bluuebunny/crossref_metadata_2025 huggingface dataset:
Vertebral anomalies in a new family with ODED syndrome
Authors: Piersall Linda D , Dowton S Bruce , McAlister William H , Waggoner Darrel J
Published: March 2003

We report a new family with oculodigitoesophagoduodenal syndrome (ODED syndrome), which associates microcephaly, abnormalities of the hands and feet, shortened palpebral fissures, tracheoesophageal fistula and duodenal atresia. In addition, previously unreported vertebral anomalies are described. This report further delineates the clinical and radiographic spectrum of this syndrome, providing useful information for diagnosis and family counseling.
A preliminary validation of a family history assessment form to select women at risk for breast or ovarian cancer for referral to a genetics center
Authors: Gilpin CA , Carson N , Hunter AGW
Published: March 2003

The medical community and general population have become aware that genetic testing is available to look for BRCA1 and BRCA2 mutations. However, criteria for who should be referred for genetic counseling and possible subsequent testing have yet to be determined, and many genetics centers have been overwhelmed by the demand for service. We set out to develop a family history assessment tool (FHAT) that could be used by physicians to select individuals for genetic counseling. Arbitrarily, we chose individuals who would have an approximate doubling of their lifetime risk for breast or ovarian cancer. The FHAT was then applied to 184 unrelated families, with an index patient who had breast or ovarian cancer and who had accepted the offer of BRCA1/BRCA2 testing. Data were compiled to compare the number of individuals who would have been referred for genetic counseling and the number of mutation‐positive individuals who would have been screened out from counseling using FHAT, the tables from Claus, and the BRCAPRO system. In this population, FHAT was effective in minimizing both the number of referrals and the likelihood of missing women who were later found to be mutation‐positive.
Factors influencing sib risks for Multiple Sclerosis
Authors: Sadovnick AD , Yee IML , Ebers GC ,   The Canadian Collaborative Study Group
Published: March 2003

Multiple sclerosis (MS) is now thought to be a complex trait determined by genetic and non‐genetic (environmental) factors.  The study group, identified from the Canadian Collaborative Project on Genetic Susceptibility to MS, consisted of 1 083 MS index cases, 2 166 of their parents and 3 112 of their sibs. The results, together with those of a previous study on an independent data set, suggest that gender, age of MS onset and having one parent with MS may individually and interactively alter sib risks for MS.  These data are important for genetic counselling and for molecular genetic (genome screens, candidate gene analyses) studies.
Late‐onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon
Authors: Ploechl E , Ploechl W , Stoeckler‐Ipsiroglu S , Pokorny H , Wermuth B
Published: March 2003

We report on late‐onset ornithine transcarbamylase (OTC) deficiency in two families with mutations in the same codon, but different base substitutions. Onset of symptoms showed great variation, and five hemizygotes finally died. Clinical diagnosis was late and difficult.  In family A, 1 patient also developed the signs of Gilbert's disease. In family B, the index case came to attention as OTC deficiency, after the transplantation of his liver when the recipient died of cerebral edema and hyperammonemia. In family A, the hemizygote males died at the ages of 12 and 18 years; in family B, they died at the ages of 20, 26, and 30 years, respectively. Diagnosis was confirmed by reduced OTC activity in liver specimens. The residual activity in autopsy liver of the index patient in family A was less than the activity in the biopsy of the transplanted liver of the index patient in family B. The molecular investigations showed mutations in exon 2 at codon 40 in the OTC gene in both families. However, different bases were substituted. In family A, the single‐base mutation was a cytosine‐to‐thymine transition (Arg 40 Cys); in family B, it was a guanine‐to‐adenine transition (Arg 40 His).  Published data on in vitro expression studies of the recurrent OTC mutation Arg 40 His have shown little effect on the protein structure of the enzyme. These studies would fit well with our observation of higher OTC activity and later age of onset of symptoms in family B.
Phenotype variability of two FAP families with an identical APC germline mutation at codon 1465: a potential modifier effect?
Authors: Martin‐Denavit T , Duthel S , Giraud S , Olschwang S , Saurin JC , Plauchu H
Published: March 2003

We report the cases of two familial adenomatous polyposis (FAP) families who presented with the same 2 base pair deletion (AG) at codon 1465 of the adenomatous polyposis coli (APC) gene, but showed phenotypic variability. The mutation was revealed by a simple nonradioactive method using a heteroduplex analysis and identified by a sequence analysis. This observation suggests the responsibility of modifier genes in FAP patients’ phenotype.
Lipoprotein(a) as a risk factor for maternal cardiovascular disease mortality in kindreds with familial combined hyperlipidemia or familial hypertriglyceridemia
Authors: Kim H , Marcovina SM , Edwards KL , McKnight B , Bradley CM , McNeely MJ , Psaty BM , Motulsky AG , Austin MA
Published: March 2003

