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1.
Transl Psychiatry ; 6: e817, 2016 05 24.
Article in English | MEDLINE | ID: mdl-27219343

ABSTRACT

Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT-BPD and SCZ-BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes, IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions-the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions.


Subject(s)
Autistic Disorder/genetics , Bipolar Disorder/genetics , Cerebral Cortex/metabolism , RNA, Messenger/metabolism , Schizophrenia/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Child, Preschool , Down-Regulation , Female , Frontal Lobe/metabolism , Gene Expression Profiling , Guanine Nucleotide Exchange Factors , High-Throughput Nucleotide Sequencing , Humans , Linear Models , Male , Microglia , Middle Aged , Prefrontal Cortex/metabolism , Sequence Analysis, RNA , Young Adult
2.
Neuroscience ; 302: 59-73, 2015 Aug 27.
Article in English | MEDLINE | ID: mdl-25463515

ABSTRACT

Parkinson's Disease (PD) is a chronic and progressive neurodegenerative disorder of unknown etiology. Autopsy findings, genetics, retrospective studies, and molecular imaging all suggest a role for inflammation in the neurodegenerative process. However, relatively little is understood about the causes and implications of neuroinflammation in PD. Understanding how inflammation arises in PD, in particular the activation state of cells of the innate immune system, may provide an exciting opportunity for novel neuroprotective therapeutics. We analyze the evidence of immune system involvement in PD susceptibility, specifically in the context of M1 and M2 activation states. Tracking and modulating these activation states may provide new insights into both PD etiology and therapeutic strategies.


Subject(s)
Immune System/physiology , Inflammation/etiology , Inflammation/pathology , Macrophages/physiology , Microglia/pathology , Parkinson Disease/complications , Animals , Humans , Macrophages/classification
3.
Neurobiol Dis ; 62: 160-71, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24121117

ABSTRACT

Recent evidence suggests that interneurons are involved in the pathophysiology of Huntington Disease (HD). Abnormalities in the function of interneurons expressing the calcium buffer parvalbumin (PV) have been observed in multiple mouse models of HD, although it is not clear how PV-positive interneuron dysfunction contributes to behavioral and synaptic deficits. Here, we use the cre-lox system to drive expression of mutant huntingtin (mthtt) in parvalbumin (PV)-positive neurons and find that mutant mice exhibit diffuse mthtt immunoreactivity in PV-rich areas at 10months of age and mthtt aggregates in PV-positive processes at 24months of age. At midlife, mutant mice are hyperactive and display impaired GABA release in the motor cortex, characterized by reduced miniature inhibitory events and severely blunted responses to gamma frequency stimulation, without a loss of PV-positive interneurons. In contrast, 24month-old mutant mice show normalized behavior and responses to gamma frequency stimulation, possibly due to compensatory changes in pyramidal neurons or the formation of inclusions with age. These data indicate that mthtt expression in PV-positive neurons is sufficient to drive a hyperactive phenotype and suggest that mthtt-mediated dysfunction in PV-positive neuronal populations could be a key factor in the hyperkinetic behavior observed in HD. Further clarification of the roles for specific PV-positive populations in this phenotype is warranted to definitively identify cellular targets for intervention.


Subject(s)
Hyperkinesis/metabolism , Inhibitory Postsynaptic Potentials , Interneurons/physiology , Motor Cortex/physiopathology , Nerve Tissue Proteins/metabolism , Nuclear Proteins/metabolism , Parvalbumins/metabolism , Age Factors , Animals , Brain/metabolism , Female , Huntingtin Protein , Hyperkinesis/physiopathology , Male , Mice , Mice, Transgenic , Mutation , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , gamma-Aminobutyric Acid/metabolism
4.
Ultrasound Obstet Gynecol ; 41(4): 366-74, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23239538

