Context:
Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive glucocorticoid replacement therapy, which might cause osteoporosis.
...Objectives:
Questions addressed by this study were: 1) Is bone mineral density (BMD) reduced in PAI and CAH on lower glucocorticoid doses than previously reported? 2) Is BMD in PAI influenced by the type of glucocorticoid used? and 3) Does DHEA treatment affect BMD in PAI women?
Design and Patients:
We conducted a prospective, cross-sectional study including 81 PAI patients and 41 CAH patients.
Main Outcome Measures:
BMD was measured by dual-energy x-ray absorptiometry. Serum levels of bone turnover markers, minerals, vitamins, hormones, and urinary crosslinks were measured.
Results:
PAI and CAH patients received average daily hydrocortisone doses of 12.0 ± 2.7 mg/m2 (range, 4.9–19.1) and 15.5 ± 7.8 mg/m2 (range, 5.7–33.7), respectively. BMD varied within the normal reference range (−2 to +2) in both cohorts. However, lower Z-scores for femoral neck and Ward's region were found in CAH compared to PAI women, but not in men. Prednisolone treatment showed significant lower osteocalcin levels and lower Z-scores for lumbar spine and femoral neck compared to PAI patients on hydrocortisone. PAI women treated with DHEA had significantly lower urinary collagen crosslinks and bone alkaline phosphatase, and significantly higher Z-scores in lumbar spine and femoral Ward's region compared to non-DHEA-treated women.
Conclusions:
Adult PAI and CAH patients on low glucocorticoid doses showed normal BMD within the normal reference range. The use of longer acting prednisolone resulted in significantly lower BMD in PAI. In addition, DHEA treatment may have a beneficial effect on bone in Addison's women.
Background: Specific immunotherapy (SIT) and treatment with anti‐immunoglobulin (Ig)E antibody are complementary approaches to treat allergic rhinoconjunctivitis, which may be used for single or ...combined treatment.
Objective: A randomized, double‐blind, placebo‐controlled trial was conducted to compare the efficacy of single and combined treatment with SIT and anti‐IgE (Omalizumab) in reducing symptom severity and rescue medication use.
Methods: A total of 221 subjects with birch and grass pollen allergic rhinoconjunctivitis aged 6–17 years were analysed during the grass pollen season. Group A (SITbirch + placebo) served as a reference group obtaining no effective treatment for grass pollen allergy. Group B received anti‐IgE monotherapy during grass pollen season, group C SIT grass pollen monotherapy, and group D the combined treatment of SIT and Omalizumab.
Results: Preseasonal treatment with grass pollen SIT alone compared with SIT with the nonrelated allergen did not reduce symptoms or rescue medication use. Anti‐IgE monotherapy significantly diminished rescue medication use and number of symptomatic days. The combined treatment with SIT and anti‐IgE showed superior efficacy on symptom severity compared with anti‐IgE alone.
Conclusions: Co‐seasonal Omalizumab therapy showed considerable effects in children with seasonal allergic rhinitis. The combination of SIT plus Omalizumab was clinically superior to each treatment alone during the first year of observation.
Background/aim: We hypothesized that a continuous 24-h infusion of 100 mg/kg per day ceftazidime (treatment C) would result in equivalent or even superior anti-infectious efficacy in chronic ...Pseudomonus aeruginosa (PA) infection in patients with cystic fibrosis (CF) in comparison to the usual application of 200 mg/kg per day ceftazidime in three doses (treatment T). Methods: This was a randomized crossover study comparing outcome after 14 days and 35 days. Tobramycin administered once daily (10 mg/kg per day) was administered concomitantly in both groups. The primary end-point was a decrease in the leukocyte count, and the secondary endpoints were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunogloblulin Ig G, C-reactive protein CRP) in serum. All patients received antibiotics electively as 14-day courses on a regular basis, not for acute exacerbations. Results: Fifty-six patients (29 females, mean patient age 14.4 years, age range 5-37) initially received treatments C or T, followed by the alternative treatment after amean interval of 37 (± 21) weeks. After 2 weeks of antibiotic treatment, the overall study group showed significant improvements compared to baseline for body weight, leukocyte counts, CRP, forced expiratory volume in 1 s (FEV₁), FVC (forced vital capacity), and bacterial load in the airways, with no significant differences between treatment groups. Both regimens were well tolerated. Threeweeks after cessation of antimicrobial therapy, leukocytes and PA density had returned to pre-treatment values. Conclusion: We conclude that continuous or thrice-daily dosing of intravenous ceftazidime, both combined with once-daily tobramycin, are equally effective application regimens for elective antipseudomonal therapy in clinically stable patients with CF.
