Intratesticular benign peripheral nerve sheath tumour in a ferret (Mustela putorius furo).

A domestic ferret was submitted for sterilisation because of right testis enlargement. Oestradiol and cortisol concentrations were within normal physiological ranges, but testosterone was below and progesterone above normal. Microscopically, the right testis, with the exception of a small part of the epididymis, was replaced with neoplastic tissue. The tumour was composed of streams and bundles of closely packed spindle to ovoid cells forming whorls around collagen and capillaries, and separated by a collagenous matrix. In some areas, cells were loosely arranged and separated by a pale myxomatous matrix. The left testis showed atrophy. The majority of neoplastic cells expressed vimentin and S-100 protein, while expression of collagen IV was moderate and there was no expression of glial fibrillary acid protein. On the basis of macroscopical and histopathological findings, and supported by immunohistochemical reactivity, the diagnosis of benign peripheral nerve sheath tumour was made. This is the first report of benign peripheral nerve sheath tumour in ferret testis.

Role of the fractalkine receptor CX3CR1 polymorphisms V249I and T280M as risk factors for early-onset coronary artery disease in patients with no classic risk factors.

OBJECTIVES: CX3CR1 is a monocyte chemokine receptor and adhesion molecule. Two CX3CR1 mutations, V249I and T280M, reportedly decrease coronary artery disease (CAD) risk independent of established risk factors. An I249 protective effect is attributed to reducing CX3CR1 binding to fractalkine, its ligand. MATERIAL AND METHODS: We examined the frequencies of V249I and T280M among early-onset CAD patients (G1; n = 149; <50 years), late-onset CAD patients (G2; n = 150; >65 years) and healthy controls (HC; n = 149, 47-93 years) without known CAD risk factors. We compared plasma total cholesterol (TC)/high density lipoprotein-C (HDL-C) and apolipoprotein B (APOB)/apolipoprotein AI (APOAI) ratios among the groups and mutation carriers and non-carriers, and the prevalence of the mutations in G1 and G2 patients with multiple coronary vessel disease (MVD) and myocardial infarction (MI). RESULTS: G1 patients had non-significantly lower frequencies of I249 versus (vs.) G2 or controls (G1; 51 %, G2: 61 %, controls: 58 %, p = 0.19), with no difference in T280M (p = 0.8). TC/HDL-C and APOB/APOAI ratios were significantly higher in G1 patients vs. G2 and controls (p<0.0001) independently of either mutation. More G2 patients had MVD than younger ones (p<0.0001); however, more G1 patients were homozygous for V249 compared to G2 patients, who more often had the I249 allele (p<0.02). There was no such association with T280M (p = 0.38). Although more G1 patients had MI, this was not mutation related. CONCLUSIONS: There were significantly higher lipid ratios in G1 compared to G2 and HC (G1>G2>HC), but not in mutation prevalence. I249 mutation was associated with MVD in older patients, while V249 homozygosity was associated with the early-onset CAD. Neither allele affected MI or lipid levels.

Relationship of the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene and early-onset coronary artery disease.

BACKGROUND: The Glu298Asp polymorphism of endothelial nitric oxide synthase (eNOS) gene has been associated with coronary artery disease (CAD) in some but not all studies. To determine the impact of the mutant Asp298 eNOS allele on the development of premature CAD, we examined the prevalence of this mutation in patients with early-onset CAD compared with those manifesting CAD later in life. If this mutation confers an increased risk of premature CAD, we hypothesized that the frequency of the homozygous mutation (Asp298Asp298) would be greater among the younger patient group. METHODS: A total of 299 patients with a history of myocardial infarction (MI) or angina pectoris plus angiographically documented CAD were studied. Patients were divided into 2 groups: group 1 (149 patients) included patients with CAD before the age of 50 years and group 2 (150 patients) included patients with a first presentation of CAD at >65 years old. Prevalence of eNOS Glu298 and Asp298 alleles was assessed by molecular analysis and compared for the 2 groups. RESULTS: There was no significant difference in the frequency of the mutant Asp298 allele between the 2 groups (G1: 42% vs G2: 42.7%, P =.79). The frequencies of the Glu298Glu298, Glu298Asp298, and Asp298Asp298 genotypes were similar in both groups (34.9%, 46.3%, and 18.8% for G1 and 29.3%, 56%, and 14.7% for G2, respectively, P =.29). CONCLUSIONS: Our study does not support the conclusion that the eNOS Asp298 allele contributes to the development of premature CAD.

