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Biomedical subjects

P A Calabresi

Publications and source records attributed to P A Calabresi.

16 recordsLinked to original sources
PubMed1999

Chemokines in chronic progressive neurological diseases: HTLV-1 associated myelopathy and multiple sclerosis.

It is hypothesized that in MS and HTLV-1, chemokine and chemokine receptor expression are important mechanisms by which T cells migrate to sites of inflammation. Preliminary evidence supports the roles of several chemokines, including MIP 1beta, in mediating the enhanced migration capacity of MS derived PBLs. In addition, the ligand CCR-5 seems to be up regulated on PBLs from some MS patients. Analysis of T cell clones does not reveal a definite correlation between cytokine phenotype and chemokine receptor profile. The chemokines and chemokine receptor family are likely to be important molecules in chronic progressive neurological diseases, in which immune cells invade the central nervous system.

Autoimmune Diseases↗
PubMed1998

Cytokine gene expression in cells derived from CSF of multiple sclerosis patients.

Cytokines are produced by numerous cell types in the peripheral blood and central nervous system (CNS), and have been implicated in the immunopathogenesis of multiple sclerosis (MS). We examined the relationship between cytokine gene expression of cerebrospinal fluid (CSF) derived cells from MS patients and disease activity as measured by contrast enhanced MRI. There was a significant correlation between the number of CSF cells and the number of contrast enhancing MRI lesions. Cytokine gene expression of TNF-alpha, IFN-gamma, and IL-10 was routinely seen, but IL-4 expression was absent except in two clinically quiescent patients. Trends were observed toward decreased TNF-alpha expression, but increased IL-10 expression, after treatment with IFN-beta1b.

Antisense Elements (Genetics)↗
PubMed1998

ELI-spot of Th-1 cytokine secreting PBMC's in multiple sclerosis: correlation with MRI lesions.

The Th1-like cytokines, interleukin 2 (IL-2), interferon gamma (IFN-gamma), and lymphotoxin alpha (LT-alpha) have been implicated in the immunopathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of immune mediated demyelination. These cytokines have been associated with opening of the blood brain barrier (BBB) in EAE and in vitro, but not in MS. We used an enzyme-linked immunospot (ELI-spot) assay to measure relative numbers of cytokine-secreting peripheral blood mononuclear cells (PBMC) from eight MS patients who were followed with serial monthly contrast-enhanced head magnetic resonance imagings (MRI) and phlebotomy. We found a significant positive correlation between changes in IL-2 secreting cells and MRI lesions over a 6-month time period. There was a weaker association between contrast-enhancing MRI lesions and IFN-gamma or LT-alpha secreting cells. These data are the first to show a significant positive correlation between any cytokine and serial gadolinium (Gd-) MRI disease activity in MS patients. The association between IFN-gamma and LT-alpha secretion and MRI lesions is less clear.

Adult↗
PubMed1998

Increased serum levels of soluble CD95 (APO-1/Fas) in relapsing-remitting multiple sclerosis.

CD95/CD95 ligand interactions are critically involved in the negative regulation of peripheral T-cell responses. Here, we report that serum levels of soluble CD95 are significantly elevated in patients with relapsing remitting multiple sclerosis. In a transectional study, CD95 levels did not correlate with clinical disability or lesion formation on magnetic resonance imaging. Longitudinally, Expanded Disability Status Scale changes were associated with high CD95 levels. Interferon-beta (IFNbeta) treatment led to an initial increase and subsequent decline of serum CD95 levels. Interestingly, patients generating neutralizing antibodies to the drug had significantly higher baseline CD95 levels before IFNbeta treatment than those without neutralizing antibodies.

Adjuvants, Immunologic↗
PubMed1998

Phase 1 trial of transforming growth factor beta 2 in chronic progressive MS.

Transforming growth factor (TGF)-beta2 is a pleiotropic cytokine associated with remissions in multiple sclerosis (MS) and amelioration of allergic encephalomyelitis. We assessed the safety of TGF-beta2 in an open-label trial of 11 patients with secondary progressive (SP) MS. Five patients had a reversible decline in the glomerular filtration rate. There was no change in expanded disability status scale or MRI lesions during treatment. Systemic TGF-beta2 may be associated with reversible nephrotoxicity, and further investigation of its therapeutic potential in MS should be performed with caution.

