Experience of a concurrent screening quality assurance programme in an emergency department.
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Ancillary Services, Hospital↗
Biomedical subjects
R L Hirsch
Publications and source records attributed to R L Hirsch.
The placebo effect during a double blind trial of recombinant alpha 2 interferon in multiple sclerosis patients: immunological and clinical findings.
A double-blind, placebo controlled trial of recombinant alpha 2 interferon in relapsing/remitting multiple sclerosis patients was performed to assess the clinical and immunological responses to treatment. This study demonstrated that natural killer (NK) cell activity, known to be enhanced by interferon (IFN) treatment, increased during the first week of treatment in both the IFN and placebo treatment groups. After the first week of treatment NK cell activity returned to baseline levels in both groups, and subsequently declined in the IFN treatment group. Patients in both groups improved clinically, as evidenced by a reduction in the exacerbation rate. Furthermore, a similar incidence of adverse reactions to treatment were reported by both groups. The mechanism underlying the response to placebo is not known. However, it is unlikely that the long term clinical improvement (one year) in either group is related to the transient increase in NK cell activity.
Adult↗
Exacerbations of multiple sclerosis in patients treated with gamma interferon.
In an open, randomised study, 18 patients with clinically definite, relapsing-remitting multiple sclerosis (MS) received 1 microgram, 30 micrograms, or 1000 micrograms doses of recombinant gamma interferon (IFN-gamma), given by intravenous infusion twice a week for four weeks. 7 patients had exacerbations during treatment. This exacerbation rate, compared retrospectively with the pretreatment rate and prospectively with the post-treatment rate, was significantly greater than expected. Exacerbations were not precipitated by fever or other dose-dependent side-effects. A concomitant increase in circulating monocytes bearing class II (HLA-DR) surface antigen suggested that the attacks induced during treatment were immunologically mediated. IFN-gamma is unsuitable for treatment of MS.
Adult↗
Vaccine-associated poliomyelitis in a household contact with Netherton's syndrome receiving long-term steroid therapy.
Paralytic poliomyelitis developed in a man 51 days after his two-month-old daughter received her first dose of trivalent live oral poliovirus vaccine. The patient was receiving long-term glucocorticosteroid therapy (tapered to 12.5 mg per day for the eight months prior to his poliomyelitis) for Netherton's syndrome, a congenital syndrome characterized by bamboo-like hair, hyperkeratotic and hyperhidrotic skin, and multiple allergies. The patient was ventilator-dependent and quadriplegic throughout most of his hospital stay and died in the hospital 10 months after the onset of paralysis. "Vaccine-like" type 3 poliovirus was isolated from a stool specimen and his serum showed a significant rise in neutralizing antibody titer against type 3 virus. This case report represents the first documented case of vaccine-associated poliomyelitis in a household contact receiving glucocorticosteroids, although evidence of immunosuppression was not documented. Nevertheless, the case reinforces current recommendations not to administer oral poliovirus vaccine to persons known to be immune deficient or suppressed or to normal persons with close contacts known to be immune deficient or suppressed.
Adult↗
OKT3 monoclonal antibody reversal of renal and hepatic rejection in pediatric patients.
The monoclonal antibody OKT3 was previously shown to be superior to conventional high-dose steroid therapy for reversal of acute rejection of renal allografts. Furthermore, OKT3 was effective in reversing acute renal or hepatic allograft rejection that was resistant to treatment with steroids, anti-thymocyte globulin, or both. Our analysis demonstrates that OKT3 is also effective in pediatric patients in reversing acute rejection of renal allografts (rescue treatment) or hepatic allografts (primary or rescue treatment).
Adolescent↗
Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system.
We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.
Adult↗
Orthoclone OKT3 treatment of acute renal allograft rejection in patients receiving maintenance cyclosporine therapy.
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Adolescent↗
Orthoclone OKT3 monoclonal antibody reversal of hepatic and cardiac allograft rejection unresponsive to conventional immunosuppressive treatments.
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Adolescent↗
Systemic recombinant alpha-2 interferon therapy in relapsing multiple sclerosis.
