various electrophoretic characteristics of LDL particles in men. METHODS AND RESULTS: LDL particles were characterized by polyacrylamide gradient gel electrophoresis (PAGGE) in a cohort of 2034 men of the Quebec Cardiovascular Study. All men were initially free of IHD and were followed up for a period of 5 years, during which 108 first IHD events were recorded. Among all LDL characteristics investigated by PAGGE, including LDL peak particle size, the cholesterol concentration in LDL particles with a diameter smaller than 255 A showed the strongest association with the risk of IHD (relative risk=4.6 in men in the third vs first tertile of the distribution, P<0.001). Multivariate logistic and survival models indicated that the relationship between LDL cholesterol levels in particles with a diameter <255 A and IHD risk was independent of all nonlipid risk factors and of LDL cholesterol, high density lipoprotein cholesterol, triglyceride, and lipoprotein(a) levels. CONCLUSIONS: Results from this large, population-based, prospective study suggest that further characterization of LDL particles by PAGGE, in addition to the traditional lipid profile, may improve our ability to predict IHD events in men.

A prospective, population-based study of low density lipoprotein particle size as a risk factor for ischemic heart disease in men.

BACKGROUND: The current interpretation of the increased risk of ischemic heart disease (IHD) associated with reduced low density lipoprotein (LDL) particle size is based entirely on data derived from relatively small case-control studies, with a lack of evidence from large, prospective, population-based cohort data. OBJECTIVES: To investigate the association between LDL particle size and incident IHD on the basis of data from the entire population-based, prospective cohort of men from the Quebec Cardiovascular Study. PATIENTS AND METHODS: Analyses were conducted in a cohort of 2057 men who were all initially free of IHD, and who were followed up over a five-year period, during which 108 first IHD events (myocardial infarction, angina or coronary death) were recorded. LDL particle size was measured by nondenaturing gradient gel electrophoresis. RESULTS: Cox proportional hazards analysis indicated that the relationship between LDL particle size and the risk of future IHD events was not linear. Men with an LDL particle size less than 256.0 A had a significant 2.2-fold increase in the five-year rate of IHD (P<0.001) compared with men having an LDL particle size greater than 256.0 A. Multivariate and subgroup analyses indicated that small, dense LDL particles predicted the rate of IHD independent of LDL cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, apolipoprotein B and the total cholesterol to HDL cholesterol ratio. Finally, the magnitude of the increase in IHD risk attributed to lipid risk factors was modulated to a significant extent by variations in LDL particle size. CONCLUSIONS: The present study provides the first large scale, population-based, prospective evidence supporting the hypothesis that small, dense LDL particles may be associated with an increased risk of IHD. The results also suggest that information on LDL diameter may improve the ability to predict IHD risk accurately over traditional lipid variables.

Bioaccumulation and locomotor effect of manganese dust in rats.

The primary goal of this study is to determine the effects of Mn exposure via inhalation. The bioaccumulation of Mn in different organs and tissues, the alteration of biochemical parameters, and the locomotor activity were assessed. A group of 26 male Sprague-Dawley rats (E) were exposed to 3750 microg/m(3) of Mn dust for 6 h/day, 5 days/wk for 13 consecutive weeks and compared to a control group of 12 rats (C) exposed to 4 microg/m(3). After exposure, neurological evaluation was carried out for 36 h (a night-day-night cycle) using a computerized autotrack system. Rats were then sacrificed by exsanguination, and Mn content in organs and tissues was determined by neutron activation analysis. Mn concentrations in lung, putamen, and cerebellum were significantly higher in E than in C (0.30 vs. 0.17, 0.89 vs. 0.44, 0.63 vs. 0.48 ppm; p <.01), as well as in the kidney, frontal cortex, and globus pallidus (1.15 vs. 0.96, 0.84 vs. 0.47, 1.28 vs. 0.55 ppm; p <.05). Potassium concentration was significantly lower in E than in C (5.11 vs. 5.79 mmol/L; p <.05), as was alkaline phosphatase (106.9 vs. 129.6 U/L; p <.01). Locomotor activity indicated higher distance covered in the first 12-h period for E (45 383 vs. 36 098 cm; p <.05) and lower resting time in the last 12-h period for E (36 326 vs. 37 393 s; p <.05). This study is the first of several ongoing studies in our laboratory that address health concerns associated with inhalation exposure to different Mn species and to different levels of exposure.

Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors.

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.

BCH-2763, a novel potent parenteral thrombin inhibitor, is an effective antithrombotic agent in rodent models of arterial and venous thrombosis--comparisons with heparin, r-hirudin, hirulog, inogatran and argatroban.

Current clinical use of heparin as an antithrombotic agent is limited by suboptimal efficacy and safety considerations. Thrombin's central role in thrombosis makes it an attractive target to develop more effective and safer antithrombotic agents. BCH-2763 is a novel, potent (Ki: 0.11 nM), low molecular weight (1.51 kDa), bivalent direct thrombin inhibitor. The antithrombotic efficacy of BCH-2763 in vivo following i.v. bolus plus infusion in rats was compared in arterial and venous thrombosis models with two other bivalent direct thrombin inhibitors, r-hirudin and hirulog, with two catalytic site-directed thrombin inhibitors, inogatran and argatroban, and with heparin. In vivo efficacy was related to inhibition in vitro of fibrin clot formation, thrombin-induced aggregation of rat or human washed platelets and activity of free and plasma clot-bound thrombin. All the direct thrombin inhibitors were effective on both arterial and venous thrombosis at markedly lower fold aPTT increases than heparin. The antithrombotic doses of all inhibitors against venous thrombosis were less than against arterial thrombosis. The rank order of potency based on doses (mg/kg/h) required for full efficacy against arterial thrombosis was BCH-2763 (1.2) > inogatran (1.5) > r-hirudin (1.8) > hirulog (3.3) > argatroban (> 3.0); heparin required a markedly higher dose (5.7). In venous thrombosis the doses required for full efficacy were substantially lower for the bivalent (BCH-2763: 0.12; r-hirudin: 0.12; hirulog: 0.18) than for the catalytic site-directed (inogatran: 0.48; argatroban: 0.90) thrombin inhibitors; the dose required for heparin was 0.19. All the direct thrombin inhibitors caused similar shifts in aPTT at doses required to inhibit arterial thrombosis, but BCH-2763 inhibited venous thrombosis at lower aPTT fold increases. In vivo antithrombotic efficacy of direct thrombin inhibitors correlated with their inhibitory activity in vitro against fibrin clot formation and platelet aggregation. In contrast to heparin, all the direct thrombin inhibitors inhibited plasma clot-bound thrombin, but the relative IC50s did not correlate with their antithrombotic efficacy. In summary, direct thrombin inhibitors are more effective than heparin in inhibiting arterial and venous thrombosis in rats with less aPTT increases. BCH-2763 is effective at lower doses than the other direct thrombin inhibitors and for venous thrombosis at a smaller aPTT increase. BCH-2763 may offer an improved therapeutic index in the treatment of thromboembolic complications over heparin and other direct thrombin inhibitors.

Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus.

BACKGROUND: Although epidural corticosteroid injections are commonly used for sciatica, their efficacy has not been established. METHODS: In a randomized, double-blind trial, we administered up to three epidural injections of methylprednisolone acetate (80 mg in 8 ml of isotonic saline) or isotonic saline (1 ml) to 158 patients with sciatica due to a herniated nucleus pulposus. All patients had Oswestry disability scores higher than 20 (on a scale of 1 to 100, with scores of 20 or less indicating minimal disability, and higher scores greater disability). RESULTS: At three weeks, the Oswestry score had improved by a mean of -8.0 in the methylprednisolone group and -5.5 in the placebo group (95 percent confidence interval for the difference, -7.1 to 2.2). Differences in improvements between the groups were not significant, except for improvements in the finger-to-floor distance (P=0.006) and sensory deficits (P=0.03), which were greater in the methylprednisolone group. After six weeks, the only significant difference was the improvement in leg pain, which was greater in the methylprednisolone group (P=0.03). After three months, there were no significant differences between the groups. The Oswestry score had improved by a mean of -17.3 in the methylprednisolone group and -15.4 in the placebo group (95 percent confidence interval for the difference, -9.3 to 5.4). At 12 months, the cumulative probability of back surgery was 25.8 percent in the methylprednisolone group and 24.8 percent in the placebo group (P=0.90). CONCLUSIONS: Although epidural injections of methylprednisolone may afford short-term improvement in leg pain and sensory deficits in patients with sciatica due to a herniated nucleus pulposus, this treatment offers no significant functional benefit, nor does it reduce the need for surgery.

