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Background: Little is known about the long-term outcome of airflow obstruction in asthma of patients with Churg–Strauss syndrome (CSS). Methods: We conducted a retrospective study of 24 consecutive patients (aged 41.1 ± 13.5 years) with CSS in a single center. All had asthma (starting 8.1 ± 9.5 years prior to the diagnosis of CSS), blood eosinophilia (6.1 ± 4.4 × 109/l) and systemic manifestations of CSS. Antineutrophil cytoplasmic antibodies were found in 7 of 22 tested patients. Seven patients had smoked (a mean of 10 pack-years). All patients received oral corticosteroids, 11 cyclophosphamide and 23 inhaled corticosteroids. Results: Airflow obstruction was found in 14 patients (70%) at diagnosis, and in 11 of 22 patients (50%) at the time of the clinical remission of CSS. The mean postbronchodilator FEV1/FVC and FEV1 were 69 ± 12% and 74 ± 21% of predicted at diagnosis ( n = 20); 71 ± 10% and 92 ± 19% of predicted at the clinical remission ( n = 22); and 64 ± 13% and 80 ± 21% at last visit ( n = 13), respectively. During follow-up, postbronchodilator FEV1 increased by 30 ± 28% in six patients with FEV1/FVC < 70% despite inhaled therapy who received higher dose of oral corticosteroids. At last visit, 5 of 13 patients (38%) with more than 3 years of follow-up had persistent airflow obstruction as defined by postbronchodilator FEV1/FVC < 70% and FEV1 < 80% of predicted. Conclusion: Airflow obstruction due to uncontrolled asthma is present despite corticosteroids in many patients at diagnosis and at clinical remission of CSS, and during follow-up. It may be still partly reversible with increased oral corticosteroid treatment. [ABSTRACT FROM AUTHOR]

Eosinophilic pneumonias (EP) encompass a wide spectrum of lung diseases characterized by peripheral blood eosinophilia (>1 × 109 eosinophils/l) and/or alveolar eosinophilia (>25%). Blood eosinophilia may be lacking, as in the early phase of idiopathic acute EP, or in patients already taking oral corticosteroids. EP may present with varying severity, ranging from almost asymptomatic infiltrates to the acute respiratory distress syndrome necessitating mechanical ventilation. Possible causes of EP must be thoroughly investigated, especially drugs and the variety of parasitic infections (considering history of travel or residence in areas of endemic parasitic infection). However, chronic EP remains idiopathic in many cases. When present, extrathoracic manifestations lead to suspect Churg–Strauss syndrome (CSS) or the hypereosinophilic syndrome (HES), the prognosis of which is dominated by cardiac involvement. Apart from the treatment of specific causes when possible, corticosteroids remain the cornerstone of symptomatic treatment for eosinophilic disorders, usually with a dramatic response, but frequent relapses when tapering or after stopping the treatment. The adjunction of immunosuppressants to corticosteroids is necessary in patients with CSS and poor prognosis factors. Imatinib has recently proven effective in the treatment of the myeloproliferative variant of the HES. [ABSTRACT FROM AUTHOR]

Chalabreysse L, Etienne-Mastroianni B, Adeleine P, Cordier J-F, Greenland T & Thivolet-Bejui F (2004) Histopathology 44, 367–374 Thymic carcinoma: a clinicopathological and immunohistological study of 19 cases To study 19 cases of primary thymic carcinoma in order to define the clinicopathological features and the precise histochemical profile of this rare and heterogeneous group of tumours of the anterior mediastinum. The study group consisted of 13 males and six females, with a mean age of 58.5 years (range 29–75 years). Superior vena cava syndrome and chest pain were the main presenting symptoms. Three patients were asymptomatic. No patient had myasthenia gravis. Six different histological types were identified: neuroendocrine tumours (six patients), epidermoid carcinoma (five patients), sarcomatoid carcinoma (three patients), lymphoepithelioma-like carcinoma (two patients), mucoepidermoid carcinoma, clear cell carcinoma, and undifferentiated carcinoma (one patient each). The clear cell carcinoma was associated with a thymic cyst. No association with thymoma was observed. Surgical resection, performed in 10 cases, was complete in two. Sixteen patients received thoracic radiation, and 11 received systemic chemotherapy. Follow-up information was available in 16 cases; 12 patients presented with local or metastatic relapse, and 10 patients died of their tumour. The overall 5-year survival was 14.5%. Primary thymic carcinoma is a very heterogeneous group of tumours of the anterior mediastinum with an aggressive clinical behaviour, and a poor overall prognosis. [ABSTRACT FROM AUTHOR]

