Early administration of an immunomodulator and induction of remission in insulin-dependent diabetes mellitus

A clinical trial was undertaken to determine whether intensive thymopentin administration enhances remission of insulin-dependent diabetes (IDDM) during the first year after diagnosis. Dosage with insulin was minimized with target control of blood glucose levels less than or equal to 7.8 mmol/l before meals. Remission was defined as a prolonged period after IDDM onset (not less than 3 months) characterized by a non-insulin-receiving (NIR) state in which target metabolic control was reached without administration of insulin and with a valid C-peptide response, evaluated after standard breakfast. Sixteen IDDM patients aged 12-31 years, recruited within 2 weeks of initiation of insulin therapy and within 5 weeks of onset of symptoms, were treated with intravenous (i.v.) thymopoietin32-36 pentapeptide (Thy) (1 mg/kg/body weight) for 7 days and twice per week for up to 3 months. A control IDDM group without initial significant differences in metabolic control parameters was also studied. No difference was observed between the two IDDM groups regarding the after-diagnosis normalization curve of HbA1c; mean daily glycemic level rates and ICA titer decreased during the observation. A reduction in anti-insulin antibodies (AIA) in Thy-treated patients was observed in comparison to conventionally treated IDDM starting from 6 months and reaching a reduction peak at 1 year (P less than or equal to 0.02). As regards the NIR remission rate, it was significantly more accelerated in Thy-treated patients, reaching 43% at 6 months and 57% at 1 year vs 12% and 6.7% respectively in the control IDDM group (P range less than or equal to 0.05-0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

A randomized trial of methotrexate in newly diagnosed patients with type 1 diabetes mellitus

The aim of this study was to determine whether low-dose, oral methotrexate therapy would prolong the remission phase at the onset of Type 1 diabetes. Ten newly diagnosed, nonacidotic, ICA-positive, Type 1 diabetics were randomly assigned to receive either methotrexate (5 mg/m(2)/week) or no immunosuppressive treatment. The study was not blinded and no placebo was given. Endogenous insulin production was assessed every 3 months by fasting and Sustacal-stimulated C-peptide levels. Methotrexate therapy was not beneficial in prolonging islet survival as assessed by fasting and stimulated C-peptide levels. Insulin requirements were generally lower in the control group, and islet failure, determined by an insulin requirement of >0.7 u/kg/day, occurred earlier for those receiving MTX (P < 0.02). Side effects of methotrexate treatment were minimal. There was no benefit from methotrexate therapy, and methotrexate therapy was associated with an earlier increase in insulin requirements.     

Cyclosporin-associated nephropathy in patients with autoimmune diseases

Summary Renal biopsy specimens were evaluated from patients with different autoimmune diseases treated with cyclosporin (CyA). Ten biopsies were done before CyA, 10 biopsies after low-dose (<7.5 mg/kg/day, initial dose or mean daily dose within the first month, respectively), and 9 after high-dose (>7.5 mg/kg/day) treatment. Definite chronic CyA nephrotoxicity (cyclosporin-associated arteriolopathy and/or interstitial fibrosis striped form with tubular atrophy) was only present in the initial high-dose group. In this group a significant serum creatinine increase was noted and 8 of the 9 patients were hypertensive. No significant correlation was found between the severity of morphologic lesions and the mean daily dose during total treatment, cumulative dose, and duration of therapy. The morphologic changes in the low-dose group did not differ from the control biopsy specimens before CyA treatment. Based on these results, it can be concluded that major nephrotoxicity can be avoided by initial low CyA doses.Abbreviations CyA Cyclosporin A - NSAID Nonsteroidal antiinflammatory drugs - SLE Systemic lupus erythematosus     

