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PubMed1994

Objective and subjective sleep disturbances in patients with rheumatoid arthritis. A reappraisal.

OBJECTIVE: To assess objective and subjective evidence of sleep disturbances in patients with rheumatoid arthritis (RA) and to examine correlations between parameters of inflammatory activity and sleep pathology. METHODS: Nineteen RA patients and 19 age-matched healthy control subjects underwent all-night polysomnography on 2 consecutive nights. RA patients were also evaluated for daytime sleepiness by mean sleep latency test and responded to a self-report questionnaire on their first night. RESULTS: Whereas normal sleep architecture is conserved in RA, we confirmed former findings of severe sleep fragmentation and an enhanced presence of primary sleep disorders. No correlation exists between RA activity and the sleep disorders. Subjective assessment was not consistent with the objective evidence of sleep disruption, unlike the findings in patients with fibrositis. CONCLUSION: Sleep is severely disturbed in patients with RA, regardless of the inflammatory disease activity. The specificity of the sleep disorders assessed needs confirmation, as does specific sleep therapy for these patients.

Adult↗
PubMed2004

Fine-needle aspiration of Riedel's disease: report of a case and review of the literature.

The cytomorphological features of a case of Riedel's thyroiditis (Riedel's disease) in a 37-yr-old woman are reviewed. The patient presented with a diffusely enlarged thyroid gland with extension to carotid and jugular vessels bilaterally. A fine-needle aspiration of the right lobe of the thyroid demonstrated moderate cellularity with fragments of fibrous tissue with bland spindle-shaped cells and myofibroblasts. The patient subsequently underwent a bilateral subtotal thyroidectomy with removal of two-thirds of both lobes of the thyroid. A frozen section diagnosis of Riedel's disease was later confirmed on paraffin sections. Here we describe the cytological findings of a case of Riedel's disease and provide some helpful clues in distinguishing it from other forms of thyroiditis such as fibrosing variant of Hashimoto's thyroiditis, subacute thyroiditis, or granulomatous thyroiditis and from malignancy with which it can be confused both clinically and cytologically.

Biopsy, Fine-Needle↗
PubMed2002

Prenatal screening for cystic fibrosis: an economic analysis.

Cystic fibrosis (CF) is the most common life-shortening genetically transmitted disease in Denmark with a birth prevalence of 1 in 4700, resulting in 12-15 new cases of cystic fibroses annually. The aim of this study is to disclose the societal resource implications of introducing a population wide prenatal screening programme for cystic fibrosis in Denmark. The present analysis is limited to the monetary consequences of introducing a screening programme, where costs of screening are compared to the potential benefits measured in cost savings involved if births of CF patients are avoided. Screening costs in a Danish setting were estimated at DKK 2 771 262 ( pound sterlings 231 438) per aborted affected fetus in the first screening round, stabilising at DKK 1 864 594 ( pound sterlings 155 383) per aborted affected fetus at subsequent screening rounds. Comparing this figure with the estimated benefits of avoiding a CF case (DKK 2.1-4.4 million; pound sterlings 175 000-366 667) suggests that introducing a screening programme for cystic fibrosis will be net cost saving irrespective of the perspective of the analysis, assumptions on replacement children and method of estimating long-term production gains/losses.

Abortion, Legal↗
PubMed2002

Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature.

BACKGROUND: Eosinophilic angiocentric fibrosis (EAF) is a rare fibroinflammatory lesion of the sinonasal tract that occurs mainly in young to middle-aged female patients. Only two previous cases affecting male patients have been reported, and its etiopathogenesis remains unknown. The authors report on the third case of the entity in a male patient and review the 12 previously reported cases. CASE REPORT: A 52-year-old male patient was initially seen with a 15 years history of allergic rhinitis, progressive nasal obstruction, and left-sided hearing loss. All laboratory tests were unremarkable, except the nasal discharge eosinophil count that showed a conspicuous eosinophilia. The video-assisted-nasofibroscopic examination and CT scans disclosed a thickened deviated nasal septum with a subjacent infiltrative lesion. The histologic analysis of the nasal septum showed a variable mixed inflammatory cellular infiltration mainly composed of eosinophils, plasma cells, and histiocytes with a perivascular distribution; in other areas, an angiocentric fibrosing lesion with a peculiar perivascular onion-skin pattern was observed. The patient had a partial resection of the lesion with symptomatic control. CONCLUSIONS: The presence of rhinitis and nasal eosinophilia in our case associated with the clinical aspects of the previously reported cases further support an allergic cause for EAF.

