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H McFarland

Publications and source records attributed to H McFarland.

At least 19 recordsLinked to original sources
PubMed2005

The role of radiotracer imaging in Parkinson disease.

Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Biomarkers↗
PubMed2004

Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials.

BACKGROUND: A European (EU) and a North American (NA) placebo-controlled study with interferon beta-1b (IFNB-1b) in secondary progressive multiple sclerosis (SPMS) showed divergent results with regard to their primary outcome of sustained Expanded Disability Status Scale (EDSS) progression, while effects were similar on relapse and MRI-related endpoints. Reasons for this discrepancy were explored in the combined dataset. METHODS: Baseline characteristics and variability in EDSS assessments were compared. Retrospective combined analyses for time to confirmed progression were performed to assess treatment effects overall and in subgroups defined by pre-study disease activity criteria and other key baseline variables. RESULTS: The variance of EDSS measurements was 6.5% higher in the NA-SPMS study. The EU study included patients in an earlier phase of SPMS and with more active disease both pre-study (relapses, MRI) as well as on study (EDSS, relapses, and MRI variables as assessed in the placebo groups). The pooled analysis showed an overall risk reduction by about 20% in patients treated with 8 MIU (250 mcg) IFNB-1b for EDSS progression confirmed at 6 months (p = 0.008). Risk reduction by 30% to 40% was found for patients with at least one relapse or change in EDSS by >1 in the 2 years prior to study entry. No other consistent across-studies relation of clinical and MRI variables at baseline to potential treatment response was found. CONCLUSIONS: Although post hoc, this combined analysis of the two large studies with IFNB-1b in secondary progressive multiple sclerosis suggests that both pronounced disability progression and continuing relapse activity might help in identifying those patients in the secondary progressive phase of the disease who are more likely to benefit from treatment.

Adult↗
PubMed2002

A pilot study of recombinant insulin-like growth factor-1 in seven multiple sderosis patients.

The purpose of this open-label, crossover study was to determine the safety and efficacy of recombinant insulin-like growth factor-1 (rhIGF-1) using magnetic resonance imaging (MRI) and clinical measures of disease activity in seven multiple sderosis (MS) patients. Monthly clinical and MPI examinations were performed during a 24-week baseline and a 24-week treatment period with rhIGF-1. The primary outcome measure was contrast enhancing lesion (CEL) frequency on treatment compared to baseline. Secondary outcome measures included dinical and MRI measures of disease activity including: white matter lesion load (WMLL), magnetization transfer ratio (MTR), T1-Hypointensity volume, cervical spine cross-sectional area and proton magnetic resonance spectroscopic (MRS) imaging for determining regional metabolite ratios. rhIGF-1 (Cephalon) was administered at a dose of 50 mg subcutaneously twice a day for 6 months. rhIGF-1 was safe and well tolerated with no severe adverse reactions. There was no significant difference between baseline and treatment periods for any MRI or clinical measures of disease activity. Although rhIGF-1 did not alter the course of disease in this small cohort of MS patients, the drug was well tolerated. Further studies using rhIGF-1 alone or in combination with other therapies may be of value because of the proposed mechanism of action of this growth factor on the oligodendrocyte and remyelination.

Aged↗
PubMed2002

Estimating cerebral atrophy in multiple sclerosis patients from various MR pulse sequences.

