Immune response during interferon beta-1b treatment in patients with multiple sclerosis who experienced relapses and those who were relapse-free in the START study

We measured immune markers in subjects with multiple sclerosis (MS) treated with IFNβ-1b for 12 months. IL-17 levels were significantly higher at Month 6 (p = 0.036) in relapsing subjects while BDNF levels were significantly higher at Month 3 (p = 0.028) in relapse-free subjects. Change from baseline in IL-4 levels inversely correlated with disability score whereas change from baseline in IL-10/IFN-gamma ratio inversely correlated with occurrence of relapses. CXCR3 + CD8 + T-cells tended to be higher but declined with treatment in relapse-free compared with relapsing subjects. Findings show the potential of cytokine and neurotrophic factors as biomarkers of clinical response to IFNβ-1b.     

Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor

Experimental and MRI evidence suggest that glatiramer acetate's (Copaxone) therapeutic effect in multiple sclerosis (MS) could be mediated by anti-inflammatory GA-reactive Th2 cells that enter the brain, cross-react with myelin antigens, and produce bystander suppression. Furthermore, a neuroprotective effect, possibly mediated by neurotrophic factors such as BDNF, has been suggested based on experimental evidence in animal models, and the observation that inflammatory cells can elaborate BDNF. Therefore, we examined BDNF production in 73 GA, 13 MBP, and 22 TT-reactive short-term T-cell lines from 12 MS patients treated with GA. Ten of 73 GA-TCL (14%), 1 of the MBP-TCL (3%), and 2 of the TT-TCL (9%) produced BDNF levels two standard deviations above the mean levels produced by resting TCL. RT-PCR analysis confirmed BDNF expression in some GA- and MBP-reactive TCL. The mean BDNF level produced by GA-TCL was significantly higher than that for MBP-TCL, or TT-TCL when lines originating from the same patients were compared (P=0.033). All 10 high BDNF-producing GA-reactive TCL were Th2-biased as determined by the IL-5/IFN-gamma levels ratio. A positive correlation was observed between BDNF and IL-5 (Th2 indicator) (P=0.006) but not with IFN-gamma Th1 indicator) levels in GA-TCL derived from MS patients during but not pre-treatment. We conclude that while BDNF production by T cells is not antigen-specific, GA-reactive TCL are more likely to produce BDNF, and to be Th2-biased.     

Histalog shock

Summary A 55-year-old woman developed shock associated with oliguria after a single injection of 100 mg. of Histalog. The case is cited to draw attention to this potential danger of Histalog. It is emphasized, however, that shock is rare and that one should not be deterred from giving Histalog for gastric analysis whenever indicated, provided patients are properly selected.Fellow in Gastroenterology, 1968–1969.     

Different virus antibodies in serum and cerebrospinal fluid of patients suffering from subacute sclerosing panencephalitis

Complement fixing (CF) antibody titers to measles, parainfluenza (PI) types I and 3, mumps, herpes type 1, and cytomegalovirus (CMV) in serum and cerebrospinal fluid (CSF) of 33 patients with subacute sclerosing panencephalitis (SSPE) were evaluated. Results were analyzed in comparison to 11 patients with neurological diseases other than SSPE and 7 normal subjects. All SSPE patients had elevated serum and CSF measles antibody titers. The number of SSPE patients manifesting elevated titers other than measles did not reach statistical significance when compared to controls, except for PI type 1. This suggests a possible dual infection with measles and PI in SSPE. The anticomplementary effect detected in the serum and CSF of some patients indirectly suggests the presence of immune complexes.     

Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy

BACKGROUND: Glatiramer acetate therapy is thought to be effective for multiple sclerosis (MS) by promoting T(H)2 cytokine deviation, possibly in the brain, but the exact mechanism and site of action are incompletely understood. Determining the site of action and effect of glatiramer on cell trafficking is of major importance in designing rational combination therapy clinical trials. OBJECTIVE: To determine whether glatiramer therapy will also act in the peripheral blood through bystander modulation of chemokine receptor (CKR) expression and cytokine production on T lymphocytes. DESIGN: Before-and-after trial. SETTING: A university MS specialty center. PATIENTS: Ten patients with relapsing-remitting MS. INTERVENTIONS: Treatment with glatiramer for 12 months and serial phlebotomy. MAIN OUTCOME MEASURES: Cytokine production, CKR expression, and cell migration. RESULTS: The glatiramer-reactive T cells were T(H)2 cytokine biased, consistent with previous studies. We found a significant reduction in the expression of the T(H)1 inflammation associated with the CKRs CXCR3, CXCR6, and CCR5 on glatiramer- and myelin-reactive T cells generated from patients with MS receiving glatiramer therapy vs baseline. Conversely, expression of the lymph node-homing CKR, CCR7, was markedly enhanced on the glatiramer-reactive T cells derived from patients with MS undergoing glatiramer therapy. There was a reduction in the percentage of CD4+ glatiramer-reactive T cells and an increase in the number of CD8+ glatiramer-reactive T cells. CONCLUSIONS: Glatiramer may suppress autoreactive CD4+ effector memory T cells and enhance CD8+ regulatory responses, and bystander modulation of CKRs may occur in the periphery.     

Occlusion of dentinal tubules and selective block of pulp innervation prevent the nociceptive behaviour induced in rats by intradental application of irritants

Objectives: Application of irritants on the exposed dentine of the incisors has been shown to produce aversive behaviour in awake rats. This study aims to demonstrate that the observed aversion is due to the infiltration of irritants through the dentinal tubules and the activation of capsaicin sensitive fibres in the tooth pulp. Methods: Different groups of rats were subjected, under anaesthesia, to cutting of the distal 2 mm of their lower incisors and the fixation of an artificial crown that allows the application of 10-15 μl of solution. Several procedures were followed to prevent the action of the irritants including occlusion of the dentinal tubules, local application of lidocaine, selective ablation of the capsaicin sensitive primary afferents (CSPA) or incisor pulpectomy; the reactions to intradental application of either capsaicin (1%) or formalin (2.5%) were tested using a newly designed behavioural score. Results: Occlusion of dentinal tubules produced significant attenuation of the nociceptive behaviour induced by dentinal application of either capsaicin or formalin. Similar results were observed following either local block with lidocaine (2%), selective ablation of capsaicin sensitive afferents or total denervation by pulpectomy. Conclusions: The present results confirm the hypothesis of infiltration of irritants to the incisor pulp through the dentinal tubules and suggest that the reported inflammatory reaction and hyperalgesia are mediated, to a large extent, by capsaicin sensitive primary afferents.     

Continuous perfusion with morphine of the orbitofrontal cortex reduces allodynia and hyperalgesia in a rat model for mononeuropathy

Recent imaging reports demonstrate the activation of the orbitofrontal cortical (OFC) area during acute and chronic pain. The aim of this study was to compare the effects of chronic perfusion of this area with morphine on nociception in control rats and in rats subjected to mononeuropathy. Chronic perfusion of morphine, using miniosmotic pumps, produced significant and naloxone-reversible depression of tactile and cold allodynias and thermal hyperalgesia, observed in neuropathic rats, while it produced significant elevation and naloxone insensitive increase of acute nociceptive thresholds in control rats. The observed results support the idea that this area is a component of a flexible cerebral network involved in pain processing and perception.     

Immunocytochemical binding to neurons of serum from spinocerebellar degeneration patients

Antineural antibodies have been described in sera of patients with neurodegenerative disorders. We looked for the presence of those antibodies in the sera of patients with spinocerebellar degeneration. Serum IgG from four patients with familial spinocerebellar degeneration showed strong binding to cerebral cortical neurons, Purkinje cells, and dorsal root ganglia of normal human tissue sections stained with the peroxidase antiperoxidase (PAP) method at serum dilution of 1:500. No binding to neuroglia cells or cells of the granular layer of the cerebellum was seen. Sera from four immediate, asymptomatic relatives (son or sibling) showed only moderate binding to Purkinje cells and to dorsal root ganglia, but not to cortical neurons. Sera from seven patients with neurological diseases other than spinocerebellar degeneration and from five healthy subjects showed no binding to neural elements. The findings may be of value in the diagnosis and screening of patients suspected of having spinocerebellar degeneration; however, the significance of these antineural antibodies in the pathogenesis of spinocerebellar degeneration is uncertain and awaits further studies.