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Mario Pescatori

Publications and source records attributed to Mario Pescatori.

17 recordsLinked to original sources
PubMed2006

Neprilysin participates in skeletal muscle regeneration and is accumulated in abnormal muscle fibres of inclusion body myositis.

Neprilysin (NEP, EP24.11), a metallopeptidase originally shown to modulate signalling events by degrading small regulatory peptides, is also an amyloid-beta- (Abeta) degrading enzyme. We investigated a possible role of NEP in inclusion body myositis (IBM) and other acquired and hereditary muscle disorders and found that in all myopathies NEP expression was directly associated with the degree of muscle fibre regeneration. In IBM muscle, NEP protein was also strongly accumulated in Abeta-bearing abnormal fibres. In vitro, during the experimental differentiation of myoblasts, NEP protein expression was regulated at the post-transcriptional level with a rapid increase in the early stage of myoblast differentiation followed by a gradual reduction thereafter, coincident with the progression of the myogenic programme. Treatment of differentiating muscle cells with the NEP inhibitor dl-3-mercapto-2-benzylpropanoylglycine resulted in impaired differentiation that was mainly associated with an abnormal regulation of Akt activation. Therefore, NEP may play an important role during muscle cell differentiation, possibly through the regulation, either directly or indirectly, of the insulin-like growth factor I-driven myogenic programme. In IBM muscle increased NEP may be instrumental in (i) reducing the Abeta accumulation in vulnerable fibres and (ii) promoting a repair/regenerative attempt of muscle fibres possibly through the modulation of insulin-like growth factor I-dependent pathways.

Aged↗
PubMed2006

Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes.

Here, we present the first study of a human neuromuscular disorder at transcriptional and proteomic level. Autosomal dominant facio-scapulo-humeral muscular dystrophy (FSHD) is caused by a deletion of an integral number of 3.3-kb KpnI repeats inside the telomeric region D4Z4 at the 4q35 locus. We combined a muscle-specific cDNA microarray platform with a proteomic investigation to analyse muscle biopsies of patients carrying a variable number of KpnI repeats. Unsupervised cluster analysis divides patients into three classes, according to their KpnI repeat number. Expression data reveal a transition from fast-glycolytic to slow-oxidative phenotype in FSHD muscle, which is accompanied by a deficit of proteins involved in response to oxidative stress. Besides, FSHD individuals show a disruption in the MyoD-dependent gene network suggesting a coregulation at transcriptional level during myogenesis. We also discuss the hypothesis that D4Z4 contraction may affect in trans the expression of a set of genes involved in myogenesis, as well as in the regeneration pathway of satellite cells in adult tissue. Muscular wasting could result from the inability of satellite cells to successfully differentiate into mature fibres and from the accumulation of structural damages caused by a reactive oxygen species (ROS) imbalance induced by an increased oxidative metabolism in fibres.

Adolescent↗
PubMed2006

Holistic approach to chronic constipation.

By "holistic approach" (greek "olos" = "all") we mean a clinical approach which is not only confined to the diseased segment of the body, say the inert large bowel or the spastic pelvic floor in case of constipation, but takes under consideration the whole "mind and body complex", which is a unique indivisible entity. According to a prospective study carried out in our Unit and under press in Colorectal Disease, 66% of the patients with obstructed defecation suffer either from anxiety or depression, thus showing the major role played by an altered psyche in the etiology of their constipation.

Adult↗
PubMed2005

Altered expression of the MCSP/NG2 chondroitin sulfate proteoglycan in collagen VI deficiency.

NG2, the rat homologue of the human melanoma chondroitin sulfate proteoglycan (MCSP), is a ligand for collagen VI (COL6). We have examined skeletal muscles of patients affected by Ullrich scleroatonic muscular dystrophy (UCMD), an inherited syndrome caused by COL6 genes mutations. A significant decrease of NG2 immunolabeling was found in UCMD myofibers, as well as in skeletal muscle and cornea of COL6 null-mice. In UCMD muscles, truncated NG2 core protein isoforms were detected. However, real-time RT-PCR analysis revealed marked increase in NG2 mRNA content in UCMD muscle compared to controls. We hypothesize that NG2 immunohistochemical and biochemical behavior may be compromised owing to the absence of its physiological ligand. MCSP/NG2 proteoglycan may be considered an important receptor mediating COL6-sarcolemma interactions, a relationship that is disrupted by the pathogenesis of UCMD muscle.

Animals↗
PubMed2004

Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy.

The most common form of autosomal recessive (AR) hereditary inclusion-body myopathy (HIBM), originally described in Persian-Jewish families, is characterized by onset in early adult life with weakness and atrophy of distal lower limb muscles, which progress proximally and relatively spare the quadriceps. AR HIBM is associated with mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE) on chromosome 9p12-13. In the present study we have identified seven novel GNE mutations in patients from five unrelated Italian families with clinical and pathologic features indicative of AR HIBM. Four were missense mutations (c.1556A>G [p.N519S], c.79C>T [p.P27S], c.1798G>A [p.A600T] and c.616G>A [p.G206S]), two consisted in a single-base deletion (c.616delG [p.G206fsX4] and c.1130delT [p.I377fsX16]) and one in an intronic single-base insertion (c.1070+2dupT). These latter findings further extend the type of GNE mutations associated with HIBM. Furthermore, in one patient we also identified the c.737G>A [p.R246Q] missense mutation that corresponds to the one previously reported in a family from the Bahamas. Interestingly, in two of our families distinct mutations affected nucleotide c.616 in exon 3 (c.616delG and c.616G>A). The possibility of specific portions of the gene being more prone to mutations remains to be elucidated.