The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a ...threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between thymic production, homeostatic T cell proliferation and TCR beta-chain diversity in young (approximately 25 years), middle-aged ( approximately 60 years), and elderly adults (approximately 75 years). TCR excision circles (TREC) as a marker of thymic output exponentially decreased by >95% between 25 and 60 years of age. The frequency of Ki67(+) cycling CD4 T cells remained steady, and surprisingly, the diversity of the naive CD4 T cell repertoire was maintained at approximately 2 x 10(7) different TCR beta-chains. After the age of 70 years, TRECs only slightly declined, but homeostatic proliferation doubled. The diversity of the T cell pool drastically contracted to 200,000 TCR beta-chains. Also, the phenotypic distinction between naive and memory CD4 T cells became fuzzy. The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment.
The immune system is equipped with an extremely large spectrum of structurally diverse receptors to recognize all potential antigens. This fundamental principle of receptor diversity is no longer ...upheld in patients with rheumatoid arthritis (RA), who have a marked contraction of the T cell receptor repertoire. In this study, the ability of RA patients to produce T cells and to maintain T cell homeostasis was examined. CD4 T cells containing T cell receptor rearrangement excision circles (TREC) were substantially reduced in RA patients; TREC levels in young adult patients matched those of controls 20 years older. Increased self-replication of T cells in RA was indicated by age-inappropriate erosion of telomeres in circulating T cells with almost complete attrition of telomeric reserves in patients 20-30 yr of age. The degree of telomere loss was not related to disease duration or the use of disease-modifying medication and was most pronounced in CD4+CD45ROnull(naive) T cells. The loss of TREC-positive T cells could be a consequence of a primary defect in peripheral T cell homeostasis. Alternatively, RA patients may have impaired thymic function with the increased turnover of peripheral T cells being a secondary compensatory event.
Aberrations in the T cell repertoire with the emergence of oligoclonal populations have been described in patients with rheumatoid arthritis (RA). However, the extent of the repertoire perturbations ...as well as the underlying mechanisms are not known. We now have examined the diversity of the peripheral CD4 T cell repertoire by determining the frequencies of arbitrarily selected T cell receptor (TCR) β -chain sequences. Healthy individuals displayed a highly diverse repertoire, with a median frequency of individual TCR β -chain sequences of 1 in 2.4 × 107 CD4 T cells. In RA patients, the median TCR β -chain frequency was increased 10-fold, indicating marked contraction of the repertoire (P < 0.001). The loss in TCR diversity was not limited to CD4 memory T cells but also involved the compartment of naive T cells, suggesting that it reflected an abnormality in T cell repertoire formation and not a consequence of antigen recognition in the synovium. Also, control patients with chronic inflammatory disease such as hepatitis C expressed a diverse repertoire indistinguishable from that of normals. Telomere length studies indicated an increased replicative history of peripheral CD4 T cells in RA patients, suggesting an enhanced turnover within the CD4 compartment. Compared with age-matched controls, terminal restriction fragment sizes were 1.7 kilobases shorter (P < 0.001). These data demonstrate an altered CD4 T cell homeostasis in RA that may contribute to the autoimmune response as well as to the immunodeficiency in these patients.
