Impaired dark adaptation in polycythemia. Improvement after treatment.

PURPOSE: To determine if dark adaptation is reduced in individuals with polycythemia and if so whether there is any improvement in dark adaptation after treatment. METHODS: Dark adaptation was recorded monocularly by automatic dark adaptometry in ten consecutive patients with polycythemia before and after treatment. Analogue investigations were performed in 31 healthy control subjects. RESULTS: Dark adaptation was markedly impaired in the patients as compared with the control subjects. After reduction of the red cell count and normalization of the hematocrit and hemoglobin the dark adaptation was markedly improved. There was no significant change in dark vision in the control subjects negating a confounding learning effect. CONCLUSION: The findings indicate a sustained but reversible neuronal hypofunction secondary to polycythemia. As the rheological abnormality was normalized, dark adaptation was improved, probably secondary to normalized microcirculation within the retina or the brain, or both, possibly with reactivation of formerly inactive neuronal cells.

Leukocyte activation: relation to cardiovascular mortality after cerebrovascular ischemia.

Activated leukocytes are believed to be involved in the pathogenesis and progression of atherosclerotic vascular disease and its consequences. In a 4-year observational follow-up study, we investigated whether markers for systemic leukocyte activation (leukocyte-derived inflammatory mediators) were related to cardiovascular mortality after cerebrovascular ischemia. Using enzyme-linked immunosorbent assays, we measured the plasma levels of soluble tumor necrosis factor receptor protein-1 (sTNFR-1), neutrophil gelatinase-associated lipocalin (NGAL) and neutrophil protease-4 (NP4) in 144 patients (90 stroke, 54 transient ischemic attack) 1-3 days after cerebral ischemia. During the 4 years of follow-up, 42 (29%) of the 144 patients died; 38 of cardiovascular causes and 4 of other causes. Patients with evidence of higher leukocyte activation (n = 47) had a higher 4-year cardiovascular mortality rate than those without evidence of leukocyte activation (n = 97; p < 0.005). Logistic regression analysis with age, sex and other significant predictors as covariates showed higher plasma levels of sTNFR1 and NGAL both to be significant independent predictors of cardiovascular mortality, the respective odds ratio, 95% confidence intervals, and p values being 2.0, 1.2-3.4, p < 0.01, and 3.6, 1.2-10.5, p = 0.02, respectively. We concluded that in patients with acute cerebral ischemia, plasma markers of leukocyte activation were significant predictors of long-term cardiovascular mortality. This may indicate an important role of activated leukocytes in the progression of these diseases.

Calf pain in middle-aged individuals as a predictor of ischemic cerebrovascular disease.

In middle-aged individuals, calf pain while walking may be an early marker of generalized ischemic vascular disease. We investigated whether the symptom of calf pain while walking was a predictor of ischemic cerebrovascular disease (CVD). In a nested case control study, part of the Malmö Prevention Program Project, we evaluated 105 patients with ischemic CVD for the symptom of calf pain reported at screening more than a decade before their illness. Their baseline characteristics were compared with those of an age- and sex-matched control group drawn from the population cohort. Calf pain while walking was reported by 16.2% of the patient group but by only 7.6% of the control group; p < 0.0001. Multiple logistic regression analysis with adjustment for all other significant risk factors showed a history of calf pain while walking to be an independent predictor of ischemic CVD (odds ratio, 1.9; 95% confidence interval, 1.3-3.7; p < 0.002). Thus, in middle-aged individuals, the symptom of calf pain while walking would seem to be a significant independent predictor of ischemic CVD. Our data serve to target a high-risk group for improved preventive efforts.

Three-year survival and recurrence after stroke in Malmö, Sweden: an analysis of stroke registry data.

