To test the value of carbohydrate-deficient transferrin (CDT) as a marker for chronic alcohol consumption, its concentration was measured in the serum of 74 patients (48 men, 26 women; mean age 48 [18-71] years) with various alcohol-related liver diseases, ten patients (six men, four women; mean age 61 [24-90] years) with non-alcohol related liver diseases and 30 healthy controls (12 men, 18 women; mean age 37 [19-84] years). In the healthy women the mean CDT concentration was 19.7 +/- 6.1 U/L, in healthy men 15.4 +/- 4.1 U/l (P < 0.05). The upper limit of normal (mean + 2 standard deviations) was 31.9 U/l in women and 23.6 U/l in men. Serum CDT levels were significantly raised in chronic alcohol abuse, depending on the degree of liver damage. The CDT level in alcohol-dependent women without liver disease was 31.1 +/- 4.3 U/l (P < 0.05), while in those with liver damage it was 42.3 +/- 14.2 U/l (not significant). The mean CDT concentration in male alcoholics without liver damage was 35.5 +/- 5.0 U/l (P < 0.01 compared with controls). In male alcoholics with liver damage the mean CDT level was 53.4 +/- 9.0 U/l (P < 0.001). In none of the ten patients with non-alcohol related liver disease was the CDT level above the upper limit of normal. The sensitivity of CDT as a marker for chronic alcohol consumption was 57% (42% for women, 65% for men) with a 100% specificity. For serum-gamma-glutamyl transferase the sensitivity was 87%, but its specificity only 73%. Because of its high specificity the serum CDT level is an added useful marker for demonstrating chronic alcohol consumption.

Treatment of hyperlipidemic patients with the thiol compound N-acetylcysteine (NAC) was previously shown to cause a significant dose-related increase in the high-density lipoprotein (HDL)-cholesterol serum level, suggesting the possibility that its disease-related decrease may result from a diminished thiol concentration and/or thiol/disulfide redox status (REDST) in the plasma. We therefore investigated plasma thiol levels and REDST in normo-/hyperlipidemic subjects with and without coronary heart disease (CHD). The thiol level, REDST, and amino acid concentrations in the plasma and intracellular REDST of peripheral blood mononuclear cells (PBMC) have been determined in 62 normo- and hyperlipidemic subjects. Thirty-three of these subjects underwent coronary angiography, because of clinical symptoms of CHD. All groups of hyperlipidemic patients under test and those normolipidemic individuals with documented coronary stenoses showed a marked decrease in plasma thiol concentrations, plasma and intracellular REDST of PBMCs, and a marked increase in plasma taurine levels. Individual plasma thiol concentrations and plasma REDST were strongly negatively correlated with the serum LDL-cholesterol and positively correlated with the serum HDL-cholesterol level. Together with the earlier report about the effect of NAC on the HDL-cholesterol serum level, our findings suggest strongly that lower HDL-cholesterol serum levels may result from a decrease in plasma thiol level and/or REDST possibly through an excessive cysteine catabolism into taurine.

Activated monocytes may contribute to the pathogenesis of ischemic stroke. We tested the hypothesis that release products and procoagulant activity of monocytes are increased in acute ischemic stroke. In patients on days 1, 3 and 7 after ischemic stroke and in age- and sex-matched healthy control subjects, we assessed plasma levels of interleukin 8 (IL-8) and neopterin (enzyme linked immunosorbent assay, ELISA) and investigated superoxidanion release (ferricytochrome C reduction), procoagulant activity (one-stage clotting assay) and tissue factor (TF) gene transcription (reverse transcriptase polymerase chain reaction) by monocytes. As compared to control subjects (n=23), IL-8 levels were increased on day 1 after stroke (n=22; p=0.005) and remained elevated on days 3 and 7. Neopterin levels were elevated on days 3 and 7 (p<0.05, respectively) but not on day 1. Neopterin and IL-8 were not correlated with monocyte counts. Superoxid anion production by stimulated and unstimulated monocytes was not different between groups. TF mRNA could neither be detected in monocytes from patients investigated within 12 h after ischemia (n=12) nor in control subjects (n=10) and procoagulant activity of cells was similar in both groups. Our results indicate increased monocyte activation after ischemic stroke although not all activation parameters were elevated. We found no support for the hypothesis that circulating monocytes express TF and possess increased procoagulant activity. Elevated IL-8 may contribute to stroke pathophysiology by activating polymorphonuclear leukocyte (PMNL) activation early after ischemia.

