bluuebunny/crossref_metadata_2025 huggingface dataset:
A PCR‐based method for detecting known mutations in the human UDP galactose‐4′‐epimerase gene associated with epimerase‐deficiency galactosemia
Authors: Henderson JM , Huguenin SM , Cowan TM , Fridovich‐Keil JL
Published: March 2003

Epimerase‐deficiency galactosemia results from impairment of the human enzyme UDP galactose‐4′‐epimerase (GALE). We report a rapid, internally controlled PCR‐based method for detection of nine naturally occurring point mutations in human GALE associated with epimerase deficiency. These mutations were derived from patients whose clinical presentations ranged from mild to severe; all but one of these mutations have been reported previously. The tests described here work well on both cDNA and genomic samples and require no specialized equipment beyond a thermal cycler and an agarose gel electrophoresis system. Finally, although these tests in no way replace the need for biochemical diagnosis in epimerase‐deficiency galactosemia, they do provide the possibility of additional molecular information to support a biochemical diagnosis and facilitate the possibility of more accurate carrier testing, should that option be desired.
A previously undescribed nonsense mutation of the HFE gene
Authors: Beutler E , Griffin MJ , Gelbart T , West C
Published: March 2003

A patient with clinically manifest hereditary hemochromatosis was found to be heterozygous for the c.845 A→G (C282Y) mutation. As simple heterozygotes for this mutation do not develop the hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed nonsense mutation was identified at c.211 C→T (R74X). The patient's brother who also had the hemochromatosis phenotype shared his HFE genotype. To determine how common such mutations might be, the coding and 5′ region of the HFE genes of 11 subjects who had been found in a large population survey to be heterozygous for the C282Y mutation and had elevated ferritin levels were sequenced. No mutations were found. Sequencing of the HFE gene also revealed two polymorphisms that had not previously been noted, − 467 C→G and − 970 T→G. Neither of these mutations appear to cause an abnormality in iron metabolism.
Effects of apolipoprotein A‐I genetic variations on plasma apolipoprotein, serum lipoprotein and glucose levels
Authors: Larson IA , Ordovas JM , Barnard JR , Hoffmann MM , Feussner G , Lamon‐Fava S , Schaefer EJ
Published: March 2003

The present authors investigated the individual and combined associations of the apolipoprotein (apo) A‐I −75 bp and +83 bp polymorphisms with plasma lipid, lipoprotein and apolipoprotein levels in 734 Caucasian men and women. The frequency of the A allele at position −75 bp (G→A) was 0.14 in women and 0.17 in men. The frequencies for the rare M2 allele at position +83 bp and/or 84 bp (C→T and G→A, respectively) were 0.04 and 0.05 in women and men, respectively. In women, the A allele was associated with significantly higher levels of apo B (P = 0.016), total cholesterol (TC) (P = 0.005), low‐density lipoprotein cholesterol (LDL‐C) (P = 0.018) and TC:high‐densisty lipoprotein (HDL) ratio (P = 0.026) compared to the G/G subjects. In men, no significant associations were detected between the −75 bp polymorphism and any lipid trait examined. The M2 allele for the +83 bp polymorphism was significantly associated in men with higher levels of apo A‐I (P = 0.002) and TC (P = 0.046). In women, a significant effect was observed for TC (P = 0.036), with M2+/– subjects having lower levels than M2+/+ subjects. Significant linkage disequilibrium (P = 0.037) between the apo A‐I −75 bp and +83 bp polymorphisms was detected. Women carrying both rare alleles (G/A M2+/–) had significantly higher TC:HDL ratios (P = 0.031) compared to the other haplotypes. In men, significant differences were observed for apo A‐I (P = 0.021) and TC (P = 0.044), with carriers of the G/G M2+/– haplotype having the highest values compared to other genotype combinations. In conclusion, the −75 bp (G/A) polymorphism appears to have a significant effect on levels of apo B, plasma TC and LDL‐C in women, while the +83 bp polymorphism seems to affect the apo A‐I levels in men, and the plasma cholesterol levels in both genders.
The relationship between plasma t‐PA and PAI‐1 levels is dependent on epistatic effects of theACE I/DandPAI‐1 4G/5Gpolymorphisms
Authors: Moore JH , Smolkin ME , Lamb JM , Brown NJ , Vaughan DE
Published: March 2003

Thrombus formation and degradation is partly due to a complex interplay between tissue‐type plasminogen activator (t‐PA) and plasminogen activator inhibitor 1 (PAI‐1). There is accumulating evidence that plasma levels of t‐PA and PAI‐1 may be influenced by an interaction between the fibrinolytic and renin‐angiotensin systems. The goal of this study was to conduct an exploratory data analysis to determine whether there is evidence that the relationship (i.e. correlation) between plasma t‐PA and PAI‐1 is influenced by interactive effects of theangiotensin converting enzyme (ACE) insertion/deletion (I/D)andplasminogen activator inhibitor 1 (PAI‐1) 4G/5Gpolymorphisms in a sample of 50 unrelated African Americans and 117 unrelated Caucasians. In a single‐locus analysis, no evidence for heterogeneity of plasma t‐PA and PAI‐1 correlations among eitherACE I/DorPAI‐1 4G/5Ggenotypes was detected. However, using the combinatorial partitioning method for exploratory data analysis, we identified evidence that is suggestive of heterogeneity of plasma t‐PA and PAI‐1 correlations among multilocusACE I/DandPAI‐1 4G/5Ggenotypes in African American females, Caucasian females, Caucasian males, but not African American males. From these results, we propose as a working hypothesis that the correlation between plasma t‐PA and PAI‐1 may be dependent on epistatic effects of theACE I/DandPAI‐1 4G/5Gpolymorphisms. This study supports the idea that interactions between the fibrinolytic and renin‐angiotensin systems play an important role in the genetic architecture of plasma t‐PA and PAI‐1.
Increased sensitivity to 4‐chloro‐m‐cresol and caffeine in primary myotubes from malignant hyperthermia susceptible individuals carrying the ryanodine receptor 1 Thr2206Met (C6617T) mutation
Authors: Wehner M , Rueffert H , Koenig F , Neuhaus J , Olthoff D
Published: March 2003