ABSTRACT

OBJECTIVE: To describe the sonographic features and pregnancy outcomes of placental mesenchymal dysplasia (PMD), an entity often misdiagnosed as molar pregnancy. METHODS: We reviewed PMD cases from our institution and performed a systematic review of the existing literature. Inclusion criteria for the review were diagnosis of PMD as defined by placental pathology, description of placental morphology on antenatal ultrasound and reporting of pregnancy outcomes. RESULTS: We found three cases of PMD at our institution. Patient 1 had elevated human chorionic gonadotropin (hCG) and an enlarged, hydropic placenta at 13 weeks, suggestive of a molar pregnancy. Patient 2 also had elevated hCG with large, vascular placental lakes on ultrasound suggesting placenta accreta or molar pregnancy. Case 3 involved placentomegaly and fetal anomalies suggestive of Beckwith-Wiedemann syndrome. From the literature review, 61 cases met the inclusion criteria. The most common sonographic features included enlarged (50%) and cystic (80%) placenta with dilated chorionic vessels. Biochemical aneuploidy screening abnormalities were relatively common as were fetal anomalies, Beckwith-Wiedemann syndrome and other genetic abnormalities. Pregnancy complications included intrauterine growth restriction (IUGR; 33%), intrauterine fetal death (IUFD; 13%), and preterm labor (33%). Pregnancies without fetal anomalies, IUGR, IUFD or preterm labor had normal neonatal outcomes despite PMD (9%). CONCLUSIONS: The differential diagnosis of PMD includes molar pregnancy and other placental vascular anomalies. PMD is associated with adverse pregnancy outcome, so heightened surveillance with genetic evaluation, serial growth scans and third-trimester assessment of wellbeing should be considered. PMD must be differentiated from gestational trophoblastic disease because management and outcomes differ.


Subject(s)
Fetal Death/diagnostic imaging , Fetal Diseases/diagnostic imaging , Hydatidiform Mole/diagnostic imaging , Placenta Diseases/diagnostic imaging , Placenta/pathology , Ultrasonography, Prenatal/methods , Beckwith-Wiedemann Syndrome/diagnostic imaging , Diagnosis, Differential , Female , Fetal Death/pathology , Fetal Diseases/pathology , Humans , Hydatidiform Mole/pathology , Infant, Newborn , Placenta/diagnostic imaging , Placenta Diseases/pathology , Pregnancy , Risk Factors
5.
Hepatology ; 48(5): 1549-57, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18846542

ABSTRACT

UNLABELLED: Primary biliary cirrhosis (PBC) is sometimes diagnosed based on a positive antimitochondrial antibody in the appropriate clinical setting without a liver biopsy. Although a liver biopsy can assess the extent of liver fibrosis and provide prognostic information, serum fibrosis markers avoid biopsy complications and sampling error and provide results as a continuous variable, which may be more precise than categorical histological stages. The current study was undertaken to evaluate serum fibrosis markers as predictors of clinical progression in a large cohort of PBC patients. Serial liver biopsy specimens and serum samples were collected every 2 years in 161 PBC subjects for a median of 7.3 years. Clinical progression was defined as development of one or more of the following events: varices, variceal bleed, ascites, encephalopathy, liver transplantation, or liver-related death. Serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and procollagen III aminopeptide were measured and entered into the previously validated enhanced liver fibrosis (ELF) algorithm. The ability of ELF, histological fibrosis, bilirubin, Model for End-Stage Liver Disease (MELD), and Mayo Risk Score to differentiate between individuals who would experience a clinical event from those who would not was evaluated at different time points. Event-free survival was significantly lower in those with high baseline ELF. Each 1-point increase in ELF was associated with a threefold increase in future complications. The prognostic performance of all tests was similar when performed close to the time of the first event. However, at earlier times in the disease process (4 and 6 years before the first event), the prognostic performance of ELF was significantly better than MELD or Mayo R score. CONCLUSION: The ELF algorithm is a highly accurate noninvasive measure of PBC disease severity that provides useful long-term prognostic information.


