bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular cytogenetic analysis of a duplication Xp in a female with an abnormal phenotype and random X inactivation
Authors: Portnoï Marie‐France , Bouayed‐Abdelmoula Nouha , Mirc Myriam , Zemni Ramzi , Castaing Henry , Stephann Julie , Ardalan Azarnouche , Vialard François , Nouchy Marc , Daoud Patrick , Chelly Jamel , Taillemite Jean‐Louis
Published: March 2003

We describe a female infant with severe abnormal phenotype with a de novo partial duplication of the short arm of the X chromosome. Chromosome painting confirmed the origin of this X duplication. Molecular cytogenetic analysis with fluorescence in situ hybridization (FISH) was performed with YAC probes, further delineating the breakpoints. The karyotype was 46, X dup(X)(p11‐p21.2).Cytogenetic replication studies showed that the normal and duplicated X chromosomes were randomly inactivated in lymphocytes. In most females with structurally abnormal X chromosomes, the abnormal chromosome is inactivated and they are phenotypically apparently normal relatives of phenotypically abnormal males having dupX. Therefore, in this case, there is functional disomy of Xp11‐p21.2 in the cells with an active dup(X), most likely resulting in abnormal clinical findings in the patient.
How men view genetic testing for prostate cancer risk: findings from focus groups
Authors: Doukas DJ , Fetters MD , Coyne JC , McCullough LB
Published: March 2003

Objective: To determine the values, beliefs, and attitudes that influence a man's intention to undergo or defer genetic testing for prostate cancer risk.  Design: Qualitative, using focus group interviews – 12 focus groups were conducted to identify key values and beliefs about genetic testing for prostate cancer risk in anticipation of its future availability.  Setting: Medium‐sized, mid‐west, US city.  Participants: Community sample of 90 lay men of diverse educational, ethnic, and age backgrounds.  Analysis: Descriptive statistics and immersion/crystallization to identify themes and sub‐themes.  Results: The major areas of concern were distilled into the following themes: beliefs about consequences, expectations, benefits for patients, beliefs about barriers, and susceptibility concerns.  Conclusion: Identifying these men's values will help health professionals anticipate the informational and ethical needs of patients in the informed consent process. Men will need to understand how such testing may affect their planning regarding future prostate health, and how medical information is used outside of the physician–patient relationship.
Analysis of genomic instability using multiple assays in a patient with Rothmund–Thomson syndrome
Authors: Grant SG , Wenger SL , Latimer JJ , Thull D , Burke LW
Published: March 2003

We report on a patient with Rothmund–Thomson syndrome (RTS) whose cytogenetic evaluation showed a normal karyotype with no evidence of trisomy mosaicism or chromosomal rearrangements. Cultured lymphocytes from the patient, her mother, and a control exposed to mitomycin C and diepoxybutane did not show increased sensitivity to the dialkylating agents. Unlike some previous reports, we found no evidence of a deficiency in nucleotide excision repair, as measured with the functional unscheduled DNA synthesis assay. Glycophorin A analysis of red blood cells for somatic mutation revealed suspiciously high frequencies of both allele loss and loss‐and‐duplication variants in the blood of the patient, a pattern consistent with observations in other RecQ‐related human diseases, and evidence for clonal expansion of a mutant clone in the mother. Discrepant results in the literature may reflect true heterogeneity in the disease or the fact that a consistent set of tests has not been applied to RTS patients.
Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressiva (FOP)
Authors: Xu M‐Q , Feldman1, G , Le Merrer M , Shugart YY , Glaser DL , Urtizberea JA , Fardeau M , Connor JM , Triffitt J , Smith R , Shore EM , Kaplan FS
Published: March 2003

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4‐interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42‐bp deletion in the protein‐coding region of the noggin gene of a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically‐affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was −2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single‐strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42‐bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42‐bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP.
A multivariate analysis of 59 candidate genes in personality traits: the temperament and character inventory
Authors: Comings DE , Gade‐Andavolu R , Gonzalez N , Wu S , Muhleman D , Blake H , Mann MB , Dietz G , Saucier G , MacMurray JP
Published: March 2003

Cloninger (Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987: 236: 410–416) proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance, and reward dependence. He suggested that novelty seeking primarily utilized dopamine pathways, harm avoidance utilized serotonin pathways, and reward dependence utilized norepinephrine pathways. Subsequently, one additional temperament dimension (persistence) and three character dimensions (cooperativeness, self‐directedness, and self‐transcendence) were added to form the temperament and character inventory (TCI). We have utilized a previously described multivariate analysis technique (Comings DE, Gade‐Andavolu R, Gonzalez N et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178–196; Comings DD, Gade‐Andavolu R, Gonzalez N et al. Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder. Clin Genet 2000: in press) to examine the relative role of 59 candidate genes in the seven TCI traits and test the hypothesis that specific personality traits were associated with specific genes. While there was some tendency for this to be true, a more important trend was the involvement of different ratios of functionally related groups of genes, and of different genotypes of the same genes, for different traits.
An association between skewed X‐chromosome inactivation and abnormal outcome in mosaic trisomy 16 confined predominantly to the placenta
Authors: Peñaherrera Ms , Barrett IJ , Brown CJ , Langlois S , Yong S‐L , Lewis S , Bruyère H , Howard‐Peebles PN , Kalousek DK , Robinson WP
Published: March 2003

