Biomedical subjects

D M Markovitz

Publications and source records attributed to D M Markovitz.

At least 37 records · Page 2Linked to original sources

PubMed1995

Meningococcal endocarditis presenting as cellulitis.

We report the case of a patient with mixed connective tissue disease who presented with two very unusual manifestations of meningococcal disease, cellulitis and endocarditis, concurrently. We also review the literature concerning Neisseria meningitidis as a causative agent of cellulitis or endocarditis. While meningococcal endocarditis or cellulitis is very rare, autoimmune disease predisposes patients to meningococcal infection. Therefore, unusual infections with this organism should be considered in the differential diagnosis of fever and rash in patients with connective tissue diseases.

Cellulitis↗

PubMed1995

Epstein-Barr virus coinfection and recombination in non-human immunodeficiency virus-associated oral hairy leukoplakia.

Human immunodeficiency virus-associated oral hairy leukoplakia (HLP) is characterized by coinfection with multiple types and strains of Epstein-Barr virus (EBV) and recombination within the EBV genome. HIV-seronegative immunosuppressed and immunocompetent patients with HLP were examined to determine the pathogenic contribution of EBV coinfection and recombination to the development of HLP. Multiple coinfecting EBV strains were detected in both HLP specimens and peripheral blood lymphocytes (PBL) of HIV-seronegative persons with HLP. One specific EBV strain was detected in HLP specimens from 3 of 4 patients. Also, viral recombination during productive replication within HLP generated variants of the latent membrane protein-1 (LMP-1) and nuclear antigen-2 (EBNA-2) genes. Some variants were also detected within PBL. Thus, EBV coinfection and recombination are consistent findings in persons with HLP regardless of immune status. Virally mediated determinants may be important features of EBV pathogenesis.

Adult↗

PubMed1995

The peri-kappa B site mediates human immunodeficiency virus type 2 enhancer activation in monocytes but not in T cells.

Human immunodeficiency virus type 2 (HIV-2), like HIV-1, causes AIDS and is associated with AIDS cases primarily in West Africa. HIV-1 and HIV-2 display significant differences in nucleic acid sequence and in the natural history of clinical disease. Consistent with these differences, we have previously demonstrated that the enhancer/promoter region of HIV-2 functions quite differently from that of HIV-1. Whereas activation of the HIV-1 enhancer following T-cell stimulation is mediated largely through binding of the transcription factor NF-kappa B to two adjacent kappa B sites in the HIV-1 long terminal repeat, activation of the HIV-2 enhancer in monocytes and T cells is dependent on four cis-acting elements: a single kappa B site, two purine-rich binding sites, PuB1 and PuB2, and a pets site. We have now identified a novel cis-acting element within the HIV-2 enhancer, immediately upstream of the kappa B site, designated peri-kappa B. This site is conserved among isolates of HIV-2 and the closely related simian immunodeficiency virus, and transfection assays show this site to mediate HIV-2 enhancer activation following stimulation of monocytic but not T-cell lines. This is the first description of an HIV-2 enhancer element which displays such monocyte specificity, and no comparable enhancer element has been clearly defined for HIV-1. While a nuclear factor(s) from both peripheral blood monocytes and T cells binds the peri-kappa B site, electrophoretic mobility shift assays suggest that either a different protein binds to this site in monocytes versus T cells or that the protein recognizing this enhancer element undergoes differential modification in monocytes and T cells, thus supporting the transfection data. Further, while specific constitutive binding to the peri-kappa B site is seen in monocytes, stimulation with phorbol esters induces additional, specific binding. Understanding the monocyte-specific function of the peri-kappa B factor may ultimately provide insight into the different role monocytes and T cells play in HIV pathogenesis.

Base Sequence↗

PubMed1994

Multiple cis-acting elements in the human immunodeficiency virus type 2 enhancer mediate the response to T-cell receptor stimulation by antigen in a T-cell hybridoma line.

