Adenosine negatively regulates duodenal motility in mice: role of A(1) and A(2A) receptors.

BACKGROUND AND PURPOSE: Adenosine is considered to be an important modulator of intestinal motility. This study was undertaken to investigate the role of adenosine in the modulation of contractility in the mouse duodenum and to characterize the adenosine receptor subtypes involved. EXPERIMENTAL APPROACH: RT-PCR was used to investigate the expression of mRNA encoding for A(1), A(2A), A(2B) and A(3) receptors. Contractile activity was examined in vitro as changes in isometric tension. KEY RESULTS: In mouse duodenum, all four classes of adenosine receptors were expressed, with the A(2B) receptor subtype being confined to the mucosal layer. Adenosine caused relaxation of mouse longitudinal duodenal muscle; this was antagonized by the A(1) receptor antagonist and mimicked by N(6) -cyclopentyladenosine (CPA), selective A(1) agonist. The relaxation induced by A(1) receptor activation was insensitive to tetrodotoxin (TTX) or N(ω) -nitro-l-arginine methyl ester (l-NAME). Adenosine also inhibited cholinergic contractions evoked by neural stimulation, effect reversed by the A(1) receptor antagonist, but not myogenic contractions induced by carbachol. CPA and 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680), A(2A) receptor agonist, both inhibited the nerve-evoked cholinergic contractions. l-NAME prevented only the CGS-21680-induced effects. S-(4-Nitrobenzyl)-6-thioinosine, a nucleoside uptake inhibitor, reduced the amplitude of nerve-evoked cholinergic contractions, an effect reversed by an A(2A) receptor antagonist or l-NAME. CONCLUSIONS AND IMPLICATIONS: Adenosine can negatively regulate mouse duodenal motility either by activating A(1) inhibitory receptors located post-junctionally or controlling neurotransmitter release via A(1) or A(2A) receptors. Both receptors are available for pharmacological recruitment, even if only A(2A) receptors appear to be preferentially stimulated by endogenous adenosine.

Retinoblastoma epidemiology: does the evidence matter?

It has been proposed that retinoblastoma is 'caused' by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic alterations. Retinoblastoma remains probably the only cancer in which the rather simplistic 'two hit' mutational model is still considered of value, although cancer is known to be associated with genomic and microsatellite instability, defects of the DNA mismatch repair system, alterations of DNA methylation and hystone acethylation/deacethylation, and aneuploidy. Moreover, as it is shown herein, the predictions made by the 'two hit' model, are not fulfilled by the clinical and epidemiological data reported so far. Moreover, while the role of mutational events in cancer has been largely questioned in the more recent literature, no serious effort has been done to investigate the role of epigenetic alterations and aneuploidy in retinoblastoma. Through the analysis of the specialised literature and a set of original epidemiological and biological data concerning retinoblastoma, the authors illustrate the evidences arguing against the 'two hit' hypothesis and propose that epigenetic factors and aneuploidy play central roles in the disease.

[Neonatal vocal cord palsy. Clinical and therapeutical approaches]. / La paralisi delle corde vocali in età neonatale. Orientamenti clinici, chirurgici e contributo casistico.

Between 1998 and 2000, four newborns have been observed for laryngeal stridor occurred some hours after birth. Otorhinolaryngologic examinations, as well as cardiac, neuroradiologic and serologic investigations have been performed to formulate the diagnosis and verify the etiology. The fiberoptic laryngoscopy showed a bilateral paralysis of the vocal cord in two newborns, a monolateral paralysis of the left vocal cord in another and in the last one, instead, a bilateral cordal hypomobility. The follow-up performed till the age of one year showed a complete remission of the symptomatology in two newborns, respectively in the one with monolateral paralysis and in the other affected by hypomobility of the vocal cords; of the two newborns with bilateral paralysis, instead, one is dead because of Haemophilus Influenzae epiglottitis, three weeks after discharge without physicians' consensus, while in the other patient, affected by lobar holoprosencephaly, it was necessary to perform a tracheotomy because of a severe obstructive apnea. The lobar holoprosencephaly, is a cerebral malformation characterized by the partial separation of the cerebral hemispheres, and it is described for the first time associated with bilateral vocal cords paralysis.