Long-term safety and efficacy of daclizumab beta in relapsing-remitting multiple sclerosis: 6-year results from the SELECTED open-label extension study.

Objective: SELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the randomized SELECT/SELECTION studies. We report final results of SELECTED.

Methods: Eligible participants who completed 1-2 years of daclizumab beta treatment in SELECT/SELECTION received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 6 years in SELECTED.

Circulating lymphocyte levels and relationship with infection status in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta.

Background: Reversible lymphocyte count reductions have occurred following daclizumab beta treatment for relapsing-remitting multiple sclerosis.

Objective: To analyse total and differential lymphocyte levels and relationship with infection status.

Methods: In DECIDE, blood samples were collected at 12-week intervals from daclizumab beta- ( n = 919) or intramuscular interferon beta-1a-treated ( n = 922) patients.

No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study.

Background: No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS).

Objective: Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 µg for 96-144 weeks.

Methods: NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd) lesions.

The translational repressor T-cell intracellular antigen-1 (TIA-1) is a key modulator of Th2 and Th17 responses driving pulmonary inflammation induced by exposure to house dust mite.

T-cell intracellular antigen-1 (TIA-1) is a translational repressor that dampens the production of proinflammatory cytokines and enzymes. In this study we investigated the role of TIA-1 in a mouse model of pulmonary inflammation induced by exposure to the allergenic extract (Df) of the house dust mite Dermatophagoides farinae. When intranasally challenged with a low dose of Df, mice lacking TIA-1 protein (Tia-1(-/-)) showed more severe airway and tissue eosinophilia, infiltration of lung bronchovascular bundles, and goblet cell metaplasia than wild-type littermates.

The purinergic G protein-coupled receptor 6 inhibits effector T cell activation in allergic pulmonary inflammation.

We show that the P2Y(6) receptor, a purinergic G protein-coupled receptor with a high affinity for the nucleotide uridine diphosphate, is an important endogenous inhibitor of T cell function in allergic pulmonary inflammation. Mice conditionally deficient in P2Y(6) receptors [p2ry6 (flox/flox);cre/+ mice] exhibited severe airway and tissue pathology relative to P2Y(6)-sufficient [p2ry6 (flox/flox)] littermates (+/+ mice) when treated intranasally with an extract of the dust mite Dermatophagoides farinae (Df). P2Y(6) receptors were inducibly expressed by lung, lymph node, and splenic CD4(+) and CD8(+) T cells of Df-treated +/+ mice.

Group V secretory phospholipase A2 reveals its role in house dust mite-induced allergic pulmonary inflammation by regulation of dendritic cell function.

We have previously shown that group V secretory phospholipase A(2) (sPLA(2)) regulates phagocytosis of zymosan and Candida albicans by a mechanism that depends on fusion of phagosomes with late endosomes in macrophages. In this study, we report that group V sPLA(2) (Pla2g5)-null mice exposed to an extract of house dust mite Dermatophagoides farinae had markedly reduced pulmonary inflammation and goblet cell metaplasia compared with wild-type (WT) mice. Pla2g5-null mice had also impaired Th2-type adaptive immune responses to D.

Fas-activated serine/threonine phosphoprotein promotes immune-mediated pulmonary inflammation.

We generated Fas-activated serine threonine phosphoprotein (FAST)-deficient mice (FAST(-/-)) to study the in vivo role of FAST in immune system function. In a model of house dust mite-induced allergic pulmonary inflammation, wild type mice develop a mixed cellular infiltrate composed of eosinophils, lymphocytes, and neutrophils. FAST(-/-) mice develop airway inflammation that is distinguished by the near absence of neutrophils.

Lung mast cells are a source of secreted phospholipases A2.

Background: Secreted phospholipases A(2) (sPLA(2)s) are released in plasma and other biologic fluids of patients with inflammatory, autoimmune, and allergic diseases.

Objective: We sought to evaluate sPLA(2) activity in the bronchoalveolar lavage fluid (BALF) of asthmatic patients and to examine the expression and release of sPLA(2)s from primary human lung mast cells (HLMCs).

