The thymus and myasthenia gravis.

Self acetylcholine receptor (AchR) is targeted by a wayward immune response in myasthenia gravis (MG). The current understanding of the pathogenesis of the AChR-directed immune response is reviewed. Furthermore, the thymus is suspected of initiating and perpetuating the disease process in the majority of patients; its role as a central and peripheral lymphoid organ in MG is discussed. MG seems to result from a failure of (1) establishing tolerance to the AChR and (2) regulating the immune response.

Long-term therapy with glatiramer acetate in multiple sclerosis: effect on T-cells.

Glatiramer acetate (GA) is an immunotherapeutic drug for multiple sclerosis (MS). Several mechanisms of action have been demonstrated which target and affect T-cells that are specific for myelin antigen epitopes. We measured the in vitro proliferation of GA-responsive T-cells from untreated MS patients and from normal healthy subjects; in addition, we determined the effect of prolonged GA therapy or interferon-beta therapy on the in vitro proliferation of GA-responsive T-cells of MS patients. We found that GA induces the proliferation of T-cells isolated from individuals who have not been previously exposed to GA, and that long-term in vivo therapy of MS patients with GA abrogates the GA-induced proliferative response of T-cells. In GA-treated patients, there is no evidence of generalized immunosuppression; both tetanus toxoid and anti-CD3 induced proliferative responses remain unaffected. We propose that prolonged in vivo exposure to GA may result in the eventual induction of anergy or deletion of a population of GA-responsive cells that may also be T-cells that are pathogenic in MS. This mechanism of action, in addition to other mechanisms that have been demonstrated, suggests that GA has pleiotropic effects on the immune system in MS.

Extracorporeal shock wave lithotripsy for difficult common bile duct stones: initial New Zealand experience.

AIM: Common bile duct (CBD) stones can usually be managed by open surgery, endoscopic retrograde cholangiopancreatography (ERCP) or radiological intervention. At times, however, these methods are either unsuccessful or inappropriate. We report our initial experience of extracorporeal shock wave lithotripsy (ESWL) for CBD stones that had either been unsuccessfully managed by conventional techniques, or in cases where these techniques were associated with a high level of risk. METHODS: A retrospective review of medical records of cases receiving ESWL for CBD was undertaken. The aspects reviewed were: indications, outcome and completions from the procedure. RESULTS: ESWL was used in the management of eight patients (three male, five female, age range 24-83, mean 54 years). The indications in five cases were failure of open surgery, ERCP or radiological techniques to clear the duct. In the other three cases, ERCP was unsuccessful and there was significant coincidental medical illness (morbid obesity with diabetes, and severe ischaemic heart disease). CBD clearance was achieved in seven cases. In one unsuccessful case, the duct was cleared after two open procedures. CONCLUSIONS: ESWL can be used to clear CBD stones. It should only be used, however, where prior CBD drainage has been achieved, preferably by endoscopic sphincterotomy. Morbid obesity is a relative contraindication to the use of ESWL. If ESWL fails, a period of time should be allowed to elapse before open surgery because of distortion of soft tissue planes. ESWL can be a useful technique in dealing with some difficult CBD stones.

Cell-surface expression of lymphocyte activation markers in myasthenia gravis.

An analysis of the cell-surface expression of activation markers on B- and T-cells was done to compare patients with myasthenia gravis (MG) and healthy non-myasthenic controls. Marker expression was determined by immunostaining of peripheral blood mononuclear cells (PBMC) isolated from MG patients and from controls. The percentage of B-cells in PBMC that expressed CD71, a transferrin receptor, was significantly greater in patients compared to controls, particularly, in patients who were seropositive for acetylcholine receptor-specific antibodies. When subgroups of MG patients were studied, our data showed that within the first year after disease onset, patients had a significantly higher percentage of T-cells in PBMC that were CD25+ (interleukin-2 receptor alpha) and CD26+ (dipeptidyl peptidase IV ectoenzyme) in comparison to patients with disease symptoms for longer than one year and to healthy controls. Our data also showed that patients with generalized MG had significantly lower percentages of gamma/delta T-cells in peripheral blood compared to healthy controls. The results of this study demonstrate important differences in the cell-surface expression of lymphocyte markers between MG patients and healthy non-myasthenic controls. In addition, differences between subgroups of patients demonstrate that patients with MG are heterogeneous in clinical presentation and in immunological parameters.

