Theoretical simulation of oxygen transport to brain by networks of microvessels: effects of oxygen supply and demand on tissue hypoxia.

OBJECTIVE: Simulations of oxygen delivery by a three-dimensional network of microvessels in rat cerebral cortex were used to examine how the distribution of partial pressure of oxygen (PO2) in tissue depends on blood flow and oxygen consumption rates. METHODS: Network geometry was deduced from previously published scanning electron micrographs of corrosion casts. A nonlinear least-squares method, using images obtained at three different angles, was used to estimate vessel locations. The network consisted of 50 segments in a region 140 microm x 150 microm x 160 microm. A Green's function method was used to predict the PO2 distribution. Effects of varying perfusion and consumption were examined, relative to a control state with consumption 10 cm3O2/100 g per min and perfusion 160 cm3/100 g per min. RESULTS: In the control state, minimum tissue PO2, was 7 mm Hg. A Krogh-type model with the same density of vessels, but with uniform spacing, predicted a minimum tissue PO2 of 23 mm Hg. For perfusion below 60% of control, tissue hypoxia (PO2 <1 mm Hg) was predicted. When perfusion was reduced by 75%, the resulting hypoxia could be eliminated by a 31% reduction in oxygen consumption rate. CONCLUSIONS: The simulations suggest that tissue hypoxia resulting from a severe decrease in brain perfusion, as can occur in stroke, may be avoided by a moderate decrease in oxygen consumption rate.

Microalbuminuria in ischemic stroke.

OBJECTIVES: To determine (1) the incidence of microalbuminuria in patients with recent ischemic stroke, (2) its relationship to risk factors for stroke, (3) its prevalence in the major subtypes of ischemic stroke, and (4) its potential for identifying patients at increased risk for recurrent stroke, myocardial infarction, or vascular death. DESIGN: Prospective case-control study. SETTING: Outpatient clinics at the medical centers affiliated with the Department of Veterans Affairs and Oregon Health Sciences University in Portland, Ore. PATIENTS: A total of 186 older men and women (median age, 65 years) who were enrolled in a prospective study of risk factors for recurrent stroke, including 97 patients with recent (6-8 weeks) ischemic stroke, 51 with similar clinical risk factors for stroke, including 24 with a history of remote stroke or transient ischemic attack, and 38 community-dwelling volunteers. RESULTS: Microalbuminuria was 3 times more prevalent in patients with recent stroke (29%) than in those with clinical risk factors for stroke (10%), and was undetectable in healthy elderly controls (P<.001). The presence of microalbuminuria in recent stroke as well as in the combined recent and remote stroke or transient ischemic attack group (n = 121) was predicted by diabetes (odds ratio [OR], 8.4; 95% confidence interval [CI], 2.6-27.0; P<.001; serum albumin levels (OR, 0.12; 95% CI, 0.03-0.50; P<.005); age (OR, 1.1; 95% CI, 1.0-1.2; P<.01), and ischemic heart disease (OR, 3.0; 95% CI, 1.0-9.1; P<.05). Among patients with recent stroke the prevalence of microalbuminuria did not differ among major ischemic stroke subtypes, ie, atheroembolic, 23%; cardioembolic, 30%; and lacunar, 33%. During a mean +/- SD of 1.5 +/- 0.9 years of follow-up, 20% of patients with recent stroke, 14% with risk factors for stroke, and 0% of healthy elderly volunteers had vascular end points (P<.004), with events being as frequent in patients with microalbuminuria (32%) as in patients with macroalbuminuria (33%). After controlling for major clinical risk factors, microalbuminuria remained an independently significant predictor of future stroke in the combined recent stroke and remote stroke or transient ischemic attack group (Cox proportional hazard ratio, 4.9; 95% CI, 1.4-17.6; P<.01). CONCLUSIONS: Microalbuminuria is a common finding in patients with cerebrovascular disease and is associated with increased risk for stroke even after correction for the presence of confounding clinical risk factors. These data suggest that microalbuminuria merits further examination as a potentially inexpensive and easily measured marker of increased risk for stroke.

Persistent inflammatory response in stroke survivors.

