Development of a Polygenic Risk Score to Predict Diverticulitis.

BACKGROUND: Despite its prevalence and associated morbidity, we remain limited in our ability to predict the course of a patient with diverticular disease. Although several clinical and genetic risk factors have been identified, we do not know how these factors relate to one another. OBJECTIVE: Our aim was to determine whether a polygenic risk score could improve risk prediction for diverticulitis and recurrent diverticulitis compared with a model using only clinical factors. DESIGN: This is an observational study. SETTING: The study examines the predictive ability of a polygenic risk score for diverticulitis developed using prior genome-wide association studies and validated using the MyCode biobank. PATIENTS: This study included patients of European ancestry in the Geisinger Health System who were enrolled in the MyCode Community Health biobanking program. MAIN OUTCOME MEASURES: The ability of a polygenic risk score to predict diverticulosis, diverticulitis, and recurrent diverticulitis was the main outcome measure of this study. RESULTS: A total of 60,861 patients were included, of whom 9912 (16.3%) had diverticulosis or diverticulitis (5015 with diverticulosis and 4897 with diverticulitis). When divided into deciles, our polygenic risk score stratified patients by risk of both diverticulosis and diverticulitis with a 2-fold difference in disease risk between the highest and lowest deciles for diverticulitis and a 4.8-fold difference for recurrent complicated diverticulitis. When compared with clinical factors alone, our polygenic risk score was able to improve risk prediction of recurrent diverticulitis. LIMITATIONS: Our population is largely located in a single geographic region and were classified by disease status, using international classification of diseases codes. CONCLUSIONS: This predictive model stratifies patients based on genetic risk for diverticular disease. The increased frequency of recurrent disease in our high-risk patients suggests that a polygenic risk score, in addition to other factors, may help guide the discussion regarding surgical intervention. See Video Abstract . DESARROLLO DE UNA PUNTUACIN DE RIESGO POLIGNICO PARA PREDECIR LA DIVERTICULITIS: ANTECEDENTES:A pesar de su prevalencia y morbilidad asociada, nuestra capacidad para predecir el curso en un paciente con enfermedad diverticular sigue siendo limitada. Si bien se han identificado varios factores de riesgo clínicos y genéticos, no sabemos cómo se relacionan estos factores entre sí.OBJETIVO:Determinar si una puntuación de riesgo poligénico podría mejorar la predicción del riesgo de diverticulitis y diverticulitis recurrente en comparación con un modelo que utiliza solo factores clínicos.DISEÑO:Un estudio observacional que examina la capacidad predictiva de una puntuación de riesgo poligénico para la diverticulitis desarrollada usando estudios previos de asociación amplia del genoma y validada usando el biobanco MyCode.ÁMBITOS Y PACIENTES:Pacientes de ascendencia europea en el Sistema de Salud Geisinger que estaban inscritos en el programa de biobancos MyCode Community Health.PRINCIPALES MEDIDAS DE VALORACIÓN:La capacidad de una puntuación de riesgo poligénico para predecir diverticulosis, diverticulitis y diverticulitis recurrente.RESULTADOS:Se incluyeron un total de 60.861 pacientes, de los cuales 9.912 (16,3%) presentaban diverticulosis o diverticulitis (5.015 con diverticulosis y 4.897 con diverticulitis). Cuando se dividió en deciles, nuestra puntuación de riesgo poligénico estratificó a los pacientes según el riesgo de diverticulosis y diverticulitis con una diferencia de 2 veces en el riesgo de enfermedad entre los deciles más alto y más bajo para diverticulitis y una diferencia de 4,8 veces para diverticulitis complicada recurrente. En comparación con los factores clínicos solos, nuestra puntuación de riesgo poligénico pudo mejorar la predicción del riesgo de diverticulitis recurrente.LIMITACIONES:Nuestra población se encuentra en gran parte en una sola región geográfica y se clasificó por estado de enfermedad utilizando códigos de clasificación internacional de enfermedades.CONCLUSIONES:Este modelo predictivo estratifica a los pacientes en función del riesgo genético de enfermedad diverticular. La mayor frecuencia de enfermedad recurrente en nuestros pacientes de alto riesgo sugiere que un puntaje de riesgo poligénico, además de otros factores, puede ayudar a guiar la discusión sobre la intervención quirúrgica. (Traducción- Dr. Ingrid Melo ).

