1-1 GLYCATED HAEMOGLOBIN, DIABETES, AND MORTALITY IN MEN IN NORFOLK COHORT OF EUROPEAN PROSPECTIVE INVESTIGATION OF CANCER AND NUTRITION (EPIC-Norfolk)
      Over 2 to 4 years, glycosylated hemoglobin concentration was a graded, continuous risk factor for death. Every increase of 1% in HbA1c above 5% was associated with a 29% increase in risk of all-cause death; a 38% increase in cardiovascular mortality; and 44% increase in ischemic heart disease mortality.
      Adequate screening for impairments in glucose metabolism should include a HbA1c in addition to a fasting plasma glucose, at least if the glucose is over 110.

1-2 "NORMAL" BLOOD GLUCOSE AND CORONARY RISK:
      Glycosylated hemoglobin provides a reliable estimate of usual glycemia and should be a more precise predictor of CHD risk. Glucose control for CHD prevention should begin in those with impaired glucose tolerance (110 to 125 mg/dL).

1-3 LONG-TERM WEIGHT LOSS AND CHANGES IN BLOOD PRESSURE: Results of the Trials of Hypertension Prevention, Phase II
      Clinically significant long-term reductions in BP and reduced risk of hypertension can be achieved with even modest weight loss (5% to 10%).

1-4 OBESITY AND HYPERTENSION: What Should We Do?
      Americans have intense interest in losing weight. Huge sums are spent in the effort. Physician's advice may produce some benefit, but weight-loss advice is frequently not given. Even in motivated persons, the motivation gradually wanes and few continue the recommended calorie restriction and the exercise program. Weight control is a major unsolved problem in clinical medicine. Primary care clinicians should set an example for weight control and physical activity, and relentlessly encourage overweight patients to lose and maintain the loss.

1-5 EFFECTS ON BLOOD PRESSURE OF REDUCED DIETARY SODIUM AND THE DIETARY APPROACHES TO STOP HYPERTENSION (DASH) DIET
      The DASH diet is rich in vegetables, fruits, and low-fat dairy products; low in meat. Adherence to the diet will decrease BP significantly in hypertensive persons as well as in those without hypertension. Adding salt restriction lowers BP still more. This has important implications for both prevention and treatment of hypertension.

1-6 ANTIHYPERTENSIVE DRUG THERAPIES AND RISK OF ISCHEMIC STROKE.
      The study suggests a particular benefit of thiazide diuretics in reducing the risk of ischemic stroke.
      Compared with those using beta-blockers alone, calcium blockers alone, or ACE inhibitors alone, users of a thiazide diuretic alone experienced a much lower incidence of ischemic stroke.
      Among users of 2 drugs, those patients who received 2 drugs other than a thiazide had a 1.3 greater relative risk than those receiving a thiazide as one of the two.
      The most recent (1997) report of the National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends diuretics as a first-line antihypertension agent.

1-7 LONG-TERM EFFECTS OF GLUCOSAMINE SULPHATE ON OSTEOARTHRITIS PROGRESSION
      Over 3 years, the combined structure-modifying and symptom-modifying effects of glucosamine sulphate suggest that it could be a disease-modifying agent in OA.

1-8 GLUCOSAMINE FOR OSTEOARTHRITIS: Dawn of a New Era?
      Recent studies have shown that a pure form of oral glucosamine sulfate has anti-inflammatory and anabolic properties on arthritic joints. A robust mechanistic explanation is lacking.
      The drug is widely available in the US as a nutritional supplement. Since it is generally self-prescribed, the results may not be generalizable due to the highly variable formulations of nutritional products bought off the counter.

1-9 EARLY STATIN TREATMENT FOLLOWING MYOCARDIAL INFARCTION AND 1-YEAR SURVIVAL.
      Early initiation of statin treatment in patients with acute MI was associated with reduced 1-year mortality. "Initiation of statin treatment before or at the time of hospital discharge should be recommended for all acute MI survivors with total cholesterol or low density cholesterol levels above current guideline levels for statin treatment as secondary prevention."