Prednisone administration in recent onset type I diabetes

The aim of our study was to investigate the efficacy of prednisone to preserve pancreatic beta-cell function in patients with recent-onset Type I diabetes mellitus (IDDM). Twenty-five patients with IDDM, aged 24 +/- 6 years, entered the trial within 8 weeks of the onset of diabetes. They were allocated, according to a single blind randomized protocol, to one of the following treatments: (A) prednisone (15 mg/day), (B) indomethacin (100 mg/day), (C) placebo. All treatments lasted 8 months and all patients achieved satisfactory metabolic control with a multi-injection regimen (three injections/day) within a few weeks, and maintained it throughout the entire period of observation. Only minor side effects were observed in the prednisone-treated patients. A lower insulin requirement was observed in the prednisone group than in other patients at 12 months (0.33 +/- 0.11 vs 0.57 +/- 0.06 U/kg/day, P less than 0.05), 18 months (0.34 +/- 0.11 vs 0.64 +/- 0.06, P less than 0.05) and 24 months (0.38 +/- 0.10 vs 0.63 +/- 0.05, P less than 0.05). Endogenous insulin release, evaluated as urinary C-peptide, was higher in the prednisone group than in other patients at 3, 6, 9, 12, 18 and 24 months (P less than 0.05). ANOVA confirmed differences among the three groups. Our study indicates that prednisone administration, at low doses and for a long period of time, effectively restored endogenous insulin release in IDDM patients.     

Presence of insulin autoantibodies at clinical diagnosis of diabetes mellitus type I predicts loss of beta cell function

Recently the spontaneous development of insulin autoantibodies (IAA) has been detected in patients at diagnosis of Type I diabetes mellitus before the beginning of insulin treatment. The present study was undertaken to investigate if the presence of IAA at clinical onset of IDDM may act as a new marker of the beta cell function. The results obtained showed that IAA were present in 44% of newly diagnosed diabetic patients before therapy. Patients without IAA displayed a higher C-peptide secretion than those with IAA, at six months (12.11 +/- 5.08 versus 5.88 +/- 3.25 ng/ml/10 min.)(X +/- SD) and at twelve months (10.45 +/- 3.05 versus 4.90 +/- 5.25 ng/ml/10 min)(X +/- SD) of the follow up period. HbA1 levels, and insulin requirements were similar in both groups (IAA+ and IAA-). We conclude that the presence of insulin autoantibodies at clinical diagnosis, before initiating insulin treatment, may well predict the loss of the beta cell function.     

Immune responses to insulin in patients with insulin-dependent diabetes mellitus

To examine the effect of the major histocompatibility locus (HLA) and the duration of insulin-dependent diabetes (IDDM) on immune responses to insulin we assayed insulin induced proliferation of blood mononuclear cells and measured insulin antibodies in 66 patients with newly diagnosed and in 56 patients with longstanding IDDM matched for the age at onset (less than or equal to 15 years). In up to two thirds of the patients blood mononuclear cells responded to insulins by proliferation, and insulin antibodies were found in two thirds of patients with IDDM of long duration. Insulin proliferation or antibodies were not associated to any particular HLA antigen. The frequency of HLA-DR3 in patients with newly diagnosed IDDM was not increased unlike in patients with IDDM of long duration. In addition, HLA-B8 was associated to HLA-DR3 nearly twice as often in patients with newly diagnosed IDDM as in patients with longstanding IDDM. Thus, patients with IDDM of recent onset and diagnosed within the last three years more frequently responded to insulin by proliferation and less often had HLA-DR3 than patients with IDDM of long duration and diagnosed about 20-25 years earlier.     

Novel therapy for insulin-dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells

Insulin-dependent diabetes mellitus (IDDM) is a metabolic disease usually resulting from autoimmune-mediated β-cell destruction requiring lifetime exogenous insulin replacement. Mesenchymal stem cells (MSC) hold promising therapy. We present our experience of treating IDDM with co-infusion of in vitro autologous adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). This was an Institutional Review Board approved prospective non-randomized open-labeled clinical trial after informed consent from ten patients. ISC were differentiated from autologous adipose tissue-derived MSC and were infused with bone marrow-derived HSC in portal, thymic circulation by mini-laparotomy and in subcutaneous circulation. Patients were monitored for blood sugar levels, serum C-peptide levels, glycosylated hemoglobin (Hb1Ac) and glutamic acid decarboxylase (GAD) antibodies. Insulin administration was made on sliding scale with an objective of maintaining FBS < 150 mg/dL and PPBS around 200 mg/dL. Mean 3.34 mL cell inoculums with 5.25 × 10⁴ cells/μL were infused. No untoward effects were observed. Over a mean follow-up of 31.71 months, mean serum C-peptide of 0.22 ng/mL before infusion had sustained rise of 0.92 ng/mL with decreased exogenous insulin requirement from 63.9 international units (IU)/day to 38.6 IU/day. Improvement in mean Hb1Ac was observed from 10.99 to 6.72 %. Mean GAD antibodies were positive in all patients with mean of 331.10 IU/mL, which decreased to mean of 123 IU/mL. Co-infusion of autologous ISC with HSC represents a viable novel therapeutic option for IDDM.     

