Immunosuppressive treatment of multiple sclerosis

Multiple sclerosis is thought, by many investigators, to be an immunologic disease. Therefore, a rationale exists for treating this disease by immunosuppressive therapy. In exacerbating-remitting multiple sclerosis, corticosteroids and adrenocorticotropic hormone are the most widely used drugs; high doses of intravenously administered methylprednisolone have recently gained favor. Chronic progressive multiple sclerosis has been treated with a number of immunosuppressive regimens, several of which have shown promise to date. Cyclophosphamide and azathioprine have been used most often and are reviewed in this report, as are other agents currently under investigation. No firm guidelines for the treatment of chronic progressive multiple sclerosis can be offered, but an approach to immunosuppressive therapy is suggested in this review.     

Stimulatory effect of counterflow centrifugal elutriation in large-scale separation of peripheral blood monocytes can be reversed by storing the cells at 37 degrees C.

Transfusion of peripheral blood monocytes may be of benefit as adjuvant treatment of leukopenic patients with serious infections. To study the feasibility of this approach, a large-scale monocyte separation procedure employing leukapheresis, density gradient centrifugation, and counterflow centrifugal elutriation was established. By processing 5 to 6 liters of normal donor blood, it was possible to obtain a mean of 1.1 x 10(9) (range: 0.5-1.7 x 10(9) cells) of mononuclear cells, of which 89% (range: 82-94%) were monocytes by Wright's stain morphology. When the elutriation was performed in XVIVO-10, a commercially available, serum-free medium developed for adoptive immunotherapy, spontaneous secretion of superoxide by the monocytes was significantly higher than for monocytes elutriated in Hanks' balanced salt solution without calcium and magnesium or non-elutriated peripheral blood mononuclear cells. This stimulated state of the monocytes was observed both immediately after elutriation and after overnight storage at 4 degrees C, and it was not affected by the type of storage vessel used. Overnight storage of the monocytes at 37 degrees C resulted in a reversal of the stimulated state of the cells. Monocytes elutriated in XVIVO-10 and kept overnight at 4 degrees C released high amounts of arachidonic acid. A subsequent decrease in this release was seen after additional storage at 37 degrees C for 18 hours. These observations demonstrate that separation and storage variables have important effects on the state of stimulation of monocytes. Further investigations of such variables may suggest improved procedures for preparation and storage of these cells, as well as possible ways to stimulate monocytes prior to transfusion.     

Circulating cardiac troponin-T in patients before and after renal transplantation

Background: The diagnostic and prognostic use of cardiac troponin T (cTnT) in patients with renal failure has been questioned. Raised serum concentrations of cTnT, with no apparent signs of cardiac damage using conventional methods of detection, have been reported. We aimed to relate circulating concentrations of cTnT to improved renal function following renal transplantation over a one-year period. Method: Plasma cTnT was analysed from patients with end stage renal disease before and after transplantation and subsequently at 1, 3, 6 and 12 months. Eight patients had diabetes, 14 had hyperlipidaemia, 8 were smokers and 4 were ex-smokers; all were hypersensitive. Results: At the time of transplantation, 3 of the 32 patients (9.4%) had plasma cTnT concentrations above 0.1 μg/l. In addition to these three patients, five others showed raised cTnT over the one-year period. Conclusions: The overall trend in circulating cTnT concentrations did not seem to be affected by improved renal function. However, all of the patients that had raised cTnT concentrations at any stage of the one-year period had explainable pathologies or were exposed to multiple cardiac risk factors.     

Cefamandole Therapy in Anaerobic Infections

Thirty-one adult patients with infections due to anaerobic bacteria were treated with cefamandole. Bacteroides fragilis group (17) and Bacteroides melaninogenicus (13) were the most frequent anaerobes isolated. Duration of therapy varied from 2 to 49 days. Results were judged satisfactory in 26 cases, and unsatisfactory in 1 case. Four cases could not be evaluated. Adverse reactions occurred in 16 patients and included positive direct Coombs' test without hemolysis, transient liver function abnormalities, phlebitis, reversible neutropenia, fever, eosinophilia, and toxic epidermal necrolysis. The more significant reactions were associated with prolonged therapy. None was lethal. These data suggest that cefamandole is effective in treatment of most anaerobic infections.     

Limitations of risk analysis in the determination of medical factors in road vehicle accidents

The purpose of risk analysis in the determination of medical factors in road vehicle accidents is to evaluate the risks that are associated with different strategies for accident reduction, so that the subsequent decision making process can be based on a best assessment of the likely benefits. However, it is vital to appreciate the limitations of such an approach, especially where the conclusions depend heavily on the accuracy of the assumptions made. In this paper the assumptions used in some recent analyses concerned with incapacitation, epilepsy, hypoglycaemia and psycho-active medication are explored, and the additional information required to reduce the uncertainty in the estimation of risk indicated. The conclusions from this analysis do not invalidate the use of risk assessment, but draw attention to its limitations and show how a sensitivity analysis can help to identify those areas where more precise information is needed before such an approach can be used confidently in a policy setting.     

A phase II,double-blind,randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies

tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Various potentially confounding factors are discussed.     

Granulocyte transfusion therapy in a child with chronic granulomatous disease and multiple red cell alloantibodies

A 7-year-old, 17-kg child with chronic granulomatous disease and nocardial pneumonia and osteomyelitis did not respond to antibiotic therapy and developed multiple red cell (RBC) alloantibodies (anti-c, -E, and -Jka). To provide daily granulocyte concentrates, a method was devised to reduce the number of incompatible RBCs per transfusion. Leukapheresis was done with hydroxyethyl starch, and the apheresis product was allowed to sediment by gravity in a plasma expressor for 90 minutes. The leukocyte-rich plasma was separated from the sedimented RBCs by transfer to a satellite bag, and the volume of the product was reduced by centrifugation to approximately 80 ml. RBC content was reduced from 29 +/- 7 to 2.5 +/- 1.0 ml (n = 22, p less than 0.01) and was accompanied by a 70 percent recovery of white cells (range, 49-90%). The final product contained 1.6 +/- 1.0 X 10(10) granulocytes. There were no clinical or laboratory signs of hemolysis during the course of 46 granulocyte transfusions, 37 of which were derived from c-, E-, or Jka-positive donors. The size of most apheresis donor pools is insufficient to provide phenotypically matched granulocyte concentrates daily for patients with RBC alloimmunization. The rapid, simple method described here may allow daily therapy with mismatched concentrates to be administered safely to such patients.