RESUMO
BACKGROUND: The neural crest is a multipotent cell type unique to the vertebrate lineage and capable of differentiating into a large number of varied cell types, including ganglia of the peripheral nervous system, cartilage, and glia. An early step in neural crest specification occurs at the neural plate border, a region defined by the overlap of transcription factors of the Zic, Msx, and Pax families. RESULTS: Here we identify a novel chick gene with close homology to double-stranded RNA-binding protein Interleukin enhancer binding factor 3 (ILF-3) in other species. Our results show that chick Ilf-3 is required for proper expression of the transcription factor, Zic-1, at the neural plate border. CONCLUSION: We have identified a novel chick gene and show it has a role in the correct specification of Zic-1 at the neural plate border.
Assuntos
Crista Neural/metabolismo , Placa Neural/embriologia , Placa Neural/metabolismo , Proteínas do Fator Nuclear 90/metabolismo , Fatores de Transcrição/metabolismo , Animais , Embrião de Galinha , Galinhas , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Crista Neural/citologia , Proteínas do Fator Nuclear 90/genética , Fatores de Transcrição/genéticaRESUMO
Generalized Arterial Calcifications of Infancy (GACI) is an extremely rare autosomal recessive genetic condition, mostly due to pathogenic variations in the ENPP1 gene (GACI1, MIM #208000, ENPP1, MIM #173335). To date 46 likely pathogenic or pathogenic distinct variations in ENPP1 have been described, including nonsense, frameshift, missense, splicing variations, and large deletions. Here we report a case of GACI in a male newborn with a homozygous stop-loss variant in ENPP1 treated in Nancy Regional University Maternity Hospital. Based on proband main clinical signs, clinical exome sequencing was performed and showed a deletion of one nucleotide leading to frameshift and stop-loss (NM_006208.3 (ENPP1):c.2746del,p.(Thr916Hisfs*23)). Clinical presentation is characterized by primary neonatal arterial hypertension resulting in hypertrophic cardiomyopathy decompensated by three cardiogenic shocks and a neonatal deep right sylvian stroke. The child died at 24 days of life. This is the first report of a pathogenic stop-loss variant in ENPP1. It is an opportunity to remind clinicians of GACI disease, a rare and severe etiology in neonates with severe hypertension, and possibility of bisphosphonates therapy.
Assuntos
Hipertensão , Acidente Vascular Cerebral , Calcificação Vascular , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Mutação da Fase de Leitura , Mutação , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/genética , Calcificação Vascular/patologiaRESUMO
Hereditary breast cancers account for up to 5-10 % of breast cancers and a majority are related to the BRCA1 and BRCA2 genes. However, many families with breast cancer predisposition do not carry any known mutations for BRCA1 and BRCA2 genes. We explored the incidence of rare large rearrangements in the coding, noncoding and flanking regions of BRCA1/2 and in eight other candidate genes--CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. A dedicated zoom-in CGH-array was applied to screen for rearrangements in 472 unrelated French individuals from breast-ovarian cancer families that were being followed in eight French oncogenetic laboratories. No new rearrangement was found neither in the genomic regions of BRCA1/2 nor in candidate genes, except for the CHEK2 and BARD1 genes. Three heterozygous deletions were detected in the 5' and 3' flanking regions of BRCA1. One large deletion introducing a frameshift was identified in the CHEK2 gene in two families and one heterozygous deletion was detected within an intron of BARD1. The study demonstrates the usefulness of CGH-array in routine genetic analysis and, aside from the CHEK2 rearrangements, indicates there is a very low incidence of large rearrangements in BRCA1/2 and in the other eight candidate genes in families already explored for BRCA1/2 mutations. Finally, next-generation sequencing should bring new information about point mutations in intronic and flanking regions and also medium size rearrangements.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Adulto , Neoplasias da Mama Masculina/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
In this study, the lifetime prevalence of stressful events and current posttraumatic stress disorder (PTSD) in the general adult population in the Netherlands were examined, and risk groups for PTSD were determined. A representative sample of 2,238 adults (>or=18 years) in the Netherlands completed digital questionnaires by computer-assisted self-interviewing. In total, 52.2% of the population reported at least one stressful event throughout their life. The estimated prevalence of current PTSD in the total population was 3.8%. Rape and physical assault were the stressful events most likely to be associated with PTSD, witness of injury the least likely. Stressful medical events were moderately associated with PTSD. Prevalence of PTSD was elevated among single women and middle-aged men.