The article discusses a study on T-cell clonality expansion in patients with eosinophilic lung disease. The study utilized monoclonal antibodies and flow cytometry to analyze T-cell expression. It states that the study is limited to the heterogeneity and small sample size of patients. Results showed that T cells with clonal T-cell receptor (TCR)-&x#03B3; rearrangements exist in patients with eosinophilic lung disease.

Discusses the Churg-Strauss syndrome (CSS), a rare systemic vasculitis which comprise of asthma, allergic rhinitis, pulmonary and systemic small-vessel vasculitis and extravascular granulomas. Pathology; Clinical features; Diagnostic criteria; Pathogenesis; Treatment and prognosis; Importance of distinguishing CSS from other systemic vasculitides.

Introduction: Diastolic dyssynchrony has correlated with pulmonary capillary wedge pressures in patients with normal cardiac anatomy. No data exist in single right ventricle (sRV) patients. Goal of this study was to determine if diastolic dyssynchrony in sRV patients correlates with ventricular end-diastolic pressures (VEDP)., Methods: Tissue Doppler imaging (TDI) and strain rate (SR) analysis of sRV patients undergoing catheterization were performed. Time interval from onset of QRS to peak TDI e'-wave was obtained. Differences in intervals were calculated: QRS (RV) - QRS (IVS) and QRS (RV) - QRS (LV). Time interval from onset of QRS to peak strain rate early diastolic wave (SRe) was obtained for the 6 segment model sRV. Standard deviation of the 6 SRe time intervals was calculated. Correlation of VEDP with timing intervals was analyzed., Results: Forty sRV patients were evaluated. Age was 2.8 ± 3.5 years. Catheterization VEDP of the sRV was 9.3 ± 3.9 mmHg (median 8 mmHg range 4-24 mmHg). QRS (RV) - QRS (IVS) was 22.3 ± 18.1 msec and QRS (RV) - QRS (LV) was 23.7 ± 19.0 msec. SRe standard deviation of the sRV was 61.6 ± 23.9 msec. There was no significant correlation with VEDP and QRS (RV) - QRS (IVS) (r = 0.1, P = NS) or with QRS (RV) - QRS (LV) (r = 0.2, P = NS). There was a significant correlation of VEDP with the SRe standard deviation value (r = 0.4, P < 0.05)., Conclusion: Diastolic dyssynchrony correlated with VEDP in patients with sRV physiology. Future studies are needed to determine the significance of these findings., (© 2013, Wiley Periodicals, Inc.)

Sphingosine-1-phosphate (S1P) is a potent and pleiotropic bioactive lysophospholipid mostly released by activated platelets that acts on its target cells through its own G protein-coupled receptors. We have previously reported that mouse striatal astrocytes expressed mRNAs for S1P1 and S1P3 receptors and proliferate in response to S1P. Here, we investigated the effect of S1P on gap junctions. We show that a short-term exposure of astrocytes to S1P causes a robust inhibition of gap junctional communication, as demonstrated by dye coupling experiments and double voltage-clamp recordings of junctional currents. The inhibitory effect of S1P on dye coupling involves the activation of both Gi and Rho GTPases. Rho-associated kinase (ROCK) also plays a critical role. The capacity of S1P to activate a Rho/ROCK axis in astrocytes is demonstrated by the typical remodeling of actin cytoskeleton. Connexin43, the protein forming gap junction channels, is a target of the Gi- and Rho/ROCK-mediated signaling cascades. Indeed, as shown by Western blots and confocal immunofluorescence, its nonphosphorylated form increases following S1P treatment and this change does not occur when both cascades are disrupted. This novel effect of S1P may have an important physiopathological significance when considering the proposed roles for astrocyte gap junctions on neuronal survival.

