Report on the joint EFPIA, DIA and EMEA pharmacogenetics workshop: moving toward clinical application.
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Clinical Trials as Topic↗
Biomedical subjects
L Hashimoto
Publications and source records attributed to L Hashimoto.
Elements of informed consent for pharmacogenetic research; perspective of the pharmacogenetics working group.
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Clinical Trials as Topic↗
Acute pancreatitis after aortic surgery.
Acute pancreatitis (AP) after aortic surgery has rarely been reported. A retrospective review of all abdominal and thoracoabdominal aortic operations complicated with AP from January 1982 to March 1992 was performed to study the presentation and outcome of this infrequently recognized complication. Thirteen cases of AP were found among 1965 abdominal aortic operations (0.7% incidence). The distribution of the original aortic operations was as follows: eight elective abdominal aortic aneurysm repairs, two aortoiliac grafts for aortoiliac occlusive disease, and three aortorenal bypasses. Two cases of pancreatitis complicated 170 thoracoabdominal aortic operations (1.2% incidence). Ten patients had mild pancreatitis, nine were discharged without any pancreatic complications after receiving supportive treatment. Five patients with severe AP died of multisystem organ failure despite aggressive surgical treatment; 4 had infected necrosis. The overall mortality was 40 per cent; severe AP resulted in a 100 per cent mortality. The diagnosis of severe AP was usually made in the second postoperative week, significantly later (P < 0.01) than for patients with mild disease. Typically, patients with mild AP presented with hyperamylasemia at a median of 5 postoperative days, and severe AP was found at reoperation or autopsy after a period of unexplained sepsis. Five patients with mild AP were found to have biliary tract stones, with one requiring endoscopic stone extraction. In conclusion, pancreatitis is an uncommon, although perhaps underreported complication. Underreporting may be due to a lack of hyperamylasemia when severe pancreatitis is diagnosed. The severe form is diagnosed late in patients with postoperative sepsis, associated with infected necrosis, and lethal. The complication may be reduced by incidental cholecystectomy for cholelithiasis.
Acute Disease↗
Evidence of a non-MHC susceptibility locus in type I diabetes linked to HLA on chromosome 6.
Linkage studies have led to the identification of several chromosome regions that may contain susceptibility loci to type I diabetes (IDDM), in addition to the HLA and INS loci. These include two on chromosome 6q, denoted IDDM5 and IDDM8, that are not linked to HLA. In a previous study, we noticed that the evidence for linkage to IDDM susceptibility around the HLA locus extended over a total distance of 100 cM, which suggested to us that another susceptibility locus could reside near HLA. We developed a statistical method to test this hypothesis in a panel of 523 multiplex families from France, the United States, and Denmark (a total of 667 affected sib pairs, 536 with both parents genotyped), and here present evidence (P = .00003) of a susceptibility locus for IDDM located 32 cM from HLA in males but not linked to HLA in females and distinct from IDDM5 and IDDM8. A new statistical method to test for the presence of a second susceptibility locus linked to a known first susceptibility locus (here HLA) is presented. In addition, we analyzed our current family panel with markers for IDDM5 and IDDM8 on chromosome 6 and found suggestions of linkage for both of these loci (P = .002 and .004, respectively, on the complete family panel). When cumulated with previously published results, with overlapping families removed, the affected-sib-pair tests had a significance of P = .0001 for IDDM5 and P = .00004 for IDDM8.
Adult↗
Genetics of insulin-dependent diabetes mellitus.
Recent studies that have focused on the detection of non-MHC susceptibility loci in insulin-dependent diabetes mellitus are reviewed. It has been confirmed that the region on human chromosome 11p contains such a susceptibility locus and recent research has attempted to identify the causative DNA variants and their functional role in disease.
Chromosome Mapping↗
Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12.
Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.
Chromosome Mapping↗
Is sporadic MS caused by an infection of adolescence and early adulthood? A case-control study of birth order position.
Birth order position was examined in 164 cases with sporadic multiple sclerosis (MS), i.e. no other family members with MS, and spousal controls, matched for sibship size, socioeconomic status and opposite sex. The results did not find an association between birth order position and the subsequent development of MS and thus do not support the concept of an infectious cause for MS where "early exposure" is protective and exposure to the infection is a single event of short duration.
Adolescent↗
A study of birth order and multiple sclerosis in multiplex families.
Birth order position for affected siblings was examined for 88 sibships having 2 or more cases of multiple sclerosis (MS). The data show that MS patients are randomly ordered by birth within these multiplex sibships. The data therefore do not support the hypothesis that MS occurs in siblings because of a common environmental exposure as defined by proximity in birth order position.