Iron may play an important role in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that the iron-transporting glycoprotein lactoferrin (LF) and its receptor are increased in the substantia nigra (SN) in PD. We investigated whether plasma levels of LF are altered in dopa-responsive PD. Plasma LF was not different between patients with PD (n = 23; 306 +/- 116 [mean +/- standard deviation] ng/ml) and age- and sex-matched healthy control subjects (n = 15; 359 +/- 126 ng/ml ). However, LF was inversely correlated with PD severity (r = -0.68, P = 0.002), an association that remained significant after adjustment for treatment with levodopa, monoaminooxidase inhibitors, and dopa agonists (r = -0.53, P = 0.017). Plasma transferrin and ferritin levels were not different between groups and neither correlated with disease severity nor with LF levels. Together with the result of increased nigral lactoferrin, this finding is compatible with the hypothesis of an imbalance between LF levels in blood and SN in progressing PD. Larger and particularly longitudinal studies and measurements of LF in cerebrospinal fluid are warranted to further examine the role of LF in PD.

OBJECTIVE:To determine the prevalence and potential diagnostic relevance of autoantibodies against serotonin, thromboplastin, and ganglioside Gm1 in patients with fibromyalgia syndrome (FM).METHODS:Sera from 203 patients with FM and 64 pain-free control subjects were analyzed with enzyme immunoassays. Clinical and psychometric data of the patients were analyzed for the presence or absence of autoantibodies.RESULTS:Compared with control subjects patients with FM had a significantly higher prevalence of autoantibodies against serotonin (20% vs 5%; p = 0.003) and thromboplastin (43% vs 9%; p < 0.001), but not against ganglioside Gm1 (15% vs 9%; p = 0.301). Differences in autoantibody prevalence between controls and FM patients were not related to age or sex. No association was found between autoantibody pattern and clinical or psychometric data, e.g., pain, depression, pain related anxiety, and activities of daily living.CONCLUSION:There is an elevated prevalence of antibodies against serotonin and thromboplastin in patients with FM. The pathophysiological significance of this finding is unknown. Calculation of positive predictive values of antiserotonin antibodies shows that measurement of these antibodies has no diagnostic relevance.

Tau protein concentration in cerebrospinal fluid was determined in 55 patients with Alzheimer's disease (AD), 18 patients with vascular dementia (VD), 19 patients with dementia caused by other disorders and 14 patients with major depression. Significantly (p < 0.05) elevated protein tau concentrations were found in AD patients (564.5 +/- 275.5 pg/ml) compared to all other patient groups (VD: 406.5 +/- 263.9 pg/ml; other dementia: 275.0 +/- 135.4 pg/ml; depression: 212.9 +/- 115.6 pg/ml). However, tau levels in AD patients covered a broad range (163.2 pg/ml-1200 pg/ml). AD patients with tau levels below the 25%-percentile of the distribution (among them a high percentage of patients with presenile onset) showed tau levels similar to those of the patients with late life depression. No significant correlations between tau levels and clinical variables such as severity of dementia, age, age of onset, duration of illness, and cerebral changes as assessed by volumetric magnetic resonance imaging could be demonstrated. Similarly, we could not find an influence of either APO-E genotype or psychotropic medication on the tau levels in AD patients. In accordance with other studies our results confirm elevated tau levels in AD compared to elderly not demented control subjects. Comparing groups, this finding applies as well with respect to VD and other dementing disorders. However, elevated tau levels cannot be detected in a subgroup of AD patients. This finding needs to be further investigated in future studies.

BACKGROUND:Clinical reports emphasize the therapeutic usefulness of granulocyte colony-stimulating factor (G-CSF) in clozapine-induced granulocytopenia. Only sparse information exists, however, on the natural course of endogenous G-CSF plasma levels in this condition.METHODS:We monitored G-CSF and white blood cell (WBC) counts in a 73-year-old patient who developed granulocytopenia while being treated with clozapine for schizoaffective disorder. Clozapine treatment was discontinued immediately, and G-CSF serum levels were determined repeatedly during the clinical course.RESULTS:Whereas WBC counts increased again within 6 days after discontinuation of clozapine, G-CSF level decreased significantly within the same period. The rapid decrease of endogenous G-CSF levels paralleled by a normalization of neutrophil count was interpreted as the result of an intact regulatory mechanism of granulocytopoesis. Therefore G-CSF therapy was not initiated. Owing to lack of therapeutic alternatives, it was decided to reintroduce clozapine. G-CSF levels decreased further, accompanied by an increase of WBCs, indicating stable bone marrow functioning.CONCLUSIONS:Based on this observation, we assume that the course of G-CSF and WBC counts indicated an abortive form of toxic bone marrow damage with subsequent recovery. We conclude that monitoring of G-CSF levels may serve as a useful tool in the follow-up of patients in whom clozapine-induced bone marrow damage is suspected.

