bluuebunny/crossref_metadata_2025 huggingface dataset:
A retrospective study of long‐term psychosocial consequences and satisfaction after carrier testing in childhood in an autosomal recessive disease: aspartylglucosaminuria
Authors: Järvinen O , Hietala M , Aalto A‐M , Arvio M , Uutela A , Aula P , Kääriäinen H
Published: March 2003

Genetic carrier testing of children is usually not recommended. However, there are no data concerning long‐term psychological consequences, experience, and satisfaction of those tested as well as their recall of the test results. We evaluated these items retrospectively 10–24 years after carrier testing performed in childhood. Study material comprised 25 families with aspatylglucosaminuria (AGU), an autosomal recessive disorder, with 35 healthy sibs from all parts of Finland tested for carriership during childhood between 1973 and 1987. Of these sibs, 25 participated in our study. The questionnaire comprised multiple‐choice and open‐ended questions. The psychosocial well‐being of the study subjects measured by the RAND 36 item Health Survey 1.0 (RAND) was, in general, at least as good as that of controls, and showed no significant differences between carriers and non‐carriers (p>0.154). All tested individuals were satisfied with the fact that they had been tested and stated that the decision to perform carrier testing on a child can be made by the parents. Of the 25 tested, 23 knew and understood their test result correctly at the time of our study. Most of the tested individuals (60%) stated that the best time for carrier testing would be in the childhood or in the teen years.  This study indicates that carrier testing in childhood for an autosomal recessive disorder (AGU) had caused no measurable disturbance of quality of life in adulthood, and those tested reported being satisfied. However, we do not recommend testing in childhood, as the result is not needed prior to the time for reproductive decisions.
Cancer worries, risk perceptions and associations with interest in DNA testing and clinic satisfaction in a familial colorectal cancer clinic
Authors: Collins V , Halliday J , Warren R , Williamson R
Published: March 2003

Multi‐disciplinary familial cancer clinics are becoming an integral part of cancer services. It is, therefore, important to assess how attendance at these clinics impacts on cancer‐related concerns, risk perceptions and behavioural intentions, and how the clinic services are being received by those using them. This study has assessed a familial colorectal cancer clinic with respect to cancer‐related worries and risk perceptions and their impact on interest in DNA testing and overall satisfaction with the clinic. Pre‐ and post‐clinic questionnaires were completed by 127 patients and relatives attending the clinic. After attending the clinic, the proportion of people ‘very’ or ‘extremely’ worried about developing bowel cancer reduced from 49 (pre‐clinic) to 34% (p=0.002). Worry about bowel cancer was positively associated with younger age, higher education level and higher perceived risk of developing cancer. A reduction in level of risk perception correlated with a lower likelihood of feeling ‘very worried’ about developing bowel cancer. Of those intending to go ahead with DNA testing, 58% were ‘very worried’ about bowel cancer compared with 15% of those not intending to proceed with testing, suggesting that worry was a motivation for interest in DNA testing. One‐third of participants indicated another session of genetic counselling would be helpful. Within this group, a higher proportion was very worried about bowel cancer (43%) than for those who did not want another session (17%). Attendance at this familial colorectal cancer clinic alleviated worry for many individuals, partly due to improved information about risk of colorectal cancer.
Human HOX gene mutations
Authors: Goodman FR , Scambler PJ
Published: March 2003

HOX genes play a fundamental role in the development of the vertebrate central nervous system, axial skeleton, limbs, gut, urogenital tract and external genitalia, but it is only in the last 4 years that mutations in two of the 39 human HOX genes have been shown to cause congenital malformations: HOXD13, which is mutated in synpolydactyly, and HOXA13, which is mutated in Hand‐Foot‐Genital syndrome. Here we review the mutations already identified in these two genes, consider how these mutations may act, and discuss the possibility that further mutations remain to be discovered both in developmental disorders and in cancer.
Split hand/split foot malformation with hearing loss: first report of families linked to the SHFM1 locus in 7q21
Authors: Tackels‐Horne D , Toburen A , Sangiorgi E , Gurrieri F , De Mollerat X , Fischetto R , Causio F , Clarkson K , Stevenson Re , Schwartz Ce
Published: March 2003

Developmental anomalies of the appendicular skeleton are among the most common and easily ascertained birth defects. Split hand/split foot malformations, distinctive in having deficiency of the central rays, occur as isolated anomalies and as one component of multisystem syndromes. The clinical and molecular characterization of a new syndrome, found in two unrelated families, consisting of split foot with hearing loss, is presented here. As in other split hand/split foot conditions, variable expression and reduced penetrance is notable. In the larger family, variably expressed split foot malformations were found in 6 of 11 gene carriers, and mild‐to‐moderate sensorineural hearing loss in 4. Split hand and cleft lip/palate in one individual and tibial deficiency in another suggest that these malformations are uncommon components of the syndrome. Ectodermal abnormalities did not occur. In the second family, variable split foot was observed in 3 of 4 gene carriers, and sensorineural deafness was present in 3. Split hand was only seen in a gene carrier who also had split foot and deafness. One gene carrier only had deafness.  The gene for split hand/split foot with sensorineural hearing loss was linked to markers in 7q21 in both families, with a combined (maximum LOD score of 4.37 at Θ=0.0 for locus D7S527) at 80% penetrance. Efforts to identify the responsible gene have not yet been successful.
Retinal detachment and cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly in a consanguinous kindred – a possible new syndrome
Authors: Schmidt H , Rudolph G , Hergersberg M , Schneider K , Moradi S , Meitinger* T
Published: March 2003

