bluuebunny/crossref_metadata_2025 huggingface dataset:
Massive Gastrointestinal Bleeding from Colonic Varices in a Patient with Portal Hypertension
Authors: Naef Markus , Holzinger Fernando , Glättli Andreas , Gysi Beat , Baer Hans Ulrich
Published: April 2003

Colonic variceal bleeding is a rarity and is most commonly due to portal hypertension. The present report describes a patient with portal hypertension due to portal vein thrombosis who, following esophageal transection and successful sclerotherapy, developed a massive lower gastrointestinal bleeding from colonic varices. The literature is reviewed, and the pathophysiology of this complication is discussed. Possible etiologies of this condition may be esophageal transection and devascularization, successful sclerotherapy, and extensive thrombosis of the portal vein resulting in obliteration of the coronary-azygous anastomotic system. In such a situation other potential sites of portosystemic anastomoses, such as the colon, may be opened up, resulting in the development of colonic varices. Indeed, the incidence of colonic varices in two series after sclerotherapy for esophageal varices was 60–100%. Of 33 candidates evaluated for liver transplantation, colonic varices were found in 1.
Proximal Gastrectomy and Gastric Tube Reconstruction for Early Cancer of the Gastric Cardia
Authors: Adachi Yosuke , Katsuta Takeshi , Aramaki Masanori , Morimoto Akio , Shiraishi Norio , Kitano Seigo
Published: April 2003

Background: Advances in diagnostics and techniques have increased the number of detections of early cancer of the gastric cardia. The aim of this report is to describe a new technique of proximal gastrectomy and gastric tube reconstruction using an autosuture stapler. Methods: At operation, the upper part of the stomach was fully mobilized, and the abdominal esophagus was transected. The stomach was cut between the points of the distal three fourths of the lesser curvature and a half of the greater curvature, and a gastric tube measuring 20 cm in length and 4 cm in width was made. A circular stapler was inserted through a stapled line, and direct anastomosis between the esophagus and gastric tube was completed. Results: When compared with the patients who underwent proximal gastrectomy and jejunal interposition, those who underwent gastric tube reconstruction showed a significantly shorter operation time. All 3 patients who underwent proximal gastrectomy and gastric tube reconstruction recovered uneventfully and took foods satisfactorily. Good passage through the gastric tube was recognized on roentgenography, and reflux esophagitis or stomal ulcer was not found on fiberscopy. Conclusions: We believe the procedure is technically simple and safe, and provides good postoperative results in patients with early cancer of the gastric cardia.
Differences between Experts and Trainees in the Motion Pattern of the Dominant Upper Limb during Intracorporeal Endoscopic Knotting
Authors: Emam Tarek A. , Hanna George B. , Kimber Chris , Cuschieri Alfred
Published: April 2003

Background: Very little research has been carried out on the ergonomics of surgeon-instrument interface. The aim of this study is to investigate the effect of experience on the motion pattern of the dominant upper limb during endoscopic intracorporeal knot tying. Methods: Two groups of 5 surgeons (expert consultants and higher surgical trainees) tied 360 surgeon’s knots inside an endoscopic trainer in a random sequence. Motion analysis at the elbow and shoulder joints of the dominant upper limb was carried out using 3-dimensional kinemetrix system. Each knot was distracted using a tensiometer. The endpoints were the execution time, knot quality score, angular velocity and range of movement. Kruskal-Wallis one-way analysis of variance and Mann-Whitney U test were used for analysis. Results: The expert group had a better knot quality score (p < 0.005) and shorter execution time (p < 0.0001) than beginners. Motion analysis at the shoulder joint showed that experts had a higher angular velocity (p < 0.05) and a wider range of movement with more adduction (p < 0.01) compared to beginners. No significant differences were found at the elbow. Conclusion: The better task performance by expert surgeons is associated with controlled rapid manipulations and a wider range of movement at the shoulder joint of the dominant upper limb.
Preoperative ERCP Approach to Common Bile Duct Stones:Results of a Selective Policy
Authors: Rijna H. , Kemps W.G.M. , Eijsbouts Q. , Meuwissen S.G.M. , Cuesta M.A.
Published: April 2003

Background: In a previous study, we made a plea for more selective indications for preoperative ERCP in patients with gallstones based on the results obtained from a liberal policy. Following 3.5 years of implementing this selective policy, a report on the results are presented here. This study was performed in a referral academic hospital. Methods: Between June 1994 and December 1997, 328 patients underwent cholecystectomy because of symptomatic cholelithiasis. Absolute indications for preoperative ERCP were: acute cholangitis (4 patients); obstructive jaundice (22 patients); gallstone pancreatitis (within the first 24 h in 14 patients), and wide common bile duct (CBD, >8 mm) with suspicion of stones in the biliary tree (2 patients). Results: In 42 patients (12.8%) a preoperative ERCP was performed for these indications. Stones were found in the CBD in 30 patients and edema in the papilla in 2 patients (total 76.2%). The stones could be extracted by endoscopic sphincterotomy in 24 of the 30 patients (80%). Complications were seen in 7 patients (16.7%). All these complications (bleeding of the papilla in 4 and mild pancreatitis in 3 patients) could be treated conservatively. During a mean follow-up of 2.5 years, CBD stones could be demonstrated postoperatively in 3 patients (0.3%). No mortality was observed in this series. Conclusions: The results of this selective policy included the expected outcome of a significant reduction in the number of ERCPs performed from 29 to 12.8% (p < 0.001, χ2 test) and a better yield of stones, from 29 to 76.2% of the patients. The mortality of the procedure decreased from 2 to 0% whereas morbidity remained the same. This selective policy seems adequate for the preoperative assessment of CBD stones.
Long-Term Results of Anterior Anal Sphincter Repair for Fecal Incontinence due to Obstetric Injury / with Invited Commentaries
Authors: Rothbarth J. , Bemelman W.A. , Meijerink W.J.H.J. , Buyze-Westerweel M.E. , van Dijk J.G. , Delemarre J.B.V.M.
Published: April 2003