BACKGROUND AND PURPOSE: Data from the Malmö Stroke Registry were analyzed to determine whether any change in survival or nonfatal stroke recurrence rates had occurred during the 4-year period from 1989 through 1992 and whether prognosis was related to area of residence. METHODS: The series comprised 2290 patients, 1051 men and 1239 women, followed up for 3 years after their first stroke during the period 1989 through 1992. RESULTS: Of the series as a whole, 959(43.4%) died and 137(6%) suffered a second nonfatal stroke. Multivariate analysis showed age, type of stroke, severity of stroke, and the presence of diabetes mellitus or cardiac disease each to be an independent predictor of mortality, and the presence of diabetes, atrial fibrillation, and history of transient ischemic attacks each to be associated with increased risk of recurrence. Treatment for hypertension was associated with a protective effect. As compared to those with first stroke in 1989, those with first stroke in 1992 were characterized by a lower recurrence rate, which was reduced by 70% in the male subgroup (P=0.003) and by 80% in the female subgroup (P=0.006), the corresponding reduction in all-cause mortality being 30% (P=0.007) and 10% (P=0.5, NS). Recurrence-free survival rates differed markedly between the 17 residential areas studied. CONCLUSIONS: The present study showed that survival rates after stroke have improved and recurrence rates have declined in this urban population. Further studies are needed to ascertain to what extent intraurban variation in the proportion of recurrence-free 3-year survivors is to be explained by differences in the severity of initial stroke and other prognostic markers, or in initial treatment and secondary preventive measures.

I. Impaired dark adaptation in symptomatic carotid artery disease.

It has been known for more than a century that even slight hypoxemia reduces dark adaptation. We studied dark adaptation in symptomatic carotid artery disease. Twenty-one consecutive patients scheduled for first-time carotid endarterectomy and 31 age-matched control subjects with normal carotid arteries were examined by dark adaptometry monocularly and were tested repeatedly on consecutive days. The average degree of internal carotid stenosis on the symptomatic side was much greater than that on the contralateral side. Dark adaptation was markedly impaired in the patients as compared with the control subjects. In the patients there was no difference in dark adaptation between the symptomatic and nonsymptomatic sides. The existence of carotid stenosis correlated to the level of dark adaptation. Pupillary size and age correlated to the dark adaptational level but did not affect the effect of carotid stenosis on dark adaptation. The decreased dark adaptation may be due to insufficient blood supply or repeated subclinical microembolization to the retinae, the brain, or both.

Leukocyte activation in atherosclerosis: correlation with risk factors.

Leukocytes have been implicated in the development of atherosclerotic vascular diseases, and numerous abnormalities of leukocytes in conjunction with atherosclerosis have been reported. The aim of this study of middle-aged asymptomatic subjects with early atherosclerosis was to determine whether a relationship exists between the levels of plasma markers of leukocyte activation, i.e. cytokines and proteases and risk factors for atherosclerosis or the degree of atherosclerotic disease. Using ELISAs we measured the plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), neutrophil protease 4 (NP4) as markers for neutrophil activation, tumor necrosis factor alpha (TNF) and soluble TNF receptor-1 (sTNFR-1) as markers of monocyte/macrophage activation in 156 subjects with asymptomatic carotid artery plaque detected at ultrasound examination. Plasma TNF and sTNFR-1 levels were found to correlate with systolic blood pressure (r = 0.32, P < 0.04 and r = 0.22, P < 0.05, respectively). plasma NGAL level to correlate with diastolic blood pressure (r = 0.22; P < 0.005), the plasma levels of sTNFR-1 and NGAL to correlate with age (r = 0.28, P < 0.001 and r = 0.20, P < 0.05, respectively). As compared with non-smokers (n = 112), smokers (n = 43) had higher plasma levels of TNF (2.9 vs. 1.4 microg/l; P < 0.02) and of NP4 (27.5 vs. 23.4 microg/l; P < 0.05). The plasma NGAL level was higher in hypertensive women (n = 7) than in normotensive women (n = 85) (109 vs. 87 microg/l; P < 0.05). We thus demonstrated that, in subjects with asymptomatic early atherosclerosis, the plasma levels of markers of systemic leukocyte activation were correlated with age and blood pressure, and were higher in smokers and hypertensives. These results support the hypothesized relationship between the level of systemic leukocyte activation and risk factors for atherosclerotic vascular disease.

Leukocyte activation detected by increased plasma levels of inflammatory mediators in patients with ischemic cerebrovascular diseases.