1-10 REVIEW OF FIRST 5 YEARS OF SCREENING FOR FAMILIAL HYPERCHOLESTEROLAEMIA IN THE NETHERLANDS.
      Primary care clinicians will inevitably encounter patients with FHC. It is common and leads to premature cardiovascular disease and death. When an unselected patient is identified with an unusually high cholesterol (eg, > 275) the family members should be screened.
      Family screening of index individuals with FHC is highly effective in identifying family members with FHC, and leads to effective prophylactic therapy.

1-11 LOW-DOSE ASPIRIN AND VITAMIN E IN PEOPLE AT CARDIOVASCULAR RISK: A Randomised Trial in General Practice.
      In women and men at risk of having a cardiovascular event because of the presence of at least one major risk factor, low-dose aspirin was effective when given as primary prevention.
      Lack of effectiveness of vitamin E is consistent with other trials on secondary prevention.

1-12 TOLERATION OF HIGH DOSES OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS IN PATIENTS WITH CHRONIC HEART FAILURE.
      ACE inhibitor therapy in most patients with HF can be successfully titrated to and maintained at high doses. More aggressive use is warranted. But start with a low dose (eg, 2.5 mg daily lisinopril) and gradually increase. Not all patients require the highest recommended dose.

1-13 CHLAMYDIA AND CERVICAL CANCER
      C trachomatis is already known to be associated with pelvic inflammatory disease, infertility, and facilitation of transmission of HIV infection. Cervical cancer may be another complication.

1-14 THE RENAISSANCE OF C REACTIVE PROTEIN
      Routine empirical measurement of CRP is a valuable aid to patient management across a broad range of clinical practice. Sensitive assay may become a new risk assessment marker for cardiovascular disease. A raised level in patients with active coronary disease identifies a high risk group likely to require interventions. "Possibly the more C reactive protein you produce, the sicker you get."

1-15 VIRAL HEPATITIS
      A refresher course. See the abstract.

1-16 CARDIORESPIRATORY FITNESS AND THE PROGRESSION OF CAROTID ATHEROSCLEROSIS IN MIDDLE-AGED MEN.
      Good cardiorespiratory fitness was associated with slower progression of early carotid atherosclerosis in middle-aged men.

1-17 INTAKE OF FISH AND OMEGA-3 FATTY ACIDS AND RISK OF STROKE IN WOMEN
      Higher consumption of fish and omega-3 polyunsaturated fatty acids was associated with a reduced risk of thrombotic infarction, primarily among women who did not take aspirin regularly. No relation to hemorrhagic stroke.

1-18 PROPHYLACTIC TREATMENT OF MIGRAINE WITH ANGIOTENSIN CONVERTING ENZYME INHIBITOR (LISINOPRIL)
      The ACE-inhibitor lisinopril had a clinically important prophylactic effect in migraine.

1-19 BIOETHICAL ASPECTS OF THE RECENT CHANGES IN THE POLICY OF REFUSAL OF BLOOD BY JEHOVAH'S WITNESSES
      The commentator concludes that if the act of receiving blood is kept strictly confidential and not made known to the religious community, expulsion is unlikely. Under the ideal protection of medical confidentiality, decisions on blood transfusion made by a patient who is a Jehovah's Witness would be known only to the patient and the medical team, not the congregation.
      Probably the most important advice to doctors at this time of flux in the policy of refusal of blood is to treat individual patients independently of the church's official policy. "Each case needs to be discussed and treated individually."

1-20 PUBMED CENTRAL:
http://pubmedcentral.nih.gov
      This new web based repository will archive, organize, and distribute peer reviewed reports from biomedical journals. It promises to archive the full texts and make them available in perpetuity. It is funded by the US National Institutes of Health and the National Library of Medicine.
      But, too much information is the bane of a working clinician's existence. Physicians, and ultimately the public do not need more articles. Instead, they need better articles, preferably from a trusted source, that give new and useful information or help put knowledge into some sort of practical context.