Assuntos
Acontecimentos que Mudam a Vida , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Estupro/psicologia , Fatores de Risco , Distribuição por Sexo , Fatores Socioeconômicos , Violência/psicologiaRESUMO
Mild cognitive impairment describes a cognitive decline greater than expected for an individual's age and education level that does not interfere significantly with activities of daily life. In the recent years concepts of "mild cognitive impairment" with divergent definitions have been discussed as potential preclinical forms of dementia. The etiology of cognitive impairment is heterogeneous and it can be promoted or caused by numerous somatic factors. Relevant somatic factors include hypertension, diabetes mellitus, heart failure, chronic obstructive airways disease and bronchial asthma. Cognitive impairment may be facilitated by hypercholesterolemia, chronic renal failure, hypothyroidism, testosterone deficiency, minimal hepatic encephalopathy, HIV- and hepatitis C-infection. Knowledge and diagnosis of these somatic factors is essential in cognitive impairment, as diligent treatment may lead to improve cognitive performance and postpone the manifestation of dementia.
Assuntos
Transtornos Cognitivos/complicações , Idoso , Doenças Cardiovasculares/complicações , Transtornos Cognitivos/sangue , Cuidados Críticos , Doenças do Sistema Endócrino/complicações , Feminino , Humanos , Infecções/complicações , Pneumopatias/complicações , Masculino , Doenças Metabólicas/complicações , Pessoa de Meia-Idade , Neoplasias/complicaçõesAssuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Deleção de Sequência , Adulto , Idoso , Idoso de 80 Anos ou mais , Reparo de Erro de Pareamento de DNA/genética , Molécula de Adesão da Célula Epitelial , Éxons , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Fatores de RiscoRESUMO
CpG island hypermethylation is a mechanism of gene silencing that can be usurped by neoplastic cells to inactivate undesirable genes. In the colon, hypermethylation often starts in normal mucosa as a function of age and is markedly increased in cancer. To test the hypothesis that subjects at increased risk of colon cancer have higher levels of methylation in their nonneoplastic mucosa, we studied methylation patterns of five genes in the normal and dysplastic mucosa of patients with ulcerative colitis (UC), a condition associated with a marked increased risk of colon cancer. One gene (Mlh1) was unmethylated in all tissues examined. All four remaining genes had low but detectable levels of methylation in the epithelium of UC patients without evidence of dysplasia, and this methylation was not different from non-UC controls. By contrast, all four genes were highly methylated in dysplastic epithelium from high-grade dysplasia (HGD)/cancer patients with UC; methylation in HGD versus controls averaged 40.0% versus 7.4% (P = 0.00003) for ER, 44.0% versus 3.0% (P < 0.00003) for MYOD, 9.4% versus 2.4% (P = 0.03) for p16 exon 1, and 57.5% versus 30.6% (P = 0.01) for CSPG2. Importantly, three of the four genes were also highly methylated in the normal appearing (nondysplastic) epithelium from these same HGD/cancer patients, indicating that methylation precedes dysplasia and is widespread in these patients. Compared with controls, methylation averaged 20.1% versus 7.2% (P = 0.07) for ER, 18.4% versus 3.0% (P < 0.008) for MYOD, and 7.9% versus 2.4% (P = 0.007) for p16 exon 1. These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. Furthermore, the data suggest that chronic inflammation is associated with high levels of methylation, perhaps as a result of increased cell turnover, and that UC can be viewed as resulting in premature aging of colorectal epithelial cells.