Malignant hyperthermia (MH) is an autosomal‐dominant disorder of skeletal muscle, triggered by volatile anaesthetics and depolarizing muscle relaxants. The causative defect lies in the control of Ca2+ release from the sarcoplasmic reticulum in skeletal muscle. Numerous mutations have been detected in the ryanodine receptor 1 (RyR1) gene, but so far an MH‐causative role has only been confirmed for 16 human RyR1 mutations. In this report we show that myotubes derived from individuals carrying the RyR1 Thr2206Met (C6617T) mutation have an abnormal response of the intracellular calcium concentration to 4‐chloro‐m‐cresol and to caffeine. Satellite cells were obtained from muscle biopsies of patients referred for diagnosing MH. The intracellular calcium concentration in response to 4‐chloro‐m‐cresol and to caffeine was investigated by fluorescence calcium imaging. In myotubes the half‐maximal activation concentration (EC50) for 4‐chloro‐m‐cresol was reduced from 203 µm (wild type) to 98 µm (Thr2206Met), and for caffeine from 3.8 mm to 1.8 mm. From the reduction of EC50 we conclude that the RyR1 Thr2206Met mutation is pathogenic for MH.
Craniofacial features in Cohen syndrome: an anthropometric and cephalometric analysis of 14 patients
Authors: Hurmerinta K , Pirinen S , Kovero O , Kivitie‐Kallio S
Published: March 2003

Cohen syndrome (Mendelian Inheritance in Man [MIM] no. 216550) is a rare, autosomal‐recessive inherited disorder with mental retardation and a typical appearance. The condition is relatively common in Finland where 35 patients have been diagnosed. We studied 22 patients in detail, obtaining anthropometric measurements of the head and face, and cephalometric radiographs of 14 patients (14–57 years of age). Measurements of patients were compared to population norms and matched controls. Anthropometric analysis confirmed and quantified the previously described syndrome features: small head size [−4 standard deviations (SD)], with varying cephalic index. Width of the upper face was close to normal, but width of the lower face was small. Philtrum length was shorter than in healthy controls (p = 0.0039 in females and p = 0.0014 in males). The measurements from standardized radiographs revealed short cranial base dimensions (−2.2 and −2.6 SD), but normal cranial base angles. Prognathism of jaws was within normal limits. Reduced head size (microcephaly), short philtrum and small cranial base dimensions are essential features in Cohen syndrome. In addition, most patients had forward‐inclined upper incisors and maxillary prognathia. We conclude that exact measurements mostly confirmed the Cohen syndrome description based previously on clinical impression.
A study of the influence of different genotypes on the physical and behavioral phenotypes of children and adults ascertained clinically as having PWS
Authors: Webb T , Whittington J , Clarke D , Boer H , Butler J , Holland A
Published: March 2003

A population‐based cohort of people with a clinical diagnosis of Prader–Willi syndrome (PWS) was genetically assessed using molecular diagnostic methods and subsequently divided into the following genetic subtypes involving chromosome 15: ‘deletion’, ‘disomy’ and genetically negative (referred to as ‘PWS‐like’). The physical and behavioral characteristics of the three groups were compared in order to evaluate the unique characteristics of the phenotype resulting from loss of expression of imprinted genes at 15q11q13 (PWS vs. PWS‐like cases), the possible effect of either haploid insufficiency of non‐imprinted genes (deletion cases), or gain of function of imprinted genes (disomy cases) located within the PWS critical region at 15q11q13. In this study, the main differences between probands with either a deletion or disomy are considered, and the possible involvement of contributing genes discussed. The differences within the PWS group proved difficult to quantify. It would appear that haploid insufficiency or gain of function are more subtle contributors than gender‐specific genomic imprinting in the production of the PWS phenotype.
Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene
Authors: Floderus Y , Shoolingin‐Jordan PM , Harper P
Published: March 2003