Diverticulitis Familiality: A Statewide Case-Control Study.

BACKGROUND: The etiology of diverticulitis is multifactorial and poorly understood. We estimated the familiality of diverticulitis using the Utah Population Database, a statewide database linking medical records with genealogy data. STUDY DESIGN: We identified patients with diverticulitis diagnosed between 1998 and 2018 and age- and sex-matched controls in the Utah Population Database. Risk of diverticulitis in family members of patients and controls was calculated using multivariable Poisson models. We performed exploratory analyses to determine the association of familial diverticulitis with severity of disease and age of onset. RESULTS: The study population included 9,563 diverticulitis patients (with 229,647 relatives) and 10,588 controls (with 265,693 relatives). Relatives of patients were more likely to develop diverticulitis (incidence rate ratio [IRR] 1.5, 95% CI 1.4 to 1.6) compared with relatives of controls. There was an elevated risk of diverticulitis among first-degree (IRR 2.6, 95% CI 2.3 to 3.0), second-degree (IRR 1.5, 95% CI 1.3 to 1.6), and third-degree relatives of patients (IRR 1.3, 95% CI 1.2 to 1.4). Complicated diverticulitis was more common among relatives of patients compared with relatives of controls (IRR 1.6, 95% CI 1.4 to 1.8). Age at diverticulitis diagnosis was similar between groups (relatives of patients 0.2 years older than relatives of controls, 95% CI -0.5 to 0.9). CONCLUSIONS: Our results indicate that the first-, second-, and third-degree relatives of diverticulitis patients are at elevated risk of developing diverticulitis. This information may aid surgeons in counseling patients and family members about diverticulitis risk and can inform the development of future risk-stratification tools. Further work is needed to clarify the causal role and relative contribution of various genetic, lifestyle, and environmental factors in the development of diverticulitis.

The Association Between Family History and Diverticulitis Recurrence: A Population-Based Study.