Assuntos
Colite Ulcerativa/genética , Ilhas de CpG , Metilação de DNA , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Fatores Etários , Idoso , Proteínas de Transporte , Proteoglicanas de Sulfatos de Condroitina/genética , Neoplasias do Colo/genética , Genes p16/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Lectinas Tipo C , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína MyoD/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares , Lesões Pré-Cancerosas/genética , Receptores de Estrogênio/genética , VersicanasRESUMO
ras oncogene mutations and microsatellite instability (MIN) have been described in pancreatic cancer studies from paraffin blocks and fresh frozen tissue. We sought to determine whether they could be detected in endoscopic retrograde cholangiopancreatography-derived pancreatic juice. ras mutations were detected in the pancreatic juice of 40% (2 of 5) of patients with pancreatic cancer and 2 of 5 patients with pancreatitis. MIN was detected at a single locus in the pancreatic juice of 40% of pancreatic cancer patients and at > or = 2 loci of 100% of pancreatitis patients. The finding of MIN in pancreatitis specimens was verified in studies performed on paraffin blocks. MIN was not detected in normal pancreas controls. All of the cancer patients who had ras mutations in their pancreatic juice also had evidence of MIN at one or more loci (P < or = 0.05), suggesting that MIN is associated with the development of a ras mutation. More importantly, the finding of MIN in pancreatitis specimens suggests that MIN can occur in nonneoplastic conditions of the pancreas and may represent the saturation of an intact mismatch repair system.
Assuntos
Adenocarcinoma/genética , DNA Satélite/genética , Genes ras , Mutação , Neoplasias Pancreáticas/genética , Pancreatite/genética , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Espécies Reativas de OxigênioRESUMO
Microsatellite instability (MIN) has been detected in many cancer types; however, recently we also observed it in the nonneoplastic but inflammatory setting of pancreatitis. Consequently, we sought to examine whether MIN was present in another inflammatory condition, ulcerative colitis (UC). MIN was found in 50% of UC patients whose colonic mucosa was negative for dysplasia, 46% of those with high-grade dysplasia, and 40% of those with cancer but in none of the ischemic or infectious colitis controls (P<0.03). Thus, UC patients may have MIN within mucosa that has no histological evidence of neoplastic change. MIN in this setting may reflect the inability of DNA repair mechanisms to compensate for the stress of chronic inflammation, and may be one mechanism for the heightened neoplastic risk in UC.
Assuntos
Colite Ulcerativa/genética , DNA Satélite/genética , Colo/química , Colo/patologia , DNA Satélite/análise , Marcadores Genéticos , Humanos , Mucosa Intestinal/química , Repetições de Microssatélites/genéticaRESUMO
Patients with long-standing ulcerative colitis (UC) are at increased risk for colon cancer. These cancers are thought to arise from preexisting dysplasia in a field of abnormal cells that often exhibits aneuploidy and p53 abnormalities. Using dual color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosomes 8, 11, 17, and 18, we demonstrate that chromosomal instability (CIN) is present throughout the colon of UC patients with high-grade dysplasia or cancer. In rectal biopsies that were negative for dysplasia, abnormalities in chromosomal arms, especially losses, were most common, whereas centromere gains were most common in dysplasia and cancer. The frequency and type of abnormalities varied between the chromosomes examined; chromosome 8 was the least affected, and 17p loss was found to be an early and frequent event. Chromosomal arm instability showed 100% sensitivity and specificity for distinguishing control biopsies from histologically negative rectal biopsies from these UC patients, raising the possibility that a screen for CIN might detect the subset of UC patients who are at greatest risk for development of dysplasia and cancer. These results suggest that dysplasia and cancer in UC arise from a process of CIN that affects the entire colon; this may provide the mutator phenotype that predisposes to loss of tumor suppressor genes and evolution of cancer.
Assuntos
Aberrações Cromossômicas , Colite Ulcerativa/genética , Neoplasias do Colo/etiologia , Lesões Pré-Cancerosas/etiologia , Centrômero , Colite Ulcerativa/complicações , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
The very low density lipoprotein/apolipoprotein-E receptor (VLDLR) is the newest member of the low density lipoprotein receptor (LDLR) family. Very little is known about VLDLR localization and regulation. Immunohistochemical analysis of human placenta with a specific polyclonal antibody detected VLDLR in syncytiotrophoblast and intermediate trophoblast cells. VLDLR transcripts were also localized in these cells by in situ hybridization histochemistry. In addition, VLDLR messenger RNA (mRNA) was detected in villous core endothelial cells and cells appearing to be Hofbauer cells. Northern blot analysis of placenta revealed a 2.6-fold increase in VLDLR mRNA at term compared to that in the first trimester. The regulation of VLDLR expression was studied in JEG-3 and BeWo choriocarcinoma cells, two trophoblast-derived cell lines. Treatment of these cells with 8-bromo-cAMP caused a profound suppression of VLDLR message, whereas LDLR transcripts were increased. Incubation of JEG-3 cells with 25-hydroxycholesterol did not lead to sterol negative feedback on VLDLR gene expression, unlike LDLR mRNA, which declined markedly. Insulin (200 mg/L) up-regulated VLDLR message in JEG-3 cells 2-fold, as did the fibrate hypolipidemic drug, clofibric acid. We conclude that 1) VLDLR is expressed in human placental trophoblast cells in a pattern consistent with a role in placental lipid transport; 2) VLDLR expression is high at term relative to that in the first trimester; and 3) the trophoblast VLDLR is subject to down-regulation by cAMP and up-regulation by insulin and fibrate hypolipidemic drugs.
