bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal‐coloboma syndrome: a multi‐system developmental disorder caused by PAX2 mutations
Authors: Eccles Michael R , Schimmenti Lisa A
Published: March 2003

Optic nerve coloboma combined with renal disease, also called renal‐coloboma syndrome (#120330 in McKusick's Mendelian Inheritance in Man Online, OMIM), a relatively recently characterized syndrome, results from autosomal dominant mutations in the PAX2 gene. Although renal‐coloboma syndrome involves both ocular and renal anomalies, some patients are affected with vesico‐ureteral reflux (VUR), high frequency hearing loss, central nervous system (CNS) anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development. We review here the clinical features of patients with renal‐coloboma syndrome and PAX2 mutation. We also review the PAX2 mutations that have been reported to date, and discuss the possible effect of PAX2 mutations on normal development.
Molecular mechanisms controlling lung morphogenesis
Authors: Perl Anne‐Karina T , Whitsett Jeffrey A
Published: March 2003

The complex process of lung formation is determined by the action of numerous genes that influence cell commitment, differentiation, and proliferation. This review summarizes current knowledge of various factors involved in lung morphogenesis correlating their temporal and spatial expression with their proposed functions at various times during the developmental process. Rapid progress in understanding the pathways involved in lung morphogenesis will likely provide the framework with which to elucidate the mechanisms contributing to lung malformations and the pathogenesis of genetic and acquired lung diseases.
Utility of the predictors of coronary heart disease mortality in a longitudinal study of elderly Finnish men aged 65 to 84 years is dependent on context defined by Apo E genotype and area of residence
Authors: Stengård Jari H , Kardia Sharon L , Tervahauta Markku , Ehnholm Christian , Nissinen Aulikki , Sing Charles F
Published: March 2003

A common assumption underlying most genetic studies is that individuals with different genotypes respond similarly to exposure to internal (epigenetic and background genotype effects) and external (ecological) environments. Here we evaluate whether this assumption is true in individuals with different genotypes of the gene coding for the apolipoprotein E (Apo E) molecule, an important determinant of the metabolic fate of plasma lipids and lipoproteins. We addressed whether the utility of known risk factors of coronary heart disease (CHD) in the prediction of CHD death in a 5‐year follow‐up is the same for the two most common Apo E genotypes, ɛ3/3 and ɛ4/3, in two cohorts of elderly Finnish men (age at baseline: 65–84 years), one in Eastern and the other in Southwestern Finland. The CHD mortality rate was higher in the ɛ4/3 than in the ɛ3/3 genotype in both cohorts (11.1 versus 7.8%, Pr=0.281 in the Eastern cohort and 19.6 versus 8.2%, Pr=0.002 in the Southwestern cohort). In the Eastern cohort, serum high density lipoprotein (HDL) cholesterol level was identified as a strong predictor of CHD death in the ɛ3/3 genotype (β=−2.155, Pr=0.019). In the Southwestern cohort, age (β=0.139, Pr=0.006), body mass index (BMI) (β=0.149, Pr=0.016), and serum total cholesterol level (β=0.453, Pr=0.051) were identified as strong predictors in the ɛ3/3 genotype, as were smoking (β=0.236, Pr=0.008) and BMI (β=−0.124, Pr=0.057) in the ɛ4/3 genotype. The latter observation indicates that in Southwestern Finland the probability of CHD death decreases with increasing BMI in elderly men with the ɛ4/3 genotype, while in their counterparts with the ɛ3/3 genotype the risk increases with increasing BMI. This difference was statistically significant (Pr=0.002). These observations clearly argue against the assumption that individuals with different genotypes respond similarly to exposures to internal and/or external environments. These observations are consistent with a complex pathobiology of CHD involving biochemical and physiological agents that are under the influence of interactions between genetic and environmental factors. Information about these interactions is necessary for developing a more precise risk assessment and ultimately to improve public health and clinical strategies to prevent this devastating disease both at the individual and population levels.
The molecular regulation of myogenesis
Authors: Sabourin Luc A , Rudnicki Michael A
Published: March 2003

Over the past years, several studies have unraveled important mechanisms by which the four myogenic regulatory factors (MRFs: MyoD, Myf‐5, myogenin, and MRF4) control the specification and the differentiation of the muscle lineage. Early experiments led to the hypothesis that these factors were redundant and could functionally replace one another. However, recent experiments using in vivo and in vitro models have demonstrated that in fact different aspects of the myogenic program are controlled by different factors in vivo, suggesting that these factors play distinct roles during myogenesis. The activity of the MRFs during proliferation and differentiation of muscle precursor cells has clearly been demonstrated to be dependent on specific cell‐cycle control mechanisms as well as distinct interactions with other regulatory molecules, such as the ubiquitously expressed E proteins and several other transcription factors. Furthermore, the observation that the MRFs can recruit chromatin remodeling proteins has shed some light on the mechanisms by which the MRFs activate gene expression. Recently, a functional role for MyoD during satellite cell activation and muscle repair has been identified in vivo, which cannot be substituted for by the other MRFs. This has put forward the hypothesis that these factors also play specific biological roles following muscle injury and repair.
Online Mendelian Inheritance in Man (OMIM) as a knowledgebase for human developmental disorders
Authors: Boyadjiev Sa , Jabs Ew
Published: March 2003

