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Objective: To evaluate literature data on the use of acetylsalicylic acid (ASA) as a primary prevention measure for cardiovascular events., Design: Literature search., Method: Using Medline, all randomised placebo-controlled trials of ASA published between 1985 and 1 May 2001, and which used cardiovascular morbidity and death as outcome measures were identified (search query: 'aspirin' and 'primary prevention'). Using the raw data presented in the source publication on death, fatal and non-fatal myocardial infarctions and cerebrovascular accidents (CVAs), all relative and absolute risk reductions were recalculated with confidence intervals., Results: In healthy middle-aged men, men with an increased cardiovascular risk profile and persons with diabetes mellitus or hypertension, the use of ASA reduces the incidence of myocardial infarction and has a neutral effect on cerebrovascular events. The protective effect of ASA seemed most marked in those persons with an increased risk of manifest atherosclerotic vascular disease., Conclusion: Notwithstanding these findings, for each patient it remains essential to weigh up the cardiovascular risk profile against the small increased risk of complications when prescribing ASA.

Objective: The development of the post-thrombotic syndrome (PTS) and recurrence of deep venous thrombosis (DVT) are not yet fully understood. The aim of the study was to identify factors that lead to the long-term complications of DVT., Methods: In a 2-year prospective follow-up study, duplex scanning and strain-gauge plethysmography were used to evaluate DVT in relation to the development of long-term complications. Each of the 12 segments examined was assigned as a thrombosis score (TS). A total TS was calculated for each leg. Patent segments were assigned a TS = 0, noncompressible vein segments with flow TS = 1 and noncompressible vein segments without flow TS = 2. The degree of resolution of DVT and the incidence, timing, and outcome of further thrombotic events were measured during 24 months of follow-up., Results: The study involved 86 legs with DVT. The 2-year follow-up was completed for 70 legs. Within 3 months, only 1% of the originally occluded proximal deep vein segments were still occluded. Between all time intervals, from month 12 to month 24, for example, thrombus regression continued in 36% of the legs and thrombus propagation continued in 27%. Multiple regression analysis revealed that an increase in age (P = .008) and proximal location of the original DVT (P = .05) was significantly related to thrombus propagation. Multiple regression analysis showed that the risk factors for clinical signs of PTS were a high venous outflow resistance after 1-month and 12-month follow-ups (P

We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase mu-1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P=0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus -0.002 mm, P=0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P=0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST mu-1 develop progression of atherosclerosis at an increased rate.

Smoking is responsible for a substantial percentage of the total morbidity and mortality in western society. In the Netherlands 34% of the population smoke. A considerable part of the smokers tried to stop smoking, but did not succeed. Since December 1999 a new type of anti-smoke therapy is available; bupropion chloride (Zyban). With this treatment an improvement in success ratio in comparison with placebo is described of 11-15% after a year in a healthy population. Combined with nicotine patches this percentage was 20%. These percentages are higher than those of nicotine replacement therapy alone (3-13%). It is very important that effects of bupropion are tested in high-risk patients with asthma, chronic obstructive pulmonary disease (COPD) and cardiovascular diseases as these groups may benefit most from cessation of smoking. Especially in the COPD group cessation of smoking makes a more substantial contribution to improvement of the disease process than the medication now available. Therefore, it might be considered to prescribe bupropion under strict control in this group even now, before definitive research results are obtained.

Background: Early in the process of atherosclerosis, changes in vessel wall stiffness and thickness may occur. The present study evaluates the effect of cholesterol reduction on artery wall stiffness and intima media thickness in patients with familial hypercholesterolaemia (FH)., Materials and Methods: Forty-five patients with familial hypercholesterolaemia (mean age 46+/-10 years) with untreated LDL cholesterol concentration > 9 mmol L(-1), were studied before and after one year of cholesterol lowering therapy with statins (simvastatin, atorvastatin 40-80 mg day(-1). The distensibility (DC in 10-3 kPa(-1) and compliance (CC in mm2. kPa(-1) of the common carotid artery (CCA) (right and left side) and common femoral artery (CFA) (right side) were determined by a wall track system (Pie Medical). The intima media thickness (IMT) (both right and left) of the CCA, bulb (BUL), internal carotid artery (ICA) and CFA were measured in mm by high-resolution ultrasound (Biosound)., Results: The mean concentration of total cholesterol (TC), LDL-cholesterol (LDL-C) and triglycerides (TG) were reduced significantly by 43%, 51% and 25%, respectively, whereas HDL-cholesterol (HDL-C) increased by 13% (P<0.001). In the CFA, the DC and CC increased significantly (DC from 7.9+/-3.0 to 9.1+/-3.7 in 10(-3) kPa(-1); CC 0.5+/-0.2-0.6+/-0.3 in mm2. kPa(-1), whereas the DC and CC did not change in the CCA. In contrast, the IMT of the CCA decreased significantly in both men and women whereas an IMT decrease was also seen in the BUL and ICA in premenopausal women. A LDL-cholesterol reduction of 44.8% and 45.4% was necessary to induce significant decreases in IMT and increases in DC and CC., Conclusions: One year of cholesterol lowering therapy in FH decreases the wall stiffness in the CFA and the arterial wall thickness in the CCA.