Effects of ginkgolide B, a platelet-activating factor inhibitor on insulitis in the spontaneously diabetic BB rat.

The BB rat spontaneously develops insulin-dependent diabetes mellitus (IDDM) in association with marked insulitis in the islet of Langerhans. Since platelet-activating factor (PAF-acether) is involved in allergic and inflammatory reactions, we tested a PAF antagonist, Ginkgolide B (BN 52021) for potential effects on islet inflammation and diabetes. Diabetes prone BB/Wor rats were treated daily from weaning at 25 days until 105 days of age with either saline (n = 30, controls), 10 (n = 25, low dose) or 20 (n = 30, high dose) mg/kg body weight of BN 52021. The overall incidence of IDDM was unaffected by treatment. Quantitative analysis of insulin area showed a dose-dependent protection of beta cells by Ginkgolide B, reflected in a 6- (low dose) to 8-fold (high dose) (P less than 0.01-0.005) increase in the insulin/glucagon cell ratio compared to the saline treated rats. Ginkgolide B reduced severe insulitis from 84% in the saline rats developing IDDM to 59% (n.s.) in the low and to 33% (P less than 0.001) in the high dose group. These data suggest that PAF inhibitors may prove useful in immunomodulator therapy of IDDM since beta cells are preserved.     

Differential effects of cyclosporine A on Langerhans cells and regulatory T-cell populations in severe psoriasis: an immunohistochemical and flow cytometric analysis

Systemic administration of cyclosporine A (Cy-A; initial dose 5 or 2.5 mg/kg/day) to patients with severe chronic plaque psoriasis produced marked reductions in psoriasis area and severity index within 4 weeks. The clinical response was accompanied, within 1 week, by progressive reductions in T-cell subpopulations (CD3+ and CD4+) and in numbers of interleukin-2 receptor (IL-2-R)-positive (CD25+) cells within lesional skin. Over the first 4 weeks of treatment, these changes were accompanied by reductions in DR+ cells within the epidermis (minor) and dermis (substantial). In contrast, numbers of epidermal CD1+ cells increased substantially during resolution of the skin lesions. Unlike lesional skin, however, no significant changes in absolute numbers of circulating immunoregulatory T-cell populations, including helper/inducer (CD45R) and suppressor/inducer (CD29W) subsets, quantified by dual immunofluorescence labelling, were detected. Moreover, numbers of blood-borne HLA-DR, IL-2-R and transferrin receptor (CD71) positive lymphocytes were unaffected by Cy-A therapy, nor were any differences detected between psoriatic patients and normal controls using these cell markers. Our data suggest that the immunoregulatory effects of Cy-A in psoriasis are mediated via lesional T lymphocytes and that epidermal CD1+ DR- dendritic cells may play an influential role in the regulation of T-cell function and keratinocyte growth during resolution of the skin lesions.     

Increased specificity and sensitivity of insulin antibody measurements in autoimmune thyroid disease and type I diabetes.

Insulin autoantibodies (IAA), a marker for insulin-dependent diabetes mellitus (IDDM), have been reported in other diseases such as thyroid disease and after treatment with sulfhydryl containing medications. Reported prevalences of IAA in non-diabetics vary widely, probably due in part to methodological differences between laboratories. In addition, certain sera may have a high non-specific binding to insulin. We compared a radioimmunoassay (RIA) for IAA which included non-specific binding with an RIA that incorporated a competitive displacement with cold insulin to remove non-specific binding. Using the RIA which measured specific plus non-specific binding, IAA positivity was found in 22/92 (23.9%) of sera from thyroid disease patients, 16/124 (12.9%) of random masked sera from a hospital laboratory, 27/335 (8.1%) of first degree relatives of IDDM patients, 63/178 (35.4%) of subjects with newly diagnosed IDDM, and 0/92 (0%) of normal controls. Insulin antibodies (IA) were found in 80/99 (80.8%) of insulin-treated diabetic subjects. In contrast, using the displacement assay which allowed measurement of specific binding, the frequency of IAA positivity was lower for subjects with thyroid disease (7/92 (7.6%)), random hospital sera (12/124 (9.8%)), and for first degree relatives of IDDM patients (8/335 (2.4%)), while higher for subjects with newly diagnosed IDDM (71/178 (39.9%)). Subjects with insulin-treated diabetes (78/99 (78.8%)) and normal subjects (1/92 (1.1%)) showed little change. Strikingly, three of the eight (37.5%) relatives of IDDM patients that were positive in the RIA measuring specific binding were detected only because cold displacement was utilized. We conclude: (1) subjects with thyroid disease and first degree relatives of IDDM patients frequently have high non-specific binding for IAA in an RIA not employing a cold displacement step, (2) in some newly diagnosed IDDM patients and first degree relatives of IDDM patients, IAA may be missed by an assay not optimized to measure specific binding, and (3) displacement with cold insulin increases both the specificity and sensitivity of RIAs measuring insulin autoantibodies.     

