Central and noncentral blood volumes in cirrhosis: relationship to anthropometrics and gender

The size of the central and arterial blood volume (CBV) is essential in the understanding of fluid retention in cirrhosis. Previously, it has been reported decreased, normal, or increased, but no reports have analyzed CBV with respect to gender and lean body mass. The aim of the present study was by means of an optimized technique to reassess it in a large group of patients with cirrhosis compared with healthy controls and matched controls in relationship to their body dimensions and gender. Eighty-three patients with cirrhosis (male/female, 60:23), 67 patients without liver disease (male/female, 22:45), and 14 young healthy controls (male/female, 6:8) underwent a hemodynamic investigation with determination of cardiac output, central circulation time, and CBV determined according to kinetic principles. Related to gender, CBV was lower in male cirrhotics (1.48 +/- 0.30 liter) than in matched and young controls (1.68 +/- 0.33 and 1.72 +/- 0.33 liter, respectively; P < 0.05-0.01). No significant differences in CBV were seen between female cirrhotics and controls. Absolute and adjusted CBVs were lower in the females than in men with cirrhosis (P < 0.001), and men with cirrhosis had lower absolute and body weight-adjusted CBVs than matched controls (P < 0.01). Normalized values of CBV (%total blood volume) were significantly lower in patients with cirrhosis (25 +/- 4%) than in matched controls (31 +/- 7%) and young controls (28 +/- 4%; P < 0.02). CBV correlated significantly with anthropometrics, including lean body mass (r = 0.68-0.82; P < 0.0001). In conclusion, the CBV of patients with cirrhosis was lower than that of controls when adjusted for body dimensions and gender. There are significant gender differences, and signs of underfilling are more pronounced in male than in female patients. The results emphasize the importance of adjustments of blood volumes for anthropometrics and gender.     

Reduced baroreflex sensitivity in alcoholic cirrhosis: relations to hemodynamics and humoral systems

In cirrhosis, arterial vasodilatation leads to central hypovolemia and activation of the sympathetic nervous and renin-angiotensin-aldosterone systems. As the liver disease and circulatory dysfunction may affect baroreflex sensitivity (BRS), we assessed BRS in a large group of patients with cirrhosis and in controls who were all supine and some after 60 degrees passive head-up and 30 degrees head-down tilting in relation to central hemodynamics and activity of the sympathetic nervous and renin-angiotensin-aldosterone systems. One-hundred and five patients (Child classes A/B/C: 21/55/29) and 25 (n=11 + 14) controls underwent a full hemodynamic investigation. BRS was assessed by cross-spectral analysis of variabilities between blood pressure and heart rate time series. The median BRS was significantly lower in the supine cirrhotic patients, 3.7 (range 0.3-30.7) ms/mmHg than in matched controls (n=11): 14.3 (6.1-23.6) ms/mmHg, P<0.001. A stepwise multiple-regression analysis revealed that serum sodium (P=0.044), heart rate (P=0.027), and central circulation time (P=0.034) independently correlated with BRS. Head-down tilting had no effects on BRS, but, after head-up tilting, BRS was similar in the patients (n=23) and controls (n=14). In conclusion, BRS is reduced in cirrhosis in the supine position and relates to various aspects of cardiovascular dysfunction, but no further reduction was observed in parallel with the amelioration of the hyperdynamic circulation after head-up tilting. The results indicate that liver dysfunction and compensatory mechanisms to vasodilatation may be involved in the low BRS, which may contribute to poor cardiovascular adaptation in cirrhosis.     

Lower capacitance response and capillary fluid absorption in women to defend central blood volume in response to acute hypovolemic circulatory stress

