Methotrexate therapy in asthma increases T cell susceptibility to corticosteroid inhibition

BACKGROUND: Concomitant methotrexate (MTX) therapy of severe, oral corticosteroid-dependent asthmatics has been shown to be corticosteroid sparing, but the mechanism is unknown. We hypothesized that MTX therapy of these patients increases the susceptibility of their T cells to corticosteroid inhibition. OBJECTIVE: To measure prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells from a group of these patients before, during and following MTX therapy. METHODS: Eighteen severe asthmatics (median (range) age 56 (33-68) years, FEV1 61 (38-69)% predicted, dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high-dose, inhaled corticosteroids) were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. After 12 weeks of MTX, oral prednisolone dosages were reduced systematically over 16 weeks, provided that asthma control did not deteriorate. Patients were followed for a further 12 weeks after MTX withdrawal. Concentration-dependent, prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells was measured just prior to MTX therapy (week 1) and at weeks 12, 28 and 40, and IC50 concentrations were interpolated. RESULTS: By week 28 of MTX therapy, patients were able to reduce oral prednisolone dosages from (median, SIQR) 15 (10-20.5) to 5.9 (1.4-9.4) mg/day (P<0.01) without alteration of lung function and symptoms, while median IC50 values for prednisolone inhibition of peripheral blood T cell proliferation were reduced from 49 (21-144) to 4 (1-9) nm (P<0.0001). These increased again to 15 (9.4-25.7) mg/day and 36 (18-67) nm, respectively, following MTX withdrawal. A correlation (P<0.01) was observed between percentage reductions in prednisolone dosages in vivo and fold changes in prednisolone IC50in vitro between weeks 12 and 28. CONCLUSION: This effect of MTX may at least partly account for its oral corticosteroid-sparing effect in severe asthma.     

Hypertension during reduction of long-term steroid therapy in young subjects with asthma.

Corticosteroids can induce hypertension, which reportedly remits as the drug is withdrawn. We studied nine patients with steroid-requiring asthma, aged 9 to 16 years, who had elevated blood pressures during corticosteroid treatment. Unlike in previous studies, all nine patients developed hypertension during corticosteroid reduction. Diastolic blood pressures were 50 to 84 mm Hg during maximum corticosteroid therapy (1 to 4 mg/kg/day); these values were in the normal range for seven of the nine patients and in the high normal range for the other two patients. Maximum diastolic pressures were 100 to 120 mm Hg, 1 to 8 weeks after corticosteroid reduction was started. Hypertension occurred at 0% to 70% of their maximum corticosteroid dose. Corticosteroid reduction was the only medication change. Renal causes of hypertension were excluded. Six patients had levels of renin and aldosterone measured before onset of treatment. All six patients had elevated levels of renin, and five patients had elevated levels of aldosterone. Blood pressure elevations were resistant to diuretic therapy but responded rapidly to angiotensin-converting enzyme inhibitors. Caretakers of subjects with asthma need to be aware that hypertension may occur both during maximum corticosteroid use and during corticosteroid reduction.     

Pulmonary toxicity syndrome in breast cancer patients undergoing BCNU-containing high-dose chemotherapy and autologous hematopoietic cell transplantation.