Most but not all epidemiologic studies have shown that lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD). Lp(a) levels are also strongly genetically influenced. The purpose of this study was to evaluate the association between Lp(a) levels in adult offspring and parental CVD mortality in 61 kindreds with familial forms of hyperlipidemia. The study sample consisted of offspring–parent pairs in which offspring had fasting Lp(a) measurements and parents had 20‐year vital status data and standardized cause‐of‐death classification if deceased. Linear regression analyses, using a robust variance estimator, were performed separately for 241 offspring with known maternal history (114 mothers) and 194 offspring with known paternal history (93 fathers). Maternal history of CVD mortality was significantly (p=0.004) associated with 2.4‐fold higher median Lp(a) levels in offspring compared with those with no maternal history, independent of diabetes, lipid‐lowering medications and hormone use. No association was observed between paternal CVD mortality and offspring Lp(a) levels (p=0.505). Adjusting for apolipoprotein(a) kringle 4 number did not alter these parent‐specific associations. In conclusion, Lp(a) levels in offspring may be associated with maternal but not paternal history of CVD mortality. This parent‐specific finding needs to be confirmed in other samples of high‐risk families.
Evaluation for sleep apnea in patients with Ehlers–Danlos syndrome and Marfan: a questionnaire study
Authors: Verbraecken J , Declerck A , Van de Heyning P , De Backer W , Wouters EFM
Published: March 2003

Sleep complaints are frequently reported by patients with Marfan and Ehlers–Danlos syndrome (EDS). We examined the exact nature of sleep complaints in these patients.  A representative sample of Marfan and EDS patients responded to a general sleep questionnaire, including the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study Short‐Form 36 (SF‐36) health‐related quality of life (QOL) questionnaire. Fifteen Marfan patients and 9 EDS patients were evaluated and compared to 24 healthy controls, matched for age, sex and body mass index. Maintaining sleep was frequently disturbed in Marfan (40%, p<0.04) as well as in EDS patients (56%, p<0.01).  Sleep apnea was exclusively reported by Marfan patients (27%, p=0.03). Periodic limb movements were much more reported in EDS (67%, p=0.02) than in Marfan (27%, p=0.25) compared to controls (8%). Pain and back complaints were highly presented in both groups, but most pronounced in EDS patients (47% in Marfan versus 77% in EDS). No differences for the scores in the ESS were found. For all SF‐36 questionnaire items, scores were much lower in patient groups, except for emotional problems. We found that sleep complaints were not rare in Marfan and EDS patients and correlated well with different QOL items. Our study calls for greater attention to the presence of apnea, pain and periodic limb movements in these patients.
Frequency of the 35delG mutation in the connexin 26 gene in Turkish hearing‐impaired patients
Authors: Barış İ , Kılınç MO , Tolun A
Published: March 2003

The 35delG mutation in the connexin 26 gene (GJB2) at the DFNB1 locus is the most common mutation in patients with autosomal‐recessive sensorineural deafness. Genetic diagnosis is crucial for genetic counseling. We have developed an easy and simple method and screened a total of 235 unrelated hearing‐impaired children. We found 48 of the subjects to be homozygous for the mutation, including 27 of 83 familial cases, 15 of 101 singletons, 4 of 9 subjects born to assortative marriages (deaf married to deaf), and 2 of 42 subjects for whom the parents claimed an environmental factor as the etiology of the condition. The high ratio of individuals homozygous for the mutation indicated that the 35delG mutation in the connexin gene accounts for more than 90% of the mutations at this locus.
Fertility and pregnancy outcome in Danish women with Turner syndrome
Authors: Birkebaek NH , Crüger D , Hansen J , Nielsen J , Bruun‐Petersen G
Published: March 2003

The aim of the investigation was to study fertility in Danish women diagnosed with Turner syndrome (TS), and to describe their offspring. In total, 410 women in the fertile age were registered in the Danish Cytogenetic Central Register with TS between January 1973 and December 1993. Their karyotype were as follows: 49% with 45,X, 23% with mosaicism and a structural abnormality of the second X, 19% with 45,X/46,XX mosaicism, and 9% with 46,XX and a structural abnormality of the second X. Thirty‐three women, one with 45,X, 27 with mosaicism and 5 with 46,XX and a structural abnormality of the second X, gave birth to 64 children. Two women had become pregnant afterin vitrofertilization, including a woman with 45,X after an egg donation. Thus, 31 women(7.6%) had achieved at least one spontaneous pregnancy, but 48% of the fertile women registered with 45,X/46,XX had 45,X in less than 10% of the analysed cells.Twenty‐five of the 64 children had a chromosome analyzed. Six of the 25 examined children, including three siblings, had chromosomal aberrations. No case of Down's syndrome was present, and only two children had malformations. Fertility in women registered with TS is higher than earlier reported. However, only women with 45,X/46,XX mosaicism or 46,XX and structural abnormality of the second X, gave birth to live children after spontaneous pregnancies.
Distribution of HFE C282Y and H63D mutations in the Balearic Islands (NE Spain)
Authors: Guix P , Picornell A , Parera M , Galmes A , Obrador A , Ramon MM , Castro JA
Published: March 2003