Influence of continuous combined estradiol-norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women

OBJECTIVE: Estrogen-progestogen replacement therapy (HRT) may be associated with deterioration of insulin sensitivity in comparison to estrogens alone, which tend to improve insulin sensitivity in postmenopausal women. Insulin sensitivity with the use of continuous combined 17-beta estradiol/norethisterone acetate (E2/NETA) preparations has not been examined before in postmenopausal women. DESIGN: In a double-blind randomized parallel study, we evaluated the effect of 2 mg E2/1 mg NETA (high dose E2/NETA), 1 mg E2/0.5 mg NETA (low dose E2/NETA), or placebo (P) on the insulin sensitivity index (SI) in three groups (18 women/group) of postmenopausal nondiabetic women (follicle stimulating hormone [FSH] > 40 mIU/mL, mean +/- SD) aged 56 +/- 3 years, BMI 25 +/- 4 kg/m2, cholesterol 233 +/- 42 mg/dL, and triglycerides 87 +/- 36 mg/dL. Insulin sensitivity was measured by means of a two-step hyperinsulinemic euglycemic glucose clamp (insulin infusion rate, 0.25 and 1.0 mU/kg/min for 120 min each) at baseline and after 3 months of daily administration of high dose E2/NETA, low dose E2/NETA, or P. Analysis was performed assuming equivalence of start-end changes of insulin sensitivity among treatment groups (Anderson-Hauck test). RESULTS: SI was 7.7 +/- 2.9, 7.5 +/- 3.4, 6.8 +/- 2.2 at baseline and 6.3 +/- 3.0, 7.9 +/- 2.5, 7.1 +/- 3.1 mL/min/m2 per mu U/mL 3 months after the administration of high dose E2/NETA, low dose E2/NETA, and P, respectively. The low dose E2/NETA group had start-to-end changes of SI which were equivalent to the P group (0.4 [95% confidence interval [CI] -0.8; 1.7] vs. 0.4 [-0.3; 1.0]) (p = 0.02). For the high dose E2/NETA group, equivalence could not be shown with either the P (p = 0.89) or with the low dose E2/NETA group (p = 0.90). SI within the high dose E2/NETA group decreased by -1.5 (95% CI -2.7; -0.2) mL/min/m2 per mu U/mL. HbAlc decreased from 5.3 +/- 0.3 to 5.1 +/- 0.3% within the high dose E2/NETA group (p < 0.03) and remained unchanged within the low dose E2/NETA and P group. Fasting plasma glucose, fasting serum insulin, and C-peptide, as well as triglycerides and BMI were comparable among the groups at baseline and after 3 months. Total cholesterol decreased by 12% and 8% in women treated with high dose and low dose E2/NETA (p < 0.02), respectively, and remained unchanged within the P group. CONCLUSIONS: These results indicate that 3 months use of a low dose continuous E2/NETA preparation does not change insulin sensitivity in postmenopausal women. At high dose of E2/NETA, a modest decrease seems possible. The effects of E2/NETA on other parameters of carbohydrate and lipid metabolism are neutral or favorable.     

