Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma

BACKGROUND: Inhaled corticosteroids (ICS) are recommended therapy for persistent asthma, although side effects can limit appropriate use. Ciclesonide, a novel ICS, is activated in the lung, thereby reducing systemic activity and side effects. This 12-week, double-blind, randomized, parallel-group, placebo-controlled study evaluated the efficacy and safety of ciclesonide in adults with persistent asthma. METHODS: After a 2-week baseline period in which current ICS treatment was continued, 329 patients were randomized to receive ciclesonide 160 microg (n = 107) or 640 microg (n = 112) (ex-actuator doses, equivalent to 200 and 800 microg ex-valve, respectively), or placebo (n = 110) once daily in the morning. Efficacy was monitored by asthma symptom scores, rescue medication use, morning and evening peak expiratory flow (PEF) measurements, spirometry, and probability of study completion without experiencing lack of efficacy. RESULTS: Morning PEF remained stable with either ciclesonide dose but decreased with placebo; the differences were significant (P < 0.0001) for both ciclesonide doses vs placebo. The forced expiratory volume in 1 s and forced vital capacity decreased significantly with placebo (P < 0.005), but were unchanged with ciclesonide. Lack of efficacy was significantly greater for patients switched to placebo (63%) than it was for those treated with ciclesonide 160 microg (30%) (P < 0.0001 vs placebo) or ciclesonide 640 microg (31%) (P < 0.0001 vs placebo). There were no significant differences between the two tested doses of ciclesonide with respect to efficacy and safety. Serum and 24-h urine cortisol were unaffected by ciclesonide treatment. Both doses of ciclesonide were well tolerated with no cases of oral candidiasis. CONCLUSION: Ciclesonide (160 or 640 microg) once daily in the morning effectively maintains asthma control, does not affect cortisol levels, and has an adverse event profile comparable with placebo in adults with primarily mild to moderate asthma.     

Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone

Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggregates. Electron microscopy reveals both types of aggregates to have a similar ultrastructure. ARQ48 aggregates sequester mitochondria and steroid receptor coactivator 1 and stain positively for NEDD8, Hsp70, Hsp90 and HDJ-2/HSDJ. Co-expression of HDJ-2/HSDJ significantly represses aggregate formation. ARQ48 aggregates also label with antibodies recognizing the PA700 proteasome caps but not 20S core particles. These results suggest that ARQ48 accumulates due to protein misfolding and a breakdown in proteolytic processing. Furthermore, the homeostatic disturbances associated with aggregate formation may affect normal cell function.     

T cell subsets in idiopathic glomerulonephritis

Determination of T lymphocyte subsets using monoclonal antibodies revealed a deficiency of suppressor cells and an elevated helper:suppressor T cell ratio in 7 patients with untreated idiopathic immune complex glomerulonephritis and nephrotic syndrome. Possible pathogenetic mechanisms of immunoregulatory cell imbalance and their implications specifically in reference to idiopathic glomerulonephritis are discussed.     

Monoclonal antibodies to human secretory "pregnancy-associated endometrial alpha 1-globulin," an insulin-like growth factor binding protein: characterization and use in radioimmunoassay, Western blots, and immunohistochemistry

Monoclonal antibodies were raised against pregnancy-associated endometrial alpha 1-globulin (alpha 1-PEG), a 32 KD insulin-like growth factor binding protein (IGF-BP), which represents a major secretory product of the human decidualized endometrium during pregnancy. This class of IGF-BP has been implicated in the modulation of action, inhibitory and stimulatory, of insulin-like growth factors. Immunization with the protein purified from pregnancy endometrium resulted after myeloma fusion in the isolation of six hybridoma clones and the antibodies produced were characterized. The Ka of the antibodies ranged between 4.75 x 10(9) M-1 and 0.7 x 10(8) M-1. In Western blots all monoclonal antibodies reacted with purified protein of molecular weight 32 KD and specifically detected this IGF-BP species in culture medium and cytosolic extracts of pregnancy endometrium and amniotic fluid. The monoclonal antibodies appear to define three epitope-bearing regions as evidenced by their reactivity to polypeptide fragments of the protein. After synthesis and secretion by tissue explants in vitro the protein is susceptible to cleavage into fragments possessing different monoclonal antibody-defined reactivity. Employing immunohistochemical techniques the protein was principally localized to decidual cells in tissue sections of pregnancy endometrium and solely to these cells after enzymic digestion of the tissue. The implications of these results are discussed with respect to potential role of IGF-BP in the action of IGF upon the IGF-1 receptor-bearing populations, including lymphocytes and trophoblast cells, D in the decidua.     

On the ultrastructural diversity and essence of residual bodies in neuronal ceroid-lipofuscinosis.

