bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal in situ Hybridization Studies of Extracellular Matrix Related Molecules in Type 1 Diabetes mellitus
Authors: Suzuki Daisuke , Yagame Mitsunori , Kim Youngki , Sakai Hideto , Mauer Michael
Published: April 2003

Background/Aim: Progressive expansion of mesangial matrix and glomerular basement membrane thickening represent alterations in the balance between synthesis and degradation of glomerular extracellular matrix (ECM) protein and are hallmarks of diabetic nephropathy. In order to elucidate the basis for this imbalance between the synthesis and the degradation of ECM in renal tissues from patients of type 1 diabetes mellitus (type 1D) with diabetic nephropathy (DN), we examined the expression of α1 chain of type IV collagen (IV-C), matrix metalloproteinase-2 and -3 (MMP-2, MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and β-actin mRNA using a high-resolution in situ hybridization with digoxigenin-labeled oligonucleotide. Methods: Patients were divided into two groups based on both of degree of mesangial expansion using electron microscopic point counting morphometric methods and duration of type 1D: 7 ‘fast-track’ patients were selected for their very rapid development of DN structural changes and 8 ‘slow-track’ patients for their very slow development of DN structural changes. Seven normal human kidney (NHK) tissues were used as controls. Results: Positive cells for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman’s capsule. The percentage of glomerular cells positive for IV-C, MMP-2 and MMP-3 mRNA was significantly greater in the ‘slow-track’ vs. ‘fast-track’ patients. No significant differences in percentage positive cells was seen for β-actin mRNA. Furthermore, to elucidate the total number of positive cells per glomerulus for each mRNA, we estimated total cell number of glomerulus using morphometric techniques on light microscopy tissues. The total cell number per glomerulus was significantly greater in ‘fast-track’ than that in ‘slow-track’ patients and NHK. The total number of positive cells per glomerulus for MMP-2 in NHK was significantly greater than that in ‘slow-track’ and ‘fast-track’ patients. Conclusion: Thus, IV-C, MMP-2, MMP-3 and TIMP-1 mRNA are expressed in resident glomerular cells in renal tissues from NHK and type 1D. Glomerular alterations in these in situ mRNA expressions sufficient to explain ECM accumulation and DN risk were not uncovered. These largely negative results could be due to methodologic quantitative imprecision or could indicate that post-translational differences account for ECM imbalance in DN. However, these studies make it clear that unraveling the nature of the ECM production/removal imbalance in DN will require careful consideration of alterations in glomerular cell number.
Familial Juvenile Gouty Nephropathy: Exclusion of 16p12 from the Candidate Locus
Authors: Ohno Iwao , Ichida Kimiyoshi , Okabe Hideaki , Moritani Maki , Itakura Mitsuo , Saito Masayuki , Kamatani Naoyuki , Hosoya Tatsuo
Published: April 2003

Background/Aims: Familial juvenile gouty nephropathy (FJGN, MIM 162000) is an autosomal-dominant renal disease characterized by underexcretion-type hyperuricemia, gouty arthritis, and progressive renal disease at younger ages. We analyzed the localization of the responsible gene for FJGN concerning the chromosomal region of 16p12 using parametric linkage analysis in our FJGN. Methods: The affected members of this family were accompanied with polyuria due to nephrogenic diabetes insipidus and without hypertension. Fifteen samples were collected from 9 affected and 6 nonaffected members of the family. By using microsatellite markers mainly focused on the short arm of chromosome 16, two point and multipoint linkage analyses were carried out. Results: All of the 2-point logarithm of odds (LOD) scores were typically negative and all of the multipoint LOD scores were less than –3.0 in our FJGN family. Conclusion: The results suggested that the localization of the responsible gene to 16p12 can be excluded in our FJGN family. This finding means that the responsible gene for FJGN is not common.
Pyloric Drainage (Pyloroplasty) or No Drainage in Gastric Reconstruction after Esophagectomy: A Meta-Analysis of Randomized Controlled Trials
Authors: Urschel John D. , Blewett Chris J. , Young J. Edward M. , Miller John D. , Bennett W. Frederick
Published: April 2003

Background/Aim: A gastric conduit is usually used to reconstruct the foregut after esophagectomy for cancer. The gastric emptying may be impaired after this operation, so some esophageal surgeons routinely add a pyloric drainage procedure (pyloroplasty or pyloromyotomy). We performed a meta-analysis of randomized controlled trials (RCTs) to determine the effect of pyloric drainage on patient outcomes. Methods: Medline and manual searches were done (completed independently and in duplicate) to identify all published RCTs that addressed the issue of pyloric drainage procedures during gastric conduit reconstruction of the esophagus. The selection process was inclusive; no trials were excluded. Trial validity assessment was done, and a trial quality score was assigned. Early outcomes assessed by meta-analysis included operative mortality, esophagogastric anastomotic leaks, pulmonary morbidity, pyloric drainage complications, fatal pulmonary aspiration, and gastric outlet obstruction. A random-effects model was used, and the relative risk was the principal measure of effect. Systematic semiquantitative review was used for late outcomes such as gastric emptying, bile reflux, nutritional status, and obstructive foregut symptoms. Results: Nine RCTs, that included a total of 553 patients, were selected, with quality scores ranging from 1 to 4 (5-point Jadad scale). Selection and validity agreement was strong. The relative risk (95% CI; p value), expressed as pyloric drainage versus no drainage (treatment vs. control), was 0.92 (0.34, 2.44; p = 0.86) for operative mortality, 0.90 (0.47, 1.76; p = 0.77) for esophagogastric anastomotic leaks, 0.69 (0.42, 1.14; p = 0.15) for pulmonary morbidity, 2.55 (0.34, 18.98; p = 0.36) for pyloric drainage complications, 0.25 (0.04, 1.60; p = 0.14) for fatal pulmonary aspiration, and 0.18 (0.03, 0.97; p = 0.046) for gastric outlet obstruction. Systematic semiquantitative review showed a nonsignificant trend favoring pyloric drainage for the late outcomes of gastric emptying, nutritional status, and obstructive foregut symptoms. For the late outcome of bile reflux, there was a nonsignificant trend favoring the no-drainage group. The scintographic gastric emptying time, expressed as a ratio (pyloric drainage/no drainage), was 0.53. Conclusions: Data synthesized from existing RCTs show that pyloric drainage procedures reduce the occurrence of early postoperative gastric outlet obstruction after esophagectomy with gastric reconstruction, but they have little effect on other early and late patient outcomes.
Isolated Roux Loop Duct-to-Mucosa Pancreaticojejunostomy Avoids Pancreatic Leaks in Pancreaticoduodenectomy
Authors: Khan Abdaal W. , Agarwal Anil K. , Davidson Brian R.
Published: April 2003