Transcription directed by the human immunodeficiency virus type 2 long terminal repeat (HIV-2 LTR) responds to T-cell antigen receptor signaling. Agents that stimulate T-cell signaling pathways activated by the antigen receptor, such as phorbol ester, plant lectin, or anti-CD3 antibody treatment, have been shown to increase transcription directed by the HIV-2 LTR. In this study, we examine the activation of the HIV-2 LTR in T cells stimulated with the physiologic ligand of the T-cell receptor, antigenic peptide presented by a major histocompatibility molecule. HIV-2 reporter plasmids were transfected into the antigen-specific T-cell hybridoma, 2B4.11, where they responded to antigen-dependent activation. This antigen-mediated transcriptional activation of the HIV-2 enhancer required the presence of at least four regulatory elements in the HIV-2 enhancer, including two purine boxes, PuB1 and PuB2, an AP-1/CREB-like element (pets), and kappa B. This finding suggests that signals emanating from the antigen receptor act coordinately on a set of transcription factors that bind to conserved HIV-2 regulatory elements. Despite differences in the organization of potentially related enhancer elements in HIV-2 and IL-2, these enhancers exploit a similar signal transduction pathway to induce gene expression in antigen-activated T cells.

Animals↗

PubMed1994

Bilateral renal parenchymal malacoplakia presenting as fever of unknown origin: case report and review.

Malacoplakia is a rare inflammatory disorder seen most often in the urinary tract, where it is highly associated with coliform infection. Although first recognized by pathologists in 1902, it has received little attention from the infectious disease community. While there remains much uncertainty regarding the specific cause of malacoplakia, it appears to be associated with a defect in intracellular killing of ingested microorganisms by macrophages. We report a case of bilateral renal parenchymal malacoplakia that presented as fever of unknown origin, and we review 33 previously identified cases. Renal malacoplakia has traditionally been associated with high morbidity and mortality. More recently, treatment with antimicrobial agents such as trimethoprim or ciprofloxacin has yielded a better outcome than had been documented with other therapy. Malacoplakia should be considered in the evaluation of fever of unknown origin or of relapsing or refractory urinary tract infection. Therapy with antimicrobial agents capable of intracellular penetration is recommended.

Anti-Infective Agents↗

PubMed1993

Infection with the human immunodeficiency virus type 2.

PURPOSE: To review the clinical, epidemiologic, and biological features of infection with the human immunodeficiency virus type 2 (HIV-2). DATA IDENTIFICATION: Studies published since 1981 identified from MEDLINE searches, articles accumulated by the author, bibliographies of identified articles, and discussions with other investigators. STUDY SELECTION: Information for review was taken from the author's own studies, data from other investigators that have been submitted for publication, and from 131 of the more than 200 articles examined. DATA EXTRACTION: Pertinent studies were selected and the data synthesized into a review format. RESULTS OF DATA SYNTHESIS: Infection with HIV-2 is prevalent in West Africa and is increasingly being identified elsewhere. The human immunodeficiency virus type 2 is spread through sexual contact and via contaminated blood but, unlike HIV-1, perinatal transmission is limited. Human immunodeficiency virus type 2 is genetically much more closely related to the simian immunodeficiency virus (SIV) than to HIV-1; biological and demographic data suggest that HIV-2 may have originally been transmitted from monkeys to man. Although HIV-2 causes the acquired immunodeficiency syndrome (AIDS), the asymptomatic incubation period after infection with HIV-2 appears to be substantially longer than that following HIV-1 infection. Consistent with these clinical observations, genetic regulation of HIV-2 differs from that of HIV-1. Therapeutic studies of patients infected with HIV-2 are lacking. CONCLUSIONS: The human immunodeficiency virus type 2 is prevalent in West Africa and is now recognized on several other continents, including North America. Its epidemiology, biology, and clinical course differ from HIV-1. Therapeutic studies are needed.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Differential regulation of the human immunodeficiency virus type 2 enhancer in monocytes at various stages of differentiation.

We have demonstrated that stimulation of the human immunodeficiency virus type 2 (HIV-2) enhancer in T cells is dependent upon at least four cis-acting elements, including two purine-rich binding sites, PuB1 and PuB2, which are capable of binding members of the ets family of proto-oncogenes, the pets (peri-ets) site, which lies just upstream of the PuB2 site, and a single kappa B site (D. M. Markovitz, M. Smith, J. M. Hilfinger, M. C. Hannibal, B. Petryniak, and G. J. Nabel, J. Virol. 66:5479-5484, 1992). In this study, we examined the regulation of the HIV-2 enhancer in cells of monocytic lineage. We found that in immature monocytic cell lines, the HIV-2 enhancer is markedly induced by phorbol esters and that all four cis-acting elements are required for activation. In mature monocytic cells, constitutive activity is high, with only modest stimulation following phorbol ester treatment. Mutation of any of the four cis-acting elements resulted in greatly reduced basal expression in mature monocytes. This is in contrast to HIV-1, in which developmentally controlled expression of the enhancer in monocytes is mediated largely through the kappa B sites alone [G. E. Griffin, K. Leung, T. M. Folks, S. Kunkel, and G. J. Nabel, Nature (London) 339:70-73, 1989]. Further, we demonstrated that although both Elf-1, an ets family member with significant similarity to the drosophila developmental regulatory protein E74, and Pu.1, a monocyte- and B-cell-specific member of the ets family, bind the purine-rich enhancer region, Elf-1 is the protein which binds predominantly in vivo. A nuclear factor(s) which binds the pets site, an element which has been described only in HIV-2, was detected in extracts of all of the monocytic cells tested. These findings indicate that the mechanism by which cellular factors regulate HIV-2 enhancer function in monocytic cells differs significantly from that of HIV-1 and may offer a partial explanation for the differences in the biological and clinical characteristics of the two viruses.