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficit of porphobilinogen deaminase (PBGD), the third of eight enzymes in the haem biosynthetic pathway. The overt disease is characterized by neuropsychiatric symptoms that are often triggered by exogenous factors such as certain drugs, stress, and alcohol. The aim of this work has been to identify the underlying genetic defect in each AIP‐affected family in order to provide early counselling to assist in the avoidance of precipitating factors. The prevalence of AIP in Sweden is in the order of 1:10 000. The major mutation in Sweden, W198X, is due to a founder effect in the northern part of the country. This mutation, together with a further 11 mutations, have been reported previously. The present communication encompasses the great majority of AIP kindreds in Sweden and includes a further 27 mutations within the PBGD gene. This includes 14 completely new mutations, as well as 11 known mutations detected for the first time in Sweden. The majority of the mutations are located in exons 10 and 12 with fewer in exon 7. The clinical and biochemical outcomes in some patients are described. We also use the three‐dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the new Swedish missense and nonsense mutations.
The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family
Authors: Uyguner O , Tukel T , Baykal C , Eris H , Emiroglu M , Hafiz G , Ghanbari A , Baserer N , Yuksel‐Apak M , Wollnik B
Published: March 2003

Dominant mutations in the GJB2 gene encoding connexin 26 (Cx26) can cause non‐syndromic hearing impairment alone or in association with palmoplantar keratoderma (PPK). We have identified the novel G224A (R75Q) mutation in the GJB2 gene in a four‐generation family from Turkey with autosomal dominant inherited hearing impairment and PPK. The age of onset and progression of hearing loss were found to be variable among affected family members, but all of them had more severe impairment at higher hearing frequencies. Interestingly, the novel R75Q mutation affects the same amino acid residue as described recently in a small family (R75W) with profound prelingual hearing loss and PPK. However, the R75W mutation was also observed in a control individual without PPK and unknown hearing status. Therefore, the nature of the R75W mutation remains ambiguous. Our molecular findings provide further evidence for the importance of the conserved R75 in Cx26 for the physiological function of the inner ear and the epidermal cells of the skin.
A new case of dup(3q) syndrome due to a pure duplication of 3qter
Authors: Faas BHW , De Vries BBA , Van Es‐van Gaal J , Merkx G , Draaisma JMT , Smeets DFCM
Published: March 2003

The characteristic clinical features of the dup(3q) syndrome include typical facial features, mental and growth retardation, and (often) congenital heart anomalies. However, pure duplication of 3qter is rare because most of the reported cases are patients who carry an unbalanced translocation and, in addition to the duplication for 3qter, have a deletion for another chromosomal segment. A new case with a pure duplication of 3q detected in a 2‐month‐old boy is presented here. Extensive cytogenetic analysis revealed an inverted duplication of the distal part of 3q (chromosomal band 3q26.3 up to the telomere), with no (detectable) loss of the original telomeric sequences. Clinical evaluation revealed several phenotypic hallmarks characteristic for the dup(3q) syndrome. By comparing the duplicated region of this patient with the duplicated regions of the other patients with a pure duplication of 3q, we were able to localize the critical region for the dup(3q) phenotype to band 3q26.3.

Alongside this new case with a pure duplication of 3q, an overview of six previous cases is given.
Involvement of a palindromic chromosome 22‐specific low‐copy repeat in a constitutional t(X; 22)(q27;q11)
Authors: Debeer P , Mols R , Huysmans C , Devriendt K , Van de Ven WJM , Fryns J‐P
Published: March 2003

Segmental duplications or low‐copy repeats (LCRs) on chromosome 22q11 have been implicated in several chromosomal rearrangements. The presence of AT‐rich regions in these duplications may lead to the formation of hairpin structures, which facilitate chromosomal rearrangement. Here we report the involvement of such a low‐copy repeat in a t(X;22) associated with a neural tube defect. Molecular analysis of the chromosomal breakpoints revealed that the chromosome 22 breakpoint maps in the palindromic non‐AT‐rich NF1‐like region of low‐copy repeat B (LCR‐B). No palindromic region was encountered near the breakpoint on chromosome X. Our findings confirm that there is no single mechanism leading to translocations with chromosome 22q11 involvement. Because LCR‐B does not contain genes involved in neural tube development, we believe that the gene responsible for the observed phenotype is most likely localized on chromosome X.
X‐linked mental retardation: vanishing boundaries between non‐specific (MRX) and syndromic (MRXS) forms
Authors: Frints SGM , Froyen G , Marynen P , Fryns J‐P
Published: March 2003

This review covers the history and nosology of X‐linked mental retardation (XLMR) in which the following, largely clinically based, subclassification was used: fragile X syndrome (FRAXA), syndromic forms (MRXS) and non‐specific forms (MRX). After the discovery of the FMR2 gene at the FRAXE site, 10 MRX genes have been identified in the last 6 years. A short description is given of the strategies used to identify the genes that cause mental retardation (MR). Furthermore, their potential functions and the association with MR will be discussed. It is emphasized that mutations in several of these MR genes can result in non‐specific, as well as in syndromic forms of XLMR. Present findings stress the importance of accurate clinical evaluation. Most considerably, genotype–phenotype correlation studies of affected individuals in XLMR families with MRX gene mutations are necessary to define the criteria of MRX vs MRXS subclassification.
Hepatocellular carcinoma: strategy for optimizing surgical resection, transplantation and palliation
Authors: Fisher Robert A , Maroney Timothy P , Fulcher Ann S , Maluf Daniel , Clay John A , Wolfe Luke G , Dawson Sherfield , Cotterell Adrian , Stravitz R Todd , Luketic Velimir A , Shiffman Mitchell , Sterling Richard K , Posner Marc P
Published: March 2003