Eosinophils↗
PubMedDate not supplied

Extrahepatic biliary atresia in a rhesus monkey (Macaca mulatta).

Extrahepatic biliary atresia was observed in a 6-week-old female rhesus monkey. Jaundice and conjugated hyperbilirubinemia were detected at the age of 6 days and persisted throughout life. At 6 weeks of age, the diagnosis of extrahepatic biliary atresia was established at exploratory laparotomy, and bile duct remnants were biopsied. Histological examination of these specimens showed inflammatory and fibrosing lesions similar to those observed in humans with extrahepatic biliary atresia. Because of serologic evidence of Reovirus 3 infection in human patients with extrahepatic biliary atresia, serum of the affected monkey was tested for antibodies to this virus. Three sequential serum samples obtained during the course of illness showed persistently high Reovirus 3 titers which are consistent with but do not prove concurrent Reovirus 3 infection. This report represents the first documented case of spontaneous extrahepatic biliary atresia in a nonhuman primate and suggests that this species may be suitable for further investigation of the pathogenesis of this disease.

Animals↗
PubMedDate not supplied

Immunologic analysis of mononuclear cells in liver tissues and blood of patients with primary sclerosing cholangitis.

Using monoclonal antibodies to surface antigens, we typed and quantitated the mononuclear cells (MNCs) infiltrating liver tissues from 23 patients with primary sclerosing cholangitis. The circulating T lymphocytes were also enumerated by flow cytometry in 12 of these patients. In blood, T lymphocytes and especially T8+ cells were decreased. T cells were the major components of MNCs (78%) in portal tracts. Few of these cells were Tac+ or HLA-DR+. Total MNCs (929 +/- 90 vs. 106 +/- 18 in controls) included 11% M1+ and 8% B1+ cells. Aggregates of T4+ and T8+ cells were common in portal areas. The portal T4/T8 ratio of 1.27 +/- 0.1 was significantly (p less than 0.01) different than that around proliferating bile ductules (0.8 +/- 0.1). The T8+ and M5+ cells localized in these areas of proliferation and infiltrated ductal epithelium. On the other hand, T4+ cells accumulated on the parenchymal side of fibrosed tissue and densely surrounded certain intralobular bile ducts. Even late in the disease, variability in the extent of MNCs infiltration, ductal proliferation and periductal fibrosis was seen in each biopsy.

Adolescent↗
PubMed1993

Contribution of sinusoidal endothelial liver cells to liver fibrosis: expression of transforming growth factor-beta 1 receptors and modulation of plasmin-generating enzymes by transforming growth factor-beta 1.

Transforming growth factor-beta 1 is an important cytokine in the pathophysiology of liver fibrosis, stimulating the production of extracellular matrix. Whether this cytokine can also control the degradation of matrix proteins in liver cells has not been investigated. Because plasmin is an important protease for the degradation of matrix glycoproteins, we investigated whether sinusoidal endothelial liver cells could contribute to fibrosing liver disease through the modulation of plasmin-generating enzymes in response to transforming growth factor-beta 1. Sinusoidal endothelial cells from guinea pig liver were investigated in pure monolayer culture. Using 125I-labelled transforming growth factor-beta, we demonstrated high-affinity binding sites on sinusoidal endothelial cells at a density of 9.3 x 10(2) per cell, and a dissociation constant of about 5.5 x 10(-11) mol/L. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the known three classes of membrane receptors for transforming growth factor-beta. Using biosynthetic labeling of proteins with 35S-methionine, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we showed that sinusoidal endothelial cells produce and secrete plasminogen activator inhibitor type 1 from the beginning of culture. Treatment of confluent cell cultures for 24 hr with transforming growth factor-beta 1 increased synthesis and release of plasminogen activator inhibitor type 1. The response was almost maximal at a concentration of 1 ng transforming growth factor-beta/ml and paralleled the increased synthesis of fibronectin. On reverse fibrin autography we proved that transforming growth factor-beta 1 stimulated the release of functionally active plasminogen activator inhibitor type 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice.