Acute hemorrhage is a leading cause of death in trauma, and women are more susceptible to hypovolemic circulatory stress than men. The mechanisms underlying the susceptibility are not clear, however. The aim of the present study was to examine the compensatory mechanisms to defend central blood volume during experimental hypovolemia in women and men. Twenty-two women (23.1 +/- 0.4 yr) and 16 men (23.2 +/- 0.5 yr) were included. A lower body negative pressure (LBNP) of 11-44 mmHg induced experimental hypovolemic circulatory stress. The volumetric technique was used to assess the capacitance response (redistribution of peripheral venous blood to the central circulation) as well as to assess net capillary fluid transfer from tissue to blood in the arm. Plasma norepinephrine (NE) and forearm blood flow were measured before and during hypovolemia, and forearm vascular resistance (FVR) was calculated. LBNP created comparable hypovolemia in women and men. FVR increased less in women during hypovolemic stress, and no association between plasma NE and FVR was seen in women (R(2) = 0.01, not significant), in contrast to men (R(2) = 0.59, P < 0.05). Women demonstrated a good initial capacitance response, but this was not maintained with time, in contrast to men [e.g., decreased by 24 +/- 4% (women) vs. 4 +/- 5% (men), LBNP of 44 mmHg, P < 0.01], and net capillary fluid absorption from tissue to blood was lower in women (0.086 +/- 0.007 vs. 0.115 +/- 0.011 ml.100 ml(-1).min(-1), P < 0.05). In conclusion, women showed impaired vasoconstriction, reduced capacitance response with time, and reduced capillary fluid absorption during acute hypovolemic circulatory stress, indicating less efficiency to defend central blood volume than men.     

Transpulmonary pyruvate kinetics

Shuttling of intermediary metabolites, such as pyruvate, contributes to the dynamic energy and biosynthetic needs of tissues. Tracer kinetic studies offer a powerful tool to measure the metabolism of substrates like pyruvate that are simultaneously taken up from and released into the circulation by organs. However, we understood that during each circulatory passage, the entire cardiac output transits the pulmonary circulation. Therefore, we examined the transpulmonary pyruvate kinetics in an anesthetized rat model during an unstimulated (Con), lactate clamp (LC), and epinephrine infusion (Epi) conditions using a primed-continuous infusion of [U-13C]pyruvate. Compared with Con and Epi stimulation, LC significantly increased mixed central venous ([v]) and arterial ([a]) pyruvate concentrations (P < 0.05). We hypothesized that the lungs, specifically the pulmonary capillary beds are sites of simultaneous production and removal of pyruvate and contributes significantly to whole body carbohydrate intermediary metabolism. Transpulmonary net pyruvate balances were positive during all three conditions, indicating net pyruvate uptake. Net balance was significantly greater during epinephrine stimulation compared with the unstimulated control (P < 0.05). Tracer-measured pyruvate fractional extraction averaged 42.8 ± 5.8% for all three conditions and was significantly higher during epinephrine stimulation (P < 0.05) than during either Con or LC conditions, that did not differ from each other. Pyruvate total release (tracer measured uptake - net balance) was significantly higher during epinephrine stimulation (400 ± 100 μg/min) vs. Con (30 ± 20 μg/min) (P < 0.05). These data are interpreted to mean that significant pyruvate extraction occurs during circulatory transport across lung parenchyma. The extent of pulmonary parenchymal pyruvate extraction predicts high expression of monocarboxylate (lactate/pyruvate) transporters (MCTs) in the tissue. Western blot analysis of whole lung homogenates detected three isoforms, MCT1, MCT2, and MCT4. We conclude that a major site of circulating pyruvate extraction resides with the lungs and that during times of elevated circulating lactate, pyruvate, or epinephrine stimulation, pyruvate extraction is increased.     

Sensorimotor function of the upper-airway muscles and respiratory sensory processing in untreated obstructive sleep apnea

Numerous studies have demonstrated upper-airway neuromuscular abnormalities during wakefulness in snorers and obstructive sleep apnea (OSA) patients. However, the functional role of sensorimotor impairment in OSA pathogenesis/disease progression and its potential effects on protective upper-airway reflexes, measures of respiratory sensory processing, and force characteristics remain unclear. This study aimed to gain physiological insight into the potential role of sensorimotor impairment in OSA pathogenesis/disease progression by comparing sensory processing properties (respiratory-related evoked potentials; RREP), functionally important protective reflexes (genioglossus and tensor palatini) across a range of negative pressures (brief pulses and entrained iron lung ventilation), and tongue force and time to task failure characteristics between 12 untreated OSA patients and 13 controls. We hypothesized that abnormalities in these measures would be present in OSA patients. Upper-airway reflexes (e.g., genioglossus onset latency, 20 ± 1 vs. 19 ± 2 ms, P = 0.82), early RREP components (e.g., P1 latency 25 ± 2 vs. 25 ± 1 ms, P = 0.78), and the slope of epiglottic pressure vs. genioglossus activity during iron lung ventilation (-0.68 ± 1.0 vs. -0.80 ± 2.0 cmH(2)O/%max, P = 0.59) were not different between patients and controls. Maximal tongue protrusion force was greater in OSA patients vs. controls (35 ± 2 vs. 27 ± 2 N, P < 0.01), but task failure occurred more rapidly (149 ± 24 vs. 254 ± 23 s, P < 0.01). Upper-airway protective reflexes across a range of negative pressures as measured by electromyography and the early P1 component of the RREP are preserved in OSA patients during wakefulness. Consistent with an adaptive training effect, tongue protrusion force is increased, not decreased, in untreated OSA patients. However, OSA patients may be vulnerable to fatigue of upper-airway dilator muscles, which could contribute to disease progression.     

