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Epstein-Barr virus (EBV) and gastric carcinoma in Malaysian patients.

Epstein-Barr virus (EBV) has consistently been detected in the tumour cells of nasopharyngeal carcinoma and lymphoepithelial-like carcinoma of the salivary glands, and have occasionally been found in similar tumours at other sites. Moreover, recent studies from various parts of the world including the Orient have shown about 10% of gastric carcinomas to be EBV-associated. We studied 50 gastric carcinomas from Malaysia to investigate its association with EBV in the Malaysian population. They comprised 37 intestinal and 13 diffuse type carcinomas from 32 male and 18 female patients, age range from 29 to 86 years with an ethnic distribution of Malay: Chinese: Indian with the ratio of 4: 27: 19. EBV gene and gene-expression were examined in sections of formalin-fixed, paraffin-embedded tissue using commercially available probes for detecting EBV encoded RNAs (EBERs) by in situ hybridization and monoclonal antibodies to EBV latent membrane protein-1 (LMP-1) by standard immunohistochemistry. Five of 50 gastric carcinomas showed EBER intranuclear positivity in all tumour cells but no cases expressed LMP-1. The EBV-associated cases were classified as intestinal type in 4 and diffuse type in one case and all were histologically unremarkable. EBV-positive tumours were found in 3 Chinese and 2 Indian patients with none in the small Malay group. Four EBV-positive tumours were in male patients, with age-range of 65 to 86 years. We conclude that our findings of about 10% of Malaysian gastric carcinomas being EBV-associated is in line with the results from other parts of the world and from other ethnic groups.

Adult↗

Effects of the N2144S mutation on backbone dynamics of a TB-cbEGF domain pair from human fibrillin-1.

The calcium-binding epidermal growth factor-like (cbEGF) module and the transforming growth factor beta-binding protein-like (TB) module are the two major structural motifs found in fibrillin-1, the extracellular matrix (ECM) protein defective in the Marfan syndrome (MFS). An MFS-causing mutation, N2144S, which removes a calcium ligand in cbEGF32, does not detectably affect fibrillin-1 biosynthesis, rate of secretion, processing, or deposition of reducible fibrillin-1 into the ECM. Since the residue at position 2144 is normally engaged in calcium ligation, it is unable to mediate intermolecular interactions. We have shown previously that this mutation does not affect the folding properties of the TB or cbEGF domains in vitro, but does decrease calcium-binding in cbEGF and TB-cbEGF domain constructs. Here, we use NMR spectroscopy to probe the effects of the N2144S mutation on backbone dynamic properties of TB6-cbEGF32. Analysis of the backbone (15)N relaxation data of wild-type TB6-cbEGF32 has revealed a flexible inter-domain linkage. Parallel dynamics analysis of the N2144S mutant has shown increased flexibility in the region joining the two domains as well as in the calcium-binding site at the N terminus of cbEGF32. This research demonstrates that a small change in peptide backbone flexibility, which does not enhance proteolytic susceptibility of the domain pair, is associated with an MFS phenotype. Flexibility of the TB-cbEGF linkage is likely to contribute to the biomechanical properties of fibrillin-rich connective tissue microfibrils, and may play a role in the microfibril assembly process.

Amino Acid Sequence↗

Characterization of Epstein-Barr virus genotype in AIDS-related non-Hodgkin's lymphoma.