We report on a consanguineous family with 6 children (out of 7) affected by a spondylo‐ocular syndrome. Clinical features include cataract, loss of vision due to retinal detachment, facial dysmorphism, facial hypotonia, normal height with disproportional short trunk, immobile spine with thorakal kyphosis and reduced lumbal lordosis. On ophthalmological examination of the index patient, a dense cataract and complete retinal detachment could be detected on the right eye. On the left eye, an absent lens nucleus was found, but no retinal detachment. On radiological examination, there was generalized moderate osteoporosis; the spine showed marked platyspondyly and the bone age was advanced. On laboratory investigations, a normal excretion of amino acids, mucopolysaccharides and oligosaccharides could be found. The phenotypical spectrum observed in the 6 affected individuals was rather uniform. The karyotype was normal in all affected children. This hitherto undescribed combination of oculo‐skeletal symptoms shows most resemblance with connective tissue disorders, suggesting a range of candidate genes for mutation analysis.
Two novel mutations in a purine nucleoside phosphorylase (PNP)‐deficient patient
Authors: Dalal I , Grunebaum E , Cohen A , Roifman CM
Published: March 2003

Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive disease, which presents clinically as severe combined immunodeficiency (SCID). We report here two novel mutations in the PNP gene that result in SCID phenotype, in a single patient. The maternal‐derived allele carries a C to T transition in exon 2 resulting in a premature stop codon at amino acid 57. The paternal‐derived mutation is a G to A transition at position +1 in intron 3, causing a complete skipping of exon 3 and a reading frameshift at the exon 2–exon 4 junction. The predicted polypeptide encoded by the aberrantly spliced mRNA terminates prematurely after only 89 amino acids. Both mutations predict severely truncated proteins resulting in a complete deficiency of PNP enzymatic activity, yet the development of profound immunodeficiency in this patient is greatly delayed.
Alpha‐1‐antitrypsin PI phenotypes S and Z in Europe: an analysis of the published surveys
Authors: Blanco I , Fernández E , Bustillo EF
Published: March 2003

The objective of the present study was to review published surveys on allelic frequencies S and Z in European populations to evaluate the validity of the reported data.  More than a hundred studies on the topic, published since 1965 until 2000, were retrieved by Medline, Index Medicus and bibliographic references consultation.  The criteria for studies selection were: 1) sample size≥250 individuals; 2) alpha‐1‐antitrypsin phenotype determination performed by means of crossed antigen–antibody or isoelectric focusing in polyacrylamide gels; 3) PI type determination performed without any previous screening procedure; 4) S and Z 95% confidence interval (CI) of the reported outcomes with a calculated coefficient of variation <42.3 for S and <95.8 for Z; 5) S and Z 95% CI of the reported outcomes comprised within 95% CI limits of comparative hypothetical surveys designed with the same sample size of the questioned surveys and the highest/lowest frequencies accepted for a specific area, according to the figures of isogen boundary maps.  Seventy studies comply with the five established criteria for analysis. According to the data of the selected studies, a geographical distribution on S and Z gene frequencies in Europe is proposed.
Consanguinity and its relevance to clinical genetics
Authors: Bittles AH
Published: March 2003

Marriage between close biological relatives is generally regarded with suspicion and distaste within Western society, reflecting historical and religious prejudice. By comparison, in many other populations there is a strong preference for consanguineous unions, most frequently contracted between first cousins, and marriage outside the family is perceived as a risky and disruptive option. The increasing importance of the genetic contribution to the overall disease profile in both developed and developing countries has highlighted potential problems associated with detrimental recessive gene expression in consanguineous progeny. This review examines the outcomes of consanguineous unions, with proposals as to how the ongoing preference for consanguinity in many communities can best be accommodated from a clinical genetics perspective.
Waardenburg syndrome type 3 (Klein–Waardenburg syndrome) segregating with a heterozygous deletion in the paired box domain of PAX3: a simple variant or a true syndrome?
Authors: Tekin M , Bodurtha JN , Nance WE , Pandya A
Published: March 2003

Klein–Waardenburg syndrome or Waardenburg syndrome type 3 (WS‐III; MIM 148820) is characterized by the presence of musculoskeletal abnormalities in association with clinical features of Waardenburg syndrome type 1 (WS‐I). Since the description of the first patient in 1947 (D. Klein, Arch Klaus Stift Vererb Forsch 1947: 22: 336–342), a few cases have been reported. Only occasional families have demonstrated autosomal‐dominant inheritance of WS‐III. In a previous report, a missense mutation in the paired domain of the PAX3 gene has been described in a family with dominant segregation of WS‐III. In this report, we present a second family (mother and son) with typical clinical findings of WS‐III segregating with a heterozygous 13‐bp deletion in the paired domain of the PAX3 gene. Although homozygosity or compound heterozygosity has also been documented in patients with severe limb involvement, a consistent genotype–phenotype correlation for limb abnormalities associated with heterozygous PAX3 mutations has not previously been apparent. Heterozygous mutations could either reflect a unique dominant‐negative effect or possibly the contribution of other unlinked genetic modifiers in determining the phenotype.
A prospective evaluation of the angiotensin‐converting enzyme D/I polymorphism and left ventricular remodeling in the ‘Healing and Early Afterload Reducing Therapy’ Study
Authors: Zee RYL , Solomon SD , Ajani UA , Pfeffer MA , Lindpaintner K , For The Heart investigators
Published: March 2003