Vascular reactivity to norepinephrine in rats with cirrhosis of the liver

Vascular reactivity to norepinephrine was studied in rats with early cirrhosis of the liver and in control rats. Cirrhotic rats showed water and sodium retention but not ascites. Studies were performed in whole animals, isolated hindquarters, and isolated femoral arteries. Plasma catecholamine levels were measured by radioenzymoassay and their urinary metabolites by gas-liquid chromatography. Plasma norepinephrine was 331 +/- 49 pg/mL (mean +/- SEM) in control rats and 371 +/- 66 pg/mL in cirrhotic animals (p greater than 0.05). No differences in plasma epinephrine or dopamine were observed. Urinary excretion of catecholamine metabolites was increased in cirrhotic rats. These data suggest a moderate activation of the sympathetic nervous system. In basal conditions, cirrhotic rats showed lower mean arterial pressure than controls (101 +/- 4 vs. 116 +/- 4 mmHg (1 mmHg = 133.3 Pa); p less than 0.01). However, perfused hindlimb resistance was similar in cirrhotic and in control animals. In the whole animal and in the perfused hindquarter, the contractile response to norepinephrine was similar for control and for cirrhotic rats. The contractile response to norepinephrine exhibited by isolated femoral arteries was similar in those from cirrhotic and control rats. This indicates that the peripheral vascular bed has a well-maintained ability to constrict in response to norepinephrine, suggesting that circulatory abnormalities in early experimental cirrhosis are not caused by refractoriness of the vascular smooth muscle to norepinephrine.     

Vasoconstriction seen in coronary bypass grafts during handgrip in humans.

In animal studies, sympathetically mediated coronary vasoconstriction has been demonstrated during exercise. Human studies examining coronary artery dynamics during exercise are technically difficult to perform. Recently, noninvasive transthoracic Duplex ultrasound studies demonstrated that 1) patients with left internal mammary artery (LIMA) grafts to the left anterior descending artery can be imaged and 2) the LIMA blood flow patterns are similar to those seen in normal coronary arteries. Accordingly, subjects with LIMA to the left anterior descending artery were studied during handgrip protocols as blood flow velocity in the LIMA was determined. Beat-by-beat analysis of changes in diastolic coronary blood flow velocity (CBV) was performed in six male clinically stable volunteers (60 +/- 2 yr) during two handgrip protocols. Arterial blood pressure (BP) and heart rate (HR) were also measured, and an index of coronary vascular resistance (CVR) was calculated as diastolic BP/CBV. Fatiguing handgrip performed at [40% of maximal voluntary contraction (MVC)] followed by circulatory arrest did not evoke an increase in CVR (P = not significant). In protocol 2, short bouts of handgrip (15 s) led to increases in CVR (18 +/- 3% at 50% MVC and 20 +/- 8% at 70% MVC). BP was also increased during handgrip. Our results reveal that in conscious humans, coronary vasoconstriction occurs within 15 s of onset of static handgrip at intensities at or greater than 50% MVC. These responses are likely to be due to sympathetic vasoconstriction of the coronary circulation.     