1-21 INTEGRATIVE MEDICINE: Orthodox Meets Alternative.
      The January 20 issue of BMJ presented 8 articles on integrative (alternative; complementary) medicine. I abstracted a few highpoints. RTJ

1-22 THE FIRST PATIENT TO UNDERGO CORONARY ANGIOPLASTY — 23 YEAR FOLLOW-UP

1-23 AN IMPORTANT NEW SERVICE FROM JOHNS HOPKINS
      Hopkins has launched an antibiotic database available to all free of charge. It offers diagnostic criteria and drug options on more than 160 drugs, and 140 diseases. It is continually updated and will immediately issue emergency alerts and drug recalls. www.hopkins-abxguide.org

RECOMMENDED READING

1-19 BIOETHICAL ASPECTS OF THE RECENT CHANGES IN THE POLICY OF REFUSAL OF BLOOD BY JEHOVAH'S WITNESSES
1-21 INTEGRATIVE MEDICINE: Orthodox Meets Alternative.
1-23 AN IMPORTANT NEW SERVICE FROM JOHNS HOPKINS

1. Prospective population study entered over 4500 men (age 45-79). Measured HbA1c at baseline in 1995-97.
2. Follow-up to 1999 (2 to 4 years).
3. Determined mortality from all causes, cardiovascular disease, and ischemic disease.

1. 135 deaths occurred. As expected, men with known diabetes had increased mortality from all causes.
2. In men without known diabetes, increasing HbA1c levels were related to subsequent all-cause, cardiovascular, and ischemic mortality
3. Compared with a HbA1c under 5%, any increase of 1% in HbA1c above 5% was associated with a 29% increase in risk of all-cause death; a 38% increase in cardiovascular mortality; and 44% increase in ischemic heart disease mortality after adjustment for age, systolic BP, cholesterol, BMI, and smoking
4. All cause mortality —

   HbA1c %	<5%	5-5.5%	5.5 to 7%	> 7%	Diabetes (self reported)
   Rate / 100 persons	1.7	2.3	3.4	4.3	5.6
   Relative risk of death	1.00	1.4	2.1	2.6	3.6

5. 82% of the excess mortality occurred in men with a HbA1c concentration of 5% to 7% (the majority of the population.)

1. HbA1c significantly predicted mortality. Risk increased as concentrations increased. The effect of HbA1c concentrations on mortality was evident even at the lower end of the population distribution. There was no apparent threshold effect.
2. "The predictive value of HbA1c for total mortality was stronger than that documented for cholesterol concentrations, BMI, and BP."
3. For established diabetes, mortality seems to be largely mediated through HbA1c levels.
4. HbA1c concentration is related to prevalent coronary disease and carotid intimal thickening in non-diabetic persons.
5. Clinical attention has focused on microvascular complications of diabetes. However, rates of myocardial infarction and stroke in diabetic persons are about twice the rates of microvascular events.
6. Control of other risk factors for cardiovascular disease is particularly beneficial in persons with HbA1c above 5% as well in those with overt diabetes. "Our data indicate that raised glycated haemoglobin concentration, even in men without diabetes, is a marker of greater absolute risk." Preventive treatment for hypertension and lipid control should be considered for such patients.
7. At a population level, lowering HbA1c by 0.1% of 0.2% would reduce prevalence of cardiovascular disease.

1. Multicenter randomized clinical trial entered over 1000 men and women age 30 to 54. Mean body mass index (BMI) was 31.
2. All had systolic BP under 140 and diastolic between 83-89. None were taking antihypertension drugs. Mean systolic = 127; mean diastolic = 86
3. At baseline, weights were 110% to 165% of ideal body weight.
4. Randomized to: 1) weight loss, and 2) usual care. Weight loss group included group meetings and individual counseling focused on dietary change, physical activity, and social support.
5. Follow-up = 3 to 4 years.

1. Mean weight change:

   	6 months	18 months	36 months
   Intervention group	-4.4 kg	-2.0 kg	-0.2 kg
   Usual care:	+0.1;	+ 0.7;	+1.8.