We performed a retrospective review to investigate pulmonary toxicity syndrome (PTS) in a cohort of breast cancer patients undergoing BCNU-containing high-dose chemotherapy (HDC). Our aim was to characterize presentation, identify risk factors, determine outcome following therapy, and find any association with differences in survival. We reviewed the data of 152 patients with stage II or III or metastatic breast cancer treated with cyclophosphamide 5625 mg/m2, cisplatin 165 mg/m2, and BCNU 600 mg/m2 followed by autologous peripheral blood hematopoietic cell transplantation. During follow-up, PTS was diagnosed when the following criteria were met: (1) presentation with typical clinical symptoms of PTS, (2) an absolute carbon monoxide diffusion capacity (DLCO) decline of 10% compared with pre-HDC DLCO, and (3) no clinical evidence of active pulmonary infection. Patients were then treated with a course of corticosteroid therapy. The incidence of PTS for all 152 patients was 59%, with a median onset at 45 days (range, 21-149 days) post-HDC. The median absolute DLCO decrement was 26% (range, 10%-73%) at diagnosis of PTS. There was no significant correlation between patient age, stage of breast cancer, pre-HDC chemotherapy regimen, pre-HDC chest wall radiotherapy, tobacco use, prior lung disease, or baseline pulmonary function test results and the development of PTS. We did observe an interesting association between PTS and the development of a noncholestatic elevation of transaminases. Of PTS patients treated with prednisone therapy for a median of 105.5 days (range, 44-300 days), 91% achieved resolution of their PTS without pulmonary sequelae. At 3 years, the overall survival (OS) of stage II or III patients who developed PTS was 84% (95% confidence interval [CI], 73%-95%); of metastatic breast cancer patients with PTS, the OS was 58% (95% CI, 38%-78%). These values were not significantly different from those of patients who did not develop PTS (91% [95% confidence interval [CI], 81%-100%] and 53% [95% CI, 32%-74%], respectively). No significant differences in disease-free or event-free survival were observed between patients with and without PTS. The incidence of PTS in breast cancer patients treated with a BCNU-containing HDC regimen can be remarkably high. Treatment with a course of corticosteroid therapy is successful in the vast majority.     

Bronchodilator and corticosteroid reversibility in ambulatory patients with airways obstruction.

With the aim of characterising subgroups, we analysed reversibility tests from 1,048 patients with airways obstruction (baseline FEV1 less than 60% of predicted normal (%pred), and FEV1 to FVC ratio less than 0.6). Spirometry before and after inhalation of salbutamol 0.3 mg and ipratropium bromide 0.06 mg was performed before and after one week of treatment with prednisone 30 mg daily. The changes in FEV1 after bronchodilators showed unimodal distribution (mean = 7.0 %pred, st.dev. = 6.6 %pred). The responses to corticosteroid were more spread out (mean = 6.3 %pred, st.dev. = 13.8 %pred). The correlation between bronchodilator responses before and after corticosteroid treatment was poor (r = 0.30), although highly significant (p less than 0.000,001). The responses to bronchodilators were virtually independent of the steroid reversibility. The corticosteroid response was inversely related to age (r = -0.20, p less than 0.000,001) and smoking habits (r = -0.17, p less than 0.000,001), and moderately associated with blood eosinophilia (r = 0.34, p less than 0.000,001). The frequency distribution of the bronchodilator responses and the steroid response and combinations of the responses were all unimodal, making any distinction between nosologic subgroups arbitrary. It is clear from the study that criteria other than just response to therapy must be employed for distinction of subgroups among patients with airways obstruction.     

Low educational level but not low income impairs the achievement of cytogenetic remission in chronic myeloid leukemia patients treated with imatinib in Brazil

OBJECTIVES:

In Brazil, imatinib mesylate is supplied as the first-line therapy for chronic myeloid leukemia in the chronic phase through the public universal healthcare program, Sistema Único de Saúde (SUS). We studied the socio-demographic factors that influenced therapy success in a population in the northeast region of Brazil.

METHODS:

Patients with chronic myeloid leukemia from the state of Piauí were treated in only one reference center. Diagnosis was based on WHO 2008 criteria. Risk was assessed by Sokal, Hasford and EUTOS scores. Patients received 400 mg imatinib daily. We studied the influence of the following factors on the achievement of complete cytogenetic response within one year of treatment: age, clinical risk category, time interval between diagnosis and the start of imatinib treatment, geographic distance from the patient''s home to the hospital, years of formal education and monthly income.

RESULTS:

Among 103 patients studied, the median age was 42 years; 65% of the patients had 2-9 years of formal education, and the median monthly income was approximately 100 US$. Imatinib was started in the first year after diagnosis (early chronic phase) in 69 patients. After 12 months of treatment, 68 patients had a complete cytogenetic response. The Hasford score, delay to start imatinib and years of formal education influenced the attainment of a complete cytogenetic response, whereas income and the distance from the home to the healthcare facility did not.

CONCLUSION:

Patients require additional healthcare information to better understand the importance of long-term oral anticancer treatment and to improve their compliance with the treatment.     