Skewed X‐chromosome inactivation (XCI) is frequently found in the diploid fetal tissues of individuals with mosaic trisomy that originated from a ‘trisomic zygote rescue’ event. This may result from a high number of trisomic cells in the embryonic cell pool at the time of XCI, which are subsequently eliminated by selection. We hypothesize that extremely skewed XCI in these mosaic cases will be associated with a poor fetal outcome due to failure to completely eliminate the trisomy from all fetal tissues. To test this hypothesis, XCI status was evaluated in 17 cases of prenatally detected trisomy 16 mosaicism. Ten of the 15 informative cases showed extreme XCI skewing (≥90% inactivation of one allele) in blood or other diploid fetal tissues compared to six of the 111 controls (p<0.001). Among these 10 ‘skewed’ cases, 6 showed an abnormal outcome, defined as developmental abnormalities and/or intrauterine or neonatal death. In contrast, of the 5 cases without extreme skewing, none showed abnormal outcome, although outcome information was incomplete in 1 case. An additional 6 cases analyzed, involving trisomy mosaicism for other chromosomes, showed similar results. Further studies are warranted to determine if XCI status adds useful information to the prediction of pregnancy outcome in prenatally detected mosaic trisomy.
Identification of a novel deletion of the entire OCRL1 gene detected by FISH analysis in a family with Lowe syndrome
Authors: Peverall J , Edkins E , Goldblatt J , Murch A
Published: March 2003

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X‐linked multisystem disorder affecting the lens, kidney and brain. The gene involved (OCRL1) has been identified and is known to encode a phosphatidylinositol 4,5‐bisphosphate 5‐phosphatase. Mutations in OCRL1 have been shown to be causative of OCRL. To date, most of the mutations identified have consisted of simple or point mutations and there is one report of a 1.4‐kb deletion. We investigated the OCRL1 gene in a male patient with OCRL by the polymerase chain reaction and found that the entire OCRL1 gene was deleted. Fluorescence in situ hybridisation analysis (FISH), with cosmid probes that span the entire OCRL1 gene, was used to confirm this deletion and subsequently identify it in the proband's mother. This is the first report of a whole gene deletion of OCRL1 and thus expands the range of mutations that give rise to OCRL. The use of the FISH technique facilitated carrier and prenatal testing for the deletion in the family.
The role of genomic imprinting in human developmental disorders: lessons from Prader–Willi syndrome
Authors: Hanel Ml , Wevrick R
Published: March 2003

Normal human development involves a delicate interplay of gene expression in specific tissues at narrow windows of time. Temporally and spatially regulated gene expression is controlled both by gene‐specific factors and chromatin‐specific factors. Genomic imprinting is the expression of specific genes primarily from only one allele at particular times during development, and is one mechanism implicated in the intricate control of gene expression. Two human genetic disorders, Prader–Willi syndrome (PWS, MIM 176270) and Angelman syndrome (AS, MIM 105830), result from rearrangements of chromosome 15q11‐q13, an imprinted region of the human genome. Despite their rarity, disorders such as PWS and AS can give focused insight into the role of genomic imprinting and imprinted genes in human development.
Mutational screening of the cationic trypsinogen gene in a large cohort of subjects with idiopathic chronic pancreatitis
Authors: Chen Jm , Piepoli Bis A , Le Bodic L , Ruszniewski P , Robaszkiewicz M , Deprez Ph , Raguenes O , Quere I , Andriulli A , Ferec C
Published: March 2003

Several missense mutations, including R122H, N29I, K23R, A16V and D22G, in the cationic trypsinogen gene (PRSS1), have been associated with certain forms of hereditary pancreatitis (HP). Their occurrence in the idiopathic chronic pancreatitis (ICP) and whether novel mutations could be identified in PRSS1 remain to be further evaluated. These were addressed by the mutational screening of the entire coding sequence and the intronic/exonic boundaries of the PRSS1 gene in 221 ICP subjects, using a previously established denaturing gradient gel electrophoresis technique. Among the known PRSS1 mutations, only the R122H was detected in a single subject and the A16V in two subjects in the cohort, strengthening that HP‐associated PRSS1 mutations are rare in ICP. Additional missense mutations, including P36R, E79K, G83E, K92N and V123M, were identified once separately. By analogy with the known PRSS1 mutations, predisposition to pancreatitis by some of them, particularly the V123M autolysis cleavage site mutation, is suspected. Functional analysis is expected to clarify their possible medical consequences.
CYP21 mutations and congenital adrenal hyperplasia
Authors: Lee HH
Published: March 2003

Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder caused mainly by defects in the steroid 21‐hydroxylase (CYP21) gene. More than 90% of CAH cases are caused by mutations of the CYP21 gene on chromosome 6p21.3. The wide range of CAH phenotypes is associated with multiple mutations known to affect 21‐hydroxylase enzyme activity. To date, 56 different CYP21 mutations have been reported, mostly point mutations, but small deletions or insertions have been described too, as well as complete gene deletions. Fifteen mutations, constituting 90–95% of alleles, are derived from intergenic recombination of DNA sequences between the CYP21 gene and the highly homologous CYP21P pseudogene, while the remaining are spontaneous mutations. A reliable and accurate detection of CYP21 mutations is not only important for clinical diagnosis, but also for carrier detection as there is a high variability in the basal level of 17‐hydroxyprogesterone between normal and heterozygous individuals. Several strategies based on polymerase chain reaction (PCR)‐driven amplification with allele‐specific oligonucleotides to the CYP21 gene have been developed. It has been demonstrated that one reaction for PCR amplification of the CYP21 gene and the chimeric CYP21P/CYP21 gene using mixed primers in combination with nested PCR and single‐strand conformation polymorphism is considered highly efficient and accurate for molecular diagnosis of CAH due to 21‐hydroxylase deficiency.
The Smith–Lemli–Opitz syndrome: a novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology
Authors: Nowaczyk MJM , Waye JS
Published: March 2003

The brief history of the Smith–Lemli–Opitz syndrome (SLOS) (MIM 270400) reflects that of latter 20th century dysmorphology and biochemical and molecular genetics: from its first description as a rare but characteristic multiple malformation syndrome known only to a handful of dysmorphologists, to a relatively common Garrodian defect with a complex molecular basis that has captured the attention of researchers and basic scientists from the fields as diverse as embryology, developmental biology, sterol biochemistry, epidemiology, and teratology. The discovery of the underlying biochemical defect – deficiency of 3β‐hydroxysteroid‐Δ7‐reductase (DHCR7), an enzyme catalyzing the last step of cholesterol biosynthesis, and the resultant generalized cholesterol deficiency – has led to an explosion of knowledge of this biochemical pathway and to a paradigm shift in the recognition of metabolic deficiencies as causes of dysmorphic syndromes. Characterization of the human DHCR7 gene and the identification of mutations in patients with SLOS have revealed a complex picture of molecular heterogeneity and provided insights into the structure and function of DHCR7. SLOS is the first metabolic malformation syndrome with profound effects on the body plan, and its discovery has paved the way to the discovery of a number of other defects of the cholesterol synthetic pathway.
Quantification of all fetal nucleated cells in maternal blood between the 18th and 22nd weeks of pregnancy using molecular cytogenetic techniques
Authors: Krabchi K , Gros‐Louis F , Yan J , Bronsard M , Massé J , Forest J‐C , Drouin R
Published: March 2003

Different types of nucleated fetal cells (trophoblasts, erythroblasts, lymphocytes, and granulocytes) have been recovered in maternal peripheral blood. In spite of many attempts to estimate the number of fetal cells in maternal circulation, there is still much controversy concerning this aspect. The numbers obtained vary widely, ranging from 1 nucleated cell per 104 to 1 per 109 nucleated maternal cells. The purpose of our project was to determine the absolute number of all different types of male fetal nucleated cells per unit volume of peripheral maternal blood. Peripheral blood samples were obtained from 12 normal pregnant women known to carry a male fetus between 18 and 22 weeks of pregnancy. Three milliliters (3 ml) of maternal blood has been processed without any enrichment procedures. Fluorescence in situ hybridization (FISH) and primed in situ labeling (PRINS) were performed, and fetal XY cells were identified (among maternal XX cells) and scored by fluorescent microscopy screening. The total number of male fetal nucleated cells per milliliter of maternal blood was consistent in each woman studied and varied from 2 to 6 cells per milliliter within the group of normal pregnancies. The number of fetal cells in maternal blood, at a given period, is reproducible and can therefore be assessed by cytogenetic methods. This confirms the possibility of developing a non‐invasive prenatal diagnosis test for aneuploidies. Furthermore, we demonstrate that it is possible to repeatedly identify an extremely small number of fetal cells among millions of maternal cells.
Trisomy 17p10‐p12 resulting from a supernumerary marker chromosome derived from chromosome 17: molecular analysis and delineation of the phenotype
Authors: Stankiewicz P , Park S‐S , Holder SE , Waters CS , Palmer RW , Berend SA , Shaffer LG , Potocki L , Lupski JR
Published: March 2003

We report a 5‐year‐old boy with a small de novo marker chromosome derived from the proximal short arm of chromosome 17. His clinical features include hypotonia, global developmental delay, oval face with large nose and prominent ears, and ligamentous laxity of the fingers. Magnetic resonance imaging of the brain demonstrated mildly delayed myelination. G‐band chromosome analysis revealed mosaicism for a small marker chromosome in 85% of the peripheral blood cells analyzed. Fluorescence in situ hybridization and microsatellite polymorphism studies showed that the der(17) was of maternal origin and included genetic material from the 17p10‐p12 region, but did not contain the PMP22 gene. One breakpoint mapped within the centromere and the second breakpoint mapped adjacent to the Charcot–Marie–Tooth disease type 1A proximal low‐copy repeat (CMT1A‐REP). We compare the clinical characteristics of our patient with those previously reported to have a duplication involving the proximal short arm region of chromosome 17 to further delineate the phenotype of trisomy 17p10‐p12.
PCR–PRINS–FISH analysis of structurally abnormal sex chromosomes in eight patients with Turner phenotype
Authors: Cervantes A , Guevara‐Yáñez R , López M , Monroy N , Aguinaga M , Valdez H , Sierra C , Canún S , Guízar J , Navarrete C , Zafra G , Salamanca F , Kofman‐Alfaro S
Published: March 2003