2. BP was significantly lower in the intervention group at all 3 periods. Participants in the quintile of greatest weight loss had reductions of 7/5 mm Hg. .
3. Risk ratio of hypertension (defined as at least 140/90, or prescription of antihypertension drugs) in the intervention group vs usual care was 0.58 at 6 months; 0.78 at 18 months; and 0.81 at 36 months.
4. Only 13% of participants were able to lose 4.5 kg and maintain the loss over 3 years. This subgroup had the greatest reduction in BP and a relative risk of hypertension of 0.35.

1. The pattern of weight loss suggests that weight loss alone, even if maintained, may not be sufficient to prevent an age-related increase in systolic pressure. Other determinants such as sodium restriction may be more important.
2. Only the individuals who maintained the weight loss over 36 months maintained significant lowering of BP. This applied to only 13% of the intervention participants.

1. Randomly assigned over 400 patients to: 1) DASH diet. or 2) a typical American diet. About half of the subjects had hypertension (140-159/90-95); half were normotensive.
2. Within the assigned diets, participants in both groups ate foods with high (3.3 g/d) intermediate (2.5 g/d) , and low (1.5 g/d) levels of sodium for 30 days each. (This is equivalent to 8.3 g, 6.3 g, and 3.7 g NaCl.)
3. Assessed the effects of the DASH diet combined with varying levels of salt intake.

1. Reducing the sodium intake from a high to an intermediate level was associated with a lower systolic BP by 2.1 mm Hg in those on the typical American diet, and by 1.3 mm Hg in those on the DASH diet.
2. Reducing the sodium intake from an intermediate level to a low level was associated with an additional reduction in systolic BP by 4.6 mm Hg in those on the typical American diet and by 1.7 mm Hg in those on the DASH diet.
3. The effect was observed in subjects with hypertension, and in those without.
4. As compared with the typical diet with a high sodium content, the DASH diet combined with low sodium intake reduced mean systolic BP by 7.1 mm in patients without hypertension, and by 11.5 mm in those with hypertension.

1. The DASH diet lowered BP at all levels of sodium intake. The benefits of the diet apply throughout the range of sodium intake.
2. Reducing NaCl intake from the usual 8 grams daily to an intermediate level of 6 grams (the currently recommended level) in persons who continue a typical American diet was associated with a lowering of BP. Further decreases in sodium intake (to 4 grams per day) were associated with a still further lowering. "These results provide a scientific basis for a lower goal for dietary sodium than the level currently recommended."
3. The combined effects on BP of a low sodium intake + the DASH diet were greater than either intervention alone, and were substantial. "In participants with hypertension, the effects were equal or greater than those of single-drug therapy."
4. "The combination of the two interventions achieved the greatest effect on blood pressure, and therefore both — not just one— merit recommendation."
5. The BP lowering effect of sodium restriction was also evident in persons with normotension. "These results should settle the controversy over whether the reduction of sodium has a worth while effect on blood pressure in persons without hypertension."
6. The benefits of sodium restriction and the DASH diet were evident in blacks. "We speculate that a greater sensitivity to the deleterious effects of diet could contribute to the high prevalence of hypertension in blacks."
7. These results should be applicable to most people in the US. Adherence to the diet should blunt the rise in BP which normally occurs with age.

Daily — low-fat dairy, olive oil, fruits, beans and nuts, vegetables, grains and starches, physical activity
Weekly — sweets, eggs, poultry, fish
Monthly — meat.

1. Population-based case-control study among hypertensive patients using antihypertension drugs.

   Case patients: Patients who sustained a first ischemic stroke. (N = 380)
   Controls: Patients with drug-treated hypertension randomly sampled. None had a history of stroke. (N = 2700)

1. Among over 1200 single-drug users, compared with users of a thiazide diuretic alone, the adjusted risk of ischemic stroke was higher among those receiving beta-blockers alone (risk ratio = 2.0); calcium blockers alone (RR = 2.3); and ACE inhibitors alone (RR = 2.8).
2. Among users of 2 drugs, those patients who received 2 drugs other than a thiazide had a 1.3 greater relative risk than those receiving a thiazide as one of the two.
3. Patients taking 1 drug:

   	Adjusted odds ratio of ischemic stroke
   Thiazide	1.00 (referent)
   No thiazide	1.40

4. Patients taking 2 drugs

   	Adjusted odds ratio of ischemic stroke
   Thiazide	1.00
   No thiazide	1.33

1. In this case-control study patients with hypertension whose treatment included a thiazide diuretic had a lower risk of ischemic stroke compared with those taking any one other drug or two other drugs. The association persisted after adjustment for many potential confounders.
2. One possible explanation — systolic BP is more strongly associated with occurrence of stroke than diastolic. Thiazides may be more effective in lowering systolic BP. The effect of thiazides on diastolic is similar to other drugs.
3. The BP effect of antihypertension drugs may not be the only reason for their benefits.

