Age-matched Normal Control Subjects Research Articles

Increased expression of non-functional killer inhibitory receptor CD94 in CD8+ cells of myeloma patients.

Different MHC class I-specific killer inhibitory receptors (KIRs) are expressed in vivo by a minor fraction of activated memory CD8+ cells. It has been postulated that KIRs may 'fine-tune' specific responses by altering their threshold of activation by the TCR-CD3 complex. We have previously shown that, in multiple myeloma (MM) patients, a large fraction of peripheral blood CD8+ cells display the phenotype of chronically activated memory T cells (CD38+, HLA-DR+, CD25-, CD45R0+, CD28-). We investigated the expression of KIRs on MM T cells and determined their possible influence on cytolytic responses elicited via the CD3-TCR complex. The expression of CD94, a molecule that is part of a heterodimeric KIR recognizing the non-classical MHC surface HLA-E molecule, was almost threefold higher in MM T cells than in age-matched normal control subjects (P < 0.0001). CD94 expression was preferentially confined to CD8+ cells but not restricted to activated (HLA-DR+) and/or memory (CD45R0+) T cells. Unlike normal T cells, in which CD94 is assembled with glycoproteins of the NKG2 family to form functional receptors with activating or inhibitory properties, most CD94+ MM T cells were devoid of both the NKG2-A and NKG2-C glycoproteins detected in the inhibitory or activating form respectively. CD94 blockade did not significantly affect either T-cell proliferation or cytotoxic T-lymphocyte generation induced by the myeloma-derived cell lines NCI and RPMI 8226. Similarly, the cytolytic activity induced by direct anti-CD3-mediated targeting of MM T cells to FCR+ P815 target cells was unaffected by the addition of anti-CD94 and/or anti-NKG2-A/C monoclonal antibodies (mAbs). These data indicate that the large majority of MM CD8+ cells do not express a functional CD94 receptor. Thus, their ability to 'fine-tune' an appropriate immune response against tumour cells can be impaired.

Glucose Hypometabolism and Neuropathological Correlates in Brains of Dementia with Lewy Bodies

Cerebral glucose metabolism using positron emission tomography (PET) with 18F-fluorodeoxyglucose was examined in 11 patients with probable Alzheimer's disease (AD), 6 patients with probable, and 1 patient with autopsy-confirmed dementia with Lewy bodies (DLB) as well as in 10 age-matched normal control subjects. Among widespread cortical regions showing glucose hypometabolism in the DLB group, the metabolic reduction was most pronounced in the visual association cortex compared to that in the AD group. Using a metabolic ratio of 0.92 in the visual association cortex as a cutoff (mean-2 SD of normal control subjects), DLB could be distinguished from AD with a sensitivity of 86% and a specificity of 91%. In contrast, apolipoprotein E4 allele frequency and cerebrospinal fluid tau levels did not differ significantly between the two groups. In order to further dissect out neuropathological correlates of the dysfunctional occipital lobe, postmortem brains from 19 patients with AD and 17 with DLB as well as 11 brains from normal controls were examined. A distinct and extensive spongiform change with coexisting gliosis was variably noted throughout cerebral white matter with relative sparing of gray matter in DLB. Notably, the white matter spongiform change and gliosis was most prominently and consistently found in the occipital region of DLB, and the severity of the spongiform change in each brain region generally paralleled to the regional difference in reduced glucose metabolism between the living AD and DLB patients. These findings suggest that (1) among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the occipital cortex may be an informative diagnostic aid to distinguish DLB from AD; and (2) a pathological process that generates widespread spongiform change and gliosis in long projection fibers may contribute, at least in part, to the characteristic imaging features of DLB.

Impaired prepulse inhibition of acoustic startle in schizophrenia

Background: Schizophrenics show deficits in sensorimotor gating, as measured by prepulse inhibition of acoustic startle (PPI). The goal of this investigation is to further characterize PPI and habituation deficits in schizophrenia, and to examine whether differing subgroups of schizophrenics would show comparable PPI deficits. Methods: PPI was measured in 24 male schizophrenic subjects (9 acutely decompensated inpatients and 15 stable outpatients) and in 20 age-matched normal control subjects. Schizophrenic subjects were rated for positive and negative symptoms at the time of testing. Results: Schizophrenic subjects showed deficits in prepulse inhibition and habituation as compared to normal subjects. Similar latency facilitation was produced by the prepulse in both groups. Acutely decompensated inpatients and stable outpatients did not differ in percent PPI. PPI did not correlate with severity of positive or negative symptoms. Conclusions: These results suggest that schizophrenic subjects have impaired central inhibitory mechanisms as measured by PPI, and support the hypothesis that periods of relative clinical remission are not accompanied by normalization of sensorimotor gating.