Base Sequence↗

PubMed1993

Differential activation of human immunodeficiency virus type 1 and 2 transcription by specific T-cell activation signals.

The human immunodeficiency virus type 1 (HIV-1) and HIV-2 enhancers are induced differentially by physiologic T-cell activation signals. In contrast to that of HIV-1, HIV-2 transcription was quite responsive to stimulation of T cells by antigen presentation but weakly induced by tumor necrosis factor alpha. Like tumor necrosis factor alpha, expression of cloned NF-kappa B subunits strongly activated the HIV-1, but not the HIV-2, enhancer. The differences in response to these physiologic T-cell activation pathways may contribute to the differences in persistence of HIV-1 and HIV-2 infection.

Base Sequence↗

PubMed1993

Activation of the human T-cell leukemia virus type I enhancer is mediated by binding sites for Elf-1 and the pets factor.

Infection with human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell lymphoma/leukemia. This disease occurs in only a small minority of people infected with HTLV-I and manifests itself many years after infection. Therefore, it appears that a fine balance exists between HTLV-I and the host T-cell factors with which it interacts. HTLV-I encodes a transactivating protein, Tax, which activates viral transcription via cellular mechanisms which are incompletely understood. As viral gene expression is negligible during latency, it is doubtful that Tax controls the initial transition to the replicative state. Tax-independent cellular factors which control HTLV-I transcription, and presumably latency, have received little study. Recently, the product of the chicken proto-oncogene ets-1 has been shown to bind to the HTLV-I enhancer and modestly activate transcription in certain cell types (S. C. Gitlin, R. Bosselut, A. Gégonne, J. Ghysdael, and J. N. Brady, J. Virol. 65:5513-5523, 1991). However, the functional significance of the ets-binding site in the intact enhancer has not previously been shown. We now demonstrate that site-specific mutation of the purine-rich ets-binding site significantly diminishes inducible enhancer function, but not Tax response, in the human Jurkat T-cell line. Similarly, mutation of the peri-ets (pets) site, not previously noted in the HTLV-I enhancer, markedly inhibits inducible enhancer function but not Tax response. Further, we show that the predominant protein binding the purine-rich HTLV-I enhancer element in human T cells is not ets-1 but Elf-1, a member of the ets family which is very similar to the Drosophila morphogen E74. Regulation of HTLV-I through Elf-1/pets enhancer motifs resembles that seen with human immunodeficiency virus type 2 (D. M. Markovitz, M. Smith, J. Hilfinger, M. C. Hannibal, B. Petryniak, and G. J. Nabel, J. Virol. 66:5479-5484, 1992; J. M. Leiden, C.-W. Wang, B. Petryniak, M. Smith, D. M. Markovitz, G. J. Nabel, and C. B. Thompson, J. Virol. 66:5890-5897, 1992), another human pathogenic retrovirus with a relatively long incubation period.

Animals↗

PubMed1993

Acquired immunodeficiency syndrome-related visceral leishmaniasis presenting in a pleural effusion.

Visceral leishmaniasis is increasingly reported in immunocompromised patients, including patients with AIDS. We report a case of visceral leishmaniasis in an AIDS patient who presented with pulmonary symptoms and bilateral pleural effusions. Histologic evaluation of pleural fluid and bone marrow revealed histiocytes with intracellular Leishmania amastigotes. Visceral leishmaniasis should be considered in AIDS patients with a significant travel history who present with unexplained pulmonary symptoms.

AIDS-Related Opportunistic Infections↗

PubMed1993

Angioedema presenting as chronic gastrointestinal symptoms.