1. Randomized, double-blind, placebo controlled trial entered 212 patients (mean age 66) with OA of the knee. All had mild to moderate OA assessed by radiography and a symptom index.
2. Randomized to: 1) oral glucosamine (1500 mg daily), or 2) placebo.
3. Permitted use of analgesics including acetaminophen and NSAIDs.
4. Measured joint-space width at baseline and at 3 years.
5. Assessed change in symptoms with an OA index.

1. 355 patients were screened; 212 randomized; 139 (39% of those screened; 65% of those randomized) completed the 3 years.
2. Outcomes at 3 years

   	Glucosamine	Placebo
   Joint space	Loss of 0.06 mm	Loss of 0.31 mm
   Symptoms	Improved by 20-25%	Worsened slightly

   (See figure 2 p 254 for visual analogue scale of pain and function.)
3. No difference between groups in use of NSAIDs.
4. No differences between groups in safety and reasons for early withdrawal. No substantial differences between groups in frequency or pattern of adverse effects. Withdrawals were equal in both groups (17% and 20%)— most because of GI complaints.

1. "We have reported that long-term administration of glucosamine sulphate over 3 years can prevent joint structure changes in patients with OA of the knee, with a significant improvement in symptoms."
2. Twice as many placebo patients had a striking joint-space narrowing as those receiving glucosamine.
3. Glucosamine is safer than standard NSAIDs.
4. Longer term studies are needed.

1. Multicenter, prospective cohort study entered over 19 000 unselected consecutive patients with a first MI who were younger than age 80 and discharged alive from the hospital. No exclusions other than age.
2. The recommended indication for statin treatment was elevated cholesterol (> 200 mg/dL) or LDL-cholesterol (> 115).
3. Over 5500 patients received a statin drug at or before discharge; over 14 000 did not.
4. Median rate of statin prescription = 27%. Several different statins were used.
5. Obtained 1-year mortality in both groups.

1. At 1 year:

   	Statin group	No statins
   Unadjusted mortality:	4.0%	9.3%
   Adjustment for multiple covariates	3.7%	5.0%

2. After adjustment for confounding factors, early statin use was associated with a reduction in 1-year mortality. (Relative risk = 0.75).
3. The benefit extended to all subgroups — age, sex, baseline characteristics, diabetes, prior MI, congestive heart failure, and other medications.

1. Possible biological benefits of statins include improved endothelial function, plaque stabilization and regression, and reduction in inflammatory activity (decrease in C reactive protein).
2. The potential benefits seem substantial. Adverse effects were few.
3. "Initiation of statin treatment before or at the time of hospital discharge should be recommended for all acute MI survivors with total cholesterol or low density cholesterol levels above current guideline levels for statin treatment as secondary prevention."

1. Identified 237 index cases with FHC over a 5-year period:
2. Lipid clinic used a uniform diagnostic protocol including LDL-cholesterol levels, physical signs (tendon xanthomas, xanthelasmas, corneal arcus) and personal and family history as well as LDL-receptor gene analysis.
3. Family history was considered positive when there were signs of CVD before age 55 in men and 60 in women.
4. Performed screening tests in first degree relatives (n = over 5000) by measurement of cholesterol and DNA analysis for LDL-receptor gene mutations.

1. Of over 5000 first degree relatives screened, 2039 individuals were identified as heterozygous for FHC, slightly more women than men. Mean total cholesterol = 285 mg/dL; LDL-cholesterol = 216; HDL-cholesterol = 42 (In mmol/L = 7.4; 1.6; and 1.1)
2. 58% were under age 40; 27% 40 to 59
3. About 1/3 of these individuals were already on lipid-controlling treatment. At 1 year 0ver 90% were receiving treatment.

