bluuebunny/crossref_metadata_2025 huggingface dataset:
Standardization of PCR amplification for fragile X trinucleotide repeat measurements*
Authors: O'Connell CD , Atha DH , Jakupciak JP , Amos JA , Richie Kl
Published: March 2003

To provide the clinical diagnostics community with accurate protocols and measurements for the detection of genetic disorders, we have established a quantitative measurement program for trinucleotide repeats associated with human disease. In this study, we have focused on the triplet repeat associated with fragile X syndrome. Five cell lines obtained from the Coriell Cell Repository were analyzed after polymerase chain reaction (PCR) amplification and size separation. These cell lines were reported to contain CGG repeat elements (ranging from 29 to 110 repeats). Our initial measurements focused on measurement variability: (a) between slab‐PAGE and capillary (CE) separation systems (b) interlane variability (slab‐PAGE) (c) intergel variability, and (d) variability associated with amplification. Samples were run in triplicate for all measurements, and the analysis performed using GeneScan™ analysis software. The repeat sizes were verified by DNA sequence analyzes. The standard deviations for interlane measurements in slab‐gels ranged from 0.05 to 0.35. There was also little variation in size measurements performed on different gels and among PCR amplifications. The CGG repeat measurements performed by capillary electrophoresis were more precise, with standard deviations ranging from 0.02 to 0.29. The slab‐PAGE and CE size measurements were in agreement except for the pre‐mutation alleles, which yielded significantly smaller sizes by CE.
Association of a polymorphism of the ecNOS gene with myocardial infarction in a subgroup of Turkish MI patients
Authors: Çine N , Hatemi AC , Erginel‐Unaltuna N
Published: March 2003

In this study we examined a possible association between a 27 base pair (bp)‐repeat polymorphism in intron 4 of the ecNOS gene and myocardial infarction (MI) in a subgroup of the Turkish population. We compared MI and control groups for the frequencies of the ecNOS alleles and their genotypes. The frequency of the ecNOS 4a/a and 4a/b genotypes was found to be significantly higher in the MI group than in the control group. Interestingly, the frequency of the ecNOS 4a/b polymorphism was found to be significantly higher in the selected MI group (patients with no known secondary risk factors) than in the control and non‐selected MI group. We found that the patients with MI had the frequency of the a/a genotype 4.3%, of the a/b genotype 26.6% and the b/b genotype 69.1%. The controls, however, showed only 0.6% for a/a, 18.0% for a/b and 81.4% for the b/b genotype (P < 0.001; χ2 = 13.626). In this study, we show that myocardial infarction is associated with one subtype of ecNOS gene polymorphism.
Complete screening of the CFTR gene in Argentine cystic fibrosis patients
Authors: Visich A , Zielenski J , Castaños C , Diez G , Grenoville M , Segal E , Barreiro C , Tsui L‐C , Chertkoff L
Published: March 2003

In order to establish the nature and the distribution of mutations causing cystic fibrosis (CF) in 220 unrelated Argentine families, the present authors conducted an extensive molecular analysis of the CF transmembrane regulator (CFTR) gene. First, a direct mutation analysis of 13 common mutations was done, enabling the detection of 319 out of 440 CF alleles (72.52%). Then an exhaustive screening of the entire coding region and the adjacent sequences of the CFTR gene was performed in all patients carrying at least one unidentified CF allele using the multiplex heteroduplex analysis assay followed by direct DNA sequencing. Thirty‐nine different CF mutations, including five previously undescribed mutations (i.e. L6V, Y362X, 1353insT, 2594delGT and 2686insT) and two novel polymorphisms (i.e. 1170G/C and 3315A/C) were identified. As a result, the overall detection rate increased by up to 83.45%. Besides ΔF508, only five mutations showed frequencies higher than 1%. In addition, a total of 49% of the mutations were rare because they were found in only one CF family. This wide spectrum of CF mutations is in agreement with the heterogeneous ethnic origin of the Argentine population. The data obtained here may have important consequences for the development of adequate strategies for the molecular diagnosis of CF in Argentina.
Familial adenomatous polyposis in two Black South African families
Authors: Grobbelaar JJ , Wilken E , De Ravel TJL , Nicholson DL , Kotze MJ
Published: March 2003

The apparent low incidence of colon cancer in the Black population of South Africa has been ascribed to a non‐Western diet. The present authors report the identification of two common 5‐bp deletions at codons 1309 and 1061 of the adenomatous polyposis coli (APC) gene in a Xhosa and Zulu patient, respectively. The in vitro transcription/translation test (PTT) and a non‐radioactive heteroduplex method, which facilitates resolution of enzymatically amplified DNA by agarose gel electrophoresis, were used for mutation detection. This study represents the first report of APC mutations in indigenous Black individuals clinically diagnosed with familial adenomatous polyposis coli (FAP). The two deletion mutations are responsible for FAP in 35% of affected South Africans, a frequency similar to that described in several other non‐African populations. The apparently low incidence of colon cancer in the African population may be ascribed either to the rare occurrence of the ‘second hit’ needed for polyp formation or to a lower incidence of mutations in the APC gene.
Cardiomyopathy in congenital complete lipodystrophy
Authors: Bhayana S , Siu VM , Joubert GI , Clarson CL , Cao H , Hegele RA
Published: March 2003