Background: Over the last decade the operative mortality associated with pancreaticoduodenectomy (PD) has decreased. Pancreatic anastomotic leaks resulting in pancreatic bed sepsis and fistulae, however, remain a significant cause of both morbidity and mortality. The optimal method of reconstruction to minimise pancreatic leaks is controversial. Aim: To review the experience of Roux loop duct-to-mucosa pancreaticojejunostomy in a consecutive series of patients undergoing pancreatic head resection. Methods: Over the 6-year period (1993–1998), 41 patients underwent pancreatic head resections for benign (n = 5) and malignant disease (n = 36). There were 19 males and the median age was 62 years (range 29–83). An isolated Roux loop pancreaticojejunostomy was performed in all cases. Results: Median duration of surgery was 8 h and the median postoperative stay was 16 days. The mean peri-operative blood transfusion was 2.9 units (SD 1.9). The incidence of major complications was 12% and there was 1 death (2.4%). There were no pancreatic leaks or fistulae. Conclusions: The low complication rate and the absence of pancreatic fistulae in this series would suggest that Roux loop duct-to-mucosa pancreatic reconstruction should be more widely adopted.
Changes in Bone Mineral Density, Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 in Kidney Transplant Recipients
Authors: Söylemezoglu Oguz , Derici Ulver , Arinsoy Turgay , Hasanoglu Alev , Ozkaya Ozan , Dalgıc Aydın , Bideci Aysun , Buyan Necla , Hasanoglu Enver
Published: April 2003

Background: Osteopenia is a major complication of renal transplantation (RTx). This cross-sectional and longitudinal study was planned to better define long-term bone status and relationship to IGF system components. Methods: Serial measurements of bone mineral density (BMD) and serum markers were performed in 30 patients prior to RTx and at 6 and 12 months following RTx. Serum concentrations of insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), vitamin D, and intact parathyroid hormone (iPTH) were measured. Results: Serum creatinine, phosphate, alkaline phosphatase and osteocalcine levels decreased, serum calcium levels increased and serum iPTH levels did not change significantly after transplantation. The mean BMD of the vertebrae was 0.97 ± 0.22 g/cm2 at the time of RTx, 0.87 ± 0.21 g/cm2 6 months post-RTx (p < 0.05), and 0.81 ± 0.21 g/cm2 12 months post-RTx (p < 0.05). Femur BMD also declined from 0.79 ± 0.16 to 0.72 ± 14 g/cm2 at 12 months (p < 0.05). There was a significant increase in the IGF-1 and a significant reduction in the IGFBP-3 concentrations at 6 months post-RTx (p < 0.05). Significant correlations between serum IGF-1 concentrations and vitamin D concentrations were noted only at 6 months. There was no significant correlation between the BMD and serum IGF system. Conclusions: These results demonstrate a significant loss of BMD after RTx. The circulating levels of IGF-1 and IGFBP-3 stimulated by the reduction in BMD and IGF-1 secretion are increased in order to restore bone formation.
Efficacy and Safety of Losartan in Patients with Proteinuria
Authors: Leu Jyh-Gang , Huang Chee-Ming , Kao Shang-Jyh , Jiang Wey-Wen
Published: April 2003

The renoprotective effect and safety of an angiotensin II receptor blocker, losartan, were studied in 11 diabetic and 14 nondiabetic patients with a daily urinary protein excretion >500 mg. Once-daily losartan was administered to all patients for 16 weeks without diuretics or other antihypertensive agents. A daily dose of 50 mg was given to those patients with a sitting systolic blood pressure of between 130 and 170 mm Hg; 25 mg was given to patients with a systolic blood pressure of between 110 and 130 mm Hg. Sixteen patients (6 diabetic and 10 nondiabetic patients) had a more than 25% decrease of their daily urinary protein excretion (response rate 64%). The mean decrease in these 16 patients was 57 ± 17% (p < 0.05). Two patients (1 diabetic and 1 nondiabetic) had more than a 25% increase of their urinary protein excretion. The trough sitting systolic blood pressure of all patients (n = 25) decreased from 142 ± 17 to 125 ± 13 mm Hg (p < 0.05) and the trough sitting diastolic blood pressure from 87 ± 11 to 78 ± 11 mm Hg (p < 0.05). Serum uric acid was measured in 16 patients; a decrease from 7.3 ± 1.6 to 6.6 ± 1.4 mg/dl (a 9.6% decrease, p < 0.05) was found after 16 weeks. Our study showed that in both diabetic and nondiabetic proteinuric patients once-daily losartan, given as monotherapy at doses of 25 or 50 mg, was effective in reducing blood pressure, serum uric acid levels, and daily urinary protein excretions.
Successful Treatment of Renovascular Hypertension due to Fibromuscular Dysplasia by Intravascular Ultrasound-Guided Atherectomy
Authors: Hoshino Yoichi , Nakamura Tetsuya , Nakano Akihiko , Isobe Zen , Suguta Masahiko , Tomita Tomoyuki , Yokoyama Tomoyuki , Hasegawa Akira , Kurabayashi Masahiko
Published: April 2003