According to cytogenetic analysis, about 50% of Turner individuals are 45,X. The remaining cases have a structurally abnormal X chromosome or are mosaics with a second cell line containing a normal or abnormal sex chromosome. In these mosaics, approximately 20% have a sex marker chromosome whose identity cannot usually be determined by classical cytogenetic methods, requiring the use of molecular techniques. Polymerase chain reaction (PCR), primed in situ labeling (PRINS), and fluorescence in situ hybridization (FISH) analyses were performed in 8 patients with Turner syndrome and 45,X mosaic karyotypes to determine the origin and structure of the marker chromosome in the second cell line. Our data showed that markers were Y‐derived in 2 patients and X‐derived in the remaining 6 patients. We were also able to determine the breakpoints in the two Y chromosomes. The use of cytogenetic and molecular techniques allowed us to establish unequivocally the origin, X or Y, of the marker chromosomes in the 8 patients with Turner phenotype. This study illustrates the power of resolution and utility of combined cytogenetic and molecular approaches in some clinical cases.
Partial Xp duplication in a girl with dysmorphic features: the change in replication pattern of late‐replicating dupX chromosome
Authors: Kokalj Vokac N , Seme Ciglenecki P , Erjavec A , Zagradisnik B , Zagorac A
Published: March 2003

In this paper we present the case of a girl at the age of 32 months with dysmorphic features, including general muscular hypotonia, developmental delay and mental retardation. The cytogenetic analysis revealed de novo partial duplication of Xp: 46,X,dup(X)(p11.23→p22.33: :p11.23→p22.33). To characterize the duplication, X painting, Kallman (KAL), yeast artificial chromosomes (YACs) and bacterial artificial chromosomes (BACs) covering Xp11.23→Xp22.33 region were used. Selective inactivation of the abnormal X chromosome using HpaII digestion of the AR gene was evident. After BrdU incorporation the abnormal X was late‐replicating in all lymphocytes examined. There was one peculiar exception observed: the break‐point region was consistently early replicating. The replicating pattern of this region corresponded to the active X chromosome. Methylation pattern of late replicating X chromosome was studied also using antibodies against 5‐methylcytosine. The pattern corresponded to the normally inactive X chromosome, with the exception of the previously observed break‐point region which revealed an early replicating pattern with strong fluorescent signal, similar to the pattern of the active X chromosome. The observed phenomenon could lead to the abnormal phenotype of the patient, with some normally inactive genes of the break‐point region escaping the inactivation process. The abnormal clinical findings could also be due to tissue‐dependent differences in the inactivation pattern.
The complexities of ocular genetics
Authors: Saleem RA , Walter MA
Published: March 2003

The cliché‘a picture is worth a thousand words’ is a testament to the power of the visual system in helping us deal with our physical environment. Rarely do perturbations to the visual system, even minor ones, go unnoticed. Major defects in eye development may occur in the absence of systemic problems which threaten health. Ocular anomalies offer a window into many developmental events which would otherwise be difficult to study.
Genetics of population isolates
Authors: Arcos‐Burgos M , Muenke M
Published: March 2003

Genetic isolates, as shown empirically by the Finnish, Old Order Amish, Hutterites, Sardinian and Jewish communities among others, represent a most important and powerful tool in genetically mapping inherited disorders. The main features associated with that genetic power are the existence of multigenerational pedigrees which are mostly descended from a small number of founders a short number of generations ago, environmental and phenotypic homogeneity, restricted geographical distribution, the presence of exhaustive and detailed records correlating individuals in very well ascertained pedigrees, and inbreeding as a norm. On the other hand, the presence of a multifounder effect or admixture among divergent populations in the founder time (e.g. the Finnish and the Paisa community from Colombia) will theoretically result in increased linkage disequilibrium among adjacent loci. The present review evaluates the historical context and features of some genetic isolates with emphasis on the basic population genetic concepts of inbreeding and genetic drift, and also the state‐of‐the‐art in mapping traits, both Mendelian and complex, on genetic isolates.
Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high‐density lipoprotein cholesterol levels
Authors: Blumenthal JB , Andersen RE , Mitchell BD , Seibert MJ , Yang H , Herzog H , Beamer BA , Franckowiak SC , Walston JD
Published: March 2003

Neuropeptide Y (NPY) appears to play a critical role in the integration of appetite and energy expenditure through NPY Y1 and Y5 receptor subtypes. Moreover, the NPY Y1 receptor is highly expressed on human adipocytes, where it inhibits lipolysis. The genes encoding these receptors are transcribed co‐ordinately in opposite directions from a common promoter in a region of chromosome 4 that has been previously linked to triglyceride and small low‐density lipoprotein (LDL) particle concentration. Therefore, the purpose of this investigation was to examine the relationship between polymorphisms in the genes encoding NPY Y1 and Y5 and the development of obesity and dyslipidemia. We screened the promoter and coding regions and identified four polymorphic variants. One of these, a cytosine to thymine (C→T) substitution in the untranslated region between the genes for NPY Y1 and Y5 (allele frequency 0.11), was significantly associated with both lower fasting triglyceride level (152 vs 125 mg/dl), and higher high‐density lipoprotein (HDL) concentrations (49 vs 45 mg/dl) (p < 0.01) in 306 obese subjects. Given the stimulatory effect of NPY on adipocyte lipoprotein lipase (LPL) activity, and the lack of association of other polymorphisms with serum lipid levels, we hypothesize that this is a gain‐in‐function polymorphism.
ATP binding cassette G5 C1950G polymorphism may affect blood cholesterol concentrations in humans
Authors: Weggemans RM , Zock PL , Tai ES , Ordovas JM , Molhuizen HOF , Katan MB
Published: March 2003