The purpose of the present study was to evaluate the relationship between calf muscle pump dysfunction (CMD) and the presence and location of valvular incompetence. Deep vein obstruction might influence CMD, and so venous outflow resistance (VOR) was measured. VOR and calf muscle pump function were measured in 81 patients, 7-13 years after venographically confirmed lower-extremity deep venous thrombosis. The supine venous pump function test (SVPT) measures CMD, and the VOR measures the presence of venous outflow obstructions, both with the use of strain-gauge plethysmography. Valvular incompetence was measured using duplex scanning in 16 vein segments of one leg. Venous reflux was measured in proximal veins using the Valsalva manoeuvre, and in the distal veins by distal manual compression with sudden release. Abnormal proximal venous reflux was defined as a reflux time of more than 1 s, and abnormal distal venous reflux as a reflux time of more than 0.5 s. No statistically significant relationship was found between the SVPT and either the location or the number of vein segments with reflux. Of the 81 patients, only nine still had an abnormally high VOR, and this VOR showed no relationship with the SVPT. In conclusion, venous reflux has a limited effect on CMD, as measured by the SVPT. The presence of a venous outflow obstruction did not significantly influence the SVPT. Duplex scanning and the SVPT are independent complementary tests for evaluating chronic venous insufficiency.

Despite the many studies on venous haemodynamics using duplex, only a few evaluated the normal values, variability and reproducibility. Therefore, the range and variability of venous diameter, compressibility, flow and reflux were measured. To obtain normal values, 42 healthy individuals (42 limbs, 714 vein segments) with no history of venous disease were scanned by duplex. To determine the reproducibility the intra-observer variability was measured in 11 healthy individuals (187 vein segments) and the inter-observer variability in 15 healthy individuals (255 vein segments) and 13 patients (169 vein segments) previously diagnosed with deep venous thrombosis. Of the 714 normal vein segments, 708 (99%) were traceable, including the crural veins. Of the traceable vein segments, 675 (95%) were compressible and in 696 (98%) flow was present. Of the 42 common femoral vein segments, in 25 (60%) the reflux duration exceeded 1.0 s, but in the other proximal vein segments the reflux duration was less than 1.0 s (95% confidence interval 3.0-10.0). With the exception of the distal long saphenous vein, in the distal vein segments the reflux duration was less than 0.5 s (95% confidence interval 3.5-8.2). The coefficient of variation of the diameter measurements ranged from 14 to 50% and that of the reflux measurements from 28 to 60%. The kappa-coefficient of the inter-observer variability in the classification of compressibility measurements in the patients was 0. 77 and that of the reflux measurements was 0.86. This study shows that almost all veins were compressible in healthy individuals, except the distal femoral veins. In healthy individuals the duration of reflux of the proximal veins was less than 1.0 s and in the distal veins it was less than 0.5 s. The inter-observer variability of the reflux and compressibility measurements in the patients was good.

Recent developments in ultrasound technology enable the noninvasive measurement of structural and functional vessel wall changes. Until now, the effect of homocysteine on the arterial wall has remained unclear: reports on intima-media thickness (IMT) yield conflicting results, whereas data on vessel wall stiffness are lacking. Because several cardiovascular risk factors result in an increased IMT or stiffness, different groups at risk for atherosclerotic disease, with special emphasis on hyperhomocysteinemia, were studied. Nineteen patients homozygous and 14 subjects heterozygous for cystathionine beta-synthase (CBS) deficiency, 21 patients with familial hypercholesterolemia (FH), 15 patients with essential hypertension, 20 smokers, and 28 control subjects were studied. The IMT values (both right and left) of the common carotid artery (CCA), bulb (BUL), internal carotid artery (ICA), and common femoral artery (CFA) were measured in millimeters by high-resolution ultrasound (Biosound). The distensibility (DC, in 10(-3). kPa-1) and compliance (CC in mm2. kPa-1) coefficients of the CCA (right and left) and CFA (right) were determined by a wall track system (Pie Medical). The mean IMT of the posterior wall in the CCA was 0.70+/-0.09 mm in healthy controls. For patients with vascular disease, FH, and hypertension and in smokers, the mean CCA IMT was larger, whereas no major differences in IMT were observed in patients either homozygous or heterozygous for CBS deficiency. The DC and CC in the right CCA were 23.5+/-6.9 (10(-3). kPa-1) and 0.9+/-0.3 (mm2. kPa-1) in healthy subjects, slightly lower in patients homozygous for CBS deficiency, and clearly lower in patients with vascular disease, FH, and hypertension. No positive correlation was found between plasma homocysteine level and either IMT, CC, or DC. Because smoking was a confounder in each risk group, a stepwise regression analysis was carried out to assess the contribution of each risk factor on IMT and arterial wall stiffness. Age explained most of the variation in IMT of the CCA (coefficient of determination R2 of 0.34), whereas R2 values for serum low density lipoprotein cholesterol, smoking (pack-years), and systolic blood pressure were 0.08, 0.07, and 0.06, respectively. Homocysteine did not contribute to variation in IMT in both the CCA and CFA. Age and smoking contributed to the variation in IMT in the CFA. The variation in DC and CC in the right CCA and right CFA could in part be explained by age, low density lipoprotein cholesterol, and blood pressure. Plasma homocysteine concentration explained only a small proportion of the variation in DC in the CCA (R2=0.02) and in CC in the CFA (R2=0.04). In this study, no relationship was found between homocysteine level and the thickness of the arterial wall, with only a marginal influence on stiffness.