A 22-year-old man presented with renovascular hypertension, based on a stenosis of the distal portion of the right renal artery with a ‘string of beads’-like appearance. An intravascular ultrasound image at the renal artery lesion revealed irregularity of the vascular wall. Directional atherectomy was performed and histopathology of atherectomised tissues showed medial fibroplasia, a common type of fibromuscular dysplasia. After atherectomy his hypertension was markedly improved. We report here a case of renovascular hypertension due to fibromuscular dysplasia, successfully diagnosed and treated with IVUS-guided renal atherectomy.
Immunohistochemical Expression of Caspase-3 as an Adverse Indicator of the Clinical Outcome in Human Breast Cancer
Authors: Nakopoulou Lydia , Alexandrou Paraskevi , Stefanaki Kalliopi , Panayotopoulou Effie , Lazaris Andreas C. , Davaris Panayiotis S.
Published: April 2003

Objective: Tumor growth is the net result of cell proliferation and cell loss by apoptosis. Caspase-3 (CPP32) has been considered as most directly correlated with apoptosis because of its location in the protease cascade pathway. The aim of this study was to examine the relation of the immunohistochemical expression of caspase-3 in 137 infiltrating breast carcinomas to patients’ clinicopathological parameters and survival. Method: A polyclonal antibody against caspase-3 was applied using a standard immunohistochemical procedure to paraffin sections. Results: By comparison with nonneoplastic breast tissue, caspase-3 appeared to be upregulated in malignant breast tissue, and its overexpression status was detected in 75.2% of the specimens. Significant statistical correlations were observed between overexpression of caspase-3 and low nuclear grade (p = 0.048), lack of p53 protein accumulation (p = 0.039), bcl-2-positive immunostaining (p = 0.027), as well as tissue inhibitor of metalloproteinase-2 immunoreactivity of neoplastic (p = 0.012) and stromal cells (p = 0.0001). Despite the above correlations, multivariate analysis revealed a significant negative influence of caspase-3 expression on patients’ overall survival (p = 0.029). Conclusions: Caspase-3 protein overexpression appears to be involved in the apoptotic pathways influenced by wild-type p53 and bcl-2 proteins. Moreover, the results show that caspase-3 overexpression in breast cancer cells seems to exert an independent adverse effect on patients’ overall survival.
Attenuation of LPS-Induced Changes in Synaptic Activity in Rat Hippocampus by Vasogen’s Immune Modulation Therapy
Authors: Nolan Yvonne , Minogue Aedín , Vereker Emily , Bolton Anthony E. , Campbell Veronica A. , Lynch Marina A.
Published: April 2003

Systemic injection of lipopolysaccharide (LPS) blocks the expression of long-term potentiation in the hippocampus of the rat. This is coupled with increased IL-1β concentration and c-Jun NH2-terminal kinase activity, as well as an increase in the number of cells displaying apoptotic characteristics in the hippocampus. Vasogen’s Immune Modulation Therapy (IMT) is a procedure involving intramuscular administration of syngeneic blood which has been exposed ex vivo to elevated temperature, oxidation and ultraviolet light. We report that Vasogen’s IMT significantly abrogates these LPS-induced effects with a concomitant increase in the concentration of the anti-inflammatory cytokine IL-10. These data suggest that Vasogen’s IMT may play a protective role against the deleterious effects of immune insults in the brain.
Preferential Survival of an MBP-Specific T Cell Clone in an HLA-DR2 Multiple Sclerosis Patient
Authors: Démoulins T. , Naccache L. , Clayette P. , Musette P. , Bequet D. , Gachelin G. , Dormont D.
Published: April 2003

Anti-myelin basic protein (MBP) autoreactive T cells play a key role in the pathogenesis of multiple sclerosis. Thus, we applied the Immunoscope strategy to cerebrospinal fluid (CSF) and peripheral blood lymphocytes (PBLs) of an HLA-DR2 patient. Both compartments showed major expansion for the Vβ13S5 chain, which was associated in peripheral blood with significant proliferation of PBLs in response to MBP and the 84–102 HLA-DR2-restricted peptide. Sequencing revealed a unique nucleotide sequence in the CSF that gives rise to the amino acid sequence Vβ13S5-RPGQGDQETQ-Jβ2.5 if translated. This CDR3 sequence had already been reported to be reactive against the 84–102 peptide. This specific sequence was not detected in PBLs on day 0, whereas it was readily detectable on day 6 culture samples. Thus, cell culture may lead to enrichment in a T cell clone identified as autoreactive.
Effect of Helicobacter pylori Infection on the Activity of Class I, III and IV Alcohol Dehydrogenase in the Human Stomach
Authors: Chrostek L. , Jelski W. , Szmitkowski M. , Laszewicz W.
Published: April 2003