Peripheral airways mucus clearance in stable asthma is improved by oral corticosteroid therapy

Inhaled 99mTc-labelled particles have been used to assess mucus clearance from peripheral, intermediate and inner lung zones of 12 patients with stable asthma. The method of analysis relies on a ventilation image with 81mKr to estimate the distribution of radioaerosol alveolar deposition so that clearance from each zone can be related just to particles deposited in the ciliated conducting airways. In calculating clearance from intermediate and inner lung zones, allowance is made for particles transported into these zones from more distal regions of the lung. Peripheral zone clearance in the asthmatic subjects improved significantly (p less than 0.01) after four weeks of corticosteroid treatment (two weeks on 15 mg prednisolone orally each day, plus two weeks on 30 mg). No significant change occurred in clearance from the inner zone when all patients were considered together. However, the six patients who prior to treatment coughed relatively infrequently did show a significant (p less than 0.05) increase in clearance from the inner zone as well as from the peripheral zone.     

Glucocorticosteroids attenuate aspirin-precipitated adverse reactions in aspirin-intolerant patients with asthma

We evaluated the effects of corticosteroid pretreatment on the intensity of adverse reactions to aspirin during carefully controlled aspirin challenges in 13 aspirin-sensitive asthmatics. Two studies were performed. First, using a double-blind crossover design, we administered to five patients 75 mg prednisone daily or placebo for two days preceding the challenge. No consistent protection against adverse reactions was achieved. In the second study, a 10-day pretreatment with 15 mg oral prednisolone and topical intrabronchial and intranasal beclomethasone offered total clinical protection against bronchospasm produced by threshold doses of aspirin in five of eight patients. In two others, the bronchospasm provoked was less severe, and only in one patient did its intensity remained unchanged. There was a significant reduction in fall of mean pulmonary function tests following the second aspirin challenge, which was performed after ten days of steroid treatment. Steroids given for ten days also prevented significantly nasal discharge and nasal blockade. When diagnostic challenge tests with aspirin are carried out in asthmatic patients on long-term corticosteroid therapy, there is an increased possibility of false negative results.     

肩锁关节劳损的诊断与注射治疗

目的 探讨肩锁关节轻度损伤的诊断与强的松龙局部注射疗法。方法选择门诊确诊为肩锁关节扭伤或劳损的患者15例，采取强的松龙混悬液25mg加1％普鲁卡因或2％利多卡因5ml注射关节腔及肩锁韧带的方法，未用其他治疗。结果多数病例在注射后1周左右痊愈。少数病例经2—3次注射，每次间隔1周，而后痊愈。个别病例数月或数年后复发，以相同方法治愈。结论对诊断正确的轻度肩锁关节损伤(劳损或扭伤)，采取局部注射强的松龙的方法，可以获得满意的效果。     

A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group.

BACKGROUND. The morbidity from obstructive airways disease (asthma and chronic obstructive pulmonary disease) is considerable, and the mortality rate is rising in several countries. It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy. METHODS. In a multicenter trial we compared three inhalation regimens in which a beta 2-agonist (terbutaline, 2000 micrograms daily) was combined with a corticosteroid (beclomethasone, 800 micrograms daily), an anticholinergic bronchodilator (ipratropium bromide, 160 micrograms daily), or placebo. Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years. RESULTS. Of the 274 patients enrolled, 56 percent had allergies. The mean forced expiratory volume in one second (FEV1) was 64 percent of the predicted value. The mean PC20 (the concentration of inhaled histamine causing a 20 percent decrease in FEV1, a measure of hyperresponsiveness) was 0.26 mg per milliliter. Withdrawal from the study, due mainly to pulmonary symptoms, was less frequent in the corticosteroid group (12 of 91 patients) than in the anticholinergic-drug group (45 of 92 patients) or the placebo group (44 of 91 patients; P < 0.001). The mean FEV1 (+/- SE) increased by 10.3 +/- 1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter, whereas it did not change in the other two groups (P < 0.001). The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups (P < 0.001). In the corticosteroid group, patients who did not smoke, who had allergies, or who were less than 40 years old benefited more from their treatment than did those who smoked, did not have allergies, or were over 40, but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group. CONCLUSIONS. The addition of an inhaled corticosteroid--but not an inhaled anticholinergic agent--to maintenance treatment with a beta 2-agonist (terbutaline) substantially reduced morbidity, hyperresponsiveness, and airways obstruction in patients with a spectrum of obstructive airways disease.     

