Cohort study of serological biomarkers for interstitial lung disease in patients with rheumatoid arthritis.

OBJECTIVE: Interstitial lung disease (ILD) is an important cause of mortality in patients with rheumatoid arthritis (RA). Early RA-ILD detection is essential to improve prognosis. Here, we investigated eight serological biomarkers that may contribute to RA-ILD detection. METHOD: Fifty-five patients from the Early Rheumatoid Arthritis Program were evaluated for ILD with high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) using the SCAPIS protocol. Blood samples were obtained for biomarker analysis, and patients' clinical records were reviewed. We defined ILD using five different models based on the measurements used to confirm ILD: Model A = HRCT; B = PFTs; C = A plus B; D = C plus symptoms; and E = D plus inhalations. RESULTS: Among 55 patients, two had an ILD diagnosis before the study, but over one-third fulfilled the ILD criteria. Cancer antigen 15-3 (CA15-3) and matrix metalloproteinase-7 (MMP-7) differentiated between RA with and without ILD (all p < 0.05). Surfactant protein D (SP-D) showed similar trends, as did macrophage inflammatory protein-1ß (MIP-1ß) and chitinase 3-like protein-1 (YKL-40). Based on Pearson's correlation coefficients, MIP-1ß and YKL-40 were significantly correlated with DAS28 (MIP-1ß: 0.3; YKL-40: 0.4), ESR (MIP-1ß: 0.3; YKL-40: 0.4), and CRP (only MIP-1ß: 0.4) (all p < 0.05). CA15-3 was correlated with rheumatoid factor and anti-citrullinated peptide antibodies (Pearson's correlation 0.3; both p = 0.03). CONCLUSIONS: CA15-3 was the most significant biomarker for ILD detection in RA patients with stable low disease activity, closely followed by MMP-7. SP-D, MIP-1ß, and YKL-40 may also contribute to RA-ILD diagnosis.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Risk of eating disorders in immigrant populations.

OBJECTIVE: The risk of certain psychiatric disorders is elevated among immigrants. To date, no population studies on immigrant health have addressed eating disorders. We examined whether risk of eating disorders in first- and second-generation immigrants differs from native-born Danes and Swedes. METHOD: All individuals born 1984-2002 (Danish cohort) and 1989-1999 (Swedish cohort) and residing in the respective country on their 10th birthday were included. They were followed up for the development of eating disorders based on out-patient and in-patient data. RESULTS: The risks of all eating disorder types were lower among first-generation immigrants compared to the native populations: Incidence-rate ratio (95% confidence interval) was 0.39 (0.29, 0.51) for anorexia nervosa, 0.60 (0.42, 0.83) for bulimia nervosa, and 0.62 (0.47, 0.79) for other eating disorders in Denmark and 0.27 (0.21, 0.34) for anorexia nervosa, 0.30 (0.18, 0.51) for bulimia nervosa, and 0.39 (0.32, 0.47) for other eating disorders in Sweden. Likewise, second-generation immigrants by both parents were at lower risk, whereas those with only one foreign-born parent were not. CONCLUSION: The decreased risk of eating disorders among immigrants is opposite to what has been observed for other psychiatric disorders, particularly schizophrenia. Possible explanations include buffering sociocultural factors and underdetection in health care.

Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety.

