James F. Burdick

Does contralateral internal carotid artery occlusion increase the risk of carotid endarterectomy

The results of every carotid endarterectomy performed contralateral to an internal carotid artery occlusion (n = 36) (group I) were compared with those performed contralateral to a patent internal carotid artery (n = 169) (group II) over the last 10 years. The patients in each group were evenly matched with respect to male gender (66% vs 69%); mean age (66.7 vs 65.9 years); and incidence of hypertension (55.6% vs 53.2%), diabetes (16.7% vs 20.1%), and hyperlipidemia (8.3% vs 11.8%). Patients in group I had a higher incidence of previous myocardial infarction (25% vs 11.8%, p less than 0.05) and exertional angina (55.6% vs 29.6%, p less than 0.01). Indications for carotid endarterectomy were equivalent, including stroke (19.4% vs 21.9%), transient ischemic attacks (36.1% vs 35.5%), amaurosis fugax (16.7% vs 11.8%), nonhemispheric symptoms (5.6% vs 8.3%), and asymptomatic stenoses (22.2% vs 22.5%), respectively. Perioperative strokes occurred in one (2.8%) patient in group I and seven (4.1%) patients in group II (NS). Among the patients in group II the incidence of perioperative stroke did not correlate directly with the degree of contralateral ICA stenosis: greater than 90% (4%); 70% to 90% (6.7%); 50% to 70% (8.7%); and less than 50% (2.8%). The operative mortality rate was 0% among patients in group I and 1.2% among patients in group II (NS). Cardiac complications occurred in two (5.6%) patients in group I and nine (5.3%) patients in group II (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphocyte responsiveness to glucocorticoids, cyclosporine, or both

The reason why some patients with glomerular diseases respond to steroid treatment and others do not remains obscure, and it is not possible to prospectively evaluate the probability of response in individual patients. One factor that might contribute to the clinical response to treatment could be the relative sensitivity of a patients immune system to the suppressive effects of steroids or other immunosuppressive agents. To evaluate this possibility, phytohemagglutinin (PHA)‐stimulated peripheral blood mononuclear cells (PBMC) from 16 patients with various biopsy‐proven glomerulopathies were cultured with prednisolone or methylprednisolone in final concentrations of 10−5 to 10−8 mol/L. From the dose—response curves, the concentration of steroid required to cause 50% inhibition (IC50) of the PHA‐induced proliferative response was determined. The PBMC from 10 patients also were cultured with 400 ng/mL cyclosporine both alone and with 10−7 mol/L steroid, and the inhibitory effects were calculated. There was considerable heterogeneity in the sensitivities of individual patients to steroid inhibition, and the mean ± SEM IC50 was significantly lower for methylprednisolone than for prednisolone. Cyclosporine caused 50% or greater inhibition in 6 of the 10 patients but had <10% inhibitory effect in 2 patients. In most patients studied, cyclosporine plus steroid was significantly more inhibitory than cyclosporine alone, but the combination was usually no more effective than 10−7 mol/L methylprednisolone alone. These results are consistent with the hypothesis that differences in the sensitivity of individual patients immune systems to the immunosuppressive effects of steroids and cyclosporine might contribute to differences in their clinical responsiveness to treatment.

Pentoxifylline Potentiates In Vitro Lymphocyte Suppression by Glucocorticoids and Immunosuppressive Drugs

Pentoxifylline, which has immunomodulatory effects in addition to its better known rheologic effects, might potentiate the effectiveness of traditional immunosuppressive drugs. We therefore studied the suppressive effect of pentoxifylline in combination with clinically relevant concentrations of prednisolone, methylprednisolone, cyclosporine, tacrolimus, rapamycin, and mycophenolic acid on mitogen‐stimulated lymphocytes from 29 patients with glomerular diseases. Inhibition of lymphocyte proliferation obtained with 10−7 and 10−8 mol/L concentrations of the glucocorticoids and with 300 ng/mL cyclosporine was significantly increased when each was combined with 5, 25, or 50 μg/mL of pentoxifylline. The additive inhibitory effect of pentoxifylline in combination with 10−7 mol/L glucocorticoids was inversely proportional to the inhibitory effect of the 10−7 mol/L concentration of glucocorticoid alone, suggesting that the less sensitive the patients cells, the greater the potentiation by pentoxifylline. The greatest degree of potentiation by pentoxifylline occurred when combined with the lower (10−8 mol/L) concentration of glucocorticoids. Pentoxifylline also significantly increased lymphocyte suppression in combination with 150 and 300 ng/mL concentrations of cyclosporine, 5 ng/mL of tacrolimus, 2.5 × 10−7 mol/L mycophenolic acid, and 10 ng/mL of rapamycin. These in vitro results suggest that pentoxifylline might have steroid‐sparing effects and contribute to improved clinical outcomes from immunosuppressive treatment of renal diseases.

A case of severe benign intrahepatic cholestasis treated with liver transplantation.

A male patient with benign recurrent cholestasis since age 2.5 yr developed unremitting cholestasis with incapacitating pruritus and hepatic fibrosis by age 21. He was tried on numerous medical therapies for pruritus with transient or no relief. He responded only temporarily to biweekly plasmapheresis, which was carried out for 4 yr. He underwent orthotopic liver transplantation at age 25 with immediate resolution of his pruritus. At age 30 he is a happy, asymptomatic, fully employed professional.