Pain management in adults with sickle cell disease in a medical center emergency department

Guidelines for pain management in adult sickle cell patients with vaso-occlusive crises suggest prompt, frequent administration of parenteral opioids. Neither the ability to implement these guidelines in a busy urban emergency department nor opioid dose requirements in uncomplicated vaso-occlusive crisis have been previously documented. Thus, a retrospective review of vaso-occlusive crisis treated in an urban medical center emergency department in 2005 was performed to define opioid requirements and barriers to guideline implementation. Fifty-seven visits by 19 patients were evaluable. Opioid treatment was not initiated for more than 2 hours during 30% of visits; the interval between the first and second opioid doses exceeded 1 hour in 26% of visits and increased with subsequent doses; and total treatment time was less than 1 hour during 21% of visits (median, 2.2 hours). Opioid doses (as intravenous morphine equivalents) ranged from 4 to 26.7 mg (0.05-0.50 mg/kg) and exceeded 10 mg during 40 visits (70%) and in 10 patients (53%). Hospitalization occurred on 25 occasions with 48% of patients admitted after 3 or fewer opioid doses and 50% of patients admitted after less than 3 hours of treatment. Moreover, return emergency department visits occurred within 3 days after 9 of 32 home discharges (28%) with treatment times uniformly less than 3 hours during the preceding visit. It is concluded that: (1) opioid dose requirements vary widely, often exceeding guideline recommendations; and (2) treatment time and timely opioid administration are often compromised, resulting in delayed pain control and premature decisions on disposition with early return visits and possibly avoidable hospital admissions.     

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a known complication of autologous hematopoietic cell transplantation (aHCT), particularly in children with neuroblastoma. We describe a pediatric single-institution experience of TA-TMA after aHCT. Data were abstracted from the medical record of patients who underwent aHCT between January 1, 2008, and July 1, 2018, at Boston Children's Hospital. TA-TMA was diagnosed using either the International Working Group criteria or the “probable TA-TMA criteria” of Cho et al. Overall, 318 aHCTs were performed in 243 patients. Nine patients (3.7%) were diagnosed with TA-TMA. TA-TMA occurred most frequently in children with neuroblastoma (n = 7; 78%), all of whom were conditioned with carboplatin, etoposide, and melphalan. The median age at aHCT in children who developed TA-TMA was 3 years, 5 months (range, 18 months to 25 years). TMA was diagnosed at a median of 35 days (range, 8 to 106 days) after stem cell infusion. On a retrospective chart review using the same criteria used by the provider, patients met criteria a median of 5 days before the clinical diagnosis (range, 0 to 58 days). Eight patients had renal involvement at presentation, including nephrotic range proteinuria and severe hypertension, requiring from 2 to 6 antihypertensive medications. Two patients presented with multiorgan failure. Six patients were treated with eculizumab a median of 0 days after TA-TMA diagnosis (range, 0 to 11 days). On retrospective review, patients were treated a median of 18 days (range, 0 to 58 days) after meeting criteria for TA-TMA. Before initiation of therapy, 4 of 6 patients checked for serum complement levels had normal values, 1 had elevated CH50 and 1 had elevated sC59-b and CH50. All patients had CH50 levels within the target range (≤3 CAE) after induction therapy. Two patients (33%) had no response to eculizumab and died of multiorgan failure. The other 4 had both a hematologic response with transfusion independence (median, 6.5 weeks; range, 4 to 9 weeks) and renal response, defined as resolution of nephrotic range proteinuria (median, 21 weeks; range, 13 to 25 weeks). Among the eculizumab-treated survivors, 2 patients remained on prolonged eculizumab therapy, and one had recurrence of TA-TMA after discontinuation of eculizumab. All 4 eculizumab treated survivors have persistent organ dysfunction. Three children were treated with supportive care only; 2 died of relapsed cancer, and the third is alive with stage 2 chronic kidney disease. The median duration of follow-up after TA-TMA diagnosis was 2.5 years (range, 9 months to 4 years). The 1-year overall survival was 78% (SE = 14%). However, regardless of treatment, no survivors had complete normalization of function in all organs. Three children with normal serum CH50 and sc5b-9 levels responded to eculizumab. This report highlights the importance of maintaining a high suspicion for TA-TMA after aHCT. Further study is warranted to identify individual risk factors for TMA after aHCT, predict the response to eculizumab, and capture long-term sequelae in survivors.     

