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Circulating monoclonal immunoglobulins in Sjögren syndrome: prevalence and clinical significance in 237 patients.

We conducted the current study to analyze the prevalence and clinical significance of circulating monoclonal immunoglobulins in patients with Sjögren syndrome (SS), focusing on the association with extraglandular features, immunologic markers, hematologic neoplasia, and hepatitis C virus (HCV) infection. We performed serum immunoelectrophoresis in 200 patients with primary SS and 37 patients with HCV-related SS. All patients fulfilled 4 or more of the 1993 European classification criteria for SS.Of the 200 patients with primary SS, 35 (18%) presented circulating monoclonal immunoglobulins. The monoclonal bands identified were 20 IgG (13 kappa, 7 lambda), 10 IgM (5 kappa, 5 lambda), 2 IgAkappa, and 3 free circulating light chains. Of the 37 SS-HCV patients, 16 (43%) had circulating monoclonal immunoglobulins. The monoclonal bands identified were 10 IgMkappa, 5 IgGlambda, and 1 free light lambda chain. Compared with primary SS patients, SS-HCV patients presented a higher frequency of monoclonal immunoglobulins (43% vs 18%, p = 0.001), with monoclonal IgMkappa being the most frequent monoclonal band. Six (12%) of the 51 SS patients with circulating monoclonal immunoglobulins presented hematologic neoplasia, compared with 3 (1.6%) of those without monoclonal immunoglobulins (p = 0.004; odds ratio = 8.13; 95% confidence intervals, 1.64-51.54). In 2 of the 6 patients with monoclonal immunoglobulins and lymphoproliferative disorders, a change of the monoclonal component was detected in previous immunoelectrophoresis determinations before the development of hematologic neoplasia. Circulating monoclonal immunoglobulins were detected in nearly 20% of patients with primary SS, with monoclonal IgG being the most frequent type of immunoglobulin detected. In SS-HCV patients, the prevalence of monoclonal immunoglobulins was higher (43%), with monoclonal IgM being the most frequent type found. SS-HCV patients presented a more restrictive monoclonal expression (limited to either monoclonal IgMkappa or monoclonal IgGlambda) than primary SS patients, who showed all types of heavy and light chains.

Adult↗

Genetic heterogeneity of hepatitis C virus.

There are four hierarchical strata in the genetic heterogeneity of hepatitis C virus (HCV): group above subgroup above isolates above quasispecies. The entire genome sequence has so far been reported for 16 isolates which are classifiable into 3 groups and 6 subgroups. Provisional classification of HCV is also possible using a partial sequence of the HCV genome. With the E1 region sequence for example, the present collection of HCV isolates can be classified into 9 groups and 23 subgroups. The rationale for these classifications and the epidemiological and clinical implications of genotyping HCV are reviewed.

Amino Acid Sequence↗

Amplification and cloning of near full-length HIV-2 genomes.

The genomes of human immunodeficiency virus type 2 (HIV-2), like those of HIV-1, are not only extremely variable but are also highly recombinogenic. Determination of subtypes based on partial genomes cannot predict the subtype classification of other regions of the genome owing to the frequent occurrence of recombinant genomes among subtypes. To fully understand the genetic variation and evolution of HIV-2s, full-length viral genomes need to be obtained for genetic analysis. Full-length HIV-2 genomes can also be used as infectious clones to study viral biological characteristics and as reference sequences for phylogenetic analysis. More important, all genes in the obtained genomes can be cloned into expression vectors to produce proteins that can be used as antigens for diagnostic reagents or as immunogens for vaccine development. The long-range polymerase chain reaction technique has recently become a more preferred method than the lambda phage cloning method to obtain near-full-length HIV-2 genomes.

Cloning, Molecular↗

Lymphoproliferative response to membrane extracts of nasopharyngeal carcinoma.

