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1.  DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity 
Cell Death and Differentiation  2012;19(11):1741-1749.
DNA single-strand breaks (SSB) formation coordinates the myogenic program, and defects in SSB repair in post-mitotic cells have been associated with human diseases. However, the DNA damage response by SSB in terminally differentiated cells has not been explored yet. Here we show that mouse post-mitotic muscle cells accumulate SSB after alkylation damage, but they are extraordinarily resistant to the killing effects of a variety of SSB-inducers. We demonstrate that, upon SSB induction, phosphorylation of H2AX occurs in myotubes and is largely ataxia telangiectasia mutated (ATM)-dependent. However, the DNA damage signaling cascade downstream of ATM is defective as shown by lack of p53 increase and phosphorylation at serine 18 (human serine 15). The stabilization of p53 by nutlin-3 was ineffective in activating the cell death pathway, indicating that the resistance to SSB inducers is due to defective p53 downstream signaling. The induction of specific types of damage is required to activate the cell death program in myotubes. Besides the topoisomerase inhibitor doxorubicin known for its cardiotoxicity, we show that the mitochondria-specific inhibitor menadione is able to activate p53 and to kill effectively myotubes. Cell killing is p53-dependent as demonstrated by full protection of myotubes lacking p53, but there is a restriction of p53-activated genes. This new information may have important therapeutic implications in the prevention of muscle cell toxicity.
PMCID: PMC3469061  PMID: 22705848
DNA damage response; DNA repair; muscle cell differentiation
2.  Prevalence of headache in an elderly population: attack frequency, disability, and use of medication 
OBJECTIVES—To assess the 1 year prevalence of tension-type headache (TTH), migraine headache (MH), and chronic daily headache (CDH), as well as of headache in general in a rural elderly population.
METHODS—A door to door two phase survey was carried out on all elderly (⩾65 years) residents in three villages in central Italy. Participants completed a standardised headache questionnaire and underwent a clinical evaluation by a neurologist. Headache diagnosis was made according to the classification of the International Headache Society, with minor modifications for the classification of patients with MH with⩾15 attacks/month.
RESULTS—Eight hundred and thirty three (72.6%) of the 1147 eligible persons completed the study protocol. One year prevalence rates were respectively 44.5% for TTH, 11.0% for MH, 2.2% for symptomatic headaches, and 0.7% for the remaining types of headache. The prevalence of headache in general was 51.0% because 62 residents had both TTH and MH attacks. Prevalence rates of patients with headache were higher in women than men (62.1% and 36.6% respectively) and decreased steadily with age for the 65-74, 75-84, and 85-96 age groups (56.7%, 45.2% and 26.1% respectively). Prevalence rates were 20.4% for patients with moderate to severe attacks, 18.0% for those with ⩾1 attacks a month, and 4.4% for those with CDH. Of the 425 with headache 52 (12.2%) had not taken any drugs for their attacks in the previous year, 195 (45.9%) had taken them regularly, and 178 (41.9%) had taken them only when the headache pain interfered with activities that could not be postponed. Medication overuse was reported by 37.8% of patients with CDH with higher proportions for transformed migraine than for patients with chronic TTH (69.2% and 23.8% respectively, p=0.009)
CONCLUSIONS—A consistent proportion of elderly people have primary headaches and consultation with a specialist is particularly recommended for patients with moderate or severe attacks, or with CDH.

PMCID: PMC1737286  PMID: 11181862
3.  Prevalence of dementia in an elderly rural population: effects of age, sex, and education. 
OBJECTIVES--To estimate the prevalence of dementia in an elderly rural population and to determine the effects of age, sex, and education. METHODS--To obtain prevalence estimates of both cognitive impairment and dementia a door to door two phase population survey was carried out in three rural villages in central Italy. Of 1147 inhabitants older than 64, 968 (84.4%) completed the protocol. RESULTS--The prevalence rates (cases per 100 population over 64) were 8.0 for dementia and 27.3 for cognitive impairment. The prevalence rate for dementia did not differ between men and women (7.9 v 8.2), but increased with age (from 1.1 at age 65-69 to 34.8 at age 90-96). Subjects with less than three years of schooling had a significantly higher prevalence of dementia (14.6; 95% confidence interval (95% CI) 10.2-19.1) than subjects with three or more years of schooling (5.9; 95% CI 4.2-7.7). At the multivariate logistic analysis, the risk related with a low level of education was still present after adjustment for age and sex (OR = 2.0; 95% CI 1.2-3.3). Alzheimer's disease was diagnosed in 64% of the 78 demented patients, vascular dementia in 27%, and other dementing diseases in 9%. CONCLUSIONS--In both Alzheimer and vascular dementia subtypes, the prevalence rates did not differ between men and women, but increased with age and were higher in subjects with a low level of education.
PMCID: PMC1073945  PMID: 8648328
4.  A new class of furoxan derivatives as NO donors: mechanism of action and biological activity. 
British Journal of Pharmacology  1995;114(4):816-820.
1. The mechanism of action and biological activity of a series of R-substituted and di-R-substituted phenylfuroxans is reported. 2. Maximal potency as vasodilators on rabbit aortic rings, precontracted with noradrenaline (1 microM), was shown by phenyl-cyano isomers and by the 3,4-dicyanofuroxan, characterized by a potency ratio 3-10 fold higher than glyceryl trinitrate (GTN). This effect was reduced upon coincubation with methylene blue or oxyhaemoglobin (10 microM). 3. The furoxan derivatives showing maximal potency as vasodilators were also able to inhibit collagen-induced platelet aggregation, with IC50 values in the sub-micromolar range. 4. The furoxan derivatives were able to stimulate partially purified, rat lung soluble guanylate cyclase; among the most active compounds, the 3-R-substituted isomers displayed a higher level of stimulatory effect than the 4-R analogues. 5. Solutions (0.1 mM) of all the tested furoxans, prepared using 50 mM phosphate buffer, pH 7.4, (diluting 10 mM DMSO stock solutions) did not release nitric oxide (NO) spontaneously; however in presence of 5 mM L-cysteine, a significant NO-releasing capacity was observed, which correlated significantly with their stimulation of the guanylate cyclase activity.
PMCID: PMC1510189  PMID: 7773542

Results 1-4 (4)