In the present study sequence variations at the C terminus of the Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1), EBV-encoded latent membrane protein 1 (LMP-1), and EBNA-2 and EBNA-3C genes were investigated in 64 cases of EBV-positive AIDS-related diffuse large cell lymphoma (AIDS-DLCL), both systemic (12) and localized primarily to the central nervous system (52), and in 12 cases of EBV-positive AIDS-related Burkitt's lymphoma (AIDS-BL). Sequence analysis of the EBNA-1 C-terminal region led to the distinction of two major unrelated EBV strains, termed strain P (prototype) and strain V (variant), and their related subtypes, namely P-ala, P-thr, V-leu, V-val, and V-pro. Analysis of the LMP-1 gene was performed to assess the frequency of the C-terminus deletion variant, whereas analysis of EBNA-2 and EBNA-3C genes led to the identification of the distribution of the EBV type 1 and type 2 strains. The frequency of EBNA-1 subtypes was assessed in 49 cases of AIDS-NHL, including 37 cases of AIDS-DLCL and 12 cases of AIDS-BL. The P strain was detected in 45 of 49 cases (91.8%) whereas the V strain was found in 4 of 49 samples (8.1%). A significant difference in the distribution of the P and V strains was found between AIDS-DLCL and AIDS-BL (p < 0.01), because of the exclusive infection by the P strain of the AIDS-DLCL samples analyzed. The frequency of LMP-1 deletion variants and of EBV type 1 and type 2 strains in AIDS-DLCL overlapped with that of the general population, and no correlation was found with the evaluated clinicoepidemiological data of patients, that is, disease site, tumor histology, CD4(+) cell counts, and HIV transmission route. In conclusion, we found that the distribution of the EBV genotype in all of the AIDS-NHL samples analyzed is similar to the viral representation found in control individuals of both immunocompetent and immunocompromised populations.

Adaptor Proteins, Signal Transducing↗

[Clinical and immunological signs of retinal lesions and possibilities of their correction by drugs in patients with chronic diffuse liver diseases of viral etiology and carriers of Australia antigen].

A total of 133 subjects aged 15 to 55 were followed up, the main group (n = 87), patients with chronic diffuse diseases of the liver caused by hepatitis B virus, and two reference groups, 26 patients with uveitis and 20 normal subjects, 13 and 4 subjects of each group, respectively, were Australian antigen (HBsAg) carriers. Functional disorders of the retina were detected in 93.2% of group 1 patients, as well as intensified local (tears) and total system (blood) autoimmune reactions to tissue-specific retinal S-antigen (mol.mass 48 kD). An increased detection rate of antibodies to S-antigen and its higher titers were found in healthy virus carriers as compared to HBsAg-seronegative donors. These data may be regarded as evidence of an increased risk of uveoretinal pathology in subjects infected with hepatitis B virus, this being confirmed by a higher incidence (50%) of latent virus carriership in the group of patients with uveoretinitis. Stabilizing effect of cavinton in functional changes of the retina was revealed, this recommending this drug for combined therapy of patients with chronic diffuse diseases of the liver and for prevention of ocular diseases. The majority of the examinees in whom retinal abnormalities were found being young, the authors draw attention to the social aspect of the problem.

Adolescent↗

Distinct patterns of viral antigen expression in Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus coinfected body-cavity-based lymphoma cell lines: potential switches in latent gene expression due to coinfection.

Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), also referred to as human herpesvirus 8 (HHV-8), are human gammaherpesviruses associated with numerous lymphomas and proliferative diseases in humans. We were interested in the protein expression patterns of specific latent and lytic proteins from the EBV genome in two body-cavity-based lymphoma cell lines, BC-1 and BC-2, which are coinfected with EBV and KSHV. BC-1 and BC-2 were analyzed using specific antibodies to latent proteins known to be essential for EBV immortalization of human primary B-lymphocytes in vitro and lytic antigens important for EBV replication and production of viral progeny. The coinfected cell lines are compared with two singly infected KSHV cell lines to determine whether antibodies against EBV-specific proteins cross-reacted against KSHV antigens. All the KSHV-infected cell lines express the KSHV-specific latency-associated nuclear antigen (LANA) with a specific pattern in the nucleus. This staining was distinct from that seen for EBNA1 in the EBV coinfected lines BC-1 and BC-2 staining the nucleus as a diffused pattern throughout the nucleus with denser staining in some regions. The coinfected cell lines all express EBNA1 and LMP1 at lower levels compared with singly infected EBV lymphoblastoid cell lines (LCLs). However, the essential latent antigens EBNA2, EBNA3A, and EBNA3C are not expressed in BC-1 and BC-2. This indicates potential regulation of EBV latent gene expression by KSHV-encoded viral or KSHV-induced cellular gene products. Additionally, lytic gene expression analysis demonstrated that BZLF1 and BMRF1 are expressed along with other early antigens (EA-D). A specific protein is detected in a singly infected KSHV cell line with cross-reactivity to antibodies that detected the EA-D complex. Moreover, in all the cell lines infected with EBV, KSHV, or EBV and KSHV, human serum with antibodies against KSHV antigens recognizes specific viral antigens approximately 110 and 41-42 kDa, suggesting that human antibodies against KSHV-specific antigens can cross-react with similar EBV antigens. Therefore these data suggest that the EBV pattern of gene expression in the coinfected cell lines is a type II pattern of latency also seen in other human tumors including nasopharyngeal carcinoma and Hodgkin's lymphoma. This distinct pattern of latent and lytic gene expression in these cell lines may provide clues as to the selection for coinfection in these body cavity based lymphomas in immunocompromised hosts.