BACKGROUND: After initial nonoperative management of diverticulitis, individuals with a family history of diverticulitis may have increased risk of recurrent disease. OBJECTIVE: This study measured the association between family history and recurrent diverticulitis in a population-based cohort. DESIGN: This is a retrospective, population-based cohort study. SETTINGS: The cohort was identified from the Utah Population Database, a statewide resource linking hospital and genealogy records. PATIENTS: Individuals evaluated in an emergency department or hospitalized between 1998 and 2018 for nonoperatively managed diverticulitis were included. INTERVENTION: The primary predictor was a positive family history of diverticulitis, defined as diverticulitis in a first-, second-, or third-degree relative. MAIN OUTCOME MEASURES: This study measured the adjusted association between family history and the primary outcome of recurrent diverticulitis. A secondary outcome was elective surgery for diverticulitis. Additional analyses evaluated risk by degree of relation of the affected family member. RESULTS: The cohort included 4426 individuals followed for a median of 71 months. Median age was 64 years and 45% were male; 17% had complicated disease, 11% had recurrence, and 15% underwent elective surgery. After adjustment, individuals with a family history of diverticulitis had a similar risk of recurrence when compared to those without a family history (HR 1.0; 95% CI 0.8-1.2). However, individuals with a family history of diverticulitis were more likely to undergo elective surgery (HR 1.4; 95% CI 1.1-1.6). This effect was most pronounced in those with an affected first-degree family member (HR 1.7; 95% CI 1.4-2.2). LIMITATIONS: The use of state-specific data may limit generalizability. CONCLUSIONS: In this population-based analysis, individuals with a family history of diverticulitis were more likely to undergo elective surgery than those without a family history, despite similar risks of recurrence and complicated diverticulitis. Further work is necessary to understand the complex social, environmental, and genetic factors that influence diverticulitis treatment and outcomes. See Video Abstract at http://links.lww.com/DCR/B876 . ASOCIACIN ENTRE LOS ANTECEDENTES FAMILIARES Y LA RECURRENCIA DE LA DIVERTICULITIS UN ESTUDIO POBLACIONAL: ANTECEDENTES:Después del tratamiento inicial no quirúrgico de la diverticulitis, las personas con antecedentes familiares de diverticulitis pueden tener un mayor riesgo de enfermedad recurrente.OBJETIVO:Este estudio midió la asociación entre antecedentes familiares y diverticulitis recurrente en una cohorte poblacional.DISEÑO:Este es un estudio de cohorte retrospectivo de la población.ENTORNO CLÍNICO:La cohorte se identificó a partir de la Base de datos de población de Utah, un recurso estatal que vincula los registros hospitalarios y genealógicos.PACIENTES:Se incluyeron individuos evaluados en un departamento de emergencias u hospitalizados entre 1998 y 2018 por diverticulitis manejada de forma no quirúrgica.INTERVENCIÓN:El predictor principal fue un historial familiar positivo de diverticulitis, definida como diverticulitis en un familiar de primer, segundo o tercer grado.PRINCIPALES MEDIDAS DE VALORACIÓN:Este estudio midió la asociación ajustada entre los antecedentes familiares y el resultado primario de diverticulitis recurrente. Un resultado secundario fue la cirugía electiva por diverticulitis. Análisis adicionales evaluaron el riesgo por grado de parentesco del familiar afectado.RESULTADOS:La cohorte incluyó a 4.426 individuos seguidos durante una mediana de 71 meses. La mediana de edad fue de 64 años y el 45% eran varones. El 17% tenía enfermedad complicada, el 11% recidiva y el 15% se sometió a cirugía electiva. Después del ajuste, los individuos con antecedentes familiares de diverticulitis tenían un riesgo similar de recurrencia en comparación con aquellos sin antecedentes familiares (HR 1,0; IC del 95%: 0,8-1,2). Sin embargo, las personas con antecedentes familiares de diverticulitis tenían más probabilidades de someterse a una cirugía electiva (HR 1,4; IC del 95%: 1,1-1,6). Este efecto fue más pronunciado en aquellos con un familiar de primer grado afectado (HR 1,7; IC del 95%: 1,4-2,2).LIMITACIONES:El uso de datos específicos del estado puede limitar la generalización.CONCLUSIONES:En este análisis poblacional, los individuos con antecedentes familiares de diverticulitis tenían más probabilidades de someterse a una cirugía electiva que aquellos sin antecedentes familiares, a pesar de riesgos similares de recurrencia y diverticulitis complicada. Es necesario seguir trabajando para comprender los complejos factores sociales, ambientales y genéticos que influyen en el tratamiento y los resultados de la diverticulitis. Consulte Video Resumen en http://links.lww.com/DCR/B876 . (Traducción-Dr. Ingrid Melo ).

COLQ and ARHGAP15 are Associated with Diverticular Disease and are Expressed in the Colon.

BACKGROUND: Diverticular disease is a common but poorly understood disease of the gastrointestinal tract. Recent studies have identified several single nucleotide polymorphisms (SNPs) that are associated with diverticular disease. MATERIALS AND METHODS: The genotypes of three SNPs (rs4662344 in ARHGAP15, rs7609897 in COLQ, and rs67153654 in FAM155A) were identified by Taqman assay in 204 patients with diverticular disease. Clinical characteristics were obtained from the medical record to study association with genotype. To evaluate gene expression in colon tissue, qPCR was performed on 24 patients with diverticulitis, and COLQ was localized using immunohistochemistry. RESULTS: The ARHGAP15 and COLQ SNPs were significantly associated with both diverticular disease and specifically diverticulitis, while the FAM155A was not associated with either. No association was found with clinical disease characteristics. Heterozygous genotypes at the ARHGAP15 SNP was associated with lower ARHGAP15 expression in colon tissues. COLQ protein localized to the myenteric plexus in the colon. CONCLUSIONS: This study confirmed association of the ARHGAP15 and COLQ SNPs with diverticular disease in our patients but could not confirm FAM155A SNP association. Neither of these SNPs appeared to associate with more severe disease, but genotype at the ARHGAP15 SNP did impact expression of ARHGAP15 in the colon. Additionally, this study is the first to localize COLQ in the colon. Its presence in the myenteric nervous system suggests COLQ SNP variants may contribute to diverticular disease by altering motility.

