bluuebunny/crossref_metadata_2025_split huggingface dataset:
JNK and c‐Jun but not ERK and c‐Fos are associated with sustained neointima‐formation after balloon injury
Authors: Watson  , Herdegen  , Buschmann  , Denger  , Wende  , Jahn  , Kreuzer  
Published: March 2003

BackgroundFormation of neointima after balloon angioplasty is regulated via inducible transcription factors (ITF), such as c‐Jun and c‐Fos, depending on mitogen activated protein (MAP) kinases, which have been shown to be activated after balloon injury. The precise localization of activated MAP‐kinases and concomitant expression of transcription factors in the vessel wall remains to be elucidated. We have now studied the localization and time‐dependent expression of MAP‐kinases together with corresponding ITFs in the rat carotid angioplasty model.DesignAnimals were sacrificed at 0.5, 6 and 24 h and 3, 5, 7, 14 and 28 days after injury. Cryocut sections were stained using antibodies directed against c‐Jun, phosphorylated c‐Jun, c‐Fos, c‐Jun amino‐terminal kinase (JNK), extracellular signal related kinase (ERK), von Willebrand factor, ki67 antigen, and α‐actin.Resultsc‐Jun expression was strongly induced in smooth muscle cells (SMC) 30 min after injury and remained upregulated for 24 h, thereafter dropping to basal levels at day 3. Re‐expression was observed at day 7 and 14 but not day 28. Expression patterns of JNK and phosphorylated c‐Jun were highly congruent to that of c‐Jun. In contrast, c‐Fos expression was restricted to 30 min and, less pronounced than c‐Jun and JNK, was visible after 7 days. Also, its expression was congruent with the presence of ERK.ConclusionsThese findings demonstrate a clear association between MAP‐kinases and their transcription factor substrates in vivo with a predominant association of JNK and c‐Jun with sustained SMC proliferation.
Assessment of human muscle glycogen synthesis and total glucose content by in vivo13C MRS
Authors: Van Den Bergh  , Tack  , Van Den Boogert  , Vervoort  , Smits  , Heerschap  
Published: March 2003

BackgroundObesity is often accompanied by a decreased ability of insulin to stimulate glucose uptake and glycogenesis in skeletal muscle. The aim of this study was to investigate the rate of glycogen formation and of muscular glucose content in relation to insulin sensitivity under euglycemic conditions.Materials and methodsWe applied a hyperinsulinemic (430 pmol m−2 min−1) euglycemic clamp with infusion of 20% glucose (30% enriched with 13C‐1‐glucose) to 8 subjects with a wide range of insulin sensitivities. Glycogen and glucose levels were monitored simultaneously by in vivo13C MRS of the calf muscle on a clinical MR system at 1.5T field strength.Results and conclusionsGlycogen synthesis rate showed a strong correlation with whole body glucose uptake during the clamp (r = 0.93, P < 0.01). With the use of 13C MRS, total muscular glucose content could be determined in vivo, and showed a positive, linear correlation with glycogen synthesis rate (r = 0.85, P < 0.01). 13C MRS provides important information regarding in vivo insulin action. Preliminary results indicate that the glycogen synthesis rate improves after treatment with troglitazone.
Effect of digoxin on circadian blood pressure values in patients with congestive heart failure
Authors: Kirch  , Grossmann  , Fischer  , Neumeister  , Kirch  
Published: March 2003

BackgroundThe aim of the study was to investigate the effect of chronic digoxin treatment on circadian blood pressure profile in normotensive patients with mild congestive heart failure.MethodsIn a randomized double‐blind, placebo‐controlled cross‐over protocol, 12 normotensive patients with mild congestive heart failure took digoxin or placebo for a total of 7 days. Automatic 24‐h ambulatory blood pressure measurements were carried out at day 7, of either digoxin or placebo.ResultsDiastolic blood pressure significantly decreased and systolic blood pressure significantly increased during overnight sleep in the digoxin phase compared to placebo. Digoxin had no effect on either systolic or diastolic blood pressure during daytime. Heart rate decreased in the overnight sleeping phase but did not differ significantly between placebo and digoxin phase.ConclusionsDigoxin significantly decreases diastolic blood pressure during overnight sleep in patients with congestive heart failure. This effect is likely to be caused by reduction of sympathetic activity or increase of parasympathetic activity. Increase of systolic blood pressure during sleep is probably caused by the positive inotropic effect of the drug.
Association between alpha‐1‐antichymotrypsin polymorphism and susceptibility to chronic obstructive pulmonary disease
Authors: Ishii  , Matsuse  , Teramoto  , Matsui  , Hosoi  , Fukuchi  , Ouchi  
Published: March 2003

