Genetic alterations of Carney complex are not present in sporadic cardiac myxomas.

Cardiac myxomas are the most frequent cardiac tumors and cause for significant morbidity and mortality. Recent evidence indicates that cardiac myxomas are, in fact, neoplasms rather than organized thrombi. Cardiac myxomas may present as solitary lesions or in association with the Carney complex. Carney complex has been linked to chromosome 2p16 and the PRKAR1A gene at 17q22-24. In this study, we analyzed sporadic cardiac myxomas to evaluate whether the genetic alterations seen in Carney complex are present in non Carney complex associated cardiac myxomas as well. We analyzed microdissected material from 13 patients with cardiac myxomas for the markers PRKAR1 9CA, D2S2153, D2S2251 and D2S123. None of the cases demonstrated loss of heterozygosity or definite band changes suggestive of microsatellite instability for any of the markers used. We conclude that sporadic cardiac myxomas are genetically not related to Carney complex and most likely do not represent an incomplete form of Carney complex.     

Effect of tetrodotoxin on cholinergic agonist-mediated colonic electrolyte transport

Muscarinic cholinergic agonists stimulate electrolyte secretion in the intestine; nicotinic agonists augment absorption. Recent studies in rabbit ileum suggest that nicotinic but not muscarinic agonists act via an intermediary neurotransmitter. These in vitro studies in rat colon were performed to determine whether tetrodotoxin (TTX), a potent neurotoxin, inhibits cholinergic agonist-induced changes in electrolyte transport. TTX did not significantly alter basal ion transport or the ion transport changes produced by either theophylline or bethanechol, a muscarinic agonist. At a concentration of 1 mM carbachol, a mixed muscarinic-nicotinic agonist, had no apparent effect on ion transport but in the presence of TTX significantly decreased net sodium absorption, similar to the effect produced by 1 microM carbachol alone. These results are consistent with the concept that in low concentrations carbachol acts predominantly as a muscarinic agonist; in high concentrations carbachol exhibits both muscarinic and nicotinic properties that are equivalent. We conclude that muscarinic agonists alter electrolyte transport by acting directly on the enterocyte and that nicotinic agonists act indirectly by stimulating the release of an intermediary neurotransmitter.     

Effects of SC-41930 on leukocyte adherence and emigration in rat mesenteric venules

This study demonstrates that SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, an orally active LTB₄ receptor antagonist, reduces LTB₄-induced leukocyte adhesion and emigration in rat mesenteric venules. The mesentery of Sprague-Dawley rats was prepared for intravital microscopic examination and venules of 25–35 m were chosen for evaluation. In control animals, LTB₄ (20nM) was superfused over the mesentery for 30 min. In the treatment group SC-41930 (5 M) was superfused for 30 min, followed by a 30 min superfusion with SC-41930 and LTB₄. The LTB₄-induced increase in leukocyte adherence and emigration in postcapillary venules was significantly attenuated by pretreatment with SC-41930. Other experiments demonstrated that platelet-activating-factor-induced leukocyte adherence was not affected by SC-41930. These results indicate that SC-41930 is a potent inhibitor of LTB₄-induced leukocyte-endothelial cell adhesive interactions in postcapillary venules.     

The categorical and dimensional models of endogenous depression

We calculated a Research Diagnostic Criteria (RDC) endogenous score for 257 depressed inpatients based on the number of endogenous criteria present. The distribution of RDC endogenous scores was unimodal. There was no association between endogenous scores and results of the Dexamethasone Suppression Test, or morbid risk for depression in the patients' first-degree relatives. The morbid risk for a family history of alcoholism tended to decrease with increasing endogenous scores, although a consistent steady decline was not observed. The results suggest that the RDC criteria do not fit either the categorical or dimensional model of endogenous classification. Potential sources of difficulty with the RDC endogenous criteria are discussed.     

Comorbid psychiatric disorders in depressed outpatients: demographic and clinical features

BACKGROUND: This study evaluated the clinical and sociodemographic features associated with various degrees of concurrent comorbidity in adult outpatients with nonpsychotic major depressive disorder (MDD). METHODS: Outpatients enrolled in the STAR*D trial completed the Psychiatric Diagnostic Screening Questionnaire (PDSQ). An a priori 90% specificity threshold was set for PDSQ responses to ascertain the presence of 11 different concurrent DSM-IV Axis I disorders. RESULTS: Of 1376 outpatients, 38.2% had no concurrent comorbidities, while 25.6% suffered one, 16.1% suffered two, and 20.2% suffered three or more comorbid conditions. Altogether, 29.3% met threshold for social anxiety disorder, 20.8% for generalized anxiety disorder, 18.8% for posttraumatic stress disorder, 12.4% for bulimia, 11.9% for alcohol abuse/dependence, 13.4% for obsessive-compulsive disorder, 11.1% for panic disorder, 9.4% for agoraphobia, 7.3% for drug abuse/dependence, 3.7% for hypochondriasis, and 2.2% for somatoform disorder. Those with more concurrent Axis I conditions had earlier ages at first onset of MDD, longer histories of MDD, greater depressive symptom severity, more general medical comorbidity (even though they were younger than those with fewer comorbid conditions), poorer physical and mental function, health perceptions, and life satisfaction; and were more likely to be seen in primary care settings. LIMITATIONS: Participants had to meet entry criteria for STAR*D. Ascertainment of comorbid conditions was not based on a structured interview. CONCLUSIONS: Concurrent Axis I conditions (most often anxiety disorders) are very common with MDD. Greater numbers of concurrent comorbid conditions were associated with increased severity, morbidity, and chronicity of their MDD.     