Assuntos
Metabolismo dos Lipídeos , Placenta/metabolismo , Receptores de Lipoproteínas/fisiologia , Trofoblastos/metabolismo , Apolipoproteínas/metabolismo , Transporte Biológico , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Previsões , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Receptores de Lipoproteínas/genética , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
Parallel to its established causal association with both infectious mononucleosis (IM) and young adulthood Hodgkin disease (YAHD), we propose a hypothesis that "delayed" primary EBV infection (i.e., primary infection occurring during adolescence or adulthood) is associated with elevated breast cancer risk. We evaluated this hypothesis with two investigations, one descriptive and the other analytic. The descriptive study used international/United States cancer registry data to assess the association between incidence rates of breast cancer and those of YAHD. The incidence rates of the seemingly unrelated neoplasms were strongly correlated (correlation coefficients of 0.74 and 0.88 for international and United States data, respectively; these were higher than the correlation coefficients of YAHD with two other cancers that we considered). Populations with higher incidence rates corresponded to those with higher likelihood of delayed primary EBV infection. The analytical study was based on a population-based case-control study of breast cancer in middle-aged women. Age-adjusted odds ratios of breast cancer in women who reported a history of IM, relative to women who did not, increased monotonically from 0.55 [95% confidence interval (CI), 0.05-6.17] for women with 0-9 years of age at IM onset to 2.67 (CI, 1.04-6.89) for women with > or =25 years of age at IM onset (P = 0.016). An older age at tonsillectomy, another surrogate of delayed EBV exposure, was also associated with increased risk of breast cancer: odds ratios, 0.92 (CI, 0.57-1.48) and 1.76 (CI, 1.15-2.69) for women with tonsillectomy at 0-4 years of age and > or =15 years of age, respectively (P = 0.018). Adjusting for additional potential confounders did not modify the associations appreciably. The implications of the findings and a potential biological mechanism are presented.
Assuntos
Neoplasias da Mama/virologia , Infecções por Vírus Epstein-Barr/complicações , Adolescente , Adulto , Idade de Início , Neoplasias da Mama/etiologia , Fatores de Confusão Epidemiológicos , Estudos Epidemiológicos , Feminino , Humanos , Razão de Chances , Fatores de Risco , Programa de SEER , Fatores de Tempo , TonsilectomiaRESUMO
Backwash ileitis and postcolectomy pouchitis are well-recognized complications of ulcerative colitis (UC), whereas inflammation of the proximal small intestine is not. In contrast, small intestinal disease at any level is common in Crohn's disease (CD). Despite this well-established and accepted dogma, rare cases of histologically proven diffuse duodenitis (DD) associated with UC appear in the literature. In this study, we report our experience with similar cases exhibiting this unusual inflammatory phenomenon. Routine histologic sections from four cases of DD associated with well-documented UC were reviewed and the findings correlated with all available medical records. Multiple endoscopic biopsies showing histologic features of UC and colectomy specimens confirming severe ulcerative pancolitis were available for all cases. Varying degrees of active chronic inflammation and architectural mucosal distortion identical to UC were observed in pre- and postcolectomy duodenal biopsies of one of four and four of four cases, respectively. Similar inflammatory patterns were present postoperatively in the ileum in three of four cases and in the jejunum in one case. Endorectal pull-through (ERPT) procedures were performed in three of four patients and an end-to-end ileorectal anastomosis was done in one patient. Despite extensive upper gastrointestinal tract involvement, none of the patients developed postsurgical Crohn's-like complications during a follow-up period of 12 to 54 months. This suggests that patients with pancolitis and DD do not necessarily have CD, but rather may have UC and, most importantly, that successful ERPT procedures may be performed in these patients.