Aims: This study is to report short- and long-term results of anterior sphincter repair for fecal incontinence due to obstetric injury and factors predicting an unsuccessful outcome. Methods: Thirty-nine consecutive patients, mean age 51 years (range 29–74), who underwent anterior sphincter repair for fecal incontinence due to obstetric injury were investigated. Duration of symptoms ranged from 9 months to 34 years. All patients underwent an anterior overlapping sphincter muscle reconstruction and in most cases a puborectal muscle plasty. Results: Three months after surgery 77% of the patients had regained continence (Parks score of 1 or 2), at 9 months 67% were continent and after 12 months or more (mean, range 12–114) only 62%. Patients with prolonged pudendal latency (>2.2 ms) did significantly worse than patients without it (p < 0.05). Patients who had had lateral episiotomy during labor had significantly better outcome than those without it (p < 0.05). Conclusion: The outcome of anterior sphincter repair deteriorates with time after surgery. Assessment should be done at least 1 year after surgery to evaluate the final results of anterior sphincter repair. Prolonged pudendal latency predicts a poor outcome of anterior sphincter repair, and a prior lateral episiotomy is possibly a good prognostic factor.
Smoking and Nicotine Dependence
Authors: Nelson Christopher B. , Wittchen Hans-Ulrich
Published: April 2003

Ths paper describes the distribution of dependence criteria and diagnoses in a sample of 14- to 24-year-olds from Munich, Germany (n = 3,021; 71% response rate), evaluates differences between nondependent and dependent smokers and examines associations of smoking with other substances, affective and anxiety disorders. Assessment was made using the M-CIDI. The lifetime prevalence of DSM-IV nicotine dependence in the total sample is 19%, rising to 52% among regular smokers. No gender differences were seen in the progression from regular smoking to nicotine dependence, although men were more likely than women to initiate regular use. Analysis of daily cigarette use identified a significant dose-response relationship with the number of endorsed DSM-IV dependence criteria with unsuccessful cut-backs being the most prevalent criterion. As compared to nondependent smokers, dependent smokers were more likely to associate negative health effects with smoking and to have a desire to change and attempt a change in their pattern of use. Regular use of nicotine was found to be significantly associated with other substance and nonsubstance disorders, although dependent regular use was more strongly associated with these disorders than nondependent regular use. These results indicate that daily smoking is a behavior which is resistant to change despite an expressed desire and repeated cut-back attempts. Although initiation of regular smoking among nonsmokers does not occur frequently after the early twenties, the risk for dependent smoking among regular users persists into adulthood and is associated with a range of mental disorders.
Overdoses and Suicide Attempts: Different Relations to Psychopathology and Substance Abuse? A 5-Year Prospective Study of Drug Abusers
Authors: Ravndal E. , Vaglum P.
Published: April 2003

Two hundred Norwegian drug abusers who consecutively applied for treatment in a therapeutic community were interviewed at intake and personally followed up on average 5 years after. Millon Clinical Multiaxial Inventory and Symptom Checklist-90 were used to assess the clients. Frequent use of opiates and number of months in inpatient treatment were associated with overdoses, while being a case on the Borderline scale or depression was related to suicide attempts. The study shows that overdoses and suicide attempts can be distinguished on the basis of their different psychopathological risk variables and their different relationship to substances. To understand the background of these phenomena is of importance in planning preventive action to hinder fatal overdose and suicide.
Cognitive-Motor Performance of Methadone-Maintained Patients
Authors: Specka M. , Finkbeiner T. , Lodemann E. , Leifert K. , Kluwig J. , Gastpar M.
Published: April 2003

Fifty-four methadone-maintained patients and 54 healthy controls, matched for age, gender and educational attainment, completed a battery of six cognitive-psychomotor performance tests. Results of previous studies were replicated in four areas. An attention task was performed less well by patients [mean difference more than 0.7 standard deviations (SD)] as was a tachistoscopic perception task (0.3 SD). On a simple-choice reaction test, patients showed higher speed in decision making and motor reaction as well as an increased number of decision errors (0.3 SD each). Performing a tracking test, patients showed less deviations (0.4 SD) combined with more time needed (0.8 SD). Our data go beyond previous (seemingly inconsistent) research findings by showing that patients did less well by more than 0.6 SD when on higher speed levels. Absolving a test on visual structuring, more patients than controls achieved a 100% accuracy level (52 vs. 30%), but at the same time patients were slower (0.6 SD) than controls. An inferior test performance of patients in methadone maintenance treatment has been confirmed in some areas, especially in attention. However, the fairly moderate size of these effects and the fact that in the majority of measures the observed variance was better explained by sociodemographic features than by group membership lead on the conclusion that belonging to the group of methadone patients alone is not necessarily sufficient to predict an impairment in cognitive-psychomotor skills. To conclude, assessment of fitness for certain tasks or occupations should be done individually for each patient and should take into account comorbidity, including the extent of alcohol and other drug use.
New European Instruments for Treatment Outcome Research: Reliability of the Maudsley Addiction Profile and Treatment Perceptions Questionnaire in Italy, Spain and Portugal
Authors: Marsden John , Nizzoli Umberto , Corbelli Claudia , Margaron Henri , Torres Miguel , Prada de Castro Isabel , Stewart Duncan , Gossop Michael
Published: April 2003