BackgroundThe antiproteases, including alpha‐1‐antitrypsin, are supposed to prevent lungs from becoming emphysematous. Genetic susceptibility to smoking injury may confer a risk for the development of chronic obstructive pulmonary disease (COPD).MethodsWe have investigated the association between the polymorphism of alpha‐1‐antichymotrypsin (AACT), one of the antiproteases, and susceptibility to the development of COPD among heavy smokers. Blood samples obtained from both patients with COPD (n = 53) and control subjects (n = 65) at the Tokyo University Hospital, the Juntendo University Hospital and the Tokyo Kenbikyoin Clinic were used for this genotyping assay. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed to genotype the AACT biallelic polymorphism in the signal peptide (−15 alanine to threonine), and the two polymorphisms of the exon (Pro229Ala and Leu55Pro).ResultsThe proportion of AACT/Ala‐15 homozygotes was significantly higher in the COPD patients than in the control subjects (COPD 37.7% vs. control 18.5%). The odds ratio for AACT/Ala‐15 homozygotes vs. all other genotypes was 2.7 (95% CI 1.2–6.2) for the COPD group. We could not find any association between the other two polymorphisms and COPD.ConclusionsGenetic polymorphism in the signal peptide of AACT may be associated with individual susceptibility to the development of COPD, because the AACT/Ala‐15 genotype is predominantly found in patients with COPD. It is suggested that AACT/Ala‐15 genotype may be less protective against smoking injury.
Microgravity inhibits intestinal calcium absorption as shown by a stable strontium test
Authors: Zittermann A. , Heer M. , Caillot‐Augusso A. , Rettberg P. , Scheld K. , Drummer C. , Alexandre C. , Horneck G. , Vorobiev D. , Stehle P. 
Published: March 2003

Little is known about the onset and degree of biochemical and functional alterations in calcium metabolism during microgravity.To evaluate the effect of microgravity on intestinal calcium absorption and calcium‐regulating hormones under metabolic ward conditions.Fractional calcium absorption (Fc240 in percentage of dose administered) was determined pre‐flight, in‐flight and post‐flight, by use of a stable strontium test in one cosmonaut who spent 20 days in space. Moreover, a sequence of blood samples was collected for the determination of serum parathyroid hormone (PTH), 25‐hydroxyvitamin D, calcitriol and serum C‐telopeptide (CTx, biomarker of bone resorption) levels. During all periods of data collection, calcium intake was held constant at a minimum level of 1·000 mg day−1 and a daily supplement of 16·6 µg vitamin D2 was given. Personal ultraviolet (UV) light exposure was measured during the whole mission using a biologically weighting UV dosimeter.Fc240 was markedly reduced on flight day 19 (4·4%) as compared to pre‐flight and post‐flight data (13·4% and 17·2%, respectively). Serum calcitriol levels fell from 40·6 pg mL−1 (mean pre‐flight level) to 1·3 pg mL−1 on flight day 18 and returned into the normal range after recovery. Serum CTx increased during the flight, while serum PTH and 25‐hydroxyvitamin D levels did not change significantly.Intestinal calcium absorption can be diminished after only three weeks of microgravity. Changes are associated with a severe suppression of circulating calcitriol levels, but are independent of exogenous vitamin D supply and serum PTH levels.
Apolipoprotein E‐deficient mice have an impaired immune response to Klebsiella pneumoniae
Authors: De Bont  , Netea  , Demacker  , Kullberg  , Van Der Meer  , Stalenhoef  
Published: March 2003