Methods: sPLA(2) activity was measured in BALF and supernatants of either unstimulated or anti-IgE-activated HLMCs as hydrolysis of oleic acid from radiolabeled Escherichia coli membranes.

Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects.

Background: Angiogenesis and lymphangiogenesis are critical for several allergic, inflammatory, and neoplastic disorders. Mast cells infiltrate the sites of inflammation and tumors.

Objective: We sought to characterize the expression and functions of vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) in human mast cells.

Expression of phospholipases A2 in primary human lung macrophages: role of cytosolic phospholipase A2-alpha in arachidonic acid release and platelet activating factor synthesis.

Macrophages are a major source of lipid mediators in the human lung. Expression and contribution of cytosolic (cPLA(2)) and secreted phospholipases A(2) (sPLA(2)) to the generation of lipid mediators in human macrophages are unclear. We investigated the expression and role of different PLA(2)s in the production of lipid mediators in primary human lung macrophages.

Lysophospholipid transacetylase in the regulation of PAF levels in human monocytes and macrophages.

The transacetylase (TA), reported to be identical to platelet-activating factor (PAF) acetylhydrolase (II), is a multifunctional enzyme with three catalytic activities: lysophospholipid transacetylase (TA(L)), sphingosine transacetylase (TA(S)), and acetylhydrolase (AH). We report that TA(L) activity participates in the control of PAF levels in monocytes and macrophages and that its regulation differs in these two types of cells. In monocytes, LPS or granulocyte-macrophage colony-stimulating factor (GM-CSF) specifically increased the TA(L) activity.

Secretory phospholipases A2 in inflammatory and allergic diseases: not just enzymes.

Secretory phospholipases A(2) (sPLA(2)s) are molecules released in plasma and biologic fluids of patients with systemic inflammatory, autoimmune, and allergic diseases. Several sPLA(2) isoforms are expressed and released by such human inflammatory cells as neutrophils, eosinophils, basophils, T cells, monocytes, macrophages, and mast cells. Certain sPLA(2)s release arachidonic acid, thereby providing the substrate for the biosynthesis of proinflammatory eicosanoids.

Differential modulation of mediator release from human basophils and mast cells by mizolastine.

Background: Basophils and mast cells play a major role in the pathogenesis of allergic disorders by releasing several proinflammatory mediators. Some histamine H1 receptor antagonists exert anti-inflammatory activities by modulating mediator release from basophils and mast cells.

Objective: To study the in vitro effects of mizolastine, an H1 receptor antagonist, on the release of eicosanoids, histamine and IL-4 from human basophils and lung mast cells.

Lung involvement in rheumatoid arthritis.

RA is a systemic autoimmune disorder primarily involving the joints. Extra-articular manifestations of RA often include lung involvement with heterogeneous clinical presentation and radiological findings. Autopsy studies reveal that the percentage of RA patients with pathological changes in the lung is significantly higher than that of patients with clinical manifestations.

Secretory phospholipases A2 as multivalent mediators of inflammatory and allergic disorders.

Phospholipases A(2) (PLA(2)s) are enzymes responsible for mobilization of fatty acids, including arachidonic acid (AA), from phospholipids. These enzymes are classified as high-molecular-weight cytosolic PLA(2)s (cPLA(2)s) and low-molecular-weight secretory PLA(2)s (sPLA(2)s). There is increasing evidence that large quantities of sPLA(2)s are released in the plasma of patients with systemic inflammatory and autoimmune diseases.

Precocious puberty in a boy with a PRL-, LH- and FSH-secreting pituitary tumour: hormonal and immunocytochemical studies.

The case of a 7-year-old boy affected with precocious puberty and a large intra- and suprasellar pituitary tumour is described. He had hyperprolactinemia and elevated serum LH, FSH and testosterone concentrations. Pre-operative dynamic hormonal studies showed a rise of PRL, LH and FSH levels after TRH (200 micrograms iv) and a rise of LH and FSH after GnRH (100 micrograms iv).

Somatomammotrophic cells in GH-secreting and PRL-secreting human pituitary adenomas.