AIMS/HYPOTHESIS: The aim of this study was to determine whether exenatide improves haemodynamic function in patients with type 2 diabetes with congestive heart failure (CHF). METHODS: The main eligibility criteria for inclusion were: male/female (18-80 years) with type 2 diabetes and CHF (ejection fraction ≤ 35%, and New York Heart Association functional class III or IV). Out of 237 patients screened, 20 male type 2 diabetic patients participated in this crossover trial design and were allocated (sequentially numbered) to i.v. infusions during two consecutive days with (1) exenatide (0.12 pmol/kg/min); and (2) placebo for 6 h followed by a washout period for 18 h, at Stockholm South Hospital, Sweden. Patients and researchers were blinded to the assignment. Cardiac haemodynamic variables were determined by right heart catheterisation. The primary endpoint was defined as an increase in cardiac index (CI) or a decrease in pulmonary capillary wedge pressure (PCWP) of ≥ 20%. Secondary endpoints were tolerability and safety of exenatide infusion. RESULTS: CI increased at 3 and 6 h by 0.4 ± 0.1 (23%) and 0.33 ± 0.1 (17%) l min(-1) m(-2), during exenatide infusion vs -0.02 ± 0.1 (-1%) and -0.08 ± 0.1 (-5%) l min(-1) m(-2) during placebo (p = 0.003); and heart rate (HR) increased at 1, 3 and 6 h by 8 ± 3 (11%), 15 ± 4 (21%) and 21 ± 5 (29%) beats per min (bpm), during exenatide infusion vs -1 ± 2 (-2%), 1 ± 1 (2%) and 6 ± 2 (8%) bpm, during placebo (p = 0.006); and PCWP decreased at 1, 3 and 6 h by -1.3 ± 0.8 (-8%), -1.2 ± 1 (-8%) and -2.2 ± 0.9 (-15%) mmHg, during exenatide infusion vs 0.3 ± 0.5 (2%), 1 ± 0.6 (6%) and 1.4 ± 0.7 (8%) mmHg, during placebo (p = 0.001). No serious adverse event was observed. Adverse events were reported in nine patients (six, nausea; two, increased HR; one, increased systolic blood pressure). CONCLUSIONS/INTERPRETATION: Infusion of exenatide in male type 2 diabetic patients with CHF increased the CI as a result of chronotropy, with concomitant favourable effects on PCWP and reasonable tolerability of the drug. The clinical implications of using exenatide in patients with CHF are still not clear and further studies are warranted. TRIAL REGISTRATION: www.isrctn.org/ISRCTN47533126

Is there change in intelligence quotient in chronically ill schizophrenia patients? A longitudinal study in twins discordant for schizophrenia.

BACKGROUND: Intellectual deficits are commonly found in schizophrenia patients. These intellectual deficits have been found to be heritable. However, whether the intellectual deficits change over time and, if so, whether the change is related with an increased genetic risk for the disease are not known. METHOD: We investigated change of intelligence quotient (IQ) in a twin sample of chronically ill schizophrenia patients, the discordant co-twins and healthy controls during a follow-up period of 5 years. A total of 52 twins completed two IQ assessments: nine patients [three monozygotic (MZ) and six dizygotic (DZ)], 10 unaffected co-twins (three MZ and seven DZ) and 33 healthy control twins (21 MZ and 12 DZ). RESULTS: A significant interaction effect over time was found between IQ measurement and illness (F=4.22, df=1, p<0.05), indicating that change in IQ over time is significantly different between the groups. A stable course in IQ over time was found in the patients with schizophrenia (mean IQ from 109.78 at baseline to 108.44 at follow-up) relative to both the healthy control twins who showed a small increase (from 114.61 at baseline to 119.18 at follow-up) (t=2.06, p<0.05) and the unaffected co-twins (from 111.60 to 117.60, t=-2.32, p<0.05). IQ change in the unaffected co-twins of schizophrenia patients was comparable with that in healthy control twins (t=-0.49, p=0.63). CONCLUSIONS: Patients with schizophrenia in the chronic phase of the disease, but not the discordant co-twins, show a lack of increase in IQ, which is probably due to environmental (non-genetic) factors related to the disease.

Correlation of light microscopic findings with transmission electron microscopy within a vascular occlusion device.

Host response to an implanted biomaterial is a complex process involving microscopic changes in extracellular matrix (ECM) composition. Reliable pathology analysis is imperative for accurate assessment of the tissue response to an implanted device. Plastic histology is commonly used for histology evaluation of medical devices to assess the device-tissue interface; however, this technique is prone to variable staining that can confound histology interpretation. Appropriately, we propose using transmission electron microscopy (TEM) to confirm histologic ECM findings in order to provide sufficient host-response data. Tissue response to an absorbable shape memory polymer intravascular occlusion device with a nitinol wire backbone was evaluated. Representative plastic-embedded, micro-ground sections from 30-day, 60-day, and 90-day timepoints were analyzed. ECM regions were selected, and ultrathin sections were created for TEM evaluation. Histological changes in ECM composition were compared for light microscopy (LM) and TEM findings; specifically, TEM fibrillary patterns for collagen and fibrin were used to confirm LM results. Throughout this study, LM reveals inconsistent staining in plastic-embedded sections. TEM, on the other hand, provides clear insight into the tissue response by morphologically discerning distinct fibrillary patterns within ECM structures; loose to dense collagen surrounds the implant as fibrin degrades, demonstrating progression of postimplant ECM maturation. Moreover, TEM serves as a definitive method for confirming tissue substrate morphology when LM findings prove ambiguous.

Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer.

Vascular endothelial growth factor (VEGF) has been shown to stimulate angiogenesis and myocardial perfusion. The short-term safety of VEGF gene therapy is excellent. However, there are only limited results regarding the long-term effects. The Kuopio Angiogenesis Trial (KAT) studied the efficiency and short-term safety of the local VEGF-A(165) gene transfer in 103 patients with coronary artery disease. Three patient groups received either VEGF as an adenoviral (n=37), or as a plasmid/liposome vector (n=28), or as a placebo (n=38), during coronary angioplasty and stenting (percutaneous coronary intervention, PCI)AQ1. The aim of this study was to examine the long-term effects and safety of VEGF gene therapy. Patients were interviewed by telephone or with a questionnaire on their current status of health, coronary and other cardiovascular events and symptoms, working ability, exercise tolerance, other diseases, such as cancer and diabetes, as well as their personal experience of the treatment. Causes of death were clarified from hospital records. The total follow-up time was 8.1 years (range 6.9-9.7 years). Overall 82% of the patients were reached across the study. Eight (7.5%) of the patients died during the follow-up, but there was no significant difference in mortality between the groups (3/32 vs 2/26 vs 3/31 VEGF-adenovirus vs VEGF-plasmid/liposome vs placebo, respectively; P=0.88). The incidence of major adverse cardiovascular events (MACEs) (10 vs 11 vs 15; P=0.85), cancer (1 vs 4 vs 2; P=0.38) or diabetes (2 vs 2 vs 2; P=0.97) did not differ between the groups. Local intracoronary VEGF gene transfer is safe and does not increase the risk of MACE, arrhythmias, cancer, diabetes or other diseases.

Rapid breakthrough of 131I in an in vitro human epidermis model.

Skin contamination with radionuclides may cause local radiation damage, but also systemic distribution if the nuclides penetrate the epidermal membrane. Detailed information of the skin absorption of radionuclides is of importance for e.g. dose estimations and development of decontamination strategies. In the present study, penetration of 131I through human epidermis was studied using an in vitro flow through diffusion chamber. Epidermis was exposed to a Na131I-solution, used in nuclear medicine, and the potential concentration-dependency of skin penetration was examined by including two concentrations of non-radioactive NaI. Penetration of 131I occurred after a few minutes of exposure and steady state penetration rate was obtained after about 50-70min independently of the iodine concentration and receptor solution used. The two receptor solutions evaluated; phosphate buffered saline solution and an ethanol and water-mixture (1:1), resulted in significantly higher penetration rate of 131I using the ethanol and water-mixture. The penetration of iodine was calculated to be concentration-dependent independently of the receptor solution utilized. In addition, radioactive iodine did not accumulate in epidermis in the in vitro-model used. In conclusion, the present study provides detailed information on the rapid iodine penetration at the early phase of radionuclide exposure, defined as the first 30min of the experiment, and is clearly suitable for decontamination studies. In addition, methodological aspects, e.g. impact of the receptor solution, should carefully be considered in studies of radionuclide skin penetration using in vitro-techniques.

Natural cell-mediated immunity to lymphoma cells. I. Characteristics of effector cells in a cytostasis assay in vitro.

