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The effect on memory of chronic prednisone treatment in patients with systemic disease.

There have been no systematic investigations of the effects of glucocorticoid treatment on memory in a clinical population despite experimental and clinical evidence that such treatment could cause memory disturbance. We conducted both cross-sectional and longitudinal studies. In Study 1, we administered tests of both hippocampal-dependent explicit memory and hippocampal-independent implicit memory to twenty-five prednisone-treated patients with systemic disease without CNS involvement and 25 matched clinical controls. All treated patients were taking doses of 5 to 40 mg of prednisone daily for at least 1 year. The glucocorticoid-treated group performed worse than the controls on tests of explicit memory, but the groups did not differ on the implicit memory task. Multiple regression analyses suggested that elderly patients are more susceptible to memory impairment with less protracted treatment. The results of Study 2, a prospective, longitudinal study of the effects of prednisone on memory across 3 months of therapy, suggest that even acute treatment can adversely affect memory. The observed alteration in memory was not secondary to inattention, affective disturbance, generalized global cognitive decline, or severity of disease. Results reported here, combined with previous clinical and experimental reports, indicate that the risk of memory impairment should be carefully considered before initiating treatment with glucocorticoids. Conversely, use of glucocorticoids should be considered in the differential diagnosis of memory loss. Finally, the potential benefit of anti-inflammatory treatment in Alzheimer's disease might be counterbalanced by possible iatrogenic memory impairment, at least when synthetic glucocorticoids are considered.

Adult↗

Prednisone pretreatment leads to histaminic airway hyporeactivity soon after resolution of the immediate allergic response.

We assessed the effect of prednisone pretreatment (50 mg/day for three days) on the development of the early increase in histamine reactivity that occurs soon after resolution of the immediate response in allergic humans. Four allergic subjects who were known to develop only isolated immediate responses upon Kentucky bluegrass inhalation, as well as four mild allergic asthmatic subjects known to develop typical dual phase responses, were evaluated. All testing was done more than nine weeks after the grass pollen season had ended. Allergen inhalation produced an immediate response in all subjects. However, upon resolution of the immediate response to allergen in these pretreated subjects, the PC200His in all dual responding asthmatics and in three of the four isolated immediate responders had substantially increased above baseline values. We conclude that prednisone pretreatment leads to histaminic hyporeactivity soon after resolution of the immediate allergic response in both dual responding asthmatics and isolated immediate responders. It would seem that this prednisone effect is independent of its potential influence on the influx of inflammatory cells into diseased airways.

Adult↗

Pulmonary complications of combination therapy with cyclophosphamide and prednisone.

Oral cyclophosphamide and prednisone are standard treatment for some neoplasms and necrotizing systemic vasculitis and are advocated with increasing frequency for idiopathic interstitial lung disease. During a 15-month period, we observed four cases of acute respiratory failure from Pneumocystis carinii pneumonia (PCP) in patients treated with oral cyclophosphamide and prednisone. One patient each had polyarteritis nodosa, Wegener's granulomatosis, bronchiolitis obliterans with organizing pneumonia, and chronic lymphocytic leukemia with red blood cell aplasia. Hypoalbuminemia (serum albumin level less than 3.0 g/dl) and daily therapy were associated with increased risk for development of PCP (p less than 0.05). None of the patients had leukopenia (less than 3,500/cu mm) or neutropenia (less than 1,000/cumm) at diagnosis. All were negative for the human immunodeficiency virus. Patients receiving oral cyclophosphamide and prednisone may be at higher or increasing risk for PCP. A high index of suspicion and aggressive evaluation for opportunistic infection are needed in these patients; consideration for trimethoprim-sulfamethoxazole prophylaxis and development of more quantitative measures of immunosuppression are needed.

Aged↗

Clinical pharmacokinetics of prednisone and prednisolone.