This report describes the field testing of two recently developed instruments for treatment evaluation research – the Maudsley Addiction Profile (MAP) and the Treatment Perceptions Questionnaire (TPQ) – in Italy, Portugal and Spain. The MAP and TPQ have been developed in the United Kingdom as brief instruments which contain measures of high face validity for research applications with the adult psychoactive substance use disorder population. The present study assesses the application of these instruments in the continental European context and assesses the internal and test-retest reliabilities of the items. A total of 206 subjects participated in the study (124 subjects participated in the MAP test-retest study, and 95 clients completed the TPQ). Thirteen subjects completed both the MAP and the TPQ questionnaires. Results of the study indicated that the MAP can be administered to clients in 15 min or less. The internal and test-retest reliabilities of the MAP and TPQ are satisfactory. Both instruments are suitable for treatment evaluation and other relevant research purposes in the European Union.
The Human Immunoglobulin Kappa Variable (IGKV) Genes and Joining (IGKJ) Segments
Authors: Barbié Valérie , Lefranc Marie-Paule
Published: April 2003

‘Human Immunoglobulin Kappa Variable (IGKV) Genes and Joining (IGKJ) Segments’, second report of the ‘IMGT Locus on Focus’ section, comprises five tables entitled: (1) ‘Number of human germline IGKV genes at 2p12 and potential repertoire’; (2) ‘Human germline IGKV gene table’; (3) ‘Human IGKV allele table’; (4) ‘Human germline IGKJ table’ and (5) ‘Human IGKJ allele table’. These tables are available at the IMGT Marie-Paule page from IMGT, the international ImMunoGeneTics database (http://imgt.cnusc.fr:8104) created by Marie-Paule Lefranc, CNRS, Université Montpellier II, Montpellier, France.
Evolution of the Terminal Complement Genes: Ancient and Modern
Authors: Hobart M.J.
Published: April 2003

The data on the structure and relationships of the TCC genes are reviewed and a model is presented for the processes of gene duplication by which the modern genes might have evolved. Data on variations of the overall gene numbers and relationships in modern species are also reviewed, together with the polymorphisms found in man. The apparent contradictions of lack of allelic association between markers and lack of direct evidence for recombination in the C6/C7 gene region is also discussed.
Multiple Sclerosis: Association to HLA DQα in a Tropical Population
Authors: Arcos-Burgos Mauricio , Palacio Guillermo , Sánchez Jorge L. , Londoño Ana C. , Uribe Carlos S. , Jiménez Martha , Villa Alfredo , Anaya Juan M. , Bravo María Luisa , Jaramillo Nicolas , Espinal Claudia , Builes Juan J. , Moreno Manuel , Jiménez Iván
Published: April 2003

Studies performed in subtropical populations have found significant association between the phenotype multiple sclerosis (MS) and the major histocompatibility complex (MHC). We present the results of a case-control study conducted on a tropical population (Antioquia, Colombia) in order to detect a possible association between MS and HLA DQα (HLA DQA1*) alleles. Forty chromosomes belonging to MS patients were compared to two sets of controls (40 and 910 chromosomes, respectively). The HLA DQA1*0101 and DQA1*0102 alleles were found in a significantly higher proportion among the cases than among the controls, whereas the HLA DQA1*0103 allele was found in a significantly lower proportion of the cases. These results suggest that the association of HLA DQA1*0101, DQA1*0102 and DQA1*0103 to the MS phenotype found in Caucasian subtropical populations remains in individuals with MS inhabiting the tropics. This finding could mean that the major genetic component associated to the MHC in subtropical populations is the same in the tropics.
Organizations and Gene Duplications of the Human and Mouse MHC Complement Gene Clusters1
Authors: Yang Zhenyu , Yu C. Yung
Published: April 2003

The MHC complement gene cluster (MCGC) in most people contains thirteen structural genes, pseudogenes and gene segments. Novel genes RD, SKI2W, DOM3Z and RP1 are organized as two head-to-head gene pairs between complement gene Bf and the first locus of C4. Southern blot analysis shows that single-copy genes for DOM3Z are detectable in primates and other mammals. Sequence analyses revealed that the exon- intron structures of human and mouse DOM3Z genes are identical. Both human and mouse DOM3Z  transcripts exhibit splice variants at the 5′ regions, although the open reading frames remain identical. Cloning and characterization of the mouse RP1 cDNA revealed a reading frame for 254 amino acids with a bipartite nuclear localization signal close to the amino terminus. The mouse RP1 gene consists of 7 exons and spans 12.9 kb. Located in intron 4 of mouse RP1 is an endogenous retrovirus that probably confers the androgen-responsive expression of the Slp protein in certain male mice. The availability of the complete human and mouse MCGC genomic and cDNA sequences allows further deliberate analyses of gene duplications and evolution. The intergenic region between mouse SLP and C4 genes is more than six times larger than the corresponding region in humans. It contains the functional gene steroid CYP21A, long stretches of repetitive DNA elements, and three partially duplicated gene segments TNXA, SKI2W2 and RP2. The modular duplications of human and mouse RP-C4-CYP21-TNX (RCCX) are sharply different as SKI2W2 is absent in the human MCGC, and TNXA and RP2 are smaller in size but higher in sequence conservation in humans.
The Human T cell Receptor Beta Variable (TRBV) Genes
Authors: Folch Géraldine , Lefranc Marie-Paule
Published: April 2003