Adult↗
PubMed1997

Increases in soluble VCAM-1 correlate with a decrease in MRI lesions in multiple sclerosis treated with interferon beta-1b.

Interferon beta-1b reduces clinical exacerbations and disease activity in multiple sclerosis as shown by magnetic resonance imaging, but the mechanism of action is unknown. We investigated the correlation between the levels of soluble adhesion molecules and a reduction in contrast-enhancing lesions on gadopentetate dimeglumine magnetic resonance images after treatment with interferon beta-1b. We determined levels of soluble vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, L-selectin, and tumor necrosis factor receptor (60 kd) in monthly serum samples from patients with definite multiple sclerosis before and during treatment with interferon beta-1b. The level of soluble adhesion molecules was correlated with the number of newly enhancing lesions on monthly contrast-enhanced images. Levels of soluble vascular cell adhesion molecule during treatment were significantly increased compared to control or pretreatment values. The median levels (ng/ml) of this adhesion molecule were 580.3 (range; 373.0-640.7) for the healthy subjects, and 551.4 (489.7-875.5) for patients prior to treatment and 847.9 (591.5-1,232.9) during treatment. Levels of the other soluble adhesion molecules and soluble tumor necrosis factor receptor were not significantly changed during treatment. The increase in soluble vascular cell adhesion molecule correlated with a decrease in the number of contrast-enhancing lesions on magnetic resonance images. These data suggest a novel mechanism of action for interferon beta-1b by direct interference with the adhesion cascade, which may prevent activated T cells from trafficking into the central nervous system.

Adult↗
PubMed1997

Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA.

Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS). This suggestion is based on (1) epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral infection; (2) geographic association of disease susceptibility with evidence of MS clustering; (3) evidence that migration to and from high-risk areas influences the likelihood of developing MS; (4) abnormal immune responses to a variety of viruses; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long incubation periods, a relapsing-remitting course, and demyelination. Many of these studies involve the demonstration of increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described beta-herpes virus that shares homology with cytomegalovirus (CMV), has been reported to be present in active MS plaques. In order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS (CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls. Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease association, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a marker of active viral infection.

Antigens, Viral↗
PubMed1997

Interferon beta results in immediate reduction of contrast-enhanced MRI lesions in multiple sclerosis patients followed by weekly MRI.

Interferon beta-1a and -1b reduce the frequency and severity of clinical exacerbations, and reduce both T2-weighted and contrast-enhanced MRI activity in patients with multiple sclerosis (MS). Several recent reports suggest that at the initiation of treatment there may be transient worsening of symptoms associated with the induction of interferon gamma-secreting cells. We studied eight MS patients with weekly brain MRI's after starting interferon beta treatment, and found immediate reduction in the number of contrast-enhancing lesions. Several patients did experience recurrence of previous symptoms without concomitant opening of the blood brain barrier on contrast-enhanced MRI. These data suggest that the symptoms described after the initiation of interferon beta are not associated with new disease activity, but rather may be related to preexisting lesions. This has implications for both understanding the immunopathogenesis of the disease and for its treatment.

Adult↗
PubMed1997

Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure.

MRI is a valuable tool to examine the pathophysiology and natural history of multiple sclerosis (MS), and several large multicenter trials have utilized MRI as a secondary outcome measures. We previously examined the effect of interferon beta-1b on contrast-enhancing lesions on MRI using a baseline versus treatment design, and found that on treatment there is a reduction in mean frequency of enhancing lesions over the group. Using an expanded number of patients and the same trial design, we examined the individual response to treatment more extensively. We find that the effect seen previously is still present, and that there is heterogeneity in the amount of decrease in contrast-enhancing lesions. This expanded number of patients and trial design allows for the discussion of new criteria for individual response to treatment, which are applied in the current trial. These approaches may be useful in the examination, early testing, and comparison of experimental therapeutic agents in MS as well as in the characterization of patients who do or do not have a response seen on MRI.

Adjuvants, Immunologic↗
PubMed1997

VLA-4 expression on peripheral blood lymphocytes is downregulated after treatment of multiple sclerosis with interferon beta.