The tumor-associated antigen (TAA) was extracted from cultured cells obtained from nasopharyngeal carcinoma (NPC), and the specific immune reaction was studied by utilizing the proliferation reaction of lymphocytes from NPC patients. The following results were obtained. (1) The stimulation of lymphocytes by membrane soluble antigen (MS-Ag) was significantly different in the group of patients with NPC and the control groups (patients with malignant tumors of the head and neck and healthy individuals). Lymphocytes from the NPC patients gave a significantly higher stimulation index (SI) value with NPC MS-Ag, but a lower value with PHA, as compared with those of normal controls. (2) No definite correlation was observed in anti-Epstein-Barr virus (EBV) antibody titers. (3) As for the correlation with various histological types, apparently enhanced reaction was noted irrespective of the histological type of the cancer. (4) In connection with stage classification, the reaction was always negative in patients in stage IV. A particularly close correlation was noted between the degree of the response and the N classification. Some inhibitory factor affecting the LP reaction might appear with the progress of N and M.

Antibodies, Viral↗

Genotyping HIV-1 and HCV strains by a combinatorial DNA melting assay (COMA).

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) strains can be genetically classified into genetic lineages known as genetic types or subtypes according to phylogenetic analyses of complete or partial nucleotide sequences of their genomes. The genetic classification of HIV-1 and HCV strains has important implications for the development of globally effective vaccines and for the management of patients. MATERIALS AND METHODS: A new method, termed combinatorial DNA melting assay (COMA), allows rapid accessing of comparative genetic information between related DNA sequences, making it possible to rapidly and accurately genotype unknown HIV-1 and HCV strains. COMA is mainly based on the differential melting properties of long DNA heteroduplexes. Combinatorial arrays of DNA heteroduplexes are formed when captured PCR-amplified reference DNA with known nucleotide sequences are combined with solution-phase complementary and antigenically labeled DNA with unknown sequences. Genetic divergence between the known and the unknown sequences is inferred as the experimentally derived melting curves of the two strands of the DNA heteroduplexes increasingly diverge. RESULTS: COMA was successfully applied to the genetic classification of HIV-1 and HCV strains into phylogenetic lineages or subtypes. CONCLUSIONS: Use of this assay should accelerate current efforts to understand the global molecular epidemiology of HIV-1 and HCV and may extend to the genetic characterization of other genetically diverse infectious pathogens associated with numerous diseases.

Base Composition↗

Epidemiology and pathologic features of Hodgkin lymphoma.

Hodgkin lymphoma (HL) has unique epidemiologic characteristics. The variation in incidence according to age, sex, race, socioeconomic status, and histologic subtype suggests an etiologic heterogeneity for this tumor. Epidemiologic studies have shown that both genetic and environmental factors play a role in the pathogenesis of HL. HL is one of the Epstein-Barr virus-associated lymphomas, but the oncogenetic mechanism of HL remains to be elucidated. Recent advances in molecular biology have revealed the peculiar nature of the nodular lymphocyte predominant subtype, and as a result this disease is separated from classic types of HL in the new World Health Organization classification. Reed-Sternberg (RS) cells and lymphocytic and/or histiocytic (L&H) cells originate from germinal center B-cells. Loss of the B-cell phenotype due to down-regulation of several B-cell-specific transcription factors is characteristic of RS cells in classic HL.

B-Lymphocytes↗

Genetic analysis of a Theiler-like virus isolated from rats.