In this review, we summarize the current genetic information on human developmental disorders found in Online Mendelian Inheritance in Man (OMIM). The OMIM catalogues human phenotypes and genotypes and relevant mouse models. Among the more than 11 005 genetic disorders and loci, we found at least 1231 human conditions with known gene mutations. We searched for human developmental disorders that present with structural defects during the perinatal period, and identified 162 such entries. We classified these entries by phenotypic features (e.g., skeletal dysplasias, axis and laterality defects, or eye disorders) and by the type of gene mutated (e.g., genes coding for transcription factors, structural proteins, enzymes, or receptors). Thirty‐eight entries have allelic variants with gene mutations causing different functional consequences, thereby altering their interactions with modifying genes. Thirty‐two entries show genetic heterogeneity due to either functional redundancy of more than one gene or genes that interact in common developmental pathways. Although many different types of genes are mutated in developmental disorders, we found that the disease genes are transcription factors in 49 entries. Mouse models are available for many of the human conditions, with the majority of these mutants being secondary to null mutations. These data allow us to begin to elucidate the complex developmental pathways involved in the molecular pathogenesis of human malformations.
The long and the short of it: developmental genetics of the skeletal dysplasias
Authors: Dreyer Sandra D , Zhou Guang , Lee Brendan
Published: March 2003

The skeletal dysplasias are a large heterogeneous group of genetic conditions characterized by abnormal shape, growth, or integrity of bones. Often, there may be prominent features associated with other organ systems as part of a more encompassing skeletal malformation syndrome. Tremendous advances have been made in the clinical and molecular delineation of these conditions over the past 20–30 years. We have progressed from initial broad clinical classifications of these conditions in the first two‐thirds of this century, to extensive delineation based on radiographic features in the 1970s and 1980s, to the present reconsideration and grouping of these conditions according to their molecular pathogenesis. This has in part been spurred on by advances in the understanding of the developmental pathways which govern skeletal development, as well as by the human genome sequencing effort, which has provided a plethora of positional candidate genes for many of these conditions. The pathogenetic correlations derived from such studies are often based on parallels between the human phenotype and mouse models of the human condition, and have sometimes revealed novel developmental functions.
Overlap of PIV syndrome, VACTERL and Pallister–Hall syndrome: clinical and molecular analysis
Authors: Killoran Ce , Abbott M , McKusick Va , Biesecker Lg
Published: March 2003

The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister–Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GLI3, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188–2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re‐evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations.
Identification of four novel mutations in five unrelated Korean families with Fabry disease
Authors: Lee J‐K , Kim G‐H , Kim J‐S , Kim K‐K , Lee M‐C , Yoo H‐W
Published: March 2003

Fabry disease is a X‐linked recessively inherited metabolic disorder, which results from the deficient activity of the lysosomal hydrolase α‐galactosidase A leading to the systemic deposition of glycosphingolipids with terminal α‐galactosyl moieties. Single‐strand conformation polymorphism (SSCP) analysis was performed, followed by DNA sequencing of PCR amplified exons of the human α‐galactosidase A gene in 5 unrelated Korean patients with classic Fabry disease. Five different mutations were identified; two nonsense mutations (Y86X and R342X), one missense mutation (D266N), and two small deletions (296del2 and 802del4). Except for R342X mutation, four were novel mutations (Y86X, D266N, 296del2, 802del4). A T to G transversion at nucleotide position 5157 in exon 2 caused a tyrosine‐to‐stop substitution at codon 86. A G to A transition at position 10 287 in exon 5 substituted an asparagine for an aspartate at codon 266. Mutation 296del2 in exon 2 resulted in a frame shift with a stop signal at the 22th codon downstream from the mutation, whereas mutation 802del4 resulted in a stop codon at the site of 4 bp deletion. In addition, the 802del4 was found to be a de novo mutation. This is the first report on mutation analysis of the human α‐galactosidase A gene in Korean patients with Fabry disease.
Cryptic duplication of 21q in an individual with a clinical diagnosis of Down syndrome
Authors: Forster‐Gibson CJ , Davies J , MacKenzie JJ , Harrison K
Published: March 2003

We describe an adult male who was diagnosed with Down syndrome (DS) at 9 months of age, but had repeatedly normal karyotypes until recent mid‐resolution chromosome studies showed a possible duplication of 21q22.13 to 21q22.3. The abnormality was investigated using fluorescent in situ hybridization (FISH) studies. These showed hybridization of a whole chromosome paint probe (wcp21, Oncor Coatasome 21) to the entire length of both chromosome 21 homologues and one very large hybridization signal of a cosmid contig probe localized within bands 21q22.13‐21q22.2(LSI‐21, Vysis) on the ?dup(21q) homologue. CGH analysis identified a ratio of 1.5 for the segment of chromosome 21 involving band 21q22, indicating a gain of part, or all, of the terminal band of chromosome 21. The karyotype was thus defined as 46,XY,?dup(21) (q22.13q22.2).ish dup(21)(LSI‐21++,wcp21+). Common DS characteristics in our case and 12 previously reported cases with duplications involving chromosome 21 included mental retardation, fifth finger clinodactyly, open mouth and oblique eye fissures. Transverse palmar creases and congenital heart defects, seen in DS less than 40% of the time, were infrequent. Presence of these features did not appear to depend on the specific portion of chromosome 21 that was duplicated. A review of 18 additional clinical features showed no consistent phenotype–genotype correlations.
Risk of obstetric cholestasis in sisters of index patients
Authors: Eloranta M‐L , Heinonen S , Mononen T , Saarikoski S
Published: March 2003

