Familial clustering of end-stage renal disease in blacks with HIV-associated nephropathy.

Human immunodeficiency virus-associated nephropathy (HIVAN) develops more often in HIV-infected blacks than whites. Blacks also show marked familial clustering of other causes of end-stage renal disease (ESRD), particularly diabetes mellitus-, hypertension-, and systemic lupus erythematosus-associated ESRD. We compared the family history of ESRD in 201 blacks with ESRD caused by HIVAN (cases) to that of 50 HIV-infected blacks without renal disease (controls) to determine whether HIV-associated ESRD shows familial aggregation. Cases were identified using the Southeastern Kidney Council/ESRD Network 6 Family History of ESRD database. Cases initiated dialysis between September 1993 and October 1998. Controls were consecutively identified, HIV-infected blacks with serum creatinine concentrations of 1.3 mg/dL or less and no proteinuria, treated in an infectious disease clinic during September 1998. Cases and controls had similar mean ages and family sizes. First- or second-degree relatives with ESRD were reported by 24.4% of the cases compared with 6% of the controls (P = 0.004). Logistic regression analysis, controlling for sex, family size, and age, showed cases were 5.4 times more likely than controls to have close relatives with ESRD (P = 0.007). The 49 HIVAN cases who reported a positive family history had a mean of 1.2 additional relatives with ESRD per case (60 total relatives with ESRD). HIVAN was not listed as the cause of ESRD in any of the 27 relatives who underwent dialysis in Network 6 facilities. We conclude that ESRD clusters in the families of nearly 25% of blacks initiating renal replacement therapy for HIVAN. This familial aggregation of ESRD appears to be independent of HIV infection. Although environmental factors cannot be excluded, it is possible an inherited susceptibility to renal failure is present in many blacks with HIV infection who subsequently develop nephropathy.

Progressive outer retinal necrosis secondary to varicella zoster virus in acquired immune deficiency syndrome.

BACKGROUND: A syndrome consisting of rapidly progressive outer retinitis in patients with suppressed immune systems has been described. The etiologic agent appears to be a member of the herpes virus family. METHODS: A 41-year-old man with acquired immune deficiency syndrome (AIDS) developed bilateral outer retinitis and choroiditis, which progressed despite antiviral treatment. A transscleral eye wall biopsy specimen and whole globe were submitted for microbiologic and histologic study. RESULTS: Polymerase chain reaction of a transscleral eye wall biopsy specimen and of the enucleated specimen determined the etiologic agent to be varicella zoster virus (VZV). Histologic studies demonstrated intranuclear inclusions consistent with viral particles in choroidal cells. CONCLUSION: Our study revealed intranuclear inclusions in choroidal cells, a previously undocumented finding in progressive outer retinal necrosis. Polymerase chain reaction was very useful in identifying the causative agent.

The correlation of breakpoint cluster region rearrangement and p210 phl/abl expression with morphological analysis of Ph-negative chronic myeloid leukemia and other myeloproliferative diseases.

The chromosome 22 derivative, the Philadelphia (Ph) chromosome, results from a reciprocal translocation t(9;22) (q34;q11) and is associated with chronic myeloid leukemia (CML). The translocation can be identified at the DNA level in Ph-positive CML by using a probe to the breakpoint cluster region (bcr). In addition, as a result of this translocation an abl-related 210-kd protein with protein tyrosine kinase (PTK) activity is produced. We analyzed 28 cases of Ph-negative CML for rearrangement of the chromosome 22 sequences and found that eight of the 28 show rearrangement of the bcr. When 12 of the Ph-negative cases were independently reviewed, five were indistinguishable from Ph-positive CML on the basis of morphology, peripheral blood film and clinical details. These five also showed bcr rearrangement. The other seven were reclassified as six atypical CML (aCML) and one chronic myelomonocytic leukemia (CMML). None of these seven showed bcr rearrangement. In addition 11 cases of bcr- CML were assayed for abl-related PTK, and no detectable activity was present, whereas p210 phl/abl PTK was observed both in Ph-positive (three cases examined) and Ph-negative, bcr + (four cases examined) CML. Therefore, bcr + CML, whether or not the Ph chromosome is cytogenetically apparent, involves a similar molecular alteration and produces the 210-kd protein with enhanced PTK activity. Furthermore, these cases can be distinguished from Ph-negative bcr- CML by careful evaluation of clinical and hematologic data.

Lineage specificity of rearrangement and expression of genes encoding the T cell receptor-T3 complex and immunoglobulin heavy chain in leukemia.

In acute lymphoblastic leukemia (ALL) diagnostic samples and cell lines with unequivocal B cell precursor (common) or T cell precursor immunophenotypes, there is inappropriate or cross-lineage IgH or T cell receptor beta gene (TCR beta) rearrangement in approximately 25% of the cases. The frequency of such rearrangements is lower in mature lymphoid neoplasms and acute myeloblastic leukemia. The most immature B lineage ALL ('null' ALL) has a much lower frequency of TCR gene rearrangement than the common variant of B cell precursor ALL and also has a high frequency of oligoclonal rearrangements of IgH genes. Non-T leukemic cells with inappropriately rearranged TCR beta gene did not necessarily have a rearranged TCR gamma gene. Inappropriately rearranged IgH or TCR genes are usually not expressed at the mRNA level, and the gene for the TCR associated protein T3 delta is not detectably expressed at the mRNA or protein level in leukemias classified unambiguously as non-T. Five cases of acute leukemia with ambiguous or mixed lineage immunophenotypes (myeloid + T or myeloid + B) are described. These five had diverse patterns of IgH, TCR beta, and TCR gamma rearrangement, and all expressed terminal transferase concomitantly with MY9 (CD33). The T3 delta gene was expressed in two cases, which also expressed other T cell markers indicating that coordinated lymphoid lineage programs had been initiated. The implications of these observations for lineage-associated regulation of genes during normal differentiation and leukemogenesis are discussed.