Abstract: In December 1997, a prospective study with informed consent was initiated to test a neoadjuvant treatment of transcatheter hepatic arterial chemo‐embolization (TACE) and thermal or chemical ablation followed by transcatheter hepatic arterial chemo‐infusion (TACI) in patients with hepatocellular carcinoma (HCC) referred for transplantation (OLT) and for resection. Patients were staged with American Liver Tumor Study Group‐modified tumour‐node‐metastasis (TNM) staging classification using serial 3–6 month physical exam, alphafetoprotein (AFP), abdominal enhanced MRI, chest CT and bone scan. Sixty‐five patients with HCC, out of 508 patients referred for OLT, were divided into five clinical groups and an incidental HCC patient group (n = 8), diagnosed on post‐transplant explant pathology. The key focus of study was safety, site of HCC recurrence and tumour free survival. One hundred and thirty three ablation, infusion procedures were performed with an overall 24.8% morbidity, including two septic deaths. There were 13 (21.6%) HCC recurrences in 60 patients having one or more ablative treatments with only 23% hepatic HCC recurrences at 43 months of study. Eighteen HCC patients were listed for OLT (Group 3), with 12 patients transplanted after 29–424 d waiting. Two patients were removed from the OLT list due to HCC metastases, waiting a mean of 145 d. Two patients, post‐OLT, had their TNM score upgraded from T2, T3 to T4. No Group 3 post‐OLT patient has died or had HCC recurrence at mean follow‐up of 27 ± 15 months. No incidental HCC group post‐OLT patient has died or had HCC recurrence at mean follow‐up of 24 ± 14 months. This neoadjuvant protocol is safe and effective in reducing HCC recurrence prior to and after OLT and resection.
An autopsy case of sudden death in renal transplant recipient
Authors: Okada Masanao , Kyakuno Miyaji , Imamura Junichi , Nakamura Takayuki , Takahara Shiro
Published: March 2003

Abstract: Few autopsy cases of sudden death in renal transplant recipients have been reported in the literature. The present case was a 50‐year‐old female recipient of a living‐related renal transplant, who died suddenly after a good post‐transplant course of 14 years. The patient was admitted in December 2000 for detailed investigation for ascites, and died unexpectedly 1 month later. She complained of mild dyspnoea approximately 3 h before death. Detailed clinical and laboratory investigations after admission showed no malignant findings in the abdominal cavity. Postmortem pathological examination also showed no tumour in the abdominal cavity. Both lungs were pneumatized. Histopathological examinations revealed metastatic calcification. Calcification was observed in the heart, lungs, kidney graft and pancreas. Calcification in the heart was found in the central fibrous body surrounding the atrioventricular node and bundle of His, as well as in the origin of bifurcating bundle. In the myocardial fibres, fibre rupture and waviness were observed. Although these findings may indicate agonal changes, they might also be a consequence of sudden cardiac death. This patient was in a state of renal failure, which presumably caused metastatic calcification involving also the cardiac conduction system. This calcification might partially account for the sudden death.
The use of positive B cell flow cytometry crossmatch in predicting rejection among renal transplant recipients
Authors: Kotb Malak , Russell Wendy C , Hathaway Donna K , Gaber Lillian W , Gaber A Osama
Published: March 2003

We performed retrospective flow cytometry crossmatch (FCXM) on 106 renal graft recipients who were transplanted based on current T cell negative serologic crossmatch. T and B cell FCXMs were performed on current and historical peak reactive post‐transplant sera using 1024‐channel flow cytometer and the shift in median channel fluorescence (SMCF) over the negative control was calculated. Cut‐off values for a positive T and B crossmatch,> 40 and> 80 SMCF, respectively, were determined based on previous retrospective analysis of the data in the context of clinical outcome in our center, and were 1.5 times the standard deviation (SD) above the mean median channel fluorescence (MCF) of normal sera controls.The 1‐yr graft survival was 95% for the total group of patients studied, and 87% for the recipients who had a positive T cell FCXM. To focus on the influence of a positive B cell FCXM on the incidence of rejection, primary transplant recipients who had a negative T cell FCXM (n=81) were studied. Fifteen of 30 (50%) recipients with a positive B cell FCXM experienced at least one rejection episode within the first year. By contrast, only 15 of 51 (29.4%) of patients with a negative B cell FCXM experienced rejection (p=0.05). The mean B cell SMCF in the group of patients who had no rejections was 45±59, while that of the group of patients who experienced at least one rejection was 97±97 (p=0.012). By comparison, the rejection rate among the retransplant patients was 44.4%, and the mean B cell SMCF in the group with rejection was 94±75 while it was 5±7 among retransplant patients who did not have rejection (p=0.031).Eighty‐six percent of sensitized (panel reactivity antibodies (PRA)>10%) patients who had a B positive/T negative FCXM experienced rejection, compared to 33% (n=6 out of 16) of the B negative/T negative sensitized patients (p=0.03). Furthermore, 62% (n=13 out of 21) of donor–recipient mismatched patients with a B positive/T negative FCXM experienced rejection, compared to 38% (n=13 out of 35) of patients with T negative/B negative FCXM who were similarly mismatched (p=0.064).These data demonstrate the value of a positive B cell FCXM for predicting post‐transplant rejections particularly when evaluated in the context of prior sensitization and/or DR mismatching. Our results suggest that B cell FCXM may have significant clinical implications, justifying its use in post‐transplant management of recipients who have other risk factors of rejection.
The impact of (1:1) cyclosporine A conversion to its microemulsion formulation on the kidney function of patients with cardiac allografts
Authors: Khajehdehi Parviz , Yip Daniel , Bastani Bahar
Published: March 2003