‘Human T Cell Receptor Beta Variable (TRBV) Genes’, the seventh report of the ‘IMGT Locus on Focus‘ section, comprises four tables: (1) ‘Number of human germline TRBV genes at 7q35 and potential repertoire’; (2) ‘Human germline TRBV genes at 7q35’; (3) ‘Human TRBV orphons on chromosome 9 (9p21)’, and (4) ‘Human TRBV allele table’. These tables are available at the IMGT Marie-Paule page from IMGT, the international ImMunoGeneTics database (http://imgt.cines.fr: 8104) created by Marie-Paule Lefranc, Université Montpellier II, CNRS, France.
Childhood Atopic Asthma: Positive Association with a Polymorphism of IL-4 Receptor α Gene but Not with That of IL-4 Promoter or Fc ε Receptor I β Gene
Authors: Takabayashi Akira , Ihara Kenji , Sasaki Yuka , Suzuki Yuzo , Nishima Sankei , Izuhara Kenji , Hamasaki Naotaka , Hara Toshiro
Published: April 2003

We examined the relative contributions of three representative candidate genes for atopy (Fc ε receptor I β, IL-4, and IL-4 receptor α) to the development of atopic asthma. Four polymorphisms of the three candidate genes including Ile50Val and Gln551Arg of IL-4 receptor α, -590C/T of IL-4 promoter and Glu237Gly of Fc ε receptor I β were studied in 100 patients with atopic asthma and 100 nonatopic controls in the northern Kyushu area in Japan. Among the four polymorphisms of the three candidate genes, the Ile50 allele of the IL-4 receptor α chain gene demonstrated an association with atopic asthma subjects (p = 0.044), especially in patients with onset at 2 years of age or earlier (p = 0.034) and in patients with moderate to severe atopic asthma (p = 0.031). Gln551Arg of IL-4 receptor α, -590C/T of IL-4 promoter and Glu237Gly of Fc ε receptor I β showed no association with atopic asthma. A slight linkage disequilibrium between Ile50Val and Gln551Arg polymorphisms of the IL-4 receptor α chain gene was observed in both patients and nonatopic controls. The identification of additional atopy genes in areas with a certain genetic background is essential for genetic diagnosis and to establish new therapeutic modalities for atopic asthma.
The Human T Cell Receptor Alpha Variable (TRAV) Genes
Authors: Scaviner Dominique , Lefranc Marie-Paule
Published: April 2003

‘Human T Cell Receptor Alpha Variable (TRAV) Genes’, the eighth report of the ‘IMGT Locus in Focus’ section, comprises four tables: (1) ‘Number of human germline TRAV genes at 14q11 and potential repertoire’; (2) ‘Human germline TRAV genes at 14q11’; (3) ‘Human TRAV allele table’, and (4) ‘Correspondence between the different human TRAV gene nomenclatures’. These tables are available at the IMGT Marie-Paule page of IMGT, the international ImMunoGeneTics database (http://imgt.cines.fr:8104) created by Marie-Paule Lefranc, Université Montpellier II, CNRS, France.
What PAX Genes Do in the Kidney
Authors: Torban Elena , Goodyer Paul
Published: April 2003

Of the nine known PAX genes, only two (PAX2 and PAX8) are expressed in the developing kidney. Genetic evidence in mice and humans indicates that PAX2 plays a critical role in normal renal development and may sit atop a molecular cascade which unfolds during the transition from undifferentiated mesenchyme to the early stages of nephrogenesis. Less is known about the role of PAX8 in kidney development; although PAX8 is expressed in the S-shaped body and early proximal tubule, preliminary data suggest that renal morphogenesis is unaffected by its absence. In this review, we discuss the basic aspects of PAX gene structure and function and how mutations of PAX2 might interfere with structure of the developing nephron.
Origin of Glomerular Capillaries: Is the Verdict In?
Authors: Woolf Adrian S. , Loughna Siobhan
Published: April 2003

Classical studies with murine embryonic kidneys (metanephroi) grown in organ culture or on the avian chorio-allantoic membrane have suggested that kidney endothelia arise by ingrowth or angiogenesis. More recent studies, however, indicate that glomerular capillaries and arterioles may form in situ by vasculogenesis when more realistic experimental conditions are deployed: these include glomerulogenesis after transplantation of metanephroi to the nephrogenic renal cortex of mice as well as development in oculo. This conclusion is supported by the finding that receptor tyrosine kinases such as VEGFR-1/2 and Tie-1, characteristic of endothelial precursors, are expressed in the metanephros at a stage when no patent vessels are apparent. Further studies are required to determine the origin of endothelial cells in renal vessels of larger calibre.
Optimizing Ribozymes for Somatic Cell Gene Therapy
Authors: Branch Andrea D. , Klotman Paul E.
Published: April 2003