The aim of the present study was to evaluate the rate of intrahepatic cholestasis of pregnancy in first‐degree relatives of index patients.  Index patients (n=65) with singleton pregnancies complicated by intrahepatic cholestasis were identified among the women (n=11 984) who gave birth at Kuopio University Hospital in 1994–1998. The pregnancy histories of relatives of 56 index patients were reviewed and the rate of cholestasis in first‐degree relatives was compared with that in the general obstetric population.  Obstetric cholestasis was experienced by 9% of the parous sisters and 11% of the mothers of the index patients. The risk per delivery was 6% in the first‐degree relatives. The rate in the general obstetric population was 0.54%. The odds ratios and 95% confidence intervals were 12.6 (5.6–28.1) for the sisters and 12.2 (6.2–24.2) for the mothers.  Obstetric cholestasis clusters within some families and is under strong genetic influence, although the precise genetic pattern remains obscure. The sisters of index patients are at an increased risk of the disorder and may benefit from close obstetric care.
When body segmentation goes wrong
Authors: Pourquié O , Kusumi K
Published: March 2003

The segmented or metameric aspect is a basic characteristic of many animal species ranging from invertebrates to man. Body segmentation usually corresponds to a repetition, along the anteroposterior (AP) axis, of similar structures consisting of derivatives from the three embryonic germ layers. In humans, segmentation is most obvious at the level of the vertebral column and its associated muscles, and also in the peripheral nervous system (PNS). Functionally, segmentation is critical to ensure the movements of a rod‐like structure, such as the vertebral column. The segmented distribution of the vertebrae derives from the earlier metameric pattern of the embryonic somites. Recent evidence from work performed in fish, chick and mouse embryos indicates that segmentation of the embryonic body relies on a molecular oscillator called the segmentation clock, which requires Notch signaling for its proper functioning. In humans, mutations in genes required for oscillation, such as Delta‐like 3 (DLL3), result in abnormal segmentation of the vertebral column, as found in spondylocostal dysostosis syndrome, suggesting that the segmentation clock also acts during human embryonic development.
To test or not to test: an ethical conflict with presymptomatic testing of individuals at 25% risk for Huntington's disorder
Authors: Lindblad AN
Published: March 2003

The first presymptomatic test for Huntington's disease was developed in the 1980s. With the detection of the gene causing the disorder in 1993, it became possible to do direct mutation tests with almost 100% sensitivity and specificity.  The author discusses some of the ethical issues that arise when an adult child at 25% risk for the disease wishes to have the test, but the parent(s) at 50% risk refuses to have one. If the child tests positive, the genetic status of the parent will also be disclosed. No matter what course of action is chosen in this situation, the ethically legitimate interests of either child or parent might be violated. The author examines different alternatives and suggests a solution that might be acceptable to all parties.
De novo supernumerary ring chromosome 7: first report of a non‐mosaic patient and review of the literature
Authors: Velagaleti GVN , Jalal SM , Kukolich MK , Lockhart LH , Tonk VS
Published: March 2003

The present authors report the case of a 12‐year‐old‐boy with a de novo, non‐mosaic supernumerary ring chromosome 7 associated with significant developmental delay and speech difficulty. A review of the literature identified a total of 18 cases with ring chromosomes 7 who can be classified into two groups: (1) patients with a cell line that has 47 chromosomes with a small supernumerary ring chromosome 7 resulting in partial trisomy; and (2) individuals had a cell line with a large ring chromosome replacing one of the normal chromosomes 7 resulting in partial monosomy. A comparison of clinical features in the two groups of patients showed several common features such as growth and mental retardation, and facial dysmorphism, including, ear and eye anomalies. However, patients with partial trisomy have speech difficulty as a distinguishing feature, while patients with partial monosomy have skin lesions as a cardinal feature. All the published cases of ring chromosome 7, irrespective whether they are supernumerary or normal modal number, are mosaics except for one. The present subject is the first case of a de novo, non‐mosaic supernumerary ring chromosome 7.
IL‐4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two‐locus haplotypes are more informative than individual SNPs
Authors: Bottini N , Borgiani P , Otsu A , Saccucci P , Stefanini L , Greco E , Fontana L , Hopkin JM , Mao X‐Q , Shirakawa T
Published: March 2003

The IL‐4RA locus encodes for the alpha chain of the IL‐4 receptor, and is both a functional and positional candidate gene for atopy and allergic disease. Recently Ober et al. have shown that the study of haplotypes at multiple loci in the IL‐4RA gene could be more informative than the separate study of single nucleotide polymorphisms (SNPs).