In 4 patients with neuronal ceroid-lipofuscinoses (NCL) (3 patients with the junvenile type, 1 patient with the late infantile type), the ultrastructural spectrum of residual bodies in the central and peripheral nervous system presented curvilinear profiles in all cases and regions investigated and many more ultrastructural patterns within and beyond regions commonly accessible to biopsy, probably due to age dependence, local tissue and cellular biochemical factors. Sampling from basal ganglia especially yielded combined curvilinear-fingerpint bodies, from peripheral ganglia additional membranous bodies. Residual bodies in NCL were present in almost every cell type, similar to the distribution of regular lipofuscin. Although the classical subgroups of NCL contain electronmicroscopically well defined residual bodies, permitting distinction of the late infantile type from the juvenile type, the ultrastructural differences are more of a quantitative than of a qualitative nature. However, they are not pathognomonic. N.m.r. spectra of ceroid and lipofuscin support the concept of their biochemical similarity, and argue against the proposition that they contain a single major component.     

Virulence of protein A-deficient and alpha-toxin-deficient mutants of Staphylococcus aureus isolated by allele replacement.

The gene coding for protein A (spa) of Staphylococcus aureus 8325-4 has been inactivated by substituting part of the spa coding sequence for a DNA fragment specifying resistance to ethidium bromide. The in vitro-constructed spa::EtBrr substitution mutation was introduced into the S. aureus chromosome by recombinational allele replacement. Southern blot hybridization showed that the in vitro-constructed mutation was present in the chromosomal spa locus. We have previously reported the inactivation of the alpha-toxin gene (hly) by allele replacement with an in vitro-constructed hly::Emr (erythromycin resistance) mutation (M. O'Reilly, J.C.S. de Azavedo, S. Kennedy, and T.J. Foster, Microb. Pathogen. 1:125-138, 1986). A double Spa- Hly- mutant was constructed by transduction. The virulence of Spa- and Hly- mutants was tested by experimental infection of mice. When subcutaneous injections were given, Hly- mutants formed a flat, darkened lesion, whereas Hly+ strains caused a raised, cream lesion. Alpha-toxin was shown to be a major factor in forming subcutaneous lesions and in causing the death of mice injected intraperitoneally. Spa- mutants were slightly less virulent than their Spa+ counterparts, which suggests that protein A is also a virulence factor of S. aureus.     

Conservation of receptor antagonist anti-tumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed

Recombinant protein production in plants such as corn is a promising means to generate high product yields at low comparable production cost. The anti-EGFR monoclonal antibody C225, cetuximab, is a well-characterized receptor antagonist antibody recently approved for the treatment of refractory colorectal cancer. We initiated a study to test and compare the functional activity of glycosylated and aglycosylated C225 produced in stable transgenic corn seed. Both corn antibodies were shown to be functionally indistinguishable from mammalian-derived C225 in demonstrating high-affinity binding to the EGF receptor, blocking of ligand-dependent signaling, and inhibiting cell proliferation. In addition, consistent with cetuximab, both corn antibodies possessed strong anti-tumor activity in vivo. Acute dose primate pharmacokinetic studies, however, revealed a marked increase in clearance for the glycosylated corn antibody, while the aglycosylated antibody possessed in vivo kinetics similar to cetuximab. This experimentation established that corn-derived receptor blocking monoclonal antibodies possess comparable efficacy to mammalian cell culture-derived antibody, and offer a cost effective alternative to large-scale mammalian cell culture production.     

Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus

A quantitative autoradiographic histological study was carried out to examine mechanisms underlying the reduction in the rates of growth and of cell acquisition, including that of granule cells, in the dentate gyrus of hypothyroid rats. Thyroid deficiency in early life had no effect on the replication of intrinsic cells present in the polymorph and granular layers. The pyknotic index was also normal in the "proliferative zone", polymorph layer and granule cell layer, indicating that thyroid hormone had no effect on the survival of replicating, migrating or maturing granule cells. By contrast, the arrival of migrating cells from the "proliferative zone" to the granular layer was severely retarded in thyroid deficiency. This deficit was rapidly restored after a physiological dose of thyroxine given to hypothyroid rats. The present findings are consistent with our previous proposal that the role of thyroid hormone in the formation and/or the maintenance of nerve cells is related to changes in either cell migration or maturation, rather than to alterations in the replication of germinal cells.     

Pediatric circulatory support systems

Ventricular assist devices (VADs) are a valid option for long term circulatory support in pediatric patients with postoperative myocardial failure or debilitating heart defects. Most clinical experience to date has involved the short-term support of patients weighing 6 kg and larger. For cases of VAD implementation in pediatric patients, the assist device showed tremendous promise in reversing cardiac failure and providing adequate support as a bridge to cardiac transplantation. The Medos-HIA system, Berlin Heart, Medtronic Bio-Medicus Pump, Abiomed BVS 5000, Toyobo-Zeon pumps, and Hemopumps have proven successful for short-term circulatory support for the pediatric population. The Jarvik 2000 and Pierce-Donachy pediatric system further demonstrate the potential to be used for pediatric circulatory support. The clinical and experimental success of these support systems provide encouragement to believe that long-term support is possible.