Birth Order↗
Pyogenic hepatic abscess: results of current management.
From 1980 to 1991, 56 cases of pyogenic liver abscess were treated at the Cleveland Clinic. The most frequently used treatment was percutaneous catheter drainage of the abscess under computed tomography (CT) guidance (39 patients), followed by CT-guided aspiration without catheter drainage (10 patients). Six patients were initially treated by open operative drainage; another five were operated upon after CT guided drainage had failed. One patient with advanced pancreatic cancer was treated with antibiotics only. The overall mortality rate was 12.5% (7/56). It is clear that the preferred method of treatment for pyogenic hepatic abscess is now CT guided catheter drainage. Operative drainage is reserved for patients who fail to respond to percutaneous drainage or in whom surgery is indicated for other purposes. Aspiration without catheter drainage is a modality that needs further evaluation to define its indications.
Adult↗
Recurrent small bowel obstruction secondary to a dilated Kock pouch: a case report.
We report a case of recurrent bowel obstruction caused by a hugely dilated Kock pouch. The approximate capacity of the pouch was at least 1300 ml. Frequent emptying of the pouch resulted in resolution of the obstructing symptoms.
Female↗
Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q.
Loci in the major histocompatibility complex (MHC) on chromosome 6 and the insulin (INS) region on chromosome 11 have been implicated in susceptibility to insulin-dependent diabetes mellitus (IDDM) through candidate gene investigations, but they may account for less than 50% of genetic risk for the disease. Genome-wide linkage studies have led to localization of more than 10 susceptibility loci for insulin-dependent diabetes in the non-obese diabetic (NOD) mouse and the BB rat. Similar studies are now possible in humans through the development of dense genetic maps of highly informative microsatellite loci obtained using polymerase chain reaction analysis. We have applied microsatellite markers from recent Généthon maps, and other highly informative markers, in a genome-wide linkage study in IDDM. Here we report evidence for the localization of a previously undetected susceptibility locus for IDDM in the region of the FGF3 gene on chromosome 11q. Our results shows the potential of genome-wide linkage studies to detect susceptibility loci in IDDM and other multifactorial disorders.
Chromosome Mapping↗
A population-based study of multiple sclerosis in twins: update.
This study is a 7.5-year follow-up of a population-based series of twins with multiple sclerosis (MS) whose mean age now exceeds 50 years. The twin pairs were identified through the Canadian nationwide system of MS clinics and were drawn from a population of 5,463 patients. After 7.5 years, the monozygotic concordance rate increased from 25.9 to 30.8% and the dizygotic-like sex concordance rate from 2.4 to 4.7%. These results are very similar to those of other population-based studies and to our own modified replication twin data reported here. We interpret the data to mean that MS susceptibility is genetically influenced, and a single dominant or even a single recessive gene is unlikely to account for this effect. The difference in concordance rates suggests that at least two or more genes are operative. These data also have important implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age and magnetic resonance imaging findings. This unambiguously demonstrates the powerful effect of nonheritable factors.
Adult↗
Identification of a CA repeat at the TCRA locus using yeast artificial chromosomes: a general method for generating highly polymorphic markers at chosen loci.
The creation of a comprehensive genetic map in human has been limited by the lack of highly polymorphic markers spaced evenly throughout the human genome. We have utilized yeast artificial chromosomes (YAC) containing large human DNA inserts to help identify highly polymorphic (CA)n repeats at a chosen locus. The DNA of a YAC containing the locus was subcloned in M13 vectors, and the recombinants were screened at high stringency to detect preferentially long (CA)n repeats (n greater than 20). These repeats, which are the most likely to be highly polymorphic, were then studied to confirm both the level of polymorphism and their precise genetic location. This strategy has permitted the identification of a new, highly polymorphic CA repeat (77% heterozygosity) at the T cell receptor alpha chain (TCRA) locus on chromosome 14q. It provides a powerful marker for assessing the role of this locus in the susceptibility to autoimmune and infectious diseases. This approach should permit the development of highly polymorphic markers at any targeted locus and rapidly improve the current human genetic map.
Base Sequence↗
Exclusion of linkage between hypokalemic periodic paralysis (HOKPP) and three candidate loci.
