Maintained exercise pressor response in heart failure

The impact of forearm blood flow limitation on muscle reflex (metaboreflex) activation during exercise was examined in 10 heart failure (HF) (NYHA class III and IV) and 9 control (Ctl) subjects. Rhythmic handgrip contractions (25% maximal voluntary contraction, 30 contractions/min) were performed over 5 min under conditions of ambient pressure or with +50 mmHg positive pressure about the exercising forearm. Mean arterial blood pressure (MAP) and venous effluent hemoglobin (Hb) O2 saturation, lactate and H+ concentrations ([La] and [H+], respectively) were measured at baseline and during exercise. For ambient contractions, the increase (Delta) in MAP by end exercise (DeltaMAP; i.e., the exercise pressor response) was the same in both groups (10.1 +/- 1.2 vs. 7.33 +/- 1.3 mmHg, HF vs. Ctl, respectively) despite larger Delta[La] and Delta[H+] for the HF group (P < 0.05). With ischemic exercise, the DeltaMAP for HF (21.7 +/- 2.7 mmHg) exceeded that of Ctl subjects (12.2 +/- 2.8 mmHg) (P < 0.0001). Also, for HF, Delta[La] (2.94 +/- 0.4 mmol) and Delta[H+] (24.8 +/- 2.7 nmol) in the ischemic trial were greater than in Ctl (1.63 +/- 0.4 mmol and 15.3 +/- 2.8 nmol; [La] and [H+], respectively) (P < 0.02). Hb O2 saturation was reduced in Ctl from approximately 43% in the ambient trial to approximately 27% with ischemia (P < 0.0001). O2 extraction was maximized under ambient exercise conditions for HF but not for Ctl. Despite progressive increases in blood perfusion pressure over the course of ischemic exercise, no improvement in Hb O2 saturation or muscle metabolism was observed in either group. These data suggest that muscle reflex activation of the pressor response is intact in HF subjects but the resulting improvement in perfusion pressure does not appear to enhance muscle oxidative metabolism or muscle blood flow, possibly because of associated increases in sympathetic vasoconstriction of active skeletal muscle.     

Regional changes in cerebral haemodynamics as a result of a visual stimulus measured by near infrared spectroscopy

Near infrared spectroscopy (NIRS) is used to measure global changes in cerebral haemodynamics. We have adapted the technique to measure regional changes in response to a visual stimulus. Ten volunteers were exposed to a computer generated visual stimulus designed to activate a large area of the visual cortex, including V1, V2, V3, V4 and V5. The stimulus was on for 30 s and off for 30 s. Changes in the concentrations of oxyhaemoglobin ([HbO2]) and deoxyhaemoglobin ([Hb]) were measured using a commercial spectrometer (NIRO500), over the occipital cortex. The data were summed over ten cycles. As a control, the experiment was repeated over the frontal cortex. For each subject [HbO2] increased during stimulation, and decreased when the stimulus was off. The mean (+/- s.e.m.) change in [HbO2] was 0.54 +/0 0.14 micromol 1(-1). The change in total haemoglobin concentration, given by [HbO2] + [Hb] was 0.61 +/- 0.21 micromol 1(-1), equivalent to a rise in cerebral blood volume of 0.04 +/- 0.01 ml 100 g(-1) which is about 2% of the total cerebral blood volume. There was no significant change in [HbO2] over the frontal cortex, implying that the changes in blood volume originated in the occipital lobe. This demonstrates that NIRS provides a non-invasive method of measuring regional changes in cerebral haemodynamics as a result of visual stimulation.     