1. FHC is frequently underdiagnosed and inadequately treated.
2. Many of the family members identified were symptomless and quite young.
3. Public health interventions to identify and help individuals with FHC are feasible.

1. Randomized, controlled, open trial entered over 4500 persons (half female) to assess effect of long-term low-dose aspirin and vitamin E in prevention of cardiovascular events. None had prior history of cardiovascular events.
2. All had at least one risk factor for cardiovascular events (hypertension, hypercholesterolemia, diabetes, obesity, family history of premature myocardial infarction). All were over age 50 (mean = 64; both male and female). All risk factors are routinely identified in primary care practice.
3. Randomized to one of 4 groups: 1) aspirin alone 100 mg daily, 2) vitamin E alone 300 mg daily, 3) aspirin + vitamin E, and 4) neither.
4. Assessed frequency of major fatal and non-fatal cardiovascular events over 3.6 years.

1. After 3.6 years the trial was prematurely stopped on ethical grounds when newly available evidence from other trials on benefit of aspirin in primary prevention was consistent with the interim results of this study.
2. Aspirin significantly lowered cardiovascular death from 1.4% to 0.8% , and total cardiovascular events from 8.2% to 6.3%. [NNT(benefit 3.6 years)=166; and 53]
3. Incidence of non-fatal stroke, angina pectoris, transient ischemic attack, peripheral vascular disease, and revascularization procedures was lower in the aspirin group.
4. Adverse events: severe bleeding was more frequent in the aspirin group (1.1% vs 0.3%). [NNT(harm 3.6 years) = 125]
5. Vitamin E showed no effect on any prespecified endpoint.

1. Aspirin was beneficial with respect to all planned endpoints.
2. Effect of vitamin E appeared to be nil.
3. "The broad recruitment criteria for our study, and the corresponding population, form a more realistic scenario of the population seen in general practice." The beneficial effect of aspirin on both fatal and non-fatal major cardiovascular events should further widen the category of candidates for aspirin prophylaxis.
4. Results also provide evidence of aspirin's preventive efficacy on angina pectoris, peripheral-artery disease, and TIA.
5. One bleeding complication among 8000 person-years of aspirin use was fatal. There was no suggestion of an excess risk for hemorrhagic cerebrovascular events.
6. "The non-conclusive evidence of our trial regarding vitamin E seems to reproduce the present state of knowledge well: there are no real reasons for including anti-oxidants among recommendable prevention strategies."

1. Multicenter, randomized, double-blind trial entered over 3500 patients. All had class II (15%); III (78%); and IV (7%) HF, and left ventricular ejection fractions no greater than 0.30.
2. Run in period (open label):

   Group A:	One group of patients had never received ACE. These were started on lisinopril 2.5 mg daily for several weeks, and, if the low dose was tolerated, gradually increased to 5.0 mg for several weeks, then to 12.5 or 15 mg for several weeks.
   Group B:	A second group had been taking ACE. They were stabilized on 12.5 to 15 mg daily

3. Both groups then randomized to a double-blind dose-titration period:

   Low dose group:	to 2.5 or 5.0 mg daily + placebo. (Total dose = 2.5 or 5.0 mg daily) Ie, in some the dose was actually decreased for purposes of comparison.
   High dose group:	gradually increased to as much as 35 mg daily.

4. Determined occurrence of adverse effects, and the need for discontinuation or dose reduction during follow-up with a focus on hypotension and renal function. .
5. Allowed continuation of other medications for HF (digitalis, beta-blockers, vasodilators)
6. Follow-up = median of 46 months.

1. Of those who had never received ACE, the beginning dose of 2.5 to 5 mg daily was well tolerated. Only 4% could not be titrated up to the next level because of symptoms related to hypotension (2%) or renal dysfunction or hypokalemia (2%).
2. In more than 90% of patients in both groups, doses were titrated to their assigned target — high as well as low dose.
3. Withdrawals:

   High dose — 27%
   Low dose — 31%.