The D/I (deletion, D, insertion, I) polymorphism of the angiotensin‐converting enzyme (ACE) gene has been extensively studied for its association with a number of cardiovascular and other disease states. However, its potential association with differential clinical efficacy of ACE inhibitors (ACE‐I) administered to patients who had suffered a myocardial infarction (MI), i.e. the prevention of left ventricular (LV) remodeling, has so far not been specifically studied. The aim of the study was to investigate whether the D/I polymorphism of the ACE gene is associated with the incidence of post‐MI LV remodeling in patients drawn from the ‘Healing and Early Afterload Reducing Therapy’ (HEART) Study. The ACE D/I polymorphism was characterized by the polymerase chain reaction (PCR) in 265 subjects from the ‘Healing and Early Afterload Reducing Therapy’ Study, a double‐blind, placebo‐controlled trial with the objective of determining whether early or delayed administration of the ACE‐I, ramipril, in patients with acute anterior wall MI would be optimal in reducing LV enlargement. Selected frequencies for the ACE D and I alleles were 0.59 and 0.41 (placebo–high dose group), 0.56 and 0.44 (low dose–low dose group), and, 0.60 and 0.40 (high dose–high dose group), respectively. All observed genotype frequencies were in Hardy–Weinberg equilibrium. There was no evidence for an association between genotype and outcome regarding LV size or function, nor with the initial blood pressure response after ACE‐I administration (adjusted for covariates). Our data provide no evidence for an association of the ACE D/I polymorphism with the risk of LV remodeling post‐MI in the presence of ACE‐I therapy, and therefore do not suggest that differential clinical efficacy of ACE‐inhibitors is related to this genetic marker.
Telomere‐specific fluorescence in situ hybridization analysis of couples with five or more recurrent miscarriages
Authors: Yakut S , Berker‐Karaüzüm S , Şimşek M , Zorlu G , Trak B , Lüleci G
Published: March 2003

Fluorescence in situ hybridization analysis using telomere specific probes has been used to detect cryptic translocations in the chromosomal telomeric regions. This study was performed in five clinically normal couples who have had five or more spontaneous abortions and whose karyotypes were found to be normal using conventional cytogenetic techniques. Using the telomere specific probes, in one couple we determined a cryptic translocation between chromosome 3 and 10, and, in another couple, the signal in chromosome 20 was detected in another chromosome, which was probably a D group chromosome. Additionally, in the latter and also in two other couples, we observed a polymorphism. The approach will be helpful for screening cryptic translocations using telomere specific multiple probe sets in couples with recurrent miscarriages. As prenatal diagnosis will be available for these couples for future pregnancies, it will be possible to help these families to have healthy fetuses.
Effects of apolipoprotein A‐IV genotype on glucose and plasma lipoprotein levels
Authors: Larson IA , Ordovas JM , Sun Z , Barnard  , Lohrmann J , Feussner G , Lamon‐Fava S , Schaefer EJ
Published: March 2003

The effects of apolipoprotein (apo) A‐IV genotype on serum glucose, total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride and glucose concentrations were ascertained in a population of 373 men and 361 women with a mean age of about 57 years. Subjects were evaluated at entry into a lifestyle intervention program. Apolipoprotein A‐IV genotype variations at residues 347 and 360 were examined, as these mutations affect the sequence of apo A‐IV, a major protein constituent of intestinal triglyceride‐rich lipoprotein and HDL. With regard to the apo A‐IV 360 mutation, 16.4% of the females and 13.4% of the males carried the apo A‐IV 2‐allele, almost entirely in the heterozygous state. No effect of the apo A‐IV 1/2 genotype was observed in either men or women on total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, the total cholesterol (TC)/HDL ratio, or on A‐I, A‐IV and apo B levels. This was also the case for the apo A‐IV 347 mutation. However, women with the apo A‐IV 360 1/2 genotype had significantly (p < 0.005) higher glucose levels (105.5 mg/dl) compared with the 1/1 wild‐type (94.0 mg/dl). All analyses were also adjusted for age, body mass index, medications, alcohol use and cigarette smoking. The prevalence of the 347 mutation was somewhat higher than the 360 mutation, with 29% of the females and 32.0% of the males being heterozygous for this mutation, and 3.9% of the females and 5.4% of the males being homozygous for this mutation.

These data are consistent with the concept that the apo A‐IV 360 and 347 genotypes have no significant effect on apo A‐IV levels and other lipid parameters in either gender. However, apo A‐IV 360 1/2 genotype did have a significant effect on serum glucose levels in women.
Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss
Authors: Bason L , Dudley T , Lewis K , Shah U , Potsic W , Ferraris A , Fortina P , Rappaport E , Krantz ID
Published: March 2003