The HFE gene contains two main missense mutations: C282Y and H63D. Individuals with these mutations carry a risk of developing hereditary haemochromatosis (HH). The common form of this disease is due to homozygosity for the C282Y mutation. Population studies have shown the variation of the prevalence of these mutations in different countries and ethnic groups. The purposes of this current study were to determine the prevalence of the C282Y and H63D mutations in the Balearic Islands and the genotypic characterization of patients diagnosed with HH, as well as those with iron overload and liver diseases. A total of 1330 Balearic chromosomes were analyzed. The results showed that the populations of the Balearic Islands were not homogeneous. No C282Y carriers were observed in a group of descendants of Majorcan Jews (Chuetas) and the frequency was very low in Minorca (1.2%) in comparison with the other islands of Majorca (4.7%) and Ibiza (6.5%). The carrier frequency of the H63D mutation was similar in the three islands and very high (43.1%) in the descendants of Majorcan Jews. The study of patients was carried out in 129 individuals. The homozygous C282Y genotype was the principal one involved in hereditary haemochromatosis (90%), whereas the other HH patients were C282Y/H63D compound heterozygous and H63D homozygous.
Gene/environment causes of cleft lip and/or palate
Authors: Murray JC
Published: March 2003

Craniofacial anomalies, and in particular cleft lip and palate, are major human birth defects with a worldwide frequency of 1 in 700 and substantial clinical impact. A wide range of studies in developmental biology has contributed to a better knowledge of how both genes and environmental exposures impact head organogenesis. Specific causes have now been identified for some forms of cleft lip and palate, and we are at the beginning of a time in which the common nonsyndromic forms may also have specific etiologies identified. Mouse models have an especially important role in disclosing cleft etiologies and providing models for environmental cotriggers or interventions. An overview of the gene–environment contributions to nonsyndromic forms of clefting and their implications for developmental biology and clinical counseling is presented.
Inherited disorders of cholesterol biosynthesis
Authors: Waterham HR
Published: March 2003

For many decades, cholesterol has been considered an important structural component of cellular membranes and myelin, and a precursor of steroid hormones and bile acids. Moreover, the recognition that high cholesterol levels (hypercholesterolemia) are a major risk factor for the development of heart disease and atherosclerosis has gained enormous attention not only in medicine, medical and pharmacological research, but also from the general public. The discovery of a crucial role of cholesterol in human embryogenesis and the recent identification of a number of inherited disorders of cholesterol biosynthesis also show that low cholesterol levels (hypocholesterolemia) may have severe consequences for human health and development. In the past few years, seven distinct inherited disorders have been linked to different enzyme defects in the cholesterol biosynthetic pathway by the finding of abnormally increased levels of intermediate metabolites in patients followed by the demonstration of disease‐causing mutations in genes encoding the implicated enzymes. Patients afflicted with these disorders are characterized by multiple morphogenic and congenital anomalies including internal organ, skeletal and/or skin abnormalities.
Endothelial nitric oxide synthase gene polymorphisms in Fabry's disease
Authors: Heltianu C , Costache G , Azibi K , Poenaru L , Simionescu M
Published: March 2003

The gene encoding endothelial nitric oxide synthase (eNOS) is involved in abnormalities in nitric oxide (NO) synthesis that mediates functional damage of vascular cells, especially of endothelial cells (ECs), a common characteristic in cardiovascular diseases. In Fabry's disease, the characteristic mutation in the alpha‐galactosidase A (alpha‐gal A) gene induces large deposits of glycosphingolipids, particularly concentrated in ECs, a process associated with endothelial dysfunction. To determine whether in addition to alpha‐gal A gene mutations, eNOS genetic variations are implicated in this process, we examined the genotypes of the missense Glu298Asp (G894T) variant in exon 7 and 27‐bp tandem repeats in intron 4 (4b/a) in 19 patients with Fabry's disease, and 39 normal volunteers. The results showed that both varials have a significant association with Fabry's disease. The frequencies of mutant Glu/Asp + Asp/Asp genotypes and Asp allele are significantly higher in Fabry's disease (68.4%, p = 0.044, and 47.4%, p = 0.022, respectively) than in controls (46.7% and 25%, respectively). The frequencies of eNOS 4b/a polymorphisms are also significantly different in Fabry's disease when compared to controls. The mutant 4b/a + 4a/a genotype frequencies are 55.5% (p = 0.032) and 4a allele 27.8% (p = 0.05) compared with controls (23.1% and 12.8%, respectively). These results indicate that more than half of the patients with Fabry's disease carry the Glu298Asp variant (∼ 68%) and/or the 4b/a polymorphism (∼ 55%). To the best of our knowledge, this is the first report showing an influence of eNOS gene polymorphisms in patients with Fabry's disease.
Mutation in the cartilage‐derived morphogenetic protein‐1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome)
Authors: Faiyaz‐Ul‐Haque M , Ahmad W , Zaidi SHE , Haque S , Teebi AS , Ahmad M , Cohn DH , Tsui L‐C
Published: March 2003

