Probiotics and immune response.

Current evidence supports the concept that oral administration of probiotic lactobacilli may be therapeutic in preventing antibiotic-associated diarrhea in children and in reestablishing normal flora in the gastrointestinal tract. Children with human immunodeficiency virus (HIV) infections may have episodes of diarrhea and frequently experience malabsorption associated with possible bacterial overgrowth; together these may interact to produce the growth abnormalities characteristic of this group. The overall objective of this investigation has been to determine whether oral administration of the probiotic Lactobacillus plantarum 299v could improve nutrient status and promote growth in children congenitally exposed to HIV. In addition, the possible beneficial effect of Lactobacillus plantarum 299v in modulating immune response was evaluated. In preliminary results described here, we report on the ability of Lactobacillus plantarum 299v to colonize children with HIV and to elicit specific systemic immune response after oral supplementation.

Atrial natriuretic peptide response to postural change and medication in familial dysautonomia.

Circulating atrial natriuretic peptide (ANP) was assayed before and after postural change and exercise in 54 patients with familial dysautonomia (FD) and 20 controls. ANP levels were compared with blood pressure, heart rate, plasma catecholamines and parameters of renal function. Compared with controls supine FD subjects had elevated blood pressures, heart rates and ANP levels (39 +/- 4 pg/ml vs. 23 +/- 3 pg/ml, p < 0.01). With the erect posture and exercise in FD subjects, blood pressure fell below control values, with ANP lowered. In FD subjects, blood pressure was correlated with ANP levels when supine and when erect and with heart rate post exercise. In controls, ANP levels did not correlate with other parameters. In FD patients on metoclopramide, supine and erect blood pressure and ANP levels were higher. FD subjects treated with fludrocortisone, had elevated supine and erect noradrenaline (p < 0.05 and p = 0.06); and those on diazepam had lower erect and post exercise noradrenaline (p < 0.05), but ANP levels were similar. In conclusion, sympathetic denervation may increase FD patients' responsiveness to other regulators of cardiovascular integrity, such as ANP. In addition, circulating ANP and catecholamines in FD subjects appear to be influenced by commonly used medications, such as metoclopramide.

Tumor necrosis factor produces homologous desensitization of lymphocyte beta 2-adrenergic responses.

The effect of tumor necrosis factor alpha (TNF alpha) on lymphocyte beta 2-adrenergic receptor response is reported. Isoproterenol-mediated cyclic-3,5-adenosine monophosphate (cAMP) production by intact lymphocytes preincubated with isotonic buffer or TNF alpha was studied. TNF alpha at 1 ng/ml and 100 ng/ml reduced isoproterenol-stimulated cAMP generation by 15% and 27% over the respective basal values. Stimulation of lymphocytes with forskolin or prostaglandin E1 was minimally affected, indicating that the effect of TNF alpha was due neither to nonspecific toxicity nor to its influence on the nucleotide regulatory protein complex or the catalytic adenylate cyclase component of the beta 2-adrenergic receptor complex system. Rather, TNF alpha appeared to affect the receptor recognition unit specifically. TNF alpha causes homologous desensitization of lymphocyte beta 2-adrenergic receptor response.

Dopamine clearance in critically ill infants and children: effect of age and organ system dysfunction.

To learn if there are age-related differences in the pharmacokinetic behavior of dopamine, plasma dopamine clearance was determined in 27 acutely ill infants and children who were receiving a continuous intravenous infusion of the drug. Steady-state clearance was calculated from dopamine concentration in arterial blood. Dopamine clearance was 60.7 +/- 28.1 ml/kg/min. The age of the patient exerted an effect on clearance of dopamine (r = -0.63; p less than 0.05), and dopamine clearance was nearly twice as rapid in children younger than 2 years as it was in older children (82.3 +/- 27.7 ml/kg/min versus 45.9 +/- 17.0 mg/kg/min). Conjugated bilirubin exerted an age-independent effect on clearance of dopamine; clearance was 44.8 +/- 28.6 ml/kg/min in children with abnormal conjugated bilirubin (greater than or equal to 0.9 mg/dl) and 70.1 +/- 2.56 ml/kg/min in children with normal conjugated bilirubin (less than 0.9 mg/dl). Clearance was lowest (29.8 +/- 5.7 ml/kg/min) in the four children who had both hepatic and renal dysfunction. Age is an important determinant of dopamine clearance, explaining in part the clinical observation that infants and young children require higher infusion rates.