One hundred and fifty subjects affected by atopic asthma and 150 healthy control subjects were studied in the English population (Oxford district). Subjects and controls were genotyped for the Ile50Val, Ser478Pro and Gln551Arg polymorphism of the IL‐4 receptor alpha chain. The distribution of haplotypes 50–478 shows a highly significant association with IgE levels. In particular, the haplotype Val50/Pro478 is much less frequent in subjects with IgE levels > 100 U mL−1 than in those with IgE levels < 100 U mL−1. Furthermore, the distribution of haplotype 50‐551 shows a weak association with IgE levels that is lacking for 478‐551 haplotypes. A lower frequency of the Val50/Pro478 haplotype is also observed among asthmatic subjects as compared to healthy controls. With regard to individual SNPs (50 478 and 551), no significant association has been observed with IgE levels or with asthma, thus confirming the higher informative value of the haplotype analysis as compared to separate study on SNPs.
Family issues in a psychoeducation group for women with a BRCA mutation
Authors: Speice J , McDaniel SH , Rowley PT , Loader S
Published: March 2003

Few services exist for women who test positive for BRCA1 and BRCA2 mutations despite the distress that they and their families may experience. We present one model of a time‐limited family‐oriented psychoeducation group to provide information and support for nine women who received positive test results. We report on five family‐oriented themes that arose from the discussions: distress about possible transmission to children; family conflict about testing; concerns about disclosure; different coping styles and decision making; and underlying family conflict and unresolved grief. We also include recommendations from these women to enhance the services available to families by expanding assessment, and providing written literature and contact information. In addition, referrals for a psychoeducation group, community support group, or psychotherapy may be useful for individuals, couples and families who are considering genetic testing for BRCA mutations.
Developing a quality scoring system for epidemiological surveys of genetic disorders
Authors: Al‐Jader LN , Newcombe RG , Hayes S , Murray A , Layzell J , Harper PS
Published: March 2003

A prototype database of published articles containing data on the frequency of human inherited disorders has been developed for use in clinical contexts, in medical research, for epidemiological studies, and in the planning of genetic services. It can be accessed at http://www.uwcm.ac.uk/uwcm/mg/fidd/. The information available in the literature comes from a wide range of publications, not all can be described primarily as epidemiological surveys. A preliminary assessment indicated that the quality of published articles was highly variable. Very few published articles describe quality‐scoring systems for epidemiological surveys in general. We have developed a new scoring system to assess the quality of published articles on genetic disease frequency based on five main criteria and nine component scores. We carried out a first pilot study, to test its feasibility, usefulness and reproducibility. Eleven assessors scored six papers on the epidemiology of Huntington disease. As a result of these findings, we modified the scoring system to define each component more clearly. This was then evaluated in a second pilot study, which utilized six assessors to score 20 papers. The consensus between assessors remained relatively poor. We feel that while it may be possible to improve the scoring system further, the degree of improvement attainable may be limited by the poor standards of content and presentation of published surveys, which led to confusion and uncertainty by assessors. This pilot exercise has shown the need to raise the awareness of researchers and clinicians about the basic quality standards to be required of epidemiological genetic surveys.
Hair as a diagnostic tool in dysmorphology
Authors: Silengo M , Valenzise M , Sorasio L , Ferrero GB
Published: March 2003

Clinical diagnosis in dysmorphology is made by the recognition of a specific pattern of malformations and through an analytic search for discrete features.We present our personal experience regarding the usefulness of hair morphology as a tool for diagnosis in some metabolic and malformation syndromes. These cases represent only a few illustrative examples; an exhaustive review of the topic can be found elsewhere (1).
Genetic heterogeneity in Malattia Leventinese
Authors: Toto L , Parodi MB , Baralle F , Casari G , Ravalico G , Romano M
Published: March 2003

Malattia Leventinese (ML) is a dominant macular dystrophy characterized by drusen at the posterior pole. ML has been associated with a single mutation (R345W) in the EGF‐containing fibulin‐like extracellular matrix protein 1 (EFEMP‐1) gene, but also the EFEMP‐2 gene, known to share genetic homology with EFEMP‐1, is considered a candidate gene for this genetic disorder. We have characterized clinically and genetically seven members of a three‐generation family affected by ML. Results showed that five family members were clinically affected but the DNA sequencing failed to reveal the typical R345W mutation. Furthermore, the linkage analysis to EFEMP‐1 (using polymorphic markers D2S337 and D2S2368) and to EFEMP‐2 (using D11S987 and D11S1314 markers) gave negative results. Therefore, our results suggest EFEMP‐1 or EFEMP‐2 genes cannot be excluded as being responsible for ML but other genes have to be considered in the pathogenesis of the disease.
Sib‐pairs in multifactorial disorders: the sib‐similarity problem
Authors: Edwards JH
Published: March 2003

Common disorders are, by definition, the major cause of ill health and death. Most can be modified by avoiding or shielding an environment, as in sunburn and coeliac disease, by replacing some deficient substance, as in diabetes or myxoedema, or by empirical methods of evident effect as in schizophrenia and depressive illness. As expected, all show an increased incidence in relatives and the identification of the more influential loci involved may define unexpected links in the metabolic map: these may be amenable to therapy, or, in autoimmune disorders and asthma, define precipitating factors by sequencing the receptor involved.

The major investment in trawling the genotype for influential loci has been by affected sib‐pairs with parents (ASPs). Over a hundred major studies have been published with very limited success. No substantial study of normal sib‐pairs has been undertaken, making this family of surveys one of the largest undertaken in the absence of controls.