Although cardioviruses related to Theiler's murine encephalomyelitis virus (TMEV) appear to be common in mice and rats, few TMEV isolates have been obtained from rat colonies. In 1991, a cardiovirus isolate designated NGS910 was obtained from sentinel rats exposed to cage bedding previously used by adult rats that were TMEV seropositive, but had never manifested clinical signs of disease. To determine to which group and subgroup of cardiovirus this virus belongs, the sequence of the viral genome was determined. The NGS910 genome consisted of 8,021 nucleotides and the 5'-nontranslated region had a predicted secondary structure that is similar to members of the TMEV group of cardioviruses. The Leader-P3D open reading frame (L ORF) of NGS910 had strong homology with L ORFs of other TMEVs (72% identity), but lower homology with EMCV cardioviruses (55 to 56%). Phylogenetic analyses on the basis of aligned nucleotide sequences of the L ORF (6,924 b) and the internal L* ORF (471 b) supported this classification of NGS910 as a TMEV strain. However, within the TMEV group, NGS910 wassufficiently divergent from other isolates that it could not be regarded as simply a mutant strain of a known TMEV. As genetic distances between NGS910 and other TMEVs were greater than those between Mengo virus of EMCV and other EMCVs, we propose to designate the NGS910 isolate as a rat Theiler-like virus.

Amino Acid Sequence↗

[Prevalence of rheumatic manifestations in human immunodeficiency virus infection].

UNLABELLED: Various rheumatic manifestations have been reported in HIV infected patients, but the prevalence of these manifestations is not well known. Therefore, we have designed a prospective study to define the rheumatic manifestations in those patients. METHODS: 121 patients (stage IV of CDC classification) were assessed by physical examination and biological tests. RESULTS: arthralgia was found in 12.4%; painful articular syndrome occurred in 4.1%; arthritis was present in 6.6%; out of 8 cases of arthritis, only 2 had spondylarthropathy. The articular manifestations were mostly oligo- or polyarticular, rarely invalidating, sometimes recurrent. No septic arthritis, no myositis and only 1 case of vasculitis was found. Raynaud's phenomenon prevalence was 17.4%, 43% of which appeared after HIV seropositivity was known. Lacrymal hyposecretion assessed by Schirmer's test was found in 49.6%. However, this did not prove the existence of a Sjogren's syndrome as no histological examination was performed. Back pain reached 38.6%. Sciatic neuralgias were noted in 17.6%. Biological and immunological results were unspecific. Low levels of antinuclear antibodies were found in 11.1% cases. They were more frequently found when articular manifestations existed. A higher level of CD8 lymphocytes was also noted when articular manifestations were present. No statistical link existed between the different rheumatic manifestations. CONCLUSION: our results show that the prevalence of rheumatic manifestations in HIV infection is slightly increased (24.7%). This study is the first to emphasize the frequency of Raynaud's phenomenon and lacrymal hyposecretion in HIV patients.

Acquired Immunodeficiency Syndrome↗

Occurrence of human papillomavirus infection in cervical intraepithelial neoplasia. A retrospective histopathological study of 317 cases treated by laser conization.

The aim of the study was to compare the histological outcome of the cone specimens with the diagnoses of the preoperative biopsies, to assess the distribution of histological features consistent with human papillomavirus (HPV) infection and, finally, to analyse the impact of cellular HPV features on classification of cervical intraepithelial neoplasia (CIN). The study comprised a population of 317 women treated for CIN by laser conization during the period 1983-85. A total of 634 cervical specimens (317 preoperative biopsies and their corresponding cones) were studied retrospectively for CIN classification and examined for morphological signs of HPV infection. For presentation of the results, we used a modified terminology for CIN. Low-grade (LG) CIN included borderline lesions and CIN I, while high-grade (HG) CIN included CIN II and CIN III. The blinded histopathological review revealed HG CIN both in the preoperative biopsies and the cones in 71% of the cases. LG CIN or benign lesions were found in the preoperative biopsies and their corresponding cone specimens in 6% of the study population. HPV features were present in 65% of the preoperative biopsies, and were most prevalent in women under 29 years of age (p < 0.001). Thirteen percent of the total biopsy material was downgraded. The downgrading was most prevalent among original CIN II (p = 0.009) and HPV-negative biopsies (p < 0.001). This study demonstrates that CIN lesions are frequently associated with HPV features, which are significantly more prevalent in the youngest women. Concomitant HPV features do not influence the CIN classification.

Biopsy↗

[Left ventricular aneurysm in human immunodeficiency virus infection: a case report].