Subject(s)
Liver Cirrhosis, Biliary/therapy , Adult , Algorithms , Bilirubin/blood , Biopsy , Disease Progression , Fibrosis , Humans , Immunosuppressive Agents/therapeutic use , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/immunology , Liver Cirrhosis, Biliary/pathology , Methotrexate/therapeutic use , Middle Aged , Multicenter Studies as Topic , Prognosis , Treatment Outcome
7.
J Comp Pathol ; 128(4): 289-92, 2003 May.
Article in English | MEDLINE | ID: mdl-12834613

ABSTRACT

The white-throated woodrat is a principal host of Whitewater Arroyo (WWA) virus, an arenavirus, in the western United States. The purpose of the present study was to investigate the pathology of WWA infection in this species. Twenty-one animals (eight newborn, seven juvenile, and six adult) were inoculated with WWA virus and killed at varying intervals after inoculation. The most striking histological findings were lymphocytic meningitis and perivascular lymphocytic cuffing in the brains of the animals killed on day 85, 113 or 121. Arenaviral antigen was detected immunohistochemically in the brain of each affected animal, suggesting that the inflammatory lesions in the brain were caused by WWA virus. Comparisons of the results of tests for infectious virus and antigen in brain and other solid tissues indicated that immunohistochemistry may be a useful method for detection of WWA viral antigen in post-mortem specimens.


Subject(s)
Arenaviridae Infections/pathology , Arenavirus , Rodent Diseases/pathology , Sigmodontinae , Animals , Animals, Newborn , Antigens, Viral/immunology , Arenaviridae Infections/immunology , Arenaviridae Infections/virology , Arenavirus/immunology , Arenavirus/isolation & purification , Cerebral Cortex/pathology , Cerebral Cortex/virology , Female , Immunohistochemistry , Kidney/pathology , Male , Meningitis/pathology , Meningitis/virology , Neurons/immunology , Neurons/pathology , Neurons/virology , Rats , Rodent Diseases/immunology , Rodent Diseases/virology , Time Factors
8.
West Indian med. j ; 51(4): 254-256, Dec. 2002.
Article in English | LILACS | ID: lil-410909

ABSTRACT

Angiomatosis is a benign vascular lesion that has been described rarely in the breast. We describe a case in a seven-year-old boy of African descent who presented with progressively increasing, unilateral breast enlargement, the first such report in a male child. The patient underwent excisional biopsy of the breast mass followed by mastectomy. Pathologic examination revealed a diffuse proliferation of variably-sized, thin-walled vascular channels lined by flattened endothelium that showed negative immunohistochemical staining for von Willebrand factor, factor VIII-related antigen, CD34 and S-100 protein. There is no evidence of recurrence after 24 months of follow-up


Subject(s)
Child , Humans , Male , Angiomatosis/diagnosis , Breast Diseases/diagnosis , Immunohistochemistry , Angiomatosis/metabolism , Angiomatosis/pathology , Angiomatosis/surgery , Breast Diseases/metabolism , Breast Diseases/pathology , Breast Diseases/surgery , Mastectomy, Subcutaneous
9.
West Indian Med J ; 51(4): 254-6, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12632645

ABSTRACT

Angiomatosis is a benign vascular lesion that has been described rarely in the breast. We describe a case in a seven-year-old boy of African descent who presented with progressively increasing, unilateral breast enlargement, the first such report in a male child. The patient underwent excisional biopsy of the breast mass followed by mastectomy. Pathologic examination revealed a diffuse proliferation of variably-sized, thin-walled vascular channels lined by flattened endothelium that showed negative immunohistochemical staining for von Willebrand factor, factor VIII-related antigen, CD34 and S-100 protein. There is no evidence of recurrence after 24 months of follow-up.