Molecular genetic studies have pointed to a relationship between congenital lipodystrophy syndromes and some cardiac disorders. For instance, mutations in LMNA cause either lipodystrophy or cardiomyopathy, indicating that different mutations in the same gene can produce these clinical syndromes. The present authors describe a 10‐year‐old female with Berardinelli–Seip congenital complete lipodystrophy (MIM 606158) caused by homozygosity for a frameshift mutation in BSCL2. In addition to the typical attributes of complete lipodystrophy, this subject had hypertrophic cardiomyopathy diagnosed in the first year of her life; its progress has been followed with non‐invasive imaging. The mechanism underlying the hypertrophic cardiomyopathy in complete lipodystrophy is unclear. It may result from a direct effect of the mutant gene or it might be secondary to the effects of hyperinsulinemia on cardiac development. The variability of the associated cardiomyopathy in patients with complete generalized lipodystrophy may be caused by differential effects of mutations in the same gene or of mutations in different genes which underlie the lipodystrophy phenotype.
Quantification of CFTR splice variants in adults with disseminated bronchiectasis, using the TaqMan fluorogenic detection system
Authors: Andrieux J , Audrézet MP , Frachon I , Leroyer C , Roge C , Scotet V , Férec C
Published: March 2003

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with different related disorders such as congenital bilateral absence of the vas deferens, chronic idiopathic pancreatitis, or disseminated bronchiectasis (DB). Many different disease‐causing mutations are associated with DB, particularly the 5T allele (IVS 8 polyT tract), a variant of the splice acceptor site at the end of intron 8 that affects the efficiency with which the site is used. It therefore affects the accuracy of exon 9 splicing and hence expression of the functional CFTR protein. In this study we quantified transcripts from nasal biopsies of patients with DB compared to normal controls. We developed a real‐time quantitative reverse transcription polymerase chain reaction assay (using the TaqMan system) to evaluate the relative amounts of accurately spliced transcript, and transcript lacking exon 9. Patients with the 5T allele had increased amounts of aberrant transcript: in genotypes 5T/7T, 7T/7T and 9T/7T, mean fractions of 38.4%, 3.5% and 0.6%, respectively, of transcripts had been spliced incorrectly. There was also some evidence that nasal biopsies can provide similar information on transcripts to bronchial biopsies. This functional test is of interest for monitoring the amount of CFTR transcript in different clinical situations or to monitor the effect of drugs on CFTR transcription.
X‐linked recessive Menkes disease: carrier detection in the case of a partial gene deletion
Authors: Poulsen L , Horn N , Møller LB
Published: March 2003

Poulsen L, Horn N, Møller LB. X‐linked recessive Menkes disease: carrier detection in case of a partial gene deletion.  Clin Genet 2002: 62: 440–448. © Blackwell Munksgaard 2002

X‐linked recessive Menkes disease is a lethal disorder of copper metabolism, caused by defects in the ATP7A gene. About 15% of the mutations causing Menkes disease are partial gene deletions. We have previously demonstrated carrier diagnosis of deletions in heterozygotes by Southern blot analysis. As this technique is very time‐consuming alternative methods are obviously of high value. Multiplex polymerase chain reaction (PCR), reverse transcription PCR (RT‐PCR) and spanning the deletion on genomic DNA can all be used for detection of partial gene deletions in male patients, but only spanning of the deletion can be applied for carrier detection. Simple multiplex PCR is not applicable for carrier detection because the normal allele of ATP7A will be PCR amplified thus masking the deletion. Here, we demonstrate, in addition to spanning of the deletion on genomic DNA, carrier detection based on the use of a previously unrecognized polymorphism in intron 13 of ATP7A in combination with previously identified intragenic polymorphic markers. We show that these intragenic markers can be used for carrier detection, not only indirectly by determining segregation of the disease related allele but also directly if located within the deleted region. We demonstrate determination of the carrier status of 21 at‐risk carriers.
The association of cholesteryl ester transfer protein polymorphism with high‐density lipoprotein cholesterol and coronary artery disease in Koreans
Authors: Park K‐W , Choi J‐H , Kim H‐K , Oh S , Chae I‐H , Kim H‐S , Oh B‐H , Lee M‐M , Park Y‐B , Choi Y‐S
Published: March 2003

Cholesteryl ester transfer protein (CETP) is a key protein involved in high‐density lipoprotein cholesterol (HDL‐C) metabolism. It is known to affect plasma HDL‐C levels, and its genetic regulation may be involved in the development of coronary artery disease (CAD). The aim of this study was to determine the frequency of the CETP Taq1B polymorphism in Koreans, and to investigate its relationship with plasma HDL‐C levels and CAD. One‐hundred and nineteen patients with significant CAD and 106 controls were examined with respect to their genotypes, lipid profiles and other risk factors of CAD. The genotype frequencies of B1B1:B1B2:B2B2 in males and females were 35.5%:50%:14.5% and 34.7%:42.6%:22.7%, respectively, which is comparable to previous reports in other ethnic groups. The B1B1 homozygote was associated with significantly lower HDL‐C levels in females (p = 0.049) and non‐smoking males (p = 0.037). After controlling for gender, body mass index (BMI) and smoking, the TaqIB polymorphism was still significantly associated with HDL‐C levels (p = 0.046) and explained 5.4% of the HDL‐C variation in this study. By univariate analysis, the B1B1 homozygote was a significant predictor of CAD (p = 0.043), and this was confirmed by multivariate analysis with traditional risk factors, i.e. the B1B1 homozygote was an independent predictor of CAD (p = 0.026, odds ratio = 1.97, 95% confidence interval: 1.08–3.57). In conclusion, the B1B1 homozygote of the CETP Taq1B polymorphism is associated with low HDL‐C levels in females and non‐smoking males, and may be an independent genetic risk factor of CAD in the Korean population.
The clinical significance of antibody to vascular endothelial cells after renal transplantation
Authors: Nakagawa Yuki , Saito Kazuhide , Morioka Testuo , Tomita Yoshihiko , Takahashi Kota , Oite Takashi
Published: March 2003