4. Subgroups presumed to be at higher risk for ACE intolerance (systolic BP <120; creatinine > 132 umol/L; age over 70, patients with diabetes) generally tolerated the high dose.

1. More than a decade has passed since the first trials demonstrated that ACE inhibitors prolong survival and improve symptoms in patients with HF. Physicians continue to underuse them. Many patients are receiving doses that have never been shown to be effective in clinical trials.
2. Patients titrated up to 35 mg daily exhibited a trend toward improved survival, and highly significant reductions in hospitalizations.
3. "High doses of lisinopril are generally well tolerated."
4. Although adverse events such as hypotension and renal dysfunction were more frequent in the high dose group, the differences between the high-dose group and the low-dose group were small for events classified as serious or leading to withdrawal.
5. Even for patients considered to be at a particularly high risk for adverse events, the occurrence of serious events was relatively low, and did not appear to be dose-related. Hypotension rarely required withdrawal of the drug, although dose reductions were frequent.
6. "Patients entering clinical trials often differ from the overall patient population in being more compliant and motivated and in having fewer comorbid conditions." Supervision during the trial may be closer that in ordinary practice. Similar degrees of tolerability may not be achieved in non-trial settings.
7. Not all patients will tolerate high doses. The study demonstrated that a strategy of titrating to and maintaining higher ACE doses than are used currently will be successful in most patients.
8. The lack of evidence that low doses of ACE improve mortality, and the additional reduction in the composite of death and hospitalizations at high doses, provide a clear message that higher ACE doses can and should be used in most patients.

1. Followed a population-based sample of over 850 men age 42 to 60,
2. At baseline, determined the maximal O2 intake (VO2 max; mLO2/kg per minute) by cycle ergometer exercise test.
3. Assessed carotid atherosclerosis using B-mode ultrasound. Used four indicators of carotid atherosclerosis:

   Maximal intimal-medical thickness (IMT). How deep the intima-media layer protruded into the lumen. (average of both sides).
   Plaque height (average of the maximal and minimal IMT) an indicator of how steeply atherosclerotic lesions protrude into the lumen.
   Surface roughness, and indicator to the variability of IMT.
   Mean IMT, an overall indicator of atherosclerosis.

4. Determined physical activity by a detailed quantitative questionnaire.
5. Determined 4-year progression of intimal markers of carotid atherosclerosis.

1. After multiple adjustments for possible confounders, VO2 max had a strong, graded, inverse association with 4-year increases in maximal IMT, surface roughness, plaque height, and mean IMT.
2. Increases in maximal IMT, surface roughness, and mean IMT (+23%; +31%, and +100%) were greater among men in the lowest quartile of VO2 max than in those in the highest quartile.
3. Weight loss, by reducing the denometer of VO2max, raises VO2max. Thus combined aerobic exercise and weight loss in obese men and women increased VO2 max. "An important finding of this trial was that the combination of aerobic exercise and dietary energy restriction increased VO2max more than either factor alone."

1. Carotid intima-media thickening — which is related to atherosclerotic risk and increased prevalence of coronary and peripheral atherosclerosis, and increased incidence of coronary heart disease and stroke — is regarded as a valid indicator of generalized atherosclerosis. These investigators previously found a strong association between higher levels of VO2max and reduced risk of a first myocardial infarction.
2. Good CRF was related to slower progression of early atherosclerosis.
3. " Low VO2max was the strongest risk factor for the progression of carotid atherosclerosis in multivariate analyses, even compared with conventional risk factors."
4. Good CRF, as assessed by work capacity, exercise test duration, or heart rate response to exercise, has been related to greatly reduced premature cardiovascular mortality.
5. Ultrasonographically assessed IMT has been associated with risk of coronary disease and stroke.
6. "Our results suggest that good respiratory fitness is associated with slower progression of atherosclerosis and therefore could reduce the risk for clinical events of atherosclerotic vascular diseases."
7. The study did not find an association between ordinary physical activity and the 4-year change in IMT. The investigators speculate that the quantity and intensity of exercise in most middle-aged men is too low to improve cardiorespiratory fitness and to slow the progression of atherosclerosis. Only amounts of exercise intensive great enough to improve cardiorespiratory fitness may be related to lowering progression of atherosclerosis.
8. Effects on systolic BP, lipids, diabetes, and plasma fibrinogen levels partly explain the inverse associations of VO2 max with IMT. Physical activity and good cardiorespiratory fitness may also: 1) enhance endothelial function by increasing production of NO and prostacyclin, 2) reduce oxidation of LDL-cholesterol, 3) decrease the atherogenic activity of blood mononuclear cells by affecting production of cytokines, 4) decrease the number of atherosclerotic lesions by reducing heart rate and pulsatile stress, and 5) decrease accumulation of collagen in the arterial wall.