Dissociation of smooth pursuit and vestibulo-ocular reflex cancellation in SCA-6

To study gaze in SCA-6 patients during pursuit and passive whole-body rotation. Smooth pursuit and vestibularly induced eye movements interact to maintain the accuracy of eye movements in space (i.e., gaze). Previous studies have implicated the cerebellum, particularly the floccular lobe and dorsal vermis, in the control of gaze velocity during pursuit and vestibulo-ocular reflex (VOR) cancellation. SCA-6 has recently been identified genetically and characterized as pure cerebellar ataxia that affects the cerebellar cortex selectively. Using infrared oculography, eye movements of five SCA-6 patients and five age-matched normal control subjects were recorded during sinusoidal pursuit and passive whole-body rotation in the horizontal plane (amplitude, +/- 10 deg; frequency, 0.2 Hz). Eye and gaze gain (eye and gaze velocity/stimulus velocity) were calculated after deleting saccades. Eye gain of all SCA-6 patients during pursuit was significantly lower than those of the control subjects (mean +/- SD, 0.26+/-0.06 versus 0.91+/-0.07). In contrast, eye gain of the patients was not significantly different from that of the control subjects either during VOR cancellation, when the subjects tracked a target that moved with the same amplitude and phase, like a chair (0.21+/-0.05 versus 0.12+/-0.07), or during visually enhanced VOR (x1), when the target remained stationary in space (0.85+/-0.06 versus 0.95+/-0.05). Moreover, there was no significant difference in mean VOR gain in total darkness between the two groups. Gaze gain of patients (0.26+/-0.06 versus 0.81+/-0.06) but not control subjects (0.91+/-0.07 versus 0.88+/-0.08), was significantly different during pursuit and VOR cancellation. SCA-6 patients show dissociation in the control of gaze tracking during smooth pursuit and VOR cancellation.

Mechanisms of blood pressure alterations in response to the Valsalva maneuver in postural tachycardia syndrome.

The postural tachycardia syndrome (POTS) is characterized clinically by orthostatic lightheadedness and tachycardia. When these patients perform a Valsalva maneuver, there is an excessive blood pressure increment after cessation of the maneuver (phase IV) that is sometimes associated with headaches. It is not known whether excessive phase IV is due to excessive peripheral vascular tone (an alpha-adrenergic mechanism) or is a manifestation of increased beta-adrenergic tone (hyperadrenergic state). The authors undertook a pharmacologic study evaluating the effect of intravenous phentolamine (alpha-adrenergic antagonist) and propranolol (beta-adrenergic antagonist) on the different phases of the Valsalva maneuver in a group of patients with POTS and age-matched normal control subjects. Patients with POTS had mean phases, when compared with controls, that were characterized by more negative II_E (p = 0.07), smaller II_L (p = 0.04), and significantly larger phase IV (p = 0.001). The effect of phentolamine was qualitatively and quantitatively different in POTS when compared with controls. Ten mg phentolamine in controls resulted in a significant accentuation of phase II_E (p = 0.001), attenuation of phase II_L (p = 0.002), and increase of phase IV (57.6 vs 30.7 mm Hg; p = 0.025). These changes resembled those of patients with POTS at baseline. In patients with POTS, the phase II abnormalities, already present, were further accentuated (p <0.001), and phase IV became smaller (50.6 vs 73.8 mm Hg; p = 0.09). Propranolol had no significant effect on phases II_E and II_L, but significantly reduced phase IV in both controls (p <0.05) and in patients with POTS (p <0.001) and improved the headache symptoms, when present, during and after phase IV. The authors conclude that phase IV is mainly under beta-adrenergic regulation and that the exaggerated phase IV in POTS is a result of a hyperadrenergic state.