Sphingosine-1-phosphate (S1P) is a potent lysophospholipid mediator mostly released by activated platelets. It is involved in several functions in peripheral tissues, but its effects in the central nervous system are poorly documented. Therefore, we have examined the effects of S1P on the proliferation of striatal astrocytes from the mouse embryo. These cells have been found to express mRNAs for the S1P receptors, Edg-1 and Edg-3. S1P stimulated thymidine incorporation and induced activation of extracellular signal-regulated kinases (Erks). Both effects were prevented by U0126, an Erk kinase inhibitor. The S1P-evoked activation of Erk1 was totally blocked in astrocytes pretreated with a combination of either phorbol ester (24 h) and LY294002, or phorbol ester (24 h) and pertussis toxin (PTX). Each individual treatment only partially inhibited Erk1 activation. This suggests that several separate mechanisms mediate this process, one involving protein kinase C and another involving Gi/Go proteins and phosphatidylinositol 3-kinase. In contrast, the stimulatory effect of S1P on astrocyte proliferation was totally blocked by either PTX or LY294002, but not by a downregulation of protein kinase C. S1P dramatically inhibited the evoked production of cyclic AMP, a response that was impaired by PTX. Finally, S1P stimulated the production of inositol phosphates and increased intracellular calcium by mobilization from thapsigargin-sensitive stores. These latter effects were mainly insensitive to PTX. Probably, Gi/Go protein activation and phosphoinositide hydrolysis are early events that regulate the activation of Erks by S1P. Altogether, these observations show that astrocytes are targets for S1P. Their proliferation in response to S1P could have physiopathological consequences at sites of brain lesions and alterations of the blood-brain barrier.

Sphingosine-1-phosphate (S1P) is a potent lysophospholipid mediator mostly released by activated platelets. It is involved in several functions in peripheral tissues, but its effects in the central nervous system are poorly documented. Therefore, we have examined the effects of S1P on the proliferation of striatal astrocytes from the mouse embryo. These cells have been found to express mRNAs for the S1P receptors, Edg-1 and Edg-3. S1P stimulated thymidine incorporation and induced activation of extracellular signal-regulated kinases (Erks). Both effects were prevented by U0126, an Erk kinase inhibitor. The S1P-evoked activation of Erk1 was totally blocked in astrocytes pretreated with a combination of either phorbol ester (24 h) and LY294002, or phorbol ester (24 h) and pertussis toxin (PTX). Each individual treatment only partially inhibited Erk1 activation. This suggests that several separate mechanisms mediate this process, one involving protein kinase C and another involving Gi/Go proteins and phosphatidylinositol 3-kinase. In contrast, the stimulatory effect of S1P on astrocyte proliferation was totally blocked by either PTX or LY294002, but not by a downregulation of protein kinase C. S1P dramatically inhibited the evoked production of cyclic AMP, a response that was impaired by PTX. Finally, S1P stimulated the production of inositol phosphates and increased intracellular calcium by mobilization from thapsigargin-sensitive stores. These latter effects were mainly insensitive to PTX. Probably, Gi/Go protein activation and phosphoinositide hydrolysis are early events that regulate the activation of Erks by S1P. Altogether, these observations show that astrocytes are targets for S1P. Their proliferation in response to S1P could have physiopathological consequences at sites of brain lesions and alterations of the blood-brain barrier.

The effects of anandamide and the cannabinoid receptor agonists WIN 55212-2 and CP 55940 on the evoked formation of cyclic AMP were compared in cultured neurons and astrocytes from the cerebral cortex and striatum of mouse embryos. The three compounds inhibited the isoproterenol-induced accumulation of cyclic AMP in neuronal cells, and these responses were blocked by the selective CB1 receptor antagonist SR 141716A. The three agonists were more potent in cortical than striatal neurons. Interestingly, WIN 55212-2, CP 55940 and anandamide also inhibited the isoproterenol-evoked accumulation of cyclic AMP in astrocytes but, in contrast to WIN 55212-2 and CP 55940, anandamide was much more potent in striatal than cortical astrocytes. Inhibition was prevented by pertussis toxin pretreatment, but not blocked by SR 141716A. Therefore, G-protein-coupled receptors, distinct from CB1 receptors, are involved in these astrocytic responses. Moreover, specific binding sites for [3H]-SR 141716A were found in neurons but not astrocytes. Furthermore, using a polyclonal CB1 receptor antibody, staining was observed in striatal and cortical neurons, but not in striatal and cortical astrocytes. Taken together, these results suggest that glial cells possess G-protein-coupled receptors activated by cannabinoids distinct from the neuronal CB1 receptor, and that glial cells responses must be taken into account when assessing central effects of cannabinoids.