Hypokalemic periodic paralysis (HOKPP) is an autosomal dominant neuromuscular disorder characterized by flaccid paralysis accompanied by lowered serum potassium levels. We have tested polymorphic markers linked to the adult skeletal muscle sodium channel (SCN4A) locus at 17q23-q25, the T-cell receptor beta (TCRB) locus at 7q35, and the H-Ras cellular proton-cogene locus (HRAS) at 11p15.5 for linkage with the affected phenotype in a single multigenerational pedigree. No evidence for genetic linkage to HOKPP was found at any of the candidate loci.
Chromosome Mapping↗
Linkage of Thomsen disease to the T-cell-receptor beta (TCRB) locus on chromosome 7q35.
The chromosomal localization of the gene for Thomsen disease, an autosomal dominant form of myotonia congenita, is unknown. Electrophysiologic data in Thomsen disease point to defects in muscle-membrane ion-channel function. A mouse model of myotonia congenita appears to result from transposon inactivation of a muscle chloride-channel gene which maps to a region of mouse chromosome 6. The linkage group containing this gene includes several loci which have human homologues on human chromosome 7q31-35 (synteny), and this is a candidate region for the Thomsen disease locus. Linkage analysis of Thomsen disease to the T-cell-receptor beta (TCRB) locus at 7q35 was carried out in four pedigrees (25 affected and 23 unaffected individuals) by using a PCR-based dinucleotide repeat polymorphism in the TCRB gene. Two-point linkage analysis between Thomsen disease and TCRB showed a maximum cumulative lod score of 3.963 at a recombination fraction of .10 (1-lod support interval .048-.275). We conclude that the Thomsen disease locus is linked to the TCRB locus in these families.
Base Sequence↗
The influence of gender on the susceptibility to multiple sclerosis in sibships.
A population-based study of pairs of relatives (siblings, second- and third-degree) concordant for multiple sclerosis did not show an excess of like-sexed pairs. In addition, data on human lymphocyte antigen typing for sibling pairs concordant for multiple sclerosis did not find an increase in haplotype sharing for like-sexed pairs. These data do not support the notion that sex-related factors influence multiple-sclerosis susceptibility in families.
Disease Susceptibility↗
Energy metabolism changes and oxidative attack after hepatic arterial embolization and chemoembolization in thioacetamide-induced cirrhotic livers.
Hepatic energy metabolism and oxidative attack were studied after transcatheter arterial embolization (TAE) and chemoembolization (TAC) of the left and median lobes of the liver using thioacetamide (TAA)-induced cirrhotic rats. TAE was carried out using gelatin sponge (1.5 mg/cm3) dissolved in saline solution (SS). TAC was performed by adding mitomycin C (MMC) (1.6 mg/kg body weight) to the previous embolic solution. The energy charge (EC) of embolized lobes decreased from 0.86 to 0.78 and 0.74 1 h after TAE and TAC, respectively, but was restored 3 h later. Adenosine 5'-triphosphate (ATP) and total adenine nucleotide content (TAN) of embolized and non-embolized lobes was also temporarily decreased. Total hepatic blood flow (THBF) of embolized and chemoembolized lobes was reduced in almost 50%, and it took 1 week to become normalized. After TAC (3 and 6 h, respectively), total glutathione (TGSH) content was reduced from 7.02 mumol/g of liver to around 4.5 mumol/g, and malondialdehyde (MDA) content increased from 196.94 nmol/g of liver to values above 300 nmol/g. TAE in cirrhotic livers did not induce any changes in these parameters. In conclusion, after TAE and TAC the hepatic energy metabolism is temporarily altered by ischemia. TAC-induced oxidative attack, in addition to ischemia and MMC, could be one of the mechanisms explaining the effectiveness of this therapy.
Adenine Nucleotides↗
[Application of high resolution liquid chromatography to the test of bile acid tolerance].
In the present paper we have evaluated the accuracy of a fully automated liquid-chromatographic method to study the variations of serum bile acid concentration after oral administration of 500 mg of chenodeoxycholic as a bile acid tolerance test. The study population consisted of 11 subjects with liver cirrhosis (L.C.), 6 with chronic active hepatitis (C.A.H.) and of 15 healthy volunteers, as a control. A clear linear correlation was observed between the integrated peak area and the concentration of each bile acid. Bile acids were detected at a minimum concentration of 5 ng. Intra-assay variation, based on 10 consecutive determinations, was limited to a range of 0.42% and 3.23%. Compared to control group, L.C. and C.A.H. patients showed significantly higher levels of total bile acids and of CDCA. Significative was also the increase of glycine- and taurine-conjugates as well as the decrease of the ratio between the two. The present method, fully automated and using a low cost enzymatic reagent, has yielded an accurate analysis of bile acid fractions on a minute volume of serum in a short examination time.
Aged↗