PURPOSE: The purpose of this study was to determine how measures reflecting cerebral atrophy (CA) are influenced by pulse sequence (PS) and segmentation algorithm (SA) used in multiple sclerosis (MS) patients and healthy control (HC)s. METHODS: Magnetic resonance imaging (MRI) scans from 10 relapsing-remitting MS (RRMS) patients and five HCs were used to determine the change in brain fractional volume (BFV) over a two-year period. T1-weighted, fluid-attenuated inversion recovery (FLAIR), and proton density (PD)/T2-weighted sequences were analysed Image segmentation to determine brain volume was performed using the following a histogram SA, an adaptive fuzzy c-means algorithm (AFCM), and an adaptive Bayesian segmentation with a K-means clustering. RESULTS: Combinations of the SA and PS in MS patents demonstrated significant differences in the per cent change in BFV from baseline. For the combination of PS and SA the per cent change in BFV for year one and year two varied from +2.05% to - 1.6% and +0.79% to -3.11%, respectively. Analysis of the HCs data revealed fluctuations in BFV varying from +0.26% to -0.29%. CONCLUSIONS: MRI estimates of CA are dependent on both the type of PS and SA; therefore, the choice of SA technique and PS should be consistent during an MS treatment trial. The progression of CA in MS should only be used as a secondary or tertiary outcome measure in treatment trials until a better understanding of how this measurement is affected by the disease, the image acquisition and analysis techniques.

Adult↗
PubMed2000

Therapeutic potential of phosphodiesterase-4 and -3 inhibitors in Th1-mediated autoimmune diseases.

Phosphodiesterase-4 (PDE4) inhibitors have the potential to modulate immune responses from the Th1 toward the Th2 phenotype and are considered candidate therapies for Th1-mediated autoimmune disorders. However, depending on the model and cell types employed, studies of atopic individuals have come to the opposite conclusion, i.e., that PDE inhibitors may be beneficial in asthma. Using in vitro immunopharmacologic techniques we analyzed the effects of PDE4 and PDE3 inhibitors on human immune cells to address these discrepancies and broaden our understanding of their mechanism of action. Our results indicate that PDE inhibitors have complex inhibitory effects within in vivo achievable concentration ranges on Th1-mediated immunity, whereas Th2-mediated responses are mostly unaffected or enhanced. The Th2 skewing of the developing immune response is explained by the effects of PDE inhibitors on several factors contributing to T cell priming: the cytokine milieu; the type of costimulatory signal, i.e., up-regulation of CD86 and down-regulation of CD80; and the Ag avidity. The combination of PDE4 and PDE3 inhibitors expresses synergistic effects and may broaden the therapeutic window. Finally, we observed a differential sensitivity to PDE inhibition in autoreactive vs foreign Ag-specific T cells and cells derived from multiple sclerosis patients vs those derived from healthy donors. This suggests that PDE inhibition weakens the strength of the T cell stimulus and corrects the underlying disease-associated cytokine skew in T cell-mediated autoimmune disorders. These new findings broaden the understanding of the immunomodulatory actions of PDE inhibitors and underscore their promising drug profile for the treatment of autoimmune disorders.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Contrast-enhanced magnetic resonance activity in relapsing remitting multiple sclerosis patients: a short term natural history study.

Magnetic resonance imaging (MRI) has been used to study the history of multiple sclerosis (MS). We analyze the relationship between MRI activity in the first scan compared to the subsequent five scans, and we evaluate whether a shorter observation period of 3 months may predict the subsequent 3 months. Monthly enhanced MRI was performed in 103 relapsing remitting (RR) MS patients for 6 months. Thirty-five per cent of patients had an inactive scan on the initial examination. More than 80% of them developed MRI activity during the following 5 months. Eighteen per cent of patients had three consecutive inactive scans; 65% of them had at least one active scan on the subsequent 3 monthly MRI's. The relationship between the first scan and all subsequent scans demonstrates a clear weakening over time. Eighty-two per cent of patients had at least one active scan during the initial 3 consecutive months, the chance of becoming inactive decreased from 23% to 0% over the subsequent 3 months, according with the mean number of enhancing lesions during the first 3 months. These results suggest that neither a single scan nor a short baseline of 3 months may adequately describe the natural history of disease in an individual RRMS patient.

Adult↗
PubMed1999

Cerebrospinal fluid somatostatin, mood, and cognition in multiple sclerosis.