Due to the large variations in the absorption and bioavailability of conventional cyclosporine A (CyA), 1:1 (mg:mg) conversion to its microemulsion formulation (Neoral) has been advocated in transplant recipients. However, the renal hazards and biochemical effects of such conversions are not known in cardiac transplant recipients. In this study, 68 cardiac transplant recipients who were receiving conventional CyA, for a period of 61.3±36.0 (mean±standard error (SE)) months, were switched to the microemulsion formulation (Neoral). The biochemical and renal function tests were evaluated at 1, 3, 6, 9 and 12 months pre‐ and post‐conversion of CyA. The results obtained post‐conversion were compared with those of the baseline (pre‐conversion). Serum creatinine and uric acid levels significantly increased post‐conversion to the microemulsion formulation. One patient required discontinuation of the microemulsion in an attempt to reverse severe renal failure. In spite of a significant decrease in the microemulsion dose at 6, 9 and 12 months, there was a significant increase in the whole blood CyA trough levels at 9 and 12 months of conversion. There was no significant change in blood pressure, serum total cholesterol or potassium post‐conversion. Our results suggest that after 1:1 (mg:mg) conversion of CyA to its microemulsion formulation, there will be a significant rise in serum creatinie, uric acid and whole blood trough CyA levels necessitating significant dose reduction. This effect is probably due to the markedly improved absorption and bioavailability of the latter.
Prospective study of microchimerism in transplant recipients
Authors: McDaniel HB , Yang M , Sidner RA , Jindal RM , Sahota A
Published: March 2003

Background. We evaluated peripheral blood microchimerism in 48 consecutive organ transplant recipients (35 kidneys, ten livers, one kidney–liver, one kidney–pancreatic islet, one kidney–pancreas) up to 12 months post‐transplantation. Patients were categorized according to the presence or absence of rejection episodes, and the patterns of microchimerism in the two groups were then compared.Methods. DNA was extracted from donor, pre‐transplant, and post‐transplant peripheral blood samples. Several polymerase chain reaction (PCR)‐based assays were developed for the detection of microchimerism. Assay sensitivities ranged from 0.0001 to 3%.Results. Microchimerism was detected only in sex‐mismatched cases (male donors and female recipients) using nested PCR for a Y‐chromosome marker. There were ten such cases (six kidneys, two livers, and two combined organ transplants). In patients without rejection (n=7), there was a peak of donor‐DNA at 1–3 wk post‐transplantation followed by a second peak between 3 wk and 4 months. In patients with biopsy‐proven rejection (n=3), the peaks were absent and the levels of microchimerism were extremely low (<0.001%). Microchimerism levels declined in all 10 patients and were barely detectable 1 yr post‐transplantation. Microchimerism was not detected in the remaining 38 patients despite using a battery of sensitive PCR‐based assays.Conclusions. In our study, microchimerism was detected using the Y‐chromosome PCR assay only and the level of donor‐DNA in a given patient varied over time. This study highlights the difficulties in establishing a correlation between microchimerism and transplant tolerance.
The national impact of the 1995 changes to the UNOS renal allocation system
Authors: Leffell Mary S. , Zachary Andrea A.
Published: March 2003

In 1995, changes in the United Network for Organ Sharing (UNOS) renal allocation policies expanded the mandatory share (MS) category to include zero antigen mismatches (0 mm), increased points for waiting time and for pediatric status, and eliminated points for certain HLA match grades. Data from the national scientific registry on 11 344 and 11 652 renal allograft recipients were analyzed for periods prior to and following the policy changes to assess the impact on organ allocation. The overall frequency of transplants going to non‐Caucasians increased between the study periods, but the increase was significant only in the MS category. The proportion of MS transplants nearly doubled for African‐Americans, increasing from 5.5% to 10.5%, while Hispanic/Latino recipients experienced a smaller increase, from 7.2% to 8.9%. The increased numbers of MS transplants clearly resulted from the inclusion of the 0 mm in the MS category. Among the NMS transplants, the average number of mismatched HLA antigens increased slightly. No effect of the additional points for waiting time was observed among recipients of non‐mandatory share (NMS) transplants. The increase in mean waiting time until transplant for NMS recipients was attributable to the growth in the size of the waiting list. In contrast, there was a significant increase in mean waiting time for MS recipients. There were no significant changes in the proportions of sensitized or pediatric recipients between the study periods.In conclusion, only the changes in the MS policies appeared to have any significant effect on renal allocation. Further efforts will be required to address increasing allocation to patients disadvantaged by sensitization and/or prolonged waiting times.
Increased incidence of allograft rejection in stable heart transplant recipients after late conversion from mycophenolate mofetil to azathioprine 1
Authors: Taylor Do , Sharma Rc , Kfoury Ag , Renlund Dg
Published: March 2003