A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus

A period of early, intensive insulin treatment is thought to improve subsequent beta-cell function in insulin-dependent diabetes mellitus (IDDM). To study this hypothesis, we randomly assigned adolescents with newly diagnosed IDDM to receive either conventional treatment (n = 14) (NPH insulin, 1 U per kilogram of body weight per day, in two divided doses) or an experimental treatment (n = 12) (a two-week hospitalization with maintenance of blood glucose levels between 3.3 and 4.4 mmol per liter by continuous insulin infusion delivered by an external artificial pancreas [Biostator]). During the two-week intervention, the experimental-therapy group received four times more insulin than the conventionally treated group, and their endogenous insulin secretion was more completely suppressed, as evidenced by a urinary C-peptide excretion rate one seventh that of the conventionally treated group. After the first two weeks, both groups were treated similarly and received similar amounts of insulin. At one year, the mean (+/- SEM) plasma level of C peptide was significantly higher after mixed-meal stimulation in the experimental-therapy group than in the conventionally treated group (0.51 +/- 0.07 vs. 0.27 +/- 0.06; P less than 0.01). The experimental-therapy group also had better metabolic control, as evidenced by lower glycohemoglobin values (7.2 +/- 0.7 vs. 10.8 +/- 1.2 percent; P less than 0.01). We conclude that suppression of endogenous insulin by intensive, continuous insulin treatment during the first two weeks after the diagnosis of IDDM may improve beta-cell function during the subsequent year.     

High dose therapy followed by autologous peripheral blood stem cell transplantation as a first line treatment for multiple myeloma: a Korean Multicenter Study

We conducted a phase II multicenter trial to estimate the response and survival of patients with newly diagnosed multiple myeloma to high dose melphalan therapy followed by autologous peripheral blood stem cell transplantation. Eligible patients who had undergone induction with vincristine, adriamycin and dexamethasone (VAD) should have adequate cardiac, pulmonary and renal function (creatinine <2 mg/dL). Melphalan at 200 mg/m2 was used as a conditioning regimen. Eighty patients were enrolled from 13 centers. The median age of the patients was 53 yr (range; 20 to 68 yr). The initial stage was IA/IIA/IIB/IIIA/IIIB in 3/8/1/54/14 patients, respectively. Beta2-microglobulin, CRP and LDH were increased in 74, 42 and 34% of the patients examined. Cytogenetic data were available in 30 patients, and 6 patients showed numeric or structural abnormalities. Two therapy-related mortalities occurred from infection. Among the 78 evaluable patients, CR/PR/MR/NC/PD were achieved in 48/26/2/1/1 patients, respectively. After a median follow-up of 30 months, the median overall and event-free survivals were 66 months (95% CI: 20-112) and 24 months (95% CI: 18-29), respectively. This study verifies the efficacy and feasibility of high dose melphalan therapy with autologous stem cell transplantation in newly diagnosed multiple myeloma.     

Initial dose of vancomycin based on body weight and creatinine clearance to minimize inadequate trough levels in Japanese adults

Our aims were to elucidate the factors that affected vancomycin (VCM) serum trough levels and to find the optimal initial dose based on creatinine clearance (CrCl) and body weight (BW) to minimize inadequate trough levels in a retrospective observational study among Japanese adults. One hundred and six inpatients, in whom VCM trough levels were measured after completing the third dosing, were consecutively recruited into our study in a tertiary hospital. We considered the frequency of <30% as low. In the generalized linear model, initial VCM total daily dose, CrCl, and BW were independent risk factors of VCM trough levels. In patients with CrCl ≥30 and <50?mL/min, 1?g/day yielded low frequencies of a trough level of ≥20?mcg/mL, regardless of BW. In patients with CrCl ≥50?mL/min, 2?g/day yielded low frequencies of a trough level of <10?mcg/mL in patients weighing <55?kg, but not in patients weighing ≥55?kg. Optimal VCM initial total daily dose may be 1?g/day in patients with CrCl ≥30 and <50?mL/min regardless of BW and 2?g/day in patients weighing <55?kg with CrCl ≥50?mL/min among Japanese adults.     