Possible reasons for this limited success and the many suggestive false positives are considered.
A novel point mutation of the androgen receptor (F804L) in an Egyptian newborn with complete androgen insensitivity associated with congenital glaucoma and hypertrophic pyloric stenosis
Authors: Gad YZ , Mazen I , Lumbroso S , Temtamy SA , Sultan C
Published: March 2003

Androgen‐insensitivity syndrome (AIS) is a major cause of male pseudohermaphroditism (MPH). Although AIS is usually reported as a monogenic disease resulting from androgen receptor (AR) mutations, on rare occasions it has been observed as part of a multiple congenital anomaly syndrome. We report here a patient who was the first newborn girl of an unrelated couple. Shortly after birth, the diagnoses of congenital glaucoma and pyloric stenosis were made. A detailed history of the father's family revealed that nine members presented glaucoma before 40 years of age. Clinical and ultrasound evaluation showed two inguinal testes, with female external genitalia and no Mullerian derivatives. The patient had a 46,XY karyotype, good testicular response to gonadotrophin stimulation and a remarkably high T : dihydrotestosterone ratio. Sequencing of the five exons of the 5α‐reductase type 2 gene (SRD5A2) was normal. Conversely, a de novo point mutation was found in exon 6 of the AR gene, resulting in an F804L substitution, which has never been described previously. To our knowledge, the association of complete AIS, congenital glaucoma and pyloric stenosis has also never been reported previously.
Very low incidence of microsatellite instability in rectal cancers from families at risk for HNPCC
Authors: Hoogerbrugge N , Willems R , Van Krieken HJ , Kiemeney LA , Weijmans M , Nagengast FM , Arts N , Brunner HG , Ligtenberg MJL
Published: March 2003

In families at risk for hereditary non‐polyposis colorectal cancer (HNPCC) that do not fulfill all clinical criteria for HNPCC, additional evidence is sought by testing cancer specimens for microsatellite instability (MSI). We investigated whether the location of a colorectal cancer (CRC) predicts the result of MSI‐testing in these families. One hundred and seven patients suspected for HNPCC were offered MSI‐testing. MSI‐testing was positive in 6/7 patients with endometrial carcinoma and in 22/100 patients with CRC. Only one out of 22 (4%) rectal cancers was MSI‐positive, and in this patient no mismatch repair (MMR) gene mutation was found. Right‐sided colon carcinomas were more likely to be MSI‐positive (14/37 or 38%), followed by left‐sided colon carcinomas (7/4 or 17%) (p < 0.05), with 6/14 and 4/7 MMR gene mutations, respectively. The likelihood that a tumor would be MSI‐positive was 3.3 times greater for right‐sided than for left‐sided colon cancer (OR 3.3, p < 0.05). Microsatellite instability was 8.1 times more frequent in colon cancers than in rectal cancers (p < 0.05). The presence of MSI was independently related to fulfillment of the Bethesda criteria (OR 7.0, p = 0.01). In families with multiple cases of colorectal cancer, the rectal cancers are only rarely MSI‐positive. This indicates that even in families with multiple colorectal cancers, rectal cancers are most commonly of sporadic origin.
One hundred consecutive living kidney donors: modern issues and outcomes
Authors: Peters Thomas G , Repper Suzanne M , Vincent Mia C , Schonberg Colleen A , Jones Kenneth W , Cruz Ivan , Charlton Ronald K , McCullough Christopher S , Hunter Richard D
Published: March 2003

Abstract:In order to define current issues and outcomes of living kidney donation, 100 consecutive living donors operated on between July 1996 and March 2001 were evaluated. The 64 women and 36 men ranged in age from 19 to 72 yr (mean 42.5 yr), and 65 were related to the recipient while 35 were unrelated donors. Hospital admission the morning of surgery and use of a minimal open approach to the donor kidney were standard, as were post‐operative epidural pain control and plans for short hospital stay. The 100 donors were hospitalized for 2 (25), 3 (48), 4 (18), 5 (8), or 6 (1) days, with an average length of stay of 3.12 d (range 2–6 d). The mean charge for kidney donor hospitalization was $14 470 (range $9671–22 808). There were no major intra or immediate post‐operative complications. Six rehospitalizations occurred for post‐donation nausea, vomiting, dehydration (n = 2); spinal headache; pneumonia and wound haematoma; and late wound reexploration (one hernia and one nerve entrapment). All donors returned to pre‐operative functional status within 6 d to 6 wk of donation. All kidneys functioned immediately in the 100 recipients (50 women, 50 men) who averaged 46.6 yr of age (range 17–69 yr); recipient length of stay averaged 3.81 d (range 2–15 d). All donors survived in excellent health; recipient graft and patient survival, respectively, are 87 and 90% through the entire 5‐yr period. Excellent long‐term outcomes for living kidney donors may be accomplished using minimal open surgical technique, post‐operative epidural pain control and plans for a brief hospitalization. Expansion of living donor resources in renal transplant programs may grow as unrelated kidney donation and non‐directed donation as well as minimally invasive (open and laparoscopic) techniques evolve.
A case of an ABO‐incompatible renal transplant with abundant intratubular basement membrane immune deposits
Authors: Shiozawa Satoshi , Ichikawa Tohru , Nakazawa Koh , Ehara Takashi , Shigematsu Hidekazu
Published: March 2003