BackgroundAll lipoproteins are able to bind to bacterial lipopolysaccharide (LPS), thereby neutralizing its deleterious effects. However, we demonstrated, recently, that in the absence of apolipoprotein E (apoE), eight‐fold increased very‐low‐density lipoprotein levels were not sufficient to protect apoE‐deficient (apoE−/−) mice against LPS. During a live Gram‐negative infection, mechanisms other than LPS‐neutralization may play a role in the pathogenesis of the disease. In the present study we further examined the role of apoE in Gram‐negative sepsis.MethodsSurvival, bacterial outgrowth in liver, spleen, kidneys and blood, and tumour necrosis factor‐α (TNF‐α) production were measured in apoE−/− mice and control C57BL/6J mice, after an intravenous infection with Klebsiella pneumoniae.ResultsMice that lack apoE showed higher mortality in response to K. pneumoniae than control mice (90% vs. 23% respectively after 2 weeks). ApoE−/− mice had 10–100 times more outgrowth of the bacteria in their organs than controls. Furthermore, circulating TNF‐α concentrations 90 min after a challenge, were almost twice as high in the apoE−/− mice compared to controls (13.0 ± 2.9 ng mL−1 vs. 7.6 ± 3.8 ng mL−1). When apoE−/− and control mice were rendered neutropenic, the discrepancy in survival and outgrowth of K. pneumoniae disappeared.ConclusionsThe apoE−/− mice were more susceptible than control C57BL/6 mice to a K. pneumoniae infection. The absence of apoE may render these mice more susceptible, since this protein is of importance in the detoxification of lipopolysaccharide of Gram‐negative bacteria. On the other hand, the phagocytic capacity of granulocytes seems to be decreased in apoE−/− mice, resulting in increased outgrowth and mortality.
LDL–apheresis in patients with nephrotic syndrome: effects on serum albumin and urinary albumin excretion
Authors: Stenvinkel P. , Alvestrand A. , Angelin B. , Eriksson M. 
Published: March 2003

BackgroundHyperlipidemia is a common feature of the nephrotic syndrome (NS). From retrospective studies, it has been suggested that aggressive lipid‐lowering with low‐density lipoprotein apheresis (LDL–A) may not only improve dyslipidemia but also decrease urinary albumin excretion and increase serum levels of albumin in patients with focal segmental sclerosis.MethodsSeven patients (6 males) aged 44 ± 7 years (SEM) with NS (duration 29 ± 11 months) of diverse etiologies were investigated in a prospective study. A fixed protocol of LDL–A was designed for treatment twice‐a‐week for 3 weeks and then once a week for 7 weeks. The effects of LDL–A on lipid parameters (cholesterol, triglycerides, HDL, Lp(a), apo A‐I, apo B) and renal parameters (iohexol clearance, serum albumin and 24‐h urinary albumin excretion) were evaluated.ResultsFollowing treatment by LDL–A a remission in the severity of the NS was observed in two patients whereas a clear improvement was observed in four of the patients. A small, but significant (P < 0.05), increase in serum albumin levels from 20 ± 2 to 24 ± 2 g L−1 was noted after LDL–A. As expected, serum lipid parameters improved during LDL–A, and significant decreases in serum cholesterol, apo B and plasma Lp(a) were observed at different time‐points of LDL–A. Conversely, no significant changes in either triglyceride, HDL or apo A‐I levels were observed during LDL–A.ConclusionsThe present uncontrolled prospective study shows that LDL–A causes a rapid 30–40% decrease in serum cholesterol and plasma Lp(a) levels in patients with NS. The present prospective study also suggests that short‐term LDL–A treatment may increase serum albumin levels in nephrotic patients.
New p53 mutations in hilar cholangiocarcinoma
Authors: Tullo  , D'Erchia  , Honda  , Kelly  , Habib  , Saccone  , Sbisà  
Published: March 2003

BackgroundInactivation of the tumour suppressor gene, p53, is the commonest genetic abnormality in human cancer. The study of the type of p53 mutation in a given tumour may provide prognostic information, clues to aetiology and become useful for therapeutics.Materials and MethodsThe molecular characterisation of p53 was performed by restriction analysis, denaturing gradient gel electrophoresis, and gene sequencing for exons 5–9.ResultsWe report, p53 mutational analysis in exons 5–9 in 29 European patients with hilar cholangiocarcinoma who underwent attempted resection. Four patients (14%) showed somatic single nucleotide substitutions with amino acid changes (146, 163, 175, 158, and 175) with one showing mutations in two different positions involving a loss of two CfoI sites. All the mutations occurred in exon 5. Three patients had a germline polymorphism (10%) with a silent substitution in codon 213 (exon 6).ConclusionsThe systematic screening for p53 mutations in European patients with hilar cholangiocarcinoma has shown that the type of mutation (except 175) is different and its incidence is much lower when compared to the pattern previously reported for intrahepatic cholangiocarcinoma in East Asian patients. A probable explanation is that the presence and type of p53 mutation is dependent on geographic and environmental factors which vary in different populations.
ACE‐inhibition modulates some endothelial functions in healthy subjects and in normotensive type 1 diabetic patients
Authors: Schalkwijk C. G. , Smulders R. A. , Lambert J. , Donker A. J. M. , Stehouwer C. D. A. 
Published: March 2003