Identification of a rare LAMB4 variant associated with familial diverticulitis through exome sequencing.

Diverticulitis is a chronic disease of the colon in which diverticuli, or outpouching through the colonic wall, become inflamed. Although recent observations suggest that genetic factors may play a significant role in diverticulitis, few genes have yet been implicated in disease pathogenesis and familial cases are uncommon. Here, we report results of whole exome sequencing performed on members from a single multi-generational family with early onset diverticulitis in order to identify a genetic component of the disease. We identified a rare single nucleotide variant in the laminin ß 4 gene (LAMB4) that segregated with disease in a dominant pattern and causes a damaging missense substitution (D435N). Targeted sequencing of LAMB4 in 148 non-familial and unrelated sporadic diverticulitis patients identified two additional rare variants in the gene. Immunohistochemistry indicated that LAMB4 localizes to the myenteric plexus of colonic tissue and patients harboring LAMB4 variants exhibited reduced LAMB4 protein levels relative to controls. Laminins are constituents of the extracellular matrix and play a major role in regulating the development and function of the enteric nervous system. Reduced LAMB4 levels may therefore alter innervation and morphology of the enteric nervous system, which may contribute to colonic dysmotility associated with diverticulitis.

Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis.

Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 × 10-18, odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 × 10-10, OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 × 10-11, OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study.

The TNFSF15 gene single nucleotide polymorphism rs7848647 is associated with surgical diverticulitis.

OBJECTIVE: To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis. BACKGROUND: A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohn's disease (CD), and pouchitis after restorative proctocolectomy. METHODS: In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 ± 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 ± 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 ± 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischer's exact test. RESULTS: In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk "G" allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity. CONCLUSIONS: The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making.

Regulated expression of leukocyte-specific transcript (LST) 1 in human intestinal inflammation.

INTRODUCTION: Leukocyte-specific transcript 1 (LST1) encoded peptides are involved in immunomodulation and nanotube-mediated cell-cell communication. The aim of this study was to assess the expression of LST1 in colonic epithelium and endothelium during intestinal inflammation. METHODS: LST1 expression was evaluated by RT-PCR, FACS, western blot analysis, and immunohistochemistry in intestinal epithelial Caco-2 cells, human intestinal microvascular endothelial cells and in human histological specimens from inflammatory bowel disease (IBD) patients and non-IBD colitis patients. RESULTS: LST1 expression was significantly increased upon proinflammatory stimulation in intestinal epithelial and endothelial cells. Furthermore, LST1 tissue expression was significantly enhanced in macroscopically inflamed colonic mucosal biopsies as compared to non-affected mucosal areas. CONCLUSIONS: This is the first report demonstrating regulated LST1 expression in human intestinal epithelial and microvascular endothelial cells and in inflamed colonic tissue from IBD patients. Proinflammatory expression of LST1 occurs in the setting of human IBD and is not restricted to immune cell populations. Future studies are needed to further elucidate the role of soluble and membrane-expressed LST1 in the regulation of mucosal intestinal immunity and inflammation as well as to reveal possible therapeutic implications.

A complex endocrine conundrum.