Mutations in the Connexin 26 (Cx26) gene have been found to account for approximately 20% of all childhood deafness. This number approaches 50% in documented recessive cases of hearing loss. Two mutations, 35delG and 167delT, account for the majority of reported mutations in this gene, but to date, more than 60 mutations have been described. No other single gene has yet been identified that contributes this significantly to the aetiology of hearing loss. Several mutations in this gene have been found to predominate in specific ethnic populations (167delT in Ashkenazi Jews and 235delC in Japanese individuals). While the majority of mutations found in Cx26 result in frame shifts and premature terminations, a number of missense mutations have also been identified. The V37I missense mutation has been reported as both a polymorphism and as a potentially disease‐causing missense mutation. The present authors have identified three unrelated individuals with sensorineural hearing loss who are homozygous for this mutation. One individual is of Philippine ancestry, another is from a Chinese and Cambodian background, while the third is of Chinese ancestry, raising the possibility that this mutation may be more frequent among populations in eastern Asia.
Interdependent effect of angiotensin‐converting enzyme and platelet‐activating factor acetylhydrolase gene polymorphisms on the progression of immunoglobulin A nephropathy
Authors: Yoon H‐J , Kim H , Kim HL , Lee SG , Zheng S‐H , Shin JH , Lim CS , Kim S , Lee JS , Lee DS , Kim YS
Published: March 2003

In order to investigate the interdependent action of the insertion/deletion polymorphism of the angiotensin‐converting enzyme (ACE) gene and polymorphism in exon 11 (C1136→T; Ala379Val) of the platelet‐activating factor acetylhydrolase (PAF‐AH) gene, which encodes a functional antagonist of PAF, on the progression of immunoglobulin A (IgA) nephropathy, we analysed both polymorphisms in patients with primary IgA nephropathy, who were followed‐up for longer than 3 years. During the follow‐up (87.3 ± 50.0 months), the disease progressed in 38 of the 191 patients (19.9%). The D allele of the ACE gene in the absence of the T allele of the PAF‐AH gene did not affect the prognosis [odds ratio (OR), 3.6; 95% confidence interval (CI), 0.8–16.4] and neither did the T allele in the absence of the D allele (OR, 3.0; 95% CI, 0.4–24.2). However, the presence of both was a significant prognostic factor (OR, 6.6; 95% CI, 1.4–31.3). After adjusting for other risk factors, the presence of both proved to be an independent risk factor (OR, 4.5; 95% CI, 1.6–12.7). These results suggest that the interdependent effects of ACE and PAF‐AH polymorphisms on the progression of IgA nephropathy might be more important than the effect of the individual polymorphisms.
Anticipation in hereditary breast cancer
Authors: Dagan E , Gershoni‐Baruch R
Published: March 2003

To determine whether familial breast cancer occurs at a younger age in successive generations, we reviewed the clinical records of 435 Ashkenazi women with breast cancer referred to our cancer genetic clinic. Ninety‐eight who reported a maternal history of breast cancer were selected for further investigation. All women were genotyped for founder BRCA1/2 mutations (185delAG, 5382insC and 6174delT). Mean age at dignosis was 55.35 ± 14.21 years in the maternal generation and 48.17 ± 9.32 years in the daughters (t = − 4.144; p < 0.001). Seventeen women carried a BRCA1 mutation and 12 the 6174delT mutation in BRCA2. Among carriers of the BRCA1 mutation, mean age at diagnosis in the mothers' generation (44 ± 10.18 years) did not differ from that recorded in the daughters (40.76 ± 76 years). Among BRCA2 mutation carriers and non‐carriers, the mean age at diagnosis in the daughters' generation (41.4 ± 7.2 and 50.7 ± 8.8 years, respectively) was younger than in the mothers (61.75 ± 14.1 and 57.08 ± 13.7 years, respectively) (t = − 4.29; p < 0.001 for BRCA2 carriers and t=−3.76; p < 0.001 for non‐BRCA1/2 carriers). Daughters who were carriers of BRCA1/2 mutations developed breast cancer at a significantly younger age than non‐carriers, whilst in the mothers' generation, carriers of BRCA1 mutations developed breast cancer at a significantly younger age than carriers of BRCA2 mutations and non‐carriers. BRCA1 mutations predispose to breast cancer at an early age in both mothers and daughters, whereas mutations in BRCA2 were associated with significantly younger age at diagnosis in the second generation. This observation could be related to gene–environmental interactions causing anticipation in BRCA2 mutation carriers.
Association of angiotensin‐converting‐enzyme gene polymorphism with the depressor response to mild exercise therapy in patients with mild to moderate essential hypertension
Authors: Zhang B , Sakai T , Miura S , Kiyonaga A , Tanaka H , Shindo M , Saku K
Published: March 2003

We studied the association of angiotensin I‐converting enzyme (ACE) gene polymorphism with the depressor response to exercise therapy in 64 Japanese subjects with mild to moderate essential hypertension. Each subject performed 10 weeks of mild (lactate threshold intensity: approximately 50% maximum oxygen consumption) exercise therapy on a bicycle ergometer. Systolic blood pressure (SPB), diastolic blood pressure (DPB), and mean arterial pressure (MAP) were significantly decreased by exercise therapy in subjects with the ACE‐II and ID genotypes but not in DD subjects. The time‐by‐genotype interaction effects were significant for DBP and MAP. According to a multiple logistic regression analysis, the age‐ and baseline plasma renin activity‐adjusted relative risk (odds ratio) for the lack of a depressor response conferred by the D allele (assuming an additive effect) was 2.72 [95% confidence interval (CI), 1.07–6.91; p = 0.034]; for DD genotypes, as compared with the DI and II genotypes (assuming that the D allele is recessive), it was 11.7 (95% CI, 2.25–60.6; p = 0.003). ACE gene I/D polymorphism is associated with the depressor response of essential hypertensives to mild exercise therapy, which suggests that genetic features may underlie, at least in part, the heterogeneity of the depressor response in essential hypertensives to mild exercise therapy.
Pathogenesis of hereditary tumors: beyond the “two‐hit” hypothesis
Authors: Tucker T , Friedman JM
Published: March 2003