NT Pro BNP Plasma Level and Atrial Volume Are Linked to the Severity of Liver Cirrhosis

Background and Aims

Plasma levels of NT-pro-BNP, a natriuretic peptide precursor, are raised in the presence of fluid retention of cardiac origin and can be used as markers of cardiac dysfunction. Recent studies showed high levels of NT pro BNP in patients with cirrhosis. We assessed NT pro-BNP and other parameters of cardiac dysfunction in patients with cirrhosis, with or without ascites, in order to determine whether the behaviour of NT pro BNP is linked to the stage of liver disease or to secondary cardiac dysfunction.

Methods

Fifty eight consecutive hospitalized patients mostly with viral or NAFLD-related cirrhosis were studied. All underwent abdominal ultrasound and upper GI endoscopy. Cardiac morpho-functional changes were evaluated by echocardiography and NT-pro-BNP plasma levels determined upon admission. Twenty-eight hypertensive patients, without evidence of liver disease served as controls.

Results

Fifty eight cirrhotic patients (72% men) with a median age of 62 years (11% with mild arterial hypertension and 31% with type 2 diabetes) had a normal renal function (mean creatinine 0.9 mg/dl, range 0.7–1.06). As compared to controls, cirrhotic patients had higher NT pro-BNP plasma levels (365.2±365.2 vs 70.8±70.6 pg/ml; p<0.001). Left atrial volume (LAV) (61.8±26.3 vs 43.5±14.1 ml; p = 0.001), and left ventricular ejection fraction (62.7±6.9 vs. 65.5±4%,; p = 0.05) were also altered in cirrhotic patients that in controls. Patients with F2-F3 oesophageal varices as compared to F0/F1, showed higher e'' velocity (0.91±0.23 vs 0.66±0.19 m/s, p<0.001), and accordingly a higher E/A ratio (1.21±0.46 vs 0.89±0.33 m/s., p = 0.006).

Conclusion

NT-pro-BNP plasma levels are increased proportionally to the stage of chronic liver disease. Advanced cirrhosis and high NT-pro-BNP levels are significantly associated to increased LAV and to signs of cardiac diastolic dysfunction. NT pro-BNP levels could hence be an useful prognostic indicators of early decompensation of cirrhosis.     

Effects of treadmill exercise on fuel metabolism in hepatic cirrhosis

We studied whole body and regional fuel metabolism before, during, and after 90 min of treadmill exercise at 50% of maximal aerobic capacity (VO2max) in four subjects with hepatic cirrhosis and in four normal volunteers. Rates of endogenous glucose production (EGP) were measured using D-[6-3H]glucose infusions and fuel oxidation using indirect calorimetry. In the basal state, cirrhotic subjects had similar rates of EGP compared with controls. Forearm release of alanine and lactate was significantly greater in cirrhotic subjects (P less than 0.05), suggesting increased basal rates of gluconeogenesis. During exercise, EGP increased 2- to 2.5-fold in control subjects (P less than 0.01) but did not increase in cirrhotic subjects. Despite lower glucose concentrations in cirrhotic subjects, progressive hypoglycemia did not occur during exercise, probably because cirrhotic subjects demonstrated increased plasma concentrations of fat-derived substrates and derived a greater percentage of total energy requirement from fat oxidation than did controls (P less than 0.05) and because forearm muscle glucose extraction was significantly lower in cirrhotic subjects compared with controls (0.5 vs. 3.6%, respectively; P less than 0.05). During recovery, control subjects demonstrated significant increases in EGP rates compared with both the basal and exercise periods, but cirrhotic subjects showed no increase. In conclusion, cirrhotic subjects failed to demonstrate the normal increase in EGP during and after exercise. Significant hypoglycemia during exercise did not occur, possibly because of the increased availability of fat-derived fuels, which may spare the requirement for circulating glucose as an oxidative fuel for exercising muscle tissues.     

Hemodynamic alterations in liver cirrhosis

In cirrhotic patients, portal hypertension is often associated with a hyperdynamic circulatory syndrome, with high cardiac output and reduced systemic vascular resistance and arterial pressure. The hyperdynamic circulatory syndrome is due to arterial vasodilation that mainly occurs in the splanchnic circulation, while vascular resistance in the other circulatory districts is normal or increased, accordingly with the degree of portal hypertension, liver impairment and activation of the renin-aldosterone and sympathetic nervous system. The mechanism(s) leading to splanchnic vasodilation is unclear. A favored hypothesis translocation of intestinal bacteria and/or some their products, such as endotoxin, into the interstitial space in the splanchnic organs results in the local release of vasodilating factors such as nitric oxide, carbon monoxide and others.     