Abstract: Vascular endothelial cells (ECs) are considered to be a primary target for injury in allograft rejection. However, the relationship between serum antibody activity to ECs and rejection episodes has not been examined extensively in renal transplantation. Twenty‐two renal transplant recipients were included in this study. Serum antibody activity to vascular endothelial cells (AECA) was measured using a cellular enzyme‐linked immunosorbent assay (ELISA) in which human umbilical vein endothelial cells (HUVEC) and human glomerular endothelial cells (HGEC) were preincubated with TNF‐α used as target cells. Serum samples were obtained just before transplantation and once a week during the immediate 1–3‐month post‐transplantation period. There was a significant correlation between the presence of AECA against HGEC and rejection episodes (P < 0.05). Patients with multi‐episodes of rejection showed significantly higher frequencies of AECA than patients with mono‐episodic rejection (P < 0.0005). It should be noted that patients suffering from multi‐episodes of rejection revealed higher AECA titres before transplantation. These findings imply that the HGEC–ELISA could be used as a prospective, informative test to identify patients with a higher risk of acute rejection in renal transplantation.
A case of acute antidonor antibody‐mediated humoral rejection after renal transplantation with specific consideration of serial graft biopsy histology
Authors: Shimizu Tomokazu , Tanabe Kazunari , Tokumoto Tadahiko , Shimmura Hiroaki , Koga Shoji , Ishida Hideki , Toma Hiroshi , Kawaguchi Hiroshi , Tokiwa Michio , Yamaguchi Yutaka
Published: March 2003

Abstract: A 61‐year‐old‐woman with end‐stage renal disease caused by IgA nephropathy received living unrelated kidney transplantation from her husband in February 2001. Pre‐transplant donor‐specific T‐ and B‐cell cross‐match was negative. Immunosuppressive treatment consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), methylprednisolone (MP) and antilymphocyte globulin (ALG). The kidney functioned immediately after kidney transplantation. On post‐operative day 9, the level of serum creatinine (S‐Cr) rose from 1.1 to 1.5 mg/dL. The allograft biopsy specimen taken on the day revealed moderate accumulations of polymorphonuclear leucocytes in peritubular capillaries (PTCs), dilatation of PTCs and transplant glomerulitis, moderate to severe. Immunofluorescent study of a frozen section of the allograft biopsy specimen showed a strong, diffusely distributed endothelial staining pattern in PTCs for the stable complement split product C4d. Post‐transplant donor‐specific T‐ and B‐cell cross‐matches performed on post‐operative day 13 were positive. From the allograft biopsy and the positive post‐transplant donor‐specific T‐ and B‐cell cross‐matching, acute humoral rejection (AHR) associated with the development of antidonor antibodies (ADA) was diagnosed. Plasma exchange (PE) treatment was initiated on day 11. After a total of 13 treatments of PE, donor‐specific T‐ and B‐cell cross‐matches became negative and the biopsy performed on day 72 revealed mild transplant glomerulopathy without accumulation of polymorphonuclear leucocytes in PTCs or a C4d staining pattern in PTCs of immunofluorescence. The allograft functioned well and the creatinine level was 1.1 mg/dL 7 months post‐transplant. This was a case of AHR after renal transplantation associated with the development of ADA, which was triggered by spousal‐donor antigens. The presence of widespread C4d deposition in PTCs in renal allograft biopsies played a role in the diagnosis of AHR and the diagnosis was confirmed by positive donor‐specific T‐ and B‐cell cross‐matches at the time of rejection, which were negative at pre‐transplantation. Several treatments of PE were effective for resolving AHR in this case and the effect of PE in the treatment of AHR could be assessed by the degree of peritubular capillaritis (PTCitis) and C4d deposits in PTCs.
Post‐transplant lymphoproliferative disorders in kidney transplantation: histological and molecular genetic assessment
Authors: Koike Junki , Yamaguchi Yutaka , Hoshikawa Masahiro , Takahashi Hiroko , Horita Shigeru , Tanabe Kazunari , Fuchinoue Shohei , Toma Hiroshi , Nihei Hiroshi
Published: March 2003

Abstract:  We performed histopathological and immunohistochemical studies, in situ hybridization (ISH) for Epstein–Barr virus (EBV) and molecular genetic analysis using the PCR method for the immunoglobulin heavy chain gene in six patients with post‐transplant lymphoproliferative disorders (PTLD) to clarify these problems. In two patients, PTLD developed in the graft, and in the remaining four it developed in systemic lymphoid tissues or organs. In terms of morphological classification, lesions in the graft of two patients were polymorphic with features of rejection in the background. In the other four patients, three of them presented monomorphic lesions and the remaining one presented features of reactive lymphoid hyperplasia. All the patients were positive for EBV as determined by ISH. The molecular genetic study could be performed for four patients, the cells in lesions of two patients were found to be monoclonal and those of the remaining two were polyclonal in IgH as determined by PCR. We conclude that PTLD are of two types, namely, intragraft PTLD and extra‐graft PTLD. In the cases of intragraft PTLD their diagnosis is relatively difficult, because lesions are mixed with features of rejection. Molecular genetic analysis and detection of EBV by ISH are useful for diagnosis. In contrast, the diagnosis of extra‐graft PTLD is easier than that of intragraft PTLD, by basing of the latest classification of malignant lymphoma. Grading of severity of PTLD should be carried out according to the newest system and protocols for treatment based on the grade of the lesion should be established as soon as possible.
Accelerated atherosclerosis with apolipoprotein(a) and oxidized low‐density lipoprotein deposition in acute rejection of transplanted kidney: analogous to atherosclerosis
Authors: Shimoyamada Hiroaki , Fan Jianglin , Watanabe Teruo , Nagata Michio
Published: March 2003