Knudson's ‘two‐hit’ hypothesis has provided extremely important insights into the pathogenesis of tumors in autosomal dominant tumor predisposition syndromes, but recent evidence suggests that some such tumors may occur without a ‘second hit’ or require more than two mutations. Inactivation of both RB1 alleles appears to be insufficient by itself to cause malignancy in the tumors that develop in patients with hereditary retinoblastoma. On the other hand, certain tumors in patients with tuberous sclerosis complex appear to develop in haploinsufficient tissues that do not have ‘second hit’ mutations of a tuberous sclerosis gene. The molecular pathogenesis of certain other tumors in patients with tuberous sclerosis complex or neurofibromatosis 1 may not be fully explained by the ‘two‐hit’ hypothesis either. Hereditary tumors, like non‐hereditary tumors, may arise by a variety of molecular mechanisms, with loss of both alleles of a particular tumor suppressor gene being a frequent, but not invariably necessary or sufficient, event. Four models are presented to explain how various tumors may arise in patients with inherited tumor predisposition syndromes such as hereditary retinoblastoma, tuberous sclerosis complex or neurofibromatosis 1. Even tumors of one particular type may develop by more than one mechanism.
Immunobiology and long‐term graft function in a transplant heterotopic renal rat model
Authors: Maluf DG , Fisher RA , Riley R , Wallace M , Tawes J , Bu D , Posner M
Published: March 2003

Abstract:Background: The Th1–Th2 paradigm proposes clonal expansion of Th2 lymphocytes as the basis of allograft tolerance. The Th2 cells have been found to be present in recipients with long‐term allograft survival. However, the presence of Th2 cells and tolerance is not a uniform finding. Previously we have shown that pre‐engraftment single dose rapamycin and a 7‐d course of cyclosporin induce transplantation tolerance to 120 d. In the present study, we investigated the immunobiology of grafts in a long‐term follow‐up (>350 d).Methods: Kidney allografts (n = 7), isografts (n = 5) and single nephrectomy (n = 3) groups were followed for 350 ± 87 d. Heterotopic kidney transplant was performed by the same surgeon in the allograft group (ACI‐Lewis) and the isograft group (Lewis‐Lewis). The left kidney was removed in the single nephrectomy group. The allograft group was treated with pre‐engraftment single dose rapamycin and a 7‐d course of cyclosporin. A kidney biopsy was performed at midpoint time for histological study and tissue was frozen for measuring intragraft cytokine expression (IL‐4, IL‐10) in all animals. Prior to biopsy, serum blood urea nitrogen (BUN) and creatinine (Cr) levels were studied. Serum BUN, Cr levels, plus 24‐h urinary protein (PRO) were measured prior to sacrifice. Randomly, four allograft rats received skin grafts (ACI, Lewis and Buffalo skin donors) after kidney biopsy. Skin grafts were studied for a mean of 6 weeks for signs of acceptance or rejection. Analysis of variance (ANOVA) with Tukey's test was used;p< 0.05 was considered statistically significant.Results: The mean follow up was 352 ± 87 d. BUN and Cr levels at biopsy time (mean 214 d) were not statistically different between the three groups (p = 0.19 andp= 0.66). At sacrifice (mean 352 d), BUN, Cr and PRO were statistically different between allograft and isograft groups (p = 0.013), and between allograft and single nephrectomy groups (p = 0.027). Functional and histological signs of graft loss occurred in three of seven (42.8%) of the allografts at 352 d. Using BANFF criteria, three allografts at biopsy time and seven allografts (100%) and four isografts (80%) at sacrifice time developed chronic histologic changes. Intragraft overexpression of IL‐4 and IL‐10 was seen at biopsy and sacrifice time in six of seven allografts and one of five isografts. All donor specific skin grafts (ACI‐Lewis) on allografts were accepted and third party (Buffalo) donor skin grafts were rejected in all animals (>95% skin necrosis).Conclusions: This highly stringent, functional, renal transplant model yields 100% normal renal function as compared with isografts at 120 d follow‐up. With the follow‐up extended to 350 d, 43% of the allografts loose function and develop a chronic allograft histology despite a demonstrated intragraft Th2 cytokine dominance and donor specific skin graft acceptance.
Conundrums with FlowPRA™ beads
Authors: Gebel Howard M , Harris Shealynn B , Zibari G , Bray Robert A
Published: March 2003