BackgroundThe usefulness of treatment with an angiotensin‐converting enzyme‐inhibitor (ACE‐inhibitor) in normotensive patients with type 1 diabetes is controversial. We investigated whether ACE‐inhibition improves endothelial function in such patients and compared the responses to those in healthy subjects.DesignWe studied 23 healthy volunteers (controls, aged 29.8 [SD 7.0] years) and 24 type 1 diabetic patients (aged 28.7 [9.6] years; HbA1c 8.1 [1.2]%; diabetes duration 13.8 [2–30] years; blood pressure < 140/90 mmHg; 7 with microalbuminuria) after 5 weeks of ACE‐inhibition (quinapril, 10 mg day−1) and placebo in a randomized, double‐blind cross‐over design. Estimates of endothelial function obtained were by flow‐mediated vasodilation and plasma levels of endothelium‐derived proteins.ResultsAs estimated from the measurements on placebo, type 1 diabetic patients, as compared to the controls, had some impairment of endothelial function: plasma tissue‐type plasminogen activator levels were lower (3.5 vs. 5.4 ng mL−1, P < 0.05), but there were no significant differences in brachial artery flow‐mediated vasodilation or plasma levels of von Willebrand Factor, endothelin‐1, plasminogen activator inhibitor‐1, soluble E‐selectin or vascular cell adhesion molecule‐1. As compared to placebo, ACE‐inhibition increased flow‐mediated vasodilation in controls (by 3.84% points [95% CI, 0.66 − 7.02], P < 0.05), but not in type 1 diabetic patients (0.82% points [95% CI, −2.72 − 4.36], P = 0.64; P = 0.08 vs. controls). On ACE‐inhibition soluble E‐selectin levels decreased both in controls (from 43.0 to 37.0 ng mL−1, P < 0.01) and in type 1 diabetic patients (from 41.0 to 39.0 ng mL−1, P = 0.09). Other endothelial markers did not change during ACE‐inhibition.ConclusionNormotensive type 1 diabetic patients with normoalbuminara or microalbuminuria have mild endothelial dysfunction. Short‐term ACE‐inhibition improves endothelial function as reflected by a decreased sE‐selectin in healthy subjects and in normotensive type 1 diabetic patients. In healthy subjects, ACE‐inhibition increases flow‐mediated vasodilation. In contrast, in type 1 diabetic patients, ACE‐inhibition does not affect flow‐mediated vasodilation.
Cellular immune–endocrine interaction in adrenocortical tissues
Authors: Marx C. , Bornstein S. R. , Wolkersdörfer G. W. 
Published: March 2003

BackgroundThe detection of important immunocompetence‐like features on endocrine steroid cells raises questions about direct intercellular communication between the adrenal and immune systems. This article summarizes our recent work and new data on immune–adrenal interactions.Materials and methodsRT‐PCR and immunohistochemistry were performed to examine MHC class II (HLA‐DR) expression in adrenocortical tumours. Coculture systems of NCI‐H295 adrenocortical carcinoma cells and HLA‐matched lymphocytes were used to examine effects on steroid production and survival of lymphocytes..ResultsHLA‐DR m‐RNA is found in both benign and malignant adrenals, except the NCI‐H295 cell line. Under direct coculture conditions with NCI‐H295 cell line, spontaneous apoptosis of immune cells was reduced. Synthesis of cortisol and especially of dehydroepiandrosterone production of tumour cells was markedly increased. Differences by separating CD4+ and CD8+ T cells were not detected.ConclusionsDirect cellular contact between lymphocytes and adrenocortical cells seems to be involved in the peripheral regulation of androgen synthesis in the adrenal. The molecular basis of this interaction is no tknown. With regard to normal adrenals, ligation of MHC class II antigens could be a potential mechanism for a peripheral regulation of androgen secretion.
Leptin and the adrenal gland
Authors: Glasow A. , Bornstein S. R. 
Published: March 2003