The present authors have previously described a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait. All affected individuals showed either reductions or absence of bones in the limbs, and appendicular bone dysmorphogenesis with unaffected axial bones. Obligate heterozygote parents were phenotypically normal. Mutations in the cartilage‐derived morphogenetic protein 1 (CDMP1) gene have been reported in two acromesomelic chondrodysplasias (i.e. Hunter–Thompson type and Grebe type) which are phenotypically related to DuPan syndrome. CDMP1, a member of the transforming growth factor β super‐family of secreted signalling molecules, has been reported to regulate limb patterning and distal bone growth. Therefore, the present authors examined genomic DNA from the family with DuPan syndrome for mutations in the CDMP1 gene. Affected individuals were homozygous for a missense mutation, T1322C, in the coding region of the CDMP1 gene. This mutation was not found in 44 control subjects of Pakistani origin. The T1322C change predicts a leu441pro substitution in the mature domain of the CDMP1 protein. This is likely to cause a conformational change in the CDMP1 protein that influences the expression of genes which are required for normal bone development. This finding extends the spectrum of phenotypes produced by defects in the CDMP1 gene.
Novel skeletal muscle ryanodine receptor mutation in a large Brazilian family with malignant hyperthermia
Authors: McWilliams S , Nelson T , Sudo RT , Zapata‐Sudo G , Batti M , Sambuughin N
Published: March 2003

Malignant hyperthermia (MH) is an autosomal dominant disorder that predisposes susceptible individuals to a potentially life‐threatening crisis when exposed to commonly used anesthetics. Mutations in the skeletal muscle calcium release channel, ryanodine receptor (RYR1) are associated with MH in over 50% of affected families. Linkage analysis of the RYR1 gene region at 19q13 was performed in a large Brazilian family and a distinct disease co‐segregating haplotype was revealed in the majority of members with diagnosis of MH. Subsequent sequencing of RYR1 mutational hot spots revealed a nucleotide substitution of C to T at position 7062, causing a novel amino acid change from Arg2355 to Cys associated with MH in the family. Haplotype analysis of the RYR1 gene area at 19q13 in the family with multiple MH members is an important tool in identification of genetic cause underlying this disease.
The TaqIB and −629C>A polymorphisms at the cholesteryl ester transfer protein locus: associations with lipid levels in a multiethnic population. The 1998 Singapore National Health Survey
Authors: Tai ES , Ordovas JM , Corella D , Deurenberg‐Yap M , Chan E , Adiconis X , Chew SK , Loh LM , Tan CE
Published: March 2003

The Singapore population comprises Chinese, Malays and Asian Indians. Within this population, Asian Indians have the highest rates of coronary heart disease, whereas Chinese have the lowest. Conversely, Indians have the lowest high‐density lipoprotein cholesterol (HDL‐C) concentrations, followed by Malays and Chinese. We studied the TaqIB and −629C>A polymorphisms at the CETP locus in 1300 Chinese, 364 Malay and 282 Asian Indian men, and in 1558 Chinese, 397 Malay and 306 Asian Indian women, to determine whether these polymorphisms are responsible for the ethnic difference in HDL‐C concentration. The frequency of the B2 allele in Chinese, Malays and Indians was 0.384, 0.339 and 0.449 in men, and 0.379, 0.329 and 0.415 in women, respectively (p < 0.001). For the A‐629 allele, the relative frequencies were 0.477, 0.423 and 0.592 in men and 0.486, 0.416 and 0.575 in women (p < 0.001). The two polymorphisms were in linkage disequilibrium (D / Dmax= 0.9772, p < 0.00001). The B2 and the A‐629 alleles were associated with increased HDL‐C concentrations in a dose‐dependent manner. The B2 allele continued to show an association with HDL‐C concentration, even after controlling for the genotype at position −629. Dietary cholesterol showed a significant interaction with the TaqIB polymorphism in determining HDL‐C concentrations in Indians and Malays, but not in Chinese. In conclusion, the high frequencies of these polymorphisms in Asian Indians could not explain the observed ethnic differences in HDL‐C concentration. Moreover, we observed an ethnic‐specific interaction among dietary cholesterol, the TaqIB polymorphism and HDL‐C concentrations.
Daclizumab induction/tacrolimus sparing: a randomized prospective trial in renal transplantation
Authors: Light Jimmy A , Sasaki Truman M , Ghasemian Reza , Barhyte Diana Y , Fowlkes Deneen L
Published: March 2003

Abstract: Tacrolimus inhibits lymphocyte responses by blocking calcium‐dependent signalling pathways important in IL‐2 generation. Daclizumab, a humanized monoclonal antibody, binds with high affinity to the Tac subunit of the IL‐2 receptor complex. We reasoned therefore that the absence of IL‐2R should permit lower doses of tacrolimus and thereby less toxicity. Twenty‐eight patients were randomized and followed for 6 months: Group 1, high dose (HD) tacrolimus (trough 12–17 ng/mL; n = 13); Group 2, low dose (LD) tacrolimus (trough 5–10 ng/mL; n = 15). All patients received daclizumab induction (2 mg/kg) on days 0 and 14, mycophenolate mofetil (2 g/d except for one patient who received 1 g) and rapid prednisone taper. Serious infections were minimal in both groups. Hospitalizations, for various reasons, were HD (n = 12) and LD (n = 6). All patients and grafts survived for the 6‐month study period. There was one rejection episode in a non‐compliant patient at 101 d. LD tacrolimus appears equally effective as HD tacrolimus in preventing rejection episodes and may be associated with fewer adverse events.
Impact of solid organ transplantation and immunosuppression on fever, leukocytosis, and physiologic response during bacterial and fungal infections
Authors: Sawyer Robert G , Crabtree Traves D , Gleason Thomas G , Antevil Jared L , Pruett Timothy L
Published: March 2003

