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K M Carbone

Publications and source records attributed to K M Carbone.

At least 37 records · Page 2Linked to original sources
PubMed1998

In vivo treatment with anti-alpha4 integrin suppresses clinical and pathological evidence of Borna disease virus infection.

Borna disease virus (BDV) infection of the rat brain induces a severe T-lymphocyte mediated inflammatory response that parallels the course of clinical Borna disease. In other models of CNS inflammation, the recruitment of T-lymphocytes from the circulation to sites of inflammation is believed to be directed, in part, by the cellular adhesion molecules alpha4 beta1 integrin (expressed on T-lymphocytes) and its ligand VCAM-1 (expressed on blood brain barrier endothelium). Since BDV-specific T-lymphocytes are known to express the alpha4 beta1 integrin, we examined the effect of in vivo treatment with an anti-alpha4 integrin monoclonal antibody (GG5/3) on the development of BDV-specific encephalitis and Borna disease. Here, we report that the inhibition of alpha4 integrin provided significant clinical benefit in slowing the progression of Borna disease. Antibody treatment greatly reduced the immune cell infiltrates in the CNS of BDV-infected animals, but we found that this inhibition of the immune response did not result in enhanced viral levels.

Animals↗
PubMed1998

Comparison of the neurovirulence of a vaccine and a wild-type mumps virus strain in the developing rat brain.

Prior to the adoption of widespread vaccination programs, mumps virus was the leading cause of virus-induced central nervous system (CNS) disease. Mumps virus-associated CNS complications in vaccinees continue to be reported; outside the United States, some of these complications have been attributed to vaccination with insufficiently attenuated neurovirulent vaccine strains. The development of potentially neurovirulent, live, attenuated mumps virus vaccines stems largely from the lack of an animal model that can reliably predict the neurovirulence of mumps virus vaccine candidates in humans. The lack of an effective safety test with which to measure mumps virus neurovirulence has also hindered analysis of the neuropathogenesis of mumps virus infection and the identification of molecular determinants of neurovirulence. In this report we show, for the first time, that mumps virus infection of the neonatal rat leads to developmental abnormalities in the cerebellum due to cerebellar granule cell migration defects. The incidence of the cerebellar abnormalities and other neuropathological and clinical outcomes of mumps virus infection of the neonatal rat brain demonstrated the ability of this model to distinguish neurovirulent (Kilham) from nonneurovirulent (Jeryl Lynn) mumps virus strains. Thus, this neonatal rat model may prove useful in evaluating the neurovirulence potential of new live, attenuated vaccine strains and may also be of value in elucidating the molecular basis of mumps virus neurovirulence.

Animals↗
PubMed1998

Clinical, serologic, and histopathologic characterization of experimental Borna disease in ponies.

Borna disease was originally described as an equine neurologic syndrome over 200 years ago, although the infectious etiology of the disorder was unproven until the early 20th century. Borna disease virus (BDV) was finally isolated from horses dying of the disorder, and that virus has been used to experimentally reproduce Borna disease in several species of laboratory animals. However, BDV has never been inoculated back into horses to experimentally and etiologically confirm the classic clinical, pathologic, and serologic characteristics of the disease in that species. Three ponies were intracerebrally inoculated with different amounts of BDV and were evaluated clinically, serologically, and neurohistopathologically. All 3 animals developed the clinical signs characteristically described for naturally occurring Borna disease, including ataxia, torticollis, postural unawareness, rhythmic repetitive motor activities, muscle fasciculation, and cutaneous hyperesthesia and hypoesthesia over several body surfaces. Two ponies died after rapid onset of these signs 28-30 days postinoculation. The third animal made a nearly complete clinical recovery. Seroconversion occurred only after the onset of signs and to a marked degree only in the convalescent animal. Virus was recovered postmortem from 2 of the 3 ponies, and a BDV-specific nucleic acid sequence was detectable in all 3 animals using a reverse transcription-polymerase chain reaction procedure. Gross neural lesions were absent, but histopathologically there was generalized intense mononuclear perivascular cuffing, glial nodule formation, and astrocytosis in all 3 brains. Confirming a diagnosis of Borna disease is difficult and perhaps best accomplished using a combination of the clinical, serologic, and histopathologic indicators of this unusual disease supported by positive reverse transcription-polymerase chain reaction findings.

Animals↗
PubMed1997

Borna disease virus antibodies and the deficit syndrome of schizophrenia.

We detected anti-Borna disease virus (BDV) antibodies at a 14.4% rate in patients with schizophrenia. The hypothesis of a higher rate of BDV seropositivity in deficit syndrome was borne out in a subset of 64 patients categorized according to the Schedule for the Deficit Syndrome with 5/15 seropositive deficit and 4/49 seropositive nondeficit (p < 0.05). This suggests that the antibodies and possibly a BDV-like virus are pathogenetically linked to this form of schizophrenia.