Objective: To investigate the effectiveness and side effects of oral versus pulse cyclophosphamide (CYC) in combination with corticosteroids (CS) in the treatment of systemic Wegener's granulomatosis (WG)., Methods: Patients with newly diagnosed systemic WG were enrolled in a prospective, randomized trial. At the time of diagnosis, prior to randomization, every patient received a daily injection of methylprednisolone for 3 days, followed by daily oral prednisone (1 mg/kg/day) and a 0.7-gm/m2 pulse of CYC. Patients were then randomly assigned to receive either prednisone plus intravenous pulse CYC (group A) or prednisone plus oral CYC (group B) as first-line treatment. CYC was given for at least 1 year and was then progressively tapered and discontinued., Results: Fifty patients were included in the study: 27 in group A and 23 in group B. At 6 months, 24 group A patients (88.9%) were in remission, versus 18 group B patients (78.3%). At the end of the trial, 18 group A patients (66.7%) and 13 group B patients (56.5%) were in remission. In group A, 66.7% of the patients experienced side effects, versus 69.6% in group B. Infectious side effects were significantly more frequent in group B (69.6%) than in group A (40.7%) (P < 0.05). The incidence of Pneumocystis carinii pneumonia was higher in oral CYC-treated patients (30.4%) than in pulse CYC-treated patients (11.1%). Nine group A patients (33.3%) and 10 group B patients (43.5%) died. Actuarial curves showed that relapses were significantly more frequent in group A (59.2%) than in group B (13%) (P = 0.02)., Conclusion: Our results indicate that pulse CYC is as effective as oral CYC in achieving initial remission of WG and is associated with fewer side effects and lower mortality. However, in the long term, treatment with pulse CYC does not maintain remission or prevent relapses as well as oral CYC.

The present study investigates the roles of protein kinase C (PKC) and A (PKA) activities in NMDA-mediated Ca2+ entry in primary cultures of mouse striatal neurons. Inhibitors of protein kinases, such as sphingosine, RO 31-8220 and staurosporine inhibited the NMDA- but also the KCl-induced rise in cytosolic Ca2+. However, the PKA antagonist Rp-adenosine-3',5'monophosphothioate (Rp-cAMPS) did not alter the NMDA+D-serine response, whereas it completely suppressed the KCl response. The NMDA+D-serine-evoked rise in cytosolic Ca2+, observed in the absence of external Mg2+, was potentiated by the PKC activator phorbol 12-myristate 13-acetate (PMA) only when submaximal effective concentrations of this agonist and co-agonist were used. In addition, the PKC activator did not alter the NMDA+D-serine-evoked response in the presence of varying concentrations of Mg2+. Confirming the dependence on PKC activity, desensitization of PKC resulting from long-term PMA treatment led to an impairment of the NMDA response, leaving the KCl-induced response intact. We therefore propose that PKC not only potentiates but is also required for the NMDA-evoked elevation in cytosolic Ca2+ in mouse striatal neurons.