Trends in the incidence of acute myocardial infarction between 1984 and 1993 - The Halifax County MONICA Project.

BACKGROUND: According to vital statistics data for Halifax County, between 1984 and 1993 the annual mortality rate decreased for ischemic heart disease and myocardial infarction (MI). OBJECTIVES: To estimate the change in MI mortality, applying standardized diagnostic criteria; to determine whether decreased case fatality or decreased MI event rate, or both, caused decreased mortality; and to determine the contribution of MI incidence rate to altered event rate. PATIENTS AND METHODS: All persons in the study area aged 25 to 74 years and admitted to hospital or dying outside hospital with suspected acute coronary syndromes were registered prospectively. Demographic, health history and clinical data were extracted from medical records or collected from medical examiner reports, next-of-kin interviews or family physicians. Definite or possible MI was diagnosed according to World Health Organization MONItoring of trends and determinants in CArdiovascular disease (MONICA) criteria. Trends in age- and sex-standardized rates were estimated by using log-linear regression analysis. RESULTS: Of 4283 patients admitted to hospital for MI, 23.9% died within 28 days; 1401 patients who had suffered an MI died before admission to hospital. MI mortality decreased annually by 3.9% (95% CI 1.9 to 5.8); two-thirds of the decline was due to MI event rates (2.6%; CI 1.3 to 3.8) and one-third to a decrease in 28-day case fatality (1.3%; CI 0.2 to 2. 3). A decrease in MI incidence rate (3.2%; CI 1.7 to 4.8), rather than a decline in MI recurrence rate (1.4%; CI 0.7 to -3.5), was the major reason for the declining event rate. CONCLUSIONS: A decrease in the incidence of MI, possibly due to primary prevention, had a major impact on the declining MI mortality. Decreased in-hospital MI fatality, possibly due to improved treatment, was responsible for the decline in case fatality.

Trends in the in-hospital treatment of acute myocardial infarction between 1984 and 1993 - The Halifax County MONICA Project.

BACKGROUND: The Halifax County MONItoring of trends and determinants in CArdiovascular disease (MONICA) Project found that between 1984 and 1988, the proportion of myocardial infarctions (MIs) that were fatal within 28 days remained constant, but declined between 1989 and 1993. The objective was to investigate association among case fatality, treatment and case severity of MI in hospitalized patients. PATIENTS AND METHODS: The MONICA MI register contains data on demographics, health history, in-hospital investigations, interventions and treatment, and vital status at 28 days after onset of symptoms for all MIs occurring in residents of Halifax County, aged 25 to 74 years. Logistic regression analysis was used to estimate trends in the use of cardioactive drugs and revascularization procedures. A case severity score was developed from patient characteristics at time of admission. Case fatality was calculated as the proportion of MIs that were fatal within 28 days. RESULTS: Between 1984 and 1988, a large increase (OR 1.3) occurred in the use of angiotensin-converting enzyme (ACE) inhibitors, acetylsalicylic acid (ASA), thrombolysis and percutaneous transluminal coronary angioplasty (PTCA); a minor increase occurred in use of calcium channel blockers (OR=1.29, 99% CI 1.19 to 1.40); beta-blocker use decreased; case fatality remained constant and case severity score increased. From 1989 to 1993, ACE inhibitor use increased (OR=1.4, 99% CI 1.27 to 1.55); minor increases occurred in use of ASA and beta-blockers, and in PTCA and coronary artery bypass grafting; case severity did not change and case fatality decreased. CONCLUSIONS: While use of beneficial treatment increased between 1984 and 1988, MI case fatality did not decrease, probably because case severity increased. Between 1989 and 1993, case severity remained constant, and the further increase in the use of beneficial therapy was associated with a decline in case fatality.