PLATELET PAROXETINE BINDING TO 5-HT UPTAKE SITES IN ELDERLY PATIENTS WITH ALZHEIMER's DISEASE WITH AGITATION AND AGGRESSION

Introduction: Currently a large body of literature supports the relationship between aggression and serotoninergic dysfunction. Furthermore, patients with AD have well-established findings regarding pathology in the serotoninergic system at the Central Nervous System level (Andersson et al. 1991.) The authors' (Mintzer et al.1998) and others (Lanctot et al. 1997) challenge data supports the presence of serotoninergic dysfunction in agitated (Mintzer et al. 1998) and agitated/aggressive AD patients (Lanctot et al. 1997). It is, however, not known if this is a state phenomenon secondary to an AD-related process or a trait phenomenon that is manifested in predisposed AD patients. This study addresses this issue by assessing 5-HT uptake sites in aggressive and nonaggressive AD patients' platelets, an organ not known to be affected by the primary AD process. Objective: Explore possible differences, specifically in binding affinity (Kd) and maximum number of binding sites (Bmax), in 5-HT uptake sites in platelets between patients with AD, AD with behavioral disturbances, and age-matched normal control subjects using [3H]paroxetine platelet binding. Methods: The authors have already recruited, rated, and obtained samples from elderly AD patients without behavioral disturbances (n=6, CMAI: 1), and 8 elderly AD subjects with agitated aggressive behaviors (n=8, CMAI: 2.96). All subjects were objectively rated for cognitive function, depression, anxiety, and behavioral symptoms. Blood samples and paroxetine binding was performed accordingly to Andersson et al. (1991) procedures. Results: All the subjects were able to tolerate the procedure. Preliminary data in the AD/Agitated group (n=5) showed a Bmax of 6,000 fmol/mg and a Kd of 0.08934 nM. In the Nonagitated group (n=4) Bmax was 4,084.5 fmol/mg and Kd was 0.056745 nM. Final data are presented by group (AD with and without behavioral disturbances and controls), and correlations are examined with disease severity.

Neutrophil migration, oxidative metabolism and adhesion in early onset periodontitis.

The aim of this study was to evaluate neutrophil function in patients suffering from the generalized form of early onset periodontitis (EOP). We investigated neutrophil migration in vivo and neutrophil superoxide production and adhesion in response to a variety of compounds; neutrophils were isolated both from blood and a skin experimental exudate of 15 patients with EOP and of 15 sex- and age-matched normal control subjects. No difference was found in neutrophil migration in vivo (71.2+/-16.4x10(6) and 68.8+/-10.7x10(6) PMN/cm2/24 h in patients affected by early onset periodontitis and normal subjects respectively) and in adhesion. The superoxide production in response to STZ and PMA was similar between the 2 groups, while superoxide production in response to fMLP was markedly lower in patients than in control subjects both in circulating neutrophils (5.6+/-2.2 versus 10.4+/-2.3 nmoles O2-/10(6) cells, p<0.0001) and in exudate neutrophils (16.3+/-4.3 versus 22.3+/-4.7 nmoles O2-/10(6) cells, p<0.005). In general, neutrophil function in patients suffering from early onset periodontitis does not differ from control subjects, suggesting that the overall defence function of these cells is normal. The only parameter that we have found to be different between the 2 groups is the low superoxide production after fMLP stimulation. The stimulus- and function-specificity of this defect in neutrophils from patients indicates the existence of a dysregulation of the signal transduction pathway distal to fMLP receptor and proximal to NADPH oxidase activation.

The circulating insulin-like growth factor system in children with coeliac disease: an additional marker for disease activity.

Chronic undernutrition resulting from coeliac disease (CD) could be associated with changes in the circulating insulin-like growth factor (IGF) system, which may participate in the pathogenesis of growth retardation occurring in these patients. We performed a cross-sectional study in CD subjects attempting to (1) document the pattern of serum IGF-I and IGF binding protein (IGFBP) 1 and 3 at diagnosis and (2) assess the response of circulating IGF system to dietary treatments, in comparison with the response of clinical and laboratory findings utilized for the diagnosis of CD. Thirty-two prepubertal CD children were divided into three groups based on the dietetic treatment: at diagnosis (D, n=18); on gluten-free diet for at least 6 months (GFD, n=7); and on gluten challenge for at least 3 months (CH, n=7). Six postpubertal CD patients were also studied at diagnosis. In prepubertal children IGF-I levels were significantly reduced (by 29%) in D vs sex- and age-matched normal control (NC) subjects, with reductions being more pronounced before 3 years of age. Likewise, serum IGFBP-3 concentrations were decreased by 22%, whereas circulating IGFBP-1 levels were increased by 60%, compared with NC, with more marked IGFBP changes in older children. Similar alterations were observed in postpubertal patients. Changes in the circulating IGF system disappeared in GFD subjects and reappeared in CH children, as positivity of disease-specific antibodies. Body mass index (BMI) also improved in GFD subjects, but did not decrease in CH children. Changes in IGF-I and IGFBPs did not correlate with each other. Levels of IGF-I, but not of IGFBPs, maintained the relation with age and correlated significantly with BMI and positivity of antibodies. These results demonstrate that CD patients show significant changes in serum IGF-I, in younger children, and IGFBPs (particularly IGFBP-1), in older children and adolescents, correlating with clinical course and response to dietary treatments. The alteration in the circulating IGF system could be implicated in the pathogenesis of growth retardation occurring in CD and may provide an additional tool in monitoring of the disease.