BACKGROUND: Cerebrospinal fluid (CSF) somatostatin (SS) levels have been shown to be decreased in multiple sclerosis (MS) during relapse as well as in disorders characterized by depression or cognitive impairment. Since MS is often associated with depression and cognitive impairment, we examined both the effect of course of illness on CSF SS as well as the variance in SS attributable to associated features (e.g., depression or cognitive impairment). METHODS: Fifteen patients with chronic progressive MS participating in a 2-year cyclosporine trial underwent lumbar punctures for CSF SS at baseline and at 12 and 24 months. Additionally, patients were evaluated by neuropsychological testing, and physical disability and mood ratings. Baseline CSF SS levels were also obtained in a group of control subjects (n = 10). RESULTS: At baseline, CSF SS levels were lower in MS patients than control subjects (p < .001). Decreased CSF SS at 24 months was correlated with decreased cognitive performance on several measures and was best and significantly predicted by cognitive deterioration at 24 months. CONCLUSIONS: Our data support those from previous studies that found lower levels of CSF SS in MS during relapse and suggest that changes in CSF SS are related to the process responsible for diminished cognitive function in MS.

Adult↗
PubMed1999

Monitoring relapsing remitting MS patients.

The availability of safe and partially effective disease modifying therapies necessitates changes in how neurologists monitor patients with relapsing remitting multiple sclerosis (RRMS). Neurologists need to make the diagnosis of MS as soon as possible to be able to initiate therapy early in the course of disease. In deciding whom to treat, neurologists should consider information on disease activity and burden acquired from the neurologic history and examination and magnetic resonance imaging (MRI). Patients not on a disease modifying therapy should undergo yearly clinical assessments and periodic cerebral MRI to monitor for changes in disease activity. Patients on disease modifying therapy should undergo regular clinical assessments to monitor for side-effects and disease activity. Cerebral MRI scanning may also be useful in assessing patients on therapy, particularly when considering changes in therapy.

Brain↗
PubMed1999

Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable antigenic environment.

Apoptosis of mature T lymphocytes preserves peripheral homeostasis and tolerance by countering the profound changes in the number and types of T cells stimulated by diverse antigens. T cell apoptosis occurs in at least two major forms: antigen-driven and lymphokine withdrawal. These forms of death are controlled in response to local levels of IL-2 and antigen in a feedback mechanism termed propriocidal regulation. Active antigen-driven death is mediated by the expression of death cytokines such as FasL and TNF. These death cytokines engage specific receptors that assemble caspase-activating protein complexes. These signaling complexes tightly regulate cell death but are vulnerable to inherited defects. Passive lymphokine withdrawal death may result from the cytoplasmic activation of caspases that is regulated by mitochondria and the Bcl-2 protein. The human disease, Autoimmune Lymphoproliferative Syndrome (ALPS) is due to dominant-interfering mutations in the Fas/APO-1/CD95 receptor and other components of the death pathway. The study of ALPS patients reveals the necessity of apoptosis for preventing autoimmunity and allows the genetic investigation of apoptosis in humans. Immunological, cellular, and molecular evidence indicates that throughout the life of a T cell, apoptosis may be evoked in excessive, harmful, or useless clonotypes to preserve a healthy and balanced immune system.

Animals↗
PubMed1998

Molecular genetic studies in lymphocyte apoptosis and human autoimmunity.

Using a genetic approach, we have studied the molecular basis of human autoimmunity with special emphasis on a disease that is due to defective lymphocyte apoptosis. Recently, we and our collaborators have found that the autoimmune/lymphoproliferative syndrome (ALPS), an inherited disease of children comprising marked lymphoid hyperplasia and autoimmune manifestations, is due to abnormalities in the CD95 gene that cause defective lymphocyte apoptosis. Our recent investigations have shown that the mutations in most families with ALPS cause either global or local changes in the structure of a cytoplasmic portion of the molecule called the 'death domain'. These death domain alterations impair binding of the adapter protein FADD/MORT1 and result in a failure to activate apoptotic caspases after CD95 (Fas/APO-1) cross-linking. Mutations in apoptotic caspases may also contribute to the pathogenesis of ALPS in individuals that have no CD95 gene mutations.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Magnetic resonance techniques to monitor the long term evolution of multiple sclerosis pathology and to monitor definitive clinical trials.