ATP binding cassette protein G5 (ABCG5) and G8 (ABCG8) may be involved in the regulation of intestinal cholesterol absorption. Therefore, genetic variation at these loci may affect blood cholesterol concentrations by influencing dietary responsiveness. We studied the association between the ABCG5 C1950G (Gln640Glu) polymorphism and blood cholesterol concentrations in 486 subjects and responsiveness to dietary cholesterol in 99 participants in dietary trials. Mean baseline cholesterol concentrations were 0.65 ± 0.22 mmol/l higher in 13 subjects with the G/G genotype than in 473 carriers of the C‐allele (95% confidence interval 0.22–1.08 mmol/l). The response of serum total cholesterol to dietary cholesterol tended to be larger in subjects with the G/G genotype as compared with carriers of the C‐allele. We suggest that the ABCG5 G/G genotype may increase serum cholesterol concentrations and, possibly responsiveness to dietary cholesterol in humans. Studies in other populations and experimental settings are required to confirm or reject this hypothesis.
Pharmacogenomics: the future of drug therapy
Authors: Tsai YJ , Hoyme HE
Published: March 2003

Pharmacogenomics aims to optimize patient management by customizing and synthesizing drugs based on genetic variations in drug response. Polymorphisms affecting metabolism, receptors, and absorption can influence drug sensitivity, toxicity, and dosing. The Human Genome Project, DNA chips, and bioinformatics advance the practice of this field by, respectively, identifying polymorphisms related to drug response, determining an individual's profile of polymorphisms, and integrating data to facilitate clinical decision making. Potential benefits of pharmacogenomics include increasing efficacy and preventing adverse drug reactions, thus improving patient care and decreasing costs. These factors imply that a thorough understanding of the principles and applications of pharmacogenomics will be an indispensable part of the future of drug therapy in clinical medicine.
Germline mutations in the PTEN gene in Israeli patients with Bannayan–Riley–Ruvalcaba syndrome and women with familial breast cancer
Authors: Figer A , Kaplan A , Frydman M , Lev D , Paswell J , Papa MZ , Goldman B , Friedman E
Published: March 2003

Germline mutations in BRCA1 or BRCA2 account for the majority of inherited breast cancer cases. Yet, in up to 40% of familial breast cancer cases, no mutations can be detected in either gene. Germline mutations in PTEN underlie two inherited syndromes: Cowden disease (CD) and Bannayan–Riley–Ruvalcaba syndrome (BRRS). The known association of CD with breast cancer risk made it plausible that germline mutations within PTEN may play a role in inherited predisposition to breast cancer. The nine coding exons of the PTEN gene were screened for harboring germline mutations using denaturing gradient gel electrophoresis (DGGE) complemented by sequencing, in two subsets of Israeli patients: 12 patients clinically diagnosed with BRRS, and 89 women with an apparent inherited predisposition to breast cancer, some with salient features of CD. Two of three familial BRRS patients exhibited novel germline mutations in PTEN: a missense mutation changing methionine to arginine at codon 134, and insertion of two nucleotides (CA) at cDNA position 1215 resulting in a frameshift at codon 61 and a premature stop at codon 99. Among 89 high‐risk women, two missense mutations were detected in exon 4: A to C change at cDNA position 1279 resulting in a change of aspargine to threonine at codon 82 (N82T), and a G to an A alteration in 1269 which alters threonine to alanine at codon 78 (T78A), a non‐conservative missense mutation. This study suggests that PTEN does not play a major role in predisposing to hereditary breast cancer in Israeli women, and that detection of PTEN mutations in BRRS patients is more likely in familial cases.
Frequency of the thermolabile variant C677T in the MTHFR gene and lack of association with neural tube defects in the State of Yucatan, Mexico
Authors: González‐Herrera L , García‐Escalante G , Castillo‐Zapata I , Canto‐Herrera J , Ceballos‐Quintal J , Pinto‐Escalante D , Díaz‐Rubio F , Del Angel RM , Orozco‐Orozco L
Published: March 2003

The C677T variant in the MTHFR gene is considered to be an associated risk factor for neural tube defects. However, the association has not been found in some ethnic groups. In order to assess the association between neural tube defects and the C677T variant, we determined the frequency of this variant in the MTHFR gene in the State of Yucatan, Mexico, where neural tube defects are highly prevalent. The study was performed on 65 subjects with spine bifida, 60 of their mothers and 110 control subjects. The presence of the C677T variant was determined by amplification and digestion with HinF1 of each subject's DNA. Genotypic and allelic frequencies were calculated for all groups. We did not observe any statistically significant difference in the genotypic or allelic frequencies between cases and controls for any of the groups studied (p > 0.05), suggesting that the thermolabile variant C677T is not an associated risk factor neither for the development of neural tube defects nor for mothers to have affected offspring in the population from Yucatan. Interestingly, the frequency of the C677T variant (54%) obtained in the Yucatan population is one of the highest reported (p < 0.01) and confirmed the high frequency of this allele throughout Mexico.
Pre‐transplant identification of risk factors that adversely affect length of stay and charges for renal transplantation
Authors: Johnson Christopher P , Kuhn Evelyn M , Hariharan Sundaram , Hartz Arthur J , Roza Allan M , Adams Mark B
Published: March 2003