Aberrant plasticity in Alzheimer's disease.

Alzheimer's disease (AD) is a region-specific degenerative disease that mainly impairs the temporal and parietal lobes, with preservation of the frontal lobes until advanced stages of disease. Since [11C]diacylglycerol PET facilitates examination of loci exhibiting plasticity, it was performed in eight patients with AD and six age-matched normal control subjects to evaluate frontal lobe function. [11C]Diacylglycerol tomograms obtained from patients with AD demonstrated strong spotty incorporation of [11C]diacylglycerol mainly in the frontal association areas. However, [18F]fluorodeoxyglucose tomograms exhibited region-specific findings such as decreased CMRGIc in the parietotemporal association areas, which are involved in impairment of cognitive function. The strong spotty incorporation of [11C]diacylglycerol suggested a compensatory plastic process in the frontal lobes in response to involvement by Alzheimer's disease of the posterior association areas.

Decreased activity of the L-arginine-nitric oxide metabolic pathway in patients with congestive heart failure.

Impaired endothelium-dependent, nitric oxide (NO)-mediated vasodilation may contribute to increased vasomotor tone in patients with heart failure. Whether decreased endothelium-dependent, NO-mediated vasodilation in patients with heart failure is due to decreased synthesis or increased degradation of NO is unknown. To specifically assess the synthetic activity of the L-arginine-NO metabolic pathway, urinary excretion of [15N]nitrates and [15N]urea was determined after a primed continuous intravenous infusion of L-[15N]arginine (40 micromol/kg) in 16 patients with congestive heart failure and 9 age-matched normal control subjects at rest and during submaximal treadmill exercise. After infusion of L-[15N]arginine, 24-hour urinary excretion of [15N]nitrates was decreased in patients with congestive heart failure at rest (2.2+/-0.5 versus 8.0+/-2.3 micromol/24 h) and during submaximal exercise (2.4+/-1.2 versus 11. 4+/-4.0 micromol/24 h) compared with control subjects (both P<0.01). After infusion of L-[15N]arginine, 24-hour urinary excretions of [15N]urea at rest in patients with congestive heart failure and control subjects were not different (1.1+/-0.3 versus 1.2+/-0.2 mmol/24 h, P>0.20). A specific decrease in synthetic activity of the L-arginine-NO metabolic pathway contributes to decreased endothelium-dependent vasodilation in patients with congestive heart failure.

Cerebrospinal Fluid Tau Protein Levels in Demented and Nondemented Alcoholics

The tau protein levels in cerebrospinal fluid (CSF-tau) were examined in 27 patients with alcohol dependence (20 demented and 7 nondemented), 36 age and dementia severity-matched patients with Alzheimer's disease (AD), and 23 age-matched normal control subjects. The CSF-tau levels in the demented alcoholic group (alcohol-induced organic brain disorders, 25.4 +/- 10.2 pg/ml) was significantly lower (p < 0.0001) than that in the AD group (96.1 +/- 53.3 pg/ml), but not significantly different from that in the nondemented alcoholics (18.1 +/- 10.2 pg/ml) or the controls (19.2 +/- 12.9 pg/ml). Using a 44.9 pg/ml as a cut-off value (mean + 2 SD of the normal control group), only one patient with alcohol-induced organic brain disorders exceeded the value, whereas 3 of 36 of the AD group showed CSF-tau levels less than this level. These findings suggest that alcohol-induced organic brain disorders are a group of dementias that are characterized by normal CSF-tau levels, and that the CSF examination for tau in combination with other clinical findings may help in differentiating alcohol-induced organic brain disorders from AD.

Abnormal performance on the PD test battery by asymptomatic first-degree relatives.