The growth of knowledge in the field of the pharmacokinetics of prednisolone/prednisone has been slow for several reasons. First, convenient and specific methods for measuring these steroids only became available with the development of high performance liquid chromatographic methods. Secondly, prednisolone is nonlinearly bound to transcortin and albumin: since the unbound concentrations of prednisolone are biologically relevant, it was necessary to determine the free fraction in each plasma sample. Thirdly, due to the short half-life of prednisolone no steady-state is achieved, and therefore area under the concentration-time curve needed to be determined in all studies. Fourthly, prednisolone and prednisone are interconvertible and prednisolone is given intravenously as an ester prodrug, features which created controversies about the correct interpretation of pharmacokinetic results. Finally, the total body clearances of total and (to a lesser degree) of unbound prednisolone increase with increasing concentrations of prednisolone. Therefore, in order to compare pharmacokinetic results between different subjects, standardised doses had to be administered. The investigations performed so far have revealed that: (1) the dose-dependent pharmacokinetics partly explain the clinical observation that an alternate-day regimen with prednisone yields fewer biological effects; (2) the interconversion of prednisone into prednisolone is not a limiting factor, even in patients with severely impaired liver function; (3) hypoproteinaemia per se does not cause increased unbound concentrations of prednisolone in vivo; (4) patients with liver failure, renal failure or a renal transplant, subjects older than 65 years, women on estrogen-containing oral contraceptive steroids or subjects taking ketoconazole have increased unbound concentrations of prednisolone-whereas hyperthyroid patients, some patients with Crohn's disease, subjects taking microsomal liver enzyme-inducing agents or patients on intravenous prednisolone phthalate (instead of prednisolone phosphate) or on some brands of enteric coated prednisolone tablets have decreased concentrations of prednisolone. The biological relevance of the altered pharmacokinetics is supported in part by altered clinical effects and altered effects on cellular immunofunctions.

Animals↗

An unusual adverse reaction to self-medication with prednisone: an irrational crime during a fugue-state.

During five years of self-medication with Prednisone, a forty-one-year old asthmatic businessman experienced periods of euphoria, psychomotor hyperactivity, and poor judgement; a period of depression and anxiety during temporary steroid withdrawal; and finally, with resumption of Prednisone, episodes of grandiosity and bizarre fugue-like behavior, with adoption of a second identity and culminating in an irrational crime. Steroids were then withdrawn, and the patient resumed his premorbid personality, but had amnesia for much of his previous behavior. The literature on hysterical fugues and corticosteroid-induced mental disturbance is reviewed. The patient's reactions are analyzed in terms of his premorbid neurotic conflicts, the psychological stresses acting upon him, and the effects of Prednisone on his central nervous system.

Adult↗

Randomized, controlled study of inhaled fluticasone propionate, oral administration of prednisone, and environmental management of horses with recurrent airway obstruction.

OBJECTIVE: To determine whether administration of glucocorticoids provides additional benefits to environmental management of horses with recurrent airway obstruction (RAO). ANIMALS: 28 horses with RAO. PROCEDURE: Horses were classified as having mild, moderate, or severe RAO. Within each category, horses were randomly assigned to receive inhaled fluticasone propionate, inhaled control substance, or oral administration of prednisone. During the 4-week study, horses were maintained outdoors and fed a pelleted feed. Clinical scores, pulmonary function, results of cytologic examination of bronchoalveolar lavage fluid (BALF), and adrenal gland function were determined before and 2 and 4 weeks after initiation of treatment. RESULTS: Clinical score and pulmonary function of all RAO-affected horses improved during the treatment period. After 4 weeks, clinical scores and pulmonary function of horses treated with a glucocorticoid were not different from those for the control treatment. In horses with severe RAO, treatment with fluticasone for 2 weeks resulted in significantly greater improvement in pulmonary function, compared with pulmonary function after treatment with prednisone or the control substance. Treatment with a glucocorticoid for 4 weeks and a low-dust environment did not have any effect on cellular content of BALF Treatment with prednisone for 2 weeks resulted in a significant decrease in serum cortisol concentration, compared with concentrations after administration of fluticasone or the control substance. CONCLUSIONS AND CLINICAL RELEVANCE: Environmental management is the most important factor in the treatment of horses with RAO. Early treatment with inhaled fluticasone can help accelerate recovery of horses with severe RAO.

Analysis of Variance↗

Prednisone effect on microvascular permeability in patients with inflammatory rheumatic diseases.