Antigens, Viral↗

[Study of antibiotic sensitivity of microorganisms by the method of diffusion in agar layers].

The proposed method for assessing microorganism sensitivity in solid and semisolid liquid nutrient media provides more accurate results and permits isolation of resistant forms of bacteria and studies of antibiotic interactions. Bacteriological study of latent growth zones of bacteria, although rather long, makes the results more reliable. The method can be used for assessing the microflora sensitivity in patients without resorting to isolation of pure cultures and in biotechnology for isolation of new antibiotics.

Agar↗

[Cardiopulmonary function disorders in pulmonary fibrosis of various etiology].

A large number of different pulmonary diseases eventually result in producing the final morphological pattern of pulmonary fibrosis. Basing on essential cardiopulmonary functional parameters, four relatively frequently encountered fibrotic pulmonary diseases are compared with each other. Patients suffering from bird breeder's lung show typical obstructive disturbances of ventilation that are even more marked in collagenoses with lung involvement. Patients suffering from electric welder's lung are notable for enhanced respiratory tract obstructions and increased residual volumes. In patients with sarcoidosis it is recommended to determine, above all, the lung compliance besides measuring the diffusion capacity. The specific compliance should be chosen as criterion to assess the compliance, so that the preliminary extension of the lung by emphysema is taken into consideration. Welder's lungs, bird breeder's lungs and collagenoses show a load-conditioned respiratory partial insufficiency and a latent pulmonary hypertonia. The examined groups of patients showed similar functional patterns, but individual parameters were disease-specifically considerably different from standard values.

Adult↗

Benign and malignant pleural effusions in former Wittenoom crocidolite millers and miners.

Serial plain chest radiographs taken between 1943 and 1982 for 280 claimants for compensation for asbestosis and 32 claimants for malignant pleural mesothelioma from the Wittenoom asbestos industry were reviewed by two observers to identify diffuse pleural thickening and pleural effusion. A pleural effusion which appeared and resolved within two years without radiographic or clinical evidence of underlying malignancy, infection or cardiac failure was seen in 15 cases by reader 1 and 24 cases by reader 2. Eighteen cases of effusion, determined from clinical records to be caused by malignant pleural mesothelioma, were seen by reader 1 and 20 by reader 2. The latent periods between commencing work and the first radiograph showing effusion were much shorter for subjects with benign asbestos pleural effusion than for subjects with effusion due to malignant pleural mesothelioma, although there was considerable overlap in the range. The longest latent period for benign asbestos pleural effusion was 22 years and the shortest period for effusion due to malignant pleural mesothelioma was 12 years. The latent period for benign asbestos pleural effusion was inversely related to total cumulative exposure, whereas that for effusion due to malignant pleural mesothelioma was significantly shorter for subjects who had worked in the mill than for those who had worked in the mine. A long latent period and a history of working in the mill were significant discriminators for a malignant as opposed to a benign basis for an effusion. The appearance of a benign asbestos pleural effusion appeared to be a risk factor for the severity of subsequent diffuse pleural thickening.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Differentiated operative therapy of thyroid autonomy (Plummer's disease).