To determine whether a sensitive and specific battery of tests (PD Battery) could identify a subset of asymptomatic first-degree relatives (FDRs) of PD patients who were significantly more impaired than age-matched normal control (NC) subjects. The PD Battery incorporates tests of motor function, olfaction, and mood. In previous studies, it has shown high specificity and sensitivity in distinguishing mildly affected PD patients from NC subjects. The PD Battery and regression analysis-derived scoring equations were applied to asymptomatic FDRs. Eighty FDRs and 100 NC subjects were tested. Of the FDRs, 22.5% scored in the abnormal range, and 9% of NC subjects had abnormal scores. This difference was statistically significant. Further analysis demonstrated that FDRs with abnormal scores on the PD Battery differed on all three components of the test battery from FDRs who had normal scores. Among the sons and daughters whose scores were abnormal, there was a much higher prevalence of the affected parent being the father. The proportion of FDRs who demonstrated abnormal performance on the PD Battery was greater than that of NC subjects. Thus, the PD Battery may detect the asymptomatic carrier state or risk for PD. Sons and daughters whose scores were in the abnormal range were more likely to have fathers with PD.

Pulmonary diffusing capacity, serum angiotensin-converting enzyme activity and the angiotensin-converting enzyme gene in Japanese non-insulin-dependent diabetes mellitus patients

We investigated the independent change in pulmonary diffusing capacity (DLCO) as one manifestation of pulmonary microangiopathy and to analyze the correlation between DLCO and serum ACE. We also examined the association between DLCO and the ACE genes. We examined pulmonary functions, especially %DLCO/VA (DLCO corrected by alveolar volume, percent predicted) in 54 NIDDM patients and 34 age-matched normal control subjects. Subjects were subdivided according to the degree of retinopathy. Serum ACE level was assayed by a colorimetric method in 54 patients and an insertion/deletion polymorphism in the ACE gene was amplified using the polymerase chain reaction in 52 of the 54 patients. There was a significant reduction of %DLCO/VA (percent predicted P<0.05) in diabetic patients. In the proliferative retinopathy (PDR) group, %DLCO/VA was significantly ( P<0.05) lower than in the no diabetic retinopathy (NDR) and simple diabetic retinopathy (SDR) groups. Although the levels of serum ACE were within normal ranges in all diabetic groups, %DLCO/VA was negatively correlated with serum ACE values ( r=0.49, P<0.0002, y=−1.4 x+109.3). Differences among DD, ID and II type of the ACE gene, with respect to the incidence of abnormal values of each clinical parameter, were not significant. DLCO was significantly reduced in patients with PDR and the serum ACE was significantly related to impaired DLCO. Our study suggests the existence of microangiopathic involvement of pulmonary vessels in NIDDM patients.

Standard osteopathic manipulative treatment acutely improves gait performance in patients with Parkinson's disease.

Patients with Parkinson's disease exhibit a variety of motor deficits which can ultimately result in complete disability. The primary objective of this study was to quantitatively evaluate the effect of osteopathic manipulative treatment (OMT) on the gait of patients with Parkinson's disease. Ten patients with idiopathic Parkinson's disease and a group of eight age-matched normal control subjects were subjected to an analysis of gait before and after a single session of an OMT protocol. A separate group of 10 patients with Parkinson's disease was given a sham-control procedure and tested in the same manner. In the treated group of patients with Parkinson's disease, statistically significant increases were observed in stride length, cadence, and the maximum velocities of upper and lower extremities after treatment. There were no significant differences observed in the control groups. The data demonstrate that a single session of an OMT protocol has an immediate impact on Parkinsonian gait. Osteopathic manipulation may be an effective physical treatment method in the management of movement deficits in patients with Parkinson's disease.

Retinal blood flow measurements in branch retinal vein occlusion using scanning laser doppler flowmetry

