Tenascin is expressed in inflammatory and fibroproliferative processes, both contributing to posttransplant obliterative bronchiolitis (OB) in association with epithelial cell injury and airway obliteration. We studied bronchial allografts to elucidate the role of tenascin during this alloimmune response. Bronchial segments were subcutaneously implanted into eight pigs. Allografts and autograft controls were serially obtained until total obliteration in allografts and processed for histology and immunocytochemistry for CD4, CD8, and tenascin. Findings were graded on a scale from 0 to 3. In autografts the operative epithelial damage recovered and bronchi stayed patent with mild-graded fibrosis and inflammation. Partial recovery was observed in allografts on day 4, thereafter the epithelial loss gradually increased. Total recovery was achieved on day 11 (P < .001). Fibroblast proliferation resulted in total luminal obliteration on day 21 (P < .001). The number of inflammatory cells increased rapidly (P < .05) with numerous CD4+ and CD8+ cells on day 14 (P < .0001). Prior to total epithelial loss in allografts, tenascin expression was observed on day 7 in 69% of epithelial cells, whereas in only 5% of epithelial cells in recovered autografts. Paralleling the most intense fibroproliferation, tenascin-positive cells were observed in the bronchial wall on day 7 and day 11 (P < .001).Tenascin expression was demonstrated during the inflammatory response and fibroblast proliferation during the early stage of obliterative bronchiolitis showing that tenascin contributes to posttransplant obliterative bronchiolitis development.

There is a multitude of data showing that coronary heart disease is affected by the quality of dietary fat. The fatty acid composition of serum lipids has been shown to reflect that of the diet. It is likely that, after myocardial infarction, both the health-care professionals and the patients themselves pay more attention to dietary guidelines. In order to assess the correctness of this assumption, we compared the composition of serum fatty acids in 40 male subjects with a history of myocardial infarction (MI) with that of 40 age-matched controls, both from the FINRISK study. The percentage composition of fatty acids of total serum lipids was analysed by gas chromatography. In comparison with the control group, the MI group had higher body mass index (BMI), a higher prevalence of diabetes, higher level of serum triglycerides and a lower level of serum high-density lipoprotein (HDL) cholesterol, all indicators of the metabolic syndrome. The MI group had higher proportions of serum palmitic (16:0) and oleic acids (18:1), and a lower proportion of linoleic (18:2 n-6) acid than the control group. The metabolic syndrome is accompanied by an elevated level of serum insulin, which is known to enhance the synthesis of saturated and monounsaturated fatty acids, such as 16:0 and 18:1, and to stimulate the activity delta-6 desaturase, decreasing the concentration of linoleic acid. Our results suggest that the observed serum fatty acid composition in subjects with coronary heart disease is dependent on metabolic factors in addition to dietary fatty acid composition.

Elevated serum inflammatory markers have been reported in coronary heart disease. Levels of serum matrix metalloproteinase-9 (MMP-9), C-reactive protein (CRP), C3-complement (C3) and autoantibodies against oxidized low-density lipoprotein (oxLDL) in 120 male subjects with a history of myocardial infarction (MI) were compared with those in 250 age-matched controls, both groups from a large cross-sectional population survey, the FINRISK study. The concentrations of serum MMP-9 and autoantibodies against oxLDL were measured by enzyme-linked immunosorbent assay, CRP and C3 by immunonephelometry. MMP-9, CRP and C3 concentrations were higher in the subjects with a history of MI than in the controls (p=0.037, p=0.004, and p=0.006, respectively). There was no difference between the groups in serum levels of autoantibodies against oxLDL. In other background characteristics, men in the MI group had higher body mass index (BMI) and serum triglyceride values and lower serum HDL cholesterol values compared to controls (p=0.009, p=0.001, and p<0.001, respectively). When analyzed by stepwise multiple logistic regression using BMI, HDL cholesterol, triglycerides, CRP, C3 and MMP-9 as independent variables, the significant predictors for MI were HDL cholesterol (p=0.002) and MMP-9 (p=0.015). These results suggest that increased serum MMP-9 may reflect inflammatory pathologic processes that are related to progression of atherosclerosis.