BACKGROUNDCervical artery dissection (CAD) is an important cause of ischemic stroke in younger patients. However, its cause is insufficiently understood.OBJECTIVETo test the hypothesis that CAD is frequently associated with recent infection.SUBJECTS AND METHODSWe compared the prevalence of infection during the preceding week in 43 consecutive patients with acute CAD and 58 consecutive patients younger than 50 years with acute cerebral ischemia from other causes (control patients). In subgroups of patients, we correlated infectious status with electron microscopic studies of skin biopsy specimens and investigated pathways potentially linking infection and CAD.RESULTSRecent infection was more common in patients with CAD (25/43 [58.1%]) than in control patients (19/58 [32.8%]; P=.01). Respiratory tract infection was preponderant in both groups. Recent infection, but not the mechanical factors cough, sneezing, or vomiting, was independently associated with CAD in multivariate analysis. Investigation of serum antibodies against Chlamydia pneumoniae, smooth muscle cells, endothelial cells, collagen types I through IV, and heat shock protein 65 and assessment of serum alpha1-antitrypsin and HLA did not contribute to the understanding of the pathogenesis of CAD. More patients with pathologic findings in skin biopsy specimens tended to have had a recent infection (13/21 [62%]) than patients without pathologic findings (2/9 [22%]; P=.11).CONCLUSIONOur results suggest a significant association between recent infection and CAD that is not explained by mechanical factors occurring during infection.

PURPOSE: Restorative proctocolectomy is a standard procedure in the surgical treatment of ulcerative colitis and familial adenomatous polyposis. The radical removal of the colorectum with construction of an ileostomy often results in high stoma losses. These may lead to changes in the electrolyte and acid-base balance and to alterations in renal and suprarenal gland function. METHODS: In this study 33 patients who received an ileoanal pouch before and after proctocolectomy were investigated at different time intervals for electrolyte changes, alteration of the acid-base balance, kidney function, and hormonal changes of the suprarenal glands. Measurements were performed before proctocolectomy, ten days after proctocolectomy with ileal pouch-anal anastomosis under protective loop ileostomy, before ileostomy closure, and 6 to 12 months after ileostomy closure. Neither acute renal failure nor other vital complications were observed. RESULTS: Statistical analysis showed a significant decrease of urine pH to 5.4±0.22 (before ileostomy closure) and metabolic acidosis (pH 7.32±0.04; base excess −1.3±5.6 (before ileostomy closure)). Likewise, we found a decrease in renal clearance to 86 ml/minute (before ileostomy closure) without signs of tubular damage. The most important change during the phase with ileostomy was a functional secondary hyperaldosteronism with aldosterone levels of 63.2±70.8 ng/dl (before ileostomy closure). In comparison with preoperative levels, there was a ten-fold increase in mineralocorticoid adrenal activity. Additionally, during the period with protective ileostomy, the hepatic synthesis of aldosterone-18-glucuronide was only slightly increased, and the cortisol/cortisone ratio was extremely decreased. CONCLUSIONS: These results show that restorative proctocolectomy with ileal pouch-anal anastomosis and protective loop ileostomy significantly influences fluid, electrolyte, and acid-base balance. Functional secondary hyperaldosteronism is of central importance for subsequent renal recompensation. Approximately one-half year after ileostomy closure, the endogenous hormones with mineralocorticoid effects returned to normal levels.

Uremia raises lipoprotein(a) (Lp(a)) serum concentration and the risk of arteriosclerosis in dialysis patients. The treatment of high Lp(a) levels is not satisfactory today. The decrease of Lp(a) in hypothyroid patients on L-T4 therapy raised the question of whether dextro-thyroxine (D-thyroxine) reduces not only serum cholesterol, but also Lp(a) serum concentration. In a single-blind placebo-controlled study, the influence of D-thyroxine therapy on Lp(a) serum concentration was evaluated in 30 hemodialysis patients with elevated Lp(a) serum levels. Lp(a) was quantified in parallel by two methods, i.e., rocket immunoelectrophoresis and nephelometry, and apo(a) isoforms were determined by a sensitive immunoblotting technique. Regardless of the apo(a) isoforms, 6 mg/d D-thyroxine reduced elevated Lp(a) levels significantly by 27 +/- 13% in 20 dialysis patients (P < 0.001) compared with 10 control subjects (-9.9 +/- 8.4%). In parallel, D-thyroxine therapy significantly lowered total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and LDL cholesterol/HDL cholesterol ratio (P < 0.01); raised T4 and T3 serum levels; and suppressed thyroid-stimulating hormone secretion without causing clinical symptoms of hyperthyroidism in any of the patients. D-Thyroxine reduces elevated serum Lp(a) concentration in dialysis patients. The effect in nondialysis patients can be expected but remains to be proven.