A morphological study has been carried out on 20 GH-secreting adenomas removed from acromegalic normoprolactinemic patients, on 29 PRL-secreting adenomas removed from hyperprolactinemic patients without signs of acromegaly and on one normal human anterior pituitary gland collected at autopsy. The protein A-gold immunoelectron microscopic technique has been utilized in order to verify the presence of mixed cells producing both GH and PRL (somatomammotrophs) in these pituitary tissues. In the normal pituitary a considerable number of somatomammotrophs (15-20%) was found, thus supporting the idea that these cells are normal components of the human anterior pituitary gland.

Growth hormone and prolactin secretion in acromegaly: correlations between hormonal dynamics and immunocytochemical findings.

A morphological study was carried out on pituitary adenomas removed from 13 normoprolactinemic and 9 hyperprolactinemic acromegalic patients whose hormonal dynamics had been carefully investigated. Double immunocytochemical labeling with the protein-A-gold electron microscopic technique was used to detect the presence of GH and PRL in the adenomas. Two morphological patterns were found; 11 adenomas contained cells positive only for GH, and 11 contained a variable proportion (from 10-98%) of cells positive for PRL.

Neural control of circulation before and after intravenous urapidil in essential hypertension.

Drugs interfering with sympathetic influences on the cardiovascular system have been shown to effectively lower blood pressure in hypertension. However, sympathetic cardiovascular control is involved in blood pressure homeostasis, which means that these drugs may produce potential adverse haemodynamic effects that may reduce the benefit of their antihypertensive action. This paper summarises the results of a study in which we examined the effects of urapidil on the arterial baroreflex and the cardiopulmonary reflex in 6 essential hypertensive patients given 25 mg of the drug intravenously.

Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas.

Gs and Gi are guanine nucleotide-binding, heterotrimer proteins that regulate the activity of adenylate cyclase, and are responsible for transferring stimulatory and inhibitory hormonal signals, respectively, from cell surface receptors to the enzyme catalytic unit. These proteins can be directly activated by agents such as GTP and analogues, fluoride and magnesium. Decreased amounts of Gs and Gi, and even the absence of Gs, have been described, whereas an altered Gs has been reported in a cultured cell line (UNC variant of S49 lymphoma cells), but has never been observed in human disease states.

Effect of calcium on adenylate cyclase of rat anterior pituitary gland.

The effect of free calcium (Ca2+) on adenylate cyclase (AC) activity of rat anterior pituitary gland have been investigated in order to shed some light on the interrelationships between the two second messengers (cAMP and calcium) which operate in pituitary cells. Anterior pituitary homogenates or crude membranes preparations (obtained using buffers free of divalent cation chelators) were assayed and the concentrations of Ca2+ in the assay mixture containing EGTA were calculated by a computer program for each addition of CaCl2. A wide range of Ca2+ concentrations (from 2 X 10(-9) to 6 X 10(-4)M) was spanned.

Morphological studies on mixed growth hormone (GH)- and prolactin (PRL)-secreting human pituitary adenomas. Coexistence of GH and PRL in the same secretory granule.

A morphological study was carried out on five mixed GH- and PRL-secreting pituitary adenomas, surgically removed from acromegalic patients with hyperprolactinemia, in order to verify whether the two hormones were contained in the same cell or in different cells. Double labeling with the protein A-gold immunotechnique was used to visualize the ultrastructural localization of the two hormones on ultrathin sections of the tumors. By means of this high resolution technique we found in all adenomas the presence of numerous (from 50-80% of the whole cell population) mammosomatotrophs, i.

Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity.

A 40-yr-old man who had acromegaly and hyperthyroidism due to a GH/TSH-secreting pituitary adenoma is described. Serum free T4 was 2.8 ng/dl, free T3 was 1.

Microvasculature of human micro- and macroprolactinomas. A morphological study.

A morphological study has been undertaken on the capillaries of 9 microprolactinomas and 9 macroprolactinomas, surgically removed from untreated patients. The study was carried out utilizing light and electron microscopic techniques and electron microscopic morphometry. The frequency of the capillaries and their structural appearance were taken into account.