The operative therapy of the autonomous thyroid deals almost exclusively with nodular goiters. There are only rare situations with purely diffuse autonomy in surgical patients. The endpoint of operative therapy is permanent elimination of clinically relevant autonomous function and thereby irreversible abolition of thyrotoxicosis, even in their latent form. Clinically relevant autonomous function normally ist linked to nodular structures of different size and different distribution, so that this aim corresponds automatically with the aim of complete removal of nodular structures, both in autonomous and in non-autonomous goiters. Function is best preserved by leaving a homogenous remnant of considerable size. In different particular clinical situations (for example pregnancy, suspicion of malignancy, recurrent goiter, intrathoracic goiter, thyrotoxic crisis, Marine-Lenhart-syndrome) the basic principal of operative strategy is varied according to the respective situations. Unsatisfactory operative results are mainly caused by incomplete removal of nodules, based on insufficient surgical performance of morphological and functional diagnostics, which is related to operative uniformity. An operative strategy, which ist "fitted to morphology" and "regarding function" and which we call "selective strategy", in our opinion ist highly appropriate, to avoid remnant nodules and remnant autonomy and to preserve an normal remnant, even in different position and of different size. This selective surgery ist applicable both to autonomous and non-autonomous goiter. Compared with the classic subtotal, uniform procedure the incidence of remnant nodules is reduced from about 50% to about 5 %. Remnant autonomy is almost excluded, when mistakes are avoided (about 1%). The incidence of recurrent goiter and recurrent thyrotoxicosis is lowered to under 5%--but up to now there are too few reliable long-term follow-up studies. The selective surgery strategy demands flexibility regarding operative tactics, which can be simply classified into 5 basic situations, which we relate to the operative procedure per thyroid lobe. It requires experience and competence in carefully dissecting and--when necessary--manipulating the recurrent laryngeal nerve und the parathyroid glands. Under these conditions it is followed by a comparatively low rate of complications (permanent recurrent laryngeal nerve paralysis and hypoparathyroidism under 1%, respectively). Thus, the old dilemma of thyroid surgery can be solved, which consists of radical operation with higher morbidity and lower frequency of recurrent disease on the one hand and more limited operative procedures with fewer complications but more frequent recurrencies on the other hand.

Female↗

Gastric carcinoma with osteoclast-like giant cells. Report of four cases.

Four cases of gastric carcinoma are described that are associated with an osteoclast-like giant cell (OGC) stromal component. The patients were all middle-aged men (range 53-63 years). Microscopically, the tumors were characterized by a bland cytologic appearance, and an either solid or cribriform pattern. Osteoclast-like giant cells were found adjacent to, or intimately intermixed with, the neoplastic cells in the primary gastric masses and in the lymph nodal metastases and were often associated with lymphocytes, histiocytes, and desmoplastic stroma. By immunohistochemistry, mononuclear cells and OGCs showed diffuse positivity for alpha-1-antichymotrypsin, alpha-1-antitrypsin, and CD68. Neoplastic cells that were positive for keratin and CEA, also showed reactivity for vimentin and the latent membrane protein of Epstein-Barr virus in one case. At follow-up, three patients had died at 13, 15, and 24 months after diagnosis, and one is still alive, without evidence of disease, after 120 months. This report describes a novel variant of gastric carcinoma with distinctive and histologic features.

Carcinoma↗

Detection of the pX gene of human T-lymphotropic virus type I in respiratory diseases with diffuse interstitial pulmonary shadows and lung cancer.

The presence of the HTLV-I gene in peripheral blood mononuclear cells was studied by polymerase chain reaction in 42 patients including 16 with lung cancer, 12 with diffuse panbronchiolitis (DPB), 11 with idiopathic interstitial pneumonia (IIP), and 3 with pneumoconiosis and hematological malignancy. Sequences equal to a part of the pX gene were found in 44% of the lung cancer cases, 50% of the DPB cases, 55% of the IIP cases, and 100% of the cases of pneumoconiosis and leukemia. In the lung cancer cases, detection of the pX gene was frequently associated with the existence of diffuse interstitial pulmonary shadows. The pX gene was detected in 100% of patients with anti-HTLV-I antibody, 50% of patients with HTLV-I-related reaction and 14% of patients who tested seronegative. It may be inferred from the results that respiratory diseases that produce diffuse interstitial pulmonary shadows are closely associated with HTLV-I infection and that the HTLV-I-related reaction to the immunofluorescent test might reflect the latent infection state of HTLV-I.

Base Sequence↗

[Electroencephalographic contribution to the differentiation of functional and structural disorders].