Background/Aims: In the human stomach various alcohol dehydrogenase (ADH) isoenzymes exist. The gastric ADH activity is affected by a number of factors including also the infection of Helicobacterpylori. The objective was to investigate the activity of alcohol dehydrogenaseisoenzymes of class I, III and IV in endoscopic specimens of gastric mucosa from the different parts of the stomach of men and women, considering the H. pylori infection. Method: Biopsy samples of gastric mucosa were taken from the corpus and antrum of 68 patients (42 of men and 26 of women) suspected for gastric ulcer. The colonization of H. pylori was present in 22 samples of men and 13 samples of women. The activity of class I isoenzyme was measured by the fluorimetric method with a specific substrate (4-methoxy-1-naphthaldehyde) and the activity of class III and IV by the photometric method with n-octanol and m-nitrobenzaldehyde as a substrates, respectively. Results: In infected samples from the antrum and corpus of men’s and women’s stomachs the activity of class IV isoenzyme was decreased as compared to non-infected specimens. The activity of class III isoenzyme was decreased in the infected samples from the corpus of male patients, but the activity of class I does not significantly differ between infected and noninfected specimens from both sexes. Conclusion:H. pylori infection leads to significant decrease in the activity of class IV ADH in the stomach of men and women.
Renal Cell Carcinoma Complicated by Emphysematous Pyelonephritis in a Non-Diabetic Patient with Renal Failure
Authors: Lin Cheng-Hao , Huang Jeng-Jong , Liu Hsin-Liang , Lee Szu-Yuan , Hsieh Ryh-Yaw , Tseng Chin-Chung
Published: April 2003

A 72-year-old non-diabetic uremic woman underwent right nephrectomy for urolithiasis at the age of 50. Because pyuria, fever, chilliness and left flank pain developed during preparing for arteriovenous fistula, she was admitted to National Cheng Kung University Hospital. Renal cell carcinoma (RCC) complicated with emphysematous pyelonephritis (EPN) was diagnosed and immediately treated with antibiotics and CT-guided percutaneous catheter drainage. Cultures of pus and blood yielded Escherichia coli. She received left radical nephrectomy later for the control of persistent sepsis and removal of left renal tumor. The pathology of the tumor was composed of a glandular arrangement of granular cells with the occasional atypism, and renal parenchyma had been totally replaced by RCC. The non-tumor part of the kidney showed chronic pyelonephritis. Five months later, multiple metastases developed. We reported this first uremic case with EPN and RCC, but without diabetes mellitus and urinary tract obstruction. The gas formation may be due to large RCC, which caused impaired tissue perfusion and E. coli infection.
Renal Transplantation of Highly Sensitised Patients via Prioritised Renal Allocation Programs
Authors: De Meester Johan , Doxiadis Ilias I.N. , Persijn Guido G. , Claas Frans H.J.
Published: April 2003

Background: Highly sensitised renal transplant candidates (HSP) have a reduced chance of receiving a transplant. In Eurotransplant (ET), two special allocation programs have been made available for such patients: the Highly Immunised Tray (HIT) program and the Acceptable Mismatch program (AM), albeit with different inclusion and exclusion criteria (HIT, current PRA% ≧85%; AM, current and/or historical PRA% ≧85%). When a suitable kidney is available for a patient, included in these special programs, the kidney is mandatory offered. In contrast, in the point score system of the standard ET kidney allocation procedure (ETKAS), HSP (PRA ≧85%) only get a marginal bonus according to their current sensitisation. It was tested whether the allocation priority of the two special allocation programs is justified from the perspective of transplant outcome. Methods: The post- transplant outcomes of recent consecutive cohorts of AM, HIT and HSP-ETKAS transplants were compared. The end points were initial graft function, rejection episodes during the first three months post-transplant, and 1-year kidney graft outcome. Results: Between January 1, 1997 and June 30, 1998, 101 HSP received a kidney-only transplant: 29 via AM, 39 via HIT and 33 via ETKAS. HLA-A,B,DR matching was more favourable in the AM and HIT allocation groups and their waiting times till transplantation were much shorter than those of the HSP-ETKAS allocation group. The incidence of initial graft non-function was similar among the three HSP allocation groups, averaging 50%. Recovery of the initial non-function was more likely for AM and HIT transplants. No difference was present with regard to the percentage of patients who experienced at least one rejection episode during the first three months post-transplant, averaging 43%. However, the AM group had less severe and/or less recurrent rejection episodes. The 1-year kidney graft survival, censored for death with functional graft, was 96% for AM, 82% for HIT and 75% for HSP-ETKAS transplants (p = 0.04). Conclusions: The two special allocation programs for HSP do yield adequate results and offer a shorter waiting time, compared to the standard kidney allocation procedure. The AM approach might be preferred because of the smoother post-transplant management and the better graft survival, keeping the HIT approach as a back up. Since the allocation priority is justified in view of efficiency, the renal transplant community should support the incorporation of a special allocation program for HSP in their respective organ exchange program.
Peritoneal Transport after Long-Term Exposure to Icodextrin in Rats
Authors: Frajewicki Victor , Kushnir Daniel , Wajsbrot Valery , Kohan Ricardo , Shostak Avshalom , Gotloib Lazaro
Published: April 2003

Background: Icodextrin, an effective osmotic substance that has been proposed as an alternative agent for peritoneal dialysis induces ultrafiltration over long dwells. This study examines the peritoneal transport after exposure to Icodextrin in rats. Methods: Animals were divided in 4 groups and injected daily for 30 days with Icodextrin 7.5 % (n = 14), Glucose 4.25 % (n = 19) or glucose 4.25% plus Icodextrin 7.5 % (n = 13). Rats of the control group (n = 15) were not exposed. A 4-hour permeability study was performed using glucose at days 1, 30 and 60. At days 2, 31 and 61 the same animals were injected with Icodextrin. Results: Slopes of effluent sodium at day 30 were significantly higher (p < 0.001) in the glucose (0.006 ± 0.016), Icodextrin (0.013 ± 0.014) and mixed groups (0.012 ± 0.017) than in the control group (–0.041 ± 0.021). Urea D/P ratio was not significantly different in the 4 groups. After 30 days, glucose effluent levels were significantly lower (p < 0.001) in the glucose (701 ± 278 mg/dl), Icodextrin (552 ± 209 mg/dl) and mixed groups (587 ± 344 mg/dl) than in control rats (1519 ± 413 mg/dl). Effluent protein (mg/l) in the mixed group (1,555 ± 357) was significantly higher (p < 0.001) than control (376 ± 33), glucose (1,015 ± 232) and Icodextrin (765 ± 75) groups at day 30. Conclusion: The long-term use of Icodextrin does not affect small molecule transport, but induces changes in the peritoneal protein excretion, especially when Icodextrin and glucose are injected together.
The Common Mutations C677T and A1298C in the Human Methylenetetrahydrofolate Reductase Gene Are Associated with Hyperhomocysteinemia and Cardiovascular Disease in Hemodialysis Patients
Authors: Haviv Y.S. , Shpichinetsky V. , Goldschmidt N. , Abou Atta I. , Ben-Yehuda A. , Friedman G.
Published: April 2003