Long-term experience providing antiretroviral drugs in a fee-for-service HIV clinic in Uganda: evidence of extended virologic and CD4+ cell count responses

OBJECTIVE: To describe the long-term experience of providing anti-retroviral (ARV) therapy, including CD4 cell count and virologic response, at St. Francis Hospital, Nsambya, Uganda. METHODS: The HIV clinic established in 1998 is a fee-for-service model where patients pay for ARVs. The care of patients who started ARVs from August 1, 1998 until October 31, 2000 was evaluated through December 31, 2002. Data were collected at the HIV clinic on standardized clinical forms. These patients had free CD4 cell count and viral load testing performed at times determined by the physician. All persons who had >/=1 CD4 cell count or viral load done >/=90 days after starting therapy were evaluated. RESULTS: Three hundred twenty-one patients (49% women, 66% ARV naive, median age = 38 years, median CD4 cell count = 79 cells/mm, and median viral load = 249,489 copies/mL) attended the HIV clinic. Two hundred sixty-three (82%) patients returned at least once after the initial visit, of whom 54 (21%) had an interruption in therapy for >1 year. One hundred thirty-five patients were in care in 2002, 69 were known to have died (9 of whom died in 2002), and 68 were lost to follow-up. The probability of remaining alive and in care at 1 year was 0.56 (95% confidence interval [CI]: 0.50-0.61), 0.46 (95% CI: 0.41-0.51) at 2 years, 0.40 (95% CI: 0.34-0.45) at 3 years, and 0.35 (95% CI: 0.29-0.41) at 4 years. In an on-treatment analysis, the median CD4 cell count increase during year 1 was +55 cells/mm, +112 cells/mm during year 2, +142 cells/mm during year 3, and +131 cells/mm during year 4. The median log viral load change from baseline during year 1 was -1.4 copies/mL, -1.32 copies/mL during year 2, -1.9 copies/mL during year 3, and -1.51 copies/mL during year 4. CONCLUSIONS: This fee-for-service HIV clinic providing ARV treatment has successfully operated and managed patients for more than 4 years. Those who survived and remained on therapy derived long-term virologic and immunologic responses to ARV drugs in a manner similar to that observed in industrialized countries. Strategies to reduce the financial burden and other barriers to uninterrupted care as well as incentives to increase such practice models should be further explored in the African context.     

Phase I Trial of Brentuximab Vedotin for Steroid-Refractory Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

We conducted a phase I study of brentuximab vedotin (BV), an antibody–drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3?+?3 study design was used with the primary endpoint to determine the maximum tolerated dose of BV in this population. Escalating doses of BV were planned, starting with .6?mg/kg every 3 weeks (dose level 0) and increasing by .3?mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent before dosing. The median number of cycles of therapy was 4 (range, 1 to 16). Reasons for stopping therapy prematurely included toxicities (n?=?9), patient decision (n?=?3), lack of response (n?=?2), and death (n?=?1). There were 2 dose-limiting toxicities observed: posterior reversible encephalopathy syndrome (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The maximum tolerated dose was not reached because the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to National Institutes of Health cGVHD response criteria, 8 patients (47%) experienced a partial response, whereas 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level before therapy was 61.5?ng/mL (range, 7.8 to 474.9); however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed.     

Antilymphocyte globulin (ALG) or antithymocyte globulin (ATG) with methylprednisone and oxymethalone in aplastic anaemia

From 1986 to 1994 we treated 26 patients of aplastic anaemia between 6 to 61 years age group with ATG/ALG, Methylprednisone and Oxymethalone. Five had very severe aplastic anaemia, 16 had severe and 5 nonsevere disease. Disease was associated with hepatitis in 5 patients and with pregnancy and drug use in 2 patients each. In others no cause could be ascertained. A total of 31 courses of treatment were given (range 1-3 courses per patient). Nine patients had complete response (34.62%) and 3 had partial response (11.54%) with an overall response rate of 46.16%. Four patients died within 2 months of starting the treatment. The median follow up was 24 months (range 6-102 months) with an overall survival probality of 45% at 2 yr. At the time of evaluation 12 patients have died, 9 are alive disease-free and 5 are alive with disease. The side effects associated with therapy were tolerable and did not require cessation of therapy in any patient. We conclude that ATG/ALG with Methylprednisone and Oxymethalone is beneficial to significant number of patients with aplastic anaemia.     