Abstract: In 1969, a study by Patel and Terasaki persuaded the renal transplant community that a pre‐transplant cross‐match should always be performed between donor and recipient to detect HLA antibodies and prevent hyperacute allograft rejection. Although the role of the cross‐match among nonsensitized patients is controversial, its importance among sensitized recipients is undeniable. Over the past 30 years, more sensitive techniques, such as the flow cytometric cross‐match (FCXM), were developed to identify low levels of antibodies undetectable by other approaches. The clinical relevance of a positive FCXM, however, has been hotly disputed, with some investigators maintaining that the FCXM is ‘too sensitive’ and rules out acceptable donor–recipient combinations. An alternative explanation is that the FCXM is non‐specific, and, at least in certain situations, identifies non‐HLA antibodies that are clinically irrelevant. Recently, a solid phase immunoassay utilizing purified HLA Class I or Class II molecules bound to microparticles (FlowPRATM) was developed. Ideally, use of the FlowPRATM for the identification of HLA antibodies in recipient sera would help ascertain whether a positive FCXM with donor cells was truly the result of an HLA‐specific antibody. As shown here, this may not always be true. In this study, two unexpected serum patterns were observed. Pattern 1: FlowPRATM beads were positive (with an associated HLA Class I specificity) and the FCXM with cells expressing the HLA antigen(s) to which the antibody was directed, was negative. Sequence analysis of the HLA antigens reactive with this unexpected antibody suggests that the epitope recognized resides on the floor of the groove, a site generally not expected to generate antibody activity. Pattern 2: FlowPRATM beads were negative yet the FCXM was T and B cell positive. Further analysis of the FlowPRATM negative/FCXM positive sera using a flow cytometric cell‐based panel reactive antibody (PRA) approach revealed those sera to have specific anti‐HLA Class I activity. We suspect that both types of antibodies described above have clinical relevance. Thus, a negative or positive FCXM (when the FlowPRATM against donor antigens is positive or negative, respectively) is not always a straightforward interpretation.
Thymoglobulin for induction or rejection therapy in pancreas allograft recipients: a single centre experience
Authors: Trofe Jennifer , Stratta Robert J , Egidi M Francesca , Lo Agnes , Gaber Lillian W , Shokouh‐Amiri M Hosein , Grewal Hani P , Honaker Marsha , Hardinger Karen , Alloway Rita R , Gaber A Osama
Published: March 2003

Abstract:Purpose: To review the safety and efficacy of thymoglobulin in pancreas transplant patients receiving tacrolimus and mycophenolate mofetil.Methods: Retrospective, single centre analysis of 45 patients transplanted between 1995 and 2000 who received 54 courses of thymoglobulin, including 36 courses in 29 solitary pancreas transplant recipients (16 pancreas alone, 13 pancreas after kidney transplants) and 18 courses in 16 simultaneous kidney–pancreas transplant patients. Thirty‐two patients (71%) were primary pancreas transplants, 10 (22%) were second transplants and three (7%) were third transplants. Of the 54 treatment courses, 19 (35%) were for induction, 27 (50%) were for primary rejection and eight (15%) were rescue therapy for rejection. All rejection episodes were biopsy‐proven in at least one organResults: The median thymoglobulin dose was 1.5 mg/kg/d with a mean of six doses (range 3–10). Dose reduction or interruption was required in 28 courses (52%), most often due to leukopenia (n = 24), fever (n = 2) and thrombocytopenia (n = 2). Thymoglobulin was resumed in all but three patients, two with persistent fever and one with infection. Infectious complications (n = 25) occurred in 17 patients (38%) within 30 days and included bacterial (n = 16), cytomegalovirus (n = 4), polyoma (n = 1), fungal (Candida albicans,n= 1), toxoplasmosis (n = 1) and ehrlichiosis (n = 2). Post‐transplant lymphoproliferative disease occurred in two patients (4%) at a mean of 70 d post‐thymoglobulin treatment. In the 19 patients that received thymoglobulin induction, one simultaneous kidney–pancreas transplant, two pancreas alone and four pancreas after kidney transplant recipients developed rejection (37% incidence), while all remaining patients followed by surveillance protocol biopsies were rejection‐free. In the 35 patients that received thymoglobulin for rejection, reversal occurred in 26 of the patients (74%). Rejection recurred within 30 d in five patients and post‐treatment biopsies revealed persistent rejection in three of 20 pancreas and two of eight renal biopsies. After a mean follow‐up of 6 months, the actual patient and pancreas graft survival rates were 93% and 71%, respectively.Conclusion: Thymoglobulin was effective as induction therapy in high‐risk pancreas transplant recipients, and resulted in initial reversal of rejection in 74% of patients. Dose adjustments were required in over half the cases and were usually due to leukopenia. Infections occurring subsequent to thymoglobulin were not uncommon and reflected the immunosuppressive burden of the patient population.
Can a pharmacokinetic approach to immunosuppression eliminate ethnic disparities in renal allograft outcome?
Authors: Emovon Osemwegie E , Op't Holt Cindy , Browne Barry J
Published: March 2003

Abstract:Although renal allograft outcome correlates more closely with area under the concentration time curve (AUC) for cyclosporin (CsA) compared with the 12‐h trough level (C0), few studies have prospectively evaluated pharmacokinetic monitoring in kidney transplantation. This paper describes a study designed to evaluate the impact of a novel approach to CsA‐based immunosuppression on ethnic differences in renal allograft outcome. Sixty (32 African Americans and 28 Caucasians) renal transplant recipients were treated with cyclosporin‐based triple therapy. Morning and evening doses were independently adjusted to reach an AUC0‐12of 6600–7200 ng h/mL and a C0of 250–325 ng/mL, respectively. AUCs were measured within 48 h of starting CsA, and as often as necessary to maintain target levels. Only two patients experienced significant adverse events related to immunosuppression. One (Caucasian) developed haemolytic uremic syndrome and was converted to tacrolimus, while another (African American) developed acute vascular rejection. One graft was lost (Caucasian) due to death with a functioning graft. An average of 8 AUCs (range 5–13) were measured in the first 3 months. AUCs were significantly higher in African Americans compared with Caucasians only in the first and second month. C0values were similar in both groups throughout the study period. A pharmacokinetic approach to immunosuppression allows individualization of CsA exposure, and appears to reduce ethnic disparities in renal allograft outcome.
Mast cells in human allografted kidney: correlation with interstitial fibrosis
Authors: Goto Eizo , Honjo Soichiro , Yamashita Hideki , Shomori Kohei , Adachi Hironobu , Ito Hisao
Published: March 2003

Abstract: Introduction: Chronic allograft nephropathy is the major cause of long‐term graft failure in human allografted kidney transplantation. In addition to macrophages and T lymphocytes, mast cells have been shown to increase in chronic allograft nephropathy. The present study examined tryptase‐positive mast cells and microvessels in the allografted kidney.

