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Fas-stimulated neutrophils from elderly individuals show impaired granulocyte macrophagecolony-stimulating factor (GM-CSF)-induced apoptosis cell rescue. Herein, this defect was found to be associated with a significant reduction in GM-CSF-mediated Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Using Akt and ERK1/2 inhibitors, we demonstrated that both kinases were critical for GM-CSF antiapoptotic effects. Whereas Akt inhibition also affected GM-CSF-dependent ERK1/2 phosphorylation, ERK1/2 inhibition did not affect GM-CSF-induced Akt phosphorylation, suggesting that phosphoinositide 3-kinase (PI3-K)/Akt and ERK1/2 are activated in series and that PI3-K is located upstream of ERK1/2 along the GM-CSF-dependent signaling pathway. No age-associated changes in GM-CSF receptor expression were observed. Interestingly, both suppressors of cytokine signaling (SOCS)1 and SOCS3 proteins were significantly higher in unstimulated neutrophils from elderly individuals and, unlike in young individuals, did not further increase following GM-CSF cell triggering. These results indicate that defective PI3-K/Akt/ERK1/2 activation, likely dependent on elevated SOCS1 and SOCS3 levels, may affect the GM-CSF capacity to delay neutrophil apoptosis in elderly persons.

Interleukin (IL)-12 is the major inducer of T helper cell (Th) 1-type responses. Despite a higher IL-12 production, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC), as well as CD[4.sup.+] or CD[8.sup.+] T cells from elderly donors released interferon (IFN)-[gamma] amounts similar to those observed in young controls, and underwent only a slight increase in IFN-[gamma] production after IL-12 costimulation. These findings were not due to an age-related reduction in IL-12 receptor expression. Interestingly, no difference in PHA-triggered signal transducer and activator of transcription 4 (STAT4) phosphorylation between young and elderly donors was found, and a significant IL-12-induced STAT4 activation occurred only in PHA-preactivated cells from the younger group. The age-related defect in IL-12 signaling was STAT4-restricted as it did not involve the p38 mitogen-activated protein kinase (MAPK) pathway. Finally, suppressor of cytokine signaling 3 (SOCS3) expression was significantly higher in unstimulated cells from elderly individuals, and it did not diminish after cell stimulation. These results indicate that a defective STAT4 activation, likely dependent on elevated SOCS3 levels, is involved in the impaired IL-12-dependent T-cell functions with aging.

N -Quaternized ketene N , O -acetals are typically an unstable, transient class of compounds most commonly observed as reactive intermediates. In this report, we describe a general synthetic approach to a variety of bench-stable N -quaternized ketene N , O -acetals via treatment of pyridine or aniline bases with acetylenic ethers and an appropriate Brønsted or Lewis acid (triflic acid, triflimide, or scandium(III) triflate). The resulting pyridinium and anilinium salts can be used as reagents or synthetic intermediates in multiple reaction types. For example, N -(1-ethoxyvinyl)pyridinium or anilinium salts can thermally release highly reactive O -ethyl ketenium ions for use in acid catalyst-free electrophilic aromatic substitutions. N -(1-Ethoxyvinyl)-2-halopyridinium salts can be employed in peptide couplings as a derivative of Mukaiyama reagents or react with amines in nucleophilic aromatic substitutions under mild conditions. These preliminary reactions illustrate the broad potential of these currently understudied compounds in organic synthesis.

A 69-year-old male was admitted to our Division because of repeated episodes of transient loss of consciousness and minimal cognitive and behavioural disturbances. Brain CT showed Fahr-type bilateral calcifications. Laboratory findings showed a phospho-calcium metabolism disorder consistent with the diagnosis of pseudohypoparathyroidism, whose correction led to a significant clinical improvement. This is the first case of Fahr's syndrome associated with syncope-type episodes. This observation suggests that a brain CT, as well as the search for a dysparathyroidism condition, should always carried out in all patients with unexplained recurrent episodes of loss of consciousness.

The coexistence of non-organ specific autoantibodies and chronic hepatitis C features raises the dilemma as to whether the pathogenesis is viral or autoimmune and consequently to be treated with interferon or corticosteroids. Two cases with autoimmune characteristics and chronic hepatitis C are reported. We discuss the possibility of classifying this overlap form in three distinct entities: viral disease with an autoimmune epiphenomenon ("false hepatitis C/autoimmune hepatitis overlap syndrome"), viral disease associated to an autoimmune pathogenic component ("true hepatitis C/autoimmune hepatitis overlap syndrome") and false serological anti-HCV positivity in classical autoimmune hepatitis. In our experience the interferon/corticosteroid association was successful.