A new potent calmodulin antagonist with arylalkylamine structure: crystallographic, spectroscopic and functional studies.

An arylalkylamine-type calmodulin antagonist, N-(3, 3-diphenylpropyl)-N'-[1-R-(3, 4-bis-butoxyphenyl)ethyl]-propylene-diamine (AAA) is presented and its complexes with calmodulin are characterized in solution and in the crystal. Near-UV circular dichroism spectra show that AAA binds to calmodulin with 2:1 stoichiometry in a Ca(2+)-dependent manner. The crystal structure with 2:1 stoichiometry is determined to 2.64 A resolution. The binding of AAA causes domain closure of calmodulin similar to that obtained with trifluoperazine. Solution and crystal data indicate that each of the two AAA molecules anchors in the hydrophobic pockets of calmodulin, overlapping with two trifluoperazine sites, i.e. at a hydrophobic pocket and an interdomain site. The two AAA molecules also interact with each other by hydrophobic forces. A competition enzymatic assay has revealed that AAA inhibits calmodulin-activated phosphodiesterase activity at two orders of magnitude lower concentration than trifluoperazine. The apparent dissociation constant of AAA to calmodulin is 18 nM, which is commensurable with that of target peptides. On the basis of the crystal structure, we propose that the high-affinity binding is mainly due to a favorable entropy term, as the AAA molecule makes multiple contacts in its complex with calmodulin.

Trends in the prevalence and treatment of hypertension in Halifax County from 1985 to 1995.

BACKGROUND: The objective of this study was to document changes in the prevalence and treatment of hypertension in Halifax County from 1985 to 1995 in an effort to observe, at the population level, the consequences of the availability of new antihypertensive medications. METHODS: The study population comprised a random sample of Halifax County residents, aged 25-64 years, who responded to the 1985 and 1995 surveys of the Halifax County MONICA Project and residents who responded to the Nova Scotia Health Survey conducted in 1995. Data from the two 1995 surveys were pooled. Information on hypertension awareness and use of medication were obtained through questionnaires, and blood pressure was measured according to a standard protocol, using phase I and V of Korotkoff sounds as respective markers for systolic and diastolic pressures. Uncontrolled hypertension was defined as a systolic pressure of 140 mm Hg or greater and a diastolic pressure of 90 mm Hg or greater. Changes in the prevalence of hypertension, prescribing trends and medication costs were examined, and the association between the type of antihypertensive treatment and characteristics of the respondents with self-reported hypertension was investigated by multivariate logistic regression. RESULTS: Of the 917 people interviewed in 1985 and the 1338 in 1995, 274 (29.9%) and 356 (26.6%), respectively, reported a history of hypertension. When age was controlled for, the proportion of respondents reporting hypertension did not differ between survey years or between men and women. The proportion of treated respondents who had uncontrolled hypertension increased between 1985 and 1995, from 32.6% to 57.4% among men and from 38.0% to 42.6% among women. An increase was seen in the use of calcium-channel blockers (from 2.1% to 19.7%) and angiotensin-converting-enzyme inhibitors (from 5.2% to 25.4%); the proportion of patients receiving combination therapy or diuretics decreased (from 39.6% to 15.6% and from 31.3% to 17.2% respectively). These changes were associated with an increase in the average daily cost of medication from $0.48 to $0.85 per patient. INTERPRETATION: The shift to new antihypertensive drugs was not associated with improved blood pressure control, but it was associated with an increase in average medication costs per patient. Uncontrolled hypertension remains a public health problem.

Relation of genetic polymorphisms of apolipoprotein E, angiotensin converting enzyme, apolipoprotein B-100, and glycoprotein IIIa and early-onset coronary heart disease.