Background: Plasma total homocysteine (tHcy) level might be an important risk factor for the development of cardiovascular disease (CVD) in dialysis patients. While both renal failure and mutations of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene may result in hyperhomocysteinemia and CVD, the distinct roles of the thermolabile MTHFR mutation at nucleotide C677T and the more recently described mutation at nucleotide A1298C have not been evaluated concurrently in patients on hemodialysis. Methods: A cross-sectional study was performed in 120 maintenance HD patients to determine the prevalence of MTHFR C677T and A1298C mutations and their relative association to hyperhomocysteinemia and CVD. Results: Both mutations, the C677T and the A1298C, were highly prevalent in HD patients with allele frequencies of 0.41 and 0.27, respectively. The prevalence of CVD in HD patients was 55% and its significant risk factors included, in descending order, hyperhomocysteinemia, MTHFR C677T mutation, low serum folate levels, diabetes mellitus, hypertension, and double heterozygote state for both MTHFR mutations (677CT/1298AC). MTHFR A1298C mutation alone and gender were not associated with either hyperhomocysteinemia or increased CVD risk, but the HD patients with homozygotes 1298CC and wild alleles 677CC (677CC/1298CC) have significant increase of tHcy (37.7 ± 12) and high prevalence of CVD. Conclusions: Hyperhomocysteinemia, serum folate levels and both C677T and A1298C MTHFR mutations are associated with CVD in HD patients.
Separation of two Cl– Currents in Cultured Human and Murine Mesangial Cells: Biophysical and Pharmacological Characteristics of ICl.vol and ICl.Ca
Authors: Cipleu Cristian D. , Palant Carlos E. , Sanders Kenton M. , Dick Gregory M.
Published: April 2003

Mesangial cells, a combined smooth muscle- and fibroblast-like phenotype, are important regulators of renal function. These cells exist in a region of variable osmolarity and may require Cl– channels for volume regulation. Additionally, Ca2+-activated Cl– channels in these cells may participate in Ca2+-dependent contractile responses to vasoactive agonists. Relatively little, however, is known about mesangial cell Cl– currents (ICl); including the biophysical description and pharmacological characterization. We used whole-cell patch clamp to study ICl in cultured human and SV40-transformed murine mesangial cells. ICl was measured in cells dialyzed and bathed with symmetrical N-methyl-D-glucamine chloride solutions to minimize cation currents. Dialysis with buffers to control intracellular Ca2+ ([Ca2+]i), extracellular solutions of varied osmolarity, and manipulation of the transmembrane Cl– gradient were used to separate two currents: ICl.vol (volume-sensitive), and ICl.Ca (Ca2+-activated). In symmetrical Cl– with low [Ca2+]i, ICl.vol was outwardly rectifying and modulated by osmolarity. ICl.vol demonstrated slight time- and voltage-dependent inactivation. In symmetrical Cl– with elevated [Ca2+]i and hypertonic bath, ICl.Ca was linear, but in asymmetrical Cl– (low [Cl–]i) was outwardly rectifying and demonstrated time- and voltage-dependent activation. Permeability sequences for both ICl.vol and ICl.Ca were I– > Br– > Cl– > F–; however, there were differences in the relative magnitudes. Tamoxifen inhibited ICl.vol more potently than ICl.Ca, whereas niflumic acid inhibited ICl.Ca more potently than ICl.vol. We have separated and characterized two types of ICl in cultured human and murine mesangial cells. ICl.Ca and ICl.vol have different biophysical and pharmacological characteristics. These observations on ICl.Ca and ICl.vol may provide insight into mesangial cell reactivity and volume regulation.
Increased Angiotensin II AT1 Receptor Expression in Paraventricular Nucleus and Hypothalamic-Pituitary-Adrenal Axis Stimulation in AT2 Receptor Gene Disrupted Mice
Authors: Armando Inés , Terrón José A. , Falcón-Neri Alicia , Takeshi Ito , Häuser Walter , Inagami Tadashi , Saavedra Juan M.
Published: April 2003