Objective: To determine the compliance with and the outcome of a practice guideline introduced for the management of hypertension., Design: Retrospective medical record survey., Setting: The outpatient clinic of general internal medicine of the Academic Medical Hospital Nijmegen, the Netherlands., Method: Daily practice in a period before (1988) and one after (1993) implementation of the guideline were compared. By means of an inventory form we evaluated the compliance with the guideline, the decrease in blood pressure after 1 year's follow-up and the number and dosages of the prescribed drugs. Total costs were approximated from the number of visits and the number of laboratory and imaging evaluations., Results: Compliance with the guideline in 1993 was 72% (24) compared with 65% (27) in 1988. This improvement was predominantly achieved by the junior residents. In 1993 in 15 patients (19%) blood pressure was measured without medication having been stopped. The guideline regarding the frequency of blood pressure measurement was observed in 7 patients (9%). The decrease in systolic and diastolic blood pressure was larger in 1993 than in 1988 (p < 0.05). This result was achieved by a larger number of blood pressure lowering drugs (1.40 (1.06) in 1993 vs. 1.17 (0.98) in 1988): the mean dose of the prescribed drugs was lower. The number of visits rose by 10% to 7.8 (3.7) and the number of diagnostic laboratory procedures by 25% to 956.

Studies measuring the fibrin degradation product D-Dimer (DD) using enzyme-linked immunosorbent assays (ELISA) in patients suspected of deep venous thrombosis (DVT) or pulmonary embolism (PE) suggest that it is possible to exclude DVT/PE when the DD level is below a certain cut-off value. However, ELISA methods are time-consuming, bare high costs, and are only available in experienced laboratories. For this reason several rapid and less costly DD assays have been recently developed. This article reviews the current literature about rapid latex and ELISA DD assays in the diagnostic approach of DVT and PE. Two new latex assays seem suitable in clinical practice. The most extensively studied assay is the so-called SimpliRed DD, an autologous red cell agglutination test that can be performed on fresh whole blood. For DVT a sensitivity (Sens) and a negative predictive value (NPV) of 89-100% and 95-100%, respectively, have been reported, for PE 94-100% and 98-100%, respectively. The second test, Tinaquant, is a quantitative latex assay. Sens and NPV for DVT of 99% and 93% have been reported in one study. Two rapid ELISA assays have been investigated. The most extensively studied is the VIDAS DD assay, a fully automated quantitative ELISA method. Sens and NPV of 94-100% and 92-100% for DVT and both 100% for PE have been reported. For the other rapid ELISA, Instant IA DD, Sens and NPV of 92-93% and 76-77% have been reported for DVT. The last one is a qualitative assay giving only positive or negative results. These results show that low concentrations of plasma DD measured by especially SimpliRed or VIDAS DD, might be used to reliably rule out DVT or PE in clinically suspected patients. Tinaquant seems promising and has to be evaluated further. As for standard ELISA, increased DD concentrations are of no use because of the low specificity of the assays. Future studies should assess the clinical usefulness of both assays in management trials under routine conditions, in the frame of clinical decision-making diagnostic processes to prove that withholding further noninvasive testing and/or anticoagulants in patients with a low or negative DD is safe. Strategies to identify patients with false-negative results should be developed.

1. In the feet of patients with diabetic neuropathy, total skin blood flow is increased due to an increased shunt flow. The question is, does this increased anastomotic shunt flow lead to either under- or overperfused nutritive capillaries. 2. To solve this question, skin microcirculation tests of the left big toe were performed in 20 healthy control subjects and in 40 insulin-dependent diabetic patients without macroangiopathy, 20 without and 20 with neuropathy. Skin temperature measurements and laser Doppler fluxmetry were performed to record mainly shunt flow and capillaroscopy to study nailfold capillary blood flow. 3. The insulin-dependent diabetic patients with neuropathy had a higher baseline skin temperature (mean +/- SEM; 30.0 +/- 0.6 degrees C) and laser Doppler fluxmetry [26.2 +/- 2.2 perfusion units (pu)] than patients without neuropathy (27.2 +/- 0.8 degrees C, P < 0.01; 16.1 +/- 2.0 pu, P < 0.01) and healthy control subjects (27.9 +/- 0.7 degrees C, P < 0.05; 18.6 +/- 2.8 pu, P < 0.05). Sympathetic stimulation (inspiratory gasp) resulted in a smaller laser Doppler fluxmetry decrease in the neuropathic patients (31.4 +/- 4.6%) compared with non-neuropathic patients (48.2 +/- 5.1%, P < 0.05) and control subjects (49.0 +/- 3.8%, P < 0.05), while no difference between the three groups was seen in the laser Doppler fluxmetry decrease during a postural vasoconstriction test. The number of visible capillaries was highest in the neuropathic patients (10.2 +/- 0.6/0.5 mm2), when compared with non-neuropathic patients (8.7 +/- 1.2/0.5 mm2, P < 0.05) and control subjects (8.3 +/- 0.3/0.5 mm2, P < 0.001). Capillary blood-cell velocity was significantly higher in the neuropathic patients (0.32 +/- 0.05 mm/s) compared with non-neuropathic patients (0.23 +/- 0.03 mm/s, P < 0.05) and control subjects (0.23 +/- 0.02 mm/s, P < 0.01). 4. We conclude that there is an overperfused nutritive capillary circulation in the feet of patients with diabetic neuropathy. This is in contradiction to the capillary steal phenomenon and favours the hyperdynamic hypothesis to explain the decreased healing potential in diabetic neuropathic foot ulceration.