OBJECTIVE: Apolipoprotein E (APOE) E4, apolipoprotein B-100 (APOB) Q3611 allele, the angiotensin converting enzyme (ACE) deletion (D) allele and glycoprotein IIIa (GP3A) P33 mutant allele are reported to predispose to early-onset coronary heart disease (CHD). These associations were not all confirmed in more recent studies. To determine the impact of these alleles on CHD, we examined the prevalence of these mutations in patients presenting with early-onset CHD and compared them to those manifesting CHD later in life. The delayed-onset was considered a sign of longevity and would serve as a comparative group to assess prevalence of the biochemical and genetic risk factors. METHODS: 300 patients with a history of myocardial infarction or angina pectoris and angiographically documented CHD were studied. Patients were divided into two groups: group 1 (G1 = 150 patients) presenting with these findings under the age of 50 years; while group 2 (G2 = 150 patients) were patients presenting for the first time over the age of 65 years. Prevalence of the alleles of APOE, APOB, ACE and GP3A was assessed by molecular analysis. An association of any of these genotypes with early onset CHD could lead to a higher prevalence in the younger age group. RESULTS AND CONCLUSIONS: None of the suspected alleles namely APOB Q3611 [G1: 10.7% vs. G2: 9.0%, p = 0.57], ACE D (G1: 52.0% vs. G2: 49.7%, p = 0.57), or the GP3A P33 (G1: 17.3% vs. G2: 15.7%; p = 0.58) showed any significant difference between the two groups. Subjects with APOE E4 were more frequent in the younger age group (G1: 18.3% vs. G2: 13.7%; p = 0.047), while APOE E2 was more frequent in G2 (G2: 10.0% vs. G1: 2.7%; p = 0.0002). Multivariate analysis showed an odds ratio of APOE E2 allele in G1 of 0.27 with a confidence interval of 0.10-0.73.

The short-term effects of a hostility-reduction intervention on male coronary heart disease patients.

This preliminary study examined the effects of a hostility-reduction intervention on patients with coronary heart disease (CHD). Twenty-two high-hostile CHD men were matched on age and hostility and then randomly assigned to a hostility intervention (N = 10) or an information-control group (N = 12). Patients were reassessed immediately and 2 months posttreatment on hostility (with self-report and structured interview) and resting blood pressure. The intervention's overall effect size was moderately strong (d' = .62). Intervention patients reported at both reassessments and were observed at follow-up to be less hostile than controls. At follow-up, intervention patients had significantly lower diastolic blood pressure (DBP) than controls. Finally, reductions in hostility were significantly and positively correlated with reductions in DBP. Replication with a larger sample and CHD outcomes is recommended.

Ten-year trends of heart disease risk factors in the Halifax County MONICA population. MONItoring of trends and determinants in CArdiovascular disease.

OBJECTIVE: To investigate trends in heart disease risk factors (RFs) in the general population of Halifax County, Nova Scotia during a 10-year period. DESIGN: Two independent random samples of the population of Halifax County were surveyed in 1985 and 1995; age ranges were 25-64 years and 25-74 years. Blood pressure, cholesterol and body weight were measured. Smoking and health history were obtained by questionnaire. MAIN RESULTS: Participation rate was 66.3% in 1985 and 1995. All RFs were negatively correlated with education attainment. RF changes from 1985 to 1995 were related to education level. Among survey participants, mean body mass index increased from 26.7 kg/m2 to 27.6 kg/m2 (P + 0.005) for men, and from 25.5 kg/m2 to 27.3 kg/m2 (P < 0.00001) for women. Average smoking rate increased from 32.0% to 34.6% (not significant) in men and from 27.7% to 29.1% (not significant) in women. Age-specific smoking rate increased by 13% (P = 0.14) in younger women and decreased by 10% in older women. (P = 0.00). Mean levels of blood cholesterol decreased by 0.2 mmol/L (P = 0.002) in men and 0.1 mmol/L (P = 0.20) in women. Systolic blood pressure increased by 6.3 mmHg (P < 0.0001) in men and by 7.9 mmHg (P < 0.0001) in women, being steepest in the lower education group. Mortality predicted from RFs declined between the survey years, but less than the observed mortality. This discrepancy may result from the effect of medical care or the delayed effect of RF changes. CONCLUSIONS: Some risk factors show a disturbing trend, indicating that an increased effort or a change in strategy is needed to combat the risk of ischemic heart disease.