The transcapillary escape rate of albumin was measured in 27 consecutive patients with inflammatory rheumatic diseases before and after 1 and 7 days of prednisone treatment in doses of 45 mg/day. The transcapillary escape rate decreased from 7.33%/h (range 5.11-9.55) before prednisone treatment to 3.11%/h (0.04-6.18) (p less than 0.05) after 1 day of treatment and 5.80%/h (4.36-7.24) after 7 days of treatment. It is concluded that prednisone inhibits vascular permeability in patients with inflammatory rheumatic diseases.

Adult↗

Quality of life outcomes associated with variable posttransplant prednisone dosing regimens.

Prednisone tapering has become more common in the management of transplant recipients. Benefits of this practice, however, must be weighed against the risks. This study identified outcomes associated with variable low dose prednisone protocols. The study sample included 98 kidney and kidney-pancreas transplant recipients 1 year after transplant. Graft function, side effects of steroid therapy, and quality of life were recorded on patients receiving 0 (n = 5), 1 to 5 (n = 4), 5 to 7.5 (n = 5), 7.5 to 10 (n = 21), and greater than 10 mg/d prednisone (n = 63). Despite the fact that patients were assigned to the low dose groups because they were at risk for or already experiencing steroid induced side effects, the low dose groups presented side effect and quality of life profiles similar to or better than those of the standard dose group.

Adult↗

Computer-assisted design of studies using routine clinical data. Analyzing the association of prednisone and cholesterol.

To facilitate the analysis of routine, longitudinal, clinical data, we developed a computer program called the RX Study Module. Our prototype uses a small online knowledge base of medicine and biostatistics to help create and execute a detailed statistical study design. The program identifies possible confounding variables, selects methods for controlling them, creates a statistical model, determines patient eligibility criteria, and retrieves data from records. We used the program to examine the hypothesis that daily prednisone administration elevates serum cholesterol. Data from 49 patients with chronic rheumatologic disorders were analyzed from a database of 1787 patients. A regression model was fitted to each patient's record. Changes in cholesterol were significantly correlated (p = 10(-5)) with changes in prednisone after a lag of at least 1 week and after recorded confounders were controlled: delta cholesterol = 18.4 loge(prednisone). Routinely collected patient data may become an important resource for generating and studying new medical hypotheses.

Artificial Intelligence↗

Prednisone withdrawal followed by recombinant alpha interferon in the treatment of chronic type B hepatitis. A randomized, controlled trial.

STUDY OBJECTIVE: To determine the efficacy of a short course of prednisone followed by recombinant interferon treatment in patients with chronic type B hepatitis. DESIGN: Randomized, controlled trial with a 5-month treatment phase and a 9-month observation period after treatment. SETTING: Two referral-based university-affiliated medical centers. PATIENTS: Thirty-nine clinically stable patients with chronic type B hepatitis, all of whom were positive for hepatitis B antigen, hepatitis B virus-associated-DNA (HBV-DNA), and DNA polymerase for at least 6 months before entry. Patients included 20 heterosexuals and 19 male homosexuals. INTERVENTIONS: Eighteen patients were treated with a 6-week tapered regimen of prednisone, followed by 90 days treatment with recombinant interferon alpha-2b; 21 patients were untreated controls. Paired liver biopsy specimens of 27 patients (pretreatment and 9 months after treatment) were blindly evaluated. MEASUREMENTS AND MAIN RESULTS: Nine treated patients had a sustained loss of HBV-DNA. In addition, eight treated patients lost hepatitis B e antigen and four became negative for hepatitis B surface antigen (HBsAg). When compared with controls the differences were statistically significant for clearance of HBV-DNA and HBsAg (P = 0.035 and 0.037, respectively). Treated patients who had a sustained loss of HBV-DNA had higher initial alanine aminotransferase lower initial DNA and DNA polymerase levels, and were more frequently heterosexual. Patients who responded to treatment with the disappearance of hepatitis B e antigen and HBV-DNA had normal liver function tests and markedly improved liver histology during follow-up. CONCLUSIONS: The immunologic priming provided by a short course of prednisone used with alpha interferon may be an effective treatment for selected patients with chronic type B hepatitis.

Adult↗

Sustained remission of membranous glomerulonephritis after cyclophosphamide and prednisone.