Adhesion molecules are likely to play a critical role in the immunopathogenesis of multiple sclerosis (MS). The interaction of vascular cell adhesion molecule-1 (VCAM-1) with its lymphocyte ligand very late antigen-4 (VLA-4) may mediate migration of lymphocytes into the CNS. We have previously demonstrated that MS patients treated with interferon beta (IFN-beta) have a significant increase in soluble VCAM-1 (sVCAM-1) soon after the initiation of treatment, and this effect correlated with the resolution of contrast-enhancing MRI lesions. We studied the cell surface expression of VLA-4 by flow cytometry in 10 MS patients before and during IFN-beta treatment. We found a significant decrease in mean VLA-4 fluorescence of MS patients' lymphocytes on treatment and no change in untreated controls. In vitro treatment of lymphocytes with IFN-beta did not reproduce this effect, but the addition of sVCAM-1 did result in a decrease in VLA-4 expression. These data indicate that the previously identified increase in sVCAM-1 may lead to a decrease in VLA-4 expression and that this effect may partially explain the mechanism of action of IFN-beta.

Adjuvants, Immunologic↗
PubMed1996

MRI studies of multiple sclerosis: implications for the natural history of the disease and for monitoring effectiveness of experimental therapies.

The use of magnetic resonance imaging (MRI) in multiple sclerosis (MS) has increased in our understanding of the natural history of the disease course and has provided and important tool for the analysis of new experimental therapies. Studies using MRI as well as pathological studies of MS indicate that the first event in the development of a new MS lesion as seen on T2 weighted images is disruption of the blood brain barrier (BBBD) which can be demonstrated by areas of increased signal on T1 weighted images done after the administration of gadolinium DTPA. When GdDTPA enhanced MRIs are used to monitor disease activity in patients with mild relapsing remitting MS, a considerable degree of disease activity is observed in clinically stable patients. These findings indicate that MS is an active and progressive disease in most patients even during the earliest phases of the disease and before significant clinical disability has occurred. MRI is also an important tool in evaluating new therapies. Using simple baseline vs treatment designs evidence for an effect of a new treatment on MRI parameters such as Gd-DTPA enhanced measure of BBBD can be achieved using a small study cohort and over a short duration. Together these advances should lead to more rapid progress in the understanding of MS and in identifying new treatments.

Adult↗
PubMed1995

Gene-modified cells for the treatment of cancer.

Gene therapy involves the insertion of a gene into an organism to treat a disease. Since its early development in the 1970s, gene therapy has expanded rapidly both in terms of the methods available and the number of candidate diseases for treatment. This report reviews gene therapy for cancer, including methodology, pre-clinical studies and experimental clinical trials.

Clinical Trials as Topic↗
PubMed1994

Ekbom's syndrome: lipomas, ataxia, and neuropathy with MERRF.

A 66-year-old woman with hereditary deafness and multiple symmetric lipomas presented with ataxia, slight myopathy, and neuropathy. Molecular genetic analysis of mitochondrial DNA revealed the adenine to guanine transition at position 8344 in the tRNA gene for lysine that has been associated with the myoclonic epilepsy and ragged red fiber (MERRF) syndrome. The deafness was transmitted by the patient's father and may have been an unrelated autosomal defect rather than a paternally transmitted mitochondrial point mutation.

Aged↗
PubMed1994

An ultrastructural analysis of human post-infectious (allergic) encephalomyelitis.

A 6-year-old boy developed post-infectious encephalomyelitis and underwent a brain biopsy (10 days after the onset of neurologic symptoms). Electron microscopic analysis of brain showed demyelinated axons, thinly myelinated axons, aberrant remyelination, and numerous phagocytes containing myelin debris. Physical stripping of myelin by pseudopodial extensions of macrophages, as reported in experimental allergic encephalomyelitis, was noted. Hypertrophic and hyperplastic astrocytes were prominent among the phagocytic cells and played an unexpectedly active role in demyelination.

Brain↗
PubMed1989

Saccade preparation inhibits reorienting to recently attended locations.

We measured manual reaction time in normal human subjects to confirm that an eccentric visual signal has a biphasic effect on covert attention and eye movements. First, it summons attention and biases a saccade toward the signal; a subsequent inhibition of return then slows responses to signals at that location. A temporal hemifield dominance for inhibition of return was shown; this finding converges with observations in neurologic patients to suggest that it is mediated by midbrain pathways. Endogenous orienting of attention, from a central arrow cue, did not activate inhibition of return, whereas endogenous saccade preparation did so as effectively as an exogenous signal, even when no saccade was made. Inhibition of return is activated by midbrain oculomotor pathways and may function as a location "tagging" mechanism to optimize efficiency of visual search.

Adult↗