一氧化氮与肝硬化门脉高压高动力循环的关系

目的 :研究肝硬化门脉高压血清NO水平与血流动力学改变之间的关系。方法 :用比色法检测35例肝硬化病人和 2 5例正常人血清NO浓度 ,用彩色多普勒检测肝硬化组及正常组门静脉横径及门静脉血流量。结果 :肝硬化门脉高压患者血清NO显著升高。结论 :检测血清NO可作为判断肝硬化门脉高压的指标 ,血清NO在高动力循环中起重要作用     

Mice with targeted deletion of eNOS develop hyperdynamic circulation associated with portal hypertension

Systemic vasodilation is the initiating event of the hyperdynamic circulatory state, being most likely triggered by increased levels of vasodilators, primarily nitric oxide (NO). Endothelial NO synthase (eNOS) is responsible for this event. We tested the hypothesis that gene deletion of eNOS and inducible NOS (iNOS) may inhibit the development of the hyperdynamic circulatory state in portal hypertensive animals. To test this hypothesis, we used mice lacking eNOS (eNOS-/-) or eNOS/iNOS (eNOS/iNOS-/-) genes. A partial portal vein ligation (PVL) was used to induce portal hypertension. Sham-operated animals were used as a control. Hemodynamic characteristics were tested 2 wk after surgery. As opposed to our hypothesis, PVL also caused significant reduction in peripheral resistance in eNOS-/- compared with sham animals (0.33 +/- 0.02 vs. 0.41 +/- 0.03 mmHg. min x kg body wt x ml(-1); P = 0.04) and in eNOS/iNOS-/- animals with PVL compared with that of the sham-operated group (0.44 +/- 0.02 vs. 0.54 +/- 0.04; P = 0.03). This demonstrates that, despite gene deletion of eNOS, the knockout mice developed hyperdynamic circulation. Compensatory vasodilator molecule(s) are upregulated in place of NO in the systemic and splanchnic circulation in portal hypertensive animals.     

Cardiovascular response to acute hypovolemia in relation to age. Implications for orthostasis and hemorrhage

Venous compliance in the legs of aging man has been found to be reduced with decreased blood pooling (capacitance response) in dependent regions, and this might lead to misinterpretations of age-related changes in baroreceptor function during orthostasis. The hemodynamic response to hypovolemic circulatory stress was studied with the aid of lower-body negative pressure (LBNP) of 60 cmH(2)O in 33 healthy men [18 young (mean age 22 yr) and 15 old (mean age 65 yr)]. Volumetric technique was used in the study of capacitance responses in the calf and arm as well as transcapillary fluid absorption in the arm. LBNP led to smaller increase in heart rate (P < 0.001) and peripheral resistance (P < 0.01) and reduced transcapillary fluid absorption in the arm (P < 0.05) in old subjects. However, blood pooling in the calf was reduced in old subjects (1.66 +/- 0.10 vs. 2.17 +/- 0.13 ml/100 ml tissue; P < 0. 01). Accordingly, during similar blood pooling in the calf (LBNP 80 cmH(2)O in old subjects), no changes in cardiovascular reflex responses with age were found. The capacitance response in the arm (mobilization of peripheral blood to the central circulation) was still reduced, however (0.67 +/- 0.10 vs. 1.37 +/- 0.11 ml/100 ml tissue; P < 0.01). Thus the reduced cardiovascular reflex response found in the elderly during orthostatic stress seems to be caused by a reduced capacitance response in the legs with age and a concomitant smaller central hypovolemic stimulus rather than a reduced efficiency of the reflex response. With similar hypovolemic circulatory stress, no changes in cardiovascular reflex responses are seen with age. The capacitance response in the arm (mobilization of peripheral blood toward the central circulation) is reduced, however, by approximately 50% in the elderly. This might seriously impede the possibility of survival of an acute blood loss.     