Abstract: We present a case of a 30‐year‐old man who received an ABO‐incompatible renal transplant from his mother in 1996 after haemodialysis for 3 years. Although his renal function was stable, a renal biopsy was performed while he was in hospital for treatment of herpes zoster in 1999. Light microscopy provided no evidence of obvious acute or chronic rejection but a double contour pattern was observed in many tubular basement membranes (TBM). Immunofluorescence microscopy revealed deposits of IgG and C3 on the TBM in the absence of glomerular deposition. Massive electron‐dense deposits were observed clearly by electron microscopy within TBM, revealing splitting and lamellation. This implies that the deposits resulted from the formation of immune complexes, but not from anti‐TBM antibody. Although the role of TBM deposits in tubular injury is controversial, careful observation of patients with such deposits may be required because of their potential ability to induce immune reactions.
Pain and health related quality of life after heart, kidney, and liver transplantation
Authors: Forsberg Anna , Lorenzon Ulrika , Nilsson Folke , Bäckmana Lars
Published: March 2003

No study has focused particularly on the sensory and affective experience of bodily pain among transplanted patients. The aim of this study was to explore pain and other factors that influence health related quality of life (HRQOL) in heart, kidney, and liver transplant recipients during the first 2 yr after transplantation, and to define similarities and/or differences in the three groups.A total of 76 patients, 18–60 yr old, undergoing heart, kidney, or liver transplantation between 1995 and 1997 with a follow‐up of 6–24 months were included. HRQOL and pain were investigated by using the Short‐Form‐36 items (SF‐36), the Hospital Anxiety and Depression Scale (HAD), and the Pain‐O‐Meter (POM).Overall, the patients show satisfactory HRQOL. There were no differences in experienced HRQOL 6–24 months after transplantation between kidney, liver, and heart transplant recipients except in the area of Role‐Physical (RP). Fifty‐three percent of all patients reported bodily pain. The most common locations were the hands, feet, and back, and sensory experiences were burning, stabbing, or dull pain. There was a correlation between number of rejections and total score for POM‐VAS (p<0.05) (rho=0.47). There was also a correlation between the number of rejection episodes and the total pain intensity score for POM‐WDS (p<0.05) (rho=0.48). Patients with pain scored higher in the area of depression (p<0.05).Bodily pain is an important problem after organ transplantation, affecting daily living even in patients with good allograft function and it limits physical function, vitality, and general health.
A double‐blind placebo controlled trial of simvastatin for the treatment of dyslipidaemia in renal allograft recipients
Authors: Lepre Frank , Rigby Russell , Hawley Carmel , Saltissi David , Brown Alison , Walsh Zoe‐ann
Published: March 2003

Background: With current techniques, renal failure patients are now able to regain near‐normal health following renal transplantation. However, the development of premature cardiovascular disease is a major problem. Dyslipidaemia may be an important contributor to this. The use of lipid lowering agents in renal allograft recipients has been limited by potential interaction of these agents with the now widely used immunosuppressive agent, cyclosporine.Aim: This study was designed to investigate efficacy and safety of simvastatin in subjects taking either cyclosporine or azothioprine post renal transplantation.Methods: Fifty‐one subjects (32 females, 19 males – mean age 51±12.5 yr) who were at least 1 yr post transplant, had creatinine ≤2.5 mmol/L and a total cholesterol ≥6 mmol/L were enrolled in a prospective, double‐blind, placebo‐controlled study. After an initial 10‐wk dietary period, the last 4 wk on placebo, subjects were randomised to receive either 5 mg simvastatin/d for 6 wk followed by 10 mg simvastatin/d for 6 wk, or matching placebo. After this 12‐wk double‐blind phase, there was an open‐label phase when all subjects were treated with 10 mg simvastatin/d for a period of 36 wk.Results: Compared to placebo, 5 mg simvastatin/d significantly decreased total cholesterol by 20% (p<0.01), low‐density lipoprotein cholesterol (LDL cholesterol) by 29% (p<0.01), and Apolipoprotein B (ApoB) by 26% (p<0.01). Increasing simvastatin to 10 mg/d did not lead to further significant changes. But high‐density lipoprotein cholesterol (HDL cholesterol) increased by 9% (p<0.01) and Apolipoprotein A1 (ApoA1) by 7% (p<0.01) only on 10 mg simvastatin/d. During the open‐label phase, subjects previously randomised to placebo achieved similar significant changes to their lipoprotein profile. The benefits achieved from simvastatin were maintained to the end of the study. There were three withdrawals from the study, all from the simvastatin/cyclosporine group. Two subjects had musculoskeletal pain and 1 had abdominal pain. Minor adverse events were similar in both the simvastatin‐ and placebo‐treated groups.Conclusion: Low‐dose simvastatin is an effective and well‐tolerated agent in the treatment of dyslipidaemia in renal allograft recipients.
Histopathology of a human allografted kidney with clinically sufficient function
Authors: Shomori Kohei , Kuratate Itaru , Sakatani Takashi , Takeuchi Ken , Tei Kaikyu , Mannami Makoto , Toshino Akihiko , Oka Akihiro , Ohoka Hiroji , Ito Hisao
Published: March 2003

