HLA-DR7 predicts the response to alkylating agents in steroid-sensitive nephrotic syndrome

There is a lack of reliable predictors of the response to alkylating agents in children with idiopathic nephrotic syndrome (NS). HLA-DR7 is strongly associated with the frequency of relapses in steroid-sensitive NS before cytostatic therapy. We therefore examined retrospectively the time to the first relapse and the incidence of subsequent relapses in 54 HLA-typed children with frequently relapsing NS, after treatment with cyclophosphamide (n = 49) or chlorambucil (n = 5) for 8 or 12 weeks; 38 patients were HLA-DR7 positive and 16 negative with 80% in both groups being steroid dependent. HLA typing was performed using serological or DNA typing methods. Renal biopsy showed minimal glomerular changes. A lower proportion of HLA-DR7 positive than negative patients remained in remission after 3 years (36% vs. 81%, P<0.02) and 5 years (36% vs. 72%, P<0.03). In the first 3 years after cytostatic therapy the mean number of prednisone-treated relapses was 1.3/patient per year in HLA-DR7-positive patients compared with 0.4 in negative patients (P<0.025). There was no statistically significant difference in the proportion of relapse-free patients with and without steroid dependency. The HLA status predicts the response of NS patients to alkylating agents better than the rate of previous relapses. Received September 19, 1995; received in revised form and accepted April 16, 1996     

Ligand-operated synthesis of 4-series and 5-series leukotrienes in human neutrophils: critical dependence on exogenous free fatty acid supply.

The influence of exogenously supplied free arachidonic acid (AA) and eicosapentaenoic acid (EPA) on the 5-lipoxygenase metabolism in human neutrophils (PMN) was investigated. Simultaneous application of A23187 with incremental concentrations of free AA caused a dose-dependent augmentation of the ionophore-elicited eicosanoid generation [release of leukotriene B4 and its omega-oxidation products, nonenzymatic hydrolysis products of leukotriene A4, and 5-hydroxyeicosatetraeneoic acid (5-HETE)]. A23187 challenge in the presence of free EPA resulted in the dose-dependent appearance of corresponding n - 3-derived metabolites, parallelled by a decrease in 4-series leukotrienes and 5-HETE. The inflammatory ligands formyl-methionyl-leucyl-phenylalanine and platelet-activating factor evoked no substantial eicosanoid generation in the absence of exogenously supplied polyunsaturated fatty acids (PUFAs). Addition of free AA or EPA in parallel with the ligand challenge evoked exclusive and dose-dependent generation of the respective leukotrienes and 5-HETE or 5-hydroxyeicosapentaenoic acid. Total amounts of 5-lipoxygenase products elicited under these conditions approached those in ionophore-stimulated PMN, with platelet-activating factor challenge surpassing the formyl-methionyl-leucylphenylalanine-evoked effect by approximately 50%. Two thirds of the maximum effect was obtained in the presence of only 10 microM free PUFA. Use of labeled fatty acids suggested exclusive origin of the eicosanoids from the exogenously provided precursor PUFA. Critical dependence on timing was noted; maximum response occurred upon simultaneous application of PUFA and ligand, and only 5 min of delay between AA or EPA addition and ligand challenge sufficed to reduce the formation of respective metabolites to less than 20%. EPA competed with AA and was noted to be the preferred substrate for ligand-evoked eicosanoid synthesis. In contrast to the simultaneous addition of free PUFAs, preloading of PMN with AA or EPA for 60 min revealed only very moderate or even no influence on ionophore- or ligand-evoked eicosanoid synthesis. We conclude that inflammatory ligands induce marked stimulation of PMN eicosanoid synthesis, with critical dependence on the presence of free precursor PUFAs. Preference of EPA over AA is observed under these conditions.     

Cardiac Surgery in Nonagenarians

A bstract Objectives and Background : The purpose of this study was to document our initial experience with patients 90 years of age and older and to determine whether cardiac surgery is justified in this age group. Cardiac surgery in octogenarians has proven to be a successful and worthwhile procedure. A small group of nonagenarians with severe coronary artery disease (CAD) and aortic valve disease refractory to medical therapy have been considered for surgery. Methods : Fourteen patients aged 90 or more underwent cardiac surgery for symptomatic CAD or aortic valvular disease refractory to medical therapy. Eight patients underwent isolated coronary artery bypass grafting (CABG) and six patients underwent aortic valve replacement (AVR). All patients were in NYHA Class IV preoperatively. Results : Hospital mortality occurred in one patient (7%). Hospital morbidity occurred in 10 patients (71%) and included 7 cardiac, 5 neurological, 1 gastrointestinal, 1 infectious, and 1 pulmonary event. All survivors left the hospital symptomatically improved. The mean length of stay was 26 days. Four CABG patients went on to die at a mean of 2 years and 2 months, and 3 remain alive at a mean of 2 years and 4 months. Three AVR patients expired at a mean of 3 years and 4 months, and 3 remain alive at 4 years and 1 month. Conclusions : Cardiac surgery in carefully selected nonagenarians is justified and can be performed with acceptable results.     

Selection of Streptococcus pneumoniae Mutants Having Reduced Susceptibility to Moxifloxacin and Levofloxacin

With Streptococcus pneumoniae, moxifloxacin was 4- and 10-fold more effective than levofloxacin at restricting selection of resistant mutants and at killing resistant mutants, respectively. The selection frequency for first-step topoisomerase mutants was 1,000 times lower for moxifloxacin than for levofloxacin; this difference was lost when second-step mutants were selected.     

Multilevel surgery for obstructive sleep apnea: short-term results.

OBJECTIVE: To determine the efficacy of a new multilevel surgical protocol for obstructive sleep apnea (OSA). STUDY DESIGN AND SETTING: Sixty patients with moderate to severe OSA because of multilevel pharyngeal obstruction were enrolled into this prospective, controlled clinical trial after clinical examination, endoscopy, and polysomnography. Surgery included uvulaflap, tonsillectomy, hyoid suspension, and radiofrequency treatment of the tongue base (group A). A second group did not receive hyoid suspension (group B). In both groups, nasal surgery was performed if necessary. Polysomnography and Epworth Sleepines Scale (ESS) were recorded at baseline and 2 to 15 months after surgery. RESULTS: In group A, the mean apnea-hypopnea index (AHI) decreased significantly after surgery (38.9 +/- 20.0 vs 20.7 +/- 20.6, P < 0.0001), whereas in group B the AHI did not. All secondary variables (minimal oxygen saturation, mean oxygen saturation, arousal index), and the ESS significantly improved in group A with only changes in arousal index and ESS reaching levels of significance in group B. CONCLUSION: The presented protocol including the hyoid suspension proved to be effective in the treatment of OSA, whereas surgery without hyoid suspension was less successful. EBM rating: B-2b.