In alcoholic steatohepatitis, hepatic microvascular changes have pathogenic significance for hepatocellular function, perisinusoidal fibrosis, and portal hypertension. It is unclear whether similar changes occur in other forms of steatohepatitis. We therefore examined whether hepatic microvascular dysfunction occurs in fibrosing steatohepatitis induced by feeding mice a high-fat methionine- and choline-deficient (MCD) diet. Using in vivo microscopic--as well as histological and electron microscopic--methods, together with measurements of alanine aminotransferase (ALT), lipid content, and oxidative stress, hepatic microvascular structure and function were studied in relation to inflammatory and fibrotic changes during evolution of steatohepatitis. At 3 weeks of MCD diet intake, serum ALT was elevated and hepatic steatosis was pronounced. By 5 weeks, necroinflammatory change was noteworthy, and by 8 weeks perisinusoidal fibrosis was established. Compared with mice receiving the high-fat diet supplemented with methionine and choline (controls), levels of hepatic lipid and lipoperoxides were elevated at 3 weeks and beyond. The numbers of perfused sinusoids were significantly reduced at each time point. Enlarged, fat-laden hepatocytes together with perivascular fibrosis narrowed sinusoidal lumens, making vessels tortuous and impairing sinusoidal perfusion. At 3 and 5 weeks, MCD diet caused significant increases in phagocytic activity of macrophages in centrilobular regions. By 8 weeks, macrophage activity was less striking, but the number of leukocytes adherent to the sinusoidal lining had increased 5-fold compared with controls. In conclusion, these results are consistent with a dysfunctional hepatic microvasculature. Thus, microvascular changes may contribute to progressive liver injury in metabolic and toxic forms of steatohepatitis.

Animals↗
PubMed2007

Hepatic fibrosis 2006: report of the Third AASLD Single Topic Conference.

The Third American Associated for the Study of Liver Diseases (AASLD)-sponsored Single Topic Conference on hepatic fibrosis was held in June 2006. The conference was both international, with 6 countries represented, and cross-disciplinary, linking the basic molecular and cellular biology of fibrogenic cells to clinical trial design for emerging antifibrotic therapies. The specific goals of the conference were: (1) to consolidate knowledge about the natural history of fibrosis; (2) to clarify potential endpoints and markers; (3) to emphasize new antifibrotic targets developed on the basis of advances in basic science; and (4) to understand current critical issues pertaining to clinical trial design. Given the tremendous growth of the field and the constraints of a 2-day format, the selection of speakers was a challenge. A number of topics not included in the oral presentations were featured at poster sessions, lending breadth and depth to the meeting as a whole. Surprising new themes emerged about molecular, clinical, and regulatory aspects of the field, and a consensus emerged that hepatic fibrosis has matured into an integrated discipline that promises to significantly improve the prognosis of patients with fibrosing liver disease.

