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Biomedical subjects

R Martin

Publications and source records attributed to R Martin.

At least 181 records · Page 10Linked to original sources
PubMed1999

Predictive value of 1H MRSI for outcome in temporal lobectomy.

OBJECTIVE: To investigate the predictive value of 1H MRSI for outcome in patients with mesial temporal lobe epilepsy (MTLE). BACKGROUND: 1H MRSI has been shown to be highly sensitive in the lateralization of temporal lob epilepsy. METHODS: The authors analyzed the relationship between the 1H MRSI findings and surgical outcome in 40 consecutive patients who underwent temporal lobe surgery for MTLE. Outcome at a mean of 24 months (range 18 to 40 months) was classified as seizure free or not seizure free. RESULTS: At follow-up, 78% of patients were seizure free. Correlations showed no predictive value for the creatine/N-acetylated compound (Cr/NA) ratio of the operated temporal lobe and outcome. However, a relationship was found between surgical failure and the Cr/NA ratio of the nonoperated temporal lobe and with a Cr/NA ratio in the nonoperated lobe above 1.21 in patients with bilateral abnormalities (p < 0.01). CONCLUSIONS: Preoperative elevations in the Cr/NA ratio in the nonoperated temporal lobe or the presence of higher metabolic ratios contralateral to the proposed surgery are associated with surgical failure. The predictive value of 1H MRSI absolute metabolite concentrations for outcome in MTLE requires further investigation.

Adolescent↗
PubMed1999

Cognitive consequences of coexisting temporal lobe developmental malformations and hippocampal sclerosis.

OBJECTIVE: To characterize patterns of cognitive functioning in a well-defined group of patients with MRI-identified coexisting left temporal lobe developmental malformations (TLDM) and mesial temporal sclerosis (MTS), and to examine neuropsychological outcome in this dual-pathology group following epilepsy surgery. METHODS: Cognitive functioning in patients with left TLDM and MTS (n = 15) was compared with patients with isolated left MTS (n = 40). TLDM and MTS were identified by high-quality MRI protocol. Patients were administered a battery of neuropsychology tests as part of their presurgical workup for possible epilepsy surgery. Unilateral temporal lobe resection was performed on 10 of the dual-pathology patients and 34 of the isolated MTS patients. Postoperative cognitive performance was also assessed. RESULTS: Both groups displayed impairments in verbal and visual memory, language, and academic achievement. Performance on measures of psychometric intelligence, executive function, and attention were not impaired and were similar between groups. Presence of dual pathology was associated with a significantly less efficient verbal encoding strategy on the word list learning task. Postoperatively, declines were noted for both groups across tasks of verbal memory and language. Groups were not different significantly in terms of neuropsychological outcome after surgery. CONCLUSION: Patients with coexisting TLDM and MTS have impaired cognitive functioning similar to MTS patients-in particular, with regard to episodic memory and language deficits. Temporal lobe resection produces similar cognitive changes in both groups.

Adult↗
PubMed1999

Lithium responsive bipolar disorder, unilineality, and chromosome 18: A linkage study.

Over the last three years several studies have investigated the hypothesis of linkage between bipolar disorder and markers on chromosome 18. Although independent groups have reported positive results, it is still not clear how these should be interpreted, as linkage spans a considerably large segment of the chromosome. In this study we have investigated linkage with chromosome 18 markers in 19 families of lithium-responsive bipolar patients, as a way to select a more homogeneous population. In addition, we have investigated whether there is evidence of a parent-of-origin effect as suggested by previous studies. Eleven markers spanning the whole chromosome were typed and linkage analysis was carried out using parametric and nonparametric methods. Analysis of the whole sample provided nonsignificant linkage results. However, when the sample included only unilineal families, and was further stratified according to parental origin, two chromosomal regions provided modestly positive lod scores. Maximum lod scores of 1.04 (P = 0.001) at D18S53 and 0.87 (P = 0.045) at D18S61 were observed for maternal and paternal pedigrees, respectively. Nonparametric analysis yielded similar results. In conclusion, our results are congruent with previous reports that suggest an advantage of unilineal pedigrees in linkage analysis of bipolar disorder and cannot rule out a parent-of-origin effect in this genomic region.

Adolescent↗
PubMed1999

Quantitative MRI in temporal lobe epilepsy: evidence for fornix atrophy.