Mycophenolate mofetil (MMF) is a safe and effective immunosuppressive agent in kidney and liver transplantation. Preliminary studies also support its use in heart transplantation. However, the cost of MMF is substantially greater than azathioprine (AZA), the current alternative. Since the majority of rejection episodes occur within the first few months of transplantation, using MMF early after transplantation and subsequently converting to AZA, after the risk of rejection has diminished, might be cost‐effective. In order to evaluate the safety of such a strategy in heart transplant recipients, we reviewed the rejection profiles of a group of patients who were converted from MMF to AZA late after transplantation.Forty‐three stable patients on chronic MMF therapy as part of an open‐label, long‐term safety study were converted to either commercially available MMF (CellCept®) or AZA, at the conclusion of the study. Demographic variables, rejection histories before and after conversion, and immunosuppressive regimens were examined.Twenty‐three patients were continued on commercial MMF and 20 were converted to AZA therapy. The average duration of MMF therapy prior to conversion was 41 months in each group. Baseline demographics were similar in the two groups. Treated allograft rejection occurred in 10 of 20 patients converting to AZA, as compared to only 1 of 23 patients remaining on MMF; p=0.002. Additionally, mean scores (1–5 scale) for the three biopsies before and after conversion favored continued MMF therapy (1.5±0.6 before and 1.2±0.4 after conversion in MMF group vs. 1.3±0.5 before and 1.7±0.9 after conversion to AZA; p=0.02). No allograft loss occurred as a result of conversion.These data suggest that conversion from MMF to AZA, even late after transplantation, can be associated with allograft rejection. The costs associated with these rejection episodes (the additional immunosuppressive agents, endomyocardial biopsies, and physician visits) may exceed the potential cost savings of converting stable heart transplant recipients from MMF to AZA.
Cold preservation of the human colon and ileum with University of Wisconsin solution
Authors: Kawashima Yoshiyuki , Takeyoshi Izumi , Furukawa Hiroyuki , Lee Randall G , Starzl Thomas E , Todo Satoru
Published: March 2003

The inclusion of the colon in the intestinal graft resulted in worsening patient and graft outcome and increased the incidence of infection and rejection. In this study, we examine the role of ischemia on the barrier function of the epithelium during cold ischemia.

Samples were collected from 15 harvested and transplanted human donor grafts (colon, 10; ileum, 6), which were immersed in University of Wisconsin (UW) solution. Ischemia (6, 12, 24, and 48 h) and reoxygenation were performed to evaluate the mucosal electrical status using the Ussing chamber technique. The functions of enterocytes and crypt cells were tested by glucose and theophylline challenge. Modified Park's classification was applied to evaluate the severity of mucosal damage under light microscopy.

The colon had higher levels of baseline potential difference, short‐circuit current, and resistance than the ileum during 6–48 h of ischemia. Colonic epithelial cells responded well to theophylline stimulation at 24 h of ischemia, while there was no ileal response. The colonic mucosa was histopathologically well preserved in UW solution for 48 h, and mucosal damage induced by reoxygenation was less than in the ileum. In conclusion, electrophysiologically and histopathologically, the colon is less susceptible to cold preservation damage than the ileum during storage with UW solution.
Transmission of malaria tertiana by multi‐organ donation
Authors: Fischer Lutz , Sterneck Martina , Claus Manfred , Costard‐Jäckle Angelika , Fleischer Bernhard , Herbst Hermann , Rogiers Xavier , Broelsch Christoph E.
Published: March 2003

In this report, transmission of malaria via a liver, a kidney, and possibly a heart allograft from a single donor is described. The donor had immigrated from Cameroon to Germany 18 months before, but had no clinical signs of active malaria infection. The liver transplant recipient and one of the two kidney transplant patients developed febrile illness with the appearance of Plasmodium vivax in blood smears 5 and 6 wk after transplantation, respectively. In the heart transplant recipient, a subclinical malaria infection was suspected based on a rise of malaria antibodies late after transplantation, whereas the recipient of the second kidney allograft had no clinical or laboratory evidence of malaria. Both liver and kidney recipients with active malaria responded to medical treatment. However, the liver transplant patient developed progressive cholestasis and died 5 months after transplantation from liver failure possibly due to side effects of the malaria medication. Other cases of malaria in solid organ recipients are briefly reviewed.
Helicobacter pylori antibodies in hemodialysis patients and renal transplant recipients
Authors: Yıldız A , Beşışık F , Akkaya V , Sever MŞ , Bozfakıoğlu S , Yılmaz G , Ark E
Published: March 2003

In this cross‐sectional, controlled study, Helicobacter pylori (H. pylori) infection, a probable factor in the development of gastrointestinal problems, was investigated in dialysis patients and renal transplant recipients. Forty‐seven dialysis patients (22 male, 25 female, mean age of 36.6±15 yr (range 18–83 yr)), 57 renal transplant recipients (39 male, 18 female, mean age of 36.8±10 yr (range 19–60 yr)) and 55 healthy individuals (34 male, 21 female, mean age of 33.4±9.6 yr (range 21–58 yr)) were included and no significant difference was found in the study groups. The mean time spent on dialysis in the hemodialysis group was 32.5±27.7 months (range 1–100 months). H. pylori antibodies were detected in 22 of 57 (38.6%) patients in the transplantation group, 31 of 47 (65.9%) patients in the dialysis group and 39 of 55 (72.5%) in the control group. No correlation was found between H. pylori infection and age, sex, primary disease, frequency of dialysis, duration and type of transplantation and the immunosuppressive therapy. However, patients with H. pylori antibodies spent a shorter time on dialysis compared to patients without the antibodies (26.6±23.5 vs 44.1±32.1 months, p=0.038). The frequency of H. pylori infection in the transplantation group was significantly lower than the control and dialysis groups (p<0.01). This finding may be explained on the basis of decreased humoral antibody response to H. pylori infection, secondary to immunosuppressive therapy rather than decreased incidence of infection in the transplantation group. Finally, we concluded that the value of the serological test for diagnosis of H. pylori infection should be interpreted cautiously in these patient groups.
Addisonian crisis in a liver transplant patient due to fluconazole withdrawal
Authors: Tiao Greg M , Martin Jill , Weber Fredrick L , Cohen Robert M , Hanto Douglas W
Published: March 2003