Animals↗
PubMed1996

Hepatitis B and C coinfections and persistent hepatitis B infections: clinical outcome and liver pathology after transplantation.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common complications after orthotopic liver transplantation (OLT), but the liver pathology and clinical outcomes of HBV infection with HCV coinfection have not been thoroughly examined. In this study, we used the polymerase chain reaction (PCR) to detect HBV and HCV in pre- and post-OLT sera of 38 patients and correlated the findings with clinical outcome and liver pathology. Of 13 patients who were HBV and HCV negative before OLT, 9 acquired HBV infection, and 4 developed acquired HBV and HCV coinfections after OLT. Persistent HBV infections were present in 10 patients. Three patients with pre-OLT HBV infections developed persistent HBV and acquired HCV coinfections after OLT; 5 with pre-OLT HCV infections developed acquired HBV and persistent HCV coinfections after OLT, and 7 had persistent HBV and HCV coinfections before and after OLT. Portal/periportal inflammation was the same in all groups; however, lobular inflammation and fibrosis were more severe in patients with persistent HBV infections and in those with acquired HBV and HCV coinfections. Two major histopathological patterns were present in patients with HBV and HCV coinfections, one with predominant features of HCV infection, and the other with those of HBV infection. Patients with post-OLT HBV and HCV coinfections had survival rates similar to those with acquired HBV infection, whereas patients with persistent HBV infections experienced more allograft loss caused by chronic hepatitis or fibrosing cytolytic hepatitis, and had a more dire clinical outcome than the others. Although the limited numbers reported in this study prevent a definitive conclusion, our data suggest that in patients with HBV and HCV coinfections, the presence of HCV may improve the clinical outcome as compared with the expected outcome of persistent HBV infection alone.

Adult↗
PubMed1996

Hepatitis B virus mutations in the pre-S genome before and after liver transplantation.

Mutational changes in the pre-S region of hepatitis B virus (HBV) were analyzed in 20 patients who experienced HBV reinfection after orthotopic liver transplantation (OLT). HBV DNA was extracted from patient sera before and after OLT. The pre-S sequence was amplified via polymerase chain reaction, subcloned, sequenced, and analyzed. In 18 of 20 patients, mutational changes were found in the pre-S region pre- or post- OLT; 11 showed point mutations (1-10) and 7 cases major changes (insertions/deletions). For the point mutations, there was no trend in the selection of wild-type (wt) HBV before or after OLT in the pre-S region. Additional HBV reinfection during hepatitis B surface antigen antibody (anti-HBS) administration had no influence on selection pressure in the pre-S region. In contrast, insertions/deletions were more frequently found before OLT. In the 7 patients with deletions/insertions, changes in the hepatocyte attachment site were not seen after OLT. Interestingly, the only patient with changes in a major virus population after OLT had changes in the CCAAT-box of the S-promoter. As shown by gel shift analysis, this mutation was associated with loss of specific binding to this element and thus probably led to dysregulation of S-gene transcription. Major changes in the pre-S genome are mainly seen before OLT, and HBV reinfection does occur with the intact hepatocyte attachment sites after OLT. Anti-HBs (hepatitis B immune globulin [HBIg]) creates no selection pressure on the pre-S region. The mutation in the CCAAT-box of the S-promoter potentially leads to its dysregulation and may be associated with the occurrence of fibrosing cholestatic hepatitis after OLT.

Adult↗
PubMed1975

Leukocyte adherence inhibition and specific immunoreactivity in malignant melanoma.

The leukocyte adherence inhibition (LAI) test has been used to assess specific anti-tumour immunoreactivity in 80 patients with malignant melanoma, 21 of whom had apparently been successfully treated by surgery, and 44 control subjects. Reaction with melanoma extracts in vitro enabled the activity of blood leukocytes to be detected by inhibition of their adherence to glass, while serum was tested for factors which modified this inhibition. Of the patients with tumours (ranging from primary melanoma in situ to advanced disseminated disease), 22/24 had active leukocytes and 50/58 has serum blocking factor; two of the sera, from patients with regressing tumours were unblocking. After surgery with no clinical recurrence, leukocytes continued to be active except when tested several years after operation. Blocking factor rapidly disappeared in 16/20 patients tested, and in several patients examined serially the serum became unblocking. In three cases, persistence of serum blocking was followed by clinical diagnosis of metastases. Leukocyte activity was nerver detected in control subjects (0/10), many of whom had other kinds of tumours or skin lesions. Blocking activity in serum was found in only 3/38 controls with no history of melanoma (1 had a fibrosing cellular blue naevus and 2 had liver disease). Thus the LAI test correlated well with clinical and pathological findings, and shows great promise for the reliable, rapid and specific immunodiagnosis of malignant melanoma.

