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.

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.

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.

T cell receptor alpha chain polymorphisms in multiple sclerosis.

Numerous studies have implicated the major histocompatibility complex (MHC) class II alleles, DR2 and DQw1, as multiple sclerosis (MS) susceptibility loci, however, the involvement of other loci is implied by twin studies and the relative lack of haplotype sharing for MHC. To evaluate the role that the TCR alpha chain genes may have in MS susceptibility, three variable (V) alpha polymorphisms were examined for associations in MS patients. Genotype and allele frequencies were compared to four different control groups: unaffected siblings and parents of the MS patients, patients with insulin-dependent diabetes mellitus (IDDM) and healthy unrelated Caucasians. No significant differences in allele and genotype frequencies at these three loci were observed in the MS population compared to the control groups. In addition, we analysed the distribution of haplotype sharing in affected sibling pairs. Among 30 informative families, there was no significant increase in haplotypes shared by affected siblings over that expected based on random segregation. Our results do not support suggestions that germline TCR alpha chain genes contribute to genetic susceptibility in MS.

Immunoglobulin heavy chain variable region polymorphisms and multiple sclerosis susceptibility.

In addition to the major histocompatibility complex (MHC), genetic susceptibility in multiple sclerosis (MS) appears to be influenced by other loci. A recent study has identified a population association with an immunoglobulin heavy chain variable region polymorphism in the VH2-B5 family, with both familial and sporadic MS patients. We have repeated this association study in a second MS patient group and used two ethnically and geographically matched control groups and the MS patients' unaffected sibs for comparisons. The VH2-B5 polymorphism was found to be over-represented in MS patients when compared to all three control groups. This VH2-B5 association was stronger when the MS patient data were combined with data from our previous study. To further explore the implications of this population association, MS sibships were analyzed for haplotype sharing by identity by descent (IBD) for VH2 and VH3f gene segment polymorphisms. The distribution of haplotype sharing did not differ from that expected based upon random segregation. The data are consistent with the IGVH locus exerting a minor effect perhaps by interacting with other loci to influence MS susceptibility or with genetic heterogeneity and a role for this complex in a subgroup of patients.

Preoperative localization of insulinomas is not necessary.

BACKGROUND: Insulinomas are infrequent but are important to recognize and surgically remove. Several diagnostic tests have been used to increase the chances of operative success. The value of preoperative testing for insulinomas is the subject of this review. STUDY DESIGN: All patients treated at the Cleveland Clinic for insulinoma between 1985 and 1995 were retrospectively reviewed. All patients had biochemical evidence of primary hyperinsulinemia. RESULTS: There were 21 patients, 10 men and 11 women, with a median age of 58 years. Eighteen patients (85%) had a single insulinoma, two patients (10%) had multiple insulinomas, and one patient (5%) had nesidioblastosis. In addition, two patients (10%) had malignant insulinoma. A total of 13 patients (62%) had successful preoperative localization of their tumors, and all of these were found during exploration either by the surgeon (12 patients) or by intraoperative ultrasonography (1 patient). The remaining eight patients (38%) did not have their lesion localized by preoperative tests. In seven patients these tumors were found at operation, three by the surgeon and four by intraoperative ultrasonography. One patient failed preoperative and intraoperative localization and was later diagnosed with nesidioblastosis. Enucleation was performed in 13 patients and distal pancreatectomy in 7; the patient with nesidioblastosis had a negative laparotomy and a subsequent distal pancreatectomy. The mortality and morbidity rates were 0% and 14%, respectively. Only two patients, including the patient with nesidioblastosis, remained symptomatic after operation. CONCLUSIONS: The diagnosis of an insulinoma does not require extensive localization studies before operation. The combination of surgical exploration and intraoperative ultrasonography identified more than 90% of insulinomas. When technically feasible, enudeation is curative and can be accomplished with low morbidity.

Presentation and management of cystic neoplasms of the pancreas.

Pancreatic cystic neoplasms are uncommon, but it is important to differentiate them from pseudocysts and ductal adenocarcinoma. A retrospective review was performed to determine distinguishing characteristics and optimal treatment. In 51 patients operated on between 1981 and 1994 at a referral center, the following cystic neoplasms were found: 20 serous cystadenomas, 10 mucinous cystadenomas, 11 mucinous cystadenocarcinomas, five cases of mucinous ductal ectasia, and five papillary cystic neoplasms. Both mucinous ductal ectasia and papillary cystic neoplasms had distinguishing features when compared to other cystic neoplasms. Mucinous ductal ectasia was seen only in men, presented with typical symptoms, and had distinctive features on endoscopic retrograde cholangiopancreatography. Papillary cystic neoplasms occurred in young women (mean age 31 years) and were larger (mean 10.3 cm). Mucinous tumors were always symptomatic, whereas 55% of serous tumors were asymptomatic (P <0.001). The overall rate of resectability was 80%, and there was one operative death (2%). Intraoperative biopsy was diagnostic in 18 (78%) of 23 cases. An actuarial 5-year survival of 52% was found for resected mucinous cystadenocarcinomas. In conclusion, papillary cystic neoplasms and mucinous ductal ectasia have distinct characteristics that differentiate them from other types of pancreatic cystic tumors. Serous cystadenoma should be considered in asymptomatic patients and these patients should be closely observed. Symptomatic neoplasms should be resected with long-term survival expected for malignant forms. (J Gastrointest Surg 1998;2:504-508.)

Histologic findings and prognostic factors in carcinoma of the upper bile duct.