BACKGROUND AND PURPOSE: Leukocytes have been implicated in the development of ischemic atherosclerotic vascular diseases. In a prospective study we investigated whether the plasma concentrations of inflammatory mediators, ie, proteases and cytokines, as markers for systemic leukocyte activation, are increased in patients with acute ischemic cerebrovascular diseases. METHODS: Using enzyme-linked immunosorbent assays, we measured the plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), neutrophil proteinase 4 (NP4), tumor necrosis factor-alpha (TNF), and soluble TNF receptor protein-1 p55 (sTNFR-1) in 120 patients with acute ischemic cerebrovascular insult (72 with stroke and 48 with transient ischemic attack [TIA]) and in 35 age- and sex-matched healthy subjects. RESULTS: Compared with the control group, plasma NGAL levels were higher in the stroke group (P < .0001) and the TIA group (P < .01); plasma NP4 levels were higher in the stroke group (P < .0001) and the TIA group (P < .01); and plasma sTNFR-1 levels were higher in the stroke group (P < .04). There was significant correlation between the plasma levels of fibrinogen and those of both sTNFR-1 (r = .32; P = .005) and NGAL (r = .40; P = .0001) and between the erythrocyte sedimentation rate and the plasma levels of both sTNFR-1 (r = .35; P = .001) and NGAL (r = .34; P = .002). CONCLUSIONS: Our study demonstrated that markers for systemic leukocyte activation, ie, plasma levels of cytokines and proteases, were higher in patients with acute ischemic cerebrovascular disease than in healthy control subjects. Activated leukocytes and leukocytic mediators may have an important role in acute cerebrovascular ischemia and its consequences.

Intraplaque haemorrhage at carotid artery surgery--a predictor of cardiovascular mortality.

OBJECTIVE: To ascertain whether carotid intraplaque haemorrhage (IH) in patients undergoing carotid artery surgery is a predictor of increased cardiac mortality over a 5.5 year follow-up. DESIGN AND SUBJECTS: Carotid artery plaques were obtained at surgery from 47 consecutive patients (41 men, six women), median age 67 (range 48-81) years, with symptoms of carotid transient ischaemic attacks (TIAs) or carotid territory minor stroke. As determined at preoperative angiography, the degree of stenosis was 50-99%. Specimens were classified histologically as manifesting severe atherosclerosis, fibrous plaque, IH, or residual IH debris. SETTING: Medical Angiology and Vascular Surgery Units, Malmö General Hospital. INTERVENTION: Carotid endarterectomy. MAIN OUTCOME MEASURE: Correlation between mortality and IH. RESULTS: At follow-up after 5.5 years, mortality was 28% (13/47) overall, 92% (12/13) in the IH subgroup [of stroke (n = 1) or myocardial infarction (n = 11)], but only 3% (1/34), of pancreatic cancer, in the non-IH subgroup (P = 0.0001). Mortality was also significantly higher in the severe atherosclerosis than in the fibrous plaque subgroup, 39% (12/31) vs. 6% (1/16) (P = 0.044), but not significantly increased in any other subgroup (fibrous plaque, residual IH, TIA, minor stroke, or acetylsalicylic acid or anticoagulant treatment). No correlation existed between IH or death and haemoglobin value or platelet count. CONCLUSIONS: Evidence of recent IH seen at carotid artery surgery may be a marker of cardiovascular mortality. As IH was also found in a post-mortem control subgroup, the difference may be due to abnormality in blood components (e.g., coagulation factors) or impaired vessel-wall healing capacity (e.g. endothelial dysfunction).

Prognostic indicators for mortality in transient ischemic attack and minor stroke.

In a prospective study, 129 consecutive patients with transient ischemic attacks (TIAs) and 80 consecutive patients with minor ischemic stroke, involving the carotid artery territory in both cases, were followed-up for six years from their inclusion during the period from January 1984 to October 1985. All patients were 40-80 years old at inclusion, the median age being 74 years in the TIA group and 76 years in the minor stroke group. Overall mortality in the TIA group was significantly higher than in the minor stroke group, [44%, (57/129) vs 20% (16/80), p < 0.0006 after correction for age], and that in the general population of Malmö. Pre-existing vascular disease was slightly more prevalent in the TIA than in the minor stroke group [27% (35/129 vs 21% (17/80), NS]. Of the 19 patients with intermittent claudication, who all died [12 (63%) of them due to myocardial infarction (MI)], 18 belonged to the TIA group and only one to the minor stroke group. The respective frequencies of the putative risk factors in the TIA and minor stroke groups were 28% (36/129) vs 9% (7/80) for hypertension (p = 0.016), 9% (12/129) vs 6% (5/80) for diabetes mellitus (NS), and 8% (10/129) vs 9% (7/80) for cardiac arrhythmia (NS). Mortality due to MI was higher in the TIA than in the minor stroke group[24% (31/129) vs 6% (5/80), p = 0.001]. Of the minor stroke patients, none without vascular disease died of MI.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic control in insulin-dependent diabetes mellitus, as reflected in the in vitro effects of platelets on endothelial cell proliferation and prostacyclin production.