Abstract: Atherosclerosis is a chronic inflammatory process affecting mainly elastic and muscular arteries. Although small arteries and arterioles are usually spared, atherosclerosis can occur in these small vasculatures for a very short period. Here we report a case of atherosclerosis‐like lesions that occurred in a transplanted kidney showing acute accelerated rejection in a 43‐year‐old man. Histologically, biopsy specimens at 14 and 28 days and nephrectomy material at 52 days post‐transplantation showed atherosclerosis‐like lesions in various‐sized arteries. The lesions were characterized by the intimal infiltration of inflammatory cells, including foamy macrophages and a variable number of T‐lymphocytes, with smooth muscle cell proliferation. Immunohistochemistry disclosed that the foam cells expressing CD68 contained oxidized LDL. In addition, apolipoprotein(a) (Lp(a)), another major atherogenic lipoprotein, was found in the intimal smooth muscle layer, suggesting that Lp(a) induced smooth muscle cell proliferation in the rejected kidney as a mechanism of atherosclerosis. This case shows that immunoinflammatory reactions during a relatively short period can mimic the chronic atherosclerotic process even in small arteries and arterioles. Furthermore, the deposition of atherogenic lipoproteins, Lp(a) and oxidized LDL in lesions of rejected tissue present an analogy between vascular rejection in transplanted kidney and atherosclerosis.
Cyclosporine and tacrolimus (FK506): A comparison of efficacy and safety profiles
Authors: Henry Mitchell L
Published: March 2003

Multicenter clinical trials conducted in the United States and Europe to compare the efficacy and safety of cyclosporine with tacrolimus (FK506) have demonstrated comparable long‐term patient survival and graft survival in liver and renal transplant recipients. Importantly, treatment with tacrolimus was associated with reductions in the incidence and severity of acute rejection episodes. However, tacrolimus‐based therapy was also associated with increased toxicities in comparison to conventional cyclosporine‐based therapy. It is becoming increasingly accepted that earlier trials may have employed high or supratherapeutic doses of tacrolimus and may have been unbalanced with respect to study design. In addition, these pivotal comparative trials were performed with the original formulation of cyclosporine, and not the cyclosporine microemulsion preparation. This critical review of the literature focuses on the United States and European tacrolimus multicenter clinical trials and examines the efficacy and safety of the two primary immunosuppressants, cyclosporine and tacrolimus, obtained in these and other studies. The preliminary findings of ongoing studies comparing the efficacy and safety of the improved formulation, cyclosporine microemulsion, with tacrolimus are also discussed. The overall efficacy of the two agents appears to be similar. The safety profile shows differing toxicities of the two medications. The availability of these two immunosuppressants allows the clinician improved options when choosing an immunosuppressive regimen in solid organ transplantation.
Clinical risk factors for recurrence of IgA nephropathy
Authors: Freese Poul , Svalander Christian , Nordén Gunnela , Nyberg Gudrun
Published: March 2003

No clinical risk factors for recurrence of immunoglobulin A (IgA) nephropathy in kidney transplants have been defined. This is a single‐centre retrospect analysis of recurrence in 104 first kidney transplant patients with biopsy‐verified IgA nephropathy. Fifty patients had living donors. All but an identical twin were treated with cyclosporin A. The median follow‐up time was 5 yr. Graft biopsies had been obtained from 35 grafts later than 6 months after transplantation, due to deteriorating graft function or gross proteinuria. Thirteen biopsies showed mesangial glomerulopathy – proliferative in eleven cases – with IgA deposits. Recurrence caused failure of six grafts. Eleven grafts with recurrence were from living donors (p=0.005). No specific human leukocyte antigen (HLA) was identified as a risk factor. Known duration of original disease until end‐stage renal failure was significantly shorter in patients with recurrence (median 5 yr, range 0–25 yr) compared with those without (median of 10 yr, range of 0–37 yr) (p=0.015). Cumulative graft survival was not reduced in living versus cadaveric donor recipients.
Peripheral vascular disease and renal transplant artery stenosis: a reappraisal of transplant renovascular disease
Authors: Becker Bryan N , Odorico Jon S , Becker Yolanda T , Leverson Glen , McDermott John C , Grist Tom , Sproat Ian , Heisey Dennis M , Collins Bradley H , D'alessandro Anthony M , Knechtle Stuart J , Pirsch John D , Sollinger Hans W
Published: March 2003