Using the Acolysis System from Angiosonics, ultrasound is a new tool in the therapy for recanalization of peripheral arterial occlusions, as it already has been used for coronary interventions in ...cardiology. This system was used on patients with peripheral arterial occlusive disease. The Acolysis device needs a 7F sheath and was introduced for ipsilateral use.
Despite increasing interest in the short-term effects of airborne environmental contaminants, experimental findings are generated at a very slow pace. This is due in part to the expense and ...complexity of most environmental chambers, which are needed for quantifying effects of wholebody exposures. We lessened this obstacle by designing, constructing, and testing a single-pass, 10-m3 stainless-steel chamber. Compressed air is purified before being sent to an air dilution olfactometer, which supplies 1000 L (1 m3) per minute (referenced to STP) while maintaining 40% relative humidity (RH) and 22.6°C. Precise control of all stimulus parameters is greatly simplified since air is not recirculated. Vapor-phase odorant concentrations are achieved by varying the proportion of total airflow passing through one or more saturators, and are verified in real time by an infrared (IR) spectrometer. An adjoining 5-m3 anteroom is used for introducing known intensities of more chemically complex vapor and/or particulate stimuli into the chamber. Prior to the point that air is exhausted from the chamber, all components are made of stainless steel, Teflon, or glass. A LabView TM program contains feedback loops that achieve document chamber conditions and document performance. Additional instrumentation and computer systems provide for the automated collection of perceptual, respiratory, eye blink, heart rate, blood pressure, psychological state, and cognitive data. These endpoints are now being recorded, using this facility, in response to ranges of concentrations of propionic acid and environmental tobacco smoke.
Adrenal insufficiency is caused by either primary adrenal failure, mostly due to autoimmune adrenalitis, or by hypothalamic-pituitary impairment of the corticotropic axis, predominantly by long-term ...pharmacodynamic glucocorticoid treatment or by pituitary tumour growth and related treatment. Despite optimized life-saving glucocorticoid and mineralocorticoid replacement therapy, health-related quality of life in adrenal insufficiency is more severely impaired than previously thought and patients with adrenal insufficiency are also threatened by an increased mortality. Optimizing hormone replacement remains one of the most challenging tasks in endocrinology. Monitoring of glucocorticoid replacement quality is hampered by lack of objective assessment tools and therefore largely based on clinical grounds. Thus, long-term management of patients with adrenal insufficiency remains a continuous challenge asking for the experienced specialist. However, diagnosis and management of suspected acute adrenal failure is an important task for all physicians. This review explains the rationale behind the current hormone replacement scheme, points to the deficits and hints at possible future therapies.
To study the genetics of atopy systematically we established a mouse model that provides the general phenotype of atopy: the early response characteristic of IgE-dependent eczema or atopic ...dermatitis, and the diagnostic test of atopy, the skin-prick test. Using an immediate cutaneous hypersensitivity test (ICHS) against birch pollen extract we could classify A/J and C57BL/6 (B6) inbred mouse strains respectively as high responder and low responders. The F1 hybrids were found to be high responders with incomplete penetrance. Backcrossing F1 mice to the low responder B6 strain yielded three classes of responders, high, intermediate, and low. A genome-wide microsatellite screen of the backcross progeny disclosed suggestive linkage to a microsatellite marker on chromosome 6 close to the locus of the IL-5 receptor alpha chain. Its allelic variation in A/J and B6 strains was investigated and two major differences were detected. Firstly, a nucleotide exchange in the 5' untranslated region of B6 mRNA resulted in increased transcription/translation of a reporter construct. Higher expression of the receptor on the cell surface would be expected to favor an allergic immune response. Secondly, the two alleles are differentially spliced so as to yield two soluble isoforms in A/J mice versus one in B6 mice. Higher expression of soluble IL-5R would be expected to reduce the level of allergy through capture of IL-5. Thus both findings conform to the expectation based on susceptibility to atopy and thus identify the IL-5R alpha chain as a likely contributor to the genetics of atopy.
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