Primitive Neuroectodermal Tumors of the Central Nervous System

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.     

Sodium hypochlorite-, chlorine dioxide- and peracetic acid-induced genotoxicity detected by the Comet assay and Saccharomyces cerevisiae D7 tests

Mutagenicity of drinking water is due not only to industrial,agricultural and urban pollution but also to chlorine disinfectionby-products. Furthermore, residual disinfection is used to providea partial safeguard against low level contamination and bacterialre-growth within the distribution system. The aims of this studywere to further evaluate the genotoxic potential of the worldwide used disinfectants sodium hypochlorite and chlorine dioxidein human leukocytes by the Comet assay and in Saccharomycescerevisiae strain D7 (mitotic gene conversion, point mutationand mitochondrial DNA mutability, with and without endogenousmetabolic activation) and to compare their effects with thoseof peracetic acid, proposed as an alternative disinfectant.All three disinfectants are weakly genotoxic in human leukocytes(lowest effective dose 0.2 p.p.m. for chlorine dioxide, 0.5p.p.m. for sodium hypochlorite and peracetic acid). The resultsin S.cerevisiae show a genotoxic response on the end-pointsconsidered with an effect only at doses higher (5- to 10-fold)than the concentration normally used for water disinfection;sodium hypochlorite and peracetic acid are able to induce genotoxiceffects without endogenous metabolic activation (in stationaryphase cells) whereas chlorine dioxide is effective in growingcells. The Comet assay was more sensitive than the yeast tests,with effective doses in the range normally used for water disinfectionprocesses. The biological effectiveness of the three disinfectantson S.cerevisiae proved to be strictly dependent on cell-specificphysiological/biochemical conditions. All the compounds appearto act on the DNA and peracetic acid shows effectiveness similarto sodium hypochlorite and chlorine dioxide. ¹Author to whom correspondence should be addressed. Tel: +39 0521 905608; Fax: +39 0521 905604; Email: mutgen{at}unipr.it Received on September 22, 2003; revised and accepted on November 27, 2003     

Saccharomyces cerevisiae as an eukaryotic cell model to assess cytotoxicity and genotoxicity of three anticancer anthraquinones

The toxicity of most drugs is associated with their enzymatic conversion to toxic metabolites. Bioactivation reactions occur in a range of cellular organs and organelles, including mitochondria. We have investigated different effects (i.e. growth inhibition, mortality and genotoxicity) of doxorubicin, epirubicin and mitoxantrone on the D7 strain of Saccharomyces cerevisiae and on its petite (rho degrees ) respiratory-deficient mutant at various cellular concentrations of cytochrome P450 and glutathione (GSH). The data confirmed the importance of oxygen production for doxorubicin toxicity. The complete absence, or a very low level, of cytochrome oxidase subunit IV conferred some resistance to doxorubicin. Low GSH levels decreased resistance to doxorubicin in both strains, suggesting that thiol depletion could potentiate membrane lipid peroxidation. Doxorubicin induction of petite colonies suggests that the drug is able to select rather than induce respiratory-deficient mutants. Epirubicin induced levels of cytotoxicity similar to those of doxorubicin. The effects did not appear to be significantly dependent on mitochondrial function or GSH levels, whereas cells were strongly protected by cytochrome P450. GSH did not induce an evident alteration. Neither were genotoxic effects induced. Mitoxantrone had reduced levels of both growth inhibition and cytotoxicity in comparison to anthracyclines and induced convertants, revertants and aberrants. All the effects considered were amplified at high cytochrome P450 cellular concentrations, although the drug was also shown to act without previous metabolism via cytochrome P450. Anthracenedione effectiveness was increased by metabolism via cytochrome P450 and partially reduced by GSH. However, further mechanisms were suggested, which might implicate mitochondrial function and/or production of electrophilic cytotoxic and/or genotoxic intermediates by means of GSH conjugation. The biological effectiveness of doxorubicin, epirubicin and mitoxantrone on S.cerevisiae was shown to be strictly dependent on cell-specific physiological/biochemical conditions, such as a functional respiratory chain and levels of cytochrome P450 and GSH.