Metabolic myopathy as a cause of the exercise limitation in lung transplant recipients

BACKGROUND: Cardiopulmonary exercise (CPEx) studies of lung transplant (LTx) recipients have found low maximum oxygen consumptions because of an as yet unexplained mechanism. Although it is likely that a significant problem resides within the mitochondria, this study determines whether a defect in oxygen uptake or utilization is present. METHODS: Six LTx recipients and six age- and sex-matched, healthy control subjects were studied to assess the possibility of a mitochondrial myopathy in LTx recipients. We used standard CPEx testing in conjunction with near-infrared spectroscopy (NIRS), a noninvasive optical technique to assess peripheral oxygen uptake in exercising muscle. NIRS analyzes the absorption spectra of hemoglobin and myoglobin at 760 and 850 nm to determine the relative oxygen saturation of these compounds during exercise with respect to baseline values. Relative changes in oxygen saturation are determined from the application of Beers law to changes in absorbance to compute changes in optical density (deltaOD). The LTx recipients and control subjects performed maximal noninvasive CPEx studies with NIRS analysis of the vastus lateralis muscle. RESULTS: All subjects had a circulatory limitation to exercise. The LTx group had a significantly lower percent predicted maximum oxygen consumption than the control group (45.3%+/-14% vs 100.8%+/-15.6%, [mean +/- SD] P < .001) and earlier onset of the anaerobic threshold (30.3%+/-7.6% vs 60.3%+/-8.0% of predicted VO2max, P < .0001) The LTx recipients demonstrated a significantly smaller deltaOD at maximum exercise as determined by NIRS analysis (0.024+/-0.005 deltaOD vs 0.054+/-0.03 deltaOD, P < .05). CONCLUSIONS: LTx recipients have an impaired maximal exercise capacity because of a disorder of peripheral oxygen utilization. This may be caused by a cyclosporine-induced mitochondrial myopathy.     

Enantioselective analysis of N-hydroxymexiletine glucuronide in human plasma for pharmacokinetic studies

CO2 reactivity of cerebral hemoglobin concentration was studied in 16 healthy term neonates on days 1 and 4 after birth using the near infrared spectrophotometry (NIRS) technique. The aim was to establish data on the physiological range of CO2 reactivity in healthy newborns and to investigate the influence of postnatal age on it. The CO2 reactivity measured by NIRS is expressed as the change of the total cerebral hemoglobin concentration (tHbR) per change of CO2 tension in micromol/l/kPa. We evaluated CO2 reactivity during increases and decreases of transcutaneous CO2 partial pressure and found in our methodological setting the data of the increases more reliable. In all infants but 1 we found a tHbR on day 1 with a mean value of 8.19 micromol/l/kPa (-1.39 to 18.87), in all infants on day 4 with a mean value of 9.54 micromol/l/kPa (2.76-25. 88). There is a trend to higher values between day 1 and day 4 (difference = 2.25 micromol/l/kPa; p = 0.08). The noninvasive NIRS technique enabled us to test the cerebrovascular CO2 reactivity of the tHbR for the first time in healthy term newborns. Data on its physiologic range and variability are presented and compared to findings from ventilated infants and other age groups. As the CO2 reactivity might be an indicator for infants at risk of cerebral damage, it is necessary to have data on the physiological range of this parameter.     

Non-invasive functional mapping of the human motor cortex using near-infrared spectroscopy

We applied non-invasive multisite near-infrared spectroscopy (NIRS) to assess oxygenation changes during performance of a sequential finger opposition task in five healthy human adults. Oxygenation response was localized anatomically using three-dimensional high-resolution magnetic resonance imaging (3D MRI). NIRS measurements showed a localized increase in [oxy-Hb] and a decrease in [deoxy-Hb] in all subjects. The largest response was obtained when the measurement position was over the primary motor and sensory cortex hand area. Interestingly, changes in [deoxy-Hb] seemed to be more localized than changes in [oxy-Hb]. We conclude that this simple, non-invasive and flexible optical bedside method may be used for functional brain mapping.     