Parametric and symptomatologic studies of the EEG in large populations have served to define stages of maturation and criteria of "normality". The younger the subjects, however, the wider are the variations. In the first stage of life only massive cerebral lesions afford unquestionable EEG evidence: in evaluating dysrhythmias it is necessary to bear in mind their high incidence in normal subjects. Hence their meaning is to be understood only by prolonged longitudinal studies. The reference here is not only to diffuse or focal slow anomalies, but also to specific pathologic rhythms. The difficulty of interpreting such anomalies is particularly evident when epileptogenic potentials are found, since they may be signs of a lesion but their clinical correlations are uncertain. The concept of "masked epilepsy" must be rejected. Only the diagnoses of latent or proven epilepsy are admissible, and these epilepsies may be without direct relationship to the clinical, psychiatric or central nervous findings in the affected subject. Numerous genetic, afferential, emotional or biologic factors are involved in the development of non-lesional disorders. Accordingly, the EEG has only a minor contribution to make in the definition of mild focal or diffuse pathologic anatomy of the brain in the very young subject.

Age Factors↗

Melting of crystalline confined plasmas.

The melting of cold, ordered arrays of up to 10 000 charges, confined in external fields, has been studied in simulations. The latent heat associated with melting and the behavior of the specific heat were obtained, along with the spatial correlation function g(r) with respect to neighbors and the diffusion rates, both as a function of temperature. The melting temperatures of finite arrays of ions are found to be lower than that for infinite Coulombic matter, by an amount that depends on the number of charges and on the fraction of ions in the surface layer, in particular.

Journal Article↗

Epstein--Barr virus-associated B-cell lymphoma in the setting of iatrogenic immune dysregulation presenting initially in the skin.

BACKGROUND: Epstein-Barr virus (EBV) has been implicated in B-cell lymphoma associated with iatrogenic immune dysregulation, primarily in the context of extracutaneous lymphoma. METHODS: We describe six patients, five transplant recipients receiving cyclosporine and one patient with rheumatoid arthritis receiving methotrexate, who developed cutaneous presentations of EBV-associated B-cell lymphoma. Human herpesvirus 8 (HHV8) and EBV thymidine kinase (vTK) expression were also explored. RESULTS: The cases comprised plasmablastic lymphoma (one case), plasmacytic marginal zone lymphoma (two cases), and diffuse large B-cell lymphoma (three cases). There was a monoclonal gammopathy in one and concurrent extracutaneous disease in two of the six patients. EBV-associated latent small nuclear RNA was detected in all cases with coexpression of HHV8 in one of the five cases and of vTK in three of the six cases. Three patients responded to a reduction in the immunosuppressive regimen and antiviral therapy. Recurrent disease developed in two, with one patient succumbing to multiorgan dissemination. CONCLUSIONS: EBV-associated cutaneous B-cell lymphoma is characterized by a long interval between the initiation of immunosuppression and the development of lymphoma. Although previous reports have reported an indolent clinical course, an aggressive clinical course may occur. HHV8 and lytic phase EBV antigens are detected in some cases, possibly suggesting a pathogenetic role.

Adult↗

A high molecular weight protease in the cytosol of rat liver. II. Properties of the purified enzyme.

The properties of a soluble endoprotease from rat liver were studied. The enzyme was purified in a latent form. It sedimented as a single component with a sedimentation coefficient (S(0)20,w) of 19.8 S. Measurement by quasi-elastic light scattering gave a diffusion coefficient (D(0)20,w) of 2.5 X 10(-7) cm2 X s-1 and an effective hydrodynamic radius of 85 A. The enzyme had an unusually high molecular weight, estimated as 743,000 by sedimentation equilibrium and 722,000 by sedimentation velocity and diffusion measurements and as 760,000 by a recently developed low-angle laser light scattering method. Judging from electron microscopic observation and the calculated frictional and axial ratios, the enzyme molecule is disc-shaped. Analysis of the far-ultraviolet circular dichroic spectrum showed that the enzyme contains 50% alpha-helical, 25% beta-sheet, and 15% unordered structures with 10% beta-turns. The isoelectric point of the enzyme is 5.0. These properties indicate that the purified enzyme is a homogeneous molecule. In addition, the enzyme is a simple protein since it contains no measurable amounts of nucleic acid carbohydrate or lipid.