Therapeutic ribozymes are created through a multistep process that requires trial and error. There are few established rules governing ribozyme design, but guidelines are emerging. It is not yet known whether hammerheads and hairpins, the two ribozymes most widely studied as potential gene therapy agents, have the inherent capability to ablate single genes. Their capacity for specificity and selectivity remains to be explored through rigorous experimentation. These experiments require a battery of control molecules, the characteristics of which are outlined here. Methods for completing the steps in the ribozyme development process, from the selection of a target gene to the quantitation of RNA levels, are also presented and discussed.
P Glycoprotein: A New Mechanism to Control Drug-Induced Nephrotoxicity
Authors: del Moral Raimundo G. , Olmo Asunción , Aguilar Mariano , O’Valle Francisco
Published: April 2003

The role of P glycoprotein (P-gp) in kidney is now being explored, and under physiological conditions, this protein is thought to be an excretory pump of cationic xenobiotics and metabolites. Functionally, two different types of P-gp have been described, but only the class I has been related to drug transport, and its overexpression confers the multidrug resistance phenotype in tumoral cells. It has been proposed that P-gp is involved in the energy-dependent transport of substrates through the cell membrane (toxic metabolites, toxins, nutrients, ions, peptides, etc.) – like a ‘hydrophobic molecule vacuum cleaner’. Several physiological functions have been attributed to P-gp: defense against xenobiotic aggression and transmembrane transport of prenylcysteine methyl esters, removing these cytotoxic metabolites from cells. A variety of substrates ranging from chemotherapeutics to steroid hormones, antibiotics, and calcium channel blockers can be transported by P-gp, suggesting the possible involvement of this protein in other unknown functions. Results from our group and others have suggested that overexpression of P-gp in renal tubular and mesangial cells prevents pharmacological nephrotoxicity by cyclosporin A (CsA). On the other hand CsA, a substrate of the pump, could act as a blocker in tubular cells by competitive inhibition. One relevant aspect in kidney is the possible relationship between P-gp and protein kinase C. Several reports suggest that protein kinase C may play a role in inducing the P-gp overexpression in cells under xenobiotic pressure, through activation of the ras oncoprotein family. This could be mediated directly by angiotensin II as a ras activator. This way, the detoxicant function of P-gp against products of the ras catabolism could mediate their accumulation when the ‘vacuum cleaner’ function is blocked by CsA or tacrolimus, contributing to the initial development of fibroblastic activation that leads to interstitial fibrosis associated with nephrotoxicity by these immunosuppressor drugs. In conclusion, P-gp expression could be an important component of a complex detoxifying system in kidney against xenobiotics or regulating the traffic of endogenous metabolites responsible for the susceptibility of subjects to the development of nephrotoxicity against different drugs.
AT1-Receptor Antagonists Abolish Glomerular MCP-1 Expression in a Model of Mesangial Proliferative Glomerulonephritis
Authors: Wolf Gunter , Schneider André , Helmchen Udo , Stahl Rolf A.K.
Published: April 2003

Background: Glomerular accumulation of macrophages/monocytes (M/M) is a typical early feature in the course of anti-thymocyte serum (ATS)-induced nephritis. We have previously shown that glomerular synthesis and expression of monocyte-chemoattractant protein-1 (MCP-1) occurs before influx of M/M and a neutralizing anti-MCP-1 antibody reduced this cell infiltrate by one third. The present study was undertaken to test the effect of two angiotensin II type 1 (AT1) receptor antagonists, losartan and irbesartan, on ATS-stimulated MCP-1 expression as well as glomerular influx of M/M. Methods: Treatment of rats with either losartan or irbesartan was started 24 h before administration of ATS. After 24 h, MCP-1 mRNA expression was evaluated by RT-PCR and Northern blots. MCP-1 protein was determined by Western blots and chemotactic factors released from isolated glomeruli were measured by chemotactic assay. Kidney sections were stained for rabbit IgG, complement C3, and M/M (ED1 antigen). Results: Both AT1-receptor antagonists caused a significant, but not total reduction in MCP-1 mRNA and protein expression 24 h after injection of ATS. Treatment with losartan or irbesartan also reduced the chemotactic activity of isolated glomeruli from nephritic animals. Quantification of ED1-positive cells revealed that losartan as well as irbesartan reduced glomerular M/M invagination in nephritic rats by approximately 30–50%. However, treatment with AT1-receptor antagonists did not influence binding of ATS to mesangial cells and subsequent complement activation indicating that the attenuated MCP-1 expression is not due to differences in delivery and binding of ATS to mesangial cells. Conclusion: Our data indicate that short-term antagonism of AT1 receptors abolished the early glomerular MCP-1 expression and M/M influx. These results indicate that angiotensin II may exert immunomodulatory effects in vivo and adds a new mechanism showing how this vasopeptide may be involved in the pathogenesis of renal diseases.
Angiotensin II Blockade Limits Tubular Protein Overreabsorption and the Consequent Upregulation of Endothelin 1 Gene in Experimental Membranous Nephropathy
Authors: Zoja Carla , Liu Xue-Hui , Abbate Mauro , Corna Daniela , Schiffrin Ernesto L. , Remuzzi Giuseppe , Benigni Ariela
Published: April 2003