Clinical utility of human polymerized hemoglobin as a blood substitute after acute trauma and urgent surgery

We have previously documented the safety of 1 unit (50 gram) of human polymerized hemoglobin (Poly SFH-P) in healthy volunteers. This report describes the first patient trial to assess the therapeutic benefit of Poly SFH-P in acute blood loss. Thirty-nine patients received 1 (n = 14), 2 (n = 2), 3 (n = 15), or 6 (n = 8) units of Poly SFH-P instead of red cells as part of their blood replacement after trauma and urgent surgery. There were no safety issues related to the infusion of Poly SFH-P. The plasma hemoglobin concentration ([Hb]) after the infusion of 6 units (300 gram) of Poly SFH-P was 4.8 +/- 0.8 g/dL (mean +/- SD). Although the red cell [Hb] fell to 2.9 +/- 1.2 g/dL, the total [Hb] was maintained at 7.5 +/- 1.2 g/dL. Poly SFH-P maintained total [Hb], despite the marked fall in red cell [Hb] due to blood loss. The utilization of O2 (extraction ratio) was 27 +/- 16% from the red cells and 37 +/- 13% from the Poly SFH-P. Twenty-three patients (59%) avoided allogeneic transfusions during the first 24 hours after blood loss. Poly SFH-P effectively loads and unloads O2 and maintains total hemoglobin in lieu of red cells after acute blood loss, thereby reducing allogeneic transfusions. Poly SFH-P seems to be a clinically useful blood substitute.     

Effects of the pH-controlled hemoglobin vesicles by CO2 gas

The hemoglobin vesicle (HbV) is a red cell substitute encapsulating purified concentrated Hb in a phospholipid vesicle. In order to improve the oxygen carrying capability of HbV, the pH value of the Hb solution should be adjusted to 7.0 in the HbV preparation, and then the pH value should be adjusted to 7.4 where HbV functions as an oxygen carrier, because the maximum value of [Hb]/[Lipid] was obtained in which the pH of the Hb solution was 7.0, and the metHb formation rate was suppressed in the pH 7.4. Generally, the pH control of the inner aqueous phase of HbV is difficult by changing the pH in the outer phase. We could control the pH of the Hb solution from 7.4 to 7.0 by dissolving CO2 into the Hb solution, and after the preparation of HbV, the pH of HbV is changed to 7.4 by reducing the pressure. The resulting pH-controlled HbV by CO2 gas showed a high [Hb]/[Lipid] value of 1.7 with a low rate of metHb formation.     

Noninvasive determination of cardiac output in patients with severe airflow limitation

The noninvasive measurement of cardiac output (Q) by the Indirect Fick CO2-rebreathing technique requires mixed venous P CO2 (P CO2) to be determined by the rebreathing maneuver, and Pa CO2 to be estimated from end-tidal P CO2 (PET CO2). Previous work has suggested that although P CO2 can be determined, Pa CO2 cannot be accurately estimated in patients with significant airflow limitation. Nineteen patients with cystic fibrosis who had severe airflow limitation (%FEV1, 29.3 +/- 7.12 SD) were studied during steady-state exercise at 50% of their measured maximal work capacity. Estimated Pa CO2 was slightly lower than Pa CO2 measured from blood samples obtained from an indwelling arterial catheter (measured: 45.2 +/- 4.92; estimate: 42.7 +/- 5.68 mm Hg). To calculate arterial blood content, the values derived from Pa CO2, pH, hemoglobin (Hb), and O2 saturation were compared with those derived from PET CO2 and O2 saturation, where (1) pH was assumed to be 7.40 and Hb was measured, and (2) pH was assumed to be 7.40 and Hb was assumed to be 15 g/dl (measured mean pH, 7.34; Hb, 14.4 g/dl). No difference in arterial CO2 content was seen between the three methods (measured: 47.53 +/- 5.17; estimate 1: 49.57 +/- 6.58; estimate 2: 49.12 +/- 6.61 ml/100 ml). As pH and Hb can also affect mixed venous CO2 content, the effect on Q was also assessed. Both estimates fit closely with measured Q (r2=0.77 and 0.76), with intercepts not different from zero and slopes not different from 1, and coefficients of variation of 13.5 and 14.6%. When viewed with regard to the confidence intervals for Q as a function of O2 consumption, Q was altered to a minor extent. We conclude that the use of PET CO2 to estimate Pa CO2 can give reasonable values for Q determined noninvasively in patients with severe airflow limitation.     