The histopathologic features of 34 resected carcinomas of the upper bile duct were reviewed. Patients with papillary adenocarcinoma showed a 3-year survival rate of 75 percent, which was better than those with poorly differentiated adenocarcinoma with no 2-year survivors. Infiltration to the serosa of the bile duct, lymph node metastasis, and vascular invasion were important prognostic factors, since the survival was better for the patients without than those with these factors. Among patients with papillary adenocarcinoma, none had hepatic infiltration and lymph node metastasis and most had no infiltration to the serosa. Patients with poorly differentiated adenocarcinoma, in contrast, had extensive association of those prognostic factors. Seventy-five percent of the patients with papillary adenocarcinoma and only 22 percent of patients with poorly differentiated adenocarcinoma were considered to have curative resection. These findings suggest that the histologic type strongly influenced the prognosis of the patients with carcinoma of the upper bile duct and can be used for the determination of the extent of this tumor.

Radial microbrain form of micrencephaly: possible association with carbamazepine.

A premature infant exposed to carbamazepine in utero had a markedly undersized brain on cranial ultrasonogram. Postmortem examination of the brain revealed no evidence of hypoxic-ischemic injury, hemorrhage, infarction, congenital infection, or calcification. The normal cortical gyral pattern, normal residual germinal matrix, and normal cortical lamination suggested the diagnosis of a radial microbrain form of micrencephaly.

Heterogeneity in multiple sclerosis: comparison of clinical manifestations in relatives.

Once diagnosed to have MS, relatives of persons who have been previously diagnosed frequently ask whether their disease course will follow that of their relative(s) with MS. The present study compared the following clinical manifestations of MS among 43 index cases and 47 of their relatives, all of whom were diagnosed to have MS and regularly attended the MS Clinic in Vancouver, British Columbia: (i) age of onset of MS, (ii) clinical course, (iii) lesion site(s) and (iv) initial symptom(s) of MS. The results from the present study are preliminary because of the small size of the study group. However, these data suggest that apart from possibly age of onset between sibling pairs, the clinical manifestations of MS are not correlated among relatives who are assessed according to the same methodology. This is significant for counselling newly diagnosed relatives of longstanding MS patients.

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.

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.

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.

Retroperitoneal mucinous cystadenoma.

Primary retroperitoneal mucinous cystadenoma is an uncommon tumor found exclusively in women. Herein, we describe a patient who had resection of a large retroperitoneal cystic mass. Histologic, immunohistochemical, and electron microscopic examination of the lining epithelial cells showed features of mesothelial cells in addition to ovarian mucinous cystadenoma. These findings suggest that these tumors arise from inclusions of mesothelial cells and subsequent mucinous metaplasia of the lining cells to form a cystadenoma. Estrogen receptors may be implicated in tumor promotion, explaining the occurrence exclusively in women.

[Application of high resolution liquid chromatography to the test of bile acid tolerance]. / Applicazione della cromatografia liquida ad alta risoluzione per il test di tolleranza degli acidi biliari.

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.

Superselective arterial embolization of the rat liver.

The superselective transcatheter arterial embolization has currently become an accepted treatment of hepatic tumors. We have developed an experimental model for the evaluation of this therapy in the rat liver. Using the retrograde catheterization of the superior pancreaticoduodenal artery, only the peripheral intrahepatic arterial branches and sinusoids of the median and left lobes of the liver were embolized with 1.2 and 1.5 mg of Gelfoam powder. This method resembles the clinical practice because the superselective embolization could be performed adequately and allows the comparative evaluation of the responses of the embolized and non-embolized lobes.

Effects of superselective arterial embolization and chemoembolization on energy charge and total blood flow of the rat liver.

The superselective transcatheter arterial embolization (TAE) and chemoembolization (TAC) of the periphery of the left and median lobes of the rat liver were performed using 1.5 mg of gelatin sponge dissolved in saline solution and mitomycin (MMC) at a dose of 1.6 mg/kg b.wt. The energy charge (EC) of the embolized and chemoembolized lobes decreased after the embolization but was restored 3 h later. The total hepatic blood flow (THBF) was reduced to about one half and required 1 week to be restored to the preembolization levels in both groups. Microscopic centrilobular necrosis and vacuolization were found. The addition of MMC did not produce marked untoward effects. Thus, the normal liver is able to restore its energy pool despite a reduction in the THBF after superselective arterial embolization, and this recovery is not altered even by the use of a high dose of MMC.

Transcatheter arterial embolization and chemoembolization induce the production of free radicals in the normal rat liver.

Superselective transcatheter arterial embolization (TAE) of the left and median lobes of the normal rat liver was performed using gelatin sponge (1.5 mg/ml). Superselective transcatheter arterial chemoembolization (TAC) of the same lobes was done adding mitomycin (MMC) at a dose of 1.6 mg/ml to the embolic solution. In another group of rats MMC alone was injected intraarterially into those lobes. It was found that both embolic procedures and the arterial injection of MMC decrease the hepatic total glutathione content. Glutathione peroxidase activity and alpha-tocopherol content remained unchanged. Lipoperoxides were detected 3 and 6 h after TAC in chemoembolized and non-chemoembolized lobes. Similar findings in both injected and noninjected lobes were found after MMC injection. The TAE lobes only showed elevated lipoperoxide content 6 h after embolization, this parameter remained unchanged in the non-TAE lobes. These findings suggest that free radicals are formed after TAE, and that the addition of MMC to the embolic solution increases the oxidative attack and/or that the oxidative reactions after TAC are mainly mediated by lipid peroxidation due to the presence of MMC.