OBJECTIVE: Goals were to determine how long acute-phase markers remain elevated after ischemic stroke and how marker levels relate to stroke risk factors, stroke mechanism, and subsequent vascular events. METHODS: Fibrinogen (FIB), C-reactive protein (CRP), leukocytes (WBC), neutrophils (PMN), interleukin-6, and interleukin-1 receptor antagonist were measured at stroke onset and at 6 weeks, 6 months, and 1 year after enrollment, or until a vascular event occurred in 136 acute ischemic stroke patients, 76 patients with comparable risk factors for stroke, and 48 age-balanced healthy subjects. RESULTS: Multivariate logistic analysis showed that prior stroke and FIB level predicted new events in stroke patients (p < 0.04 for both), whereas congestive heart failure (p < 0.02) and creatinine level (p < 0.006) were predictive in at-risk patients. After controlling for infection, FIB, CRP, and PMN levels at baseline were higher in at-risk but not in stroke patients with recurrent events (p < 0.05 for all). At 1 year, FIB levels remained elevated in event-free stroke survivors compared with levels in the risk and control groups (p < 0.001 for both). FIB also remained higher in stroke survivors who had atheroembolism (AE) compared with non-AE stroke survivors (381+/-72 versus 342+/-78 mg/dL, p < 0.02). Peripheral vascular disease was an independent predictor (p < 0.0001) of longitudinal FIB in stroke survivors. Of note, both WBC and PMN levels were chronically elevated in patients with stroke risk factors and in stroke survivors (p < 0.0001 for both) compared with healthy elderly subjects. CONCLUSIONS: Most acute-phase markers decline gradually after stroke, but FIB remains significantly elevated and is associated with increased risk for recurrent vascular events.

The initial acute phase response predicts long-term stroke recovery.

Indicators of an acute phase response (APR) in acute ischemic stroke have been shown to correlate with infarct size and predict stroke recurrence. In this study, we examined how well the APR indicators predicted long-term stroke recovery compared with standard clinical predictors of recovery. Plasma levels of interleukin-6 (IL-6), fibrinogen, white blood cells (WBCs), and serum albumin were measured within 4+/-2 days of onset in 131 stroke patients who were free of apparent infections. Standard clinical predictors included initial National Institutes of Health Stroke Scale (NIHSS), infarct size on computed tomography (CT), and Glasgow scale. The individual correlations with 6-month Glasgow outcome were IL-6, 0.42; fibrinogen, 0.24; WBC, 0.35; albumin, 0.47; NIHSS, 0.53; infarct size, 0.19; and initial Glasgow, 0.57. (all P<.005). Multiple regression analysis yielded an adjusted R(2) of .31 for the APR indicators, compared with .38 for the clinical variables. These results indicate that the initial APR is highly correlated with 6-month stroke recovery and that this correlation approaches that observed with standard clinical predictors.

Interleukin-6 and interleukin-1 receptor antagonist in acute stroke.

Elevated plasma levels of interleukin-6 (IL-6), a key regulator of the acute phase response that includes increased fibrinogen synthesis, have recently been detected in patients with acute stroke. Nevertheless, the role of the acute phase response in stroke has been controversial, with some studies suggesting that preexisting infection accounts for most of the acute phase response. Increased IL-6 could signal the involvement of antiinflammatory activity, since IL-6 stimulates the production of endogenous antiinflammatory mediators such as interleukin-1 receptor antagonist (IL-1RA). To better understand the interaction of pro- and antiinflammatory acute phase processes in brain infarction, plasma levels of IL-1RA, IL-6, and acute phase proteins including fibrinogen and c-reactive protein (CRP) were measured within 4 +/- 2 days of onset in 50 patients with acute ischemic stroke and in 20 age-matched healthy controls. After excluding patients with evidence of infection, both IL-1RA and IL-6 were significantly elevated in stoke patients compared with controls (p < 0.0001). IL-1RA and IL-6 were both significantly correlated with levels of CRP, p < 0.05 and p < 0.001, respectively, but not with each other. Levels of IL-6 and IL-1RA, together with fibrinogen and CRP were higher in patients with infarcts of greater than 3 cm and lowest in patients with lacunar syndromes.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokine and superoxide production in clinical stroke.

Cytokines appear to play an important role in a variety of central nervous system (CNS) diseases and may be involved in ischemia. Activated leukocytes are a major source of cytokines and other inflammatory mediators that may directly injure ischemic CNS tissue. To investigate the importance of these substances in clinical stroke, we compared spontaneous secretion of IL-lß, IL-6, IL-8, and superoxide production from neutrophils (PMN) and mononuclear cells (MNC) isolated from either acute stroke patients (n = 10) or matched controls (n = 10). Cytokine production from 5 × 10(6) cells incubated for 24 h was determined by ELISA. MNC from acute stroke patients secreted significantly less IL-1ß, IL-6, and IL-8 than MNC from control patients. No significant cytokine production was detected from PMN. Superoxide production from 1.25 × 10(5) cells was determined over 1 h measuring cytochrome C reduction. There was a trend toward higher superoxide production in PMN from acute stroke patients, whereas the superoxide production in MNC from acute stroke patients was significantly higher than that of control MNC. This difference persisted even when various agonists were added preincubation. This study suggests that MNC spontaneous cytokine secretion is reduced in acute stroke patients, whereas superoxide production is increased. This decreased cytokine production may be secondary to the effects of a cytokine inhibitory factor.