Immunosuppressed solid organ transplant patients may exhibit a blunted response to infection compared to non‐transplant patients. To test this hypothesis, we prospectively identified all episodes of bacterial and fungal infection on the in‐patient abdominal organ transplant service in our hospital, in 1997, and compared them to infected general surgery and trauma admissions treated simultaneously on the same wards. Eighty‐two infections occurred in transplant patients versus 463 in non‐transplant patients. Transplant patients demonstrated an overall greater physiologic response [Acute Physiology and Chronic Health Evaluation (APACHE II) and Acute Physiology Scores (APS) at the time of infection of 17.0±0.7 and 10.3±0.6, respectively, vs. 12.2±0.4 and 8.0±0.3 for non‐transplant patients, p≦0.003], with a similar maximum temperature (38.0±0.1 vs. 38.2±0.1°C, p=0.2) and white blood cell (WBC) count (12.1±1.0 vs. 13.9±0.4 k/mL, p=0.08). Upon further analysis of subgroups, patients receiving mycophenolate or azathioprine had significantly lower maximum temperatures (37.9±0.2°C) and WBC counts (11.0±0.9 k/mL) when compared to non‐transplant patients, while steroids appeared to have little effect on the systemic inflammatory response. Overall mortality was similar between groups. In general, solid organ transplant recipients exhibit a physiologic response to bacterial or fungal infection (as measured by the APS) at least as great as that seen in non‐transplant surgical patients, although mycophenolate and azathioprine appear to slightly depress the ability to respond with fever and leukocytosis. None of these differences appeared to affect overall mortality.
Long‐term results of famciclovir for recurrent orde novohepatitis B virus infection after liver transplantation
Authors: Rayes N , Seehofer D , Bechstein Wo , Müller Ar , Berg T , Neuhaus R , Neuhaus P
Published: March 2003

Since the introduction of famciclovir in the treatment of hepatitis B virus (HBV) infection after liver transplantation, promising results have been published. In this study, the long‐term efficacy and safety of famciclovir were assessed. Twenty‐four patients with recurrent hepatitis B and 6 patients withde novoinfection after liver transplantation were enrolled in an open prospective trial. Patients received oral famciclovir, 500 mg three times daily. Serum HBV‐DNA, viral serology, and liver enzymes were measured sequentially; liver histology was taken before and during treatment in 12 patients. In the reinfected patients, 17 patients initially responded well to treatment, with a mean decrease of HBV‐DNA of 82%, 5 patients became HBV‐DNA negative. The drug was effective for 1–51 months (mean 16 months), then viral replication increased again in 13 out of 17 patients. One patient did not respond to treatment. Six out of 24 patients already had severe cirrhosis at the time of enrolment and died shortly afterwards, due to the HBV infection. The 6 patients withde novoinfection all had a decline of HBV‐DNA for 2–42 months (mean 14 months); 1 patient converted to HBV‐DNA negative. Five out of 6 patients experienced a viral breakthrough later on. No severe side‐effects were observed. Therefore, famciclovir is effective in certain HBV‐infected patients after orthotopic liver transplantation (OLT), but in the long term, most of the patients relapse.
An active liver transplant programme for hepatocellular carcinoma in cirrhotic patients: is it justified?
Authors: Chui Akk , Rao Arn , McCaughan Gw , Waugh R , Verran Dj , Koorey D , Painter D , Sheil Agr
Published: March 2003

Even at an early stage, hepatocellular carcinoma (HCC) in patients with cirrhosis is often deemed unresectable because of limited liver reserve. In these circumstances, liver transplantation (LTx) offers some hope for palliation or cure. The results of LTx for selected cirrhotic patients with HCC were analysed. The outcomes were compared with those of patients who underwent LTx for other forms of hepatic malignancy and those who underwent LTx for non‐malignant conditions. Four hundred and eighty LTx were performed in 441 patients between January 1986 and December 1998. Twenty‐eight LTx recipients (25 males, 3 females) of mean age 51 (14–63) yr had cirrhosis and HCC. Twenty‐seven patients had underlying predisposing conditions (11 had hepatitis B, 10 had hepatitis C, 2 had hepatitis B and C, 1 had haemochromatosis, 1 had autoimmune hepatitis, 1 had alcoholic cirrhosis and 1 had α‐1 antitrypsin deficiency). In 22 patients, HCC was diagnosed pre‐LTx, and in 6 patients, the cancers were discovered incidentally. The average tumour size and number were 2.8 (0.4–11.5) cm and 1.3 (1–4), respectively. Two patients with known HCC died during and shortly after the LTx operation. Of the other patients, 3 died; 1 died of HCC recurrence 18 months post‐LTx, 1 died of graft failure from recurrent hepatitis C and 1 died of fungal sepsis. Twenty‐three (82%) patients survived to 22.5 (0.5–96) months post‐LTx without HCC recurrence and with 1‐ and 3‐yr actuarial patient survival rates of 87 and 76%, respectively. Equivalent survival rates of patients who underwent LTx for other malignancies (n=11) were 82 and 46% (p=NS), and for those who underwent LTx for benign causes (n=402), they were 77 and 73% (p=NS). All 15 patients with known HCC, who met the selection criteria now in use, survived. LTx can result in prolonged, cancer‐free survival in a good proportion of patients with cirrhosis and HCC, particularly when the cancers are incidental, or when diagnosed pre‐LTx, conforming to established selection criteria. An active LTx programme for this group of patients is justified.
Correlation between von Willebrand factor levels and early graft function in clinical liver transplantation
Authors: Basile John , Busuttil Ashley , Sheiner Patricia A , Emre Sukru , Guy Stephen , Schwartz Myron E , Boros Peter , Miller Charles M
Published: March 2003