OBJECTIVE: To investigate whether the fornix and mamillary bodies, being part of the limbic system, are abnormal in patients with mesial temporal lobe epilepsy (MTLE). BACKGROUND: The limbic system comprises the hippocampal formation, fornix, mamillary bodies, thalamus, and other integrated structures. This system is implicated in complex functions, including memory and emotion, and in diseases such as MTLE. METHODS: The authors performed volumetric measurements of hippocampus, amygdala, fornix, and mamillary bodies in 50 patients with MTLE and compared the results with normal controls and patients with extratemporal lobe epilepsy. RESULTS: Control (n = 17) measurements of the amygdala, hippocampus, and fornix revealed larger volumes of the right hemisphere structures (p < 0.001). Normalized fornix volumes revealed atrophy in 86% of studies concordant with hippocampal atrophy in all cases but one. Similarly, the mean hippocampal and fornix volumes for the group discriminated the epileptogenic temporal lobe (p < 0.001). Limbic volumes were normal in all patients with extratemporal lobe epilepsy. CONCLUSIONS: Quantitative MRI findings support the concept that MTLE is not a process limited to the hippocampus but also involves other interrelated limbic system structures, in particular, the fornix.

Adolescent↗
PubMed1999

Differential effects of phosphodiesterase type 4-specific inhibition on human autoreactive myelin-specific T cell clones.

Proinflammatory cytokines, secreted by autoreactive CD4+ T lymphocytes may contribute to the pathogenesis of several human autoimmune diseases, including multiple sclerosis (MS). Since the antigen specificities of these T cells are not known at present, therapeutic strategies aiming at common effector pathways, in particular cytokine secretion, may be more feasible in the near future. We have studied the influence of the isoenzyme-specific phosphodiesterase inhibitor rolipram on the proliferation and cytokine secretion of human myelin basic protein-specific T cell clones. The inhibition of proliferation correlated with interference with the IL-2/IL-2 receptor system, while the effects of rolipram on several T helper 1-(TNF-alpha, TNF-beta, IFN-gamma) and T helper 2-like cytokines (IL-4, IL-13) as well as IL-10 revealed an interesting drug profile, with preferential inhibition of TNF-beta, TNF-alpha and IL-10. This profile suggest that rolipram differs from other currently used immunomodulatory drugs.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

The effect of vesnarinone on TNF alpha production in human peripheral blood mononuclear cells and microglia: a preclinical study for the treatment of multiple sclerosis.

Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNF alpha) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNF alpha and interferon-gamma (IFNgamma) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNgamma can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNF alpha. In this study, we demonstrate that while vesnarinone enhances basal TNF alpha levels, it inhibits TNF alpha production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNgamma and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNF alpha production in primary adult human microglial cultures. However, in contrast to rolipram, another TNF alpha inhibiting agent, vesnarinone failed to inhibit TNF alpha production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.

Adjuvants, Immunologic↗
PubMed1999

Serial TCR engagement and down-modulation by peptide:MHC molecule ligands: relationship to the quality of individual TCR signaling events.

In the present study, we examined the relationships among quantitative aspects of TCR engagement as measured by receptor down-modulation, functional responses, and biochemical signaling events using both mouse and human T cell clones. For T cells from both species, ligands that are more potent in inducing functional responses promote TCR down-modulation more efficiently than weaker ligands. At low ligand density, the number of down-modulated TCR exceeds the number of available ligands by as much as 80-100:1 in the optimal human case, confirming the previous description of serial ligand engagement of TCR (Valitutti, et al. 1995. Nature 375:148-151). A previously unappreciated relationship involving TCR down-modulation, the pattern of proximal TCR signaling, and the extent of serial engagement was revealed by analyzing different ligands for the same TCR. Functionally, more potent ligands induce a higher proportion of fully tyrosine phosphorylated zeta-chains and a greater amount of phosphorylated ZAP-70 than less potent ligands, and the number of TCR down-modulated per available ligand is higher with ligands showing this full agonist-like pattern. The large number of receptors showing partial zeta phosphorylation following exposure to weak ligands indicates that the true extent of TCR engagement and signaling, and thus the amount of sequential engagement, is underestimated by measurement of TCR down-modulation alone, which depends on full receptor activation. These data provide new insight into T cell activation by revealing a clear relationship among intrinsic ligand quality, signal amplification by serial engagement, functional T cell responses, and observable TCR clearance from the cell surface.

Amino Acid Sequence↗
PubMed1999

Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults.