Relation of a common mutation in methylenetetrahydrofolate reductase to plasma homocysteine and early onset coronary artery disease.

OBJECTIVE: In the presence of low serum folate, mutant 5,20-methylenetetrahydrofolate reductase (MTHFR + [A223V/C677T]) in the homozygous state (+/+), may predispose to higher plasma homocysteine (tHct) levels and coronary artery disease (CAD). To determine the impact of this relationship on predisposition to early-onset CAD, we examined the prevalence of the mutation and plasma tHct in patients with early-onset CAD and compared them to patients manifesting CAD later in life. METHODS: Three hundred patients with history of acute myocardial infarction or angina pectoris and angiographically documented CAD were studied. Patients consisted of two groups: group 1 (G1 = 150 patients) presenting with these findings under age 50; while group 2 (G2 = 150) presented for the first time over age 65 years. Prevalence of the MTHFR+ mutation was assessed by molecular analysis, and plasma tHct and folate were measured. An association of the +/+ genotype with early onset CAD could lead to its higher prevalence in the younger age group. RESULTS: There was no significant difference in the frequency of the (+/+) genotype between the two groups (G1: 11.3% vs. G2: 11.3%). However, patients with the (+/+) genotype in both groups had higher tHct when plasma folate was below the mean value (G1: p < 0.0001 while G2: p < 0.01). CONCLUSION: The mutant MTHFR genotype was not found to be a determining factor in early-onset CAD. Higher tHct values were obtained in the older age group, which is expected because other studies have shown that tHct levels increase with age. A significant relation was shown between MTHFR genotype and low folate status yielding high tHct levels in those with the (+/+) genotype. As this relation was seen in both groups, although to a lesser extent in the older G2, it does not explain the underlying cause of early-onset CAD.

Relation of HFE gene mutations, high iron stores and early onset coronary artery disease.

OBJECTIVE: To determine the impact of mutations in the HFE gene (human leukocyte antigen H) on predisposition to coronary artery disease (CAD) in patients not diagnosed with hereditary hemochromatosis. BACKGROUND: Elevated iron stores can predispose to acute myocardial infarction. Two mutations (C282Y and H63D) in the novel major histocompatibility complex (MHC) class 1 gene HFE were found in most patients with hereditary hemochromatosis causing high iron stores. The effect of these mutations on predisposition to CAD has not been investigated previously. METHODS: Three hundred patients with a history of myocardial infarction or angina pectoris and angiographically documented CAD were studied. Patients were divided into two groups: group 1 (150 patients), manifesting early onset CAD and presenting with these findings under age 50 years; and group 2 (150 patients), presenting for the first time over age 65 years. Prevalence of the C282Y and H63D mutations was assessed by molecular analysis, and plasma ferritin was measured immunochemically. RESULTS: There was no difference in the prevalence of homozygous, heterozygous or compound heterozygous (C282Y/H63D) states between the groups. Males in group 1 had higher plasma ferritin than those in group 2 (234 +/- 174 micrograms/L versus 136 +/- 103 micrograms/L, P < 0.0001), but this was not significantly different in females (75 +/- 54 micrograms/L versus 92 +/- 73 micrograms/L, P = 0.26). Ferritin remained higher in group 1 than in group 2 males after exclusion of mutation carriers (195 +/- 121 micrograms/L versus 109 +/- 76 micrograms/L, respectively, P < 0.0001), but did not change in females. CONCLUSIONS: Higher iron stores were found in males with early onset CAD. This association was not related to the C282Y or H63D mutation in HFE. It is suggested that association of the MHC locus with delayed onset CAD is probably unrelated to HFE in these patients, and that HFE mutations are not a major risk factor in the development of high iron stores in early onset CAD.

Decreasing mortality from acute myocardial infarctions: effect of attack rates and case severity.