OBJECTIVE: To determine the effect of cyclophosphamide and prednisone on progressive renal failure and on nephrotic features in patients with membranous glomerulonephritis. DESIGN: Prospective, nonrandomized time series. SETTING: Outpatient clinic at a university medical center. PATIENTS: Eleven consecutive patients with biopsy-proven membranous glomerulonephritis and rising plasma creatinine levels over at least 6 months. INTERVENTION: Cyclophosphamide and prednisone in ten patients and cyclophosphamide alone in one patient. MEASUREMENTS AND MAIN RESULTS: In ten patients treated with both agents, the median plasma creatinine rose 53 mumol/L (0.6 mg/dL) over the months before treatment from 141 to 194 mumol/L (1.6 to 2.2 mg/dL) (95% CI, 27 to 141 mumol/L; P = 0.002). After combined therapy for 6 months, the median plasma creatinine fell to 133 mumol/L (1.5 mg/dL) for a median decline of 62 mumol/L (0.7 mg/dL) (CI, 44 to 150 mumol/L; P = 0.006). Pretreatment plasma creatinine levels, which ranged from 159 to 371 mumol/L (1.8 to 4.2 mg/dL), decreased in the ten patients by 6 months and remained stable in seven of the eight patients followed 24 to 54 months after therapy was completed. The median urine protein excretion decreased by 9.6 g/d with 12 months of therapy in the ten patients from 11.9 to 2.3 g/d (CI, 6.0 to 15.1 g/d; P less than 0.001). The median plasma albumin rose by 14 g/L from 24 to 38 g/L (CI, 11 to 19 g/L; P less than 0.001). The median plasma cholesterol fell by 3.26 mumol/L (140 mg/dL) from 10.45 to 6.52 mumol/L (405 to 252 mg/dL) (CI, 1.42 to 7.16 mumol/L; P = 0.01). One patient who had a relapse 30 months after completing therapy responded to re-treatment with renal function and nephrotic variables returning toward normal. The eleventh patient received cyclophosphamide alone and had a course similar to that of the combined therapy group. CONCLUSION: Cyclophosphamide plus prednisone can promote prolonged remissions in membranous glomerulonephritis even when renal function is already declining.

Adult↗

Short-term influence of prednisone and phenobarbital on thyroid function in euthyroid dogs.

The short-term effects of prednisone and phenobarbital on serum total thyroxine (tT4), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were evaluated in euthyroid dogs. Twenty-six beagles were randomly divided into 3 groups receiving, respectively, a placebo, prednisone (1.2 to 2 mg/kg body weight, per os, every 12 hours for 3 weeks), or phenobarbital (1.8 to 3 mg/kg body weight for 1 week, then 2.7 to 4.5 mg/kg body weight, per os, every 12 hours for 2 weeks). Blood samples taken over a 6-week period were assayed for serum tT4, fT4, and TSH. Phenobarbital therapy in our study did not affect serum tT4, fT4, or TSH concentrations. Prednisone therapy, however, significantly decreased serum tT4 and fT4, but did not affect serum TSH concentrations.

Animals↗

Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma.

BACKGROUND: This Phase II study was undertaken to assess the efficacy and toxicity of chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone (EPOCH regimen) in patients with advanced, refractory cutaneous T-cell lymphoma (CTCL). METHODS: Fifteen patients were treated with a 96-hour continuous infusion of etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone, followed by granulocyte-colony stimulating factor support and trimethoprim/sulfamethoxazole prophylaxis. The median age of the patients was 53 years (range, 17-82 years). Six patients had Sézary syndrome (SS), four patients had visceral involvement, and four patients had anaplastic large cell morphology, three with Ki-1 (CD30) positivity. All patients had disease that was refractory to prior chemotherapy or electron beam irradiation and eight of these patients had received cyclophosphamide, doxorubicin, vincristine, and prednisone. Seven patients had received prior interferon therapy and nine patients had received fludarabine and/or 2-CDA. RESULTS: After a median of 5 cycles (range, 1-9 cycles), 4 patients achieved a complete response (27%) and 8 patients achieved a partial response (53%) for an overall response rate of 80% (95% confidence interval, 52-96%). Three patients with visceral involvement, two of three patients with anaplastic large cell morphology, and one patient with human T-cell lymphoma virus leukemia/lymphoma did not respond. All 12 responders had improvement in skin disease; 2 of 6 patients with SS had complete disappearance of circulating Sézary cells. The median progression free survival was 8.0 months (range, 3-22 months). After a median follow-up of 11.4 months (range, 2-56+ months), the median patient survival was 13.5 months. Grade 3 or 4 hematologic toxicity occurred in 8 patients (61%); 5 of these 8 patients had febrile neutropenia. Six patients developed staphylococcal bacteremia, two patients had disseminated herpes infection, and one patient had Pneumocystis carinii pneumonia. Grade 3 neurotoxicity occurred in one patient. Two patients had a significant decrease in left ventricular ejection fraction and one patient had supraventricular tachycardia. CONCLUSIONS: EPOCH chemotherapy has a high response rate with acceptable toxicity in patients with advanced and refractory CTCL.