We tested the hypothesis that the degree of metabolic control in diabetes mellitus may be a determinant of the ability of platelets to stimulate proliferation of endothelial cells (ECs) and smooth muscle cells (SMCs). Platelets were obtained from 24 patients (two groups of 12 patients each) with insulin-dependent diabetes mellitus (IDDM) and increased blood glucose concentrations (HbA1c > 10% Hb), duration of disease 2-45 years, on no other medication than insulin at the time of blood sampling or during the preceding 6 months, and with no signs of coronary artery disease, nephropathy, hypertension or retinopathy. The patients served as their own controls, platelets being obtained from them again 2-4 months later when their mean glucose values were lower (HbA1c < 6.5% Hb). EC proliferation was significantly reduced after exposure to platelets obtained from the patients when their metabolic control had improved, whereas no significant differences were seen in either SMC proliferation or prostacyclin production. There was no correlation between changes in insulin dosage and either cell proliferation or prostacyclin production, or between changes in lipid values and cell proliferative capacity. It is concluded that, EC proliferation will be greater, owing to the platelet effects found in vitro, when metabolic control in diabetics is poor than when it is good, which may be of importance regarding the repair of endothelial lesions.

Effects of platelets from men with risk factors for atherosclerosis on endothelial cell proliferation and prostacyclin production in vitro.

The hypothesis that variations in platelet size or composition might affect some endothelial cell (EC) functions was tested. Large and small platelets stimulated cell proliferation and prostacyclin production to the same extent at the same amount of protein. Endothelial cells exposed to platelet factors from healthy men at statistically high risk of cardiovascular disease (n = 30) manifested significantly less DNA synthesis than did EC exposed to platelet factors from men at statistically low risk (n = 30) (p = 0.007). There was no difference in prostacyclin production between the groups. Nor were there any difference in EC or smooth muscle cell (SMC) proliferation or in prostacyclin production between cells exposed to platelet factors from smokers and those exposed to platelet factors from non-smokers. In stepwise regression of the results for high risk groups, with thymidine incorporation as the dependent variable, including diastolic blood pressure, s-triglycerides and s-cholesterol, s-triglycerides were inversely correlated to thymidine incorporation. We suggest that the decreased endothelial cell DNA synthesis after exposure to platelet factors from high risk individuals may imply a decreased capability for damage repair in the vascular wall, and that the differences in platelet effects on EC proliferation may be due to differences in lipids, especially triglycerides.

Differences in cardiac disease prevalence and in blood variables between major and minor stroke patients.

In 310 patients with carotid territory stroke, we investigated whether a history of cardiac disease was more frequent among those with major stroke (n = 169) than among those with minor stroke (n = 141), and whether the two groups differed in values for blood variables directly or indirectly associated with stroke, each variable being adjusted for age and sex. A history of angina pectoris was more frequent in the major stroke than in the minor stroke group, 16% vs. 9% (p < 0.042; odds ratio, 2.2); and among female patients, a history of atrial fibrillation was more common in those with major stroke than in those with minor stroke, 35% vs. 13% (p < 0.033; odds ratio, 2.8). ESR (erythrocyte sedimentation rate) values were higher in the major than in the minor stroke group, 21 +/- 21 (mean +/- SD) vs. 15 +/- 14 mm/h (p < 0.028), as were WBC (white blood cell) counts, 9.4 +/- 3.2 vs. 7.9 +/- 2.3 x 109/l, p < 0.001. WBC counts were also higher in stroke survivors than in non-survivors, 9.6 +/- 3 vs. 8.3 +/- 3 x 109/l (p < 0.0027), as were serum creatinine values, 115 +/- 59 vs. 95 +/- 21 mumol/l (p < 0.0094). The differences between major and minor stroke patients may reflect differences in the degree of atherosclerosis and thrombogenicity.