Spleen cells from normal, nonimmune, CBA or (CBA X AKR)F1 mice markedly and rapidly inhibited the incorporation of [3H]thymidine by two different T-cell lymphomas in an in vitro cytostasis assay. These were the I-529 lymphoma of spontaneous AKR origin and the Moloney murine leukemia virus-induced YAC lymphoma of A mouse origin. Spleen cells were the most efficient inhibitors for both types of target cells, whereas lymph node cells were much less active and thymus cells showed little or no activity. Granulocytes, as well as conventional T- and B-lymphocytes, were excluded as important contributors to the cytostatic cell population. Spleen cells were separated on nylon wool, Sephadex G-10 columns, or plastic petri dishes and tested for activity in the cytostasis assay or for cytotoxicity against 51Cr-labeled lymphoma target cells. Adherent cells carried almost all cytostatic activity against the AKR lymphoma but also showed significant cytotoxic activity against these target cells. In addition, the cytostatic activity against the YAC lymphoma was mainly due to adherent spleen cells, but nonadherent cells were relatively more active against this target than against I-529 cells. Such nonadherent spleen cells further showed increased cytotoxic activity, compared to the whole spleen cell population.

Interactions in the renal and biliary elimination of digoxin: stereoselective difference between quinine and quinidine.

The interactions between digoxin and quinine and quinidine that affect the renal and biliary clearances of digoxin were investigated in eight healthy subjects. Digoxin (0.5 to 0.75 mg/day) was given alone and with concomitant administration of quinine (750 mg/day) to reach a steady-state level. In four of the subjects, the study was repeated by administration of equimolar doses of the diastereoisomer quinidine together with digoxin, enabling a within-subject comparison of the effects of the two isomers on digoxin clearance. The biliary excretion of digoxin was studied by use of a modified duodenal marker perfusion technique. A marked reduction was found in the steady-state biliary clearance of digoxin from control value 134 +/- 57 ml/min (mean +/- SD) to 87 +/- 39 ml/min during treatment with quinine (p less than 0.05) and from 95 +/- 24 to 55 +/- 27 ml/min during treatment with quinidine (p less than 0.01; n = 4). Quinidine reduced the renal clearance of digoxin (155 +/- 26 versus 110 +/- 21 ml/min) (p less than 0.05; n = 4), whereas quinine had no such effect (177 +/- 40 versus 185 +/- 53 ml/min; not significant). These findings explain the difference in magnitude between quinidine and quinine in regard to the interaction with digoxin and imply a different degree of stereoselectivity for these isomers in the renal and biliary secretory systems of digoxin.

Nortriptyline and debrisoquine hydroxylations in Ghanaian and Swedish subjects.

Eleven Ghanaian and 12 Swedish subjects phenotyped with a debrisoquine (D) hydroxylation test were given a single oral dose of nortriptyline (NT). Much the same percentage of the given NT dose was excreted as 10-hydroxy-NT (10-OH-NT) by Ghanaians (43.1%) and Swedes (49.2%). There was a close correlation between plasma clearance of NT by 10-hydroxylation and the D metabolic ratio (D/4-OH-D in urine) in the Ghanaians (rs = -0.95; P less than 0.01) and Swedes (rs = -0.84; P less than 0.01). The E-isomer of 10-OH-NT is the major isomer in both Ghanaians (76% to 92% of total 10-OH-NT) and Swedes (78% to 95%). It is suggested that the E-10-hydroxylation of NT and the 4-hydroxylation of D are similarly coregulated in Ghanaians and Swedes.

Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans.

The interaction between digoxin and verapamil was studied in six patients (mean age +/- SD, 61 +/- 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady-state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady-state plasma concentrations of digoxin, from 0.80 +/- 0.24 to 1.15 +/- 0.40 nmol/L (p less than 0.01). The biliary clearance of digoxin decreased by 43%, from 187 +/- 89 to 101 +/- 55 ml/min (p less than 0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 +/- 31 versus 173 +/- 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route.

Alterations in skeletal muscle morphology in glucose-tolerant elderly hypertensive men: relationship to development of hypertension and heart rate.