Effects of Glucocorticoids and Cyclosporine on IL‐2 and IκBα mRNA Expression in Human Peripheral Blood Mononuclear Cells

To evaluate molecular mechanisms that might account for the heterogeneity in the in vitro responsiveness of individual subjects peripheral blood mononuclear cells (PBMC) to immunosuppressive drugs, the authors quantitated in normal human cells the suppressive effects of the glucocorticoids prednisolone and methylprednisolone and of cyclosporine on interleukin‐2 (IL‐2) mRNA expression and IL‐2 production, as well as the stimulatory effect of these drugs on IκBα mRNA expression. As expected, cyclosporine was significantly more suppressive than either glucocorticoid of IL‐2 mRNA expression and IL‐2 production by mitogen‐stimulated PBMC, with variable degrees of inhibition in cells from individual subjects. The authors confirmed in human PBMC the stimulation of IκBα mRNA expression by the glucocorticoid reported by others in HeLa and transfected Jurkat cell lines. In addition, the authors observed a stimulatory effect on IκBα mRNA expression by cyclosporine as well in 8 of 10 PBMC preparations studied, suggesting a possible role of calcineurin in the regulation of IκBα a production. Interindividual variability in the intracellular mechanisms of action, possibly based on molecular polymorphisms, might be one factor contributing to differences among patients in their clinical responses to treatment with such drugs.

Lymphocyte suppression by glucocorticoids with cyclosporine, tacrolimus, pentoxifylline, and mycophenolic acid

Methylprednisolone has been found to be significantly more suppressive than prednisolone (the pharmacologically active metabolite of prednisone) of mitogen‐stimulated human lymphocyte proliferation. In this study, peripheral blood mononuclear cells (PBMC) from end stage renal disease patients were cultured with phytohemagglutinin (PHA) alone and with methylprednisolone and prednisolone individually, as well as each glucocorticoid (10−7 mol/L) in combination with 300 ng/ml cyclosporine, 10 ng/ml tacrolimus, 25 μg/ml pentoxifylline, and 10−7 mol/L mycophenolic acid. Under each experimental condition, the mean ± SD % inhibition of PHA‐stimulated 3H‐thymidine incorporation was significantly greater with methylprednisolone than with prednisolone: methylprednisolone 55 ± 17 versus prednisolone 28 ± 14, p < 0.001; methylprednisolone + cyclosporine 76 ± 18 versus prednisolone + cyclosporine 52 ± 18, p < 0.001; methylprednisolone + tacrolimus 74 ± 18 versus prednisolone + tacrolimus 50 ± 20, p = 0.001; methylprednisolone + mycophenolic acid 69 ± 14 versus prednisolone + mycophenolic acid 46 ± 15, p < 0.001. These results confirm and extend previous observations and suggest that methylprednisolone might be more effective than prednisone in treatment protocols used to suppress allograft rejection.

Lymphocyte Suppression by Rolipram with Other Immunosuppressive Drugs

Pentoxifylline, a nonselective phosphodiesterase inhibitor, has immunomodulatory activity in vitro and in vivo and potentiates the suppressive effects of glucocorticoids and cyclosporine on lymphocyte proliferation in vitro. Since phosphodiesterase isotypes 3 and 4 predominate in lymphocytes, the authors measured the suppressive effect of rolipram alone and in combination with low concentrations of methylprednisolone and calcineurin enzyme inhibitors, compared to that of pentoxifylline on mitogen‐stimulated lymphocyte proliferation. The percent inhibition of 3H‐thymidine incorporation by both 10−5 and 10−6 mol/L concentrations of rolipram were significantly greater than that by both 10−4 mol/L pentoxifylline and 10−8 mol/L methylprednisolone. The percent inhibition by the combination of 10−5, but not 10−6, mol/L rolipram and methylprednisolone was significantly greater than that by 10−4 mol/L pentoxifylline and methylprednisolone. Potentiation of the suppressive effects of cyclosporine and tacrolimus by rolipram was less consistent. Measurement of cell culture supernatant concentrations of interferon gamma and interleukin‐10 indicate that one of the mechanisms underlying the immunosuppressive activity of rolipram is a significantly disproportionate inhibition of the proinflammatory cytokine, interferon gamma.

Suppression of lymphocyte interleukin-2 receptor expression by glucocorticoids, cyclosporine, or both.

Although glucocorticoids and cyclosporine are frequently used to treat patients with various types of glomerulopathy, clinical responses to treatment vary considerably. Considerable interindividual heterogeneity in the suppressive effects of glucocorticoids on lymphocyte proliferation in vitro has been previously reported, suggesting that differences in the pharmacodynamic responsiveness of the immune system to these agents might be an important determinant of how well an individual patient responds to treatment. It also has been shown that methylprednisolone is significantly more suppressive than prednisolone. To identify cellular mechanisms by which these drugs act, a study of the suppressive effects of prednisolone, methylprednisolone, and cyclosporine on lymphocyte proliferation and the expression of the cell surface receptor for interleukin‐2 (IL‐2R) was conducted using phytohemagglutin‐stimulated peripheral blood mononuclear cells (PBMCs) from 13 patients with glomerulopathy and 12 control subjects. Heterogeneity among individuals in both parameters of lymphocyte responsiveness to these drugs was again found, and the significantly greater suppressive effect of methylprednisolone was confirmed for both proliferation and IL‐2R expression in patients and control subjects. Cyclosporine alone was moderately suppressive. For most individuals, the greatest degree of suppression occurred when cells were exposed to both cyclosporine and glucocorticoid. Further studies are being conducted to determine whether pretreatment assessment of in vitro lymphocyte responsiveness has any predictive value regarding therapeutic efficacy of each drug in individual patients and to identify of those patients likely to require a more intensive or multidrug immunosuppressive regimen.