Background. In the current era of renal transplantation, increasing attention is being focused on resource utilization. The purpose of this study was to identify demographic, medical and immunologic risk factors that are associated with changes in length of stay (LOS) and charges for renal transplantation.Method. The study was a retrospective analysis of 311 consecutive renal transplants performed at a single institution. Univariate and multivariate analyses were used to examine relationships between risk factors, LOS, charges and post‐operative complications.Results. The following pre‐transplant variables were found to be independently significant in predicting increased LOS and/or charges: African–American race, obesity for women, chronic obstructive pulmonary disease (COPD), presence of cardiac disease or previous stroke, pre‐transplant dialysis time ≥1 yr, a 10% increase in panel reactive antibody (PRA), cadaver donor and retransplantation. The analyses were performed with and without adjustment for key outcome variables such as delayed graft function (DGF) and use of induction antibody therapy. Increased LOS or charges for specific risk factors could be attributed to increased complication rates, including delayed graft function seen with various co‐morbidities, or increased immunologic risk and more frequent use of induction antibody therapy.Conclusion. Analysis of linked financial and clinical databases can reveal demographic, medical and immunologic risk factors that correlate with LOS, charges and complications for renal transplantation. Efforts to establish quantitative relationships for various risk factors relative to resource utilization will become important in managed care and/or capitated healthcare delivery systems.
Male recipients of kidneys from female donors are at increased risk of graft loss from both rejection and technical failure
Authors: Vereerstraeten P , Wissing M , De Pauw L , Abramowicz D , Kinnaert P
Published: March 2003

The aim of the present retrospective study was to uncover the factor(s) responsible for the poor outcome of cadaver kidney grafts from female donors in male recipients.The 741 transplantations performed at our center from August 1983 to September 1997 were distributed into four groups according to recipient and donor gender: female donor to female recipient (F to F: n=117), male donor to female recipient (M to F: n=172), female donor to male recipient (F to M: n=170), and male donor to male recipient (M to M: n=282). All the patients received immunosuppressive therapy based on corticosteroids and cyclosporine, associated or not with either azathioprine or prophylactic anti‐lymphocyte globulin.Overall graft survival was lower in the F to M group than in the three other groups (p=0.009). Failures due to rejection were more frequent during the 1st post‐transplant trimester in female than in male donor grafts, irrespective of recipient gender (p=0.025). All failures due to technical problems occurred during the first 3 months post‐transplantation: they were more frequent in the F to M group than in the three other groups (p=0.040); this could be related to the older age of the donors in the former group. After the first post‐transplant year, failures due to causes other than rejection remained low in the F to F group but increased steadily in the three other groups (p=0.007). Specific survival rates were not correlated with the time‐evolution of mean serum creatinine values, daily doses and trough levels of cyclosporine in the four groups of grafts. In conclusion, the poor outcome of F to M grafts results from combined immunologic and technical factors exerting their effects early in the course of transplantation.
The prognostic importance of severity and type of post‐transplant proteinuria
Authors: Yıldız A , Erkoç R , Sever Mş , Türkmen A , Ecder St , Türk S , Kılıçarslan I , Ark E
Published: March 2003

Proteinuria, developing after renal transplantation may influence allograft and patient outcomes. This study aimed to investigate the effect of proteinuria on patient and allograft survival. Among 514 patients, 56 (11%) patients with good allograft function and proteinuria were evaluated retrospectively. Patients with proteinuria were classified as group P (20 patients with permanent proteinuria, Male/Female: 16/4) and group T (36 patients with temporary proteinuria, M/F: 29/7) according to the type of proteinuria. Also, considering the amount of proteinuria, patients were classified as group M (32 patients with massive proteinuria, M/F: 29/3) and group NM (24 patients with non‐massive proteinuria, M/F: 16/8). The mean time interval between transplantation and appearance of proteinuria was 23.7 months (range 0–121 months) and no difference was found between groups. Two‐ and 5‐yr allograft survival rates were found to be 85 and 80% in group M, and 95 and 82% in group NM, respectively (p=0.24). In terms of type of proteinuria, 2‐ and 5‐yr allograft survival rates were found to be 70 and 58% in group P and 92 and 87% in group T, respectively. The difference between groups P and T was found to be statistically significant (p=0.02). Most (85%) of the patients with permanent proteinuria also had massive proteinuria. In conclusion, we found a significant relation between type and severity of proteinuria. The type of post‐transplant proteinuria had a stronger effect on allograft outcome than the severity of proteinuria.
Delayed graft function: risk factors and the relative effects of early function and acute rejection on long‐term survival in cadaveric renal transplantation
Authors: McLaren Aj , Jassem W , Gray Dwr , Fuggle Sv , Welsh Ki , Morris Pj
Published: March 2003