Hypohidrosis predisposes to hyperthermia and may indicate generalized thermoregulatory failure. To assess the sweating capacity in human poikilothermia, we performed a quantitative analysis of the central and peripheral sudomotor pathways in four women with acquired poikilothermia (aged 29 to 38 years) and nine controls. Heat challenge in a climatic chamber (ambient temperature 40 degrees C, 50% relative humidity) for 180 minutes revealed that both sweat secretion and evaporative weight loss were significantly lower in the patients than in the controls (p < 0.01). Temperature thresholds for thermal sweating were markedly elevated in at least two patients, whereas a third patient showed no sweating response. Stimulation of the eccrine sweat glands by intradermally injected acetylcholine during reduced core temperature (34.9 +/- 0.7 degrees C) revealed a significantly reduced sweating response in all patients (p < 0.01); the sudomotor response to pilocarpine iontophoresis was reduced or absent in three patients. We conclude that the generalized thermoregulatory sudomotor failure in these patients was attributable primarily to disorders of the central sudomotor drive; the impaired postganglionic sudomotor response is temperature related and possibly secondary to (long-standing) poikilothermia. Quantification of heat-dissipating capacity is pivotal for diagnosing severe thermolability and may help to prevent serious heat illness.

Objective: To describe the patients with Takayasu's disease in the University Hospital Nijmegen, and to compare these patients with literature., Design: Retrospective, descriptive., Setting: University Hospital Nijmegen., Methods: All patients with Takayasu's disease in the period of 1980-1993 were traced via medical registration codes. These patients are described and compared with the literature., Results: Five patients with Takayasu's disease were found, 3 women and 2 men, 4 Dutch and I Turkish female. The diagnosis in all patients was made before the age of 21 and confirmed by angiography. Four of the 5 patients presented initially with general complaints, and, except for patient A, all had a pulse or blood pressure difference (left-right) to the disadvantage of the left arm. Occlusion of the left subclavian artery occurred finally in all cases. Four patients had associated diseases as described in the literature. Four of the 5 showed no progression on prednisone therapy. Until now no patient has died, with a mean follow-up of 10 years., Conclusions: Takayasu's disease is rare in the Netherlands. First symptoms are general fatigue and a pulse/blood pressure difference. Early detection by medical history, physical examination and angiography appears beneficial, because early treatment may have a favourable effect on prognosis.

The outcome is described of a 1993 consensus meeting regarding the role and value of functional non-invasive vascular investigations in the assessment of severity and localization of arterial obstructions and in the selection of a therapeutic strategy in patients with arterial obstructive disease of the lower extremities. Since symptoms and clinical investigation alone are unreliable in assessing the severity of peripheral arterial disease, complementary functional vascular examinations are needed. Measurement of the systolic blood pressures at ankle level by means of a sphygmomanometric method and a Doppler flowmeter allows reliable determination of the presence or absence of haemodynamically significant arterial obstructions. In the case of minor obstructions the sensitivity of ankle pressure measurements can be increased by examination during a period of hyperaemia, preferably induced by a treadmill walking test. In the case of unreliable ankle pressure measurements due to non-compressible arteries determination of the toe blood pressure is indicated. Segmental blood pressure measurements as well as Doppler analysis of the blood flow at various levels of the leg were not considered reliable enough for the localization of arterial obstructions, unless the obstructive disease is restricted to one single arterial segment. Accurate non-invasive localization of arterial obstructions and the determination of their haemodynamic severity are only possible by means of a combined echo-Doppler (duplex) examination of the arteries. Duplex examination can also be helpful in choosing between surgery and percutaneous transluminal angioplasty of localised stenoses and short occlusions.

In a 71-year-old woman suffering from recurrent fever, dry cough, pain during sighing, hoarseness and later severe inflammation of the cartilage of both auricles 'relapsing polychondritis' was diagnosed. This is a rare disease of cartilage and connective tissue. Most frequent symptoms are inflammation of the auricles and nasal septum, joint disorders and inflammation of eye structures, larynx and trachea. The aetiology may be autoimmunity. The clinical diagnosis can be confirmed by a cartilage biopsy. The disease is recurrent and causes substantial morbidity and mortality. Therapy consists of NSAIDs, steroids, and sometimes immunosuppressive agents.

The effects of sex, the menstrual cycle, oral contraceptives, pregnancy, and the menopause on skin perfusion in healthy women and in patients with Raynaud's phenomenon suggest a role of female sex hormones. However, no clear relation between skin blood flow and circulating concentrations of oestrogens or progestogens has yet been found. The aim of this study was to investigate the effect of orally administered 17 beta-oestradiol and progesterone on finger skin blood flow before and during heat and cold challenge in 17 healthy normotensive women and in 12 women with Raynaud's phenomenon. In each subject standardized finger heating (45 degrees C water bath, 10 min) and cooling tests (15 degrees C water bath, 5 min and 20 min recovery) were performed twice on the second (or third) day of two consecutive menstrual cycles. 17 beta-Oestradiol (9 mg) or progesterone (300 mg) were given before the second test, after a first test with placebo. Both hormonal doses resulted in (high) physiological concentrations. Fingertip skin temperature and laser Doppler flux were measured. There were no significant differences in the test results after placebo and after progesterone. Although values of fingertip skin temperature and laser Doppler flux after 17 beta-oestradiol tended to be higher only the precooling values in the healthy subjects reached significance: fingertip skin temperature respectively with placebo and with oestradiol (mean (SD)): 32.7 (1.0) and 33.1 (0.8) degrees C; laser Doppler flux with placebo and with oestradiol: 33.6 (11.7) and 42.2 (9.5) perfusion units; both P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Objective circulatory tests in patients with Raynaud's phenomenon have only rarely been related to subjective complaints., Methods: In 55 Raynaud patients the correlation between daily self-recorded frequency, duration and severity of vasospastic attacks and the measurement of finger skin blood flow during local cooling was investigated., Results: No significant correlations were found between complaints as registered in the diaries and finger skin temperature and laser Doppler flux before, during and after a standardized local cooling procedure., Conclusion: Finger skin blood flow measurements do not necessarily reflect digital vasospasm in daily life. Besides studies on the diagnostic value and reproducibility of skin blood flow measurements in Raynaud's phenomenon, the relationship of test results to subjective complaints should be established.