Angiotensin II AT2 receptor gene-disrupted mice have increased blood pressure and response to angiotensin II, behavioral alterations, greater response to stress, and increased adrenal AT1 receptors. We studied hypothalamic AT1 receptor binding and mRNA by receptor autoradiography and in situ hybridization, adrenal catecholamines by HPLC, adrenal tyrosine hydroxylase mRNA by in situ hybridization and pituitary and adrenal hormones by RIA in AT2 receptor-gene disrupted mice and wild-type controls.To confirm the role of adrenal AT1 receptors, we treated wild-type C57 BL/6J mice with the AT1 antagonist candesartan for 2 weeks, and measured adrenal hormones, catecholamines and tyrosine hydroxylase mRNA. In the absence of AT2 receptor transcription, we found increased AT1 receptor binding in brain areas involved in the regulation of the hypothalamic-pituitary-adrenal axis, the hypothalamic paraventricular nucleus and the median eminence, and increased adrenal catecholamine synthesis as shown by higher adrenomedullary tyrosine hydroxylase mRNA and higher adrenal dopamine, norepinephrine and epinephrine levels when compared to wild-type mice. In addition, in AT2 receptor gene-disrupted mice there were higher plasma adrenocorticotropin (ACTH) and corticosterone levels and lower adrenal aldosterone content when compared to wild-type controls. Conversely, AT1 receptor inhibition in CB57 BL/6J mice reduced adrenal tyrosine hydroxylase mRNA and catecholamine content and increased adrenal aldosterone content. These results can help to explain the enhanced response of AT2 receptor gene-disrupted mice to exogenous angiotensin II, support the hypothesis of cross-talk between AT1 and AT2 receptors, indicate that the activity of the hypothalamic-pituitary-adrenal axis parallels the AT1 receptor expression, and suggest that expression of AT1 receptors can be dependent on AT2 receptor expression. Our results provide an explanation for the increased sensitivity to stress in this model.
Photoprotection of UV-Irradiated Human Skin: An Antioxidative Combination of Vitamins E and C, Carotenoids, Selenium and Proanthocyanidins
Authors: Greul Anne-Katrin , Grundmann Jens-Uwe , Heinrich Felix , Pfitzner Inka , Bernhardt Jürgen , Ambach Andreas , Biesalski Hans-Konrad , Gollnick Harald
Published: April 2003

Endogenous antioxidants are decreased in skin and blood during UV exposure. Combined supplementation of β-carotene, α-tocopherol and ascorbic acid in addition to topical sunscreens may help to lower the risk of sunburning. Acute UV erythema with sunburn reaction are the most important factors in conjunction with the cumulative life-long UV dose for inducing skin damage resulting in photoageing and precancerous and cancerous lesions. Therefore, a clinical, randomized, double-blind, parallel group, placebo-controlled study was conducted in healthy young female volunteers (skin type II) investigating the preventive, photoprotective effect of supplementation with Seresis®, an antioxidative combination containing both lipid and water-soluble compounds: carotenoids (β-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins. In this study, the oral administration of Seresis appeared to be well tolerated. The preparation contains antioxidant compounds in quantities occurring at physiological levels and can therefore be used safely over a long period of time. Despite the fact that the assessment of the light sensitivity (minimal erythemal dose, chromametry) of the skin did not show any statistically significant differences between the Seresis and the placebo group, a clear statistical trend, however, could be demonstrated, i.e. Seresis was able to slow down the time of the development and grade of UVB-induced erythema. The primary efficacy parameter matrix metalloproteinases 1 (MMP-1) between treatment and placebo group following UV irradiation showed a significant difference (p < 0.05), which occurred due to the fact that after a 2-week UV irradiation, MMP-1 slightly increased (p < 0.03) in the placebo group and decreased (p < 0.044) in the treated group. The MMP-9 changes showed a clear tendency of decrease in the Seresis group (p < 1.393) and increase (p < 0.048) in the placebo group. These data emphasise that supplementation with Seresis decreases the UV-induced expression of MMP-1 and 9, which might be important in photoprotective processes. From our data, we thus finally draw the conclusion that by the combination of antioxidants, such as in the formulation of Seresis, a selective protection of the skin against irradiation can be achieved. This might be important for future recommendations for immediate suppression of the early phase of UV-induced erythema, that means pharmacological prevention of sunburn reaction as well as subsequent chronic skin damage.
Trioxsalen in the Presence of UVA Is Able to Induce Nuclear Factor kappa B Binding Activity in HaCaT Keratinocytes
Authors: Sánchez Ruderisch H. , Schwarz C. , Shang J. , Tebbe B.
Published: April 2003

It has been described that treatment of cells with high dose psoralen and UVA induce the production of reactive oxygen species (ROS) leading to DNA damage. Transcription factor nuclear factor kappa B (NFĸB) plays a crucial role in regulating not only cell growth but also cell differentiation, and ROS seem to be partly involved in these mechanisms. The aim of this research was to find out the effect of a combined treatment with trioxsalen (TMP)/UVA on NFĸB binding activity in HaCaT keratinocytes. HaCaT keratinocytes were treated with 27 µg/l TMP. This concentration did not affect the proliferation rates, nor was it toxic, as shown by cytotoxicity assays. After treatment with TMP with or without UVA (1 J/cm2), NFĸB binding activity in nuclear protein extracts was measured by electrophoretic mobility shift assays. The effect on cytokines and cytokine receptor genes was investigated using cDNA expression arrays. An inhibitory effect on NFĸB binding activity was found between 30 and 60 min after TMP supplementation of the culture media. UVA irradiation induced a 2-fold increase in NFĸB binding activity in TMP supplemented HaCaT keratinocytes compared with the non-irradiated control. In addition, NFĸB binding activity was higher after UVA irradiation with TMP than in UVA irradiated cells in the absence of TMP. TGF-α, IL-1R, IL-2Rα, IL-12β and PDGF expression was induced by UVA. However, all of them except PDGF were inhibited by combined TMP/UVA treatment. Using an inhibitor of NFĸB activation, we found out that under these conditions, these cytokines or cytokine receptor genes are apparently not regulated by NFĸB. Our results indicate that a combined TMP/UVA treatment of HaCaT keratinocytes induces NFĸB binding activity, and that this is a synergistic effect. The investigated cytokines, and cytokine receptor genes do not seem to be NFĸB regulated; however, TMP shows anti-inflammatory capacities in vitro.
Molecular Mechanisms Involved in UV-Induced Apoptotic Cell Death
Authors: Kulms Dagmar , Schwarz Thomas
Published: April 2003