Administration, Oral↗

Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia.

BACKGROUND: The authors report the occurrence of fatal or near-fatal sepsis in 16 of 38 children with newly diagnosed acute lymphoblastic leukemia (ALL) treated with a new induction regimen that differed from its predecessor by the substitution of dexamethasone for prednisone. METHODS: The frequency of septic deaths among 38 children who received multiagent remission induction therapy, including dexamethasone (6 mg/m(2)) daily for 28 days (pilot protocol 91-01P), was compared with the frequency of septic deaths among children previously treated (protocol 87-01) and subsequently treated (protocol 91-01) in consecutive Dana-Farber Cancer Institute (DFCI) ALL trials with induction therapy that included 21 and 28 days of prednisone (40 mg/m(2)), respectively. Except for dexamethasone in protocol 91-01P, the remission induction agents used were identical in substance to those used in protocol 87-01. Protocol 91-01, the successor 91-01P, was also similar, with the exception of the deletion of a single dose of L-asparaginase. RESULTS: Sixteen of the 38 children (42%) treated on the DFCI 91-01P had documented gram positive or gram negative sepsis (17 episodes) during remission induction, including 4 toxic deaths (11%). In contrast, there were 4 induction deaths among 369 children (1%) treated on protocol 87-01 (P = 0.0035) and 1 induction death among 377 children (<1%) treated on protocol 91-01 (P = 0.0003). CONCLUSIONS: Substitution of dexamethasone for prednisone or methylprednisolone in an otherwise intensive conventional induction regimen for previously untreated children with ALL resulted in an alarmingly high incidence of septic episodes and toxic deaths. Awareness of this complication, considering that the substitution has no apparent benefit in the efficacy of remission induction, argues against its routine use in intensive induction regimens for children with ALL.

Antineoplastic Agents, Hormonal↗

[Fibrinolytic system in bronchial asthma after prednisone treatment].

Forty one patients with recently recognised bronchial asthma were studied. Activity of plasminogen activator inhibitor (PAI-1), platelet adhesion and aggregation, antigens of tissue and urokinase plasminogen activators (respectively, t-PA Ag and u-PA Ag), euglobulin lysis time (ELT), complexes of plasmin-antiplasmin (PAP) and fibrin degradation products (FDP) were tested before and after fourteen days administration of 20-30 mg/d prednisone. Statistical significant increase of PAI-1 activity, on the average about 75%, was found (8.35 +/- 9.38 U/ml before, and 14.6 +/- 13.3 U/ml after treatment; p < 0.02). In 31 asthmatic patients (75.6%), after prednisone treatment, increased of PAI-1 activity together with platelet adhesion and aggregation were observed. Among other studied fibrinolysis factors no statistical significant differences before and after treatment were found. These results suggest that in asthmatic patients after prednisone treatment raises PAI-1 activity, probability because of releasing of the increased amount of PAI-1 from activated platelet.

Adult↗

Cyclosporin A plus prednisone treatment of steroid-sensitive frequently relapsing nephrotic syndrome in children.