In striatal astrocytes, receptors for the vasoactive peptide endothelin (ET) are associated with several intracellular signalling pathways: ET-1 increases the breakdown of phosphoinositides, induces a sustained influx of Ca2+ and inhibits the isoproterenol-induced formation of cAMP (Marin et al., J. Neurochem., 56, 1270 - 1275, 1991). In the present study, it will be shown that ET-1 and ET-3 markedly stimulate the release of arachidonic acid (AA) from cultured astrocytes from the mouse striatum (EC50=3 and 7 nM for ET-1 and ET-3, respectively), mesencephalon and cerebral cortex. The ET-1-evoked release of AA probably resulted from the activation of a phospholipase A2, since it required extracellular Ca2+ and was prevented by mepacrine but not by RHC 80267, an inhibitor of diacylglycerol lipase. The ET-1-induced release of AA was shown to be partially mediated by a guanine nucleotide-binding protein sensitive to pertussis toxin but not to cholera toxin. A cAMP-dependent process is not involved since the ET-1-evoked release of AA was not affected when cells were incubated with either isoproterenol or 8-bromo-cAMP. The ET-1-evoked release of AA could be mimicked by the co-application of a calcium ionophore and a protein kinase C activator. However, staurosporine, a potent inhibitor of protein kinase C, which blocked the release of AA induced by the combined application of ionomycin and phorbol 12-myristate 12-acetate (PMA), was without effect on the ET-1-evoked response, indicating that protein kinase C is not directly involved in the ET-1-induced release of AA. Furthermore, the responses induced by ET-1 and by PMA were found to be additive. These results suggest that (1) ET-1 receptors are coupled to the release of AA by a mechanism independent of both protein kinase C activation and the adenylate cyclase pathway, possibly via the activation of phospholipase A2, (2) different mechanisms (or different phospholipase A2 subtypes) are involved in the control of AA release in astrocytes.

Endothelins, a family of potent vasoconstrictor peptides initially characterized in peripheral tissues, have also been reported to be synthesized in the brain. In this structure several cell types, including astrocytes, endothelial cells and certain neurons, are potential targets for these peptides. In astrocytes, endothelins induce changes in the concentration of several second messengers (calcium, diacylglycerol, arachidonic acid, cAMP) known to be involved in the regulation of gap junction channels. Using the scrape loading/dye transfer technique we have observed that two isoforms of endothelin, endothelin-1 and endothelin-3, strongly inhibit the extent of dye-coupling between confluent astrocytes, suggesting that gap junction permeability was reduced. This inhibitory effect on dye coupling was reproduced by the snake venom sarafotoxin. When used at 10-7 M, these three compounds had inhibitory effects on gap junction channels which were comparable to those induced by the well known uncoupling agents octanol and halothane. In the absence of extracellular calcium, the effects of endothelins were largely prevented, suggesting that second messengers linked to the activation of phospholipases C and/or A2, which both are dependent on external calcium, could be involved in the uncoupling mechanism.

Adenosine has a broad array of actions on neurons but astrocytes also possess adenosine receptors. We have previously shown that adenosine, by acting on astrocytes in the striatum, can modulate neuronal responses mediated by receptors coupled to phospholipase C through an astrocyto - neuronal interaction. In addition, adenosine was found to potentiate the alpha1-adrenergic production of inositol phosphates in astrocytes. The mechanism involved in this potentiation was further investigated by examining the effects of adenosine and alpha1-adrenergic receptor agonists on cytosolic Ca2+ in cultured striatal astrocytes from the embryonic mouse in primary culture. When used alone, methoxamine, a selective agonist of alpha-adrenergic receptors or 2-chloroadenosine, a stable analogue of adenosine, induced a transitory increase in cytosolic Ca2+, but their combined addition led to a sustained increase in cytosolic Ca2+, which seems to be due to a Ca2+ influx, because it was not observed in the absence of external Ca2+. Voltage independent Ca2+ channels contribute to this process and different blockers of voltage-operated calcium channels, such as dihydropyridines, phenylalkylamines, La3+ or Co2+ were ineffective in suppressing the sustained cytosolic Ca2+ elevation. Three observations suggest the implication of arachidonic acid in the observed potentiation: (i) arachidonic acid induced a sustained elevation of cytosolic Ca2+ similar to that evoked by the coapplication of methoxamine and 2-chloroadenosine; (ii) the addition of arachidonic acid during the calcic plateau produced by the combined application of the agonists did not increase further cytosolic Ca2+ levels; (iii) in the presence of methoxamine, 2-chloroadenosine induced a release of arachidonic acid. The stimulation of phospholipase C and the resulting activation of protein kinase C induced by methoxamine seem to be required for the potentiating effect of 2-chloroadenosine on cytosolic Ca2+. In fact, the direct activation of protein kinase C by an exogenous diacylglycerol analogue mimicked the effect of methoxamine because, in this condition, 2-chloroadenosine alone evoked a sustained elevation of cytosolic Ca2+. Therefore, methoxamine, through the successive activation of phospholipase C and protein kinase C, could allow a lipase, probably phospholipase A2, to be stimulated by 2-chloroadenosine. Arachidonic acid has already been shown to trigger the opening of K+ channels and the formation of inositol phosphates in other cell types. Therefore, in striatal astrocytes, 2-chloroadenosine, through an arachidonic acid-mediated hyperpolarization, could increase the Ca2+ driving force and thus improve Ca2+ influx through inositol phosphate-gated channels. This hypothesis is further supported by the suppressing effect of a 50 mM KCI-induced depolarization on the long lasting elevation of cytosolic Ca2+ seen in the combined presence of 2-chloroadenosine and methoxamine.