AIMS:To clarify the relationship of alcohol consumption with serum antibodies to oxidized low-density lipoprotein (oxLDL) and the inflammation marker C-reactive protein (CRP).METHODS:The study population consisted of 280 men with evidence of alcohol misuse by having self-reported alcohol consumption values over 280 g absolute ethanol per week and 250 age-matched moderate drinkers from a population of Finnish men participating in the FINRISK survey study. Serum samples were analysed for antibodies to oxLDL, C-reactive protein (CRP), total cholesterol, HDL-cholesterol, triglycerides, carbohydrate-deficient transferrin (CDT) and gamma-glutamyl transferase (GGT). The characteristics of the top and bottom half of the alcohol misusers, in regard to weekly alcohol consumption, were compared with the controls.RESULTS:Serum antibody titres to oxLDL were higher in the top half and the levels of CRP, HDL-cholesterol, triglycerides, GGT and CDT were elevated in both the top half and the bottom half of the alcohol misusers, compared to controls.CONCLUSION:We propose that alcohol misuse may result in increased inflammation leading to oxidation of LDL.

The purpose of the present study was to compare and evaluate the new Helsinki Alcohol Use Test (HAUT) and Alcohol Use Disorders Identification Test (AUDIT) as screening instrument in the general working population. The relationship between the HAUT and serum gamma-glutamyl transferase (GGT), and carbohydrate-deficient transferrin (CDT) was also evaluated. Our results seem to indicate that the HAUT has good performance as screening instrument for alcohol-related problems in the general population.

BACKGROUNDNitrous oxide gas (N2O) has been proposed to be effective in the treatment of the alcohol withdrawal syndrome (AWS). This has not been proved, however, in studies performed according to good clinical practice guidelines. Moreover, previous studies have not measured end tidal N2O concentrations or physiologic responses during N2O treatment. We have recently reported that in a double-blind, randomized, controlled setting, N2O was not superior to placebo in relieving AWS symptoms. In this previous study, we did not find significant differences between the treatments either in the Clinical Institute Withdrawal Assessment of Alcohol scores or in the total use of benzodiazepines (diazepam and temazepam). The aim of the present study was to characterize other effects and side effects of the N2O treatment using several objective measures and to study the possible long-term efficacy of the treatment.METHODSA total of 105 inpatients who had AWS and were admitted to the A-Clinic detoxification center were included in the study. The subjects were randomly assigned to one of the following three treatments: (1) N2O/oxygen (from 30 to 70% in oxygen), (2) air/oxygen (30%/70%), and (3) medical (normal) air. During the single 45-min treatment period, end-tidal N2O, carbon dioxide, and oxygen concentrations were measured. The physiologic responses were studied by measuring heart rate, blood pressure, pulse oximetric saturation, frontal muscle electromyographic activity, and plethysmographic pulse amplitude. Long-term effects were studied by measuring craving with the Obsessive-Compulsive Drinking Scale; severity of dependency with Severity of Alcohol Dependence Data; and liver enzymes with aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase 3 and 6 months after the treatment.RESULTSPatients in the N2O group demonstrated significantly higher facial muscle electromyographic activity and higher pulse amplitude than the air-treated subjects. Self-reported side effects between the gas treatments, however, did not differ between the groups. Regarding long-term effects of the treatments, there were no differences between the groups.CONCLUSIONSContrary to previously published data, N2O treatment did not decrease craving or liver enzymes during the 6-month follow-up. At the concentration used, N2O treatment produced signs of arousal instead of strong sedation.

BACKGROUND:The susceptibility to alcoholism can be explained partially by genetic factors. Neuropeptide Y (NPY) has emerged as one potential factor contributing the development of alcoholism. A recent study indicated that the NPY gene variant producing a leucine-to-proline substitution (T to C at position 1128) was associated with 34% higher average alcohol consumption.METHODS:The subjects consisted of 122 alcoholics classified as type 1 and type 2 subtypes by psychiatric evaluation. A random sample of 59 social drinkers was used as a control group to compare the distribution of NPY genotypes with those of alcoholics.RESULTS:In a logistical regression model, there was a significantly lower frequency of the leucine(7)/proline(7) heterozygotes among well characterized type 2 alcoholics, compared with the controls (10.8 vs. 24.1%, p = 0.028).CONCLUSIONS:We speculate that the genetic polymorphism producing the proline(7) substitution of NPY might not predispose to alcoholism, but indeed retard the transition to alcoholism.

Background Elevated serum homocysteine concentrations have been related to coronary heart disease. However, the association has not indisputably been proven, and the mechanisms by which homocysteine may be atherogenic have only partially been elucidated. The objective of the present study was to investigate whether serum homocysteine is associated with angina pectoris and myocardial infarction. Methods We compared serum homocysteine concentrations in subjects with clinical evidence of angina pectoris or history of myocardial infarction to age‐matched controls. The study included 248 males, who participated in a large cross‐sectional risk factor survey carried out in five geographic areas in Finland. Results Serum homocysteine concentration was significantly higher in subjects with a history of myocardial infarction compared to controls (15·3 μmol L −1 and 13·9 μmol L −1 respectively, P = 0·037). In a logistic regression model including several cardiovascular risk factors, serum homocysteine was significantly associated with myocardial infarction (95% CI 1·0157–1·2990, P = 0·027). Serum homocysteine concentrations did not differ between subjects with angina pectoris and age‐matched controls (13·9 μmol L −1 and 14·2 μmol L −1 respectively). Conclusions Our results suggest that elevated serum homocysteine is associated with myocardial infarction but not with uncomplicated coronary heart disease.