Ultraviolet radiation (UV) induces a variety of biological effects which include the induction of programmed cell death. UV-induced apoptosis seems to represent a controlled scavenging mechanism which protects cells from malignant transformation in human skin. To exert these effects on a cellular base, UV uses a variety of signaling pathways, involving nuclear DNA damage as a predominant pathway, since experimental reduction of DNA damage is associated with a loss of these effects. On the other hand, UV has been found to utilize extranuclear components located in the cytoplasm or at the cell membrane for signaling. UV can directly activate cell surface death receptors, thereby triggering the apoptotic machinery. Oxidative stress accompanied by mitochondrial changes and cytochrome c release are further involved in UV-mediated apoptosis. The following review will briefly discuss current aspects of the interplay between the different signaling pathways involved in UV-induced apoptosis.
Clinical Potential of Biological Response Modifiers Combined with Chemotherapy for Gastric Cancer
Authors: Shibata Masahiko , Nezu Takeshi , Fujisaki Shigeru , Andou Katsuyuki , Tomita Ryouichi , Fukuzawa Masahiro
Published: April 2003

The most effective treatment for gastric cancer is complete surgical resection with lymphadenectomy. However, a number of patients experience recurrence of the cancer even after curative surgery. This review focuses on comparative trials studying the use of adjuvant therapy with chemotherapy plus immunotherapy in the treatment of patients with curatively resected gastric cancer. Preoperative and intraperitoneal therapy, and therapy for advanced or recurrent gastric cancer are also discussed. At present, some subset analyses of adjuvant trials have shown favorable results suggesting that the biological response modifiers (BRMs), PSK or OK-432, add a benefit to chemotherapy. For advanced gastric cancer, although gastric cancer cells are generally not very sensitive to most of the currently available chemotherapeutic agents, it has been reported that biochemical modulation with treatments including low-dose cisplatin + 5-FU (fluorouracil) have high response rates and exert an immunomodulatory effect especially when used in combination with BRMs. The impact of splenectomy and some of the promising newly developed drugs are discussed.
Results of Combined Gastrectomy and Pancreatic Resection in Patients with Advanced Primary Gastric Carcinoma
Authors: Piso P. , Bellin T. , Aselmann H. , Bektas H. , Schlitt H.J. , Klempnauer J.
Published: April 2003

Background/Aims: Although the incidence of primary gastric carcinoma is decreasing, the majority of patients in Western countries are still diagnosed with advanced tumor stages. In many cases surgical therapy can be performed only by multivisceral resections including the pancreas. Methods: Between April 1986 and April 1997, thirty-three patients with primary gastric carcinoma underwent gastric resection and segmental/total pancreatectomy at our institution (21 males, 12 females; median age 57 years). The operative and pathologic findings and clinical course in these patients were analyzed retrospectively. Results: In all patients total gastrectomy with D2 lymphadenectomy was performed. In 26 patients (79%) the pancreatic tail was also resected. Other resections included the pancreatic head in 5 patients (15%) and the whole pancreas in 2 cases (6%). Radical (R0) resections were possible in 73% of all cases (n = 24). 22 patients (67%) had stage-IV disease due to liver/peritoneal metastases (n = 11) or to extensive lymph node metastases (N3, n = 11). Histology showed a predominance of the diffuse type according to Laurén (n = 16, 49%). Intraoperatively suspected tumor infiltration of the pancreas was confirmed by histology only in 39% (n = 13) of the examined resection specimens. Postoperative morbidity was 36% (n = 12) and mortality was 9% (n = 3). Five patients developed pancreatitis or peripancreatic abscess, 2 with a lethal outcome. Overall the median survival was 13 months. Following R0 resection median survival was 17 months. If the pancreas was microscopically not infiltrated, median survival was 23 months. Conclusion: Pancreatic invasion in patients with gastric carcinoma is often associated with positive lymph nodes and liver metastases or peritoneal carcinomatosis. Intraoperatively, true pancreas invasion is difficult to differentiate from inflammatory reactions. Postoperative morbidity and mortality are increased by pancreatic resection, mainly due to pancreatitis or peripancreatic abscess. Curative (R0) resection improves prognosis and even long-term survival can be achieved in selected individual cases. Palliative resections can be performed for local complications like bleeding or obstruction refractory to other therapies.
Early Surgical Correction for Isolated Gastric Stricture following Acid Corrosion Injury
Authors: Tseng Yau-Lin , Wu Ming-Ho , Lin Mu-Yen , Lai Wu-Wei
Published: April 2003

Objective: To evaluate the feasibility and long-term results of early gastric surgery for patients with isolated gastric stricture following acid corrosion injury. Materials and Methods: Upper gastrointestinal (UGI) series was routinely performed around the 4th week after acid corrosion injury. Patients with gastric stricture and no risk of delayed esophageal stricture underwent early solitary gastric surgery, which was defined when performance of the procedure took place within 2 months of the injury. Results: From June 1988 to June 2000, 35 of 378 patients with acid corrosion injury developed isolated gastric stricture. Twenty-four (68.6%) lesions were located in the antrum, and 11 (31.4%) in the gastric body. Postprandial vomiting presented earlier for the antral stricture group (17.6 ± 1.1 versus 25.4 ± 3.4 days after injury; p = 0.005). The UGI series was performed from 16 to 41 days after injury (average 25 days). Of the 35 acid corrosion injury patients in this study, 4 were excluded because of late referrals to our institution or the patient’s hesitation which resulted in delayed surgery. The remaining 31 patients underwent gastric surgery 35.7 ± 3.2 days after ingestion (34.6 ± 3.6 and 38.1 ± 3.4 days for cases of antral and gastric body stricture, respectively). Surgical procedures consisted of hemigastrectomy (n = 16), antrectomy (n = 2), gastroenterostomy (n = 2), subtotal gastrectomy (n = 6), and total gastrectomy (n = 5). There were 4 cases of postoperative complications (12.9%) including adhesion ileus (n = 2), wound infection (n = 1), and massive, postoperative UGI bleeding (n = 1). Surgical mortality was zero. All patients tolerated oral intake well after surgery. During the minimum follow-up period of 1 year, 1 patient developed esophagojejunostomy stenosis, which was resolved by dilation, and there was 1 case of dumping syndrome, which was treated by diet control. Conclusion: Early surgery correction is feasible and safe if patients with isolated gastric stricture following acid corrosion injury are carefully selected. All patients in our study recovered early, with a low morbidity rate.
Motor Cortex Stimulation for Phantom Limb Pain: Comprehensive Therapy with Spinal Cord and Thalamic Stimulation
Authors: Katayama Yoichi , Yamamoto Takamitsu , Kobayashi Kazutaka , Kasai Masahiko , Oshima Hideki , Fukaya Chikashi
Published: April 2003