Fluconazole is an antifungal agent commonly used in liver transplant patients. In addition to its antifungal activity, it is a potent inhibitor of the liver cytochrome P450 enzymes. These enzymes degrade a wide range of metabolically active compounds including glucocorticoids. In this report, we identify an episode of Addisonian crisis that occurred in a liver transplant patient receiving prednisone immunosuppression after fluconazole was discontinued. We postulate the mechanism for the crisis was a reversal of the fluconazole‐induced suppression of the P450 enzymes. The resulting increased activity altered the patient’s glucocorticoid metabolism leading to an Addisonian crisis.
Commerce in transplantation: how does it affect European legislation?
Authors: Cohen Bernard , G Persijn Guido , Vanrenterghem Yves
Published: March 2003

Commerce in transplantation is well known, if not well defined. Although the word commerce suggests an exchange of money, in reality it often simply signifies a non‐profit‐making transaction. Nevertheless, money, and therefore profit, may be involved in some human organ transactions, and the buying and selling of organs for transplantation remains common in too many countries. Clearly, if such transactions were allowed to continue only those who could afford to pay would benefit. They would probably also lead to an increase in the number of media horror stories. A number of such stories have appeared in the past. Although they are rarely based on hard evidence, they do influence politicians and, as a consequence, affect legislation and the availability of organs for transplant. They may also diminish the willingness of the general public to become organ donors and contribute to the persistent poor supply of organ donors. Organ exchange organizations, such as Eurotransplant, have made many efforts to prevent unethical transactions. Nevertheless, stories of such transactions continue to appear and are unlikely to abate while there is a high demand and poor supply of organs for transplantation. An international donor surveillance committee – a clearing house for information on malpractice – could be one solution to the problem as it would prevent doctors from taking part in unethical transplant procedures.
Steroid withdrawal in pancreas transplant recipients
Authors: Humar Abhinav , Parr Elizabeth , Drangstveit Mary Beth , Kandaswamy Raja , Gruessner Angelika C , Sutherland David Er
Published: March 2003

Background. Numerous studies of steroid withdrawal have been carried out in kidney and liver transplant recipients, but only a few in pancreas transplant recipients. Yet, pancreas transplant recipients could have significant long‐term benefits from steroid withdrawal.Methods. We performed a retrospective analysis to determine the feasibility of steroid withdrawal in pancreas transplant recipients.Results. Of 360 recipients who underwent a pancreas transplant between January 1, 1994 and June 30, 1998, 14 attempted steroid withdrawal (12 simultaneous pancreas–kidney [SPK]; 2 pancreas transplant alone [PTA]). Reasons for steroid withdrawal were bone fractures (n=3), psychiatric disorders (n=2), severe acne (n=1), recurrent infections (n=4), and problems with hypercholesterolemia or hypertension (n=4). All 14 were maintained on tacrolimus and mycophenolate mofetil (MMF) immunosuppression, except for 1 who was on tacrolimus and azathioprine (AZA). Of the 14 recipients, 11 had no episodes of acute rejection before steroid withdrawal. The remaining 3 had one or more acute rejection episodes.Of the 14 recipients, 10 (72%) currently remain off steroids (mean follow‐up 18 months, range 5–51 months). However, 4 recipients have resumed steroids: 2 after an acute rejection episode (at 2 and 21 months post‐withdrawal) and 2 because of leukopenia (WBC<3 000) and an inability to tolerate full‐dose MMF. Steroid withdrawal was unsuccessful in both PTA recipients and in 2 of the 12 SPK recipients. All 14 recipients currently have a functioning pancreas graft. However, 1 of the SPK recipients, in whom steroid withdrawal failed, has developed chronic kidney rejection and is now back on hemodialysis awaiting a retransplant.Conclusion. Steroid withdrawal is possible in up to 70% of pancreas transplant recipients. Further studies are necessary to define ideal candidates for steroid withdrawal. Based on the results of this analysis, we have launched a prospective, randomized trial of steroid withdrawal in pancreas transplant recipients.
Failure of ganciclovir prophylaxis to completely eradicate CMV disease in renal transplant recipients treated with intense anti‐rejection immunotherapy
Authors: Isenberg Andrew L , Shen Gary K , Singh T Paul , Hahn Amy , Conti David J
Published: March 2003