Alcohol and other drugs of abuse in pregnancy.

This paper presents an overview of the Mother-Baby Chemical Health Program (MBCHP), which was designed to decrease preterm births among pregnant women who use and abuse drugs. Three hundred and fifty-two patients enrolled in the program between January 1990 and December 1992 were followed. More than 90% of the women involved in the MBCHP did not use substances during their pregnancies. Approximately 93% of the participants delivered at 37 or more weeks gestation, and over 91% of the infants weighed 2500 grams or more.

Interscalene block for pain relief after shoulder surgery. A prospective randomized study.

A prospective randomized study undertaken in 30 patients who underwent outpatient decompressive acromioplasty demonstrated the efficacy and safety of interscalene block post-operatively. Interscalene block improved the postoperative condition and well being of these patients. Their use decreased the hospitalization rate. There were no complications or side effects.

Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate. METHODS: We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5-5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups. RESULTS: Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%, P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups. CONCLUSION: The methotrexate-leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.

11p13 deletion, Wilms' tumour, and aniridia: unusual genetic, non-ocular and ocular features of three cases.

Three cases of Wilms' tumour and sporadic aniridia were followed up for periods ranging from 32 months to seven years. All had a deletion of the short arm of the eleventh chromosome 11p13, including one case with mosaicism, a cytogenetic feature that has not been previously described in the Wilms' tumour and sporadic aniridia association. Unusual non-ocular features found in all patients included tracheomalacia and delayed closure of the anterior fontanelle. In two cases tracheomalacia was responsible for respiratory distress after general anaesthesia. Wilms' tumour developed bilaterally in one patient and on the isthmus of a horseshoe kidney in another patient. In addition to the more commonly observed ocular features the presence of a corneal pannus was noted before 38 months of age in all patients and as early as 17 months in one case. An iridocorneal adherence with an overlying corneal opacity (presumably related to abnormal developmental cleavage of the anterior segment) was noted in one eye only of the mosaicism case.

Delay in hearing loss following drug administration. A consistent feature of amikacin ototoxicity.

The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.

Drug abuse in pregnancy. Detection and intervention.

Drug abuse in the obstetric population of a large urban HMO is discussed. Marijuana metabolites were detected in 9.1% of urines submitted for routine pregnancy testing, while cocaine use was detected in 1.3%. A separate group of urines submitted for urine culture at the time of the first obstetric visit were tested and showed levels of 5.0% and 0.2%, respectively. Cocaine use was associated in an estimated 1-2% of all live births. The unexpected magnitude of this problem led to the creation of an outreach clinic and a process of care. The preliminary experience of our program forms the basis of this report.

Incidence of amikacin ototoxicity: a sigmoid function of total drug exposure independent of plasma levels.

A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.

Facial expressions of emotions and ethological behavioral categories.

The purpose of this study was to measure the capacity of human subjects to match facial expressions of emotions and behavioral categories that represented the motivational states they are supposed to illustrate. 100 university students were shown facial stimuli they had to classify using ethological behavioral categories. The results showed that accuracy of judgment was over-all lower than what was usually found when fundamental emotional categories were used. The data also indicated that the relation between emotional expressions and behavioral tendencies was more complex than expected.