Adult↗
PubMed1997

Flow cytometric analysis of major histocompatibility complex (MHC) class II antigen expression on brain cells from Borna disease virus-infected rats without an intervening in vitro culture step.

Borna disease virus (BDV) infects astrocytes in the Lewis rat brain. BDV-infected astrocytes have been shown to express MHC class II in vitro but not in vivo. Using a sensitive fluorescence-activated cytometric technique, we now report the detection of MHC class II on freshly harvested S100-positive cells from BDV-infected rat brain, without an intervening in vitro culture step. These data support the hypothesis that astrocytes from BDV-infected rats express MHC class II on their surface and, thus, are potential participants in the encephalitic response to BDV infection.

Animals↗
PubMed1996

Career development for women in academic medicine: Multiple interventions in a department of medicine.

OBJECTIVE: To determine the gender-based career obstacles for women in an academic department of medicine and to report the interventions to correct such obstacles (resulting from the evaluation) and the results of these interventions. DESIGN: Intervention study, before-after trial, with assessment of faculty concerns and perceived change through structured, self-administered questionnaires. SETTING: The Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md. PARTICIPANTS: Full-time faculty. INTERVENTIONS: Multifaceted intervention from 1990 through 1995 to correct gender-based career obstacles reported by women faculty, including problem identification, leadership, and education of faculty, and interventions to improve faculty development, mentoring, and rewards and to reduce isolation and structural career impediments. MAIN OUTCOME MEASURES: Retention and promotion of deserving women faculty, salary equity, quality of mentoring, decreased isolation from information and colleagues, integration of women faculty into the scientific community, and decreased manifestations of gender bias. RESULTS: Junior women were retained and promoted, reversing previous experience, with a 550% increase in the number of women at the associate professor rank over 5 years (from 4 in 1990 to 26 in 1995). Interim 3-year follow-up showed a 183% increase in the proportion of women faculty who expected they would still be in academic medicine in 10 years (from 23% [7/30] in 1990 to 65% [30/46] in 1993). One half to two thirds of women faculty reported improvements in timeliness of promotions, manifestations of gender bias, access to information needed for faculty development, isolation, and salary equity. Men also reported improvements in these areas. CONCLUSIONS: The outcomes reported here indicate that it is possible to make substantive improvements in the development of women's careers, that an institutional strategy to this end can be successful in retaining women in academic medicine, and that such interventions are likely to benefit all faculty. Long-term interventions appear essential.

Academic Medical Centers↗
PubMed1995

Developmental injury to the cerebellum following perinatal Borna disease virus infection.

In rats infected as neonates, Borna disease virus (BDV) infection causes neuroanatomical, behavioral and physiological abnormalities without encephalitis. Neonatal infection with BDV provides a powerful model for studying the effects of virus replication on brain development without inflammation-induced brain damage. Here we report that neonatal BDV infection interfered with cerebellar development in the Lewis rat. Based on cerebellar cross-sectional area measurements, abnormal cerebellar growth was first noted between 7 and 14 days after infection. Reactive astrocytosis was evident by three days after infection, even without encephalitis, and even before identification of viral proteins in the cerebellum. While neonatal BDV infection caused a significant loss in granule cells, infected granule cells were not identified. BDV proteins were readily detected in the Purkinje cells. Thus, persistent BDV infection of Purkinje cells, but not granule cells, was associated with loss of granule cells during cerebellar development, in the absence of encephalitis.

Age of Onset↗
PubMed1995

Hematologic consequences of Borna disease virus infection of rat bone marrow and thymus stromal cells.

Borna disease virus (BDV) was previously believed to have a strict tropism for the nervous system. BDV has recently been identified by a reverse transcription-polymerization chain reaction-enzyme immunosorbent assay (RT-PCR-EIA) in bone marrow cells and peripheral blood mononuclear cells (PBMC) in BDV-infected Lewis rats. We now report the identification of BDV RNA and infectious virus in thymus cells from rats infected either as neonates (PTI-NB) or as adults (4 weeks of age). Based on in vitro studies, we determined that the BDV-infected cells in bone marrow and thymus tissue are fibroblastic stromal cells. Bone marrow stromal cells are nonhematopoietic, fixed-tissue elements that support hematopoiesis, and, thus, it was not surprising that BDV infection altered the recovery from granulocytopenia and leukocytopenia after myelosuppressive treatment. Notably, unlike other immunotropic and neurotropic viruses, BDV does not appear to infect cells of myeloid or lymphoid lineages. We also report the association between BDV in the thymus with the lack, or loss, of encephalitis in neonatally inoculated rats or adult-inoculated rats during the chronic stage of disease.

Alkaline Phosphatase↗
PubMed1995

Borna disease virus and schizophrenia.