Glipizide does not affect absorption of glucose and xylose in diabetics without residual beta-cell function

We have previously demonstrated that oral glipizide suppresses the absorption of xylose in diabetics treated with diet alone. We suggested that glipizide might influence postprandial glucose levels by interfering with absorptive mechanisms. In the present study we have extended our observations to insulin-dependent diabetics (IDDM). Nine non-obese diabetics without residual beta-cell function and with normal respiratory sinus arrhythmia and Valsalva ratio were studied on two occasions. Their ordinary insulin treatment was discontinued 24 hours before the study and glucose control was maintained by i.v. insulin infusion. The experiments began at 8 a.m. after an overnight fast. Insulin was given as a continuous i.v. infusion of 0.01 U/kg/h at 8-11 a.m. and 0.005 U/kg/h at 11 a.m. -2 p.m. At 8 a.m. the patients ingested 25 g of xylose and 15 g of glucose in 300 ml of water. Glipizide (5 mg) or placebo were given 30 min prior to the glucose-xylose load in random order, each patient serving as his own control. Blood samples were taken every 60 min for analysis of glucose, xylose, C-peptide and glipizide. The rise in blood glucose in the control experiment was similar to that previously seen in non-insulin-dependent diabetics (NIDDM) given the same xylose-glucose load. Glipizide did not exert any effects on either blood C-peptide, glucose or xylose levels. We conclude that oral glipizide administered in a therapeutic dose does not reduce xylose absorption in IDDM, in contrast to its previously demonstrated effect in NIDDM.     

Treatment of autoimmune thrombocytopenic purpura

One hundred and two patients with newly diagnosed autoimmune thrombocytopenic purpura (ATP) were treated with prednisone (1.5-2 mg/kg/day for 4 weeks). A favourable response, lasting more then 12 months, was obtained in 22,5% of the cases. Different therapeutic strategies, such as immunosuppressive drugs, high dose immunoglobulins, splenectomy and others, were applied in unresponsive or relapsed patients. In our case study, splenectomy has proved the most satisfactory (87% of positive results) thus representing, in our opinion, the only effective therapy for resistant or relapsed case.     

A case of intravenous immunoglobulin-resistant Kawasaki disease treated with methotrexate

Kawasaki disease, an acute febrile vasculitis of unknown etiology, is usually treated with high doses of immunoglobulin (IVIG) and aspirin. However, 20% of children show persistent or recurrent fever despite IVIG, and coronary artery aneurysm progression. In such cases of resistance to IVIG treatment, repeated IVIG administration or the initiation of steroid therapy, and the use of cyclophosphamide have been reported. We aimed to show in this study that methotrexate (MTX) may be used as a treatment for Kawasaki disease resistant to IVIG treatment. We report the case of a 6-year old boy who was admitted at another hospital with an initial complaint of a fever for 5 days and skin rashes for 3 days. The patients fever persisted despite three courses of IVIG (2 gm/kg, 1 gm/kg, 1 gm/kg, respectively) over a 14-day period. On day 14 of his illness he showed a dilated right coronary artery, and on day 19 dexamethasone, at a daily dose of 0.3 mg/kg, was given but this resulted in defervescence. However, upon stopping the dexamethasone treatment, his fever recurred and he was transferred to our hospital. On days 31 and 38 of his illness, IVIG (400 mg/kg for 5 days, twice) was administered and from day 38 onwards the patient was given dexamethasone (0.6 mg/kg, daily) and MTX (10 mg/BSA, once weekly) whereupon his fever subsided and did not recur. On day 48 dexamethasone was replaced with prednisolone, which was subsequently tapered. The patient is now taking MTX and being observed on an outpatient basis. We report the case of a boy with IV-globulin resistant Kawasaki disease, who after repeated infusions of IVIG and steroid therapy showed fever recurrence, which that subsided after MTX treatment.     

Antipseudomonal therapy in cystic fibrosis: Aztreonam and amikacin versus ceftazidime and amikacin administered intravenously followed by oral ciprofloxacin

In order to determine the optimal antipseudomonal therapy in patients with cystic fibrosis aztreonam plus amikacin was compared to ceftazidime plus amikacin, and these two-week hospital regimens were followed by oral ciprofloxacin given for four weeks. Fifty-six cases of acute pulmonary exacerbation of the disease in 42 patients associated with isolation ofPseudomonas aeruginosa from the sputum were randomly treated with either aztreonam or ceftazidime (300mg/kg/day i.v.; maximum daily dose 12g) in combination with amikacin (36 mg/kg/day i.v.; maximum daily dose 1,500mg). Other aspects of the two-week treatment were constant. The two therapy groups were comparable in all respects. Both regimens were well tolerated and resulted in similar improvements in clinical, bacteriologic, radiologic and laboratory findings, and pulmonary function. Fifty patients could be reevaluated after subsequent outpatient therapy consisting of oral ciprofloxacin (30 mg/kg/day; maximum daily dose 1,500mg) given for four weeks. During this period, the clinical and laboratory improvements persisted, and the rate of eradication ofPseudomonas aeruginosa from sputum decreased from 62% to 34%. Ciprofloxacin was well tolerated and there was no drug toxicity or serious adverse effect. In the 25 prepubertal patients there was neither subjective nor objective evidence of skeletal drug toxicity. In patients with cystic fibrosis, aztreonam or ceftazidime in combination with amikacin represents an effective and safe systemic anti-pseudomonal therapy. Subsequent oral ciprofloxacin therapy for four weeks prolongs the beneficial effects and is well tolerated.     