BackgroundLeptin is involved in the maintenance of energy balance acting on food intake, thermogenesis and energy expenditure. Via its receptor in the hypothalamus, leptin modulates the functioning of the hypothalamic–pituitary–adrenal axis and the systemic sympathetic/adrenomedullary system, which are closely linked to the regulation of energy balance and body weight. In regard of potential interactions of leptin and adrenal hormones this study intended to characterize the role of leptin in the human adrenal gland.Materials and methodsA novel technique of laser capture microdissection was used to separate cortical and chromaffin cells for mRNA expression studies of leptin receptor isoforms and leptin mRNA in adrenal tissue and cell line NCI‐H295. Immunostaining was used to localize leptin receptor in human adrenal slices. The influence of leptin on basal and ACTH‐stimulated steroid hormone secretion and enzyme expression was assessed. The effect of leptin on proliferation and viability of adrenal cells in primary culture and of the NCI‐H295 cell line was studied by the WST‐1 assay and by 3H‐thymidine test.ResultsOur data demonstrate that leptin can regulate the human adrenal function directly, via its receptors on adrenocortical cells. Leptin decreased the corticotropin‐stimulated release of steroid hormones in vitro without any effect on cell proliferation. No influence of leptin on the expression of cytochrome P45017α and P450SCC mRNA was detected.ConclusionsThe adipo–adrenal interaction mediated by leptin further underscores the close link of metabolism and stress regulation in humans.
Molecular adrenocortical tumourigenesis
Authors: Reincke M. , Beuschlein F. , Slawik M. , Borm K. 
Published: March 2003

Adrenocortical neoplasms are the most frequent abnormality of the adrenal cortex. Most of these lesions are clinically silent and are detected incidentally by ultrasound or computed tomography. The prevalence of these so‐called ‘incidentalomas’ in the general population is around 1%, increasing with age and reaching 6% among those in the age range 60–70 years. In contrast, primary adrenocortical carcinoma, a highly malignant tumour, is rare, having an incidence of one case per million per year. Recent progress has been achieved in the understanding of adrenocortical tumourigenesis by mapping and identification of genes responsible for hereditary tumours that involve the adrenal gland. Investigation of the clonal composition of adrenal tumours demonstrates that adrenal carcinomas are monoclonal, whereas adrenal adenoma may be polyclonal in approximately 25–40% of cases. Oncogenes and tumour‐suppressor genes involved in adrenal carcinomas include mutations in the p53 tumour‐suppressor gene and rearrangements of the chromosomal locus 11p15.5 associated with IGF II hyperexpression. Constitutive activation of the ACTH receptor‐G protein‐cAMP signal cascade does not play a role in adrenal tumour formation. Conversely, deletions of the ACTH receptor gene have recently been found in undifferentiated adenomas and in aggressive adrenocortical carcinomas, and, more recently, confirmed in a larger series of tumours. The available literature indicates that the signalling pathways of adrenocortical tumours are different from those of other endocrine neoplasms, such as pituitary and thyroid adenomas.
Closed‐circuit organ perfusion technique for gene transfer into the lungs. An experimental trial on farm pigs
Authors: Parpala‐Spårman T. , Pääkkö P. , Kortteinen P. , Salonurmi T. , Lukkarinen O. , Tryggvason K. 
Published: March 2003

In an attempt to develop gene therapy for lung diseases, we have explored a closed‐circuit surgical perfusion method for gene transfer into the lung.For gene transfer we used a replication defective type 5 adenovirus carrying the E. coliβ‐galactosidase gene as a reporter gene. The middle lobe of the right lung of eight young farm pigs was perfused in vivo via thoracotomy for up to 60 min with the viral solution. The gene transfer was performed using a closed‐circuit organ perfusion method in vivo. The efficiency of gene transfer was assessed visually by analysis of histologic sections after X‐gal, PAS and immunohistochemical stainings.The lung perfusion resulted in transgene expression in the alveolar epithelial cells, capillary endothelial cells, airway epithelial cells and alveolar macrophages of the lung examined seven days after perfusion.The present results suggest that operatively performed closed‐circuit warm lung perfusion method may be used for gene transfer in treatment of diseases that have pulmonary manifestations.