DNA Mutational Analysis↗
PubMed2004

Insulin-like growth factor I in inclusion-body myositis and human muscle cultures.

Possible pathogenic mechanisms of sporadic inclusion-body myositis (sIBM) include abnormal production and accumulation of amyloid beta (A beta), muscle aging, and increased oxidative stress. Insulin-like growth factor I (IGF-I), an endocrine and autocrine/paracrine trophic factor, provides resistance against A beta toxicity and oxidative stress in vitro and promotes cell survival. In this study we analyzed the IGF-I signaling pathway in sIBM muscle and found that 16.2% +/- 2.5% of nonregenerating fibers showed increased expression of IGF-I, phosphatidylinositide 3'OH-kinase, and Akt. In the majority of sIBM abnormal muscle fibers, increased IGF-I mRNA and protein correlated with the presence of A beta cytoplasmic inclusions. To investigate a possible relationship between A beta toxicity and IGF-I upregulation, normal primary muscle cultures were stimulated for 24 hours with the A beta(25-35) peptide corresponding to the biologically active domain of A beta. This induced an increase of IGF-I mRNA and protein in myotubes at 6 hours, followed by a gradual reduction thereafter. The level of phosphorylated Akt showed similar changes. We suggest that in sIBM. IGF-I overexpression represents a reactive response to A beta toxicity, possibly providing trophic support to vulnerable fibers. Understanding the signaling pathways activated by IGF-I in sIBM may lead to novel therapeutic strategies for the disease.

Amyloid beta-Peptides↗
PubMed2002

Anal continence after rectocele repair.

INTRODUCTION: Rectocele may be associated with both chronic constipation and anal incontinence. Several different surgical procedures have been advocated for rectocele repair. The aim of the present study was to evaluate anorectal function and clinical outcome in a consecutive series of patients who underwent selected endorectal or transperineal surgery for rectocele for whom operative treatment was determined by clinical and proctographic features. Attention was paid to the cohort of rectocele patients presenting with incontinence as a leading symptom. METHODS: Sixty consecutive patients with symptomatic rectocele underwent surgical treatment at our institution. Fifty-eight of the patients were female (mean age 56; range, 21-70 years). Incontinence was graded according to a previously reported scoring system that accounts for the type and frequency of incontinence episodes. Preoperative anorectal manometry was performed using an open perfused polyethylene probe. Rectal sensation was recorded by balloon distention. Endoanal ultrasonography was performed with a 7.5-MHz probe. Preoperative defecography was performed at rest and on maximal squeeze and straining. Patients with obstructed defecation as their principal symptom, with associated mucosal rectal prolapse, underwent an endorectal procedure. For patients with associated anal incontinence (Grade B2 or greater), and without a rectal mucosal prolapse, a transperineal approach was performed with either an anterior external overlapping sphincteroplasty or levatorplasty. The median follow-up was 48 (range, 9-122) months. RESULTS: There was no operative mortality. Postoperative complications occurred in 18 patients (30 percent). Of 43 patients with incontinence, 34 (79 percent) were available for postoperative evaluation. None were fully continent. However, in 25 patients (73.5 percent), continence improved after surgery; half had only mucus soiling or loss of gas. Incontinence scores decreased (i.e., improved) from 4.8 +/- 0.9 to 3.9 +/- 0.9 (P = 0.002). A significant improvement was found both after transanal and perineal procedures. Only ten initially continent patients were available for postoperative assessment. All patients stated that they had clinical improvement in constipation. Their preoperative mean anal resting pressure was 62.5 +/- 3.9 (standard error of the mean) mmHg, with a postoperative mean of 75.5 +/- 7 mmHg. The preoperative mean squeeze pressure was 83.1 +/- 8.5 mmHg, with a mean postoperative squeeze pressure of 88.5 +/- 7.9 mmHg (P = not significant). The maximal tolerable volumes were all within normal limits, confirming the proctographic evidence that there were no cases of megarectum in our patient series. The pudendal nerve terminal motor latency was abnormal in all but two patients with incontinence (mean pudendal nerve terminal motor latency = 3.1; range, 1.2-4 milliseconds). Rectoceles recurred in six patients (10 percent): five after a Block procedure and one after a Sarles-type operation. The postoperative endosonographic appearance varied according to the nature of the procedure performed. CONCLUSION: There are few data concerning patients with rectocele who have associated anal incontinence, however, surgical decision analysis resulted in improvement in both constipation and incontinence in the majority of our patients with rectocele. Nevertheless, because none of the patients gained full continence postoperatively, pelvic floor rehabilitation might be also needed to achieve better sphincter function in patients with incontinence.

Adult↗