Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death.

To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia. At a high glucose concentration, O-glycosylation of p53 occurred between 10 and 20 min, reached its peak at 1 h, and then decreased with time. Angiotensin II synthesis increased at 45 min and 1 h, resulting in p38 mitogen-activated protein (MAP) kinase-driven p53 phosphorylation at Ser 390. p53 phosphorylation was absent at the early time points, becoming evident at 1 h, and increasing progressively from 3 h to 4 days. Phosphorylated p53 at Ser 18 and activated c-Jun NH(2)-terminal kinases were identified with hyperglycemia, whereas extracellular signal-regulated kinase was not phosphorylated. Upregulation of p53 was associated with an accumulation of angiotensinogen and AT(1) and enhanced production of angiotensin II. Bax quantity also increased. These multiple adaptations paralleled the concentrations of glucose in the medium and the duration of the culture. Myocyte death by apoptosis directly correlated with glucose and angiotensin II levels. Inhibition of O-glycosylation prevented the initial synthesis of angiotensin II, p53, and p38-MAP kinase (MAPK) phosphorylation and apoptosis. AT(1) blockade had no influence on O-glycosylation of p53, but it interfered with p53 phosphorylation; losartan also prevented phosphorylation of p38-MAPK by angiotensin II. Inhibition of p38-MAPK mimicked at a more distal level the consequences of losartan. In conclusion, these in vitro results support the notion that hyperglycemia with diabetes promotes myocyte apoptosis mediated by activation of p53 and effector responses involving the local renin-angiotensin system.

Prevalence of HTLV type I infection in Iran: a serological and genetic study.

Several publications describe the presence of the human T cell lymphotropic virus type I (HTLV-I) in Jewish individuals born in Mash-had, Iran. We report here the results of HTLV-I serological and genetic studies in the non-Jewish population of Mash-had as well as a neighboring area: Gonbad-Kavous. Seven hundred and seven serum samples from Mash-had (694 healthy individuals and 13 patients with lymphoma) and 90 from Gonbad-Kavous were tested for HTLV antibodies by gelatin particle agglutination assay (PA) and confirmatory Western blots (WBs). Seropositive rates of 3.0% (21 of 694) in Mash-had, 0% (0 of 90) in Gonbad-Kavous, and 100% (13 of 13) in lymphoma cases were observed. HTLV-I DNA sequence were amplified by polymerase chain reaction directly from the fresh PBMCs of seropositive individuals. Phylogenetic analysis of the viral DNA sequence indicated that the HTLV-I present in Mash-had belong to the HTLV-I cosmopolitan clade. Altogether, these data indicate that Mash-had, located in northeastern Iran, is a newly recognized endemic center for HTLV-I.

Clinical manifestations of Kaposi's sarcoma.

Major investigative studies have yielded considerable data on various aspects of Kaposi's sarcoma (KS), including cellular and molecular events leading to the development of HIV-associated KS, histopathologic features, clinical characteristics, as well as epidemiologic patterns. Recent developments in research on KS are summarized, and a coherent model for its pathogenesis is proposed.

Histologic predictors of survival in acquired immunodeficiency syndrome-associated Kaposi's sarcoma.

The relationship between 22 histologic variables and survival was investigated in 93 patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). All the patients were homosexual men in whom KS was the initial manifestation of AIDS. All patients were followed for at least 12 months or until death. Histologic specimens of the initial KS biopsy were reviewed in a blind manner by two of the authors and were evaluated for the presence of a number of histologic features. In a univariate analysis nodular lesions of KS (upsilon patch or plaque lesions), the absence of hemosiderin, the absence of irregular vascular spaces, and the presence of spindle cell nodules were all significantly associated with increased length of survival. Two variables previously shown to be related to survival (CD4:CD8 cell ratio, initial lesion on lower extremities) were included in a multivariate analysis (Cox model) in addition to the histologic variables. Complete data were available from 85 patients. In the multivariate analysis a higher helper to suppressor T-cell ratio, initial lesion on lower extremities, presence of spindle cell nodules, and nodular histology (upsilon patch or plaque histology) were all significantly associated with increased length of survival. These data suggest that in AIDS-associated KS, as in reticuloendothelial neoplasms, histologic features may be useful in identifying prognostically different subgroups of patients.

HIV-related malignancies.

Since the recognition of Kaposi's sarcoma as a manifestation of the acquired immunodeficiency syndrome, subsequent malignancies such as non-Hodgkin's B-cell lymphoma and primary central nervous system lymphoma have been found to be associated with individuals infected with the human immunodeficiency virus (HIV). The epidemiology, clinical manifestations, and current concepts of pathogenesis are reviewed in this article. In addition, the relation between HIV and other malignancies, including Hodgkin's lymphoma, T-cell lymphomas, and anorectal carcinoma, is discussed. In general, HIV-related malignancies are more aggressive, respond poorly to treatment, and are associated with an extremely high rate of mortality.

Interferon in the treatment of AIDS-associated Kaposi's sarcoma: the American experience.

This report is intended to summarize the use of Interferon in the treatment of Kaposi's sarcoma (KS) associated with AIDS. The review is basically focused on the trials in the United States, which resulted in approval by the Food & Drug Administration (FDA) of the use of recombinant interferon alpha for the treatment of Kaposi's sarcoma.

Lymphoma and other HIV-associated malignancies.