Changes in tissue oxyhaemoglobin concentration measured using multichannel near infrared spectroscopy during internal carotid angiography

OBJECTIVE: To develop an in vivo model for testing spatially resolved spectroscopy and quantified near infrared spectroscopy (NIRS) cerebral blood flow measurements. METHOD: Multiple detector NIRS has been used to study changes in tissue oxyhaemoglobin (O2Hb) concentration during selective internal carotid angiography. A significant reduction in O2Hb occurred in tissue interrogated by detectors situated between 0.7 and 4.1 cm from the NIRS light source. RESULTS: The time course of O2Hb concentration change was consistent with displacement of oxygenated blood by the radiocontrast medium from vascular beds of differing flow and NIR light attenuation. Increasing changes in O2Hb concentration per unit photon path length--predicted to occur at greater emitter-detector separations if those changes had occurred predominantly in cerebral tissue--were found in the first four seconds after injection of radiocontrast medium. However, later changes (6-10 s) were larger and were not proportional to emitter-detector separation. CONCLUSION: The findings indicate that simple assumptions regarding the distribution of the internal carotid artery blood supply to cerebral and extracerebral tissues, the photon path length through those tissues, and their relative contributions to attenuation of NIR light may not be justified.     

Myofibroblastoma of the breast revisited: an etiologic association with androgens?

In order to test the hypothesis that normal gravity is an important influence on human serum [Erythropoietin] ([Epo]), the hematologic response to 16 d of 6 degrees head-down tilt (HDT, n = 6 men) was compared with 16 d of normal gravity exposure (CON, n = 7 men). Prior to bed rest, CON and HDT subjects, respectively, were similar in the following characteristics (mean +/- SD): age = 40 +/- 3, 39 +/- 6 yr; height = 181 +/- 5, 182 +/- 6 cm; weight = 88.5 +/- 11.3, 81.7 +/- 12.0 kg; maximal oxygen consumption in supine 6 degrees head-down tilt position (VO2max) = 2.63 +/- 0.38, 2.67 +/- 0.52 L.min-1; hematocrit = (Hct) 41.6 +/- 2.4, 43.0 +/- 3.4%; hemoglobin ([Hb]) = 15.1 +/- 1.0, 14.5 +/- 1.0 g.100 ml-1; plasma volume (PV) = 3829 +/- 857, 3768 +/- 512 ml; and [Epo] = 11.6 +/- 2.9, 10.0 +/- 6.2 mU.ml-1. Calculated red cell volume (RCV) was greater in HDT than CON (2845 +/- 410 vs. 2139 +/- 253 ml, p < 0.05) at baseline. Decreases in PV (-15%, 580 ml, p < 0.05) and an insignificant decrease in RCV (-12%, 354 ml, p = 0.07) were observed in the HDT group, with a concurrent 6% increase in [Hb] (p < 0.05). PV, RCV and [Hb] remained unchanged in the CON group. [Epo] remained unchanged during HDT (12.2 +/- 3.2; 10.8 +/- 3.8; 11.2 +/- 3.1; 11.2 +/- 2.6 mU.ml-1 for HDT days 1, 2, 8 and 16, respectively). There was no difference between CON and HDT groups in [Epo] before or during HDT. It was concluded that the insignificant change (-12%) in RCV observed during HDT was insufficient to stimulate an increase in [Epo], probably because the content of oxygen in arterial blood remained unaffected. The observation that [Epo] remained unchanged despite this loss of RCV during HDT also suggests a possible decrease in the responsiveness of the erythropoietic system to [Epo].     

Detection of synaptophysin-producing cells in human thymus by immunohistochemistry and nonradioactive in situ hybridization

Hemoglobin A2 (Hb A2) and hemoglobin F (Hb F) are important analytes in the diagnosis and follow up of Hb diseases. We evaluated a new capillary zone electrophoresis (CZE) kit for Hb A2 and Hb F measurements. The imprecision ranged from 3% to 6% for Hb A2 and Hb F at physiological and pathological concentrations. The method compared well with cation-exchange HPLC for Hb A2 and Hb F and with anion-exchange chromatography in microcolumns (MAEC), for Hb A2. Nevertheless, higher results were obtained [Hb A2 CZE (%) = 1.233 Hb A2 HPLC - 0.2; Hb A2 CZE (%) = 1.190 Hb A2 MAEC + 0.1; Hb FCZE (%) = 1.118 Hb FHPLC + 0.4], and new reference values had to be determined (Hb A2 2.7-3.8%; Hb F <1.2%). Quantification of Hb A2 was not influenced by Hb S. Measurement of Hb F was accurate and precise except at low concentrations in Hb AS patients. This new CZE kit is rapid, precise, and reliable, and seems appropriate for use in clinical laboratories.     