Magnetic resonance has provided a literal window on the brain to visualise the actual pathology of MS as it evolves in the living patient. Natural history studies disclosed that MRI visualised pathological activity was seen at 5 to 10x the rate of clinical relapses. Utilising that knowledge, systematic MRI monitoring has been used to supplement clinical monitoring to show the treatment effect in several clinical trials. This chapter explains how MR techniques can be used to further explore the evolution of in vivo pathology both in clinical trials and natural history studies.

Axons↗
PubMed1997

Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone.

CD4+ class II-restricted T cells specific for self antigens are thought to be involved in the pathogenesis of most human autoimmune diseases and molecular mimicry between foreign and self ligands has been implicated as a possible mechanism for their activation. In this report we introduce combinatorial peptide libraries as a powerful tool to identify cross-reactive ligands for these T cells. The antigen recognition of a CD4+ T cell clone (TCC) specific for myelin basic protein peptide (MBP) (86-96) was dissected by the response to a set of 220 11-mer peptide sublibraries. Based on the results obtained with the libraries for each position of the antigen, artificial peptides were found that induced proliferative responses at much lower concentrations than MBP(86-96). In addition stimulatory ligands derived from protein sequences of self and microbial proteins were identified, some of them even more potent agonists than MBP(86-96). These results indicate that: (a) for at least some autoreactive CD4+ T cells antigen recognition is highly degenerate; (b) the autoantigen used to establish the TCC represents only a suboptimal ligand for the TCC; (c) a completely random and unbiased approach such as combinatorial peptide libraries can decrypt the spectrum of stimulatory ligands for a T cell receptor (TCR).

Amino Acid Sequence↗
PubMed1997

Modifications of peptide ligands enhancing T cell responsiveness imply large numbers of stimulatory ligands for autoreactive T cells.

In this report, we demonstrate for autoreactive T cell clones that single amino acid modifications of the antigenic ligand can result in not only abrogated, decreased, or unmodified, but also increased, T cell responsiveness (superagonist ligands). We further studied the effects of combinations of multiple substitutions with different effects in single peptides. Experiments with peptides carrying multiple amino acid exchanges revealed that the final outcome of TCR ligation by a given ligand is the integration of negative, neutral, and positive effects of each single residue. In addition, the introduction of superagonist substitutions together with nonconservative modifications of primary and secondary TCR contacts resulted in stimulatory ligands. These findings indicate that: 1) the specificity of a single TCR is highly degenerate; 2) ligands exist for autoreactive T cells that have higher agonist activity than the autoantigen itself; 3) the rules to search for cross-reactive epitopes in autoimmunity should take into account that amino acids at certain positions within an antigenic peptide may exert superagonist activity and compensate for the negative effects of residues at other positions that would otherwise not be tolerated.

Amino Acid Sequence↗
PubMed1997

Clinical safety of serial monthly administrations of gadopentetate dimeglumine in patients with multiple sclerosis: implications for natural history and early-phase treatment trials.

Serial contrast magnetic resonance imaging (MRI) has played an increasingly important role in understanding natural-history and early-treatment trials of multiple sclerosis patients. The purpose of this study is to determine whether the serial administration of gadopentetate dimeglumine at the conventional dose has any demonstrable effect on routine hematologic or serum chemistries. This study followed 56 patients with multiple sclerosis in a longitudinal natural-history trial using contrast-enhanced MRI scans over a four-year period between 1988 and 1993. Patients received between 3 and 53 doses of gadopentetate dimeglumine at 0.1 mmol/kg intravenously. A retrospective review of regular blood screening tests over this period identified no significant effect either on routine hematologic studies, as defined by complete blood count (hemoglobin, hematocrit, platelet and white blood cell counts, and mean corpuscular volume); standard serum chemistry studies, including electrolytes (sodium, potassium, chloride) and renal and liver function tests; or serum iron profiles. We conclude, therefore, that serial contrast-enhanced MRIs can be used safely as an outcome measure for Phase I/II evaluations of new therapies for multiple sclerosis.