OBJECTIVE: To study the acute and steady-state cognitive effects of three new antiepileptic drugs (AEDs): gabapentin, lamotrigine, and topiramate. BACKGROUND: Several newer antiepileptic medications approved recently by the Food and Drug Administration are gaining attention as efficacious alternatives to established AEDs. Greater tolerability with fewer side effects are reported in some. However, the potential cognitive effects of these newer AEDs have received limited attention. METHODS: Healthy young adults randomized to either of the three drugs were administered tests of attention, psychomotor speed, language, memory, and mood at baseline (predrug), acute single-dose period, and after 2 and 4 weeks on the drug. RESULTS: Compared with baseline, the topiramate group had selective, statistically significant declines on measures of attention and word fluency at acute doses, whereas the other two AED groups had no performance changes. At the 2- and 4-week test periods, only the topiramate subjects continued to display neurocognitive effects from drug administration. CONCLUSIONS: Results demonstrate potential acute and steady-state adverse cognitive effects for topiramate, whereas minimal effects were displayed for either gabapentin or lamotrigine in young healthy adults.

Acetates↗
PubMed1999

Determination of growth and lysis kinetics in plant cell suspension cultures from the measurement of esterase release.

The death of Medicago sativa L. cells cultivated in a batch culture was investigated by measuring both the appearance of intact dead cells determined on the basis of the trypan blue (TB) dye exclusion, and the release of the cytoplasmic esterase activity into the culture medium upon cell death. Taking into account the strong instability of this released esterase activity, the total dead cell and lysed cell densities have been estimated. A mechanism for cell death and lysis is proposed and the specific rates of cell growth, death and lysis estimated. The specific rate of appearance of TB dead cells was low and essentially constant (0.25 day(-1)) during the first 8 days of the batch culture, and then increased above 1.5 day(-1) after 2 weeks of cultivation. Whereas no lysis occurred during the first seven days, this phenomenon occurred during the second period and accounted for about 20% of the total cell death by the end of the process. Thus, the viability determined by the trypan blue exclusion method appeared to be invalid after 7 days of culture. When lysis of viable cells is taken into consideration, the specific growth rate was significantly increased and growth was shown to continue for a further 8 days. Increased sensitivity of the cells to shear stresses and consequent cell lysis could be the result of a 35% increase in the cell size

Bioreactors↗
PubMed1999

Correlates of the disability index of the health assessment questionnaire: a measure of functional impairment in systemic sclerosis.

OBJECTIVE: To evaluate functional impairment in systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma at the time of entry into a trial of a therapeutic intervention (D-penicillamine). METHODS: The 20-item Disability Index of the Health Assessment Questionnaire (HAQ-DI) was administered to 134 patients as they entered a multicenter trial of high-dose versus low-dose D-penicillamine. All patients had diffuse SSc of < 18 months' duration. SSc patients who had severe organ system involvement and recent renal crisis and who were receiving prednisone > 10 mg/day were excluded from entry. Logistic regression modeling was used to examine the relationship of HAQ-DI scores to SSc skin and organ system involvement. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to estimate effects. RESULTS: The mean (+/-SD) HAQ-DI score at entry was 1.04 +/- 0.67. Fifty-three percent of patients had HAQ-DI scores > or = 1.0 (signifying moderate-to-severe functional impairment). Multivariate logistic regression demonstrated that impaired fist closure > or = 23 mm (OR 4.24, 95% CI 1.68-10.70), reduced handspread < or = 175 mm (OR 4.5, 95% CI 1.80-11.24), joint tenderness count > or = 1.0 (OR 2.93, 95% CI 1.16-7.40), age > or = 43 years (OR 2.44, 95% CI 1.01-5.95), platelet count > or = 330,000/mm3 (OR 2.30, 95% CI 0.96-5.57), and female sex (OR 2.43, 95% CI 0.77-7.73) were the most important correlates of HAQ-DI scores > or = 1.0. CONCLUSION: Increased HAQ-DI scores at baseline were correlated with reduced fist closure, reduced hand-spread, elevated platelet count, presence of tender joints, older age, and female sex. The most important contributor to functional impairment was hand dysfunction. Even within the first 18 months after SSc onset, moderate-severe functional impairment (HAQ-DI scores > or = 1.0) was frequent (53%) in this group of diffuse SSc patients. In early diffuse SSc, the self-administered HAQ-DI is therefore a valuable assessment of function that correlates with objective physical and laboratory measures of SSc disease involvement. Abnormal HAQ-DI scores may support patient claims of functional impairment, help to focus physician attention on implementing measures to reduce functional impairment, and be useful in reflecting the disease course over time.