Assuntos
Colite Ulcerativa/complicações , Duodenite/etiologia , Adolescente , Adulto , Biópsia , Criança , Colectomia , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Doença de Crohn/etiologia , Duodenite/patologia , Endoscopia Gastrointestinal , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Understanding the pathology of familial pancreatic carcinoma may provide important insights into pancreatic tumorigenesis. We now describe in detail the pancreatic pathology of an autosomal dominant pancreatic carcinoma kindred with distinct clinical, genetic, and pathologic manifestations differing from all other reported forms of sporadic or familial pancreatic neoplasia. Affected individuals develop a prodrome of diabetes mellitus, pancreatic exocrine insufficiency, and characteristic pancreatic imaging abnormalities. Eleven family members have undergone total pancreatectomy, revealing a unique and characteristic fibrocystic, lobulocentric pancreatic atrophy. This was patchy to diffuse in distribution and was invariably associated with a nesidioblastosis-like endocrine cell hyperplasia. All but one resected pancreas demonstrated glandular epithelial dysplasia: 10 had low-grade dysplasia (pancreatic intraductal neoplasia grade II of III or PanIN II) and seven also had high-grade dysplasia (pancreatic intraductal neoplasia grade III of III or PanIN III). Dysplasia was multifocal in small-to medium-sized duct-like structures within areas of acinar atrophy, microcystic change, and mucinous hyperplasia. Two pancreata had carcinomas of multiple and unusual histologic subtypes, including small cell undifferentiated carcinoma and giant cell anaplastic carcinoma. The findings in this kindred yield important information on a distinctive and previously unrecognized pancreatic cancer precursor. Recognition of this entity may help identify additional kindreds and perhaps the underlying genetic defect. As is the case for other familial cancers, the as yet unknown specific genetic defect may have wider implications for pancreatic cancer in general.
Assuntos
Carcinoma/patologia , Fibrose Cística/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Predisposição Genética para Doença , Ilhotas Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Adulto , Atrofia/patologia , Biomarcadores/análise , Carcinoma/complicações , Carcinoma/genética , Fibrose Cística/complicações , Fibrose Cística/genética , Feminino , Genes Dominantes , Humanos , Hiperplasia/patologia , Imuno-Histoquímica , Ilhotas Pancreáticas/química , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Linhagem , Lesões Pré-Cancerosas/patologiaRESUMO
BACKGROUND: Although most studies have not demonstrated decreased patient or graft survival in kidney-alone allograft recipients infected with hepatitis C virus (HCV), the impact of HCV infection on patient and graft survival in HCV-infected kidney-pancreas recipients has not been studied. METHODS: We undertook a retrospective cohort analysis of 137 kidney-pancreas transplant recipients who were transplanted between January 1989 and May 1996. HCV infection was determined by a positive polymerase chain reaction. Relative risk of death and graft failure was calculated using the Cox proportional hazards model with time-dependent covariates. Relative risks were adjusted (aRR) to control for the number of OKT3-treated rejections and cytomegalovirus status of the recipient at the time of transplantation. RESULTS: Mean length of follow-up was 30.4 months in the HCV-infected patients compared with 31.7 months in noninfected patients. Seven (5.1%) patients were infected with HCV before transplant, one (1%) relapsed after transplantation, and four (2.9%) acquired the infection after transplantation. The HCV-infected group had a 3.7-fold (95% confidence interval [CI], 1.0-13.5) increased risk of death after transplant compared with the HCV-negative group, with an aRR of 5.5 (95% CI, 1.5-20.0). Death in the HCV-infected group (n=3) was generally the result of liver failure and sepsis, whereas death for those in the uninfected group (n=11) was primarily of cardiovascular origin. Patients infected with HCV were 3.4-fold (95% CI, 1.1-10.1) more likely to develop kidney graft failure than HCV-negative patients with an aRR of 5.1 (95% CI, 1.7-15.4). The risk of pancreatic allograft failure was not significantly increased. CONCLUSIONS: We conclude that HCV infection in kidney-pancreas transplant patients results in a significantly increased risk of kidney allograft failure and death.