Tongue necrosis in temporal arteritis provoked by ergotamine.

A case of tongue necrosis in a patient with temporal arteritis who was taking ergotamine is described, and the role of ergotamine tartrate in provoking the tongue necrosis is considered. The literature on this unusual complication is critically reviewed, and the value of a carotid angiography in assessing the tongue ischaemia is exemplified.

Cardiovascular disease in male patients with carotid transient ischemic attacks or minor strokes.

The authors tested the hypothesis that coronary heart disease and lower extremity atherosclerosis occur more frequently in patients with transient ischemic attacks (TIA) than in patients with minor stroke. Thirty-three consecutive male patients with TIA and 36 with minor stroke from the carotid artery territory were examined with ultrasonography of the cardiac, iliac, and femoral arteries; echocardiography (UCG); electrocardiogram (ECG); thallium scintigraphy (TS) of the myocardium; and assessment of the ankle/arm index (A/AI). TS showed myocardial infarctions to be more common among TIA patients than among minor stroke patients, 54% vs 19%, p = 0.019. UCG showed the frequency of left ventricular and atrial dilatation to be higher in the TIA group than in the minor stroke group, 64% vs 27%, p = 0.0084. Significant artery stenosis (greater than or equal to 50%) was not, however, more frequent in the TIA group than in the minor stroke group, nor was there any significant difference between the groups in A/AI. The frequency of TS-verified myocardial infarction (MI) was higher in the subgroup with greater than or equal to 50% carotid artery stenosis than in that with less than 50% stenosis, 61% vs 25%, p = 0.022, and also higher in the pathological UCG subgroup than in the normal UCG subgroup, 50% vs 15%, p = 0.025. Thus, there was a greater incidence both of TS-verified MI and of UCG-verified cardiac dilatation in the TIA group than in the minor stroke group but no difference between the groups in the degree of atherosclerosis either in the carotid or lower extremity regions.(ABSTRACT TRUNCATED AT 250 WORDS)

High frequency of asymptomatic visual field defects in subjects with transient ischaemic attacks or minor strokes.

The hypothesis that asymptomatic visual field defects can be found in patients with carotid transient ischaemic attacks (TIA) or minor strokes was tested. Twenty-two consecutive male patients with TIA and 18 patients with minor strokes from the carotid artery territory were examined by perimetry, cerebral computerised tomography and regional cerebral blood flow. Asymptomatic visual field defects were found in many TIA and minor stroke patients, 29% (5/17) and 57% (8/14), respectively (NS). Eighty-five per cent (11/13) of the scotomas were solely or predominantly located in the upper part of the visual field (P = 0.008 for absolute defects and P = 0.03 for relative defects). We conclude that both carotid territory TIA and minor stroke patients have a high frequency of asymptomatic visual field defects, predominantly located in the upper part of the visual field.

[Serum creatinine content of questionable value in screening for renal disease]. / Serumkreatinin av begränsat värde vid screening för njursjukdom.

In a health screening programme for men aged 28-48 years, a check of serum creatinine values was included as a renal function test. Of 21,362 men screened, 114 (0.53 per cent) had two values greater than or equal to 120 mumol/l, and were further investigated vis-à-vis possible kidney disease. Of the 114 cases, renal disease including essential hypertension was present in 63, though only 29 cases had not been diagnosed previously, and in only seven cases was there no albuminuria, hypertension or history of renal disease. These findings raise doubts as to the value of analysing s-creatinine when screening for renal disease.

Interactions between cultured bovine arterial smooth muscle cells and endothelial cells; studies on the release of growth inhibiting and growth stimulating factors.