Background: Renal transplant artery stenosis (RTAS) continues to be a problematic, but potentially correctable, cause of post‐transplant hypertension and graft dysfunction. Older transplant recipients, prone to peripheral vascular disease (PVD), may have pseudoRTAS with PVD involving their iliac system.Methods: We retrospectively analyzed 819 patients who underwent kidney transplantation between 1993 and 1997 to determine the contribution of pseudoRTAS to renal transplant renovascular disease. Univariate analyses were performed for donor and recipient variables, including age, weight, gender, race, renal disease, cholesterol and creatinine values, human leukocyte antigen (HLA) matching, cytomegalovirus (CMV) infection, and immunosuppressive medications. Significant variables were then analyzed by a Cox proportional hazards model.Results: Ninety‐two patients (11.2%) underwent renal transplant arteriogram (Agram) or magnetic resonance angiography (MRA) for suspected RTAS. RTAS or pseudoRTAS, defined as one or more hemodynamically significant lesions in the transplant artery or iliac system, was evident in 44 patients (5.4%). Variables significantly associated with RTAS by univariate analysis were weight at the time of transplant (p=0.0258), male gender (p=0.034), discharge serum creatinine> 2 mg/dL (p=0.0041), and donor age (p=0.0062). Variables significantly associated with pseudoRTAS by univariate analysis were weight at the time of transplant (p=0.0285), recipient age (p=0.0049), insulin‐dependent diabetes mellitus (IDDM; p=0.0042), panel reactive antibody (PRA) at transplant (p=0.018), and body mass index (p=0.04). Weight at transplant and donor age remained significantly associated with an increased risk for RTAS in a multivariate stepwise Cox proportional hazards model. IDDM, transplant PRA, weight at transplant, and donor age were significantly associated with an increased risk for pseudoRTAS in a multivariate stepwise Cox proportional hazards model. Importantly, both RTAS and pseudoRTAS were associated with poorer graft survival (p<0.007 for each).Conclusions: Renal transplant renovascular disease encompasses pre‐existing PVD acting as pseudoRTAS, as well as classical RTAS. Efforts to identify and correct renal transplant renovascular disease of either nature are important, given its negative impact on graft survival.
Renal function one year after switching from Sandimmun® to Neoral®
Authors: Seydoux Charles , Stumpe Frank , Hurni Michel , Ruchat Patrick , Fischer Adam , Mueller Xavier , Von Segesser Ludwig , Goy Jean‐Jacques
Published: March 2003

Background. The replacement of Sandimmun®by Neoral®in 1995 was thought to cause subsequent renal function deterioration due to the better bioavailability of the new drug. We prospectively analyzed the effect of a dose‐to‐dose drug replacement on renal function over 12 months.Methods and results. The renal function of 47 consecutive heart transplanted patients was prospectively evaluated before (T0), at 1 (T1), 3 (T3), and 12 (T12) months after drug replacement. Mean serum creatinine was not significantly different at T0 and T12 (142±55 and 154±60 μmol/L, p=0.1). We were able to reduce cyclosporine total and weight‐indexed doses by, respectively, 11% and 14% between T0 and T12 (274±86 to 244±72 mg/d, p=0.0003; and 3.7±1.4 to 3.2±1.2 mg/kg/d, respectively, p=0.0005).Conclusions. This study demonstrates that the dose‐to‐dose replacement of Sandimmun by Neoral is feasible, with no direct influence on renal function over a 1‐yr follow‐up.
Carvedilol treatment of kidney graft recipients with chronic rejection
Authors: Zezina Lilija , Vessby Bengt , Larsson Erik , Backman Ulla , Fellström Bengt
Published: March 2003

Carvedilol is an antihypertensive drug with properties that may be potentially beneficial for kidney graft recipients. The purpose of the study was to investigate if progression of an established chronic rejection may be attenuated or reversed by carvedilol.An open, single‐centre, phase II, pilot study, with a 2‐yr follow‐up, was performed in 25 kidney graft recipients with chronic rejection or accelerated transplant atherosclerosis.Seventeen patients had stable graft function assessed by serum creatinine levels. Eight patients withdrew from the study due to lack of efficacy (increase in serum creatinine 174–477 μmol/L (46–191%) from the initial levels). However, these patients had higher serum creatinine levels and proteinuria already at the start of the study. Both systolic and diastolic blood pressure, as well as heart rate, were stable in all study patients. Low density lipoprotein (LDL)/high density lipoprotein (HDL) cholesterol ratio decreased from 4.7±1.9 at 1 month to 3.5±1.2 at 18 months (p<0.05), and MDA plasma levels decreased from 0.714±0.119 to 0.493±0.073 μmol/L after 3 months of carvedilol treatment (p<0.05). No attenuation of progression of chronic graft rejection by carvedilol treatment was observed in the study. It is suggested that the process of chronic rejection could not be reversed by carvedilol because the patients included in the study already had severe morphological and functional changes of the graft.In conclusion, our study demonstrated that carvedilol provides a good control of blood pressure in renal transplanted patients. Carvedilol treatment had a beneficial effect on lipid pattern and reduced lipid oxidation, but there was no obvious effect on progression of chronic rejection.
Lung transplantation for patients with end‐stage Sauropus androgynus‐induced bronchiolitis obliterans (SABO) syndrome
Authors: Luh S‐P , Lee Y‐C , Chang Y‐L , Wu H‐D , Kuo S‐H , Chu S‐H
Published: March 2003

Sauropus androgynus (SA), a vegetable of the Euphorbiaceae family, is a common food source in Malaysia. In Taiwan, over 30 patients have developed progressive respiratory failure after consuming the extract from raw SA leaves as a means of losing weight. Symptoms consistent with a severe obstructive ventilatory defect progressed, despite cessation of SA intake and treatment with bronchodilators, corticosteroids, cytotoxic agents and plasmaphresis. Five patients with end‐stage Sauropus androgynus‐induced bronchiolitis obliterans (SABO) syndrome underwent lung transplantation. There was no early mortality. One patient died of post‐transplant lymphoproliferative disorder and another patient died of bronchial stenosis with infection, 5 and 3.5 months, respectively, post‐transplantation. The remaining 3 patients have been followed from 29 to 34 months, with improved general condition and pulmonary function. Perfusion/ventilation scans revealed that these improvements were exclusively attributed to the functional grafts. We believe that lung transplantation is the only effective modality of treatment for patients with end‐stage SABO syndrome.
Induced hypothermia in the management of cerebral oedema secondary to fulminant liver failure
Authors: Roberts Drd , Manas D
Published: March 2003