Adult↗
PubMed1991

Fetal myofibroblast-like cells isolated from post-radiation fibrosis in human breast cancer.

Cells were isolated from post-radiation fibrosis biopsies of patients with recurrent breast carcinoma. These cells were identified as fibroblasts and compared with fibroblasts from normal breast tissues for their proliferative activities, chromosome number and for the presence of various components of the extracellular matrix and cytoskeleton. The proliferative activity of the fibrosis-derived fibroblasts did not significantly differ from that of normal breast fibroblasts. Both cell types required serum to grow and did not form colonies in soft agar. Cells from 2 of the 3 fibroses analyzed displayed aneuploid karyotypes with multiple structural abnormalities. All of the fibroblastic cells produced types I, III and V collagen, fibronectin and vimentin. However, in contrast to normal breast fibroblasts, fibrosis-derived cells produced high amounts of oncofetal fibronectin. In addition, fibrosis of fibroblasts also expressed the alpha-actin isoform which is specific for smooth-muscle cells. These results suggest that post-radiation fibrosis in malignant breast contains atypical fibroblasts with fetal and myofibroblastic characteristics.

Breast Neoplasms↗
PubMed1991

Relative quantification of collagen mRNA in fibroblasts by a radioactive polymerase chain reaction technique.

A radioactive polymerase chain reaction (PCR) method has been developed for the relative quantification of the human alpha-2 chain of type I collagen [hu alpha-2(I)] in cells. cDNAs generated by reverse transcription from the total pool of cytoplasmic RNA serve as a template for polymerase chain reaction amplification of a hu alpha-2(I) cDNA primed by two sequence-specific synthetic oligonucleotides. The distinctive 390 bp hu alpha-2(I) cDNA and two Aval fragments of 220 and 170 bp are identified by agarose gel electrophoresis. alpha-32P-dCTP of defined specific activity is included in the PCR reaction and the 390 bp cDNA is excised from the electrophoresis gel to permit direct radioactive quantification of hu alpha-2(I) mRNA. The amount of hu alpha-2(I) mRNA expressed in as few as 111 fibroblasts was determined reliably. In contrast, the hu alpha-2(I) mRNA from at least 5 x 10(5) fibroblasts was required for detection by Northern blot analysis developed with the same cDNA probe radiolabelled with alpha-32P-dCTP by random priming. Human bronchoalveolar lavage (BAL) fluids of six patients with fibrosing lung diseases stimulated the level of expression of hu alpha-2(I) mRNA in cultured human fibroblasts as determined by this technique. The radioactive PCR method thus quantifies hu alpha-2(I) mRNA in fibroblasts with sufficient sensitivity to study fibroblast activation in vitro and detect fibroblast stimuli in human clinical samples.

Autoradiography↗
PubMed2005

Increased serum levels of endostatin in patients with idiopathic pulmonary fibrosis.

Endostatin is an angiogenesis inhibitor that is an endogenously produced proteolytic fragment of type XVIII collagen. Serum levels of endostatin have been studied extensively in patients with malignant diseases. Recently, elevated serum endostatin levels were observed in patients with systemic sclerosis accompanying pulmonary fibrosis. To determine whether elevated serum endostatin can be observed in patients with idiopathic pulmonary fibrosis (IPF), we measured serum levels of endostatin in 69 patients with benign respiratory disease using an ELISA kit. The median of the serum endostatin levels in these patients was 50.8 pg/mL. Seven of 11 patients (63.6%) with collagen disease-associated pulmonary fibrosis (CDPF), and 19 of 24 patients (79.2%) with IPF had higher serum endostatin levels than the median level of the 69 patients. There was no statistical difference in serum endostatin levels between the patients with IPF and those with CDPF (P=0.7898). Serum endostatin levels in 24 patients with IPF were significantly higher than those in 34 patients with respiratory diseases other than IPF and CDPF (P=0.0001). Elevated serum levels of endostatin were observed in patients with IPF. Although the mechanisms are unclear, elevated serum levels of endostatin may be related to the fibrosing process in the lung.