Subject(s)
Angiomatosis/diagnosis , Breast Diseases/diagnosis , Angiomatosis/metabolism , Angiomatosis/pathology , Angiomatosis/surgery , Breast Diseases/metabolism , Breast Diseases/pathology , Breast Diseases/surgery , Child , Humans , Immunohistochemistry , Male , Mastectomy, Subcutaneous
10.
Gastroenterol Clin North Am ; 30(3): 637-64, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11586550

ABSTRACT

Chronic HIV-associated diarrhea is currently a field in flux. Improved noninvasive diagnostic tests, improved pathogen-specific regimens, and better empiric therapies may change some of the assumptions used to select algorithms for diagnostic evaluation and management. Any shift in the cause of diarrhea from pathogen-associated to idiopathic or a reduction in the overall incidence of diarrhea would have considerable impact. It is unclear how significant the problem of pathogen relapse in previous responders will become. Existing studies reviewed in this article show that the high diagnostic yield of endoscopy when stool tests are negative, coupled with significantly better outcomes when pathogens are identified, support the current practice of routine endoscopic evaluation. There currently are scant data on the economic impact of HIV-associated diarrhea as it relates to pathogen-specific and empiric therapy in the era of protease inhibitors. Such data would be integral to future evaluation of the impact of diagnostic and therapeutic strategies.


Subject(s)
AIDS-Related Opportunistic Infections/microbiology , Diarrhea/microbiology , AIDS-Related Opportunistic Infections/diagnosis , AIDS-Related Opportunistic Infections/drug therapy , Anti-Infective Agents/therapeutic use , Diarrhea/diagnosis , Diarrhea/drug therapy , Endoscopy, Gastrointestinal/methods , Feces/microbiology , Feces/virology , Humans
11.
Cancer Epidemiol Biomarkers Prev ; 10(10): 1055-62, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11588131

ABSTRACT

Incidence rates for adenocarcinoma of the esophagus and gastric cardia have been rising rapidly. We examined nutrient intake as a risk factor for esophageal and gastric cancers in a population-based case-control study in Connecticut, New Jersey, and western Washington state. Interviews were completed for cases with histologically confirmed esophageal adenocarcinoma (n = 282), adenocarcinoma of the gastric cardia (n = 255), esophageal squamous cell carcinoma (n = 206), and noncardia gastric adenocarcinoma (n = 352), along with population controls (n = 687). Associations between nutrient intake and risk of cancer were estimated by adjusted odds ratios (ORs), comparing the 75th versus the 25th percentile of intake. The following nutrients were significantly inversely associated with risk of all four tumor types: fiber, beta-carotene, folate, and vitamins C and B6. In contrast, dietary cholesterol, animal protein, and vitamin B12 were significantly positively associated with risk of all four tumor types. Dietary fat [OR, 2.18; 95% confidence interval (CI), 1.27-3.76] was significantly associated with risk of esophageal adenocarcinoma only. Dietary nitrite (OR, 1.65; 95% CI, 1.26-2.16) was associated with noncardia gastric cancer only. Vitamin C supplement use was associated with a significantly lower risk for noncardia gastric cancer (OR, 0.60; 95% CI, 0.41-0.88). Higher intake of nutrients found primarily in plant-based foods was associated with a reduced risk of adenocarcinomas of the esophagus and gastric cardia, whereas higher intake of nutrients found primarily in foods of animal origin was associated with an increased risk.


Subject(s)
Adenocarcinoma/epidemiology , Carcinoma, Squamous Cell/epidemiology , Diet/adverse effects , Esophageal Neoplasms/epidemiology , Stomach Neoplasms/epidemiology , Adenocarcinoma/etiology , Adult , Age Distribution , Aged , Carcinoma, Squamous Cell/diagnosis , Case-Control Studies , Confidence Intervals , Connecticut/epidemiology , Esophageal Neoplasms/etiology , Female , Humans , Incidence , Male , Middle Aged , New Jersey/epidemiology , Odds Ratio , Population Surveillance , Reference Values , Risk Assessment , Risk Factors , Sex Distribution , Stomach Neoplasms/etiology , Washington/epidemiology
12.
Eur J Hum Genet ; 9(9): 659-66, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11571553