The effect of propionyl L-carnitine on skeletal muscle metabolism in renal failure

The effect of propionyl L-carnitine on skeletal muscle metabolism in chronic renal failure. Carnitine deficiency, resulting in defective oxidative ATP synthesis, has been implicated in the myopathy of chronic renal failure. Using 31P magnetic resonance spectroscopy we examined calf muscle metabolism in 10 dialysed patients before and after 8 weeks of propionyl L-carnitine (PLC) 2 g.p.o. daily. Resting phosphocreatine/ATP (4.41 +/- 0.20 [SEM]) decreased to normal control levels on PLC (3.98 +/- 0.14; controls 4.00 +/- 0.06). In contrast, there was no effect of PLC on aerobic and anaerobic metabolism of muscle during or following 2-10 min exercise. The maximal calculated oxidative capacity (Qmax) remained below normal (28 +/- 3 mM/min before and 24 +/- 3 mM/min after PLC; controls 49 +/- 3 mM/min). Qmax correlated positively with hemoglobin concentration ([Hb]) after PLC (p < 0.03). Oxidative capacity assessed by phosphocreatine recovery T significantly improved with PLC administration (0.93 +/- 0.1 to 0.74 +/- 0.08 min) in those patients (n = 6) with [Hb] > 10 g/dl. [Hb] was rate limiting to oxidative metabolism in recovery from exercise but only following treatment with PLC. Patients with anemia or those subjects who use relatively more non-oxidatively synthesized ATP during exercise, do not respond to PLC. Oxidative metabolism did not normalize on PLC suggesting that anemia and carnitine deficiency are not the only causes of mitochondrial dysfunction in renal failure.     

Transformation of cooperative free energies between ligation systems of hemoglobin: resolution of the carbon monoxide binding intermediates

A strategy has been developed for quantitatively "translating" the distributions of cooperative free energy between different oxygenation analogs of hemoglobin (Hb). The method was used to resolve the cooperative free energies of all eight carbon monoxide binding intermediates. These parameters of the FeCOHb system were determined by thermodynamic transformation of corresponding free energies obtained previously for all species of the Co/FeCO system, i.e., where cobalt-substituted hemes comprise the unligated sites [Speros, P. C., et al. (1991) Biochemistry 30, 7254-7262]. Using hybridized combinations of normal and cobalt-substituted Hb, ligation analog systems Co/FeX (X = CO, CN) were constructed and experimentally quantified. Energetics of cobalt-induced structural perturbation were determined for all species of both the "mixed metal" Co/Fe system and also the ligated Co/FeCN system. It was found that major energetic perturbations of the Co/Fe hybrid species originate from a pure cobalt substitution effect on the alpha subunits. These perturbations are transduced to the beta subunit within the same dimeric half-tetramer, resulting in alteration of the free energies for binding at the nonsubstituted (Fe) sites. Using the linkage strategy developed in this study along with the determined energetics of these couplings, the experimental assembly free energies for the Co/FeCO species were transformed into cooperative free energies of the 10 Fe/FeCO species. The resulting values were found to distribute according to predictions of a symmetry rule mechanism proposed previously [Ackers, G. K., et al. (1992) Science 255, 54-63]. Their distribution is consistent with accurate CO binding data of normal Hb [Perrella, M., et al. (1990b) Biophys. Chem. 37, 211-223] and also with accurate O2 binding data obtained under the same conditions [Chu, A. H., et al. (1984) Biochemistry 23, 604-617].     