The use of mild hypothermia in the management of blunt head trauma has been shown to significantly improve clinical outcomes. The use of moderate controlled hypothermia in the patient with severely raised intracranial pressure (ICP) secondary to fulminant hepatic failure (FHF) has similar potential benefits, but is not a widely accepted practice. We report a case where the use of hypothermia in the management of severely raised ICP both before and after liver transplantation was thought to effect a beneficial outcome.
Human parvovirus B19 infection in organ transplant recipients
Authors: Marchand Sylvie , Tchernia Gil , Hiesse Christian , Tertian Gérard , Cartron Jeanine , Kriaa Faiçal , Boubenider Samir , Goupy Christophe , Lecointe Didier , Charpentier Bernard
Published: March 2003

We report a 61‐yr‐old kidney transplant recipient with human Parvovirus B19 (HPV B19) infection presenting as a severe pancytopenia 1 month after transplantation. Bone marrow aspiration revealed severe erythroid hypoplasia with giant and dystrophic proerythroblasts. Bone marrow cells were positive for HPV B19 DNA detected by polymerase chain reaction (PCR). Pancytopenia resolved shortly after administration of intravenous immunoglobulins. Nineteen cases of HPV B19 infection in organ transplant recipients have been so far reported in the literature. Immunocompromised patients should be considered at risk from developing symptomatic HPV B19 infections. In such patients, specific anti‐HPV B19 IgM and IgG antibodies may be absent or transient and therefore their negativity cannot rule out the diagnosis of HPV B19 infestation. Bone marrow smear morphological findings may suggest the diagnosis but testing for viral DNA by PCR is mandatory. Patients may spontaneously recover. However, since specific anti‐viral therapy is not currently available, intravenous immunoglobulin administration appears to be the more efficacious treatment.
Cytokine mRNA profiles in Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorders
Authors: Nalesnik Michael A , Zeevi Adriana , Randhawa Parmjeet S , Faro Albert , Spichty Kathy J , Demetris Anthony J , Fung John J , Whiteside Theresa L , Starzl Thomas E
Published: March 2003

Cytokine mRNA patterns were analyzed in 11 post‐transplant lymphoproliferative disorder (PTLD) specimens using qualitative reverse‐transcriptase polymerase chain reaction (RT‐PCR). In each case, a pattern of IL2−, IFNΓ−, IL4+, IL10+was seen. A similar pattern was observed in a spleen sample from 1 patient with contemporaneous PTLD elsewhere. Semiquantitative RT‐PCR for cytokine message was performed using RNA from bronchoalveolar lavage (BAL) specimens obtained from 2 patients with pulmonary PTLD. In both cases, IL4 message predominated. Reduction of message coincided with resolution of the tumors. The pattern differed from that seen in 1 patient with acute pulmonary rejection, in which RT‐PCR of BAL cells showed predominance of IL6 and IFNΓ. We conclude that at least some PTLDs exist within a T‐helper cell type 2 (Th2)‐like cytokine microenvironment. The presence of a similar mRNA pattern in an extratumoral specimen at the time of PTLD suggests that it may reflect a systemic phenomenon. Disappearance of this pattern following PTLD resolution indicates its dynamic nature and is consistent with the hypothesis that specific cytokines contribute to the development of PTLDs.
A case of relapse of C‐ANCA‐associated glomerulonephritis in post‐transplant patients
Authors: Oka Kazumasa , Moriyama Toshiki , Izumi Masaaki , Sugiura Toshihiro , Nakamura Hiroyuki , Nagatoya Katsuyuki , Toki Kiyohide , Kyo Masahiro , Kokado Yukito , Takahara Shiro , Okuyama Akihiko , Imai Enyu , Hori Masatsugu
Published: March 2003

We experienced a case of relapse of proteinase 3‐specific antineutrophil cytoplasmic autoantibody (C‐ANCA)‐associated rapid progressive glomerulonephritis (RPGN) in a patient after renal transplantation. A 19‐yr‐old man, who underwent a living donor kidney transplantation, presented a rapid renal function deterioration along with a sign of infection. Initially he was treated as acute rejection, but renal function did not improve. Renal biopsy revealed crescentic glomerulonephritis, and C‐ANCA titer was 12 EU/mL, resulting in the diagnosis of C‐ANCA‐associated RPGN. He was treated with three consecutive methylprednisolone pulses twice in addition to the basal immunosuppressive medications (cyclosporine A and mizoribine), then his renal function improved to normal. Bearing the possibility of recurrence of glomerulonephritis in mind, we re‐evaluated the nature and disease course of renal failure of original kidney. He experienced a rapid deterioration of renal function in 1992, and eventually CAPD was started in 1992. His serum in 1992 revealed high titer of C‐ANCA (24 EU/mL), and renal biopsy performed in 1992 showed a crescentic glomerulonephritis. Taken together, we diagnosed this event as a relapse of C‐ANCA‐associated GN.  Lessons from our experience are: 1) steroid pulse and high‐dose corticosteroid therapy may be useful for the treatment of relapse of C‐ANCA‐associated GN patients after renal transplantation; 2) the possibility of a relapse of C‐ANCA‐associated GN following renal transplantation has to be kept in mind, especially when infection precedes the deterioration of allograft kidney function.
Super long‐term surviving two renal grafts with severe arteriolosclerosis and glomerulosclerosis
Authors: Koike Junki , Yamaguchi Yutaka , Horita Shigeru , Tanabe Kazunari , Fuchinoue Shohei , Toma Hiroshi , Agishi Tetsuzo
Published: March 2003