Ethnic composition, age and sex, together with location and standard of housing as determinants of HLTV-I infection in an urban Trinidadian community.

The presence of antibody to human T-cell leukaemia virus (HLTV-I) has been assessed in 2,143 men and women who represent 83% of all adults aged 35 to 69 years resident in a defined urban community in Trinidad. Individuals of African descent had a higher sero-positivity rate (7.0%) than those originating from India (1.4%), Europe (0%) or of mixed descent (2.7%). Women were infected more frequently than men, and the prevalence of infection increased with age in both sexes. Sero-positivity rates were significantly increased in adults who lived in housing of poor quality (p less than 0.001) or close to water courses (p less than 0.025). These data and others raise the possibility that one route of HLTV-I transmission may be via insect vectors under particular domestic circumstances.

Bolus intramuscular methylprednisolone acetate as a therapeutic adjunct in rheumatoid arthritis.

Eighty adult patients with classical or definite rheumatoid arthritis were given 200 bolus injections of intramuscular methylprednisolone acetate (MPA) over four years. This was used strictly as a therapeutic adjunct for polyarticular flares (greater than or equal to 5 swollen joints), not as a singular form of long-term treatment. Good clinical responses, lasting an average of eight weeks, were obtained in the vast majority of patients. Severe toxicity was minimal. Postbolus responses to intravenous ACTH stimulation were measured in 12 patients. We believe that intramuscular bolus injections, used cautiously in carefully selected patients with rheumatoid arthritis, are relatively useful, convenient, inexpensive, and safe.

Gram-negative bacillary meningitis in the adult: review of 39 cases.

From 1976 through 1984, the period covered in this report, we reviewed our total experience with gram-negative meningitis in adult patients, looking especially at how treatment and mortality had changed. Thirty-nine adults had 45 episodes of gram-negative meningitis. Twenty-five patients had had a dura-arachnoid disruption, 12 a septic episode, and two a bacterial mastoiditis. The overall mortality was 35.9%. Thirteen patients were treated with a full course of intrathecal antibiotics (five or more days) and eight patients with an abbreviated course (one or two doses). The use of chloramphenicol was associated with poor patient outcome, a finding consistent with both experimental and clinical findings of others.

Contribution of immunophenotype to the classification and differential diagnosis of acute leukaemia.

The diagnostic value of a panel of monoclonal antibodies was assessed in 100 consecutive patients with acute leukaemia. 97 patients were clearly phenotyped. Clinical and haematological feedback showed that the immunological data made a critical contribution to the final haematological diagnosis in 19 patients and provided useful confirmatory data in another 78. Immunophenotype also provided the basis for a subset classification of known prognostic relevance to acute lymphoblastic leukaemia (ALL). Immunophenotype and haematological findings conflicted in 2 cases, and 3 cases were unclassifiable with the antibody panel. In these difficult cases leukaemic-cell DNA was investigated for immunoglobulin gene rearrangement. Immunophenotyping with selective probes may be used in conjunction with other laboratory analyses (eg, karyotyping) in the routine investigation of patients with acute leukaemia.

The human leucocyte-common (LC) molecule: dissection of leukaemias using monoclonal antibodies directed against framework and restricted antigenic determinants.

Monoclonal antibodies have previously been raised against two separate antigenic determinants on the human LC molecule. One, F10.89.4, recognizes a 'framework' epitope on all LC molecules; these are found on the majority of leucocytes. The other, F8.11.13, recognizes only a 'restricted' epitope present on a subset of these molecules; this subset is found on B lymphocytes and a subpopulation of T lymphocytes. LC molecules on myeloid cells do not carry the 'restricted' antigenic determinant. We have investigated the differential expression of these LC epitopes on human leukaemias, using immunofluorescence on fresh leukaemic blasts and established cell lines. Our study shows that, as on normal haemopoietic cells, LC molecules on B leukaemias bear both 'framework' and 'restricted' epitopes, while the majority of T leukaemias bear only the 'framework' determinant. The small proportion of T cells that are F8.11.13+ ('restricted' epitope) are relatively mature, being of either OKT4+ or OKT8+ phenotype, and may be in an activated state (HLA-DR+). However, in contrast to normal haemopoietic cells, some myeloid leukaemias carry both 'framework' and 'restricted' epitopes (30% AML and AMML samples are F10.89.4+, F8.11.13+), and it is within this group that all TdT+ AML and AMML cases lie. Thus, these monoclonal antibodies should be useful for studying haemopoiesis in man and for analyzing human haemopoietic malignancies.

A monoclonal antibody (WT1) for detecting leukemias of T-cell precursors (T-ALL).

The selectivity of a monoclonal anti-T antibody, designated WT1, has been assessed in a series of 906 leukemias and lymphomas. In acute lymphoblastic leukemias, WT1 reacts comprehensively and selectively with thymic acute lymphoblastic leukemia (ALL) cells in untreated or relapsed patients, thus overriding the extensive antigenic diversity of this cancer and the immaturity of the cell type involved. All 80 cases of thymic ALL examined were WT1-positive. In addition, 18 cases of presumptive prethymic ALL were also WT1-positive, but were unreactive with other maturation-linked T-cell markers. The phenotype WT1+ HLA-DR TdT+ appears to be unique to T-ALL and can therefore be used systematically for the differential diagnosis of this poor prognosis subtype of ALL. Virtually all ALL cases can now be placed into one of two major subgroups representing transformed precursors of either the T- or B-cell lineage. WT1 identifies a single polypeptide of approximately 40,000 mol wt and is similar to two previously described monoclonal antibodies.