Gastrointestinal complaints may be the presenting feature of patients with acquired or hereditary angioedema. We describe two patients with episodic nausea, abdominal pain, and cramping secondary to C1 inhibitor deficiency. In one patient, an acquired deficiency arose as a paraneoplastic syndrome with abdominal complaints preceding the diagnosis of an occult lymphoma. The second patient presented at age 61 with abdominal complaints secondary to a hereditary deficiency of C1 inhibitor. The patients' symptoms were due to gastrointestinal angioedema, resulting from episodic unregulated complement activation. The biochemical mechanism of this unusual syndrome and its diagnostic importance are discussed. A C1 inhibitor deficiency should be considered in patients with unexplained abdominal symptoms suggestive of intestinal pseudo-obstruction.

Abdominal Pain↗

PubMed1992

Osteomyelitis and intervertebral discitis caused by Pseudomonas pickettii.

Pseudomonas pickettii, a nonfermenting, gram-negative rod, is rarely pathogenic. Previous reports of infection with P. pickettii have largely involved direct contamination of supplies presumed to be sterile. We describe a case of vertebral osteomyelitis and intervertebral discitis caused by P. pickettii in a debilitated patient. The aggressive nature of this infection demonstrates that P. pickettii may be a more invasive organism than previously noted, particularly in hosts with weakened immunity secondary to underlying disease.

Aged↗

PubMed1992

A novel Ets-related transcription factor, Elf-1, binds to human immunodeficiency virus type 2 regulatory elements that are required for inducible trans activation in T cells.

Human immunodeficiency virus type 1 (HIV-1) and HIV-2 are structurally related retroviruses which both cause AIDS in humans. Although both viruses establish latency in quiescent human-peripheral-blood T cells, the asymptomatic phase of HIV-2 infection may be more prolonged than that of HIV-1. The latent phases of both HIV-1 and HIV-2 infection have been shown to be disrupted by T-cell activation, a process that requires host cell transcription factors. In the case of HIV-1, the transcription factor NF-kappa B is sufficient for inducible transcriptional activation. In contrast, factors in addition to NF-kappa B are required to activate HIV-2 transcription in infected T cells. In this report, we demonstrate that a novel Ets-related transcription factor, Elf-1, binds specifically to two purine-rich motifs in the HIV-2 enhancer. Mutagenesis experiments demonstrated that these Elf-1 binding sites are required for induction of HIV-2 transcription following T-cell-receptor-mediated T-cell activation. Moreover, Elf-1 is the only factor present in activated T-cell nuclear extracts that binds to these sites in electrophoretic mobility shift assays. Thus, Elf-1 is a novel transcription factor that appears to be required for the T-cell-receptor-mediated trans activation of HIV-2 gene expression. These results may explain differences in the clinical spectra of diseases caused by HIV-1 and HIV-2 and may also have implications for the design of therapeutic approaches to HIV-2 infection.

Adult↗

PubMed1992

Activation of the human immunodeficiency virus type 1 enhancer is not dependent on NFAT-1.

The function of a putative NFAT-1 site in the human immunodeficiency virus type 1 enhancer has been analyzed. Activation by the T-cell antigen receptor is minimal in Jurkat cells and is mediated by the kappa B sites. The putative NFAT-1 region is not required for the response to anti-CD3 or to mitogens in T-cell, B-cell, or monocyte/macrophage leukemia lines, nor is it a cis-acting negative regulatory element.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1992

Activation of the human immunodeficiency virus type 2 enhancer is dependent on purine box and kappa B regulatory elements.

Human immunodeficiency virus type 2 (HIV-2) displays several features which distinguish it from HIV-1. Among the differences in these two viruses are the responses of their enhancer regions to T-cell activation. For example, stimulation of HIV-1 transcription is largely dependent on two kappa B regulatory elements. In contrast, the HIV-2 enhancer has a single kappa B site and contains additional cis-acting sequences responsive to induction. One of these sites, previously termed CD3R, is a purine-rich site, also called PuB1, which is responsive to stimulation of the CD3 component of the T-cell receptor complex and binds Elf-1, a member of the ets proto-oncogene family. In this report, we examine the interaction of the PuB1 site with other sites in the HIV-2 enhancer. We demonstrate that the PuB1 site confers responsiveness to T-cell activators only in cooperation with additional enhancer elements. Induction of the HIV-2 enhancer is dependent on at least two other cis-acting regulatory elements in addition to PuB1 and kappa B. One of these elements is another purine-rich site (PuB2), which also binds recombinant Elf-1. An adjacent region, proximal to the PuB2 ets (pets) site, shows protection in DNase footprinting experiments with extracts from Jurkat T cells. Mutation of either the kappa B, PuB1, PuB2, or pets site significantly reduces the response of the HIV-2 enhancer to T-cell stimulation, an effect which is mediated at the RNA level. Therefore, activation of the HIV-2 enhancer is dependent on at least four cis-acting elements, only one of which is found in HIV-1, which act in synergy with one another. Despite their sequence similarity, the organization and function of the HIV-2 enhancer have diverged considerably from those of HIV-1.