To clarify the clinico‐pathological significance of protocol biopsy and clinically silent rejection in the management of renal graft recipients, we selected a total of 139 (23%) from 604 biopsy specimens according to the following criteria: 1) less than 1.4 mg/dL of serum creatinine and 2) more than 1 500 mL/d of urine volume at time of biopsy. Clinical indications for the biopsy were classified into five categories: i) protocol biopsy (73 specimens), including 69 cases at discharge post‐transplantation; ii) slight increase in serum creatinine (32); iii) proteinuria (20); iv) evaluation of pulse‐therapy (13); and v) fever elevation (1). Except for the last category, the specimens were histopathologically diagnosed as being normal in 50 (68%), 6 (17%), 1 (5%), and 5 (38%) specimens, respectively. Even borderline changes, and mild acute rejection, as well as drug‐induced nephropathy were included, implying the existence of clinically silent rejection or drug‐induced nephropathy. Obvious diversity in the histopathological diagnosis was noted in category iii) showing proteinuria, which was mainly caused by chronic rejection, drug‐induced nephropathy and glomerulonephritis. The graft survival rate was no different among the four categories, except for category v). These results indicate that biopsies obtained from functionally sufficient renal grafts could provide useful information in the management of the recipients. The clinical significance of protocol biopsy awaits further clarification by the analysis of a large number of cases.
Successful cadaveric renal transplantation of patients highly sensitized to HLA Class I antigens
Authors: Bryan Cf , Shield Cf , Pierce Ge , Warady Ba , Aeder Mi , Martinez J , Luger Am , Nelson Pw , Ross G , Muruve N , Mitchell Si
Published: March 2003

The purpose of our investigation was to evaluate long‐term graft survival and the role of histocompatibility in patients who were highly sensitized to human leukocyte antigen (HLA) Class I antigens and received a cadaveric renal transplant. Our multi‐institutional study evaluated 7‐yr graft outcomes and the histocompatibility requirements of 61 (6.1%) highly sensitized (anti‐human globulin panel reactive antibody [AHG PRA], ≥80%) cadaveric renal transplantation patients, transplanted between 1988 and 1997, among 999 consecutive cadaveric renal transplants.One‐ and 7‐yr graft survival in the high PRA group (n=61) was 76 and 59%, and was not significantly different from that in the low PRA group (n=938), 86 and 59% (Wilcoxon=0.11; log‐rank=0.45) (died with a functioning graft [DWFG] not censored). When those data were divided into primary and regrafts, 1‐ and 7‐yr graft outcomes for high and low PRA groups were not significantly different [(primary, 1‐ and 7‐yr survival: high PRA=83 and 74%, n=30, and low PRA=87 and 61%, n=825; log‐rank=0.37 for DWFG not censored) (regrafts, 1‐ and 7‐yr survival: high PRA=70 and 42%, n=31, and low PRA=80 and 43%, n=113; log‐rank=0.36 for DWFG not censored)]. We did observe a subgroup of the high PRA patient group that had inferior graft outcomes. Graft outcome at 1 and 6 yr in the high PRA group for patients who had one to two DR mismatches (65 and 50%, n=41) was significantly worse than for high PRA patients who had zero DR mismatches with their donors (100 and 78%, n=20) (log‐rank=0.01 for DWFG not censored). Furthermore, the mean number of HLA‐A and ‐B mismatches was significantly greater in the high PRA/DR‐mismatched group (1.7±1.2, n=41) compared with the high PRA/zero DR‐mismatched group (0.5±1.1, n=19) (p<0.001). Overall, these data suggest that the patient who is highly sensitized to HLA Class I antigens has a long‐term graft outcome that is equivalent to less sensitized patients, but that HLA‐DR mismatching and a higher degree of Class I mismatching may be poor prognostic indicators in such patients.
Towards a specific immunosuppression for pancreas and islet grafts
Authors: Jindal Rahul M , Dubernard Jean‐Michel
Published: March 2003

This brief article is a summary of the presentations at a meeting organized in Lyon, France, to discuss strategies of reducing post‐transplant diabetes mellitus and to suggest an ideal immunosuppressive therapy for pancreatic and islet allografts.
Implication of advanced donor age on the outcome of liver transplantation
Authors: Oh Chang‐Kwon , Sanfey Hilary A , Pelletier Shawn J , Sawyer Robert G , McCullough Christopher S , Pruett Timothy L
Published: March 2003