Recently, there have been numerous reports on the use of cyclosporin A (CyA) in children with nephrotic syndrome (NS). In this prospective study, we wanted to evaluate the efficacy of CyA together with prednisone therapy in children with steroid-sensitive frequently relapsing NS. A total of 11 children (7 boys, 4 girls) with steroid-sensitive NS were included in this study. The patients ranged in age from 3.5 to 15 years (average 8.45 +/- 4.26 years). Renal biopsy showed minimal change disease in five, mesangial proliferation in four, focal glomerulosclerosis in one and membranous glomerulonephritis in one. The NS had lasted from 13 to 113 months (average 50.27 +/- 38.60 months). The number of relapses varied from three to 10 episodes with an average of 5.9 +/- 3.3 episodes. Patients received 5 mg/kg CyA daily in two divided doses for five months and prednisone for a total of eight weeks (30 mg/m2 daily for 4 weeks followed by 30 mg/m2 on alternate days for 4 weeks). After the completion of the treatment protocol, no therapy was given unless a relapse was observed. Mean follow-up period was 14.9 +/- 5.99 months with a range from six to 26 months. Before this combined treatment, there was a mean relapse rate of 0.144 +/- 0.05 relapses month with a range from 0.088 to 0.238. After discontinuation of therapy, the relapse rate dropped to a mean of 0.0179 +/- 0.031 with a range of 0 to 0.083. In conclusion, it would appear that a combination of CyA and prednisone is effective, sustaining the remission in steroid-sensitive NS. Corticosteroids in combination with CyA may be a better approach than conventional steroid treatment in such patients.

Adolescent↗

Effect of methyl-prednisone and cyclosporine on the lipid pattern and polyunsaturated fatty acid biosynthesis in the rat.

The hyperlipidemia posttransplant has been largely attributed to immunosuppressant agents. In the present work we evaluated the effect of oral administration of cyclosporine (5 mg/kg/day) and/or methyl-prednisone (1 mg/kg/day) on lipid composition and polyunsaturated fatty acid biosynthesis in normal adult male rats. The results obtained showed that both agents produced a delay on the growth together with a significant loss of body weight. In liver microsomal fraction from rats treated with methyl-prednisone, a depression in delta 6 and delta 5 desaturation activities, was observed. This effect was corroborated in the fatty acid pattern through the enhancement of linoleic and dihomo-gamma-linolenic acids, and a depression of arachidonic acid. Similar results were noticed in those rats treated with both drugs when compared to the controls. No changes were observed either in the amount of liver microsomal total lipids or in the fatty acid composition of kidney and testis microsomes, as well as in erythrocyte membranes, among the different groups studied. Cyclosporine alone produced a significant depression in plasma triglycerides and showed no modifications in the other lipid parameters studied compared to the controls. Fluorescence anisotropy measured in the different membranes was not modified by the several treatments used. In view of the aforementioned data, it can be stated that methyl-prednisone would be the responsible for many of the lipid disorders that can be observed in posttransplant patients when they are subjected to the combined immunotherapy with cyclosporine.

Animals↗

Mechanisms of corticosteroid action on lymphocyte subpopulations. II. Differential effects of in vivo hydrocortisone, prednisone and dexamethasone on in vitro expression of lymphocyte function.

The present study was undertaken to determine what, if any, differential effect various commonly used corticosteroid preparations had on the numbers and specific functions of lymphocyte subpopulations when these agents were administered in equivalent pharmacological dosages. Normal volunteers received a single dose of either 320 mg of hydrocortisone intravenously, 80 mg of prednisone orally, or 12 mg of dexamethasone orally. There was a marked lymphocytopenia and monocytopenia maximal 4-6 hr following administration of all three corticosteroid preparations with almost identical kinetics and degree of fall in total cell numbers as well as proportions of thymus-derived and bone marrow-derived lymphocytes. Hydrocortisone and prednisone caused only a slight suppression of phytohaemagglutiinin (PHA) induced lymphocyte blastogensis which could be reversed at supra-optimal concentrations of PHA. On the contrary, dexamethasone administration casued a marked suppression of PHA responses which was not reversed by supra-optimal PHA stimulation. In addition, hydrocortisone and prednisone administration did not suppress non-specific PHA-induced cellular cytotoxcity, while dexamethasone caused a marked suppression (P less than 0.001) of cytotoxicity. These studies show that although equivalent anti-inflammatory doses of these three corticosteroid preparations cause almost identical suppression of the numbers of circulating lymphocyte populations, they have a differential effect of the numbers of circulating lymphocyte populations, they have a differential effect on a certain in vitro functional correlates of cell-mediated immunity.

Adult↗