OBJECTIVE: To compare the muscle morphology in hypertensive subjects with that in controls and to test the hypothesis of a relation between heart rate, development of hypertension and muscle morphology that is independent of glucose intolerance. PATIENTS AND METHODS: We studied 43 glucose-tolerant, untreated hypertensive subjects and 113 healthy controls in a longitudinal cohort of 70-year-old men. Metabolic status (oral glucose tolerance test and euglycemic, hyperinsulinaemic clamp test), muscle fibre distribution (myosin ATPase staining) and capillary supply (amylase-PAS method) were evaluated. Blood pressure and heart rate data were available from both ages 50 and 70 years. RESULTS: Hypertensive subjects had a significantly smaller mean number of capillaries per fibre than controls (1.53 versus 1.64; P = 0.04). In hypertensive subjects, the proportions of type I and type II fibres were correlated to mean arterial pressure (r = -0.56 and r= 0.52, respectively, P < 0.05 for both). The increase in mean arterial pressure over 20 years was closely correlated to capillary density in mm2 (r= -0.62; P< 0.0001). Capillary supply was inversely related to resting heart rate both at ages 50 and 70 years. CONCLUSIONS: Skeletal muscle of glucose tolerant hypertensive subjects showed a lower capillary supply than that of controls. This capillary rarefaction was correlated to increase in mean arterial pressure over two decades and to supine heart rate. This is compatible with the suggestion that higher sympathetic drive might generate structural alterations in muscle capillarization.

Increased renal clearance of cefsulodin due to higher glomerular filtration rate in cystic fibrosis.

The steady-state renal clearance of cefsulodin was studied in 6 patients with cystic fibrosis and 8 healthy controls. The drug was administered by constant rate infusion to obtain 2 values of plasma concentration, 2 and 30 mg/L. As an estimate of the glomerular filtration rate, the renal clearance of inulin was measured simultaneously. The results showed the figures for inulin clearance to be approximately 30% higher in cystic fibrosis patients than in healthy controls at both concentrations, and a corresponding increase in the renal clearance of cefsulodin was seen in patients over controls. The ratio between the renal clearances of the 2 substances was on average 0.9 in both groups. The correlation found between the 2 renal clearances (r = 0.75; p less than 0.001) indicates that glomerular filtration rate has considerable influence on the renal elimination of cefsulodin. This finding emphasises the importance of glomerular filtration rate for the renal clearance of drugs in cystic fibrosis.

Influence of the glomerular filtration rate on renal clearance of ceftazidime in cystic fibrosis.

The renal handling of ceftazidime was studied in 8 patients with cystic fibrosis and 10 healthy controls. The renal clearance of ceftazidime (CLRcz) was measured after an intravenous single dose and during low and high plasma concentration steady-state infusions. The glomerular filtration rate (GFR) was simultaneously estimated by inulin clearance (CL inul). The average CLRcz (mean +/- SD) was higher in cystic fibrosis patients (125 +/- 20 ml/min/1.73 m2) than in healthy controls (100 +/- 9 ml/min/1.73 m2) [p less than 0.005]. Also CL inul (mean +/- SD) was increased in cystic fibrosis patients (132 +/- 30 ml/min/1.73 m2) compared with healthy controls (103 +/- 8 ml/min/1.73 m2) [p less than 0.02]. The mean renal clearance ratios of ceftazidime to inulin were close to unity after both the single dose and low and high dose steady-state infusions both in cystic fibrosis patients and in controls. These findings suggest that the glomerular filtration rate is the principal determinant of the elimination rate of ceftazidime. However, in all cystic fibrosis patients with a CL inul exceeding 125 ml/min/1.73 m2 the clearance ratio was below unity, indicating tubular reabsorption of ceftazidime occurs in these individuals. The results demonstrate a higher but also more variable GFR in cystic fibrosis patients (74 to 174 ml/min/1.73 m2), resulting in increased and accordingly variable ability to eliminate ceftazidime in cystic fibrosis. However, these pharmacokinetic changes are not large enough to call for special dosage considerations for ceftazidime in cystic fibrosis.

Relation of mean heart rate and heart rate variability in patients with left ventricular dysfunction.