Assuntos
Hepatite C/complicações , Transplante de Rim/efeitos adversos , Transplante de Rim/imunologia , Transplante de Pâncreas/efeitos adversos , Transplante de Pâncreas/imunologia , Adulto , Biópsia , Estudos de Coortes , Feminino , Sobrevivência de Enxerto/fisiologia , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/patologia , Humanos , Transplante de Rim/mortalidade , Fígado/patologia , Masculino , Transplante de Pâncreas/mortalidade , RNA Mensageiro/sangue , Estudos Retrospectivos , Fatores de Tempo , Transplante Homólogo/mortalidadeRESUMO
Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted >2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.
Assuntos
Glomerulonefrite Membranoproliferativa/virologia , Hepatite C/fisiopatologia , Transplante de Fígado , Adulto , Biópsia , Creatinina/urina , Feminino , Mesângio Glomerular/patologia , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Glomerulonefrite Membranoproliferativa/urina , Antígenos HLA-DQ/imunologia , Hepatite C/induzido quimicamente , Hepatite C/urina , Humanos , Hipertensão/etiologia , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteinúria/urina , Proteínas Recombinantes , Estudos Retrospectivos , EscleroseRESUMO
The CYP4A1 isoenzyme induced in rodents by peroxisome proliferators is known to be repressed at a pretranslational level by interferon. Interleukin-1beta (IL-1beta) also reduces CYP4A1-related 12-laurate hydroxylase activity in cultured fetal rat hepatocytes after induction by clofibric acid. In this fetal hepatocyte model, IL-1beta and interleukin-6 (IL-6) were tested for their ability to reduce 12-laurate hydroxylase activity, CYP4A1 apoprotein content, and the CYP4A1 mRNA level. IL-1beta and IL-6 strongly diminished CYP4A1 activity and apoprotein and mRNA levels in a dose- and time-dependent manner. CYP4A1 expression is thus down-regulated at a pretranslational level by these cytokines. As it has been shown that the peroxisome proliferator-activated receptor alpha (PPAR alpha) mediates the induction of the CYP4A1 gene by a peroxisome proliferator, the capacity of IL-1beta or IL-6 to modulate the PPAR alpha mRNA level was tested. It was found that IL-1beta and IL-6 both repress the induction of PPAR alpha expression exerted by the combined action of clofibric acid and dexamethasone. However, even at the highest concentration (10 ng/mL) tested for both cytokines, IL-1beta as well as IL-6 failed to abolish the induction of CYP4A1 by dexamethasone. The mechanism of the protective effect of the synthetic glucocorticoid on CYP4A1 repression by interleukins is discussed.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Dexametasona/farmacologia , Interleucina-1/farmacologia , Interleucina-6/farmacologia , Oxigenases de Função Mista/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Ácido Clofíbrico/farmacologia , Citocromo P-450 CYP4A , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fígado/citologia , Fígado/embriologia , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-DawleyRESUMO
Morphologic assessment of dysplasia in Barrett esophagus, despite limitations, remains the basis of treatment. We rigorously tested modified 1988 criteria, assessing intraobserver and interobserver reproducibility. Participants submitted slides of Barrett mucosa negative (BE) and indefinite (IND) for dysplasia, with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and with carcinoma. Two hundred fifty slides were divided into 2 groups. The first 125 slides were reviewed, without knowledge of the prior diagnoses, on 2 occasions by 12 gastrointestinal pathologists without prior discussion of criteria. Results were analyzed by kappa statistics, which correct for agreement by chance. A consensus meeting was then held, establishing, by group review of the index 125 slides, the criteria outlined herein. The second 125-slide set was then reviewed twice by each of the same 12 pathologists, and follow-up kappa statistics were calculated. When statistical analysis was performed using 2 broad diagnostic categories (BE, IND, and LG v HG and carcinoma), intraobserver agreement was near perfect both before and after the consensus meeting (mean kappa = 0.82 and 0.80). Interobserver agreement was substantial (kappa = 0.66) and improved after the consensus meeting (kappa = 0.70; P =.02). When statistical analysis was performed using 4 clinically relevant separations (BE; IND and LGD; HGD; carcinoma), mean