Background: The objective of this study was to determine the prevalence of migraine headache in a family practice patient population. In addition, this study evaluated the simultaneous presence of Raynaud's phenomenon (RP) and migraine and examined the influence of sex hormonal status on migraine symptoms., Methods: Data from the Continuous Morbidity Registration Project (CMR) of Nijmegen, the Netherlands, were used to identify all patients in the registration who had migraine headache and a comparison group of patients with nonvasospastic tension headache. Questionnaires were used to verify the diagnosis and to determine signs and symptoms of both headaches., Results: There was an average annual prevalence of migraine headache of four per 1,000 men and 16 per 1,000 women. Eighty-five percent of patients diagnosed by family physicians as having migraine were found to fulfill the International Classification of Health Problems in Primary Care (ICHPPC) criteria for migraine headache. Migraine differed from tension headache with regard to the duration of the attacks, concomitant photo- and phonophobia, provoking factors, and the need to use analgesic medications. RP was present in 15% of the migraine group and in 16% of the tension headache group and occurred almost exclusively in women. The headaches were worse during and before menstruation in both groups and improved during pregnancy and menopause in the migraine group to greater extent than in the tension headache group., Conclusions: The use of the ICHPPC criteria for migraine headache is reliable in morbidity surveys in family practice. Although there was an overlap, migraine differed in various aspects from tension headache. Digital vasospasm and the influence of female hormonal changes were present in both headache groups.

Two instruments for laser Doppler fluxmetry were compared; a diode laser (Diodopp) with a He-Ne gas laser (Periflux Pf1d). Spatial variability during baseline registration and temporal variability during 3 standardized provocation tests (suprasystolic occlusion, tilting and inspiratory gasp) were evaluated in 20 healthy volunteers. The coefficient of variation (= CV) of the registrations on four adjacent places did not show any significant difference between both instruments. The biological zero obtained during 5 minutes vascular occlusion was always zero with the Diodopp and 4 (3-5) (median, [minimum-maximum]) Perfusion Units with the Periflux. The hyperaemic response measured by both instruments was less pronounced during the Diodopp registration (percentage LDF increase 173% (15-350) vs 354% (86-1100), p < 0.001). Although the CV of the LDF parameters obtained by the Diodopp during the standardized provocation tests was almost always lower then with the Periflux, only occasionally the differences reached statistical significance. We concluded that both laser Doppler instruments are of equal value. The reproducibility of the Diodopp is slightly better, but the hyperaemic response after occlusion is registrated in a different way by both instruments.

The pathophysiology of afterdrop of core temperature during rewarming in patients with induced or accidental hypothermia remains controversial. We studied the effect of cooling and rewarming in four female patients with acquired poikilothermia and in four normal females. Exposure to cold air (16.5 degrees C) induced shivering and adequate vasoconstriction in normal individuals, without a fall in rectal temperature (Tr; 36.3 +/- 0.2 degrees C [mean +/- SD]); subsequent heating (40 degrees C) induced a rise in Tr to 37.0 +/- 0.3 degrees C and generalized sweating. The four patients all had spontaneous hypothermia (Tr 34.1 +/- 0.9 degrees C) before cooling. Tr decreased by 0.3-0.9 degrees C during cold exposure, and a marked afterdrop of Tr (0.3-0.5 degrees C) occurred during rewarming: this did not occur in normal individuals. Cooling failed to induce shivering and vasoconstriction in three patients. No patient showed visible sweating during heating despite a Tr of up to 38.0-38.5 degrees C and skin temperature of up to 37.7-38.5 degrees C. The basal metabolic rate was decreased by 71-82% in all patients during steady-state hypothermia and remained lowered during normothermia in two patients. We conclude that during hypothermia three of the four patients showed severe disorders of peripheral vasomotor function and shivering response. These data provide evidence for thermal conduction as the major mechanism of afterdrop during hypothermia.

Recent studies with standardized laboratory measurements of skin blood flow suggest an influence of female sex hormones on vasospasm. Therefore we evaluated the influence of sex hormonal status on the subjective complaints of Raynaud's phenomenon and furthermore the combined presence of Raynaud's phenomenon and migraine. A detailed questionnaire was filled in by 130 primary Raynaud patients (31 males, 99 females), while 27 females, with regular menstrual cycles without the use of oral contraceptives, kept a diary with daily registration (during three months) of frequency, severity and duration of the vasospastic attacks. Complaints improved during pregnancy in 6 out of 23 females. No influence of the menopause or the use of oral contraceptives was found. An exacerbation in some phases of the menstrual cycle was present in 15 out of 80 females. The diaries, however, did not show such influence of menstrual cycle phase. Migraine was present in 21% of the Raynaud patients. In contrast to most reports in the literature and contrary to the results of laboratory research, this study shows that most females do not experience an important subjective influence of sex hormonal status on vasospastic attacks.