The authors report the case of a 30 year old man with a left ventricular aneurysm who was seropositive to HIV 1 and HIV 2. The patient was stage IVC 1 (AIDS related complex) by the "Center for Disease Control" classification. The clinical presentation was pyrexia, loss of weight, micropolyadenopathy and cardiac failure. The electrocardiogramme showed low voltage in the peripheral leads with a QS morphology in S2, S3 and aVF and abrasion, of the R wave in the precordial leads. Doppler echocardiography demonstrated a large left ventricular aneurysm with a wide neck. Despite treatment with a diuretic, angiotensin converting enzyme inhibitor and anticoagulants, the patient died suddenly. Autopsy confirmed the wide necked left ventricular aneurysm. This would appear to be the first report of this form of cardiac disease during HIV infection. However, a simple coincidence of the two pathologies cannot be excluded.

Adult↗

Cytotoxic T-cell lymphoma diffusely involving the entire gastrointestinal tract associated with Epstein-Barr virus and tubercle bacilli infection.

We describe a rare case of cytotoxic gastrointestinal T-cell lymphoma with protein-losing enteropathy. Initial examination revealed the coexistence of T-cell lymphoma and tuberculosis in the mesenteric lymph node and liver. Despite anti-tuberculosis and anti-cancer treatment, the patient experienced chronic diarrhea and malabsorption and died approximately 3 years after onset. Autopsy specimens revealed medium-sized lymphoma cells, with a phenotype of CD3+, CD4-, CD7+, CD8+, CD30-, CD56-, CD103 (HML-1)-, TIA-1+, and granzyme B+, proliferating primarily and consistently in the mucosa of the entire bowel tract from esophagus to rectum. Interestingly, Epstein-Barr virus (EBV)-encoded small nuclear RNAs were detected in the tumors by in situ hybridization. Southern blot analysis revealed monoclonal proliferation in the EBV-infected T cells. Although the present case can possibly be categorized as an intestinal T-cell lymphoma according to the Revised European-American Lymphoma Classification, the case showed a unique clinical course and distribution of lymphoma cells. We present here an interesting case of gastrointestinal cytotoxic T-cell lymphoma and examine the possible association with infectious agents.

Digestive System↗

Splenic lymphoproliferative disorders in human T lymphotropic virus type-I endemic area of japan: clinicopathological, immunohistochemical and genetic analysis of 27 cases.

Primary splenic involvement in lymphoid neoplasms is rare and the clinicopathologic features of splenic lymphoma are not well described compared to nodal non-Hodgkin's lymphoma (NHL). Here we characterized splenic lymphomas in an human T lymphotropic virus type-I (HTLV-I) endemic area of Japan. To assess the pattern of splenic involvement and evaluate prognosis, we reviewed 27 specimens consisting of 26 splenectomies and one necropsy, which were classified using REAL classification. Cases were divided into primary splenic lymphoma in 11 patients and secondary in 16 patients. The incidence of primary splenic lymphoma was 0.3% (11 of approximately 4,000 malignant lymphomas). Primary splenic lymphomas included 7 diffuse large B cell lymphoma (DLBL), 2 follicular lymphomas (FL), and 1 each of splenic marginal zone lymphoma (SMZL) and anaplastic large cell lymphoma (ALCL). Secondary splenic lymphomas included 6 DLBL, 4 mantle cell lymphoma (MCL), 2 FL, 2 Hodgkin's disease (HD), 1 each of hairy cell leukemia and ALCL. Gross examination showed two patterns of splenic involvement; solid type (formation of large nodular mass, n=16) and disseminated type (multiple nodules with diffuse infiltration but no large nodular formation, n=10). The type could not be determined in one case. Most solid types were DLBL or FL, while MCL was of the disseminated type. Immunohistochemistry showed all but each 2 cases of ALCL and HD were of B lineage. Follow-up of 26 patients indicated that all but one patient with primary lymphoma were still alive (range, 1-89 months) and 8 of 15 patients with secondary lymphomas died due to the progression of malignant lymphoma; the survival rate at 2 years was 50% in these patients. No elevation of anti-HTLV-I antibody was found. In situ hybridization for Epstein-Barr virus (EBV) showed no reactivity of lymphoma cells, although a few small lymphocytes were positive for EBV. Hepatitis C virus was observed in 6 of 20 (30%) patients examined and 4 of 11 (36%) cases of primary splenic lymphoma. Our findings indicate that patients with primary splenic lymphoma have a favorable prognosis after splenectomy.