Proteinuric renal diseases are associated with excessive renal synthesis of endothelin 1 (ET-1) either in experimental animals or humans. This has been interpreted as an upregulation of ET-1 gene in proximal tubular cells secondary to overreabsorption of an unusual amount of filtered proteins. Here we used a model of chronic proteinuria, passive Heymann nephritis (PHN), to localize the structure of the kidney responsible for excessive ET-1 expression and synthesis and to clarify whether drugs that reduce glomerular protein trafficking modified the distribution of ET-1 mRNA and the corresponding peptide in the kidney. PHN was induced in Sprague-Dawley rats after injection of rabbit anti-Fx1A antibody. Group 1 (n = 5) was untreated, group 2 (n = 5) was given daily the angiotensin-converting enzyme inhibitor lisinopril (40 mg/l) plus the angiotensin II receptor antagonist L-158,809 (50 mg/l) from day 7 – when rats were already proteinuric – to month 12. An additional group of normal rats (n = 5) was used as controls. Urinary excretion of ET-1 was significantly increased in PHN rats as compared with controls and normalized by the treatment. By in situ hybridization a weak signal for ET-1 mRNA was detectable in glomeruli, distal tubular segments, and proximal tubules of control kidneys. By contrast, a strong labeling was found in the kidneys of rats with PHN which was mainly localized to proximal tubules and renal interstitium. The pattern of renal ET-1-like immunoreactivity was remarkably consistent with ET-1 mRNA expression. In animals with PHN given the angiotensin II blocking therapy, the urinary excretion of proteins normalized, and the structural integrity of the kidney was well preserved. In the kidney tissue taken from these animals, both ET-1 mRNA and protein staining were quite comparable to controls. These data suggest a link between excessive protein tubular reabsorption and enhanced renal ET-1 in chronic nephropathies and provide a novel explanation for the renoprotective effect in vivo of drugs that, by blocking the biological activity of angiotensin II, reduce glomerular protein traffic and possible deleterious effects of excessive tubular protein overloading.
Prostaglandin Receptors in the Kidney: A New Route for Intervention?
Authors: Breyer Matthew D.
Published: April 2003

Prostaglandins comprise a structurally diverse family of cyclooxygenase metabolites of arachidonic acid, including thromboxane A2, PGD2, PGE2, PGF2α and PGI2. These prostaglandins are now known to act via different G-protein-coupled receptors. PGE2, the major prostaglandin synthesized along the nephron, interacts with at least four E-prostanoid (EP) receptors, three of which are highly expressed in distinct regions of the kidney. Each EP receptor also preferentially couples to a different signal transduction pathway, including stimulation of cAMP generation by the EP2 and EP4 receptors; inhibition of cAMP generation, via Gi by EP3 receptors, and activation of phosphatidylinositol hydrolysis by EP1 receptor. Other intrarenal prostanoid receptors include the thromboxane A2 receptor and the prostacyclin receptor. These receptors also exhibit a discrete intrarenal distribution. The possibility of pharmacologically targeting each renal prostanoid receptor may provide a unique approach to modifying renal function in disease states.
Adeno-Associated Virus Gene Transfer into Renal Cells: Potential for in vivo Gene Delivery
Authors: Langer Jessica C. , Klotman Mary E. , Hanss Basil , Tulchin Natalie , Bruggeman Leslie A. , Klotman Paul E. , Lipkowitz Michael S.
Published: April 2003

The human parvovirus adeno-associated virus (AAV), type 2, has a number of features that make it an attractive choice as a vector for gene delivery to the kidney. AAV vectors permit long-term gene expression in vivo by integration into the host genome, have potential for site-specific integration on chromosome 19, do not express viral genes or generate a cellular immune response, and demonstrate enhancement of gene expression by chemotherapeutic agents that are approved for use in vivo. These properties confer advantages to AAV over other viral and nonviral methods for gene transfer. Preliminary experiments in our laboratory suggest that AAV is able to transfer genes to both renal cells in culture and the kidney in vivo. Thus, AAV has the potential to be an important gene transfer vector for the kidney in vivo.
Endogenous Inhibitors of Nitric Oxide Synthesis:How Important Are They?
Authors: MacAllister Raymond J. , Vallance Patrick
Published: April 2003

In animals and humans, inhibition of nitric oxide (NO) production has widespread effects. Reduced activity of the NO:cyclic GMP pathway has been documented in disease states, including hypertension, diabetes and certain types of renal disease. Inhibitors of NO synthesis occur endogenously, and have been implicated in the regulation of the NO pathway in health and disease. Here we review the possible biological roles of endogenous NO synthase inhibitors, with particular reference to renal disease.
Production of Inflammatory Mediators and Cytokine Responsiveness of an SV40-Transformed Human Proximal Tubular Epithelial Cell Line
Authors: Gerritsma Jort S.J. , van Kooten Cees , Gerritsen Arnout F. , Mommaas A. Mieke , van Es Leendert A. , Daha Mohamed R.
Published: April 2003