We describe a case of recurrent primary hyperparathyroidism, manifested as 3 metachronous parathyroid adenomata, in a 50 year-old woman who also had Hashimoto hypothyroidism, gastric gastrointestinal stromal tumour (GIST), cysts in liver and kidneys, 5 intestinal polyps (one of these a villous adenoma), diverticulitis and telangiectasia of lips. She did not have medullary thyroid carcinoma (MTC). Genetic analysis of the CDC73 gene [for Hyperparathyroidism-jaw tumor (HPT-JT)], MEN1 for Multiple Endocrine Neoplasia Type1, CDKN1B for MEN4, SDHB and SDHD for Paraganglioma/Pheochromocytoma susceptibility, VHL for von Hippel-Lindau Syndrome, BMPR1A and SMAD4 for Juvenile Polyposis Syndrome (JPS) (sequencing and MLPA), karyotype and array CGH (44 K) were all normal. She was found to be homozygous for a synonomous germline variant in exon 14 (p. Ser836Ser) of the RET oncogene. This RET variant is of unclear clinical significance, and has been previously reported both in normal individuals and in individuals with MTC. It is unlikely that homozygosity for the RET variant has been casual in the multiple pathologies that our patient has developed.

Downregulation of the ubiquitin-proteasome system in normal colonic macrophages and reinduction in inflammatory bowel disease.

BACKGROUND: In normal mucosa, intestinal lamina propria macrophages (IMACs) maintain tolerance against food antigens and the commensal bacterial flora. Several mechanisms have been identified that mediate tolerance. The ubiquitin-proteasome system (UPS) is a large multiprotein complex that degrades cellular proteins. As the UPS may modulate immune functions of IMACs, we performed a detailed investigation of UPS expression and function under normal conditions and in cells derived from patients suffering from inflammatory bowel disease (IBD). METHODS: IMACs were isolated from intestinal mucosa. mRNA expression of macrophages differentiated in vitro (i.v. MACs) and IMACs was compared by Affymetrix® oligonucleotide arrays. Quantitative Taqman-PCR was performed on five exemplary proteasomal and five ubiquitinylation genes each. Proteins were analyzed by immunohistochemistry and Western blotting. Proteasome function was assessed by a fluorimetric test. RESULTS: Affymetrix analysis showed downregulation of mRNA expression of almost all represented proteasomal and of 22 ubiquitination-associated genes in IMACs as compared to i.v. MACs and monocytes. By quantitative PCR, up to tenfold higher mRNA expression of 10 exemplary genes of the UPS (UBE2A, UBE2D2, UBE2L6, USP14, UBB and ATPase2, ß2, ß5, ß2i/MECL-1, ß5i/LMP7) was demonstrated in i.v. MACs as compared to IMACs. Immunohistochemistry and Western blots confirmed these findings in intestinal mucosa of controls and patients suffering from diverticulitis. In contrast, a significant increase in protein amounts was found in mucosa of patients with IBD. CONCLUSION: Reduced expression of subunits of the UPS in IMACs of normal mucosa supports the concept of the presence of a nonreactive, anergic macrophage phenotype in the gut under normal conditions. Reinduction in IMACs of IBD mucosa reflects activated IMACs which can present antigenic peptides and thus support inflammation.

Comparative analysis of the expression of metalloproteases and their inhibitors in resected crohn's disease and complicated diverticular disease.

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), are expressed in the gastrointestinal tract by different cellular types. Nevertheless, the imbalance between MMPs and TIMPs plays an important role in the physiopathology of diverse intestinal inflammatory processes. METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. Immunohistochemical staining of intestinal samples from surgical interventions from 30 patients with complicated Crohn's disease (CD) and 25 patients with diverticulitis were performed at the inflamed mucosa and in adjacent noninflamed mucosa. A reverse-transcription polymerase chain reaction (RT-PCR) analysis was performed to confirm the results obtained by immunohistochemistry. In addition, western blot experiments were carried out. RESULTS: CD inflamed mucosa showed higher global expression of MMP-2, MMP-9, and MMP-13 than diverticulitis inflamed mucosa. However, inflamed and noninflamed diverticulitis mucosal samples showed higher global expression of MMP-1, TIMP-1, and 3 than the CD samples. Epithelial cells of inflamed mucosa showed higher expression of MMP-2, 9, and 13 in CD than diverticulitis. However, the latter showed higher expression of TIMP-1. Similar differences for fibroblast-like cells and mononuclear inflammatory cells were found. CD samples presented an increased expression of MMPs and a decreased expression of TIMPs compared to diverticulitis. CONCLUSIONS: These results indicate a differential pattern of expression of MMPs and TIMPs in CD and diverticulitis and the necessity to study the potential role of MMP inhibitors as new protective agents in both diseases.