Spontaneous echo contrast and hemorheologic abnormalities in cerebrovascular disease.

BACKGROUND AND PURPOSE: Spontaneous echo contrast (SEC) is thought to represent a risk factor for cardioembolic stroke. In vitro studies suggest that SEC results from interaction between red cells and fibrinogen. To better understand the relation between SEC and stroke and to investigate the in vivo genesis of SEC, we examined the relation between SEC, the constituents of the blood, and plasma and serum viscosity in patients with acute stroke or chronic cerebrovascular disease. METHODS: Fifty patients with acute stroke or chronic cerebrovascular disease referred for transesophageal echocardiogram (TEE) were studied by transthoracic echocardiography and TEE. Complete blood count, fibrinogen, albumin, gamma-globulin, and plasma and serum viscosity determinations were made. Left atrial SEC was graded as absent, mild, or marked by means of TEE. RESULTS: SEC was absent in 31 patients, mild in 10 patients, and marked in 9 patients. Higher grade of SEC was associated with a significantly greater percentage of patients with atrial fibrillation and larger left atrial dimension. Atrial fibrillation was present in 23% of the patients in the SEC absent group, 50% of the patients in the mild SEC group, and 78% of the patients in the marked SEC group (P < .01). Left atrial diameter averaged 3.8 +/- 0.6 cm in the SEC absent group, 4.3 +/- 1.1 in the mild SEC group, and 4.9 +/- 0.7 in the marked SEC group (P < .001). Hematocrit, white blood cell count, and platelet count did not differ among the three groups. Fibrinogen, gamma-globulin, plasma viscosity, and serum viscosity values were all significantly higher in the presence of SEC (P < .05). Fibrinogen values were 361 +/- 97 mg/dL in the SEC absent group and 427 +/- 135 mg/dL in the marked SEC group. gamma-Globulin levels were 0.75 +/- 0.23 g/dL in the SEC absent group and 1.06 +/- 0.48 g/dL in the marked SEC group. Both plasma viscosity (1.97 cp) and serum viscosity (1.64 cp) were higher in the marked SEC group than in the SEC absent group (1.77 and 1.50 cp, respectively). CONCLUSIONS: In patients with acute stroke or chronic cerebrovascular disease, the severity of SEC was not related to albumin, hematocrit, white cell count, or platelet count but rather to elevated fibrinogen levels and concomitant increases in both plasma and serum viscosity. Moreover, increasing grade of SEC was associated with significantly increased left atrial diameter and a higher percentage of patients in atrial fibrillation.

Prostacyclin infusion in acute cerebral infarction.

We gave prostacyclin infusions to seven patients with acute cerebral infarction. Patients without CT evidence of infarction improved, but those who already had hypodensities on CT did not benefit. Increased platelet activity, measured by plasma beta-thromboglobulin, decreased significantly (p less than 0.01) during prostacyclin administration to normal levels, but rose again after the infusion. These results indicate that prostacyclin can be given safely in doses adequate to suppress platelet function. Our findings encouraged us to proceed with a controlled trial of its clinical efficacy.

Serum concentrations of oestradiol and progesterone during the normal oestrous cycle and early pregnancy in the lion (Panthera leo).

During a 6-month study period weekly serum samples demonstrated 9 oestradiol surges above 14 pg/ml (range 19-108 pg/ml) among 3 lionesses isolated from male lions. Intervals between peaks ranged from 3 to 8 weeks. Progesterone surges of more than 17 ng/ml (range 17-282 ng/ml) and lasting for 2-6 weeks were recorded after 7 of the oestradiol peaks. Sexual behaviour correlated well with the oestradiol peaks. Except for cornification following oestradiol peaks, there was no obvious vaginal cytology pattern at other times of the cycle. Pregnancy occurred after a 12-h contact with a male during behavioural oestrus. During gestation (108 days) oestradiol values remained low, while progesterone was elevated to 49 ng/ml within 12 h after mating, reaching a peak of 143 ng/ml at the 4th week, and remaining elevated during the next 2 months.