Two long‐term renal transplant survivors, for about 20 yr, with unusual histological features in the allograft kidney are reported.  In both cases, marked hyalinosis was observed in the arterioles of the transplanted kidney, despite never having been administered cyclosporine or tacrolimus. The cause remains unknown at the present time, but we think that the changes could be multifactorial in origin, including due to aging of the graft, hypertension, hyperlipidemia and chronic rejection.  We conclude that histological analysis of the allograft kidney must be performed in long‐term renal transplant survivors, in order to understand the histological changes in the chronic phase after kidney transplantation and to predict the prognosis of the graft.
Delphi‐panel analysis of appropriateness of high‐dose chemotherapy and blood cell or bone marrow autotransplants in women with breast cancer
Authors: Gale Robert Peter , Edward Park Rolla , Dubois Robert , Bitran Jacob D , Buzdar Aman , Hortobagyi Gabriel , Jones Stephen E , Lazar Gary S , Spitzer Gary , Swain Sandra M , Vaughn Clarence B , Vogel Charles E , Martino Silvana
Published: March 2003

Background: There is controversy whether high‐dose chemotherapy and a blood cell or bone marrow autotransplant is a better treatment than conventional‐dose chemotherapy for women with local/regional or metastatic breast cancer. Subject selection and time‐to‐treatment biases make definitive comparison impossible. Recent results of randomized trials are contradictory.Objective: Determine appropriateness of high‐dose chemotherapy and a blood cell or bone marrow autotransplant in women with breast cancer.Panelists: Nine breast cancer experts from diverse geographic sites and practice settings.Evidence: Boolean MEDLINE searches of ‘breast cancer’ and ‘chemotherapy’ and/or ‘blood cell’ or ‘bone marrow transplants’.Process: We used a modified Delphi‐panel group judgement process. Clinical variables were permuted to define 2058 clinical settings. Each panelist rated appropriateness of high‐dose therapy and an autotransplant versus conventional therapy on a 9‐point ordinal scale (1: most inappropriate, 9: most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning.Conclusions: In women with local/regional breast cancer autotransplants were rated: 1) appropriate in those with ≥10 cancer‐involved lymph nodes; 2) uncertain in those with 4–9 cancer‐involved nodes; and 3) inappropriate in women with ≤3 cancer‐involved lymph nodes. In women with metastatic breast cancer autotransplants were rated: 1) appropriate in those with metastases to ‘favorable’ sites (skin, lymph node, pleura) and a complete or partial response to chemotherapy; 2) uncertain in women with metastases to ‘unfavorable’ sites (lung, liver, or central nervous system) and a complete response to chemotherapy or those with bone metastases and a complete or partial response or stable disease after chemotherapy; and 3) inappropriate in other settings.
Quality of life in long‐term survivors after liver transplantation: impact of recurrent viral hepatitis C virus hepatitis 1
Authors: Paterson David L , Gayowski Timothy , Wannstedt Cheryl F , Wagener Marilyn M , Marino Ignazio R , Vargas Hugo , Laskus Tomasz , Rakela Jorge , Singh Nina
Published: March 2003

Post liver transplant recurrence of infection with hepatitis C virus (HCV) occurs in approximately 50% of patients transplanted because of HCV‐related liver disease. The aim of this study was to assess long‐term quality of life, psychologic distress, and coping in patients with recurrent HCV after liver transplantation in comparison to patients transplanted for other etiologies of underlying liver disease. All liver transplant recipients transplanted at a University affiliated Veterans Affairs Medical Center who had greater than 6 months follow‐up were sent a questionnaire investigating quality of life (assessed by Medical Outcomes study health survey SF‐36), depression (assessed by Beck Depression Inventory), total mood disturbance (assessed by Profile of Mood States scale), coping (assessed by Billing and Moos Inventory of coping with illnesses), and employment status. Lower Beck Depression Inventory score (p=0.001), lower mood disturbance score (p=0.0001), overall satisfaction with present work (p=0.0001), and lesser use of avoidant coping (p=0.06) were predictors of better quality of life in long‐term survivors of liver transplantation. At a mean follow‐up of 4 yr after liver transplantation, patients with histopathologically diagnosed recurrent viral HCV hepatitis had significantly lower global quality of life score (mean score of 76.4 versus 86.2, p=0.011) and physical functioning score (mean score 20 versus 25, p=0.015), as compared to all other patients. In summary, quality of life and physical functioning were significantly impaired in liver transplant recipients with histopathologically diagnosed recurrent HCV hepatitis, as compared to those whose HCV hepatitis had not recurred or those transplanted for other reasons.
Excellent long‐term graft survival in low risk, primary renal allografts treated with prednisolone‐avoidance immunosuppression
Authors: Elias Tony J , Bannister Kym M , Clarkson Anthony R , Russ Graeme R , Mathew Timothy H , Barratt Lindsay J , Faull Randall J
Published: March 2003