Hum;in serum paraoxonase (PON) is an antioxidative enzyme, which circulates on high-density lipoproteins and appears to use oxidized phospholipids as physiological substrates. PON M/L55 substitution changes the ability of PON to prevent lipid oxidation. Urinary 8-iso-PGF(2 alpha) (one of F-2-isoprostanes) may represent a non-invasive in vivo index of free radical generation and we propose that PON might influence the biosynthesis of 8-iso-PGF(2 alpha), in the vasculature. We studied the urinary excretion of 8-isn-PGF(2 alpha) and related it to PON M/L55 genotypes in patients with type 2 diabetes mellitus (n = 55) and non-diabetic control subjects (n = 55). Urinary 8-iso-PGF(2 alpha) was determined by competitive ELISA and the PON genotype by a PCI;: based restriction enzyme digestion method. LL homozygotes were compared to M-allele carriers (ML hetero-zygotes and MM homozygotes). The urinary excretion of 8-iso-PGF(2 alpha) among non-diabetic non-smoking LL homozygotes tvas 3995.5 +/- 3352.5 ng/24-hour and among M-allele carriers 1689.11 +/- 1051.3 ng/24-hour (p = 0.017, ANCOVA; gender, hypertension, total cholesterol, triglycerides and LDL cholesterol as covariates). The excretion of 8-iso-PGF(2 alpha), was increased in type 2 diabetes mellitus compared to non-diabetic control subjects. PON may thus protect against oxidative stress by destroying some biologically active lipids. Excretion of 8-iso-PGF(2 alpha) is increased in type 2 diabetes, which ma!: reflect oxidant injury.

Depletion of noradrenaline in newborn rats by 6-hydroxydopamine (6-OHDA) affects the postnatal development and reduces the granular cell area in the neocerebellum (lobules V–VII). During the first postnatal month, Bergmann glial fibers guide the migration of immature granule cells to the internal granule cell layer. Microglia and Bergmann glia may play an important role in this process, but the exact mechanism behind this phenomenon is not known. We studied the effect of systemic administration of 6-OHDA on the expression and localization on microglia and Bermann glia in the neonatal cerebellum by immunohistochemistry. In the neocerebellum, 6-OHDA treatment caused a significant increase in the number of activated microglia. The increase was observed mainly in the granule cell layer and the cerebellar medulla. Bergmann glial cells in treated brains were abnormally located, did not form intimate associations with Purkinje cells, and the glial fibers were structurally different. Our findings indicate that a noradrenergic influence may be necessary for the normal maturation and migration of granule cells, and abnormal migration may be the result of Bergmann glia destruction and the activation of microglia. Activated microglia in the granule cell layer may be used as a marker for an injured cerebellar area.

Background: Moderate consumption of alcohol may reduce mortality from vascular diseases. The beneficial effects of alcohol may partly be mediated by its effects on lipoprotein metabolism. We studied the connection between alcohol consumption and the serum lipid profile from a well-documented national health program study. Methods and results: Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. The laboratory analyses were carried out on 5675 subjects (3097 males and 2578 females). The subjects were divided into quartiles on the basis of CDT or GGT value. The highest CDT quartile and the lowest GGT quartile seemed to be associated with a favorable lipid profile and the lowest CDT quartile and the highest GGT quartile were associated with an unfavorable lipid profile. Serum high density lipoprotein (HDL) cholesterol values were significantly higher and triglycerides lower with increasing serum CDT concentrations for both men and women. Increasing serum GGT was associated with higher serum total cholesterol and higher triglycerides in both men and women and lower HDL cholesterol in men. Conclusions: CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may lead to a better understanding of the effects of alcohol consumption on lipids as well as mechanisms behind favorable and detrimental effects of alcohol on vascular diseases. Condensed abstract: Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. A total of 3097 males and 2578 females were divided into quartiles on the basis of their CDT or GGT values. The highest CDT quartiles had higher HDL and lower triglycerides, whereas the highest GGT quartiles appeared to be associated with higher total cholesterol and triglycerides in both genders and lower HDL in men. CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may have important clinical and public health implications.