Cold preservation/reperfusion leads to sinusoidal endothelial cell (SEC) activation and damage in nearly every liver transplantation; the extent of these changes influences early graft function. Upon reperfusion, activated SEC show increased expression of adhesion molecules, including von Willebrand factor (vWF) which is released into the circulation. This study was designed to evaluate the levels of vWF measured in the caval effluent and correlate these findings with known markers of SEC damage and early graft function. Data were obtained from 35 patients undergoing orthotopic liver transplantation (LTx). Two samples were taken from each patient for measurement of vWF: a) from the portal vein immediately prior to reperfusion; and b) from the first 50 ml of the caval effluent. Commercial assays were used to measure vWF, as well as hyaluronic acid (HA), thrombomodulin (TM), IL‐1β, IL‐6, IL‐8 and TNF‐α. Patients were divided into two groups based on early graft function. Poor early graft function (PEGF) was defined as a peak aspartate transaminase (AST) or alanine transaminase (ALT) level> 2500 U/L during the first three postoperative days (POD) and a prothrombin time (PT)> 16 s on POD 2 (n=8). The remaining 27 patients had good early graft function (GEGF). In patients with GEGF, vWF levels dropped significantly between the two time points. This change was not observed in those with PEGF. A positive linear correlation was observed in the PEGF group between vWF and HA and IL‐6. The different pattern of change in vWF between the two groups, as well as the positive correlation between HA, IL‐6 and vWF in PEGF, suggest that vWF may be a useful marker of early graft function.
Screening for basiliximab exposure–response relationships in renal allotransplantation
Authors: Kovarik JM , Moore R , Wolf P , Abendroth D , Landsberg D , Soulillou J‐P , Gerbeau C , Schmidt A‐G
Published: March 2003

The immunosuppressant basiliximab – a chimeric monoclonal antibody specific to the interleukin‐2 receptor on activated T‐lymphocytes – significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure–response relationships was performed within a randomized, blinded, placebo‐controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre‐transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient’s pharmacokinetic parameters. Biopsy‐confirmed acute rejection episodes were recorded to month 6 post‐transplant. Forty basiliximab‐treated patients were evaluated, 30 men and 10 women, aged 48±12 yr (range, 24–73) and weighing 72.4±12.9 kg (range, 52.5–107.5). The basiliximab distribution volume was 7.5±1.7 L, the half‐life 7.5±2.5 d and the clearance 33±12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor‐saturating serum basiliximab concentrations (>0.2 μg/mL) were maintained for 41±23 d. Twenty‐five patients remained rejection‐free over the 6‐month observation period, while a total of 26 biopsy‐confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed (range, 0.1–9.0 μg/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection‐free: 32±11 versus 45±26 d, respectively (p=0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure–response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure–effect relationships in a larger population is warranted.
Iliac artery stenosis masquerading as diuretic resistant congestive heart failure
Authors: Koushik Rahul S. , Matas Arthur J. , Rosenberg Mark E.
Published: March 2003

Iliac artery stenosis is a rare cause of renal dysfunction in renal allograft recipients. Its presence can mimic renovascular hypertension and yet alter the very radiologic tests used to diagnose renal artery stenosis. We investigate a case of iliac artery stenosis that presented with diuretic resistant fluid overload, hypertension and limb claudication that exposed the pitfalls in the diagnosis and management of this condition. Successful stent placement, 8 months after transplant, resulted in return of the serum creatinine below the post‐transplant nadir.
Monitoring of anti‐HLA class I and II antibodies by flow cytometry in patients after first cadaveric kidney transplantation
Authors: Müller‐Steinhardt M , Fricke L , Kirchner H , Hoyer J , Klüter H
Published: March 2003