The development of a new serological assay method to detect antibodies in human sera recognizing Borna disease virus (BDV) proteins and a clinical pilot study are presented. Psychiatric patients from a schizophrenia research clinic in Baltimore, Maryland, were examined for antibodies to BDV antigen with traditional indirect immunofluorescence assays (IFA) that used both single and double labeling techniques and also with a Western blot assay capable of detecting antibodies to the three BDV proteins from a human neuroblastoma cell line. Thirteen of 90 (14.4%) patients and 0/20 control subjects had antibodies that recognized more than one BDV protein on the Western blot. Three patients had antibodies that recognized all three BDV proteins. Magnetic resonance imaging assessments of the volume of the putamen (with controls for total cranial volume) differentiated BDV+ from BDV- patients, and there were trend differences for bilateral amygdalae and the left amygdala-hippocampal process. We conclude that: (1) the Western blot assay is superior to IFA assays in BDV serology studies, (2) detection of antibodies to more than one BDV protein is a useful working criterion for seropositivity, (3) the 14.5 kDa BDV protein is 10 times more predictive of seropositivity than either the 38/40 kDa or the 24 kDa protein, (4) there is tentative evidence for a schizophrenia-control difference in the prevalence of anti-BDV antibodies, and (5) it is likely that there are neuroanatomical/behavioral features that differentiate seropositive from seronegative schizophrenic patients.

Adult↗
PubMed1995

Polymerase chain reaction (PCR) search for viral nucleic acid sequences in schizophrenia.

BACKGROUND: Previous studies looking for evidence of viral infection in schizophrenics have yielded conflicting results. We searched for viral nucleic acids to test the hypothesis of the viral aetiology of schizophrenia. METHOD: We used the polymerase chain reaction (PCR) to search for cytomegalovirus (CMV), human immunodeficiency virus (HIV), influenza A, Borna disease virus (BDV), and bovine viral diarrhoea virus (BVDV) in: hippocampus from three schizophrenic and three non-schizophrenic subjects; cerebrospinal fluid (CSF) from 48 schizophrenic patients; CSF and peripheral blood mononuclear cells (PBMC) from nine sets of identical twins discordant for schizophrenia; and SK-N-SHEP cells co-cultured with schizophrenic and non-schizophrenic brain homogenates. All patients met DSM-III-R criteria. RESULTS: Virus-specific nucleic acids were not found in any of the samples tested. CONCLUSIONS: The absence of viral nucleic acids in the samples tested suggest that, in these patients, schizophrenia is not associated with a persistent or latent infection due to these viruses.

Adult↗
PubMed1994

Borna disease virus p24 and p38/40 synthesized in a baculovirus expression system: virus protein interactions in insect and mammalian cells.

To facilitate studies of the individual viral proteins, two Borna disease virus proteins, p24 and p38/40, were synthesized in vitro by means of a baculovirus expression system and examined for antigenic identity to viral proteins from BDV-infected cells. Recombinant proteins p24 and p38/40 were nearly identical in size to the viral proteins from BDV-infected cells. Immunoblot and immunocytochemistry analysis of BDV proteins from infected tissue culture cells and rat brain showed binding of antisera directed against the recombinant proteins. Specific recognition of the recombinant proteins by Borna disease virus-specific convalescent antisera and monoclonal antibodies further demonstrated that the antigenic characters of the p24 and p38/40 had been conserved. Polyclonal antibody directed against either of the recombinant proteins recognized only the protein used as immunogen, without cross reactivity with the other recombinant protein, indicating no common epitopes. Moreover, these data confirmed the proposed gene coding assignments of ORF I and II of BDV p38/40 and p24, respectively. Both of the recombinant proteins were secreted into the media of insect cells in tissue culture, but secretion of recombinant p24 was evident only as a dimeric form and not with the monomeric form. Immunoprecipitation studies performed with monoclonal antibodies and BDV proteins from infected rat brain suggested that a heterodimer forms via binding of p40 to the p24.

Animals↗
PubMed1994

Borna disease virus-specific T cells protect against or cause immunopathological Borna disease.

In this report we show that passive immunization of Lewis rats with viable CD4+, Borna disease virus (BDV)-specific T cells before infection with BDV resulted in protection against BD, whereas inoculation of these T cells after BDV infection induced clinical disease with more rapid onset than seen in BDV control animals. The protective as well as encephalitogenic effector functions of BDV-specific CD4+ T cells were mediated only by viable BDV-specific T cells. The protective situation was obtained by passive transfer of BDV-specific T cells into animals inoculated later with virus, whereas the immunopathological situation was observed when virus-specific T cells developed normally or after adoptive transfer, and appeared on the scene after considerable virus replication in the brain.

Animals↗
PubMed1994

Early and persistent abnormalities in rats with neonatally acquired Borna disease virus infection.