PURPOSE: To determine capillary blood flow measurements in eyes with branch retinal vein occlusion using a scanning laser Doppler flowmeter. METHODS: Retinal capillary blood flow in branch retinal vein occlusion areas and corresponding ipsilateral nonbranch retinal vein occlusion areas, 11 equivalent areas of the contralateral fellow eye of 12 consecutive untreated branch retinal vein occlusion patients, and 16 eyes of 11 age-matched normal control subjects were measured with scanning laser Doppler flowmetry. A template consisting of eight squares, each with a field of 100 × 100 μm (10 × 10 pixel) with space interval of 500 μm equidistant horizontally and vertically was used to obtain blood flow measurements in all subjects. Mean blood volume, flow, and velocity were obtained by averaging the mean values measured in each field. We avoided measurement over large retinal vessels to prevent the aliasing artifact of blood cells from moving faster than the sampling frequency. RESULTS: Branch retinal vein occlusion areas have significantly decreased microvascular blood volume ( P = .0009), flow ( P = .02), and velocity ( P = .016) compared with ipsilateral nonbranch retinal vein occlusion areas in the same eye. Branch retinal vein occlusion areas also have decreased blood volume ( P = .001), flow ( P = .0042), and velocity ( P = .0044) compared with areas of contralateral fellow eyes of branch retinal vein occlusion subjects. Branch retinal vein occlusion areas have significantly decreased blood volume ( P = .0012), flow ( P = .008), and velocity ( P = .02) compared with age-matched normal areas. CONCLUSION: Average retinal blood volume, flow, and velocity in areas of branch retinal vein occlusion are significantly lower than in healthy retinas. The ability to noninvasively measure hemodynamic changes in the retinal capillary bed may be relevant to development of new therapies for retinovascular disease.

Influence of residual insulin secretion and duration of diabetes mellitus on the control of luteinizing hormone secretion in women.

The aim of the present study was to establish whether the persistence of residual beta-cell activity after long-term diabetes mellitus (DM) exerts a protective role on luteinizing hormone (LH) secretion. The LH responses to stimulation with gonadotropin-releasing hormone (Gn-RH) (100 microg in an i.v. bolus) or naloxone (4 mg injected in an i.v. bolus, followed by the constant infusion of 8 mg in 2 h) were measured in C-peptide-positive (CpP) and C-peptide-negative (CpN) normally menstruating women with short-term (group 1 < 3 years, CpP n = 11, CpN n = 11) or long-term (group 2 > 10 years, CpP n = 11, CpN n = 11) DM and in age-matched normal control subjects (n = 11). Gn-RH induced significant increments in LH secretion in all groups. Significant LH responses to naloxone were observed in all groups, except in group 2 CpN patients. However, the LH response to either Gn-RH or naloxone was significantly lower in group 1 CpN, group 2 CpP and group 2 CpN patients than in the normal control subjects. Furthermore, the LH response was significantly lower in group 2 CpP than in group 1 CpP patients and in group 2 CpN than in group 1 CpN subjects. These results indicate a role for both deficiency in residual endogenous insulin secretion and duration of diabetes in the derangement of LH secretory control. The data suggest that the protective role exerted by residual beta-cell activity on LH secretion during the early years of DM diminishes with time elapsed after the onset of diabetes mellitus.

Cerebral accompaniments to simple and choice reaction tasks in Parkinson's disease

In order to clarify the nature and basis of the delayed reaction time that occurs in Parkinson's disease, we measured reaction times and cerebral responses in six parkinsonian patients and six normal age-matched control subjects. Each participated in one simple reaction task and three choice reaction tasks of different complexity. The reaction times were delayed in the parkinsonian patients in all conditions but especially in the more difficult choice tasks. In addition, the cerebral responses showed delayed latencies of the N1, N2, and P3 components of the event-related cerebral potential. These findings are similar to the changes that we observed previously in patients with both Parkinson's disease and dementia, and suggest that bradyphrenia may account, in part, for the slowing of response time in Parkinson's disease.