While the relevance of pre‐formed anti‐human leukocyte antigen (HLA) antibodies has been studied extensively, the role of anti‐HLA class I and II antibodies produced after cadaveric kidney transplantation is still a matter of discussion. As it has been proposed that they are involved in a considerable number of cases, it should be investigated whether a post‐transplant monitoring is a sensitive parameter for the early diagnosis of acute rejection episodes. Additionally, it has been suggested that antibodies are a major cause for chronic rejection; thus, it would be of interest to correlate antibody detection and graft survival. We retrospectively investigated 59 patients after a first cadaveric kidney transplantation without known anti‐HLA antibodies (complement‐dependent cytotoxicity [CDC] testing). The panel reactivity was determined with a new highly sensitive and specific flow‐cytometric technique (Flow‐PRA Screening Test©, One Lambda, Canoga Park, USA) in sequentially collected serum samples pre‐ and post‐transplant. In patients with acute rejection episodes during the clinical course, the last sample prior to rejection, and in patients without rejection, the last sample prior to discharge, was analyzed. Furthermore, we analyzed 3‐yr graft survival and several clinical parameters such as cold ischemia time (CIT).Twenty‐four of 59 patients (41%) experienced acute rejections during the clinical course. Five of 59 died with a functioning graft within the first 3 yr. Seven of 54 patients, still alive after 3 yr, lost their graft. Anti‐HLA antibodies were detectable in only 7/59 patients and a correlation between antibody positivity and acute rejections (p=0.32 and 0.54 for anti‐HLA class I and II, respectively) could not be identified (sensitivity 12.5 and 8.3%). However, we found a significant correlation between the detection of anti‐HLA class II and graft loss within 3 yr (p=0.005, specificity 97.9%). Additionally, anti‐HLA class II positive patients had significantly longer CIT (p=0.003).Whether the detection of anti‐HLA class II antibodies in the early post‐transplant phase is of great value for the identification of patients at high risk for early graft loss needs additional investigation. However, we found that anti‐HLA antibodies are detectable only in a minority of unsensitized patients and we conclude that flow‐cytometric monitoring with Flow PRA is not a sensitive parameter for the early diagnosis of acute rejection episodes in patients after first cadaveric kidney transplantation.
Assistance programs available for medications commonly used in transplant patients
Authors: Chisholm Marie A , Tackett Kimberly L , Kendrick Bridgett D , DiPiro Joseph T
Published: March 2003

Pharmaceutical manufacturers have programs available to supply medications to indigent patients at little or no cost. Enrolling needy patients into these programs should increase patient compliance to medications, minimize patient and institution financial burdens, and decrease adverse events associated with medication noncompliance. However, access to assistance programs by patients in need is limited if physicians and other health care providers are unaware of the existence of such programs or not informed of each program's enrollment process. The literature is void of a manuscript describing assistance programs available for commonly prescribed medications used in transplant patients. This article offers a concise summary of medication assistance programs available through the pharmaceutical industry to assist in the procurement of medications that are commonly prescribed for the transplant population, including immunosuppressants, antibacterials, gastrointestinal, cardiovascular, and hypoglycemic agents. This article should be used by health care professionals as a guide to the availability and requirements of medication assistance programs.
Further improvements in laparoscopic donor nephrectomy: decreased pain and accelerated recovery
Authors: Ashcraft E. E. , Baillie G. M. , Shafizadeh S. F. , McEvoy J. R. , Mohamed H. K. , Lin A. , Baliga P. K. , Rogers J. , Rajagopalan P. R. , Chavin K. D.
Published: March 2003

Fear of postoperative pain is a disincentive to living donor kidney transplantation. Laparoscopic donor nephrectomy (LDN) was developed in part to dispel this disincentive. The dramatic increase in the number of laparoscopic donor nephrectomies performed at our institution has been in part due to the reduction in postoperative pain as compared to traditional, open donor nephrectomy. We sought to further diminish the pain associated with this surgical technique. The purpose of this study was to compare the efficacy of three different postoperative pain management regimens after LDN. All living kidney donors performed laparoscopically (n=43) between September 1998 and April 2000 were included for analysis. Primary endpoints included postoperative narcotic requirements and length of stay. Narcotic usage was converted to morphine equivalents (ME) for comparison purposes. Patients received one of three pain control regimens (group I: oral and intravenous narcotics; group II: oral and intravenous narcotics and the On‐Q™ pump delivering a continuous infusion of subfascial bupivicaine 0.5%; and group III: oral and intravenous narcotics and subfascial bupivicaine 0.5% injection). Postoperative intravenous and oral narcotic use as measured in morphine equivalents was significantly less in group III versus groups I and II (group III: 28.7 ME versus group I: 40.2 ME, group II: 44.8 ME; P<0.05). Postoperative length of stay was also shorter for group III (1.8 days) versus group I (2.5 days) and group II (2.9 days). LDN has been shown to be a viable alternative to traditional open donor nephrectomy for living kidney donation. We observed that the use of combined oral and intravenous narcotics alone is associated with greater postoperative narcotic use and increased length of stay compared to either a combined oral and intravenous narcotics plus continuous or single injection subfascial administration of bupivicaine. The progressive modification of our analgesic regimen has resulted in decreased postoperative oral and intravenous narcotic use and a reduction in the length of stay. We recommend subfascial infiltration with bupivicaine to the three laparoscopic sites and the pfannenstiel incision at the conclusion of the procedure to reduce postoperative pain. We believe this improvement in postoperative pain management will continue to make LDN even more appealing to the potential living kidney donor.
End‐stage renal disease in liver transplants
Authors: Lynn Melissa , Abreo Kenneth , Zibari Gazi , McDonald John
Published: March 2003