OBJECTIVE To examine the association of renal function in diabetic patients with apolipoprotein (apo) E polymorphism. RESEARCH DESIGN AND METHODS Apo E genotypes, lipid and lipoprotein serum levels, creatinine clearance (CCr), and excretion of marker proteins were determined in German type 1 (IDDM; n = 162) and type 2 (NIDDM; n = 124) diabetic patients. Albumin and immunoglobulin (Ig) G are considered to reflect charge-size permselectivity of the glomerular capillary basement membrane, and increased alpha 1-microglobulin (MG) excretion indicates compromised reabsorptive capacity of the renal tubules. RESULTS Patients with NIDDM had higher lipid levels and lower CCrs than patients with IDDM. In patients with IDDM, age- and sex-adjusted analysis of variance showed an association between apo E genotypes and CCr, and the Jonckheere-Terpstra test demonstrated a decreasing glomerular filtration rate in the following order of genotypes: ε4ε4/ε4ε3 > ε3ε3 > ε2ε2/ε2ε3. Multiple linear regression analyses revealed that in patients with IDDM, the ε2 allele was a negative predictor of CCr and a positive predictor of urinary excretion of albumin, IgG and α 1-MG independent from HDL and LDL cholesterol, TG concentration, age, and sex. CONCLUSIONS Apo E polymorphism influences serum lipoprotein levels in patients with IDDM and NIDDM. Apo E polymorphism may be a renal risk factor of clinical relevance in normolipidemic patients with IDDM.

the glycoprotein laminin, a cross-shaped complex of three genetically different polypeptide chains, is a structural component of the capillary basement membrane. Serum laminin concentrations of healthy controls (n = 60) and adult type I diabetic patients (n = 170) were not age-dependent. Laminin was correlated with hemoglobin A1 (HbA1) values in normooalbuminuric patients (rS = .33, P < .0005, n = 116). Type I diabetic patients without nephropathy or retinopathy in good metabolic control had normal laminin levels. However, increasing stages of microangiopathy were associated with higher laminin levels. The molecular size distribution of serum laminin of control subjects (n = 4) and type I diabetic patients (n = 15) was analyzed by molecular-sieve chromatography. Laminin was eluted in two peaks with a molecular mass of 900 and 300 kd, most likely representing intact laminin and its P1 fragment, respectively. The areas of the two peaks were determined by two—gaussian function fitting. In patients without microangiopathy in poor metabolic control, an increase in the high—molecular weight (HMW) fraction could be detected as compared with healthy subjects and patients with acceptable metabolic control. Furthermore, the HMW laminin fraction and the ratio between the areas of the first and second peak increased with the stage of nephropathy (P < .001, Jonckheere-Terpstra test). These results provide evidence that (1) laminin concentration is increased in chronic hyperglycemia, (2) laminin may be a marker of microangiopathic lesions, and (3) elevated laminin levels may reflect an increased synthesis and/or a defective incorporation of laminin into the capillary basement membrane.

We performed a case-control study to investigate the role of recent infection as stroke risk factor and to identify pathogenetic pathways linking infection and stroke. We examined 166 consecutive patients with acute cerebrovascular ischemia and 166 patients hospitalized for nonvascular and noninflammatory neurologic diseases. Control subjects were individually matched to patients for sex, age, and season of admission. We assessed special biochemical parameters in subgroups of stroke patients with and without recent infection (n = 21) who were similar with respect to demographic and clinical parameters. Infection within the preceding week was a risk factor for cerebrovascular ischemia in univariate (odds ratio [OR] 3.1; 95% confidence interval (CI), 1.57 to 6.1) and age-adjusted multiple logistic regression analysis (OR 2.9; 95% CI, 1.31 to 6.4). The OR of recent infection and age were inversely related. Both bacterial and viral infection contributed to increased risk. Infection elevated the risk for cardioembolism and tended to increase the risk for arterioarterial embolism. Stroke patients with and without preceding infection were not different with respect to factor VII and factor VIII activity, fibrin monomer, fibrin D-dimer, von Willebrand factor, C4b-binding protein, protein S, anticardiolipin antibodies, interleukin-1 receptor antagonist, soluble tumor necrosis factor-alpha receptor, interleukin-6, interleukin-8, and neopterin. In conclusion, recent infection is an independent risk factor for acute cerebrovascular ischemia. Its role appears to be more important in younger age groups. The pathogenetic linkage between infection and stroke is still insufficiently understood.