BACKGROUND AND AIMS:This study was to assess whether the tissue obtained with an ultrathin cutting needle, that is as thin as used for aspiration cytology and bacteriology, can give enough material to diagnose acute pancreatitis in rat model and in a human case.METHODS:Wistar rats were randomly allocated into control group (n = 6), cerulein group (n = 6), ligation group (n = 6) and bile salt group (n = 6). In the cerulein, ligation and bile salt groups acute pancreatitis was induced by cerulein intraperitoneal injections, low ligation of common biliopancreatic duct and sodium taurodeoxycholate intraductal injection, respectively. Serum amylase activity was measured and a large cut specimen and two ultrathin needle biopsy specimens were obtained from the pancreas for light microscopic histology. Oedema, acinar cell necrosis, haemorrhage or fat necrosis, and leukocyte infiltration were evaluated semiquantitatively and compared with large cut specimens.RESULTS:The pancreatitis groups revealed different severity in oedema, acinar cell necrosis, haemorrhage or fat necrosis, and leukocyte infiltration. The needle biopsy showed 100% sensitivity and 100% specificity in the diagnosis of acute pancreatitis. The histopathologic scores showed a good and significant correlation between ultrathin biopsy and large cut specimens in all the four histologic parameters, especially in oedema and acinar cell necrosis. A human case is presented, whose percutaneous ultrathin needle biopsy histology was successfully applied for diagnosing acute pancreatitis.CONCLUSIONS:The ultrathin needle biopsy histology can give enough material for the diagnosis of acute pancreatitis. Further studies with ultrasonography guided percutanous or endosonography guided transduodenal technique will be needed to assess the role of tissue sampling in acute pancreatitis.

BACKGROUND:Apoptosis may be involved in the mechanism of acinar cell injury in acute experimental pancreatitis.AIM:This study was to investigate whether apoptosis also is involved in human acute pancreatitis.METHOD:A needle biopsy pancreatic specimen was obtained from a patient with acute oedematous pancreatitis. The specimen was stained with In Situ Cell Death Detection Kit. Similar specimen from a patient undergoing pancreatoduodenectomy for bile duct cancer served as a control.RESULTS:Extended acinar cell apoptosis was found in the pancreatitis specimen. No single apoptotic cell was found in the control pancreas.CONCLUSION:Apoptosis probably is involved not only in acute experimental pancreatitis but also in human acute oedematous pancreatitis. The induction and role of apoptosis in pancreatis is discussed based on literature.

The influence of neonatal administration of 6-hydroxydopamine (6-OHDA) on the maturation of GABAA receptors in the frontal cortex and hippocampus was studied using 5- to 40-day-old rats. In situ hybridization with antisense oligonucleotide probes was performed for α1, α2, α5, β2, β3 and γ2 subunit mRNAs of the GABAA receptor. We demonstrated that neonatal treatment with 6-OHDA temporarily delays the postnatal transcription of the α1 and γ2 subunits in the rat prefrontal cortex, as assessed by in situ hybridization histochemistry. The effect was selective for these subunits (the α2, α5, β2, and β3 subunit mRNAs remained unchanged) and for this region (the mRNA levels in the hippocampus were not changed). The reduction in mRNA levels at early postnatal stages (postnatal day 5, PD5, and PD10) also affected the subunit protein levels, as shown by immunohistochemistry for the α1 subunit, and the formation of GABAA receptor-associated picrotoxinin-insensitive TBPS binding sites, as shown by autoradiography. Our findings indicate that without a noradrenergic influence, the maturation of GABAergic interneurons in the frontal cortex is transiently delayed (from PD5 to PD40). However, it is possible that this transient reduction of the expression of certain GABA subunits – caused by depletion of noradrenergic innervation – cannot cause a lasting alteration to the GABAergic function in the prefrontal cortex.

Furosemide increases the basal tert-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and reverses the inhibition of the binding by gamma-aminobutyric acid (GABA) in the cerebellar GABA(A) receptors containing the alpha6 and beta2/beta3 subunits. These effects are less pronounced in the alcohol-sensitive (ANT) than in the alcohol-insensitive (AT) rat line. The difference between the rat lines in the increase of basal [35S]TBPS binding was removed after a longer preincubation with ethylendiaminetetraacetic acid (EDTA) containing buffer, but long preincubation did not reduce the GABA content of the incubation fluid or remove the difference in GABA antagonism by furosemide. The GABA sensitivity of the [35S]TBPS binding did not differ between the rat lines. There was no nucleotide sequence difference in the beta2 or beta3 subunits between the rat lines and similar beta2/3 subunit-dependent agonistic actions by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in the rat lines were detected. The data suggest that there are still unknown structural alterations in the cerebellar GABA(A) receptors between the AT and ANT rat lines, possibly associated with differential alcohol sensitivity.