Studies that present prevalence rates for Raynaud's phenomenon show great variation. Figures range from a few to more than 20%. In this study, 508 patients who attended their general practitioner filled in a questionnaire dealing with symptoms of Raynaud's phenomenon. When strict criteria (cold digits, numbness and at least a biphasic discolouration) were applied, prevalence was 0.5% in males and 2.9% in females. When a monophasic white discolouration was included, prevalence rates increased by 5.4% in males and by 7.5% in females. The respective percentages became 10.4% and 21.2% when subjects with cold digits and at least a monophasic white or blue discolouration were included. Complaints of cold digits were present in 22.7% of the males and in 35% of the females. We conclude that a great deal of the variation in prevalence of Raynaud's phenomenon can be explained by differences in its definition.

In a double-blind, randomized, placebo-controlled study, the authors investigated the effects of different beta-adrenoceptor blocking drugs on the peripheral circulation. A single intravenous injection of the nonselective beta-blocker propranolol (0.20 mg/kg), the beta 1-selective adrenoceptor blocker metoprolol (0.25 mg/kg), and the nonselective beta-blocker with partial agonistic activity (PAA) pindolol (0.04 mg/kg) and of placebo (saline) was given to eight patients with a primary Raynaud's phenomenon and to nine untreated patients with primary hypertension. The authors measured finger skin temperature (FST), and laser Doppler estimated finger skin blood flux (LDF) before, during, and after a standardized finger cooling test, performed 25 minutes after the administration of the drugs. In both patients groups propranolol, metoprolol, and pindolol had no significant effect on FST and LDF in the first 25 minutes after administration both in comparison to baseline value and to placebo. Also, no significant differences were found in the recoveries of FST and LDF after cold challenge between all drugs and placebo in both groups. The authors conclude that no adverse effect of any type of beta-adrenoceptor blocker in comparison to placebo could be detected after a single administration on both the baseline finger skin perfusion and the recovery after cold-induced vasoconstriction. In addition, the authors could not demonstrate a favorable effect of beta 1-selectivity or PAA in comparison to a nonselective beta-adrenoceptor blocker without PAA, in any group.

The microcirculatory responses to systemically administered alpha-human atrial natriuretic factor [99-126)hANF) (ANF) were investigated in the skin of eight young (18-25 years) and eight elderly (71-84 years) healthy volunteers in a double-blind, randomized, placebo-controlled study. Laser-Doppler flux (LDF), transcutaneous oxygen pressure (TcPO2), and skin temperatures on the finger (Td) and on the cheek (Tc) were measured during 60 min of i.v. ANF administration at a low rate (0.25 micrograms/min), resulting in plasma ANF concentrations in the upper normal range, and at a high rate (2.0 micrograms/min), inducing a 17- to 23-fold increase in plasma ANF. ANF infusion did not induce consistent changes in TcPO2 or Td at either rate. Placebo-corrected LDF increased significantly following low-rate ANF infusion in the elderly but remained unchanged in the young (mean +/- SD) +22 +/- 21% (p less than 0.05) and +7 +/- 32% (p greater than 0.1), respectively; following high-rate ANF infusion in LDF the changes were greater, with +28 +/- 56% and +19 +/- 42%, respectively. Because of the large SD the increases were no longer significant. During high-rate ANF infusion Tc remained unchanged in the young, but in the elderly Tc decreased--1.1 +/- 1.3% (p less than 0.05), which is probably due to the fall in blood pressure, which was more pronounced in the elderly than in the young: mean arterial blood pressure (MAP) decreased -9 +/- 3% (p less than 0.05) in the elderly and just -6 +/- 3% (p less than 0.05) in the young, both corrected for placebo changes.(ABSTRACT TRUNCATED AT 250 WORDS)

A patient is described with Sjögren's syndrome and an IgM-kappa gammopathy. With time cryoglobulins, the cause of acute renal failure, could be detected. The kidney biopsy showed a proliferative glomerulonephritis as is frequently seen with mixed cryoglobulinaemia. Plasmapheresis and immunosuppression resulted in long-term improvement of kidney function. The differential diagnosis of acute renal failure of glomerular origin in a patient with Sjögren's syndrome is discussed. This case report illustrates once more the consequences of monoclonal B-cell lymphocyte activation in Sjögren's syndrome.