Adolescent↗

Detection and genetic relationship of dengue virus sequences in seventeen-year-old paraffin-embedded samples from Cuba.

This study describes the use of the reverse transcriptase-polymerase chain reaction (RT-PCR) to generate dengue 2 amplicons from paraffin-embedded autopsy tissues collected in Cuba 17 years ago. The presumptive diagnoses had been made only by clinical evolution without serologic confirmation. This study confirms once again that dengue 2 virus was directly associated with the fatal cases in children and illustrates the potential of the RT-PCR for retrospective diagnosis of dengue cases 17 years after death. A close similarity in the genomic sequences of the dengue 2 RNA detected in tissue samples from fatal cases and those dengue 2 Cuban strains that had been previously investigated confirms the appropriate genomic classification of the etiologic agent associated with the 1981 dengue hemorrhagic fever Cuban epidemic.

Amino Acid Sequence↗

Artificial neural network prediction of viruses in shellfish.

A database was probed with artificial neural network (ANN) and multivariate logistic regression (MLR) models to investigate the efficacy of predicting PCR-identified human adenovirus (ADV), Norwalk-like virus (NLV), and enterovirus (EV) presence or absence in shellfish harvested from diverse countries in Europe (Spain, Sweden, Greece, and the United Kingdom). The relative importance of numerical and heuristic input variables to the ANN model for each country and for the combined data was analyzed with a newly defined relative strength effect, which illuminated the importance of bacteriophages as potential viral indicators. The results of this analysis showed that ANN models predicted all types of viral presence and absence in shellfish with better precision than MLR models for a multicountry database. For overall presence/absence classification accuracy, ANN modeling had a performance rate of 95.9%, 98.9%, and 95.7% versus 60.5%, 75.0%, and 64.6% for the MLR for ADV, NLV, and EV, respectively. The selectivity (prediction of viral negatives) was greater than the sensitivity (prediction of viral positives) for both models and with all virus types, with the ANN model performing with greater sensitivity than the MLR. ANN models were able to illuminate site-specific relationships between microbial indicators chosen as model inputs and human virus presence. A validation study on ADV demonstrated that the MLR and ANN models differed in sensitivity and selectivity, with the ANN model correctly identifying ADV presence with greater precision.

Adenoviruses, Human↗

Posttransplantation B lymphoblastic leukemia with Burkitt-like features.

BACKGROUND: Posttransplantation Epstein-Barr virus-associated lymphoproliferative disease (PTLPD) occurs as a spectrum of disease ranging from benign, polyclonal, localized lymphoid hyperplasia to malignant, monoclonal, disseminated lymphoma, sometimes involving the bone marrow. To our knowledge, PTLPD has not been previously reported to present as acute lymphoblastic leukemia. METHODS: We report the case of a boy who developed PTLPD in the form of acute lymphoblastic leukemia 6 years after cardiac transplantation. He had greater than 90% bone marrow invasion by Epstein-Barr virus-positive B lymphoblasts with Burkitt-like features and a t(8;14) translocation. RESULTS: He was successfully treated with combination chemotherapy but unfortunately died, 6 months after completing treatment, from ischemic heart disease. CONCLUSIONS: B lymphoblastic leukemia may occur as a manifestation of PTLPD and should be included in the classification of these diseases. Bone marrow examination should be an essential part of the investigation of patients suspected of having PTLPD.

Administration, Oral↗