Delayed graft function (DGF) and acute rejection have both been associated with reduced renal allograft survival. In some studies, they have been shown to have an interactive effect. We studied the risk factors for DGF and the relative impact of DGF and rejection on both short‐ and long‐term survival in recipients of cadaveric renal transplants.Data from the Oxford Transplant Centre Database were assessed on 710 cadaver allografts over a 10‐yr period, during which time all recipients received cyclosporin‐based immunosuppressive protocols. The interaction between DGF and acute rejection was examined using logistic and Cox multivariate regression.Long cold ischaemia time (CIT), sensitisation and older donor age were found to be independent predictors of DGF. The occurrence of DGF resulted in a reduced 5‐yr survival (56 vs. 75%). However, the effect of DGF was confined to the first year post‐transplant, as there was no significant difference in survival, as measured by half‐life (t1/2) of grafts functioning at 1 yr, with DGF alone and a group with good early function (t1/2=21.3 vs. 20.0 yr). There was no increase in acute rejection in grafts with DGF. However, the combination of DGF and acute rejection resulted in the worst short‐term graft survival (68% at 1 yr, compared to 92.3% in those grafts with no DGF or acute rejection) and this continued over the long term (t1/2=10.5 yr).These data suggest that early function is critical to the success of renal transplantation. The effects of DGF are limited to the first year post‐transplant. Long‐term graft survival may be improved by efforts to limit CITs, particularly for grafts from older donors and sensitised recipients.
Allograft pancreatectomy after pancreas transplantation with systemic‐bladder versus portal‐enteric drainage
Authors: Stratta Robert J , Osama Gaber A , Hosein Shokouh‐Amiri M , Sudhakar Reddy K , Francesca Egidi M , Grewal Hani P
Published: March 2003

From 1989 to 1997, we performed 159 pancreas transplantations (PTXs), including 117 simultaneous kidney–PTX (SKPT), 25 PTXs alone (PTA), and 17 sequential PTXs after kidney transplantations (PAKT). A total of 73 PTXs were performed with systemic‐bladder (S‐B) and 86 with portal‐enteric (P‐E) drainage. The need for allograft pancreatectomy (PCTY) may be considered as an index of technical morbidity after PTX. A total of 37 PCTYs (23%) were performed at a mean of 4.7 months after PTX. Twenty‐seven PCTYs were performed within 1 month, 30 (81%) within 3 months, and the remaining seven more than 6 months after PTX. The incidence of PCTY did not differ according to type of transplantation: simultaneous kidney–PTX (SKPT) (23%), PTA (24%), and PAKT (23.5%). Indications for PCTY were thrombosis (23), rejection (9), infection (3), and pancreatitis (2). During the study, a total of 70 pancreas grafts were lost, with PCTY performed in 37 (53%). PCTY was directly related to the timing of graft loss; 77% of grafts lost within 3 months of PTX required PCTY, while 25% of grafts lost after 3 months resulted in PCTY (p<0.01). The incidence of graft failure resulting in PCTY was similar according to type of transplantation: SKPT (55%), PTA (46%), and PAKT (50%). The incidence of PCTY was also similar according to technique of transplantation: 26% S‐B versus 21% P‐E, p=NS. However, the incidence of graft failure resulting in PCTY was higher in P‐E (69%) versus S‐B (43%) (p<0.05) PTX recipients. Patient and kidney graft survival and pancreas retransplant graft survival rates were higher in PTX recipients with P‐E drainage.Conclusions: PCTY is performed in over half of cases of pancreas allograft loss and is directly related to the timing and cause of graft loss. The incidence of PCTY is neither related to the type nor technique of PTX. The lower overall incidence of graft loss after PTX with P‐E drainage is offset by a higher incidence of PCTY in these grafts that fail. These results suggest that whole‐organ PTX with P‐E drainage does not place the patient at an increased risk for PCTY and does not preclude successful pancreas retransplantation.
Cost–utility analysis of living‐donor kidney transplantation followed by pancreas transplantation versus simultaneous pancreas–kidney transplantation
Authors: Douzdjian Viken , Escobar Francisco , Kupin Warren L , Venkat KK , Abouljoud Marwan S
Published: March 2003

For a type I diabetic with end‐stage renal disease, the choice between a kidney‐alone transplant from a living‐donor (KA–LD) and a simultaneous pancreas–kidney (SPK) transplant remains a difficult one. The prevailing practice seems to favor KA–LD over SPK, presumably due to the superior long‐term renal graft survival in KA–LD and the elimination of the lengthy waiting time on the cadaver transplant list. In this study, two treatment options, KA–LD followed by pancreas‐after‐kidney (PAK) and SPK transplant, are compared using a cost–utility decision analysis model. The decision tree consisted of a choice between KA–LD+PAK and SPK. The analysis was based on a 5‐yr model and the measures of outcome used in the model were cost, utility and cost–utility. The expected 5‐yr cost was $277 638 for KA–LD+PAK and $288 466 for SPK. When adjusted for utilities, KA–LD+PAK at a cost of $153 911 was less cost‐effective than SPK at a cost of $110 828 per quality‐adjusted year. One‐way sensitivity analyses were performed by varying patient and graft survival probabilities, utilities and cost. SPK remained the optimal strategy over KA–LD+PAK across all variations. Two‐way sensitivity analysis showed that in order for KA–LD+PAK to be at least as cost‐effective as SPK, 5‐yr pancreas and patient survival rates following PAK would need to surpass 86 and 80%. In conclusion, according to the 5‐yr cost–utility model presented in this study, KA–LD followed by PAK is less cost‐effective than SPK as a treatment strategy for a type I diabetic with end‐stage renal disease. For patients interested in the benefits of a pancreas transplant, it would be reasonable to offer SPK as the optimal treatment, even if a living kidney donor is available.
Should I accept this kidney?
Authors: Matas Arthur J , Gillingham Kristen , Payne William D , Humar Abhinav , Dunn David L , Sutherland David Er , Najarian John S
Published: March 2003