The immunodeficient state that evolves in persons infected with the human immunodeficiency virus (HIV) appears to increase their risk of certain types of cancer. Among these are primary lymphoma of the central nervous system, undifferentiated non-Hodgkin's lymphoma, squamous cell carcinoma, anorectal carcinoma, and cutaneous malignancies. These malignancies are similar in incidence to those seen in other immunodeficient patients. Lymphoma, in particular, is associated with a more aggressive disease state. In HIV-infected patients, the disease is usually diagnosed at a more advanced stage, frequently has extranodal involvement, and usually responds poorly to chemotherapy. Viruses, such as Epstein-Barr virus and papillomavirus, have been implicated in the pathogenesis of lymphoma and other malignancies in immunosuppressed patients, including those with HIV infection.

Angiocentric T-cell lymphoma associated with human T-cell lymphotropic virus type I infection.

We describe two patients who presented with vasculitic, ulcerative skin lesions that had the histologic features of lymphomatoid granulomatosis or angiocentric T-cell lymphoma. These patients were found to have antibodies to human T-cell lymphotropic virus type I.

Histology of early lesions of AIDS-associated Kaposi's sarcoma.

The original cutaneous biopsy specimens of 93 patients who presented themselves to the Memorial Sloan-Kettering Cancer Center with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) were systematically reviewed for 23 histologic variables. KS was the initial manifestation of AIDS in all of the patients. The vast majority of patients presented with plaque histology of KS. Early lesions of KS were characterized by the presence of dilated vascular spaces haphazardly arranged in the biopsy specimen, a sparse inflammatory cell infiltrate composed of lymphocytes (usually without plasma cells), and aggregates of cuboidal cells with the appearance of epithelioid cells. Individually necrotic tumor cells were present in nearly every case. Spindle cells arranged in fascicles or nodules were seen in a minority of cases. These data provide an overview of the different histologic patterns seen in initial lesions of AIDS-associated KS and may lead to better understanding of the pathogenesis of this tumor.

No evidence for true HTLV-I or HIV-1 antibodies in Finnish Lapps.

Previous seroepidemiologic studies have suggested that in addition to certain subtropical and tropical parts of the world, human T cell leukemia virus type I (HTLV-I) may be endemic in the arctic regions, too. We studied 111 sera collected from original inhabitants of Finnish Lapland with ELISA and Western blot analysis for antibodies to HTLV-I and human immunodeficiency virus type 1 (HIV-1). No true positive sera for either virus were found in the confirmatory Western blot assays, albeit 6 and 2%, respectively, were positive in the screening ELISA assays. Despite the small sample size this survey does not support the hypothesis that HTLV-I would be endemic in the Arctic.

Basal cell carcinomas and lymphoma: biologic behavior and associated factors in sixty-three patients.

The relationship between basal cell carcinoma and lymphoma was investigated in 63 patients with both diagnoses who were seen at Memorial Sloan-Kettering Cancer Center between 1949 and 1984. The majority of patients were diagnosed with lymphoma before the onset of their first basal cell carcinoma. Multiple basal cell carcinomas developed in most patients. The overall recurrence rate of basal cell carcinoma was high (17%), and metastatic disease developed in one patient. These data support a more aggressive behavior of basal cell carcinomas in patients with lymphoma than in otherwise healthy individuals.

AIDS-associated Kaposi's sarcoma: variables associated with survival.

The records of 187 consecutive patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma were analyzed retrospectively for a number of prognostic variables. In a multivariate analysis, the initial site of disease was found to be related to survival. Initial lesions on the skin of the lower extremities or in the lymph nodes were associated with longer survival (p = 0.005 and p = 0.01, respectively). Higher helper/suppressor T cell ratios were strongly associated with longer survival (p less than 0.0001). Age and serum IgG antibody levels to cytomegalovirus did not appear to correlate. These results suggest that there are different subgroups of patients with AIDS-associated Kaposi's sarcoma, and that the initial site of disease, as well as immunologic parameters, may be useful in prognosis.

Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin.

In 15 months we encountered eight patients with intracranial tumors who developed erythema multiforme (EM) or erythema multiforme bullosa (Stevens-Johnson syndrome). All occurred shortly after use of phenytoin (DPH) and brain radiation therapy (WBRT). The clinical picture differed from the classic form of EM in that the erythema began on the scalp and spread to the extremities, progressing in three cases to extensive bullous formation. There were no cases of EM among patients who received either DPH or radiotherapy alone. The combination of DPH, WBRT, and tapering of steroids seems to predispose to EM. The pathogenesis of the disorder is probably immunologic. In the absence of seizures, anticonvulsants should not be given routinely to patients with brain tumors. When anticonvulsants are necessary in patients scheduled for WBRT, DPH may not be the drug of choice.

Cancers-associated with HIV infection.

The spectrum of neoplastic disease seen in patients with the acquired immune deficiency syndrome (AIDS) is similar to that seen in several congenital and iatrogenic immunodeficiency states and provides a human model for studying neoplastic transformation in the immune compromised host. High grade lymphoid neoplasia, particularly of the central nervous system (CNS), as well as a virulent form of Kaposi's sarcoma (KS) and several types of squamous cell carcinomas, are appearing at an alarming rate in patients with AIDS. There is substantial serologic, pathologic and molecular evidence linking cytomegalovirus (CMV) to KS and Epstein-Barr virus (EBV) to squamous cell carcinoma and high-grade B-cell non-Hodgkin's lymphoma (NHL). The human T-cell lymphotropic virus type III/lymphadenopathy associated virus (HTLV-III/LAV) may be responsible for the permissive immune deficient state allowing for opportunistic neoplasia and the aggressive biologic behavior and atypical anatomic distribution these neoplasms exhibit. The clinical features as well as potential etiopathogenetic mechanisms of these malignancies are reviewed.