Newborn rats inoculated with Borna disease virus (BDV) develop a persistent, tolerant nervous system infection (PTI-NB), with no signs of encephalitis or Borna disease. We measured body weight, body length, taste preferences, and spontaneous locomotor activity over a 4-month period in PTI-NB and control rats. PTI-NB rats had decreased weight and length but not detectable disturbances in growth hormone and insulin-like growth factor-1 biosynthesis as compared to control rats. In single bottle taste acceptance tests, PTI-NB rats did not differ from controls and drank normal amounts of all solutions. When offered a choice of solutions in two-bottle taste preference tests, PTI-NB rats exhibited a normal preference for saccharin and a normal aversion for quinine, but an exaggerated preference for saline. At 1 and 4 months of age, PTI-NB rats were significantly more active than normal rats, although only 1-month-old PTI-NB rats had increased daytime activity. Thus, even in the absence of encephalitis, BDV infection of the PTI-NB rat is associated with a number of physiological and behavioral abnormalities.

Animals↗
PubMed1993

Borna disease virus in peripheral blood mononuclear and bone marrow cells of neonatally and chronically infected rats.

Borna disease virus (BDV) establishes a persistent infection in cells of the nervous system in rats. The response, or lack thereof, of the immune system to BDV infection of neurons is responsible for the presence or absence, respectively, of Borna disease. We recently demonstrated transmission of BDV by bone marrow cells from neonatally infected rats. Our findings suggested the possibility of a heretofore unsuspected interaction between BDV and the immune system, that of direct effects of BDV infection on the cells of the immune system. This report enlarges upon the previous findings and confirms the presence of BDV RNA in bone marrow cells of neonatally infected rats, using a reverse transcription-polymerization chain reaction-enzyme immunosorbent assay (RT-PCR-EIA). In addition, we detected BDV RNA in peripheral blood mononuclear cells of neonatally infected rats, and in rats inoculated as adults in the chronic, but not the acute, stage of infection. In addition, the RT-PCR-EIA technique identified BDV RNA in cerebrospinal fluid, nasal secretions, saliva, urine and stool. BDV-sequences were not detected in the plasma of infected animals nor in the body fluids and tissues of normal rats.

Aging↗
PubMed1993

Borna disease virus in mice: host-specific differences in disease expression.

We developed a mouse model of Borna disease to facilitate immunopathogenesis research by adaptation of Borna disease virus to mice through serial passage in mouse brain tissue. Borna disease virus replication, antibody production, inflammation, and Borna disease expression in several different strains of mice were examined.

Animals↗
PubMed1993

Characterization of a glial cell line persistently infected with borna disease virus (BDV): influence of neurotrophic factors on BDV protein and RNA expression.

Borna disease virus (BDV) infects cells of the nervous system in a wide range of species. Previous work suggests that there are differences in BDV replication in neuronal cells and glial cells. Many neurons are lysed by the immunopathologic response to BDV; lysis of dentate gyrus neurons in the absence of encephalitis is seen in rats inoculated with BDV as neonates. In contrast, persistently BDV-infected astrocytes increase over the course of BDV infection. Therefore, we compared BDV replication in neuronal (SK-N-SH and SK-N-SHEP) and astrocytic (C6) cell lines. While SK-N-SH cells produced more infectious virions per cell, the C6 cells contained more BDV proteins and RNA. BDV sequences in the supernatants of both cell types were identified, despite low titers of infectious virus, suggesting the release of incomplete virions into the medium. C6 cells secreted a factor or factors into the medium that enhanced the production of BDV proteins and RNA in other cell lines. In addition, nerve growth factor treatment produced the same enhancement. Thus, BDV replication in certain neural cells in vitro may be linked to the production of cell-specific factors which affect viral replication.

Animals↗
PubMed1991

Borna disease virus replicates in astrocytes, Schwann cells and ependymal cells in persistently infected rats: location of viral genomic and messenger RNAs by in situ hybridization.

Borna disease (BD) is an immune-mediated neurological disease caused by infection of the nervous system with a negative strand RNA virus, Borna disease virus (BDV). The host range for BDV is broad and extends from birds to primates. A BDV-like agent may cause disease in humans. Until recently, BDV-infected neural cells could only be identified immunocytochemically using serum from BDV-infected animals. The advent of BDV cDNA clones allowed definition of the relationship between viral nucleic acids and viral proteins in vivo. In situ hybridization with strand-specific RNA probes from a BDV cDNA clone, pAF4, identified BDV genomic RNA and BDV mRNAs in neurons, astrocytes, Schwann cells and ependymal cells in an anatomic distribution consistent with that of BDV proteins. Genomic RNA was contained primarily within the nucleus, whereas mRNAs were found in both the nuclear and cytoplasmic compartments. Viral RNAs were demonstrated in neurons expressing BDV proteins and in glial cells by combined techniques of immunocytochemistry and in situ hybridization.

Animals↗