1. Prospective cohort study of women (age 34 to 59 at entry) in the Nurses' Health Study followed over 79 000 women for 14 years.
2. At baseline, all were free from prior diagnosis of cardiovascular disease, cancer, diabetes, and hypercholesterolemia.
3. Food frequency questionnaires determined consumption of fish and other frequently eaten foods.

1. Documented 574 incident strokes — 119 subarachnoid, 62 intraparenchymal hemorrhagic, and 313 ischemic (264 thrombotic; 62 embolic).
2. Among the thrombotic strokes — 142 lacunar infarctions and 90 large artery occlusive infarctions were identified.
3. Compared with women who ate fish less than once a month, those with higher intake had a lower risk of total stroke,

   	Adjusted relative risks for fish intake
   1 to 3 times monthly	0.93
   Once a week	0.78
   2 to 4 times a week	0.73
   5 or more times a week	0.48

4. Among stroke subtypes, a significantly reduced risk of thrombotic stroke was found in women who ate fish 2 or more times a week. (RR = 0.49)
5. Women in the highest quintile of long chain omega-3 fatty acid intakes had a reduced risk of total stroke and thrombotic infarction. (RR = 0.72 and 0.67)
6. The dietary questionnaire segregated types of fish:

   	Content of omega-3 per serving
   Dark meat fish: mackerel, salmon, sardines, blue fish, and swordfish	1.5 g
   Canned tuna	0.42 g
   Other fish (flounder, whiting)	0.48 g
   Shrimp. lobster, and scallops.	0.32 g

7. No association with hemorrhagic stroke.

1. There was a significant inverse association between fish intake and risk of stroke (protective effect), primarily thrombotic stroke. After adjustment for cardiovascular risk factors, risk of thrombotic stroke was reduced by 48% among women who ate fish 2 to 4 times weekly.
2. There was a reduced risk of stroke among women who had the highest quintile of omega-3 fatty acids. There may be other unknown components of fish which reduce risk of stroke.
3. Among the subgroup of women who took aspirin, the difference in risk of stroke in those who ate a lot of fish and those who did not eat much fish was blunted. (Ie, benefits of fish in preventing stroke was noted mainly in women who did not take aspirin. Aspirin reduced the risk of stroke. This obscured the benefit of fish.)

1. Double-blind, placebo-controlled, cross-over study entered 60 patients with migraine. All had 2 to 6 episodes per month.
2. Randomized (cross-over) to: 1) lisinopril (Prinivil) 10 mg once daily for 1 week, then 10 mg twice daily for 11 weeks, or 2) placebo.

1. Complete data was obtained on 47 subjects.
2. Hours with headache, days with headache, and headache severity index were significantly reduced by about 20% with lisinopril compared with placebo. Use of triptans also decreased.
3. Days of migraine were fewer by at least 50% in 14 participants when taking lisinopril. Quality of life scores improved.
4. Lisinopril was well tolerated. Cough severe enough to cause withdrawal occurred in 3 patients.

1. ACE-inhibitors have actions in addition to blocking conversion of angiotensin I to angiotensin II. These include alterations in sympathetic activity, increases in prostacyclin synthesis, and blocking bradykinin degradation.
2. It has recently been shown that migraine without aura may be more frequent in people having the angiotensin converting enzyme DD gene. Migraineurs with this gene have higher angiotensin converting enzyme activity and a higher frequency of attacks.