Effect of Long-term Corticosteroid Therapy on Monocyte Chemotaxis in Man

The influence of prednisolone on monocyte chemotactic activity in vitro at prednisolone concentrations comparable with those achieved in man following oral dosage has been investigated. Chemptactic activity of monocytes from each of sixteen normal subjects was suppressed by concentrations of prednisolone as low as 25 ng/ml (suppression of chemotaxis, 20%). Maximal suppression occurred at 100 ng/ml (suppression of chemotaxis, 48%) and no significant increase in suppression was produced by increasing the concentration to 200 ng/ml (suppression of chemotaxis, 53%). In contrast, monocytes isolated from ten patients receiving corticosteroid therapy showed no significant suppression of chemotactic activity when exposed to these concentrations of prednisolone, even though they exhibited a normal ability to respond to a chemotactic stimulus. The lack of suppression of monocyte chemotaxis in patients receiving corticosteroid therapy is unexplained, but may represent a change in the circulating monocyte or lymphocyte populations.     

Comparison of effects of chronic inflammation and long-term prednisolone administration on zinc metabolism in rats

It is well known that plasma zinc is depressed in animals following administration of endotoxin, endogenous pyrogen, interleukin-1, and glucocorticoids. The modification is related to an induction of liver metallothionein causing an accumulation of the element in this organ. The changes in zinc metabolism induced by adjuvant arthritis in rats evidenced a redistribution of body zinc with a rapid and sustained decrease in plasma zinc that occurred simultaneously with an increase in liver zinc levels, and slower modification in erythrocyte and femur zinc concentrations. These effects were compared to those induced by a long-term corticosteroid administration in healthy rats. Male Wistar rats received either a commercially available complete maintenance diet or the same diet enriched with prednisolone at a level providing 1 mg prednisolone/kg body weight. Groups of animals were sacrificed after 3 or 5 weeks' treatment. Ingested food quantity, total body weight, total serum proteins and serum albumin were similar in treated and control rats. No significant modifications in parameters of zinc status could be observed after 3 weeks of treatment. However after 5 weeks, plasma zinc was significantly lower in treated rats as compared to controls, but modifications in liver, erythrocyte and femur zinc did not reach statistical significance. Changes induced by long-term corticosteroid administration are therefore less intense than those due to the inflammatory process of adjuvant arthritis.     

Administration of thyroxine in treated Graves' disease. Effects on the level of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism

BACKGROUND. Antibodies to thyroid-stimulating hormone (TSH) receptors that stimulate the thyroid gland cause hyperthyroidism in patients with Graves' disease, and their production during antithyroid drug treatment is an important determinant of the course of the disease. One factor that might contribute to the persistent production of antibodies to TSH receptors is stimulation of the release of thyroid antigens by TSH during antithyroid drug therapy. We therefore studied the effect of the suppression of TSH secretion by thyroxine on the levels of antibodies to TSH receptors after thyroid hormone secretion had been normalized by methimazole. METHODS AND RESULTS. The levels of antibodies to TSH receptors were measured during treatment with methimazole, either alone or in combination with thyroxine, in 109 patients with hyperthyroidism due to Graves' disease. The patients first received 30 mg of methimazole daily for six months. All were euthyroid after six months, and their mean (+/- SD) level of antibodies to TSH receptors decreased from 64 +/- 9 percent to 25 +/- 15 percent (P less than 0.01; normal, 2.9 +/- 1.4 percent). Sixty patients then received 100 micrograms of thyroxine and 10 mg of methimazole and 49 received placebo and 10 mg of methimazole daily for one year. In the thyroxine-treated group, the mean serum thyroxine concentration increased from 108 +/- 16 nmol per liter to 145 +/- 11 nmol per liter (P less than 0.01), and the level of antibodies to TSH receptors decreased from 28 +/- 10 percent to 10 +/- 3 percent after one month of combination therapy. In the patients who received placebo and methimazole, the mean serum thyroxine concentration decreased and the level of antibodies to TSH receptors did not change. Methimazole, but not thyroxine or placebo, was discontinued in each group 1 1/2 years after the beginning of treatment. The level of antibodies to TSH receptors further decreased (from 6.6 +/- 3.2 percent at the time methimazole was discontinued to 2.1 +/- 1.2 percent one year later) in the patients who continued to receive thyroxine, but it increased (from 9.1 +/- 4.8 percent to 17.3 +/- 5.8 percent during the same period) in the patients who received placebo. One patient in the thyroxine-treated group (1.7 percent) and 17 patients in the placebo group (34.7 percent) had recurrences of hyperthyroidism within three years after the discontinuation of methimazole. CONCLUSIONS. The administration of thyroxine during antithyroid drug treatment decreases both the production of antibodies to TSH receptors and the frequency of recurrence of hyperthyroidism.     