Contribution of PO2, P50, and Hb to changes in arteriovenous O2 content during exercise in heart failure

Arteriovenous O2 content (a-vCO2) differences increase during exercise in normal subjects through several mechanisms including PO2, O2 pressure at which hemoglobin (Hb) is half saturated with O2 (P50), and Hb concentration changes. The present study was undertaken to evaluate how much these biochemical changes are relevant to a-vCO2 difference through exercise in patients with heart failure. Twenty-seven patients with congestive heart failure [10 patients in functional class A (peak exercise O2 uptake >20 ml x kg-1 x min-1), 9 in class B (20-15 ml x kg-1 x min-1), and 8 in class C (15-10 ml x kg-1 x min-1)] underwent a cardiopulmonary exercise test with once-per-minute simultaneous blood sampling from the pulmonary and systemic arteries for determination of Hb, PO2, PCO2, pH, O2 content (CO2), Hb saturation and lactic acid (pulmonary artery only), and calculation of P50. Analysis of data was done at six exercise stages: the first at rest, the last at peak exercise, and the second to the fifth at one-, two-, three-, and four-fifths of O2 consumption increase. a-vCO2 difference at peak exercise was 14.3 +/- 2.1, 16.9 +/- 2.4, and 14.7 +/- 2.1 (SD) ml/dl in class A, B, and C patients, respectively. The contribution of Hb, P50, and PO2 changes to the increments of a-vCO2 difference during exercise was 21, 17, and 63%, respectively; the only interclass difference observed was for P50, which plays a greater role in a-vCO2 difference in class A. Hb changes act mainly at the arterial site, whereas P50 and PO2 act at the venous site. Hb increase was constant through the test, venous P50 increase was greater above anaerobic threshold, and venous PO2 reduction was most remarkable at the onset of exercise; in class C patients, no venous PO2 change was recorded in the second half of exercise. Thus a-vCO2 difference increase during exercise is notable in patients with heart failure but unrelated to the severity of the syndrome. Hb, P50, and, to the greatest degree, PO2 changes participate in the increment of a-vCO2 difference. In class C patients, the lack of PO2 reduction in the second half of exercise suggests the achievement of a "whole body critical venous PO2."     

Integration of schistosomiasis-control activities into the primary-health-care system in the Gizan region, Saudi Arabia

This study compares the effects of polyethylene glycol (PEG) modified bovine hemoglobin on vascular half-life and renal function in rabbits to those of unmodified bovine hemoglobin. Renal function was assessed by the measurement of the glomerular filtration rate, urinalysis, blood chemistries, hemoglobin (Hb) excretion rates, and tissue histology. The influence of infusion rates on hemoglobin excretion rates and organ morphology was also examined. The mean half-life of unmodified bovine hemoglobin was 3.0 +/- 0.1 (mean +/- SEM) h, which was extended 14-fold to 43.2 +/- 1.7 h following PEG conjugation. The glomerular filtration rate, urinalysis, and blood chemistries were not greatly affected by either the unmodified bovine hemoglobin or the PEG modified bovine hemoglobin. However, unmodified bovine hemoglobin did demonstrate significant hemoglobinuria (Hb excretion levels in excess of 1.0% of the infused dose [p < 0.05]) at all infusion rates given while PEG modified bovine hemoglobin did not. In addition, histological examination by light microscopy indicated that the most severe morphological changes occurred in animals that received unmodified bovine hemoglobin. This data suggests that PEG modification of bovine hemoglobin significantly reduced some of the adverse effects of bovine hemoglobin on renal physiology and morphology.     

Routine erythrocyte measurements in diagnosis of iron-deficiency anemia and thalassemia minor

A study was made of the routine electronic measurements of erythrocyte size and hemoglobin concentration in blood samples from 122 patients with decreased transferrin saturation and 66 patients with elevated levels of hemoglobin A2 or F. The medical histories of these patients were reviewed to identify 52 cases of uncomplicated iron-deficiency anemia and 39 cases of uncomplicated thalassemia minor. Four decision functions were compared for separating these two disorders. The functions evaluated were: D.F'. = MCV--[5 X Hb]-RBC; ratio MCV/RBC; ratio MCH/RBC, and RBC. The rules performed better in the uncomplicated cases than in the routine laboratory defined cases. Only minor differences in the performances of the various decision functions were observed. None was sufficiently accurate for final diagnosis, but they should have value in screening patients and in determining which additional test should be considered.     

