Mesenchymal Stem Cell Engagement Modulates Neuroma Microenviroment in Rats and Humans and Prevents Postamputation Pain.

Postamputation pain is currently managed unsatisfactorily with neuron-targeted pharmacological and interventional therapies. Non-neuronal pain mechanisms have emerged as crucial factors in the development and persistence of postamputation pain. Consequently, these mechanisms offer exciting prospects as innovative therapeutic targets. We examined the hypothesis that engaging mesenchymal stem cells (MSCs) would foster local neuroimmune interactions, leading to a potential reduction in postamputation pain. We utilized an ex vivo neuroma model from a phantom limb pain patient to uncover that the oligodeoxynucleotide IMT504 engaged human primary MSCs to promote an anti-inflammatory microenvironment. Reverse translation experiments recapitulated these effects. Thus, in an in vivo rat model, IMT504 exhibited strong efficacy in preventing autotomy (self-mutilation) behaviors. This effect was linked to a substantial accumulation of MSCs in the neuroma and associated dorsal root ganglia and the establishment of an anti-inflammatory phenotype in these compartments. Centrally, this intervention reduced glial reactivity in the dorsal horn spinal cord, demonstrating diminished nociceptive activity. Accordingly, the exogenous systemic administration of MSCs phenocopied the behavioral effects of IMT504. Our findings underscore the mechanistic relevance of MSCs and the translational therapeutic potential of IMT504 to engage non-neuronal cells for the prevention of postamputation pain. PERSPECTIVE: The present study suggests that IMT504-dependent recruitment of endogenous MSCs within severely injured nerves may prevent post-amputation pain by modifying the inflammatory scenario at relevant sites in the pain pathway. Reinforcing data in rat and human tissues supports the potential therapeutic value of IMT504 in patients suffering postamputation pain.

Transforming growth factor ß1 and coronary intimal hyperplasia in pediatric patients with congenital heart disease.

BACKGROUND: Congenital heart defects or the process of their repair leads to an increased risk for adult cardiovascular disease compared with the general population. Intimal hyperplasia is a preatherosclerotic lesion that may be produced as a consequence of transforming growth factor ß1 (TGF-ß1) pathway activation. We studied the presence of intimal hyperplasia in arteries from a pediatric population with congenital heart disease (CHD) and TGF-ß1 expression to enlighten its possible role in the genesis of these lesions. METHODS: Coronary arteries from 10 controls and 98 CHD patients (54% cyanotic type, 32% surgically repaired) were stained, and the presence and degree of intimal thickening were analyzed. The expression of TGF-ß1 was studied by immunohistochemistry. RESULTS: The difference between the presence of coronary intimal hyperplasia in patients with cyanotic (35; 66.1%) and noncyanotic CHD (29; 64.3%) was not significant. However, surgically repaired CHD presented a higher rate of coronary intimal hyperplasia (80%) than did the group without surgical intervention (47.3%), P = 0.0002. The immunostaining for TGF-ß1 analyzed in samples of patients with cyanotic and noncyanotic CHD showed no significant differences. However, TGF-ß1 expression was more intense on the intimal layer of patients with surgically repaired CHD than on that of those without surgery (intimal area positive for TGF-ß1, 50.43% vs 15.91%, respectively; Mann-Whitney U test P = 0.0005). CONCLUSION: The high incidence of intimal hyperplasia in patients with surgically repaired CHD is correlated with TGF-ß1 expression and may contribute to the development of atherosclerotic coronary artery disease in CHD patients.

Coronary intimal thickening in newborn babies and

We performed a morphological characterization of intimal thickenings in coronary arteries in the very early stages of life to obtain insights into initial coronary atherogenesis. We examined specimens from 67 infants who had died of noncardiac causes within their first year of life. Serially cut sections were stained with hematoxylin-eosin, Azan, Alcian blue, acetic orceine, and immunotypified for CD68, CD34, and alpha-smooth muscle (SM) actin. Substantial changes were detected in about 1 of 3 participants. Alterations ranged from focal areas with mild myointimal thickening to diffuse moderate thickening. In those lesions, smooth muscle cells (SMCs) showed loss of polarity, infiltrating the subendothelium, mostly with rupture of the internal elastic lamina and without neoangiogenesis. Morphometrically, in musculoelastic intimal thickenings, neointimal thickness averaged 58.3 +/- 17.8 microm, affecting 46% of the internal elastic membrane perimeter; lumen stenosis averaged 13.7% +/- 5.0%. These lesions can be present very early in life and SMCs seem to play an essential role.

Classifying musculocutaneous nerve variations.

A total of 56 upper limbs from fetuses and adult cadavers were dissected to record anatomical variations in the musculocutaneous nerve (MC). A systematic literature review was performed to identify current classifications of MC variations. Communications were seen between the MC and median nerves in 53.6% of the dissections from which 84.6% were proximal, 7.7% distal, and 7.7% had one proximal and one distal communication to the point of entry of the MC into coracobrachialis muscle. In six out of 54 dissections where the MC was present, the nerve did not pierce the coracobrachialis muscle. In two cases, the MC was absent and in one case the MC and the median nerve had a distal origin. This article describes current classifications of MC variations and their problems. A new classification is proposed combining preexisting ones into an integrated and more detailed overview. Clinical manifestations of isolated MC injury with and without the presence of anatomical variations are thoroughly discussed. The knowledge of these variations will allow physicians to correctly interpret anomalous innervation patterns of the upper limb.

[Migration flow and imported diseases: chronic chagasic cardiomyopathy]. / Flussi migratori e nuove patologie di importazione: la cardiomiopatia chagasica cronica.

Chagas disease, caused by the parasite Trypanosoma cruzi, is transmitted by triatomine bugs in endemic regions of the American continent and less frequently by blood transfusion and congenital transmission. Immigration rates explain why the disease can be found worldwide. Non-endemic countries that receive a significant amount of Latin American immigrants should be familiarized with the disease to allow prevention, diagnosis and early treatment. In Italy, where no serologic screening is routinely performed to detect Trypanosoma cruzi in blood donations, a special consideration must be held. Accordingly, attention to congenital transmissions of the disease should be drawn considering the lack of newborn screening. Though commonly unrecognized, chronic chagasic cardiomyopathy is the most common type of chronic myocarditis in the world.