Results of Treatment on 56 Sarcomas of the Uterus between 1953 and 1977Behandlungsergebnisse von 56 Uterussarkomen der Jahre 1953 bis 1977

At the Frauenklinik Finkenau Hamburg a total of 56 women were treated for sarcoma of the uterus between 1953 and 1977. Accounting for 1.2% of all malignancies, sarcoma is a rare tumor. The different histological types are analysed with respect to age distribution, endocrine status, preceding pregnancies, etc. Treatment results over a 15 years period and a subsequent 10 years period were compared. Symptoms and local findings show great variability. Preoperative diagnostic procedures frequently did not result in final diagnosis.The mode of therapy changed over the long period of 25 years. Forty-nine patients were followed up over a period of more than 10 years. In Patients with sarcomas which had derived from preexisting myomas, the 10 year survival rate was 89% (16/18). The total 10 year survival rate was 57% (28/49). Effectiveness of different therapeutic approaches such as operation, irradiation, and cytostatic therapy is demonstrated. Local recurrences and distant metastases usually occurred within 2 years after primary treatment. One case with successful chemotherapy of pulmonary metastases of leiomyosarcoma is demonstrated showing complete remission over a period of 28 months.     

Prolonged corticosteroid treatment in the management of temporal arteritis

Summary Twenty-four patients with biopsy proven temporal arteritis were followed for 7 years and the effect and duration of corticosteroid treatment was evaluated. An initial dose of 35 mg prednisone daily was sufficient to control symptoms and signs in most of the patients. Flare-up rates upon corticosteroid reduction were high, especially in the first 24 months of treatment. Flare-ups were more common (>twice) in non-western Jews as compared to western Jews. Serious corticosteroid side effects were uncommon. Corticosteroid treatment was withdrawn from 7 patients after 5 years; two of these patients suffered flare-ups within 16 months. Nineteen patients remained on prednisone, in an average dose of 4 mg/day, 7 years after diagnosis. Thus, corticosteroid treatment in temporal arteritis should be prolonged in the majority of patients.Abbreviations T.A. Temporal arteritis - N.S. none significant - E.S.R. erythrocyte sedimentation rate     

Effect of single dose of prednisolone on hospitalisation in patients of acute bronchial asthma

The present study was undertaken to assess the effect of stat dose of oral prednisolone on rate of hospitalisation in patients of acute bronchial asthma. 259 patients, aged 1-65 years presenting with acute exacerbation of asthma were randomised in a double blind fashion to receive a stat dose of oral prednisolonev (30 mg if age < 5 years; 60 mg if age > 5 years) or equivalent placebo. Then, nebulbutamol (0.15 mg/kg in 2 m/l normal saline) was given to all patients and patients were re-examined after 4 hours to decide about the hospitalisation. The study revealed that only 37 (26.42%) patients required hospitalisation and further management in prednisolone group compared to 50 (42.01%) patients in placebo group (p < 0.01). This suggests that prompt use of single oral dose of prednisolone along with routine bronchodilator therapy can significantly reduce morbidity and need for hospital admission in patients of acute bronchial asthma.