The balance of growth stimulating and growth inhibiting factors in the arterial wall might be of importance in the pathogenesis of atherosclerosis. A method using different dialysis steps was used to allow the simultaneous study of micromolecular (dialysable) and macromolecular (non-dialysable) substances in conditioned media from bovine and human arterial endothelial cells and smooth muscle cells in culture. Micromolecular substances inhibited the proliferation of aortic smooth muscle cells and endothelial cells, while the macromolecular substances were growth stimulating. The effect of the micromolecular and macromolecular factors was dose dependent, but only the micromoleculars were affected by conditioning time. The micromoleculars were heat stable. The effect of macromoleculars was completely abolished by heating to 100 degrees C for 5 minutes. Confluent cells released relatively more growth inhibiting and less growth stimulating activity while the balance was changed in subconfluent cells showing an increased release of growth stimulating activity per cell. A co-culture model for endothelial and smooth muscle cells demonstrated that the confluent aortic endothelial cells released relatively more growth inhibiting activity. These models seem suitable for the study of interactions of growth inhibition and stimulation between arterial cells in vitro in the normal or pathological state.

Advanced carotid stenosis in TIA and minor stroke as a predictor of coronary heart disease: a 3-year follow-up.

Eighty-six patients with transient ischemic attacks (TIA) or minor stroke from the carotid artery territory, examined in the extracranial carotid arteries by duplex ultrasound, were prospectively followed for 3 years to find out whether a higher degree of carotid stenosis in these patients might predict mortality and morbidity in myocardial infarction (MI). Thirty-three of these (38%) had carotid stenosis greater than or equal to 50% on one or both sides. In these patients, 36% (12/33) suffered MI during follow-up compared to 7% (4/53) in the patients with lesser degree of stenosis. 75% (12/16) of the MI's were fatal. The total mortality in MI was 30% (10/33) in patients having a stenosis greater than or equal to 50%, in TIA-patients it was 24% (12/51) and in patients with TIA + greater than or equal to 50% stenosis it was 36% (10/28). It is suggested that the presence of high degree stenosis in the carotid arteries might predict mortality and morbidity in MI among TIA and minor stroke subjects.

Differences in mortality and cardiovascular morbidity during a 3-year follow-up of transient ischemic attacks and minor strokes.

We prospectively followed 78 patients with transient ischemic attacks (TIAs) from the carotid artery territory and 45 patients with minor ischemic strokes for 3 years. The mean +/- SD age of the patients in the TIA group was 66.9 +/- 7.9 years compared with 68.8 +/- 6.7 in the minor stroke group. Mortality among the TIA patients was significantly higher than that among minor stroke patients (18 of 78 compared with two of 45, p less than 0.01); mortality in the minor stroke group was not higher than that in the background population, whereas mortality in the TIA group was almost twice as high. The most common cause of death in the TIA group was myocardial infarction, and morbidity due to myocardial infarction and new TIA was higher in the TIA group than in the minor stroke group (35 events compared with seven), whereas no difference was found regarding stroke (five strokes compared with eight). Preexisting vascular disease implied an increased risk of mortality and morbidity in the TIA group. We conclude that carotid-territory TIA indicates a worse prognosis than minor stroke as mortality is higher in TIA patients at the same preexisting vascular disease prevalence and stroke frequency.

Effects of a competitive inhibitor (mevinolin) of 3-hydroxy-3-methylglutaryl coenzyme A reductase on human and bovine endothelial cells, fibroblasts and smooth muscle cells in vitro.

Mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, is a potent inhibitor of cholesterol synthesis. We have tested the effects of mevinolin on cell replication (3H-thymidine incorporation), prostacyclin production (6-keto-PGF1 alpha) and cell death (51Cr release) in cell cultures (human umbilical vein endothelial cells, bovine endothelial cells, human fibroblasts and bovine smooth muscle cells). Mevinolin concentrations ranging from 0.05 mumol/l (reported therapeutic concentration) to 20 mumol/l were used. In human endothelial cells the replication was reduced by 11% at a concentration of 2.0 mumol/l (P less than 0.01). In fibroblasts and smooth muscle cells the reduction was significant already at 0.1 mumol/l (10%, P less than 0.01). The prostacyclin production was reduced in endothelial cells at 1.0 mumol/l (19%, P less than 0.01) and in smooth muscle cells at 2.0 mumol/l (15%, P less than 0.05). At 20 mumol/l both cell replication and prostacyclin production was markedly reduced by about 40% in all cell types. No effects on 51Cr release or trypan blue staining was seen at any concentration. It is concluded that mevinolin has an effect on DNA synthesis and prostacyclin production on the tested cell types in vitro. These effects were, however, observed only at concentrations higher than those recommended for therapeutical use.