Proximal tubular epithelial cells (PTEC) play a central role in the physiology of the renal tubulointerstitium. To be able to study the relationship between tubular cells and inflammatory renal diseases the availability of cultured cells is of importance. This study describes an immortalized proximal tubular epithelial cell line which was generated using SV40 DNA. To determine whether the transformation altered the cell line, the transformed cell line was characterized phenotypically using different monoclonal antibodies directed against peptidases, which are characteristic of PTEC, such as adenosine deaminase binding protein (CD26), leucine amino peptidase and carboxy peptidase M by immunofluorescent staining and FACS analysis. All peptidases were clearly present on the parental cell line and the transformed cell line. However, the level of expression of the peptidases was lower on the transformed cell line as compared to the parental nontransfected cells. The morphology of the transformed cell line, determined using a transwell culture system and electron microscopy, showed a polarized morphology of the tubular cells, tight junctions and microvilli. The transformed cell line was compared with the parental proximal tubular epithelial cells in its ability to respond to inflammatory cytokines such as IL-1α, TNF-α, IFN-γ. Stimulation with these cytokines resulted in enhanced production of complement components C2, C3, C4 and factor H, IL-6 and the chemokines IL-8 and MCP-1. The transformed cell line responded in a similar fashion as the parental cell line, although the amount of the different proteins produced was significantly higher in the transformed cell line. Overall, the transformed tubular cell line seems to be a suitable model to study different effects on tubular cells in relation to inflammatory kidney diseases.
Expression of Cytoskeletal Proteins Differentiates between Progressors and Non-Progressors in Treated Idiopathic Membranous Nephropathy
Authors: Tamimi N.A. , Stevens P.E. , O’Donnell P.L. , Strange P.G. , Muchaneta-Kubara E.C. , El Nahas A.M.
Published: April 2003

Myofibroblasts play an important role in wound healing in a variety of tissue injuries. They have also been implicated in tissue fibrosis including renal scarring. This study was aimed at defining their role in one of the commonest forms of nephrotic syndrome in adults, namely membranous nephropathy. We have studied 21 patients with biopsy proven idiopathic membranous nephropathy who were treated with glucocorticoids, attempting to define the role of myofibroblasts (α-smooth muscle actin-positive as well as vimentin-positive cells) in the progression of this form of nephropathy. There were 13 non-progressors (NP) and 8 progressors (P). The clinical, histological, and immunohistochemical characteristics of both groups were compared. Immunohistochemical staining for myofibroblasts cytoplasmic markers α-smooth muscle actin (α-SMA) and vimentin relied on an avidin-biotin-peroxidase method. The level of blood pressure, degree of proteinuria, severity of interstitial infiltrate and interstitial fibrosis did not differentiate P from NP. However, vascular sclerosis was more severe in P compared to NP (p < 0.016) and its severity predicted the subsequent functional outcome (slope of the 1/serum creatinine against time; r2 = 0.618, p < 0.01). Mesangial α-SMA was significantly higher in P (31 ± 18.6%) than in NP (14.5 ± 9.8%), p < 0.015. Interstitial α-SMA immunostain was also higher in P but did not reach statistical significance. However, the number of interstitial myofibroblasts (α-SMA positive cells) closely predicted the subsequent rate of the progression of chronic renal failure (r2 = 0.919, p < 0.0001). Mesangial vimentin expression was not different between both groups. By contrast, interstitial vimentin immunostain was higher in P (19.1 ± 8.8%) compared to NP (7.9 ± 5.6%), p < 0.002. These data suggest that the expression of mesangial and interstitial cytoskeletal proteins (α-SMA and vimentin) may have useful prognostic implications as they appear to differentiate between patients with membranous nephropathy who respond to immunosuppression and those who continue to progress.
Reversal of Convention: From Man to Experimental Animal in Elucidating the Function of the Renal Amiloride-Sensitive Sodium Channel
Authors: Hummler Edith
Published: April 2003

The kidney plays a dominant role in maintaining sodium homeostasis. Despite wide variation in environmental exposure, the osmolality of the extracellular fluid that is determined by the sodium ion concentration is maintained within narrow margins. Derangement in function of proteins that transport Na+ and of those regulating the activity of these sodium-transporting proteins are likely to be responsible for a number of clinical disorders of fluid and electrolyte homeostasis. The amiloride-sensitive epithelial sodium channel (ENaC) is implicated in the control of blood pressure as demonstrated by the analysis of two genetic diseases, Liddle’s syndrome and pseudohypoaldosteronism (PHA-1). Mutations have been identified in the genes coding for the α-, β- or γ-subunit of ENaC. ENaC constitutes the limiting step for sodium reabsorption in epithelial cells that line the distal nephron, distal colon, ducts of several exocrine glands and lung airways and might play an important role in pathophysiological and clinical conditions such as hypertension or lung edema.
Is Angiotensin II a Key Regulator of Proximal Tubular Function? Some Answers and New Questions
Authors: Yanagawa Norimoto
Published: April 2003

Recent studies have revealed the existence of intrarenal renin-angiotensin system and broadened our understanding on the role of angiotensin II in the regulation of proximal tubular functions. The aims of the present review are to summarize these recent findings and to highlight new questions that have arisen therefrom.
Autoimmune Tubulointerstitial Nephritis: Insight from Experimental Models
Authors: Wüthrich Rudolf P. , Sibalic Vladimir
Published: April 2003

Many forms of tubulointerstitial nephritis (TIN) may have an autoimmune origin. To understand the pathogenesis of autoimmune TIN it is important to examine suitable animal models where the initiation and development of tubulointerstitial diseases can be assessed with precision. Experimental models of autoimmune anti-tubular basement membrane (anti-TBM) disease for example have allowed to define the nephritogenic role of antibodies which target tubulointerstitial moieties. Several tubulointerstitial antigens which are recognized by specific anti-TBM antibodies have been characterized at a molecular level in these models. The CBA/CaH-kdkd mouse strain represents another model of TIN where complex T-cell networks are uniquely altered, resulting in cell-mediated interstitial nephritis. Characteristic tubular alterations (up-regulation of adhesion molecules and CD44, cytokine and chemokine secretion) are prominent in several models of experimental TIN, promoting T-cell and monocyte infiltration. The complex interplay between tubular epithelial cells and immune cells is probably a prerequisite for a coordinated immune response in many forms of TIN, resulting in autoimmune renal tubulointerstitial injury and ultimately in renal failure.
Changes in Kidney Volume during Pregnancy in Non-Diabetic and Diabetic Rats Measured by Magnetic Resonance Imaging
Authors: Christiansen Thora , Stødkilde-Jørgensen Hans , Klebe Joachim G. , Flyvbjerg Allan
Published: April 2003