Renal dysfunction is one of the most significant problems following orthotopic liver transplantation (OLTx). Since the major risk factor for delayed renal dysfunction following OLTx is presumed to be cyclosporine (CsA) nephrotoxicity, it has been suggested that CsA is the most probably cause of end‐stage renal disease (ESRD) in this population of patients. To test this hypothesis the records of OLTx patients in our center who developed ESRD requiring dialysis were reviewed. There were 132 consecutive adult patients with end‐stage liver disease (ESLD) who received 146 OLTxs between 1990 and 2000. Five patients (3.4%) developed ESRD requiring dialysis. Four of the five patients developed nephrotic range proteinuria prior to reaching ESRD. Renal biopsy in four patients showed focal segmental glomerulosclerosis, diabetic nephropathy, membranous nephropathy and cyclosporine toxicity. The underlying hepatic and metabolic disease may have played a role in the genesis of glomerular diseases in these OLTx patients. Perhaps if more renal biopsies are performed in OLTx patients with chronic renal failure, we might discover that, although CsA/tacrolimus therapy is a definite risk factor for post‐transplantation chronic renal failure, other disease processes may also play a significant role.
Inherited factor H dysfunction and complement‐associated glomerulonephritis in renal grafts of first and second transplantations
Authors: Watanabe Seiji , Yamaguchi Yutaka , Suzuki Toshiaki , Ikezoe Masaya , Matsumoto Naoko , Chikamoto Hiroko , Nagafuchi Hiroyuki , Horita Shigeru , Hattori Motoshi , Shiraga Hiroshi , Tokumoto Tadahiko , Tanabe Kazunari , Toma Hiroshi , Ito Katsumi
Published: March 2003

Watanabe S, Yamaguchi Y, Suzuki T, Ikezoe M, Matsmoto N, Chikamoto H, Nagafuchi H, Horita S, Hattori M, Shiraga H, Tokumoto T, Tanabe K, Toma H, Ito K. Inherited factor H dysfunction and complement‐associated glomerulonephritis in renal grafts of first and second transplantations. Clin Transplantation 2001: 15 (Supplement 5): 45–50. ©Munksgaard, 2001

A 38‐yr‐old man with factor H dysfunction and unknown glomerular disease received first and second renal transplantations (Tx) from living‐related donors. His examination showed a low percentage activity of factor H (31%). Factor H dysfunction has been known to be associated with type II or III membranoproliferative glomerulonephritis (MPGN), haemolytic uraemic syndrome and IgA GN. The first graft from his mother showed diffuse mesangial deposit of IgA. His son has had IgA GN and his data also revealed a low percentage activity of factor H (33%). He and his son both showed a low activity of C3. Moreover, his father, who was the donor of the second Tx, had a low percentage activity of factor H (25%), and presented with mild glomerular deposit of C3 at operation, while he has been healthy through his entire 67 yr of life. Each of them had a low percentage activity of factor H. These findings through three generations suggested the inheritance of factor H dysfunction. The patient presented with proteinuria 3 months after the first Tx. At the first biopsy 30 months after the first Tx, light microscopy revealed minor glomerular abnormalities with electron dense deposits in subepithelial, intramembranous and mesangial regions, while immunofluorescence showed massive glomerular deposits of C3. In the second biopsy 51 months after the first Tx, the glomerulonephritis developed mesangial proliferation and crescent formation, accompanied by more massive C3 deposit and intramembranous, mesangial and subepithelial dense deposits. He then required redialysis. At the second and third biopsies within 2 months after the second Tx, the renal graft showed similar findings to the first biopsy after the first Tx. He perhaps presented with a recurrence of complement‐associated GN, showing an atypical form of MPGN after Tx. These findings suggest that factor H dysfunction may play an important role of a certain pathogenesis of GN.
Peri‐operative cardiac morbidity in kidney transplant recipients: incidence and risk factors
Authors: Humar Abhinav , Kerr Stephen R , Ramcharan Thiagarajan , Gillingham Kristen J , Matas Arthur J
Published: March 2003

Background: Renal transplant recipients are known to be at increased risk for developing cardiac disease. In both general and peripheral vascular surgery, pre‐operative risk stratification (and intervention when indicated) has decreased the incidence of peri‐operative cardiac complications. In this study, we set out to identify subsets of patients at high risk for peri‐operative cardiac complications after a renal transplant.   Methods: We retrospectively reviewed the records of 2694 adult renal transplants performed at the University of Minnesota between January 1, 1985 and December 31, 1998. We determined the incidence of peri‐operative (within 30 d post‐transplant) cardiac complications, including myocardial infarction (MI). Risk factors for the development of these complications were determined by multivariate analysis.   Results: We found 163 peri‐operative cardiac complications, for an overall incidence of 6.1%. Specific cardiac complications included MI (n=43, 1.6%), arrhythmia (n=74, 2.7%), angina (n=31, 1.2%), cardiac arrest (n=13, 0.5%), and congestive heart failure (n= 2, 0.1%). By multivariate analysis, significant risk factors for any cardiac complication were age≥50 yr (relative risk (RR)=3.0, p=0.0001) and pre‐transplant cardiac disease (RR=3.3, p=0.0001). Not significant were diabetes mellitus (DM), cadaver donor source, pre‐transplant dialysis, a history of smoking, and hypertension. Significant risk factors for peri‐operative MI were age≥50 yr, pre‐existing cardiac disease, and DM. Diabetic patients with pre‐existing cardiac disease were at especially high risk for peri‐operative cardiac events.   Conclusions: Patients>50 yr and those with pre‐existing cardiac disease, especially if diabetic, are at significantly increased risk for developing peri‐operative cardiac complications after a renal transplant. Such patients require aggressive pre‐operative investigations, which may include coronary angiography, to decrease the risk of post‐transplant complications.