Phagocyte oxidative metabolism in cyclosporine- or placebo-treated patients with insulin-dependent (type I) diabetes mellitus of recent onset

Several lines of evidence suggest that phagocyte-mediated oxidative processes are involved in damage to pancreatic islet cells of Type I insulin-dependent diabetes mellitus (IDDM). This hypothesis, however, has not yet been explored at the clinical onset of IDDM. Similarly, the possibility that cyclosporine A (Cy-A) might exert a selective influence on these phagocyte-mediated oxidative reactions has also not yet been investigated as compared to a placebo. The present study tested both hypotheses in 32 patients with recently diagnosed IDDM who were part of the recent French multicenter randomized therapeutic trial of Cy-A. The production of reactive oxygen intermediates (ROI) by circulating polymorphonuclear (PMN) and mononuclear (MN) phagocytes was determined by luminol-dependent chemiluminescence (CL), both directly within microamounts of whole blood and in purified PMN or MN phagocyte suspensions. Lastly, CL production was measured in the absence (resting CL) and the presence of a panel of particular and soluble phagocyte membrane-stimulating agents. We found that on entry into the trial, i.e. within less than 2 months of the clinical onset of IDDM, patients had normal whole blood CL production in the absence of a stimulating agent and upon phagocytic challenge with latex or opsonised zymosan particles. By contrast, whole blood CL responses to soluble stimuli such as phorbol myristate acetate (PMA), concanavalin A (Con-A) and F Met-Leu-Phe (FMLP) were significantly higher than in the control group of 52 normal subjects (P less than 0.01). In purified PMN and MN phagocyte suspensions, both resting and stimulated CL productions were normal, regardless of the type of stimulating agent. After 3 months of treatment, whole blood CL responses to Con-A and FMLP returned to almost normal levels in patients treated with Cy-A (15 cases) but not in those receiving the placebo (17 cases); PMA-induced CL responses were also decreased, but this was found in both groups of patients. In purified phagocyte suspensions we detected no effect of Cy-A on PMN, whereas MN phagocytes from Cy-A-treated patients showed reduced CL responses to FMLP but not to other stimuli. Altogether, these results demonstrate for the first time that the capacity of circulating PMN and MN phagocytes to generate ROI is normal at the clinical onset of IDDM and suggest that circulating substances increase oxidative responses to soluble, but not particulate, stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)     

Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus

We randomly assigned 46 patients (mean age, 11.7 years; range, 4.5 to 32.8) with newly diagnosed insulin-dependent diabetes mellitus within two weeks of beginning insulin to receive either corticosteroids for 10 weeks plus daily azathioprine for one year or no immunosuppressive therapy. Half the 20 immunosuppressed patients completing the one-year trial had satisfactory metabolic outcomes (hemoglobin A1c less than 6.8 percent; stimulated peak C peptide greater than 0.5 nmol per liter; insulin dose less than 0.4 U per kilogram of body weight per day) as compared with only 15 percent of the controls. Three of 20 immunosuppressed patients, but no controls, were insulin independent at one year. Two of these continue to receive azathioprine without insulin after more than 27 months of follow-up. The response to immunosuppression correlated with older age, better initial metabolic status, and lymphopenia (less than 1800 lymphocytes per cubic millimeter) resulting from immunosuppression. The side effects of azathioprine included vomiting in one patient and mild hair loss in several others. Prednisone use resulted in a transient cushingoid appearance, weight gain, and hyperglycemia. The growth rate remained normal in all patients. We conclude that early immunosuppression with short-term use of corticosteroids plus daily azathioprine can improve metabolic control in some patients with insulin-dependent diabetes mellitus, but results from this unblinded study are preliminary and require further confirmation and long-term follow-up.