Insulin-Mediated Venodilation Is Impaired in Patients With High Cholesterol

Recently we have reported that insulin attenuates norepinephrine (NE)-induced vasoconstriction via a cyclic GMP-NO synthase pathway. Because hypercholesterolemia has been associated with abnormal endothelial function, we investigated whether insulin-mediated vasodilation is impaired in hypercholesterolemia. To assess vasoreactivity, NE (12.5, 25, 50, and 100 ng/min), NE (100 ng/min) combined with insulin (8, 16, 24, and 32 microU/min), and NE (100 ng/min) combined with sodium nitroprusside (0.01, 0.1, 1, 10, and 100 ng/min) were infused into dorsal hand veins. Changes in venous diameter were measured by ultrasonography, using a 7.5-MHz transducer. Twenty-two healthy, normotensive hypercholesterolemic subjects (HC; mean total cholesterol 6.93 mmol/L, HDL 1.45 mmol/L, LDL 4.81 mmol/L) and 18 age-matched normal control subjects (NC; mean total cholesterol 4.81 mmol/L, HDL 1.16 mmol/L, LDL 3.18 mmol/L) were studied. All HC had normal glucose tolerance test results. Baseline vein diameters were similar between groups, and the vasoconstrictor response to NE was not significantly different between HC and NC. Insulin significantly attenuated NE-induced vasoconstriction in NC but not in HC (P<0.01). Both groups were able to venodilate with sodium nitroprusside. To investigate the effects of cholesterol reduction on vascular reactivity, venoreactivity studies were repeated in 12 HC after treatment with 20 to 40 mg/d lovastatin for 6 weeks. There were no significant venoreactivity changes with the treatment. Plasma LDL cholesterol concentration was inversely correlated to venodilator effect of insulin (r=-0.42, P<0.02). In conclusion, insulin-mediated vasodilation is impaired in patients with high cholesterol. Absence of normal insulin-mediated but not sodium nitroprusside-induced venodilation in hypercholesterolemia suggests that insulin-mediated vasodilation is endothelium dependent.

Cardiac Output Responses During Exercise in Volume-Expanded Heart Transplant Recipients

The mechanisms responsible for immediate adjustments in cardiac output at onset of exercise, in the absence of neural drive, are not well defined in heart transplant (HT) recipients. Seven male HT recipients (mean ± SD 57 ± 6 years) and 7 age-matched sedentary normal control subjects (mean age 57 ± 5 years) performed constant load cycle exercise at 40% of peak power output (Watts). Cardiac output and plasma norepinephrine were determined at rest and every 30 seconds during the first 5 minutes of exercise and at minutes 6, 8, and 10. All subjects were admitted to the General Clinical Research Center for determination of plasma volume. After 3 days of equilibration to a controlled and standardized diet, plasma volume was measured using a modified Evans Blue Dye (T-1824) dilution technique. Heart rate at rest was higher in the HT group (105 ± 12 vs 74 ± 6 beats/min), but during submaximum exercise, heart rates in the control group increased more rapidly (p ≤0.05) and to a greater magnitude (54 ± 7% vs 17 ± 4% above rest). Stroke volume at rest was lower in HT recipients (45 ± 4 vs 68 ± 9 ml) but was significantly augmented immediately after onset of exercise (30 seconds) and the relative increase was greater than controls at peak exercise (61% vs 38% greater than baseline). Cardiac output at rest was within the normal range in both groups (4.58 ± 0.27 vs 4.94 ± 0.40 L/min). Relative increases in cardiac output were similar (p ≥0.05) for the HT (106 ± 12%) and control groups (97 ± 10%). Plasma norepinephrine did not become significantly greater than resting values until approximately 4 minutes after onset of exercise in both groups. Blood volume, normalized for body weight, was 12% greater in the HT group. Thus, HT recipients with expanded blood volume (12%) augment stroke volume immediately after the onset of exercise. Plasma norepinephrine levels contribute negligibly to the rapid adjustment in cardiac output. Rather, we speculate that abrupt on-transit increases in stroke volume are due to augmented venous return, secondary to expanded blood volume.

Reduced Levels of Norepinephrine Transporters in the Locus Coeruleus in Major Depression

The norepinephrine transporter (NET) is a membrane protein responsible for termination of the action of synaptic norepinephrine and is a site of action of many drugs used to treat major depression. The present study determined whether the binding of [3H]nisoxetine to the NET is altered in the locus coeruleus (LC) in major depression, using brain tissue collected postmortem from subjects diagnosed with major depression and from age-matched normal control subjects. Thirteen of the 15 major depressive subjects studied died by suicide. The distribution of [3H]nisoxetine binding along the rostro-caudal axis of the nucleus was uneven and was paralleled by a similar uneven distribution of neuromelanin-containing cells in both major depressives and psychiatrically normal control subjects. The binding of [3H]nisoxetine to NETs in the midcaudal portion of the LC from major depressive subjects was significantly lower than that from age-matched, normal control subjects. The binding of [3H]nisoxetine to NETs in other regions of the LC was similar in major depressives and control subjects. In contrast to reductions in binding to NETs, there were no significant differences in the number of noradrenergic cells at any particular level of the LC between major depressives and normal control subjects. The decreased binding of [3H]nisoxetine to NETs in the LC in major depression may reflect a compensatory downregulation of this transporter protein in response to an insufficient availability of its substrate (norepinephrine) at the synapse.