This report describes the first use of recombinant-DNA-produced human interferon in patients with multiple sclerosis (MS). Ninety-eight patients who were clinically definite for MS with two or more documented exacerbations during the preceding two years were admitted to this placebo-controlled double-blind randomized trial. Although both groups were similar, placebo patients had later MS onset. Patients injected themselves with 2 X 10(6) IU of alpha-2 interferon or placebo three times each week for up to 52 weeks. This dose of interferon was well tolerated in that side effects were minimal. During the trial, the exacerbation rate was sharply reduced in both groups. In the three-month follow-up period after stopping treatment, more patients who were receiving interferon than placebo became worse neurologically. More patients who were receiving interferon than placebo changed from exacerbating MS to progressive MS during the trial. Thus, no clear therapeutic benefit of alpha-2 interferon for MS was detected.
Adult↗
Activation of the alternative complement pathway by mumps infected cells: relationship to viral neuraminidase activity.
An inverse relationship exists between the sialic acid content of a particle and its ability to activate the alternative complement pathway. The present studies were performed to determine if the neuraminidase (NANase) activities of different mumps virus strains could influence the ability of mumps virus infected cells to activate the alternative pathway. CV-1 cells were infected with three different mumps virus strains (RW, O'Take, and Kilham) and after 24 hours, 10 percent guinea pig serum (GPS) treated with EGTA/MgCl2 or GPS lacking the 4th component of complement (C4DGPS) was added to the cell monolayers. After 30 minutes, the percentage C3 consumed was determined by a functional hemolytic assay. Cells infected with RW (high NANase) consumed significantly more C3 (23.2 per cent) than cells infected with Kilham (5.7 percent, low NANase). Cells infected with O'Take were intermediate in their ability to activate C3. The degree of C3 deposition on the surface of infected cells, detected by fluorescence microscopy, was also greater for cells infected with the RW than the Kilham strain of mumps virus. These studies suggest that the NANase activity of mumps virus can influence the ability of infected cells to activate the alternative pathway and thereby, the ability of complement to participate in host defense against mumps virus infection.
Animals↗
The effects of long-term administration of recombinant alpha-2 interferon on lymphocyte subsets, proliferation, and suppressor cell function in multiple sclerosis.
The immunological effects of long-term treatment with recombinant alpha-2 interferon (rIFN-alpha 2) were investigated in multiple sclerosis (MS) patients treated with 2 X 10(6) units of IFN or a placebo three times per week for one year. A mild lymphopenia was observed in IFN patients who also showed a decrease in the absolute number of total T cells in the blood (OKT3 binding cells); however, the percentage of cells reacting with OKT3, OKT4, and OKT8 antibodies did not change significantly during the study. The percentage of cells reacting with the Leu-7 antibody, which recognizes NK cells, was unchanged. During MS exacerbations, placebo patients showed a tendency for decreased levels of OKT3 and OKT8 cells. In contrast, IFN patients did not demonstrate a decrease in either OKT3 or OKT8 cells during disease attacks. Concanavalin A (ConA)-induced suppressor cell activity was depressed in both IFN and placebo-treated patients during attacks. Lymphoproliferative responses to phytohemagglutinin, pokeweed mitogen, and ConA were unchanged. These studies demonstrate that long-term treatment with rIFN-alpha 2 induces a generalized T-cell lymphopenia, but at this dose does not significantly affect the profiles of T-cell subsets and suppressor cell function in MS patients.
Adult↗
Defective autologous mixed lymphocyte reactivity in multiple sclerosis.
T cells from patients with multiple sclerosis (MS) and normal controls were assessed for their ability to respond in the autologous mixed lymphocyte reaction (AMLR). Cells from stable MS patients demonstrated a significant defect in their proliferative response to non-T cells in comparison to normal controls. Despite the defective AMLR response, T cells from MS patients reacted as well as T cells from normal controls to allogeneic stimuli. Furthermore, MS non-T-cells were fully capable of stimulating allogeneic MLR responses by normal and MS T cells. Since the T4+ cell is the major subpopulation which proliferates in the AMLR, these studies suggest a functional defect in a subpopulation of T4+ cells in MS patients. Since the AMLR may represent an important mechanism by which immune responses are regulated, a defect in the ability of MS T cells to respond to autologous cells could account for several of the autoimmune features of the disease.
Autoimmune Diseases↗
Lymphocytes from multiple sclerosis patients produce elevated levels of gamma interferon in vitro.