Materials and methods:  We selected 131 biopsy specimens obtained from 100 allografted, 14 non‐grafted renal biopsy specimens and nine nephrectomy specimens due to renal cell carcinomas. Formalin‐fixed, paraffin‐ embedded specimens were immunostained using primary antibodies for mast cell tryptase, mast cell chymase and CD34. The number of the mast cells and microvessels was counted in at least 20 high‐power fields (10 × 40).

Results:  Tryptase‐positive mast cells outnumbered chymase, toluidine blue or naphthol‐AS‐D choloacetate‐positive mast cells. The mean number of the tryptase‐positive mast cells was significantly higher in the 36 specimens with chronic allograft nephropathy (5.1 ± 3.5) among the grafted kidneys with other disease categories (P < 0.001). In the chronic allograft nephropathy, the mean numbers of mast cells was significantly higher in Ci 2 + Ci 3 (n = 20; 6.4 ± 3.89) than in Ci 1 (n = 16; 3.6 ± 2.65) (P < 0.01). In the non‐grafted kidney, the number of mast cells was highest in the four specimens with diabetic nephropathy. Mast cells and microvessels were analysed in the two representative cases, which subsequently developed chronic allograft nephropathy. Both of the cases showed the highest number of mast cells in chronic allograft nephropathy. In contrast, the mean number of microvessels tended to decrease along with interstitial fibrosis.

Conclusions:  This study demonstrated clearly a close association between renal interstitial fibrosis and mast cells, which might play an important role in the development of chronic allograft nephropathy.
Review of immunosuppressive usage in pancreas transplantation
Authors: Stratta Robert J
Published: March 2003

Throughout 1997, nearly 10 000 pancreas transplants have been performed worldwide, with 88% being simultaneous kidney transplants (SKPT). The current 1 yr patient survival rate exceeds 90% and pancreas graft survival (complete insulin independence) rate exceeds 80% for SKPT, 70% for sequential pancreas after kidney transplant (PAKT), and 65% for pancreas transplant alone (PTA). According to registry data, rejection accounts for 32% of graft failures in the first year after pancreas transplantation. However, improvements are expected to continue with the evolution of treatment protocols. Most pancreas transplant centers employ quadruple drug immunosuppression with anti‐lymphocyte induction with either a monoclonal or polyclonal antibody agent. In recent years, there has been an overall decline in the use of antibody induction therapy from 90% during the period 1987–1993 to 83% of pancreas transplants performed during 1994–1997. Maintenance immunosuppression is triple therapy consisting of a calcineurin inhibitor (cyclosporine or tacrolimus), corticosteroids, and an anti‐metabolite (AZA or MMF). Prior to 1995, nearly all pancreas transplant recipients were managed with Sandimmune. In the last 2 yr, tacrolimus‐based therapy has been used in approximately 20% of cases and a new microemulsion formulation of cyclosporine (Neoral) has replaced Sandimmune in contemporary post‐transplant immunosuppression. In addition, MMF is replacing AZA as part of the standard immunosuppressive regimen after pancreas transplantation. At present, a number of centers are conducting various trials with new drug combinations including either Neoral or tacrolimus in combination with steroids and MMF with or without antibody induction therapy. From 1994 to 1997, the 1 yr rates of immunologic graft loss have decreased to 2% after SKPT, 9% after PAKT, and 16% after PTA. The current array of new immunosuppressive agents are providing more effective control of rejection and permitting solitary pancreas transplantation to become an accepted treatment option in diabetic patients without advanced complications. The apparent potency of new drug combinations has also resulted in a resurgence of interest in steroid withdrawal. Immunosuppressive strategies will continue to evolve in order to achieve effective control of rejection while minimizing injury to the allograft and risk to the patient. In addition, new regimens must not only address the issue of specific drug toxicities but also long‐term economic, metabolic, and quality of life outcomes. Pancreas transplantation will remain an important alternative in the treatment of diabetic patients until other strategies are developed that can provide equal glycemic control with less immunosuppression and overall morbidity.
Living‐unrelated kidney donation: a single‐center experience
Authors: Peters Thomas G , Jones Kenneth W , Walker George W , Charlton Ronald K , Antonucci Laurel E , Repper Suzanne M , Hunter Sr Richard D
Published: March 2003