Adult↗
PubMed1987

Immunological mediators of wound healing and fibrosis.

T-lymphocytes, monocytes, and macrophages, which are the central constituents of immunological and chronic inflammatory reactions, generate numerous polypeptides and other factors capable of stimulating and modulating the proliferation and functions of fibroblasts. These principles differ widely in structure, target cell preference, and functional specificity. The involvement of immunological mediators of fibroblast activities in normal wound healing has not been defined, but a role in some chronic fibrosing disorders, including rheumatoid arthritis, has been suggested by the findings of functionally relevant concentrations in affected tissues. The elucidation of both the pathways of production of fibroblast-activating factors (FAFs) and the determinants of fibroblast responses will permit new approaches to the diagnosis and treatment of deficiencies in wound healing and of abnormal fibrosis.

Antigens, Neoplasm↗
PubMed1990

Inhibition of alveolar macrophage cytotoxicity by asbestos: possible role of prostaglandins.

Asbestosis and silicosis are chronic, fibrosing lung diseases due to prolonged inhalation of asbestos fibers or silica particles. However, little is known about the implication of these toxic dusts on cell-mediated cytotoxicity. Among the first types of cells that are in contact with the dusts are the alveolar macrophages (AM). We studied the effect of different concentrations of UICC chrysotile asbestos and silica on 18-h cytotoxicity of AM against tumor necrosis factor (TNF)-resistant P815 target cells or TNF-sensitive L929 target cells. Rat AM, obtained by bronchoalveolar lavage, were incubated for 2 h with 20, 50, or 100 micrograms/ml chrysotile or silica before the addition of target cells. AM cytotoxicity was significantly inhibited at greater than 20 micrograms/ml of chrysotile. In contrast, silica did not inhibit AM-mediated cytotoxicity at any concentration used. Asbestos, but not silica, caused significant production of PGE2 by macrophages and target cells. Addition of the cyclooxygenase inhibitor indomethacin to our system abolished all inhibition by asbestos. These results suggest that the inhibition of AM-mediated cytotoxicity by chrysotile was caused by prostaglandins, and that fibrogenic particles differ in their capacity to modulate AM function.

Animals↗
PubMed2005

Liver transplantation in HIV-infected recipients.

Liver transplantation is being evaluated as a therapeutic option for human immunodeficiency virus (HIV)-infected patients with end-stage liver disease, but experience is still scarce. We describe the outcome of 4 HIV-infected patients who underwent liver transplantation in our hospital between July 2002 and April 2003. HIV-infected liver transplant recipients meet the same standard criteria for transplantation as do HIV-negative candidates. In addition, HIV infected persons are required to have a CD4 T-cell count greater than 100/mL (CD4 T-cells are targets for HIV infection). Immunosuppressive regimens, perioperative surgical prophylaxis, and prophylaxis for opportunistic infections are standard in the Liver Transplantation Unit in our hospital. Four patients, including 3 former intravenous drug users, received a liver transplant (2 from deceased donors and 2 from living donors), with a median follow-up of 510 days. Three patients (75%) are alive, with 1 death occurring 17 months posttransplantation in a patient who developed fibrosing cholestatic hepatitis. Rejection occurred in 1 patient, and was managed with no complications. Hepatitis C virus (HCV) recurrence occurred in 3 patients. HIV-infection has remained under control with antiretroviral treatment. A combination of 3 nucleoside analogs was used in 3 patients, with no need for drug adjustments. No opportunistic infections or other significant infectious complications developed. In conclusion, orthotopic liver transplantation seems a safe therapeutic option in the short term for HIV-infected persons with end stage liver disease, including patients with a history of drug abuse. If indicated, an antiretroviral regimen consisting of 3 nucleosides could be used to avoid interactions with immunosuppressive drugs.

Adult↗