The effects of spinal cord stimulation (SCS), deep brain stimulation (DBS) of the thalamic nucleus ventralis caudalis (VC) and motor cortex stimulation (MCS) were analyzed in 19 patients with phantom limb pain. All of the patients underwent SCS and, if the SCS failed to reduce the pain, the patients were considered for DBS and/or MCS. Satisfactory pain control for the long-term was achieved in 6 of 19 (32%) by SCS, 6 of 10 (60%) by DBS and 1 (20%) of 5 by MCS. SCS and DBS of the VC sometimes produced a dramatic effect on the pain, leading to a long pain-free interval and infrequent use of stimulation. The effects of both DBS of the VC and MCS were tested in four. One patient of them reported better pain control by MCS than by DBS, whereas two reported the opposite results. There is no evidence at present for an advantage of MCS over SCS and DBS of the VC in controlling phantom limb pain.
Neurophysiological Monitoring for Epilepsy Surgery: The Talairach SEEG Method
Authors: Guenot Marc , Isnard Jean , Ryvlin Philippe , Fischer Catherine , Ostrowsky Karine , Mauguiere François , Sindou Marc
Published: April 2003

Object of the Study: In some candidates for epilepsy surgery in whom the decision to operate is difficult to make, invasive presurgical investigations, namely depth electrode recordings, may be needed. The SEEG (StereoElectroEncephaloGraphy) method consists of stereotactic orthogonal implantation of depth electrodes (5 to 15, 11 on average). The object of this study is to clarify the indications for SEEG, to expose its complications, and to display its usefulness in terms of surgical strategy and results. Patients and Methods: 100 patients, suffering from drug-resistant epilepsy and selected as candidates for surgical resection, underwent SEEG between 1996 and 2000. A total of 1,118 electrodes were implanted. For each single case, the sites of implantation of the electrodes were chosen in order to determine either the side of the onset of seizures, or the uni- or multilobar feature of them, or a possible operculo-insular propagation from a temporal onset, and also, using direct electrode stimulation, the proximity of speech or motor area. Results: Complications occurred in 5 patients (2 superficial infections, 2 breakages of electrodes, and 1 intracerebral hematoma responsible for death). SEEG was helpful in most (84%) of the 100 patients to confirm or annul surgical indication, and to adjust the extent of the resection. In some cases (14%), SEEG allowed to propose a resection that might have been disputable based solely on noninvasive investigation data. For frontal epilepsy, SEEG was crucial in all cases to delineate the extent of resection. Conclusion: SEEG proved to be a relatively safe and a very useful method in ‘difficult’ candidates for epilepsy surgery. In addition, in some cases the implanted electrodes can be used to perform therapeutic RF thermocoagulation of epileptic foci or networks.
Genetics of Movement Disorders: An Abbreviated Overview
Authors: Thyagarajan Dominic
Published: April 2003

Linkage of the Huntington’s disease gene to chromosome 4 in 1983 marked the birth of modern genetics in movement disorders. The discovery that an expanded trinucleotide DNA repeat was central to the mechanism of this disease has been repeated over and over in a growing list of inherited ataxias. In 1997, a different mutation and genetic mechanism was discovered in a severe type of generalized primary torsion dystonia – Oppenheim’s dystonia. Before this, only the genetic cause for rare metabolic dystonias was known, notably dopa-responsive (Segawa’s) dystonia. In the same year, from the identification of mutation in the α-synuclein gene in rare pedigrees with autosomal dominant parkinsonism, arose the concept that Parkinson’s disease may be part of a broader group of ‘synucleinopathies’, in which there is a fundamental defect in protein processing. In the following year, mutations in autosomal recessive juvenile onset parkinsonism were found in a gene called ‘parkin’. Parkin mutations are a more common cause of parkinsonism than the rare α-synuclein mutations, particularly in young-onset disease. However, a most important understanding, occurring in the last year, has been the relationship between the parkin gene product, α-synuclein and abnormal protein degradation in the cell. A unified theory of neuronal death in Parkinson’s disease is emerging, pointing to potential new therapies in the future.
Microelectrode Recording for Pallidotomy: Mandatory, Beneficial or Dangerous?
Authors: Honey C.R. , Berk C. , Palur R.S. , Schulzer M.
Published: April 2003

There is an active debate regarding whether pallidotomy should be performed with microelectrode recording or macroelectrode stimulation. A meta-analysis was performed on the published reports (1992–2000) of unilateral pallidotomy for Parkinson’s disease to determine if the outcome or complications of this procedure significantly differed between these two techniques. Papers were excluded if they followed a cohort of less than ten patients, had follow-up less than three months, or included previously reported patients. There were no significant differences between the two techniques in improvement of dyskinesia (p = 0.66) or UPDRS motor score (p = 0.62). Microelectrode recording had a significantly higher (p = 0.012) intracerebral hemorrhage rate (1.3 ± 0.4%) compared to macroelectrode stimulation (0.2 ± 0.2%).