Stereoselective renal tubular secretion of quinidine and quinine.

Quinidine and quinine are stereoisomers. When given sequentially or simultaneously, the renal clearance of values of quinidine and quinine were measured in seven healthy volunteers and when given simultaneously, to an additional five elderly men. Analytic specificity was provided by an HPLC drug assay. Protein binding was measured by equilibrium dialysis. The quinidine clearance exceeded the quinine clearance in every individual. The mean (+/- SD) ratio of these clearances was 4.2 +/- 1.4 when the drugs were given together and 4.4 +/- 2.3 when they were given separately in the younger subjects and 3.4 +/- 0.5 when given simultaneously to the elderly. Calculating clearance of drug in serum water (unbound drug clearance) revealed a quinidine clearance of 6.1 +/- 2.3 times that of creatinine measured simultaneously, and for quinine it was 1.5 +/- 0.6 times that of creatinine. We conclude that there is stereoselective net renal tubular secretion of quinidine over quinine indicating stereoselectivity of this renal tubular transport process.

Action of complement in the lysis of mouse sarcoma cells sensitized with H-2 alloantibody.

A modified cytotoxicity assay was adapted from classical erythrocytolytic assays, in which complement components were added in sequence to antibody-sensitized cells. This assay was applied to a model system in which mouse sarcoma cells were sensitized with H-2 alloantibody. The stepwise presentation of complement components combined with the stabilization of C2 by iodine treatment considerably augmented the lytic efficiency of human complement. More generally, the techniques adopted for this study provide a new model for obtaining basic information about selective reaction steps concerned in lysis of nucleated cells by alloantibody and complement. Comparisons of the lysis of sheep erythrocytes by xenoantibody with the lysis of mouse sarcoma cells by H-2 alloantibody, in our assay system with oxidized or untreated human complement, disclosed a difference in the kinetics of C142 formation, manifest in a lag phase and a protracted tmax for the sarcoma cells. These data may suggest that multiple complement-mediated functional lesions are necessary for immune lysis of nucleated cells.

Immunologic defect of the alternate pathway-of-complement activation postsplenectomy: a possible relation between splenectomy and infection.

Total hemolytic complement (CH50) and activation of the alternate mechanism were measured in eight patients before and after splenectomy and compared to similar measurements made in a control group of patients following other abdominal surgery. In the splenectomy group, alternate-pathway-mediated activation of C3 was significantly different from the controls. The mean five-day postsplenectomy value of 16 percent for the immunoelectrophoretic conversion of C3 to C3i was depressed (p<0.001) from the presplenectomy value of 85 percent and five-month postsplenectomy level of 71 percent (p<0.01). The difference between presplenectomy and five-month postsplenectomy values was not significant. Further, activation of C3 in patients five days postsplenectomy was significantly less (p<0.01) than in the five-day postoperative controls. In both the splenectomized patients and control group, five-day postoperative determinations indicated an increase in CH50 values and a decrease in degree of activation of Factor B. The spleen appears to manufacture certain substances required for activation of C3 via the alternate mechanism. That the manufacture is eventually assumed by other immune-competent organs is shown by the eventual increase of activation toward preoperative levels five months postsplenectomy. This defect in C3 activation may account for the tendency of splenectomized patients to have an increased incidence of bacterial infections and sepsis in the postoperative period.

Alternative pathway activation in sickle cell disease and beta-thalassemia major.

Total hemolytic complement activity (CH50), immuno-electrophoretic conversion of Factor B (C3PA), and of C3 were studied in 16 patients with sickle cell disease in a steady state, eight patients in crisis, and ten patients with ß-thalassemia major anemia maintained on a constant transfusion regimen. Patients with sickle cell disease in a steady state have moderatley 56 (percent) depressed conversion of Factor B in addition to markedly decreased conversion of C3 in four of ten patients. One of the three sickle cell patients and two of the four thalassemia patients with low C3 conversion levels have died subsequent to the studies. The combination of chronically decreased Factor B conversion in the face of markedly decreased C3 conversion may make these patients occasionally vulnerable to overwhelming infection analagous to the situation seen in postsplenectomy cases.