intraobserver kappa improved from 0.64 to 0.68 (both substantial) after the consensus meeting, and mean interobserver kappa improved from 0.43 to 0.46 (both moderate agreement). When statistical analysis was performed using 4 diagnostic categories that required distinction between LGD and IND (BE; IND; LGD; HGD and carcinoma), the pre-consensus meeting mean intraobserver kappa was 0.60 (substantial agreement), improving to 0.65 after the meeting (P <.05). Interobserver agreement was poorer, with premeeting and postmeeting mean values unchanged (kappa = 0.43 at both times). Interobserver agreement was substantial for HGD/carcinoma (kappa = 0.65), moderate to substantial for BE (kappa = 0.58), fair for LGD (kappa = 0.32), and slight for IND (kappa = 0.15). The intraobserver reproducibility for the diagnosis of dysplasia in BE was substantial. Interobserver reproducibility was substantial at the ends of the spectrum (BE and HG/carcinoma) but slight for IND. Both intraobserver and interobserver variation improved overall after the application of a modified grading system developed at a consensus conference but not in separation of BE, IND, and LGD. The criteria used by the group are presented. HUM PATHOL 32:368-978.
Assuntos
Esôfago de Barrett/diagnóstico , Algoritmos , Esôfago de Barrett/patologia , Técnicas de Laboratório Clínico/normas , Humanos , Fixação de TecidosRESUMO
Paraffin-embedded surgical biopsy material from 17 Hürthle cell tumors of the thyroid was examined for DNA content by flow cytometry to assess the diagnostic and prognostic utility of ploidy determinations in these rare tumors. Both adenomas (11 cases) and carcinomas (6 cases) were studied. As a control for methods, ten randomly selected normal autopsy thyroids were analyzed, all of which demonstrated normal diploid DNA content. Among the Hürthle cell tumors, however, aneuploid peaks were present in six adenomas (55%) and in four carcinomas (67%). Similarly, polyploid DNA peaks in the absence of other aneuploid peaks were present in two adenomas and two carcinomas (18% and 33%, respectively). These findings demonstrate the limited value of aneuploidy or polyploidy as diagnostic features for malignancy in Hürthle cell tumors of the thyroid. As for prognosis, there does not appear to be any unfavorable prognostic significance for abnormal DNA content in histologically benign Hürthle cell tumors treated by surgical excision because no metastases or recurrences occurred in this group at a mean disease-free follow-up of 50 +/- 19 months for six aneuploid lesions and 19 +/- 7 months for two polyploid adenomas. Preliminary data suggest that aneuploidy may, however, have an important prognostic value for histologically defined Hürthle cell carcinomas, because the only patient to die from the tumor in this series had an aneuploid Hürthle carcinoma. Thus, the authors' data indicate that the diagnostic utility of DNA content in Hürthle cell tumors is extremely limited and that there does not appear to be any negative prognostic significance for aneuploidy in histologically defined Hürthle cell adenomas.
Assuntos
Adenoma/patologia , Carcinoma/patologia , DNA/análise , Citometria de Fluxo , Neoplasias da Glândula Tireoide/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
With improving therapeutic protocols, confirmation of microsporidiosis has become increasingly important. We designed a study to determine the best screening method(s) for microsporidian detection in biopsy specimens. Forty-two small intestinal biopsy specimens from 31 immunocompromised patients (68% AIDS) were stained (hematoxylin-eosin [H & E], modified trichrome, Warthin-Starry, and Brown-Brenn) and polarized. Polymerase chain reaction and Southern blot assays were performed on all positive cases. Microsporida were detected in nine cases (21%) by modified trichrome (all patients with AIDS). Of these, seven were Brown-Brenn positive, and five Warthin-Starry positive. Two cases polarized on H & E and three on special stains. Four of nine positive cases were confirmed by molecular studies. We found polarization to be the least sensitive screening method. The modified trichrome was the most sensitive when screening for microsporidiosis in paraffin-embedded biopsy specimens. Furthermore, combining Brown-Brenn or Warthin-Starry with the trichrome stain helps exclude false-positive results due to granular artifacts (eg, eosinophils, Paneth cells).