ABSTRACT

Parkinson's disease (PD) is a common neurodegenerative disorder with clinical features of bradykinesia, rigidity, resting tremor and postural instability resulting from the deficiency of dopamine in the nigrostriatal system. Previously we mapped a susceptibility gene for an autosomal dominant form of PD to a 10.6 cM region of chromosome 2p (PARK3; OMIM 602404). A common haplotype shared by two North American kindreds (Families B and C) genealogically traced to Southern Denmark and Northern Germany suggested a founder effect. Here we report progress in the refinement of the PARK3 locus and sequence analysis of candidate genes within the region. Members of families B and C were genotyped using polymorphic markers, reducing the minimum common haplotype to eight markers spanning a physical distance of 2.5 Mb. Analysis of 14 genes within the region did not reveal any potentially pathogenic mutations segregating with the disease, implying that none of these genes are likely candidates for PARK3.


Subject(s)
Adaptor Proteins, Signal Transducing , Chromosomes, Human, Pair 2/genetics , Genetic Predisposition to Disease/genetics , Parkinson Disease/genetics , Proteins , Alcohol Oxidoreductases/genetics , Amino Acid Transport Systems/genetics , Chaperonins/genetics , Chromosome Mapping , DNA/chemistry , DNA/genetics , DNA, Complementary/chemistry , DNA, Complementary/genetics , DNA-Binding Proteins/genetics , Dynactin Complex , Early Growth Response Transcription Factors , Endosomal Sorting Complexes Required for Transport , Family Health , Female , Genotype , Haplotypes , Humans , Male , Membrane Proteins/genetics , Microsatellite Repeats , Microtubule-Associated Proteins/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Pedigree , Phosphoproteins/genetics , Poly(A)-Binding Proteins , Protein Tyrosine Phosphatases/genetics , RNA-Binding Proteins/genetics , Receptors, Retinoic Acid/genetics , Sequence Analysis, DNA , T-Cell Intracellular Antigen-1 , Transcription Factors/genetics , alpha-Glucosidases/genetics
13.
Int J Surg Pathol ; 9(2): 149-54, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11484503

ABSTRACT

A 71-year-old man with intestinal pseudo-obstruction was found to have a diffusely thickened adynamic small bowel with AA-amyloid in submucosal vessels and muscularis propria, foreign body giant cell reaction to amyloid, and necrotizing angiitis. The mucosa was unremarkable. Immunostains demonstrated numerous CD68+ monocyte/macrophages and CD8+ T cells associated with the amyloid deposits. The patient had no evidence of systemic vasculitis and no underlying cause for AA-amyloidosis was identified. Necrotizing angiitis coexistent with amyloid angiopathy has been reported in brain and temporal arteries, but not in the gastrointestinal tract and not with AA-amyloid. The inflammatory cell infiltrates in this case are consistent with a foreign-body and/or cell-mediated immunologic reaction to AA-amyloid, although a role for these cells in amyloid formation cannot be excluded.


Subject(s)
Amyloidosis/pathology , Gastrointestinal Diseases/pathology , Intestine, Small/pathology , Serum Amyloid A Protein/analysis , Vasculitis/pathology , Aged , Gastroscopy , Humans , Male
14.
Int J Cancer ; 93(1): 148-52, 2001 Jul 01.
Article in English | MEDLINE | ID: mdl-11391635