1. alpha 2-Adrenoceptors on platelet membranes and beta 2-adrenoceptors on lymphocytes were studied in 24 patients with primary Raynaud's phenomenon and in 24 age- and sex-matched control subjects. In two subgroups, a standardized mental arithmetic test and a finger-cooling test were performed. 2. Baseline blood pressure, heart rate and forearm blood flow did not differ between the two groups. 3. Baseline skin microcirculation (laser Doppler flux) was decreased in primary Raynaud's phenomenon (19 +/- 15 arbitrary units) compared with control subjects (33 +/- 14 arbitrary units) (P less than 0.01). 4. Baseline plasma noradrenaline concentration (2.00 +/- 1.44 versus 1.16 +/- 0.36 nmol/l) and alpha 2-adrenoceptor density (301 +/- 119 versus 210 +/- 82 fmol/mg) were increased in patients with primary Raynaud's phenomenon in comparison with the control subjects. The alpha 2-adrenoceptor density/beta 2-adrenoceptor density ratio in patients with primary Raynaud's phenomenon was, with a value of 0.37 +/- 0.04, higher than in the control subjects, where a value of 0.25 +/- 0.02 was measured (P less than 0.001). Plasma adrenaline concentration, beta 2-adrenoceptor density and the antagonist affinity to both receptor subtypes did not differ between both groups under baseline conditions. 5. Whereas during the finger-cooling test no differences were seen in the responses of the parameters measured, the mental arithmetic test induced an increase in laser Doppler flux in patients with primary Raynaud's phenomenon and a decrease in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Laser Doppler flux measurements were used to determine skin blood flow in 12 patients with primary Raynaud's phenomenon and in 12 healthy age and sex matched control subjects. The vasoconstrictor response to standing, the Valsalva maneuver and a deep breath were used to diagnose local abnormalities of peripheral nerve sympathetic function and were found normal together with a normal catecholamine response to standing upright. However, baseline laser Doppler measured skin blood flow was lower in patients with primary Raynaud's phenomenon (p less than 0.01 in all 3 tests) while resting norepinephrine levels were higher (2.25 +/- 0.33 nmol/l) than in normals (1.31 +/- 0.11 nmol/l; p less than 0.01). These results are consistent with the existence of an elevated sympathetic nervous system activity at rest and a decreased baseline skin blood flow without signs of an excessive sympathetic and skin vascular responsiveness to sympathetic nervous system stimulation.

To investigate the thermoregulatory mechanisms underlying poikilothermia in man, we have studied 4 female patients (age 28-37 yr) with poikilothermia, most probably of hypothalamic origin, as well as 4 female volunteers of similar age. In a climatic chamber the participants were subjected to cold stress (16.5 degrees C) and subsequent heat exposure (40 degrees C). In the volunteers cold stress did not influence the rectal temperature; cooling induced a marked shivering response and an immediate peripheral vasoconstriction. Subsequent heat challenge induced a slight rise in the rectal temperature (from 36.3 +/- 0.2 to 37.0 +/- 0.3 degrees C) and a marked sweat secretion in all control subjects. All patients were hypothermic at the start of the experiment. Cooling induced a decrease in the rectal temperature of 0.3-0.9 degrees C. Three patients showed neither peripheral vasoconstriction nor a shivering response to cold stress. In contradistinction to the control subjects, in all patients an afterdrop of the rectal temperature of 0.3-0.5 degrees C was observed once heating of the environment had started; thereafter a progressive rise in core temperature occurred up to 38.5 (38.0) degrees C. In none of the patients sweat secretion was clinically visible. These results reveal that in these patients with poikilothermia the disorder of thermoregulation is accompanied by inadequate cutaneous vasomotor adjustment and disturbed sweat response and likely reduced metabolic response to cold stress.

Patients presenting with Raynaud's phenomenon pose differential diagnostic problems. The question is whether the discolorations are a symptom of the benign primary type or a symptom of an underlying disease, mostly a connective tissue disease or an atherosclerotic occlusive disease, both having major prognostic implications. To evaluate whether Raynaud patients can be classified properly in the above-mentioned categories on clinical grounds we evaluated 225 patients using a checklist dealing with signs and symptoms supposed to be specific for primary Raynaud's phenomenon or the two major types of the secondary form. Complaints that started before the age of 20, reactive hyperaemia at the end of an attack and discolorations of the earlobes and the nose have a high predictive value for primary Raynaud's phenomenon. Trophic skin disturbances are rare in the latter but are rather specific for connective tissue diseases. In the case of arterial obstructive disease, the feet are always involved and risk factors associated with atherosclerosis are often present, whereas this type is specifically encountered in men in whom the complaints started over the age of 50 [corrected], and in whom signs of atherosclerotic vessel wall disease were seen elsewhere. In conclusion, in most patients who present with a Raynaud's phenomenon a complete history and physical examination are sufficient for a correct diagnosis. Supplementation with determination of anti-nuclear antibodies, measurements of the capillary perfusion and of the finger skin systolic pressure completes the diagnostic classification.

To investigate the hypothesis of a sympathetic imbalance in the pathophysiology of digital vasospasms during stress we measured vascular and sympathetic nervous system reactivity during a standardized mental arithmetic test in 12 patients with primary Raynaud's phenomenon in comparison to 12 healthy control subjects. Blood pressure, heart rate, forearm blood flow and fingertip laser Doppler flux were measured together with the venous concentrations of norepinephrine and epinephrine from the back of the hand before and during mental arithmetic in a climate room. No significant differences in circulatory or sympathetic reactivity were found between both groups except for fingertip skin circulation with a small decrease of laser Doppler flux (-11.6%) in controls, whereas it increased in PRP (46.6%; p less than 0.05 between both groups). Baseline skin blood flow was inversely correlated with changes in laser Doppler flux (R = -0.91; p less than 0.001; no. 24) irrespective of the diagnosis when baseline skin bloodflow is low a vasodilatory response occurs and when it is high a vasoconstrictive response is seen. Initial laser Doppler flux was lower while baseline diastolic blood pressure, heart rate and (nor)epinephrine concentrations were significantly higher in Raynaud-patients suggesting an increased sympathetic activity at rest in primary Raynaud's phenomenon.