For 140 consecutive renal transplants performed from January 1995 to October 1997, 25 (18%) were from living‐unrelated donors (15 women, 10 men, aged 25–63, mean 43 yr). All donors had pre‐transplant imaging evaluation of renal anatomy following renal function assessment (minimal creatinine clearance 75 cm3/min). Admission to the hospital on the day of donation preceded nephrectomy under general anesthesia using an anterior flank, extra‐retroperitoneal approach (no rib resection). Post‐operative epidural pain control was used for all but 1 donor. The 25 kidney donors were hospitalized for 2 (n=1), 3 (n=12), 4 (n=7), or 5–8 d (n=5) (average 3.9 d) and had a mean hospitalization charge of $15 501 (range $10 808–$29 579). One intra‐operative hemorrhage required transfusion; 1 late neural‐related pain syndrome required outpatient wound exploration. Two kidneys were lost: a husband recipient from repetitive acute rejections at 3 months; a friend recipient from chronic rejection at 2.5 yr; both await cadaver transplant. The other 23 kidneys are functioning with a mean serum creatinine of 1.8 (range 1.0–3.3) at 3–36 months (patient survival 100%; graft survival 92%). While most donors were spouses (8 husbands and 10 wives), friends, distant cousins, in‐laws, and adoptive relatives did well as donors and recipients. Transplantation may increase by 20% or more at centers which encourage broad application of living donor nephrectomy.
Phaeohyphomycosis in kidney transplant patients
Authors: Mesa A , Henao J , Gil M , Durango G
Published: March 2003

Dematiaceous fungi are being increasingly recognized as pathogens in organ transplant recipients. This investigation reports five cases of subcutaneous phaeohyphomycosis that occurred in five kidney transplant recipients in the Renal Unit at the San Vicente de Paul Hospital, Medellin, Colombia. Fungi of the genus Exophiala were isolated in three cases, but the agent was not identified in two cases. Physicians are likely to develop increased awareness of the clinical manifestation of infection with the dematiaceous fungi as the population of immunocompromised hosts continues to grow.
Acute humoral rejection of kidney allografts in patients with a positive flow cytometry crossmatch (FCXM)
Authors: Takeda Asami , Uchida Kazuharu , Haba Toshihito , Tominaga Yoshihiro , Katayama Akio , Kobayashi Takaaki , Oikawa Tadashi , Morozumi Kunio
Published: March 2003

The patients with a positive flow cytometry crossmatch (FCXM) are categorized as a high‐risk group causing hyperacute or accelerated acute rejection after kidney transplantation. According to the successful results of ABO‐incompatible renal transplantation, we have performed the living related transplant operations in the recipients with positive FCXM for donor T cells, but having a negative complement‐dependent lymphocytotoxic reaction test. We have followed the clinical course of 4 FCXM‐positive patients, and 2 of them have developed acute humoral rejection. We report the strategies for FCXM‐positive living kidney transplantations and the characteristics of pathological findings of acute humoral rejection in FCXM‐positive renal transplants. We have had few episodes of acute humoral rejection in ABO‐incompatible kidney transplantations under immunosuppressive regimens, including cyclophosphamide, but 2 patients of 4 with FCXM‐positive kidney transplantations developed acute humoral rejections. The differences in immunosuppressive regimen between ABO‐incompatible and FCXM‐positive kidney transplantations concern anti‐lymphocyte globulin (ALG) and splenectomy. We have not performed splenectomy and ALG administration in FCXM‐positive kidney transplantations. Severe acute rejection episodes have been experienced on post‐operative days 7 and 9 in 2 of 4 FCXM‐positive recipients. The early acute rejection episodes were clinically and pathologically diagnosed as typical humoral rejections. We have examined an immunofluorescent study to prove the diagnosis of humoral rejection in FCXM‐positive kidney transplantations; both immunoglobulin M and C3 were positive for the whole course of humoral rejection. The 2 patients with acute humoral rejection recovered after treatment with double filtration plasmapheresis or plasma exchange to remove their anti‐donor antibodies. The gold standard of success in FCXM‐positive kidney transplantations is to suppress the production and reduce the level of anti‐donor antibodies after transplant operations.
Plasma homocysteine levels in renal transplanted patients on cyclosporine or tacrolimus therapy: effect of treatment with folic acid
Authors: Fernández‐Miranda Consuelo , Gómez Pilar , Díaz‐Rubio Pilar , Estenoz Juana , Luis Carrillo Juan , Andrés Amado , Morales José M
Published: March 2003

Hyperhomocysteinemia, an independent risk cardiovascular factor, has been reported in renal transplanted patients (RTP). The aim of the present study was to evaluate homocysteine levels in RTP treated with cyclosporine or tacrolimus, and the changes observed in the two groups of patients after treatment with folic acid. Forty‐two RTP with stable function (21 treated with cyclosporine and 21 with tacrolimus, matched by gender and age) were studied. Forty healthy control subjects were matched by age and gender with the patients. In RTP, homocysteine was increased compared with the controls (16.4±5.2 vs 8.0±1.8 μmol/L; p<0.001), but there was no difference in vitamin B12 and folic acid levels. Thirty‐three patients and one control showed hyperhomocysteinemia (78.5 vs 2.5%; p<0.001). Homocysteine correlated negatively with creatinine clearance in the patients (p=0.04), but no correlation was found with vitamin B12, folic acid and lipoproteins. By univariate analysis, patients treated with cyclosporine had higher homocysteine than those treated with tacrolimus (p=0.03), but multivariate analysis did not confirm these results. In 21 patients with hyperhomocysteinemia and folate levels similar to those of the controls, folic acid (5 mg/d for 3 months) was administered. Homocysteine decreased significantly (19.1±4.8 vs 13.2±3.4 μmol/L; p<0.001), with a median reduction of 31% and with no differences observed in patients treated with either cyclosporine or tacrolimus. We concluded that hyperhomocysteinemia is very frequent in RTP, but homocysteine levels are not different in patients treated with cyclosporine or tacrolimus. Folic acid therapy produces a significant decrease in homocysteine concentrations, in the absence of clear folate deficiency, without differences in relation to immunosuppressant therapy.