ABSTRACT

The worldwide rates for histology- and subsite-specific types of esophageal and gastric cancer reveal strikingly divergent patterns. The contribution of environmental and genetic factors has been explored in several high-incidence areas, but data on genetic influences are scarce for Western countries. Using data from a multicenter, population-based, case-control study on 1,143 cases and 695 controls in the United States, we evaluated whether a family history of digestive or other cancers was associated with an increased risk of esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261) or non-cardia gastric adenocarcinoma (n = 368). After adjusting for other risk factors, individuals reporting a family history of digestive cancers experienced no increased risk of either type of esophageal cancer but they were prone to adenocarcinomas of the gastric cardia [odds ratio (OR) = 1.34, 95% confidence interval (CI) 0.91-1.97] and non-cardia segments (OR =1.46, 95% CI 1.03-2.08). This familial tendency, particularly for non-cardia gastric tumors, was largely explained by an association with family history of stomach cancer (OR = 2.52, 95% CI 1.50-4.23). In addition, family history of breast cancer was associated with increased risks of esophageal adenocarcinoma (OR = 1.74, 95% CI 1.07-2.83) and non-cardia gastric adenocarcinoma (OR = 1.76, 95% CI 1.09-2.82). Also seen were non-significant familial associations of esophageal squamous-cell cancer with prostate cancer as well as non-cardia gastric cancer with leukemia and brain tumors, though these relationships must be interpreted with caution. Our data point to the role of familial susceptibility to gastric cancer, but not to any form of esophageal cancer, in the United States.


Subject(s)
Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/genetics , Neoplasms/epidemiology , Neoplasms/genetics , Stomach Neoplasms/epidemiology , Stomach Neoplasms/genetics , Adenocarcinoma/epidemiology , Adenocarcinoma/genetics , Adult , Age Distribution , Aged , Alcohol Drinking , Case-Control Studies , Confidence Intervals , Demography , Family , Family Characteristics , Female , Humans , Income , Male , Middle Aged , Odds Ratio , Racial Groups , Risk Assessment , Risk Factors , Smoking , United States/epidemiology
15.
Gastroenterology ; 120(7): 1657-65, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11375947

ABSTRACT

BACKGROUND & AIMS: To assess the prevalence of flat and depressed (F&D) colorectal adenomas in the United States, we performed a prospective study of 211 American patients. METHODS: Dye-assisted colonoscopy was performed in the presence of both an American and a Japanese investigator. RESULTS: F&D lesions were found in 22.7% of patients, and these were more likely to be adenomatous than polypoid lesions (82% vs. 67%; P = 0.03) and contained more invasive cancer (4.5% vs. 0%; P = 0.04), which also appeared to be at a disproportionately advanced stage. The average size of all F&D advanced lesions (high-grade dysplasia and cancer) was significantly smaller than comparable polypoid lesions (10.75 +/- 2.7 mm vs. 20 +/- 2.9 mm; P < 0.05). F&D adenomas showed significantly stronger fragile histidine triad (FHIT) expression and lower p53 reactivity than similarly sized polypoid adenomas, whereas proliferative and apoptotic indices were similar in both groups. CONCLUSIONS: We conclude that there is a significant prevalence of colonic F&D colorectal adenomas in this country and that these lesions have significantly different biologic features than polypoid lesions. The clinical and epidemiologic implications of these findings for American patients need to be addressed in further studies.


Subject(s)
Acid Anhydride Hydrolases , Adenoma/pathology , Colorectal Neoplasms/pathology , Neoplasm Proteins , Adenoma/epidemiology , Adult , Aged , Colorectal Neoplasms/epidemiology , Female , Humans , Incidence , Male , Middle Aged , North America/epidemiology , Prevalence , Prospective Studies , Proteins/analysis , fas Receptor/analysis
16.
J Clin Invest ; 107(5): 585-93, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11238559

ABSTRACT

The epithelial cells of the gastrointestinal tract are exposed to toxins and infectious agents that can adversely affect protein folding in the endoplasmic reticulum (ER) and cause ER stress. The IRE1 genes are implicated in sensing and responding to ER stress signals. We found that epithelial cells of the gastrointestinal tract express IRE1beta, a specific isoform of IRE1. BiP protein, a marker of ER stress, was elevated in the colonic mucosa of IRE1beta(-/-) mice, and, when exposed to dextran sodium sulfate (DSS) to induce inflammatory bowel disease, mutant mice developed colitis 3-5 days earlier than did wild-type or IRE1beta(+/-) mice. The inflammation marker ICAM-1 was also expressed earlier in the colonic mucosa of DSS-treated IRE1beta(-/-) mice, indicating that the mutation had its impact early in the inflammatory process, before the onset of mucosal ulceration. These findings are consistent with a model whereby perturbations in ER function, which are normally mitigated by the activity of IRE1beta, participate in the development of colitis.