The new finding was that mean heart rate and heart rate variability were more closely coupled in patients with more advanced LV dysfunction. Mean heart rate explained a larger portion of variance in heart rate variability in patients in the lowest LVEF quartile than in those in the highest one. These results support our hypothesis that sympathetic activation in patients with more severe LV dysfunction results in closer correlation between heart rate and heart rate variability. Generally, the correlation between mean heart rate and heart rate variability is weak because heart rate and heart rate variability represent different modalities of cardiovascular regulation. Mean heart rate is normally determined by the interactions of both the sympathetic and parasympathetic nervous systems, whereas modulation of these activities, with different gains, determines the magnitude of heart rate variability. This results in great complexity in control of the heart by the autonomic nervous system. However, heart rate is likely to be more dominantly regulated by the sympathetic nervous system because of vagal withdrawal in patients with more severe LV dysfunction. The effect of sympathetic cardiac modulation has been shown to be more sluggish than that of the parasympathetic nervous system in beat-to-beat regulation of heart rate. This may result in more blunted heart rate variability concomitantly with elevated mean heart rate. Thus, variation in heart rate variability in any given mean heart rate is likely to be lower than in patients with more preserved LV function, and hence with more complex cardiac autonomic regulation with involvement of the parasympathetic nervous system. Indeed, even the slopes of regression lines between mean heart rate and heart rate variability were similar in the first and fourth LVEF quartile; the intercept of the regression line was significantly higher in the fourth quartile than in the first one. This further supports our hypothesis.

Cardioversion of atrial fibrillation and its effect on right ventricular function as assessed by tricuspid annular motion.

In patients with atrial fibrillation, the reduced right ventricular function determined by tricuspid annular motion before cardioversion returns to normal 1 month after successful cardioversion to sinus rhythm. The simplicity of recording the tricuspid annular motion provides an easy opportunity to assess right ventricular function following electroconversion of atrial fibrillation to sinus rhythm.

Insulin-mediated changes in leg blood flow are coupled to capillary density in skeletal muscle in healthy 70-year-old men.

The aim of this study was to investigate to what degree the capillarization in the skeletal muscle explains the leg blood flow (LBF) changes during hyperinsulinaemia. Fifteen normotensive men from a population-based cohort of 70-year-old men in Uppsala, Sweden, were investigated. Their metabolic status (oral glucose tolerance test and euglycemic, hyperinsulinaemic clamp test results), serum lipid profile, muscle fiber distribution (myosin adenosine triphosphatase staining), and capillary supply (amylase-periodic acid-Schiff method) was evaluated. Doppler ultrasound was used before and after the clamp test to detect insulin-induced changes in LBF. Physiologic hyperinsulinemia (serum insulin, 107 mU/L) caused a moderate increase in LBF (15% +/- 11%; P =.07). Change in LBF was closely related to capillary density (r =.66; P <.01) independent of obesity, smoking and level of physical activity. An association was observed between LBF and serum free fatty acid (FFA) concentrations (r = -.57; P <.05). In multiple regression analysis, capillary density and serum FFA level together explained 71% of the variation in insulin-mediated LBF changes. Capillary rarefaction and elevated serum FFA values were associated with a vasoconstrictive effect of insulin. In conclusion, capillarization in skeletal muscle and serum FFA concentration seem to be determinants of endothelial function.

Stereoselective inhibition by the diastereomers quinidine and quinine of uptake of cardiac glycosides into isolated rat hepatocytes.

The pharmacokinetic interaction between quinidine and digoxin in patients is well-known, in general requiring a dose reduction of digoxin in patients concomitantly treated with quinidine. Quinine, the diastereomer of quinidine, has not been as extensively studied in this respect. In addition to an interaction with the renal clearance of digoxin by quinidine, both diastereomers have been reported to inhibit the biliary clearance of digoxin in man. To further investigate the mechanisms of these hepatobiliary transport interactions at the cellular level, we compared the effects of quinidine and quinine, as well as of the calcium antagonist verapamil, on the uptake of digoxin and ouabain in isolated rat hepatocytes. Initial uptake rates of digoxin and ouabain were determined in the presence of various concentrations of quinine and quinidine. A concentration dependent inhibition of the cellular uptake of both cardiac glycosides by quinine and quinidine was found, quinine being a more potent inhibitor than quinidine. Our results indicate a stereoselective inhibition of the hepatocellular uptake by the two diastereomers quinidine and quinine, the latter being about equipotent to verapamil. This unequal inhibitory potency of the two basic drugs was detected earlier in oocyte studies with the cloned organic cation transporter OCT1.