Primary avoidance of oral corticosteroids for renal transplant recipients is uncommon. The South Australian renal transplant service used a double therapy (DT) regimen of cyclosporin and azathioprine from August 1986 to July 1996 for low risk (first graft, PRA<50%) allografts. Oral corticosteroid, prednisolone (P), was reserved for severe rejection or two mild rejection episodes, but could be later withdrawn at the physician's discretion. This regimen is associated with more early acute rejection (Russ et al., Clin Transplant 1990: 4: 26). We have now analysed long‐term patient survival (PS) and graft survival (GS) for this group. Of 448 transplants in South Australia between August 1986 and July 1996, 295 commenced DT regimen. Ninety‐four (31.8%) never received P at any stage post‐transplantation (group 1), 96 (32.5%) were placed on P and later weaned (group 2), and 97 (33%) remained on long‐term P (group 3). Technical losses, eight (2.7%), within 30 d of transplantation, were excluded from sub‐group analysis. PS for the total DT cohort at 1, 5 and 9 yr post‐transplantation was 97, 88 and 74%, respectively. GS over the same time period was 88, 75 and 55%, respectively. There was no statistically significant difference in survival compared to other ‘low risk’ grafts in the rest of Australia during the same time period. Mean serum creatinine concentration (CrC) for the DT group at 3 and 6 months and 1, 3, 5 and 10 yr was not significantly different to the rest of the Australian ‘low risk’ grafts. In the DT cohort, there were 334 acute rejections (<90 d) in 206 patients (70%), but only 42 (12.5%) required anti‐lymphocyte antibody therapy (OKT3 or ATG) for rejection. PS at 9 yr was not statistically significantly different between groups 1 and 2, but both groups survived better than group 3 (p<0.0043). GS for group 1 at 1, 5 and 9 yr post‐transplantation was 90, 81 and 73%, respectively; for group 2, 98, 87 and 66%, respectively; and for group 3, 84, 63 and 29%, respectively. Statistical significance was reached in group 1 versus 3 (p<0.001) and group 2 versus 3 (p<0.001). In summary, a DT regimen in low risk, first renal allografts gives excellent long‐term patient and GS and minimises long‐term P, despite a high rate of early acute rejection.
Health related quality of life (HRQOL) of kidney transplanted patients: variables that influence it
Authors: Rebollo Pablo , Ortega Francisco , Baltar José M , Badía Xavier , Alvarez‐Ude Fernando , Díaz‐Corte Carmen , Naves Manuel , Navascúes Rafael A , Ureña Ana , Alvarez‐Grande Jaime
Published: March 2003

The incidence and prevalence of patients on renal replacement therapy (RRT) who receive a renal transplant are continuously increasing in Spain. At the moment, they are the main group of end‐stage renal disease (ESRD) patients in our region (60% of total RRT patients). The aim of the present study was to assess the health related quality of life (HRQOL) of kidney transplanted patients of our region, and to identify socio‐demographic and clinical variables that influence it. The intention was also to compare the HRQOL of these patients with that of chronic haemodialysis (HD) patients and of the general population.  Methods. Two hundred and ten kidney transplanted patients and 170 HD patients were evaluated using the Karnofsky performance scale (KPS), sickness impact profile (SIP), and SF‐36 Health Survey (SF‐36). Socio‐demographic and clinical data, including a comorbidity index (CI), were also collected. To compare our patients with the general population we used SF‐36 mean scores from an aleatory sample taken from our region.  Results. Transplant patients had lower mean scores on SIP dimensions and higher scores on SF‐36 dimensions than chronic HD patients. In transplant patients, we found significant differences on SIP and SF‐36 scores in gender, educational level, haematocrite and haemoglobin, CI, time since transplantation, and KPS.  Conclusions. The HRQOL of transplant patients is clearly better than that of chronic HD patients and similar to that of the general population. Differences in the HRQOL within transplant patients did not appear to be as a result of patient's age, but rather it would appear to be a consequence of gender, analytic figures, CI, KPS score, time with transplant, and educational level.
Peripheral endothelial dysfunction in heart transplant recipients: possible role of proinflammatory cytokines
Authors: Holm Torbjørn , Aukrust Pål , Andreassen Arne K , Ueland Thor , Brosstad Frank , Frøland Stig S , Simonsen Svein , Gullestad Lars
Published: March 2003

Endothelium‐dependent vasodilation in the peripheral circulation may be impaired in heart transplant recipients (HTx rec). Conflicting results have been obtained and the mechanisms involved have not been examined. In the present study, we examined whether long‐time survivors of heart transplantation (Tx) show signs of endothelial dysfunction in the peripheral microcirculation, and further investigated the possible role of endothelium‐related markers and proinflammatory cytokines in this process. The vasodilatory responses to acetylcholine (Ach) (endothelium‐dependent) and sodium nitroprusside (SNP) (endothelium‐independent) were evaluated by skin laser–Doppler perfusion measurements in 63 clinically stable HTx rec 6 yr (range 1–13 yr) after Tx, and compared with 20 healthy controls. Ten HTx rec were also followed prospectively with three repeated measurements during the first year after Tx. Plasma von Willebrand factor, big‐endothelin (b‐ET), and proinflammatory cytokines were measured by enzyme immunoassays. Vascular responses to both Ach and SNP were significantly attenuated in the HTx rec compared with controls. In longitudinal testing, there was a significant reduction in endothelium‐dependent vasodilation, but not independent vasodilation from 1 to 12 months after Tx. Plasma levels of vWF and b‐ET, as well as levels of proinflammatory cytokines, tumor necrosis factor (TNF)‐α, interleukin (IL)‐6 and IL‐1β, were all markedly increased in HTx rec. HTx rec responses to Ach were negatively correlated to TNF‐α levels in plasma (r=−0.39, p<0.01). Moreover, there was also a significant positive correlation between plasma b‐ET and TNF‐α (r=0.34, p<0.01). In the long‐term follow‐up of HTx rec, endothelial dysfunction is demonstrated by both regulation of blood flow in the skin microcirculation and by raised markers of endothelial activation in plasma. This endothelial dysfunction may be related to enhanced levels of proinflammatory cytokines in these patients.