The production of gamma interferon (IFN) by mononuclear cells (MNC) from patients with exacerbating/remitting multiple sclerosis (MS) and controls was evaluated. After 3 days of culture with concanavalin A, the amount of gamma IFN in supernatant fluids was determined by radioimmunoassay. MNC from MS patients produced significantly (P less than 0.001) more gamma IFN than MNC from either normal controls or patients with other neurologic diseases. Levels of gamma IFN in the serum and CSF were also measured. Despite the relative absence of gamma IFN in serum (4 positive of 30), all CSF samples tested had low, but detectable, levels of gamma IFN (0.3 to 1.4 U/ml). These studies suggest that some of the autoimmune features and immunologic abnormalities in MS may be related to elevated gamma IFN production.
Adult↗
Natural killer cell activity in multiple sclerosis patients treated with recombinant interferon-alpha 2.
Natural killer (NK) cell activity was evaluated in multiple sclerosis (MS) patients during a phase II trial of recombinant interferon-alpha 2 (IFN). Spontaneous NK activity against the K562 myeloid target cell increased significantly during the first week of treatment in the IFN treatment group. However, NK activity was also increased in the placebo treatment group. Long-term administration of IFN caused a decline of NK activity, below the pretreatment values. This decline was not paralleled by a decline in the percentage of Leu-7 cells in the peripheral blood. The ability of IFN to enhance NK activity during treatment was also evaluated. Enhancement of NK activity by IFN was depressed for the duration of the study in the IFN treatment group. After treatment was stopped, IFN enhancement of NK activity returned to the pre-study value. These studies demonstrate that spontaneous and IFN enhanced NK activity are profoundly affected by the administration of recombinant IFN-alpha 2 in MS patients.
Adult↗
Changes in plasma IgE levels during complicated and uncomplicated measles virus infections.
Plasma IgE levels were measured in 214 samples from 182 Peruvian patients with acute measles virus infections. Plasma IgE levels were significantly elevated early in infection compared to later time points. Plasma levels of IgG from the same patients rose during the same time period, whereas levels of IgA and IgM did not change. In patients with postmeasles encephalomyelitis, IgE remained elevated longer than it did in patients either with uncomplicated measles or measles complicated by pneumonia. It is proposed that the elevation of IgE is another manifestation of the altered immunoregulatory function in patients with measles.
Adolescent↗
T8 antigen density on peripheral blood lymphocytes remains unchanged during exacerbations of multiple sclerosis.
Fluorescence-activated cell sorter (FACS) analysis was used to quantitate the antigen density of the lymphocyte markers T3, T4, T8, and Leu 7 on the surface of peripheral blood mononuclear cells (MNC) from exacerbating/remitting multiple sclerosis (MS) patients. Serial studies showed that the mean fluoresce intensity for all the markers studied did not change significantly during exacerbations. There was a tendency for a generalized decline in T-cells, evidenced by a drop in both T8+- and T4+-cells; however, these changes were not statistically significant. It appears, therefore, that the lymphocyte markers studied here are not useful as markers of disease activity in exacerbating/remitting MS.
Adult↗
The effect of recombinant alpha 2-interferon on defective natural killer cell activity in multiple sclerosis.
Natural killer (NK) cell activity was evaluated in exacerbating/remitting MS patients. Peripheral blood mononuclear cells (MNC) from MS patients had impaired NK-cell cytotoxicity against the K562 myeloid target cell. NK activity was depressed, irrespective of the interval (2 to 13 months) after the last exacerbation. Recombinant alpha 2-interferon (100 U/ml) enhanced NK activity of both MS and control MNC. Cytotoxicity mediated by interferon-treated MS MNC was increased to the level of untreated control MNC. These studies show that MNC from exacerbating/remitting MS patients possess a defect in NK-cell activity that can be corrected in vitro by treatment with interferon.
Adult↗
Measles encephalomyelitis--clinical and immunologic studies.
We studied 19 patients with postinfectious encephalomyelitis complicating natural measles-virus infections, and our results support the hypothesis that this demyelinating disease has a pathogenesis similar to that of experimental allergic encephalomyelitis. Early myelin destruction was demonstrated by the presence of myelin basic protein in cerebrospinal fluid, and lymphocyte proliferative responses to myelin basic protein were found in 8 of 17 patients tested. A lack of intrathecal synthesis of antibody against measles virus suggests that measles encephalomyelitis may not be dependent on virus replication within the central nervous system. Similar lymphoproliferative responses to myelin basic protein of lymphocytes from single patients with encephalomyelitis after rabies vaccine or after varicella or rubella virus infections suggest a common immune-mediated pathogenesis for the perivenular demyelinating disease that can follow the injection of neural tissues or infection by a variety of viruses.
Adolescent↗