In three patients with either hypertension or Raynaud's phenomenon who were treated with different types of vasodilatory drugs, i.e. prazosin, nifedipine and prostacyclin, a decrease in rectal body temperature was measured. Overt hypothermia occurred in one patient. Because we found a pronounced improvement of arteriovenous shunt flow within the skin vessels in two of these patients, increased heat loss seems the most reasonable explanation for the observed decrease in body temperature. These observations point to an adverse effect of vasodilatory drugs. One should be aware of this possibility in patients being treated with these drugs who have complaints suggestive of hypothermia.

To determine whether measurements of transcutaneous pO2 (TcPO2) by Tacomette (Novametrix Medical Systems Inc., Connecticut, U.S.A.) could be a valuable method to evaluate nutritive skin perfusion, baseline TcPO2 was measured under standardized conditions in normals and in patients with several types of Raynaud's phenomenon (RP). The control group (n = 41; TcPO2 = 34.4 +/- 14.3 mm Hg) and the patients with primary RP (n = 81; TcPO2 = 25.0 +/- 9.7 mmm Hg) had a significantly higher baseline TcPO2 (p less than 0.05) in comparison to the secondary RP-patients with a connective tissue disease (n = 54; TcPO2 = 10.5 +/- 7.9 mm Hg). In RP patients the group with trophic skin lesions showed a significant lower TcPO2 (p less than 0.01). The reproducibility expressed as the standard error of a single observation was moderate (13-27%). After 20 minutes acclimatization it took 32 minutes before a stable baseline value was reached which makes the procedure a lengthy one. Its non-invasive nature is severely hampered by the skin injuries observed in 3 patients, while the abolition of vascular tone induced by the heating makes the interpretation of intervention studies difficult. In conclusion baseline TcPO2 measurements were found lower in patients with disturbances of nutritional skin blood flow. However, because of the overlap of values between groups the discriminative value of this method is limited. Comparative studies with other techniques that determine capillary perfusion like the 133Xenon wash out technique and dynamic capillary microscopy are necessary to validate this technique as a reliable alternative.

The selective hemodynamic effects of an intravenous infusion of prostacyclin on skin and on forearm blood flow during increasing doses up to 6 ng.kg.-1 min.-1 were evaluated in 12 healthy volunteers. The highest dose raised total skin blood flow (p = 0.0001) as measured by laser Doppler with a concomitant rise in finger skin temperature (p = 0.02). Capillary perfusion as measured by transcutaneous oxygen monitoring remained relatively unaffected (p = 0.25). Cold-induced vasoconstriction and the recovery thereafter were not influenced. Diastolic blood pressure tended to decrease (p = 0.06), but there was no change in systolic blood pressure, forearm blood flow, and calculated forearm vascular resistance. The authors conclude that prostacyclin may have dissimilar vasoactive potencies in different vascular beds as shown by a pronounced increase in total skin blood flow, owing to vasodilation of shunt vessels, simultaneously with an insignificant change in nutritional skin blood flow and forearm muscle blood flow.

In a dose-response study of prazosin in 24 patients with Raynaud's phenomenon, the clinical effectiveness and side effects of 3, 6, and 12 mg prazosin administered daily were compared. Diary analysis and measurement of finger skin blood flow and temperature before, during, and after cold challenge showed no major differences among these three dose regimens. Standing systolic blood pressure decreased significantly during the 12-mg period in comparison with the 6-mg (P less than .05) and with the 3-mg period (P less than .02), whereas heart rate increased in the 6-mg and 3-mg periods (P less than .05). In the higher dosage ranges, spontaneous mentioned side effects were noticed most often, which was in accordance with the results of a checklist analysis on adverse effects. Three patients withdrew from the study because of complaints that might be due to orthostatic hypotension. Most patients that wanted to continue prazosin after this study (n = 13) did so on a 3-mg basis (n = 10). Because prazosin 3 mg daily is more effective in treating of Raynaud's phenomenon than is placebo, the study shows that in a dosage of 3 mg daily, the best balance between clinical effectiveness and side effects is obtained.

Because complaints of cold extremities are a frequent side effect of beta-adrenoceptor blocking drugs, we assessed Finger Skin Temperature (FST) during a standardized Finger Cooling Test (FCT) in 51 normals and in 50 hypertensive patients after long term treatment with beta-adrenoceptor blockers. In the 29 hypertensive patients with complaints of cold extremities the recovery of FST after cold challenge was significantly worse as compared to the 21 hypertensive patients without complaints. Hypertensive women who used beta-adrenoceptor blocking agents showed lower FST-values after the cold test in comparison to hypertensive men. No difference in recovery of FST were found between the users of non-selective and selective beta-adrenoceptor blockers. We conclude that the FCT is a suitable method to detect a decreased ability of vasodilate during chronic beta-adrenoceptor blockade in hypertensive patients.

We performed a randomized, double-blind, placebo-controlled, crossover study of the therapeutic efficacy of prazosin (1 mg t.i.d.) in 24 patients with Raynaud's phenomenon. Comparison of prazosin vs. placebo showed a moderate subjective improvement with a reduction of the daily number (P = 0.003) and duration (P = 0.02) of attacks. Patients showed a marked preference (P = 0.0002) for prazosin. Finger skin temperature and laser Doppler estimated finger skin blood flow, assessed during a standard finger cooling test, revealed a beneficial effect of prazosin (P = 0.0001 and P = 0.003, respectively). No differences in reaction to therapy could be found between patients with Raynaud's disease and secondary Raynaud's phenomenon. We conclude that prazosin is useful in the treatment of digital vasospastic disease, with an overall good response in two thirds of patients.