Subject(s)
Colitis/chemically induced , Dextran Sulfate , Heat-Shock Proteins , Inflammatory Bowel Diseases/etiology , Intestinal Mucosa/metabolism , Membrane Proteins , Protein Serine-Threonine Kinases/physiology , Animals , Carrier Proteins/biosynthesis , Colitis/metabolism , Colitis/pathology , Colon/metabolism , Colon/pathology , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Chaperone BiP , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Intercellular Adhesion Molecule-1/biosynthesis , Intestinal Mucosa/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Chaperones/biosynthesis , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism
17.
Gastroenterology ; 119(6): 1537-47, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11113075

ABSTRACT

BACKGROUND & AIMS: Enteropathy is a frequent complication of diclofenac and other nonsteroidal anti-inflammatory drugs, yet little is known about the underlying mechanism. One possibility is that reactive metabolites of diclofenac form adducts with enterocyte macromolecules, as previously shown for liver. We addressed this possibility by using immunohistochemistry to detect diclofenac adducts. METHODS: Rats were treated orally with diclofenac (10-100 mg/kg) and killed after 1-24 hours, and their gastrointestinal (GI) tracts were evaluated for ulcer number and area. Adduct distribution and intensity were assessed by immunohistochemistry by using a technique to simultaneously process and stain multiple intestinal rings. RESULTS: Drug treatment led to dose-dependent formation of both adducts and ulcers only in small intestine and only in animals with intact enterohepatic circulation. Adducts formed within enterocytes by 1 hour, translocated to the brush border, preceded ulceration and vascular protein leakage, and were intense at sites of ulceration. Adducts and ulcers exhibited a parallel distribution within intestinal quintiles: 3rd > 5th >> 1st. CONCLUSIONS: Diclofenac treatment resulted in the formation of drug adducts in enterocytes. Because this molecular change occurred before ulceration, was dose dependent, and exhibited concordant distribution with extent of ulceration, the results suggest a causal role for drug adduct formation in diclofenac enteropathy.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Diclofenac/adverse effects , Diclofenac/metabolism , Enterocytes/metabolism , Intestinal Diseases/chemically induced , Ulcer/chemically induced , Animals , Bile/metabolism , Dose-Response Relationship, Drug , Intestinal Diseases/pathology , Male , Rats , Rats, Sprague-Dawley , Time Factors , Tissue Distribution , Ulcer/pathology
18.
J Clin Microbiol ; 38(8): 3110-1, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10921991

ABSTRACT

West Nile virus was recovered from the brain of a red-tailed hawk that died in Westchester County, N.Y., in February 2000. Multiple foci of glial cells, lymphocytes, and a few pyknotic nuclei were observed in the brain. Three to 4 days after inoculation of Vero cells with brain homogenates, cytopathic changes were detected. The presence of West Nile virus antigen in fixed cells or cell lysates was revealed by fluorescent antibody testing or enzyme-linked immunosorbent assay, respectively. Furthermore, Reverse transcriptase-PCR with primers specific for the NS3 gene of West Nile virus resulted in an amplicon of the expected size (470 bp). Electron microscopy of thin sections of infected Vero cells revealed the presence of viral particles approximately 40 nm in diameter, within cytoplasmic vesicles. The demonstration of infection with the West Nile virus in the dead of the winter, long after mosquitoes ceased to be active, is significant in that it testifies to the survival of the virus in the region beyond mosquito season and suggests another route of transmission: in this case, prey to predator.