Carbon monoxide fatalities in medicolegal autopsies.

All post-mortem medicolegal reports issued by Jordan University Hospital (JUH) during the period 1978-96 were reviewed. Carbon monoxide (CO) as a silent killer was responsible for 31.5% (n = 110) of poisoning fatalities. These were due to unintentional exposure to CO sources in confined spaces (bedrooms (24.6%), worker lodgings (23.6%) and bathrooms (16.4%), and without the victims being aware of CO hazards. Sixty-five per cent of CO fatalities occurred during December to February and 30% of the cases involved the age group 20-29 years, followed by the age group 30-39 years (20%). Non-Jordanians constituted 50% of CO fatalities and Egyptian workers accounted for 78%. Being unaccustomed to cold climates, and on low incomes, they had been using simple and unsafe heating devices. Many of these deaths could have been prevented. Safety educational campaigns to increase awareness of the general population of CO sources, their hazards and how to avoid them should be held continuously during the cold months of the year. All health and safety sectors are advised to be involved.

Fatal poisoning with alcohol and drugs in the Greater Amman County.

A study of fatal poisoning due to alcohol and drugs was carried out, to examine the mortality resulting from alcohol and drugs in the Greater Amman County, Jordan. A retrospective review of all autopsy records and certified deaths issued by the Department of Forensic Medicine at Jordan University Hospital in the greater Amman county was undertaken. During the 18 years (1978-1996) 6109 postmortem cases were performed in our department. A total of 60 cases were identified and analyzed according to age, race, sex, manner of death of the victims along with blood alcohol concentration, the drug detected at autopsies, the scene circumstances, and the geographic location of the accident and death.

The role of cytokines in Schwann cell damage, protection, and repair.

Cytokines, proteins that are secreted by many cells, including inflammatory and glial cells, mediate interactions between cells, generally through paracrine and autocrine networks. Their effects are highly pleiotropic, with overlap of some activities. The pathogenesis of Guillain-Barré syndrome (GBS), especially the classic inflammatory demyelinating polyneuropathy form, seems to involve lymphocytes and macrophages, which are rich sources of cytokines. Macrophages likely have a role in the pathogenesis of the primarily axonal, less inflammatory forms of GBS. Cytokines appear to be involved in damage to Schwann cells, myelin, and axons, although the exact roles of the different cytokines is uncertain. There is increasing evidence that cytokines, including some proinflammatory cytokines that ordinarily cause damage, may also protect the cells of the peripheral nervous system and aid in its repair. The evolution of inflammatory and demyelinating disorders, including the degree of recovery, is probably dependent on the interactions of the different cytokines.

Interleukin-1 alpha, but not interleukin-1 beta, is a co-mitogen for neonatal rat Schwann cells in vitro and acts via interleukin-1 receptors.

The culture of neonatal rat Schwann cells (SC) with unfractionated cytokines induces an increase in SC proliferation. Previous studies demonstrated that while incubation of SC with interleukin-1(IL-1) does not result in enhanced SC mitogenesis, a mixture of antibodies to IL-1 alpha plus IL-1 beta inhibits cytokine-induced proliferation. We undertook the current studies to: (i) confirm that neither isoform of IL-1 directly causes SC proliferation; (ii) determine if there is a difference in the effect of antibodies to IL-1 alpha versus IL-1 beta; and (iii) determine if IL-1 contribution to cytokine-induced proliferation of SC is mediated via IL-1 receptors. IL-1 alpha or IL-1 beta from several sources, over a wide range of concentrations, failed to induce SC proliferation. Polyclonal antibodies to IL-1 alpha from several suppliers and a monoclonal antibody to IL-1 alpha inhibited SC proliferation, whereas similar antibodies to IL-1 beta had no effect on cytokine-induced SC proliferation. Addition of excess IL-1 alpha to an incubation mixture of unfractionated cytokines plus anti-IL-1 alpha abolished the inhibitory effect of the antibodies. Addition of IL-1 receptor antagonist (IL-1 Ra) to unfractionated cytokines inhibited SC proliferation. Therefore, while neither IL-1 alpha nor IL-1 beta is a solitary mitogen for neonatal rat SC, IL-1 alpha but not IL-1 beta acts as a co-mitogen. Moreover, IL-1 alpha seems to exert its co-mitogenic effect via receptors for IL-1.