Using primary neuronal or astrocyte cultures from the striatum of the embryonic mouse, we have observed that the beta-adrenergic agonist isoprenaline (10-5 M) induced a more pronounced accumulation of cAMP in astrocytes than in neurons. In both cell types, the alpha-adrenergic selective agonist methoxamine (10-4 M), which alone did not affect the production of cAMP, potentiated the isoprenaline-evoked response. In support of these observations, when associated alpha2-noradrenergic and D1-dopaminergic responses were prevented, the mixed alpha1- and beta-adrenergic agonist noradrenaline (10-5 M) induced a production of cAMP which was totally blocked by propranolol (10-6 M) and partially abolished by prazosin (10-6 M). Since experiments were made in the presence of 3-isobutyl-1-methylxanthine (1 mM), the observed effects of cAMP accumulation were not related to a modulation of phosphodiesterase activities. In addition, both in astrocytes and in neurons, the potentiation by alpha1-adrenergic agonists of the beta-adrenergic-evoked response required external calcium. Using INDo 1 as a fluorescent probe, methoxamine (25 microM) was shown to induce in astrocytes an increase in cytosolic calcium concentration which was prolonged by isoprenaline (10-5 M) only in the presence of external calcium. These results suggest that the prolonged increase in cytosolic calcium concentration linked to the activation of alpha1- and beta-adrenergic receptors is responsible for the potentiation of the beta-adrenergic-induced production of cAMP, which is partially dependent on external calcium.

Embryonic striatal neurons from the mouse grown in primary culture (6 day old culture) were used in order to investigate the effects of 17-beta oestradiol (17-beta E2) on biogenic amine-sensitive adenylate cyclases. Pretreatment (28 h) of intact cells with 17-beta E2 (10-9 M) enhanced cyclic AMP production induced by either dopamine, isoproterenol, serotonin, or 2-chloro-adenosine (maximal effective concentrations). These effects of 17-beta E2 on biogenic amine-sensitive adenylate cyclases occurred after several hours (8 h at least) and were seen in most cases with a concentration as low as 10-11 M (EC50: 10-10 M). They were additive with those induced by phenol red (5.6 microg/l) and chemically specific since 17alpha-oestradiol, 2(OH)17-beta E2, progesterone, and dexamethasone were without effect. In addition, they were not seen in cells which had been pretreated (30 h) with cycloheximide or alpha-amanitin, suggesting an involvement of de novo protein synthesis. Since 17-beta E2 did not influence cyclic AMP production induced by either forskolin or manganese ions, the stimulatory effects of 17-beta E2 pretreatment on biogenic amine-sensitive adenylate cyclases were not linked to an increase in the amount of enzyme catalytic units. 17-beta E2 pretreatment enhanced twofold the number of beta-adrenergic receptors (as estimated by the specific binding of (125I)iodocyanopindolol) but did not, in contrast, affect either the number or the affinity of dopaminergic receptors (as estimated by (125I)SCH 23982 binding). Therefore, the enhancing effects of 17-beta E2 pretreatment on biogenic amine-sensitive adenylate cyclases could be related either to an increased number of coupled receptors or to modifications of the adenylate cyclase transducing system (occurring probably at the G-protein level) or to a combination of the two.