Base Sequence↗

PubMed1990

Differential regulation of human immunodeficiency viruses (HIVs): a specific regulatory element in HIV-2 responds to stimulation of the T-cell antigen receptor.

The human immunodeficiency viruses (HIVs) types 1 and 2 have similar genetic organization but differ significantly in nucleic acid sequence. Although infection by either agent leads to symptoms of immunodeficiency, recent studies suggest potential differences in the time course and severity of these diseases. In this report, the transcriptional regulation and induction of these retroviruses were analyzed. We report that the regulation of HIV-2 differs from that of HIV-1: a distinct T-cell activation pathway, triggering of the CD3 component of the T-cell receptor complex, stimulates HIV-2 but not HIV-1 gene expression. The response to T-cell receptor stimulation in HIV-2 is mediated partly by an upstream regulatory element, termed CD3R, which is recognized by a sequence-specific DNA binding protein, NF-CD3R. Jurkat T leukemia cell lines containing HIV-2 provirus also showed increased viral replication after stimulation of the T-cell receptor complex, in contrast to HIV-1. These findings suggest that transcriptional regulation and induction of HIV-2 differ from HIV-1 and raise the possibility that different cofactors contribute to the activation of HIV-1- and HIV-2-associated AIDS.

Antigens, CD↗

PubMed1989

Disparate effects of two herpesvirus [corrected] immediate-early gene trans-activators on the HIV-1 LTR.

The BMLF1 region of the Epstein-Barr virus (EBV) genome and the immediate-early (IE) region of human cytomegalovirus (HCMV) both encode proteins which can trans-activate heterologous promoter/chloramphenicol acetyl transferase (CAT) constructs, including a human immunodeficiency virus type-1 promoter/CAT construct. We demonstrate here that this trans-activation by the EBV BMLF1 gene product, which we have previously shown to be largely post-transcriptional, is reporter gene dependent. In contrast, trans-activation by the HCMV-IE gene product(s), previously shown to be mediated at the RNA level, is seen regardless of whether CAT, human growth hormone, or beta-galactosidase is used as the reporter gene. Mutational analysis revealed no specific cis-acting sequences within the HIV-1 promoter which were required for trans-activation by the HCMV-IE gene product(s).

Carcinoma↗

PubMed1987

Children with influenza A infection: treatment with rimantadine.

Treatment with rimantadine of influenza in children and the potential development of resistance in clinical isolates associated with therapy have not been previously studied. We compared rimantadine to acetaminophen therapy in a controlled, double-blind study of 91 children with influenza-like illness. Of 69 children with proven influenza A/H3N2 infection, 37 received rimantadine and 32 received acetaminophen for five days. Children receiving rimantadine showed significantly greater reduction in fever and improvement in daily scores for symptoms and severity of illness during the first three days. Viral shedding also diminished significantly during the first two days but subsequently increased such that by days 6 and 7 the proportion of children shedding virus, as well as the quantity of virus shed, was significantly greater in the rimantadine group. During the seven-day study, of the 22 children in the rimantadine group with serial isolates tested, ten (45.5%) had resistant isolates compared with two (12.5%) of those with serial isolates in the acetaminophen group (P less than .03). Thus, of the total 37 children in the rimantadine group, 27% were found to have resistant isolated compared with 6% in the total group receiving acetaminophen (P less than .04). Furthermore, the mean inhibitory concentration of rimantadine increased with time in the rimantadine group (r = .4, P = .002) but not in the acetaminophen group. Rimantadine therapy, thus, appears to be significantly more effective than acetaminophen in ameliorating the clinical signs and symptoms of influenza in children. Treatment with rimantadine was also associated with increased viral shedding after the medication was discontinued and with the development of resistance in the clinical isolates, the significance of which is unknown.

Acetaminophen↗