Subject(s)
Bird Diseases/virology , Raptors/virology , West Nile Fever/veterinary , West Nile virus/classification , West Nile virus/isolation & purification , Animals , Brain/virology , New York
19.
Cancer Causes Control ; 11(3): 231-8, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10782657

ABSTRACT

OBJECTIVE: The incidence of esophageal adenocarcinoma has risen rapidly in the past two decades, for unknown reasons. The goal of this analysis was to determine whether gastroesophageal reflux disease (GERD) or the medications used to treat it are associated with an increased risk of esophageal or gastric cancer, using data from a large population-based case-control study. METHODS: Cases were aged 30-79 years, newly diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or non-cardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were chosen by random digit dialing and from Health Care Financing Administration rosters. Data were collected using an in-person structured interview. RESULTS: History of gastric ulcer was associated with an increased risk of non-cardia gastric adenocarcinoma (OR 2.1, 95% CI 1.4-3.2). Risk of esophageal adenocarcinoma increased with frequency of GERD symptoms; the odds ratio in those reporting daily symptoms was 5.5 (95% CI 3.2-9.3). Ever having used H2 blockers was unassociated with esophageal adenocarcinoma risk (OR 0.9, 95% CI 0.5-1.5). The odds ratio was 1.3 (95% CI 0.6-2.8) in long-term (4 or more years) users, but increased to 2.1 (95% CI 0.8-5.6) when use in the 5 years prior to the interview was disregarded. Risk was also modestly increased among users of antacids. Neither GERD symptoms nor use of H2 blockers or antacids was associated with risk of the other three tumor types. CONCLUSIONS: Individuals with long-standing GERD are at increased risk of esophageal adenocarcinoma, whether or not the symptoms are treated with H2 blockers or antacids.


Subject(s)
Adenocarcinoma/epidemiology , Carcinoma, Squamous Cell/epidemiology , Esophageal Neoplasms/epidemiology , Gastroesophageal Reflux/epidemiology , Histamine H2 Antagonists/therapeutic use , Stomach Neoplasms/epidemiology , Adenocarcinoma/etiology , Adult , Aged , Antacids/therapeutic use , Carcinoma, Squamous Cell/etiology , Case-Control Studies , Esophageal Neoplasms/etiology , Female , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/drug therapy , Humans , Male , Middle Aged , Risk Factors , Stomach Neoplasms/etiology , Stomach Ulcer/complications , Washington/epidemiology
20.
Dig Dis Sci ; 45(3): 614-20, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10749341

ABSTRACT

Although clinical reports note aging and gender as risk factors for NSAID therapy associated gastroenteropathy, neither variable has been examined in an animal model. We addressed this unknown by comparing the responses of young (4 months) and old (22 months) rats of both genders to oral treatment with diclofenac (10 or 50 mg/kg). Diclofenac produced gastric ulcers only in old rats, with markedly larger lesions in females. In contrast, the small intestines in old rats of both genders given the 50 mg/kg dosage had >30% fewer ulcers and a fourfold decrease in area of ulceration compared to young rats. The small intestine was the only site of lesions after the 10 mg/kg dosage and showed one gender influence, namely, a transiently faster time course of ulcer development in females. Old and young rats given 50 mg/kg showed similar declines in serum levels of the vascular permeability indices-total protein and albumin-despite reduced intestinal damage in the old animals, which suggests additive vascular leakage across the gastric lesions that were evident only in old animals. Serum biochemistry showed no evidence of hepatotoxicity or dysfunction, consonant with small intestine as the primary target for diclofenac toxicity in rats. We provide the first experimental evidence for an aging influence on the gastrointestinal target site of a nonaspirin NSAID.


Subject(s)
Aging/physiology , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Diclofenac/adverse effects , Intestinal Diseases/chemically induced , Intestine, Small/drug effects , Stomach Ulcer/chemically induced , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Capillary Permeability/drug effects , Diclofenac/pharmacology , Female , Intestine, Small/pathology , Male , Rats , Rats, Sprague-Dawley , Sex Factors , Stomach Ulcer/pathology , Ulcer/chemically induced
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