Amino Acids↗

Serum responses to the combination of Epstein-Barr virus antigens from both latent and acute phases in nasopharyngeal carcinoma: complementary test of EBNA-1 with EA-D.

Elevated serum IgA to antigens of EBV is associated with nasopharyngeal carcinoma (NPC). We have tested 620 NPC sera by ELISA for the presence of antibodies to EBV-encoded DNA binding protein, EBV-specific DNA polymerase, early antigen-diffused (EA-D), EBV nuclear antigen 1 (EBNA-1), EBV-specific thymidine kinase, and BamHI Z fragment EBV replication antigen. Sensitivity of these proteins was in the range of 51.5-79.5% for IgA and 69.4-82.8% for IgG. The complementary use of EBNA-1 with EA-D, however, could increase the sensitivity significantly to 98.1%. Western blot analysis further showed that the combination of EBNA-1 and EA-D is most useful for the detection of NPC. This is the first report of using double biomarkers including EBV gene products from both latent and active infections. The results of this study suggest that EBV in NPC may not be latent alone and that the method may be valuable for the early detection, early treatment, and better survival rate of patients with NPC. Because the application of recombinant EBV protein in ELISA is cost-effective and feasible for mass screening, the method may be of worth for further clinical investigation.

Adult↗

Critical effects from lipid-protein interaction in membranes. I. Theoretical description.

The ordered-fluid phase transition in lipid membranes is described within the framework of the Landau theory, a general theory for phase transitions. The long-range order of lipids is characterized by the orientational order of the hydrocarbon chains implying the ordered-fluid transition to be of first order. Approaching the transition from either side, thermodynamic fluctuations and response functions are shown to increase, e.g. the specific heat, the lateral compressibility, the permeability, and the lateral diffusion coefficient. A protein molecule incorporated in the membrane is represented as a boundary condition on the lipid order at the protein surface. In the surrounding lipid the perturbation falls off exponentially with the coherence length. Assuming the protein molecules to be distributed homogeneously in the membrane plane and the boundary condition to be temperature independent, the protein-induced shift of the transition temperature and the latent heat is calculated. The latent heat decreases linearly with the protein concentration until it vanishes at a critical point. The critical protein concentration is determined by the ratios of the coherence length to lipid and protein radii in the membrane plane. At the critical point the lipid specific heat, lateral compressibility, permeability, and lateral diffusion coefficient become maximal.

Mathematics↗

Severe focal sialadenitis and dacryoadenitis in NZM2328 mice induced by MCMV: a novel model for human Sjögren's syndrome.

The genetic and environmental factors that control the development of Sjögren's syndrome, an autoimmune disease mainly involving the salivary and lacrimal glands, are poorly understood. Viruses which infect the glands may act as a trigger for disease. The ability of sialotropic murine CMV (MCMV) to induce acute and chronic glandular disease was characterized in an autoimmune-prone mouse strain, NZM2328. MCMV levels were detectable in the salivary and lacrimal glands 14-28 days after i.p. infection and correlated with acute inflammation in the submandibular gland. After latency, virus was undetectable in the glands by PCR. At this stage, NZM2328 female mice developed severe chronic periductal inflammation in both submandibular and lacrimal glands in contrast to the much milder infiltrates found in female B6-lpr and male NZM2328. The focal infiltrates consisted of CD4+ and B220+ cells as opposed to diffuse CD4+, CD8+, and B220+ cells during acute infection. Salivary gland functional studies revealed a gender-specific progressive loss of secretory function between days 90 and 125 postinfection. Latent MCMV infection did not significantly affect the low incidence of autoantibodies to Ro/SSA and La/SSB Ags in NZM2328 mice. However, reactivities to other salivary and lacrimal gland proteins were readily detected. MCMV infection did not significantly alter the spontaneous onset of kidney disease in NZM2328. Thus, chronic inflammation induced by MCMV with decreased secretory function in NZM2328 mice resembles the disease manifestations of human Sjögren's syndrome.

Acute Disease↗