Distinct differences in tachykinin gene expression in ulcerative colitis, Crohn's disease and diverticular disease: a role for hemokinin-1?

BACKGROUND: In the intestine, the tachykinins substance P (SP) and neurokinin A (NKA) are found in neurons and have key roles in motility, secretion, and immune functions. A new tachykinin, hemokinin (HK-1), has been identified in non-neuronal cells in recent years and its role in intestinal inflammation is unclear. We aimed to examine the expression of genes encoding tachykinin peptides and receptors in colon from patients with ulcerative colitis (UC), Crohn's disease (CD), and acute diverticular disease (DD). METHODS: Human colon segments were dissected into mucosa and muscle, and evaluated for tachykinin and tachykinin receptor gene expression by real-time PCR. KEY RESULTS: In UC mucosa, the TAC4 gene (encoding HK-1) was 10-fold more abundant than in control mucosa (P < 0.01). Similarly, TAC1 (encoding SP and NKA) and TACR1 (encoding NK1 receptor) displayed 6-fold and 12-fold upregulation, respectively, in UC mucosa, but no change occurred in UC muscle. In contrast to UC, no difference was observed for any tachykinin genes in CD mucosa. In CD muscle, expression of TAC1 (P < 0.01), TAC4 and TACR1 (both P < 0.05) were moderately upregulated. In DD, there was a decrease in TACR1 (P < 0.05), and TACR2 (encoding NK2 receptor, P < 0.0001) in muscle compared with control. Histological staining showed increased collagen fibers between muscle bundles in DD smooth muscle. CONCLUSIONS & INFERENCES: We provide evidence for the first time that HK-1, like SP, may be involved in the pathophysiology of inflammatory bowel disease. Distinctly different expression patterns of tachykinin-related genes occur in UC, CD and DD.

Over-utilization of the J delta 3 gene-segment in Crohn's disease.

A majority of normal human intestinal intraepithelial lymphocytes (iIEL) are CD8+, express the alpha beta-T cell receptor (TCR) and are oligoclonal. The remainder of normal iIELs, which are also oligoclonal, express the gamma delta-TCR and preferentially utilize variable regions (V delta 1 and V delta 3) which are different from adult peripheral blood lymphocytes (V delta 2). The junctional region usage of gamma delta-TCRs in intestinal diseases is largely unknown. The aim of this study was to examine gamma delta-T cell clonality and junctional region usage of V delta 1 and V delta 3 transcripts in Crohn's Disease (CD) in comparison to several other chronic inflammatory diseases of the colon by polymerase chain reaction amplification, cloning and sequencing. As previously observed in normal subjects, all inflammatory cases examined, including CD (n = 3), ulcerative colitis (n = 1), diverticulitis (n = 1) and lymphocytic colitis (n = 1), the V delta 1 and V delta 3 transcripts contained reiterated sequences consistent with the expansion of gamma delta-T cells expressing these receptors. In 2/3 CD cases, but none of the non-CD inflammatory cases, transcripts containing J delta 3, a rarely used J delta, was observed among the V delta 1 and/or V delta 3 transcripts. Thus, in a subset of CD, gamma delta-T cells expressing J delta 3 may be expanded implicating a role for unique ligands that drive the expansion of T cells expressing these receptors.

Cochleo-saccular degeneration in one of three sisters with hereditary deafness, absent gastric motility, small bowel diverticulitis and progressive sensory neuropathy.

This is a report of cochleo-saccular degeneration found in temporal bones from a patient who had suffered from slowly progressive and total sensorineural deafness which had an inherited origin. At age 8, this patient began to complain of hearing loss, and by age 10 she was totally deaf. The patient was 1 of 3 female siblings who have suffered from an exactly identical progressive disease: deafness, absent gastric motility, small bowel diverticulitis and ulceration, and sensory neuropathy. The temporal bone pathology found in this case was the degenerative change in the cochlear duct and sacculus. No pathology was found in the utriculus and semicircular canals.