Mortality from myocardial infarction (MI) has declined in many countries and the reasons for the decline have not been fully quantified. We used the database of the Halifax County MONICA Project to test the hypothesis that the decline of in-hospital mortality from MI can be explained by a trend toward less severe disease as opposed to improved treatment. During the study period 1984-1993, 14,130 people aged 25-74 had been admitted to hospital with suspected MI. Of these, 3774 were diagnosed as definite MI by standardized criteria (480 fatal). For each patient, clinical history, serial cardiac enzymes, and ECG treatment regimen during hospital stay were extracted from patient charts. Survival status 28 days after onset of symptoms was determined. A severity index predicting 28-day case fatality was derived from health status at admission time. During the study period the rate of definite MI in the MONICA target population showed a general downward trend from 221 to 179 per 100,000/year (p = 0.0002). The severity index increased during the observation time (p < 0.0001), predicting 25% higher mortality. Case fatality fluctuated, but showed a marginally significant decline. We conclude that part of the decreased in-hospital mortality from MI is due to lower attack rates. The remainder occurred despite increased case severity and is possibly due to improved in-hospital treatment.

PROTECT (Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial): a randomized, double-blind clinical trial of diltiazem versus atenolol in secondary prophylaxis post non-Q wave myocardial infarction.

OBJECTIVE: To describe the rationale and design of the Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial (PROTECT). DESIGN: A multicentre, randomized, double-blind, parallel-group comparison of once daily beta-therapy versus heart rate lowering calcium channel blocker therapy, in the reduction of one-year nonfatal reinfarction and cardiovascular death (combined primary end-point) initiated 24 to 96 h post non-Q wave myocardial infarction. SETTING: One hundred and twenty hospitals across Canada. PATIENTS: Over 7500 women and men aged 21 years or older with enzyme-confirmed non-Q wave infarction and without significant left ventricular systolic dysfunction will be recruited over two years. INTERVENTIONS: Once daily beta-blocker therapy (oral atenolol, 50 to 200 mg) versus once daily calcium channel blocker therapy (oral diltiazem 120 to 360 mg) with follow-up for up to three years. CONCLUSIONS: The PROTECT will be the largest all-Canadian cardiovascular trial to date and will compare two commonly prescribed agents for secondary prophylaxis following non-Q wave infarction. The scientific question addressed by the PROTECT is of major public health importance and the results of the study will directly affect current clinical practice.

Gender differences in the presentation, treatment, and short-term mortality of acute chest pain.

The Halifax County MONICA database was used to estimate the gender bias in presentation, prehospital and in-hospital treatment, and 28-d mortality of patients suffering an episode of acute chest pain. The study population consisted of all county residents aged 25-74, admitted between 1984 and 1990 to a CCU, or suffering a myocardial infarction anywhere in a hospital. The mean age for men was 58.5 (n = 6561), for women 61.5 (n = 3176). Women of all age groups were more likely to have a history of diabetes or hypertension, and below age 55 had a higher prevalence of peripheral vascular disease. Typical symptoms for infarction were present in 30.8% of women and 38.1% of men (p < 0.0001). More women were taking beta-blockers, Ca-antagonists, digitalis, diuretics, and nitrates (p < 0.001), and more men were on antiarrhythmics. A gender difference was observed for coronary arteriography (24% in men, 18% in women) and for the exercise stress test (23% in men, 18% in women). In hospital, men had more episodes of severe arrhythmias (OR = 1.52). Except for aspirin and antiarrhythmics, the difference in hospital medication and 28-d mortality (9.6% in women vs. 7.8% in men) could be explained by the existing clinical conditions.

Coronary artery fistula as a complication of percutaneous transluminal coronary angioplasty.

A patient underwent successful percutaneous transluminal coronary angioplasty (PTCA) of the left anterior descending and the right coronary arteries for worsening angina and was discharged without any apparent complication. Repeat cardiac catheterization, done four weeks later for recurrent angina, showed a coronary artery fistula to the right ventricle at the site of moderately severe subintimal dissection. The patient was managed conservatively. At cardiac catheterization 18 months after the PTCA procedure, there was no evidence of the fistula.