Background. Transplant candidates frequently ask whether they should, based on information available at the time, accept a cadaver kidney or wait for a potentially better one.Methods. We analyzed 937 first and second cadaver transplants done between January 1, 1984 and December 31, 1997 to determine if information available at the time an offer is made could be used to predict long‐term graft survival.Results. By Cox regression, risk factors for worse long‐term graft survival were older donor age, cardiovascular or cerebrovascular cause of donor death, and delayed graft function (DGF). HLA‐ABDR mismatch was marginally significant. Whether DGF will occur is not known at the time of an offer, but risk factors can be determined; we found these to be older donor age and> 10% panel‐reactive antibodies (PRA) at transplantation (by Cox regression). Using these variables (PRA, ABDR mismatch, donor age, and donor cause of death) known at the time of an offer, we calculated the relative risk of worse long‐term graft survival for each subgroup (Table 3in manuscript). In general, older age and donor death from cardiovascular or cerebrovascular disease were associated with worse outcome. Kidneys from donors of <50 yr had the best outcome, irrespective of match.Conclusion. The data provided can be used to help guide patients as to whether they are better off accepting an offered kidney or waiting for a potentially better one. If an offer is declined, the next kidney may have a potentially worse outcome.

Relative risk for worse or poor long‐term graft survival, based on information known at the time of a kidney offer

Donor 18–50 yr, other cause of deathDonor 18–50 yr, CVD cause of deathDonor ≥50 yr, other cause of deathDonor ≥50 yr, CVD cause of deathTx PRA (%)ABDR mm (n)RRRankRRRankRRRankRRRank00111.16 31.28 62.262501–61.1941.38101.52142.69271–1001.2151.41111.55172.74281–101–61.44131.67191.84233.253111–7501.1221.30 71.43122.532611–751–61.3391.54161.70213.013076–10001.3281.54151.69203.002976–1001–61.57181.82222.01243.5532

CVD, cerebrovascular or cardiovascular disease; Tx, transplant; PRA, panel‐reactive antibody; mm, mismatch; RR, relative risk.
Mycophenolate mofetil for the prophylaxis of acute GVHD in HLA‐mismatched bone marrow transplant patients
Authors: Basara N , Blau WI , Kiehl MG , Schmetzer B , Bischoff M , Kirsten D , Günzelmann S , Fauser AA
Published: March 2003

Mycophenolate mofetil (MMF), a new immunosuppressive drug successfully used in renal and heart transplant recipients, was used in combination with cyclosporin A (CsA), methotrexate (MTX) and prednisolone for the prophylaxis of acute graft‐versus‐host disease (aGVHD) after bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen (HLA)‐mismatched, unrelated (n=9) and related donors (n=4) in an open single‐centre phase II study. Thirteen patients, transplanted from HLA‐mismatched donors of 18–57 yr of age, received 1 g MMF daily, starting at day 10, in addition to CsA and prednisolone for aGVHD prophylaxis. All patients were engrafted between days 13 and 15. Four of the 13 patients experienced aGVHD grade I/II (n=2) and grade III (n=2). All patients except 3 were alive on day 100 post‐transplantation. No severe adverse effects of MMF were recorded. In our pilot study, we demonstrated that MMF can be used safely for the prophylaxis of aGVHD.
Levels of HBV‐DNA and HBsAg after acute liver allograft rejection treatment by corticoids and OKT3
Authors: Gonzalez Rafael A , De La Mata Manuel , De La Torre Julian , Miño Gonzalo , Pera Carlos , Peña José , Muñoz Eduardo
Published: March 2003

The aim of this work was to analyze whether the treatment of acute rejection of orthotopic liver transplants (OLT), either with corticoids or OKT3, has any effect on the levels of hepatitis B virus (HBV)‐DNA and HBsAg in individuals which were originally affected by cirrhosis or fulminant hepatic failure as a result of B virus.  We have found that HBV‐DNA is present in macrophages, B cells and both CD4+and CD8+T cells after OLT in all cases studied. Interestingly, the levels of HBV‐DNA and HBsAg in the serum analyzed were increased extremely rapidly in the patients treated with OKT3 in an acute rejection episode. However, the serum levels of HBV‐DNA and HBsAg found were lower when the patients were treated with steroids, and were not found in non‐treated patients. As the serum levels of HBV‐DNA increase, the process of liver reinfection could be accelerated; therefore, these results may help to understand how OKT3 and corticoids immunosuppressive therapy may accelerate the reinfection of OLT by HBV.  In conclusion, our results suggest that special care must be taken in the use of OKT3 in the treatment of acute liver rejection episodes in chronic or fulminant HBV transplanted patients.