Consecutive magnetic resonance images were obtained in pregnant animals and their respective controls, and changes in kidney, cortex, medulla, and pelvis volumes were calculated. In non-diabetic pregnant animals, a marked increase in kidney and cortex volumes was observed within the first 15 days of pregnancy (29 and 20%, respectively), while no significant changes were seen in medulla or pelvic volumes. Five days later (near term) and after delivery, kidney and cortex volumes had decreased to values before pregnancy. In pregnant diabetic animals, a 26% increase in renal volume was seen over the first 15 days of pregnancy when compared to the increase seen in non-diabetic pregnant animals. Pregnant diabetic animals had a parallel increase in cortex and medulla volumes, but still no changes in the pelvis volume. In contrast to non-diabetic pregnant animals a non-heterogeneous pattern in renal volume was seen post partum, as not all animals normalized their renal volume.
Quantitative Morphology of Renal Cortical Structures during Compensatory Hypertrophy
Authors: Pfaller Walter , Seppi Thomas , Ohno Akihiro , Giebisch Gerhard , Beck Franz X.
Published: April 2003

The compensatory hypertrophy in different renal cortical structures was studied in rats 10 and 21 days after unilateral nephrectomy (UNX). Quantitative morphological/stereological analysis revealed significant increases in total renal cortical volume – 33% on day 10 and 48% on day 21 – after UNX. These changes were paralleled by significant increments in the volumes of proximal convoluted tubule (PCT, 55%), distal convoluted tubule (DCT, 114%), and cortical collecting duct (CCD, 106%) segments on day 10. The corresponding changes on day 21 were 76, 122, and 212%, respectively. These alterations were accompanied by increases in segment length; 3% PCT, 23% DCT, and 50% CCD on day 10 and 9% PCT, 30% DCT, and 142% CCD on day 21 after UNX. The total luminal and basolateral cell membrane surface areas also exhibited a time-dependent increase after UNX. The increments in both luminal and basolateral membrane domains in PCT and DCT after 10 days were not significant, but reached significance after 21 days (PCT: luminal membrane 21%, basolateral membrane 63%; DCT: luminal membrane 98%, basolateral membrane 63%). In contrast, CCD membrane areas had increased substantially already 10 days after UNX (luminal membrane 92%, basolateral membrane 71%). It declined subsequently by day 21 (luminal membrane 57%, basolateral membrane 32%). The cell rubidium concentration after a 30-second rubidium infusion, an index of Na-K-ATPase activity, as well as sodium concentrations were unaltered in cells of all nephron segments investigated. Altogether the stereological analysis shows that the compensatory increase in organ volume can be attributed primarily to an increase in nephron epithelial volume. The PCT responds with ‘radial’ hypertrophy (thickening of the tubular epithelial wall), while the DCT undergoes ‘length’ hypertrophy (increase of tubular length without thickening of the tubular wall and without an increase in number of cells). This type of hypertrophy is especially prominent on day 21 after UNX for the CCD which doubles in length. Only on day 10 does the CCD seem to respond with hyperplasia. Adaptive changes in response to UNX develop gradually. Only a few of the morphological parameters studied had completed their change by 10 days, the majority required longer.
Apoptosis in Glomerular Endothelial Cells during the Development of Glomerulosclerosis in the Remnant-Kidney Model
Authors: Kitamura Hiroshi , Shimizu Akira , Masuda Yukinari , Ishizaki Masamichi , Sugisaki Yuichi , Yamanaka Nobuaki
Published: April 2003

Capillary obsolescence with subsequent glomerulosclerosis is a common finding in most progressive glomerular diseases. In this study we investigated apoptosis, focusing on glomerular endothelial cells during the development of glomerulosclerosis in five-sixths nephrectomized rats for 6 months. Apoptosis was recognized by light and electron microscopy. Biochemical labeling of apoptosis was morphologically confirmed by in situ end labeling of fragmented DNA using terminal deoxynucleotidyltransferase. Glomerular endothelial cells were identified by electron microscope and immunostaining for thrombomodulin which is known to be an endothelial cell surface glycoprotein. Glomerular hypercellularity occurred by month 2, peaking by month 3, and an extracellular matrix accumulation was evident by month 3. Subsequently, most of the glomeruli progressed to diffuse sclerosis by months 4–6. During the progression of the disease, the glomerular endothelial cells decreased in number and finally could not be detected in the sclerotic lesion, and apoptotic cells apparently increased in number in the lesion. Significant apoptosis was present from month 3, thereafter it gradually increased to peak by month 6. Double immunostaining for apoptosis and thrombomodulin demonstrated that apoptosis occurred in the glomerular endothelial cells as well as in mesangial cells and infiltrating cells. The number of glomerular endothelial cells with apoptosis increased with the development of glomerulosclerosis, and maximum expression was observed by month 6. We conclude that the depletion of glomerular endothelial cells is associated with apoptosis in the remnant-kidney model, and apoptosis in glomerular endothelial cells may contribute to the development of glomerulosclerosis.