Historically, age has been considered to be a relative contraindication for organ donors. The use of elderly donors for liver transplantation remains controversial due to the fear of inferior outcome. According to United Network for Organ Sharing (UNOS) data, the proportion of older donors has been increasing annually. This study describes the short‐ and long‐term outcomes for transplantation of elderly donor livers. Three hundred and seventy‐four primary liver transplantations, which had been performed at the University of Virginia Health System from 7 February 1988 to 31 December 1998, were included. Graft survival, incidence of primary non‐function, and hepatic artery thrombosis (HAT) after transplantation according to the different age groups of liver donors were analyzed. Cases were analyzed by donor age (group I, n=106: aged <20 yr; group II, n=217: aged between 20 and 49 yr; group III, n=51: aged ≥50 yr), and by donor age in comparison with recipient age (group IV, n=65: recipients transplanted with organs from donors within 5 yr of their age; group V, n=266: recipients from donors> 5 yr younger than their age; group VI, n=43: recipients from donors> 5 yr older than their age). Group III or VI (group of advanced donor age) and group II or V (control group) were compared by age, gender, race, body weight, height, pre‐transplantation cytomegalovirus (CMV) status of the recipients donors, cause of brain death of donors, total or warm ischemic time, ABO matching, and degree of human leucocyte antigen (HLA) mismatching. No significant difference in 5 yr graft survival was found between the groups by donor age (p=0.604) and by donor age compared with recipient age (p=0.567). Moreover, no significant differences in the incidence of primary non‐function and HAT after transplantation were found between the groups by donor age and by donor age compared with recipient age. Older donors were more likely to be women and to have antibodies to CMV, as well as to have died by cerebrovascular causes. Race, body weight, height of both recipients and donors, total or warm ischemic time of grafts, ABO matching, and degree of HLA mismatching were not significantly different between the groups. We conclude from this study that advanced donor age is not a contraindication to liver transplantation if careful assessment of donors is made on a case‐by‐case basis. There is a need to maintain an open mind with regard to the use of livers from older donors due to the current situation of serious organ shortages.
International sharing of split liver grafts in Asia: initial experience
Authors: De Villa Vh , Chen Cl , Chen Ys , Wang Cc , Wang Sh , Chiang Yc , Cheng Yf , Jawan B , Cheung Hk , Fan St , Lo Cm
Published: March 2003

The donor shortage problem is particularly serious in Asia and has markedly limited progress in liver transplantation. The increasing demand has, in fact, made it necessary to resort to living donor liver transplantation in both pediatric and adult recipients. Nevertheless, expanding the use of split liver allografts is yet another option to increase the supply. This has a wide potential application on a regional level because most liver transplant programs are still small and may have limited resources in terms of being able to do two transplants in one sitting. The first experience of overseas sharing of split liver grafts in Asia took place in January 1999. The graft was from a 35‐yr‐old donor from Kaohsiung, Taiwan, who sustained irreversible brain damage in a vehicular accident and had optimal conditions for multiorgan donation. The liver was split ex vivo and the left lateral segment was given to a 3‐yr‐old girl with biliary atresia at the Chang Gung Memorial Hospital. The extended right lobe split graft was transported to Hong Kong and transplanted into a 51‐yr‐old male patient with end‐stage hepatitis C cirrhosis who was then in a state of acute failure with hepatorenal syndrome. Graft function was excellent in both recipients and the patient from Taiwan was discharged without any complications. Unfortunately, the Hong Kong recipient developed a cerebrovascular accident and required a reoperation for bile leakage from the cut surface of the liver in the early postoperative period. He has made a steady recovery since then; graft function has remained good and his kidneys have recovered. Both patients are currently alive and well 11 months post‐transplant.  This initial experience of overseas sharing of split liver grafts in Asia demonstrates its feasibility. It has a potentially wide applicability and could lead to the establishment of a formal organ‐sharing network in the region. Established competence and mutual trust among the participating liver transplant teams would be essential in perpetuating such a graft‐multiplying strategy on an organized basis.
Transplantation of livers from HBc Ab positive donors into HBc Ab negative recipients: a strategy and preliminary results
Authors: Loss George E. , Mason Andrew L. , Blazek Jamie , Dick Debbie , Lipscomb Jeane , Guo Linsheng , Perrillo Robert P. , Eason James D.
Published: March 2003

Here we describe a strategy for using livers from hepatitis B core antibody (anti‐HBc) positive donors in anti‐HBc negative recipients and report our preliminary results. Adult anti‐HBc negative recipients were immunized against hepatitis B virus (HBV) prior to transplantation. Liver biopsies from anti‐HBc positive, HBs Ag negative donors were performed at the time of procurement to rule out acute hepatitis or chronic liver disease. Donor serum and liver samples were collected for HBV DNA analysis by PCR.

Recipients were given HBIG (10 000 units, i.v.) during the anhepatic phase of transplantation. Patients were treated with lamivudine (150 mg) beginning on postoperative day (POD) 1. If HBV DNA was not detected in either donor liver or serum by PCR, recipient antiviral therapy was stopped. If donor liver and serum were positive for HBV DNA by PCR, the recipient was maintained on combination lamivudine and HBIG therapy. If HBV DNA was detected in donor liver but not in donor serum, the patient was managed on lamivudine therapy alone. Between February 1999 and June 2000, six anti‐HBc negative recipients received liver transplants from anti‐HBc positive donors. PCR analysis of serum from the six donors was negative for HBV DNA in each, while donor liver PCR analysis was positive in five of six for HBV DNA. Accordingly, all patients were given HBIG in the anhepatic phase of transplantation and five of six were maintained on daily lamivudine therapy. Follow‐up periods have ranged from 2 to 18 months. There has been no emergence of de novo hepatitis B. Serial serum HBs Ag and HBV DNA assays have all proven negative. Moreover, while on lamivudine therapy, 2 patients now have undetectable HBV DNA in hepatic allograft biopsies by PCR analysis. Our strategy for using livers from anti‐HBc donors has yielded promising initial results. De novo hepatitis B has not occurred and our data suggest residual hepatitis B virus may be eradicated in recipients maintained on lamivudine therapy.