Adolescent↗
PubMed1999

Molecular mimicry and multiple sclerosis: degenerate T-cell recognition and the induction of autoimmunity.

Various mechanisms have been proposed for the initiation of autoimmune responses by autoreactive T-cell clones. One of these, the molecular mimicry hypothesis, postulates that myelin-reactive T-cell clones are activated by foreign antigens. Until recently, sequence homology between self- and foreign antigens was considered necessary for cross-recognition to occur in multiple sclerosis. This article reviews current progress in T-cell receptor immunology that led to modify this view and proposes a role for degenerate T-cell antigen recognition in the induction of autoimmunity.

Amino Acid Sequence↗
PubMed1999

Molecular mimicry and multiple sclerosis--a possible role for degenerate T cell recognition in the induction of autoimmune responses.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. The etiology is unknown, but several lines of evidence support the hypothesis that the pathogenesis is mediated by autoreactive T lymphocytes. Molecular mimicry has been proposed as a possible mechanism for the development of an autoimmune response to myelin antigens. According to this model, an immune reaction to self antigens could be initiated by T cells that cross-react with infectious agents that "mimic" the autoantigen, i.e. they share immunologic epitopes. It was previously thought that, in order for a cross-reaction of T cells to two different antigens to occur, a substantial amino acid sequence homology between the two antigens was required. More recent studies on the basic mechanisms of T cell antigen recognition have shown that, at least for some T cell clones, antigen recognition is more "degenerate" and sequence homology is not required for crossreactivity to occur. This article reviews the relevance of these recent advances in basic T cell receptor immunology to the occurrence of autoimmunity in the central nervous system.

Amino Acid Sequence↗
PubMed1999

[Age related changes in cellular signal transduction of glucocorticoid hormones in rat brain].

Chronic or repeated stress can induce a damage of neurons, especially in hippocampus, by which the degree of damage differs in various species. Sapolski has reported that there is a correlation between hippocampal degeneration, disturbed feedback reaction, and hypersecretion of glucocorticoids. The aim of this study was to investigate if the signal transmission via glucocorticoid receptors (GR) in the brain of male wistar rats of two age groups (5-6 and 17-24 months, respectively) is changed in aging and which cytoplasmic factors/modulators participate in this process. The binding of 3H-dexamethasone to cytosolic GR, the transformation, translocation, and nuclear binding of GR complexes (GRC) were studied before and after physiological stress. The influence of cytoplasmic modulators ASTP1) and HSP 70(1)), isolated from brain cytosol and purified, and of exogenous PK C1) was also tested in parallel incubation systems. Whereas old control animals showed a higher cytosolic concentration of unoccupied GR than young ones, this was significantly reduced only in old stressed rats 60 min after stress compared to old controls. The part of transformed GRC, bound to isolated nuclei, was somewhat lower in old than in young rats before and after stress. The nuclear GRC binding could be slightly elevated by addition of ASTP and HSP 70, resp., at the heat transformation of GRC; however, by simultaneous addition of PK C it was significantly increased in both age groups. The GRC binding also rose significantly in stressed animals compared to controls, after simultaneous addition of PK C to more than double of initial assays in young animals. Purified ASTP, isolated from brain cytosol of young animals, showed a higher 32P-incorporation after phosphorylation in vitro than that from old animals. The reduced phosphorylation of ASTP could be one possible cause of the retarded transformation/translocation and the reduced nuclear binding of GRC together with the restricted expression of HSP 70 and decreased PK C activity in the old rat brain.

Adrenocorticotropic Hormone↗
PubMed1999

Nucleo-cytoplasmic translocation of histone H1 during the HeLa cell cycle.