Renal blood flow in heart failure patients during exercise

During exercise, reflex renal vasoconstriction maintains blood pressure and helps in redistributing blood flow to the contracting muscle. Exercise intolerance in heart failure (HF) is thought to involve diminished perfusion in active muscle. We studied the temporal relationship between static handgrip (HG) and renal blood flow velocity (RBV; duplex ultrasound) in 10 HF and in 9 matched controls during 3 muscle contraction paradigms. Fatiguing HG (protocol 1) at 40% of maximum voluntary contraction led to a greater reduction in RBV in HF compared with controls (group main effect: P <0.05). The reduction in RBV early in HG tended to be more prominent during the early phases of protocol 1. Similar RBV was observed in the two groups during post-HG circulatory arrest (isolating muscle metaboreflex). Short bouts (15 s) of HG at graded intensities (protocol 2; engages muscle mechanoreflex and/or central command) led to greater reductions in RBV in HF than controls (P <0.03). Protocol 3, voluntary and involuntary biceps contraction (eliminates central command), led to similar increases in renal vasoconstriction in HF (n=4). Greater reductions in RBV were found in HF than in controls during the early phases of exercise. This effect was not likely due to a metaboreflex or central command. Thus our data suggest that muscle mechanoreflex activity is enhanced in HF and serves to vigorously vasoconstrict the kidney. We believe this compensatory mechanism helps preserve blood flow to exercising muscle in HF.     

Facial cooling-induced bradycardia does not slow pulmonary V.O2 kinetics at the onset of high-intensity exercise.

The mechanism(s) underlying the attenuation of the slow component of pulmonary O2 uptake (Vo2) by prior heavy-intensity exercise is (are) poorly understood but may be ascribed to either an intramuscular-metabolic or a circulatory modification resulting from "priming" exercise. We investigated the effects of altering the circulatory dynamics by delayed vagal withdrawal to the circulation induced by the cold face stimulation (CFS) on the Vo2 kinetics during repeated bouts of heavy-intensity cycling exercise. Five healthy subjects (aged 21-43 yr) volunteered to participate in this study and initially performed two consecutive 6-min leg cycling exercise bouts (work rate: 50% of the difference between lactate threshold and maximal Vo2) separated by 6-min baseline rest without CFS as a control (N1 and N2). CFS was then applied separately, by gel-filled cold compresses to the face for 2-min spanning the rest-exercise transition, to each of the first bout (CFS1) or second bout (CFS2) of repeated heavy-intensity exercise. In the control protocol, Vo2 responses in N2 showed a facilitated adaptation compared with those in N1, mainly attributable to the reduction of slow component. CFS application successfully slowed and delayed the heart rate (HR) kinetics (P < 0.05) on transition to exercise [HR time constant; N1: 55.6 +/- 16.0 (SD) vs. CFS1: 69.0 +/- 12.8 s and N2: 55.5 +/- 11.8 vs. CFS2: 64.0 +/- 17.5 s]; however, it did not affect the "primary" Vo2 kinetics [Vo2 time constant; N1: 23.7 +/- 7.9 (SD) vs. CFS1: 20.9 +/- 3.8 s, and N2: 23.3 +/- 10.3 vs. CFS2: 17.4 +/- 6.3 s]. In conclusion, increased vagal withdrawal delayed and slowed the circulatory response but did not alter the Vo2 kinetics at the onset of supra-lactate threshold cycling exercise. As the facilitation of Vo2 subsequent to prior heavy leg cycling exercise is not attenuated by slowing the central circulation, it seems unlikely that this facilitation is exclusively determined by a blood flow-related mechanism.     

EEG Findings of Reduced Neural Synchronization during Visual Integration in Schizophrenia

Schizophrenia patients exhibit well-documented visual processing deficits. One area of disruption is visual integration, the ability to form global objects from local elements. However, most studies of visual integration in schizophrenia have been conducted in the context of an active attention task, which may influence the findings. In this study we examined visual integration using electroencephalography (EEG) in a passive task to elucidate neural mechanisms associated with poor visual integration. Forty-six schizophrenia patients and 30 healthy controls had EEG recorded while passively viewing figures comprised of real, illusory, or no contours. We examined visual P100, N100, and P200 event-related potential (ERP) components, as well as neural synchronization in the gamma (30-60 Hz) band assessed by the EEG phase locking factor (PLF). The N100 was significantly larger to illusory vs. no contour, and illusory vs. real contour stimuli while the P200 was larger only to real vs. illusory stimuli; there were no significant interactions with group. Compared to controls, patients failed to show increased phase locking to illusory versus no contours between 40-60 Hz. Also, controls, but not patients, had larger PLF between 30-40 Hz when viewing real vs. illusory contours. Finally, the positive symptom factor of the BPRS was negatively correlated with PLF values between 40-60 Hz to illusory stimuli, and with PLF between 30-40 Hz to real contour stimuli. These results suggest that the pattern of results across visual processing conditions is similar in patients and controls. However, patients have deficits in neural synchronization in the gamma range during basic processing of illusory contours when attentional demand is limited.     

Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiotensin-converting enzyme inhibition

Acute physiological hyperinsulinemia increases skeletal muscle capillary blood volume (CBV), presumably to augment glucose and insulin delivery. We hypothesized that insulin-mediated changes in CBV are impaired in type 2 diabetes mellitus (DM) and are improved by angiotensin-converting enzyme inhibition (ACE-I). Zucker obese diabetic rats (ZDF, n = 18) and control rats (n = 9) were studied at 20 wk of age. One-half of the ZDF rats were treated with quinapril (ZDF-Q) for 15 wk prior to study. CBV and capillary flow in hindlimb skeletal muscle were measured by contrast-enhanced ultrasound (CEU) at baseline and at 30 and 120 min after initiation of a euglycemic hyperinsulinemic clamp (3 mU.min(-1).kg(-1)). At baseline, ZDF and ZDF-Q rats were hyperglycemic and hyperinsulinemic vs. controls. Glucose utilization in ZDF rats was 60-70% lower (P < 0.05) than in controls after 30 and 120 min of hyperinsulinemia. In ZDF-Q rats, glucose utilization was impaired at 30 min but similar to controls at 120 min. Basal CBV was lower in ZDF and ZDF-Q rats compared with controls (13 +/- 4, 7 +/- 3, and 9 +/- 2 U, respectively). With hyperinsulinemia, CBV increased by about twofold in control animals at 30 and 120 min, did not change in ZDF animals, and increased in ZDF-Q animals only at 120 min to a level similar to controls. Anatomic capillary density on immunohistology was not different between groups. We conclude that insulin-mediated capillary recruitment in skeletal muscle, which participates in glucose utilization, is impaired in animals with DM and can be partially reversed by chronic ACE-I therapy.     

Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response

The hepatic arterial buffer response (HABR) effectively controls total blood perfusion in normal livers, but little is known about blood flow regulation in cirrhosis. We therefore studied the impact of HABR on blood perfusion of cirrhotic livers in vivo. After 8-wk CCl(4) treatment to induce cirrhosis, 18 anesthetized rats (and 18 noncirrhotic controls) were used to simultaneously assess portal venous and hepatic arterial inflow with miniaturized ultrasonic flow probes. Stepwise hepatic arterial blood flow (HAF) or portal venous blood flow (PVF) reduction was performed. Cirrhotic livers revealed a significantly reduced total hepatic blood flow (12.3 +/- 0.9 ml/min) due to markedly diminished PVF (7.3 +/- 0.8 ml/min) but slightly increased HAF (5.0 +/- 0.6 ml/min) compared with noncirrhotic controls (19.0 +/- 1.6, 15.2 +/- 1.3, and 3.8 +/- 0.4 ml/min). PVF reduction caused a significant HABR, i.e., increase of HAF, in both normal and cirrhotic livers; however, buffer capacity of cirrhotic livers exceeded that of normal livers (P < 0.05) by 1. 7- to 4.5-fold (PVF 80% and 20% of baseline). Persistent PVF reduction for 1, 2, and 6 h demonstrated constant HABR in both groups. Furthermore, HABR could be repetitively provoked, as analyzed by intermittent PVF reduction. HAF reduction did not induce changes of portal flow in either group. Because PVF is reduced in cirrhosis, the maintenance of HAF and the preserved HABR must be considered as a protective effect on overall hepatic circulation, counteracting impaired nutritive blood supply via the portal vein.     