Adult↗
PubMed1996

A novel population of CD4+CD56+ myelin-reactive T cells lyses target cells expressing CD56/neural cell adhesion molecule.

CD56 is a member of the neural cell adhesion molecule family expressed on cells of the central nervous system and also on NK cells. Previous studies suggest the involvement of CD56 in effector-to-target cell conjugation mediated by NK cells. It was shown recently that CD56 is also expressed by subpopulations of CD8+ and CD4+ T cells. The present study describes the functional characteristics of CD4+CD56+ T cell lines established from blood of multiple sclerosis patients by stimulation with myelin basic protein (MBP). CD4+CD56+, MBP-specific T cell lines were able to lyse MBP-pulsed target cells in an HLA class II-restricted fashion. At the same time, they mediated MHC-unrestricted lysis of CD56+ target cells such as CD56+ lymphoid or glial tumor cells, but not of the typical NK target, K562. A number of experimental results including separation of CD4+CD56+ T cells into CD56 high and low expressing populations, cold target inhibition, as well as killing of CD56-transfected cells indicate that homotypic CD56 interactions are involved in the MHC-unrestricted lysis. CD56 interactions are not sufficient but are required for effector/target interaction. Our findings raise the possibility that CD4+CD56+ T cells sharing properties of both typical Ag-specific Th0-like T cells and NK cells might be involved in damage of tissues expressing CD56/neural cell adhesion molecule, such as the central nervous system. Thus, we provide evidence for a novel mechanism that could lead to organ-specific autoreactivity.

Biomarkers↗
PubMed1996

Experimental immunotherapies for multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease affecting the central nervous system (CNS) principally in young adults. Although its etiology is as yet unknown current evidence suggests that tissue damage is mediated by autoimmune T cells. The examination of an experimental animal model for MS, experimental allergic encephalomyelitis (EAE), has demonstrated that myelin basic protein (MBP)- or proteolipid protein (PLP)-specific T cells mediate the destruction of CNS myelin. In recent years, elegant studies in EAE have shown that encephalitogenic T cells recognize short peptides of MBP or PLP in the context of MHC/HLA-class II molecules, express a restricted number of T cell receptor (TCR) molecules and secrete interferon-gamma and tumor necrosis factor-alpha/beta. Understanding the pathogenetic steps in lesion development at the molecular level led to highly specific immunotherapies for EAE targeting each individual molecule. It has been the hope of many investigators that immunological events resembling those in EAE can be found in patients with MS and that the specific immunotherapies effective in EAE could also be applied to MS. However, to date, the evidence for a unique immunological abnormality in MS is not strong. Although MBP- and PLP-specific T cells with properties similar to those that are encephalitogenic in animals can be isolated from patients, they are not specific for MS and occur with similar frequency in controls. In addition, the variability in specificity and TCR usage has raised questions regarding the relevance of these cells in patients. The importance of the T cell responses to myelin antigens in MS may not be established until the effects of abrogating their activity through specific therapies targeting the trimolecular complex (TMC) have been demonstrated. Consequently, attention has begun to focus on modifying the biology of the MS lesion rather than targeting the initiating event at the level of the TMC, and the success of this approach is reflected by the effect of interferon-beta on lesion development in MS. The recent approval for the use of interferon-beta for the treatment of relapsing-remitting MS has raised great interest in examining novel strategies for immunotherapies in MS. The basic concepts as well as the current candidates for such new immunotherapies will be outlined in this short review.

Humans↗