The distribution of unphosphorylated and phosphorylated isoforms of linker histone H1 protein was examined during the cell cycle of HeLa cells by quantitative light and electron microscopic immunocytochemistry. Immunolabeling with a monoclonal antibody directed against the globular domain of H1 (anti-H1), which recognized predominantly unphosphorylated H1, and a polyclonal antibody directed against hyperphosphorylated H1 (anti-H1P) revealed that: (1) H1 immunolabeling was lowest at the start of S phase (S(S)), and then increased progressively during the middle (S(i)) to end of S phase (S(e)), mitosis (M) and telophase (T) to reach the highest level in G1 phase, at which time there was a sudden reduction in H1 immunolabeling before the start of S phase; (2) H1P immunolabeling paralleled this progressive increase, but only until M phase, after which it abruptly disappeared and was virtually absent in G1; (3) H1P immunolabeling in S and M phase was found on both nuclear chromatin or chromosomes and in the cytoplasm, while H1 immunolabeling was found only on nuclear chromatin or chromosomes where it was predominantly localized on condensed chromatin. Our study indicates that H1 dissociates from the DNA to a large extent during replication and chromosome condensation, but not in interphase when cells are transcriptionally active.

Biological Transport↗
PubMed1999

Multiple Sclerosis: Immunotherapy.

Given our current knowledge, there is a need for the early institution of immunomodulatory therapy, especially for patients with poor prognostic factors (motor and cerebellar symptoms, frequent disease exacerbations, and a high level of activity on magnetic resonance imaging ). Patients who progress despite immunomodulatory therapy should be reevaluated in terms of diagnosis, development of neutralizing antibodies, or compliance. If a patient has a partial response to immunomodulatory therapy but his or her disease, as assessed by clinical and MRI criteria, remains very active, every effort should be made to modify disease progression by searching for an immunosuppressive therapy regimen before irreversible and considerable disability has accumulated. For the majority of patients, multiple sclerosis (MS) is a chronic condition. Therefore, until a curative treatment has been developed, the available repertoire of immunosuppressive or immunomodulatory treatments should be assessed with respect to the possibility of long-term use. This is particularly important for new immunosuppressive drugs, such as cladribine or mitoxantrone, or for invasive procedures, such as total lymphoid irradiation or autologous bone marrow transplantation. For the latter treatments, experience with long-term administration is not available or the potential side effects (eg, cardiotoxicity with mitoxantrone) limit the cumulative dose. These considerations may limit long-term administration and thus the general usefulness of some drugs. Even with proven efficacy, we need to define the next step once treatment has to be discontinued. We should also address whether exacerbating disease by discontinuing an effective therapy is a potential hazard. What other therapeutic options remain once the current treatment is discontinued? Answers are not readily available at the moment, but the question should influence our decisions in the selection of traditional, well-studied or new, potentially promising therapies.

Journal Article↗
PubMed1999

Preferential expansion of autoreactive T lymphocytes from the memory T-cell pool by IL-7.

We have developed a new technique that allows us to quantify antigen-specific T cells, and to determine their functional phenotype and origin from naive versus memory populations. Using this methodology, we have characterized a total of 286 T-cell lines specific for myelin basic protein (MBP) and influenza hemagglutinin from 16 multiple sclerosis (MS) patients and nine healthy donors. Our data support the notion that MBP-specific T cells undergo in vivo activation in MS patients and indicate a presence of immune dysregulation that renders MS patients prone to develop autoimmunity. Our methodology offers a way to study antigen-specific T-cell characteristics as a surrogate marker in immunotherapy trials.

Adult↗
PubMed1999

Neurofilament phosphorylation and axon diameter in the squid giant fibre system.

Electron energy loss spectroscopic analysis of squid giant axons in a phosphorus energy window yielded bright signals, which were shown to originate from highly phosphorylated neurofilaments. The frequency and distribution of these signals were analysed at defined intervals in cross-sections of the giant axon, starting from its origin in the stellate ganglion and extending distally along the stellar nerve. The analysis revealed a proximodistal gradient of increasing neurofilament phosphorylation. Within the stellate ganglion and for some distance beyond, the increase in frequency of signals correlated with the widening of the neurofilament meshwork and the radial growth of the axon. This agrees with the hypothesis that neurofilament phosphorylation regulates axon calibre by affecting interfilament spacing. In distal axon domains where the axon diameter diminished, contrary to expectations, the spacing of signals increased and the signals were significantly larger. Hyperphosphorylation apparently compensated for a diminishing supply of neurofilament protein. Contrary to predictions, the presynaptic terminal of the giant synapse contained a distinct and highly phosphorylated neurofilament meshwork. We conclude that the growth of the axon diameter is a function of neurofilament phosphorylation, interfilament spacing and neurofilament density. A mature and highly phosphorylated neurofilament cytoskeleton completely filled the presynaptic terminal of the giant synapse.

Animals↗