Effect of clinical status and treatment on the frequency of CD5+ B cells in patients with myasthenia gravis.

CD5+ B cells comprise a subset of B lymphocytes that may play a pathogenetic role in the development of human autoimmune disease. We previously reported a high-frequency phenotype (greater than 30% CD5+ B cells) in the peripheral blood of 57% of myasthenia gravis (MG) patients and 13% of controls. We have now examined additional patients (n = 41) and controls (n = 27) and continue to find that 44% of MG patients have a high-frequency phenotype of CD5+ B cells compared with 7% of controls. Serial studies showed that the frequency of CD5+ B cells in peripheral blood remained fairly stable for controls and that it may decrease with immunosuppressive therapy of MG patients. In patients receiving anticholinesterase only or no therapy (n = 21), the age at onset of MG, presence or absence of detectable serum anti-acetylcholine receptor antibody, clinical extent of MG, and the duration of disease may affect the frequency of CD5+ B cells in the blood.

Sudden unexpected death due to papillary fibroma of the aortic valve. Report of a case and review of the literature.

The case of the sudden unexpected death of a 21-year-old man due to embolization of segments of an aortic valve papillary fibroma to the left main and anterior descending coronary artery is presented. The literature regarding cardiac papillary fibroma is reviewed with particular reference to those cases associated with sudden death.

The frequency of CD5+ B lymphocytes in the peripheral blood of patients with myasthenia gravis.

A subset of human B lymphocytes expresses Leu-1 (CD5), a pan-T cell marker, which is the equivalent of the murine Lyt-1 molecule. CD5+ B cells produce autoantibodies in vitro; therefore, they may play a role in the pathogenesis of autoimmune disorders. In myasthenia gravis (MG), autoantibodies are directed against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. We examined the peripheral blood leukocytes of MG patients (n = 21) and controls (n = 15) for the presence of Leu-1+ B lymphocytes. A fraction of B-1 (CD20)+ cells expressed Leu-1 at a low density. There was a statistically significant difference in the frequency of Leu-1+ B cells between patients and controls. We observed 2 frequency ranges of Leu-1+ B cells (0 to 30% and above 30%), which were not related to the total percentage of B-1+ cells in the blood. Fifty-seven percent of MG patients had a high frequency of Leu-1+ B cells compared with 13% of controls.

Interactions between adherent mononuclear cells and lymphocytes from granulomas of mice with schistosomiasis mansoni.

T-lymphocyte-adherent mononuclear cell interaction was analyzed in the vigorous and immunomodulated liver granulomas of Schistosoma mansoni-infected mice. Collagenase-dispersed granulomas contained 15% lymphocytes, 30% macrophages, 50% eosinophilis, and some neutrophils. Dispersed granuloma cells stimulated with concanavalin A or soluble worm egg antigens (SEA) did not proliferate unless plate-adherent, esterase-positive mononuclear cells were removed before culture. To analyze the granuloma adherent cell-mediated suppression, vigorous granuloma cell cultures partially depleted of adherent mononuclear cells were supplemented with indomethacin, catalase, superoxide dismutase, levamisole, and anti-murine alpha/beta interferon antiserum. In concanavalin A and SEA-stimulated cultures, only the addition of indomethacin or anti-alpha/beta interferon antiserum alleviated the adherent cell-mediated suppression of vigorous granuloma lymphocyte response. In contrast, these agents only minimally alleviated the suppressed response of SEA-stimulated, immunomodulated granuloma lymphocytes. Moreover, coculture of equal numbers of vigorous and immunomodulated granuloma cells partially depleted of adherent suppressor cells abrogated the alleviated response of vigorous granuloma lymphocytes. These findings indicate that, within the schistosome egg-induced vigorous granulomas, the adherent mononuclear cells exert regulation over lymphocyte responsiveness by alpha/beta-interferon and an indomethacin-sensitive, probably prostaglandin-mediated pathway. Within the immunomodulated granulomas, the adherent suppressor cell-mediated regulation of lymphocyte proliferation appears to play a lesser role.