Abnormal Fas/FasL and caspase-3-mediated apoptotic signaling pathways of T lymphocyte subset in patients with systemic lupus erythematosus

OBJECTIVES: To explore the relationships between Fas-FasL-mediated signaling pathway and apoptosis disturbance of T lymphocyte subset in patients with SLE. METHODS: Flow cytometry was used to determine the percentage of apoptotic lymphocytes and necrotic lymphocytes by AnnexinV-FITC/PI double staining. Cell surface expression rates of Fas, FasL, and intracellular expression rates of activated caspase-3 were evaluated by two-color flow cytometry analysis in peripheral T lymphocyte subsets of SLE patients with inactive disease (n=22) and with active disease (n=17). The serum concentration of anti-nucleosome antibodies in SLE patients were assayed by ELISA immunoassay methods. Health volunteers (n=13) served as controls. RESULTS: The percentage of early apoptotic cells was enhanced in patients with active disease (P=0.001, vs. control) and in patients with inactive disease (P=0.004, vs. control). Compared with health control, the percentage of necrotic cells was significant higher in patients with active disease (P=0.001). The percentages of CD4(+)T cells expressing Fas (P=0.023, vs. control) and FasL (P=0.001, vs. control) were increased in patients with active disease. But there were no obvious differences of expression rates of Fas and FasL on T cell subset between two disease groups (P>0.05). In patients with active disease the percentage of CD4(+)T cells or CD8(+)T cells expressing intracellular activated caspase-3 significantly increased compared to inactive disease patients (P=0.018, P=0.027, respectively) and health controls (P=0.001, P=0.001, respectively). The serum concentration of anti-nucleosome antibodies was strikingly higher in patients with active disease (P=0.002, vs. patients with inactive disease; P=0.001, vs. control, respectively), however, the serum concentration of anti-nucleosome antibodies was not obviously different between patients with inactive disease and health control group (P=0.473). The percentage of apoptotic cells correlated with the serum concentration of anti-nucleosome antibodies in SLE patients (r(s)=0.350, P=0.031). CONCLUSIONS: Apoptosis of T lymphocyte subset in SLE patients increases. CD4(+)T cells are a state of active apoptosis. Fas/FasL-mediated apoptotic pathways are especially important for CD4(+)T cells undergoing apoptosis in SLE patients with active disease. Increased Fas expression results in a higher susceptibility to Fas-mediated apoptosis, which contributes to the increased levels of intracellular activated caspase-3 and accelerates apoptosis of T lymphocytes. The degree of lymphocytic apoptosis disturbance correlates with the level of anti-nucleosome antibodies in the circulation. Acceleration of lymphocytic apoptosis plays important roles in immune pathologic injury and immune regulation dysfunction.     

Control of cerebral blood velocity with furosemide-induced hypovolemia and upright tilt

The purpose of this study was to test the hypothesis that exacerbated reductions of cerebral blood velocity (CBV) during upright tilt with dehydration are associated with impaired cerebrovascular control. Nine healthy men were tilted head-up (HUT) to 70° for 10 min on two occasions separated by 7 days under euhydration (EUH) and dehydration (DEH; 40 mg of furosemide and water restriction) conditions. Beat-by-beat arterial pressures and CBV were measured during a 5-min supine baseline and during the first (T1) and last (T2) 5 min of HUT. Cerebral autoregulation and arterial baroreflex sensitivity were assessed in the frequency domain with cross-spectral techniques. DEH reduced plasma volume by 10% (P = 0.008) and supine mean CBV (CBV(mean)) by 11% (P = 0.002). Mean arterial pressure (MAP), stroke volume, and baroreflex sensitivity decreased during HUT (P ≤ 0.002), but absolute reductions were similar between hydration conditions, with the exception of stroke volume, which was lower at T1 during DEH than EUH (P = 0.04). CBV(mean) during DEH was lower (7 cm/s) over the course of the entire 10 min of HUT (P ≤ 0.004) than during EUH. Low-frequency oscillations (0.07-0.2 Hz) of MAP and CBV(mean) and MAP-CBV(mean) coherence were higher during DEH than EUH at T1 (P ≤ 0.02), but not at T2. Our results suggest that increased coherence between arterial pressure and CBV with the combination of DEH and HUT are indicative of altered cerebrovascular control. Increased CBV oscillations with DEH may reflect acute protective mechanisms to ensure adequate cerebral perfusion under conditions of reduced central blood volume.