Ganciclovir prophylactic regimens have been shown to be effective in renal transplant recipients at risk for primary (donor seropositive/recipient seronegative) and secondary (recipient seropositive) cytomegalovirus (CMV) disease. However, in addition to serologic factors, the type and intensity of the administered immunosuppression is a strong risk factor for CMV disease. Since January 1995, we have utilized a potent immunosuppressive protocol selectively in recipients at high risk for immunologic graft loss, defined as retransplant recipients, recipients with delayed graft function, non‐Caucasian recipients, and recipients suffering from acute rejection.  Between January 1995 and December 1996, 110 consecutive renal transplants were performed in recipients who were either CMV seropositive or received an allograft from a CMV‐seropositive donor. All recipients received ganciclovir prophylactic therapy for 3 months post‐transplant. Group I (N=43) consisted of recipients at high‐immunologic risk for graft loss as defined above. These recipients were treated with an intense anti‐rejection immunotherapeutic regimen consisting of Cellcept, Neoral, and prednisone, with the frequent addition of antilymphocyte antibody therapies and intravenous methylprednisolone. The remaining 67 recipients (group II) were treated with a less intense immunotherapeutic regimen consisting of azathioprine, Neoral, and prednisone. The incidence and severity of CMV disease and the patient and allograft survival were compared.  The incidence of CMV syndrome was greater in group I (28%) compared with group II (7%), and was statistically significant (p<0.05). The 1‐yr patient and graft survival were similar, 95 and 91%, respectively, for group I compared with 97 and 97%, respectively, for group II.  These data suggest that 3 months of ganciclovir prophylactic therapy is significantly less effective for the prevention of CMV disease in renal transplant recipients at high risk for acute rejection treated with an intense immunotherapeutic regimen. These data suggest that more effective prevention of CMV disease in these high‐risk recipients will require the addition of other anti‐viral agents, such as immunoglobulin preparation to the prophylactic regimen.
Cost‐benefit analysis of a clinical pharmacist‐managed medication assistance program in a renal transplant clinic
Authors: Chisholm Marie A , Vollenweider Leslie J , Mulloy Laura L , Wynn James J , Wade William E , DiPiro Joseph T
Published: March 2003

Medicare pays for 80% of the cost of immunosuppressant agents needed within the first 3 years of solid organ transplantation; however, many patients cannot afford the remaining 20%. Furthermore, many patients who are beyond 3 years post‐transplantation and have prescription coverage cannot afford the co‐payment for these medications. Other patients may not be able to afford their medications due to limited or no insurance coverage. The Medical College of Georgia (MCG) has been giving immunosuppressant medications to renal transplant patients if they cannot afford to pay for them. To assist MCG with drug cost for medications and maintain quality care for renal transplant patients, a clinical pharmacist‐managed medication assistance program was implemented to procure immunosuppressants from pharmaceutical manufacturers.  Methods: All patients enrolled in medication assistance programs from 1 January 1998 through 31 December 1998 were included in this analysis. Medication acquisition costs with and without Medicare reimbursement and the cost of implementing the clinical pharmacist‐managed medication assistance program were used to determine the value of implementing this service.  Results: Sixty‐one patients were enrolled in manufacturers’ assistance programs and a net cost avoidance of $124,793 was realized for the year of the program (benefit‐to‐cost ratio of 7.5:1). Assuming that the hospital collected the maximum amount allowed for patients receiving Medicare benefits, a cost avoidance of $69,233 was calculated (benefit‐to‐cost ratio of 4.16:1).  Conclusions: A clinical pharmacist‐managed medication assistance program in a renal transplant clinic produced substantial cost savings over this 1‐year study period. For each dollar spent in pharmacist's time, a minimum of $4 was returned to the institution.
Microchimerism and rejection: a meta‐analysis
Authors: Sahota Amrik , Gao Sujuan , Hayes John , Jindal Rahul M
Published: March 2003

Aims. To study the relationship between graft rejection and microchimerism with and without donor bone marrow infusion in recipients of kidney, liver, heart and lung transplants.  Selection of manuscripts. Thirty‐seven manuscripts presenting clinical data on microchimerism and rejection, published between 1991 and 1997, were identified. Of these, 16 were excluded due to duplication or insufficient data. Inclusion criteria were data on microchimerism, bone marrow infusion and rejection episodes.  Statistical tests. A mixed effect logistic model was used to test for homogeneity of transplant centers. The centers were found to be homogeneous for rejection rates controlling for microchimerism and bone marrow infusion. Using rejection episodes at 3, 6, and 12 months post‐transplant as the outcome, we evaluated logistic regression models to derive odds ratios for rejection with microchimerism and with bone marrow infusion for each organ.  Results. Microchimerism was generally associated with a higher incidence of acute rejection for heart, lung, and kidney transplants and a lower incidence for liver transplants, especially at 12 months and above. Bone marrow infusion decreased the risk of acute rejection for heart transplants and increased the risk for lung and, to a lesser extent, for liver transplants. No consistent effect was seen in kidney transplants. At 12 months and longer, microchimerism was associated with a decreased incidence of chronic rejection in recipients of lung transplants, but there were insufficient data to determine this outcome for other organs.  Conclusions. (i) Microchimerism was detected in the majority of patients. (ii) The effect of microchimerism and bone marrow infusion on rejection episodes varied with the organ and, for a given organ, it was time‐dependent. (iii) These findings demonstrate the need for more extensive studies on microchimerism and donor‐specific hyporesponsiveness.