Covalent binding of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline to albumin and hemoglobin at environmentally relevant doses. Comparison of human subjects and F344 rats

Covalent binding of the food-borne heterocyclic amine 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to albumin and hemoglobin (Hb), 3.5-6.0 hr after oral administration of a single dose of either 21.3 or 228.0 microg of [14C]MeIQx (304 and 3257 ng/kg of body weight, respectively, based on a 70-kg subject weight), was studied in human volunteers using accelerator mass spectrometry. Human protein adduct levels were compared with data obtained for male F344 rats 4.5 hr after oral administration of 0.94-11,420 ng/kg of body weight [14C]MeIQx. Dose-dependent levels of MeIQx-albumin and MeIQx-Hb adducts were detected in both humans and rats. In each case, the regression coefficient (slope) of the dose-response curve was approximately 1. The highest levels of adduct formation per unit dose of MeIQx occurred with human albumin, followed by rat albumin, human Hb, and rat Hb (in that order). Although the human subjects were elderly and underwent colon resection surgery during the study period, the results indicate that formation of albumin and Hb adducts is dose dependent and that a trend exists for higher adduct levels per unit dose in humans, compared with F344 rats. Furthermore, MeIQx-albumin adducts are likely to provide a more sensitive marker of exposure to MeIQx than are MeIQx-Hb adducts.     

Euphorigenic doses of cocaine reduce [123I]beta-CIT SPECT measures of dopamine transporter availability in human cocaine addicts

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [123I]beta-CIT ([123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n = 6) were injected with [123I]beta-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28 +/- 0.03 and 0.56 +/- 0.07 mg/kg) produced significant (P < 0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V3" (6 +/- 6 and 17 +/- 3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.     

Diagnosis and treatment of soft tissue tumors

Alterations in [Hb], which are mediated through changes in arterial oxygen content, and alterations in BV, which are mediated through changes in cardiac output (Q), have a significant effect on both VO2max and aerobic performance. If BV is held constant, a decrease in [Hb] (anaemia) causes a decrease in VO2max and aerobic performance, while an increase in [Hb] (blood doping) causes an increase in VO2max and aerobic performance. If [Hb] is held constant, an increase in BV can cause and increase in both VO2max and aerobic performance, while a decrease in BV can cause a decrease in VO2max and aerobic performance. In addition, an increase in BV can compensate for moderate reductions in [Hb] through increase in Q, allowing VO2max to remain unchanged or even increase. Also, a large portion of the difference in the enhanced cardiovascular function of endurance athletes is due to their high BV and the resultant enhancement of diastolic function. Hence, optimizing both [Hb] and BV is a very important consideration for endurance performance.     

Kinetic and allosteric cooperativity in L-adenosine transport in chromaffin cells. A mnemonical transporter

In cultured chromaffin cells and plasma membrane vesicles from chromaffin tissue, the transport of D-[3H]adenosine followed Michaelis-Menten saturation kinetics, with Km values of 1.5 +/- 0.3 microM and 1.9 +/- 0.2 microM, respectively. The transport of the isomer, L-[3H]adenosine, showed sigmoidal kinetics in both preparations. In plasma membrane vesicles the S0.5 was 2.5 +/- 0.2 microM with a Hill coefficient of 2.8 and the Vmax value of 0.26 +/- 0.01 pmol s-1 (mg of protein)-1. In cultured chromaffin cells the kinetic parameters for L-[3H]adenosine were S0.5 = 6.2 +/- 0.2 microM and a Vmax 19.7 +/- 0.5 pmol/min per 10(6) cells, with a pronounced positive cooperativity. The Hill coefficient was 4.9. The transport of the L-isomer in cultured cells followed Michaelis-Menten kinetics at the lowest concentrations employed, below 2 microM. On the basis of these results, we propose a kinetic model whereby the adenosine transporter functions mnemonically.