The phenotype and potential origin of nestin cardiac myocyte-like cells following infarction.
Nestin((+)) cardiac myocyte-like cells were detected in the peri-infarct/infarct region of the ischemically damaged heart. The present study was undertaken to elucidate the phenotype and potential origin of nestin((+)) cardiac myocyte-like cells and identify stimuli implicated in their appearance.
In the infarcted human and rat heart, nestin((+)) cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the beta1-adrenergic receptor and associated with an aberrant pattern of connexin-43 expression and/or organization.
Nestin((+)) cardiac myocyte-like cells were detected 24 hrs post ischemic injury and persisted in the infarcted rat heart for 9 months. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin((+)) neural stem cells.
Following an ischemic insult, nestin((+))/Nkx2.5((+)) neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin((+)) cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O2) for ten days failed to promote the appearance of nestin((+)) cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin((+)) cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss.
Thus, ischemia-induced appearance of nestin((+)) cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin((+)) cardiac myocyte-like cell.
"The phenotype and potential origin of nestin(+) cardiac myocyte-like cells following infarction".
J Appl Physiol. 2009 Aug 13; Beguin PC, El-Helou V, Assimakopoulos J, Clement R, Gosselin H, Brugada R, Villeneuve L, Rohlicek CV, Del Duca D, Lapointe N, Rouleau JL, Calderone A (Hubmed.org)
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In the infarcted human and rat heart, nestin((+)) cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the beta1-adrenergic receptor and associated with an aberrant pattern of connexin-43 expression and/or organization.
Nestin((+)) cardiac myocyte-like cells were detected 24 hrs post ischemic injury and persisted in the infarcted rat heart for 9 months. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin((+)) neural stem cells.
Following an ischemic insult, nestin((+))/Nkx2.5((+)) neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin((+)) cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O2) for ten days failed to promote the appearance of nestin((+)) cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin((+)) cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss.
Thus, ischemia-induced appearance of nestin((+)) cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin((+)) cardiac myocyte-like cell.
"The phenotype and potential origin of nestin(+) cardiac myocyte-like cells following infarction".
J Appl Physiol. 2009 Aug 13; Beguin PC, El-Helou V, Assimakopoulos J, Clement R, Gosselin H, Brugada R, Villeneuve L, Rohlicek CV, Del Duca D, Lapointe N, Rouleau JL, Calderone A (Hubmed.org)
Related:
Cardiac Myocyte-Specific Expression of Inducible Nitric Oxide
The cannabinoid receptor type 2 promotes cardiac myocyte
Cardiac Myocyte-Specific Expression of Inducible Nitric Oxide
Reversal of cardiac myocyte dysfunction as a unique mechanism
Redox Sensing and Cardiac Myocyte Loss: Some Recent Insights
Left Ventricular Hypertrophy, Cardiac Myocyte Adaptation
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Axonal guidance for sympathetic neuron to cardiac myocyte
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Protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes.
Regulation of expression of the close homolog of adhesion molecule L1 (CHL1) by reactive astrocytes in the glial scar reduces axonal regeneration and inhibits functional recovery after spinal cord injury (SCI).
Here, we investigate the molecular mechanisms underlying upregulation of CHL1 expression by analyzing the signal transduction pathways in vitro. We show that astrogliosis stimulated by bacterial lipopolysaccharide (LPS) upregulates CHL1 expression in primary cultures of mouse cerebral astrocytes, coinciding with elevated protein synthesis and translocation of protein kinase delta (PKCdelta) from cytosol to the membrane fraction.
Blocking PKCdelta activity pharmacologically and genetically attenuates LPS-induced elevation of CHL1 protein expression through a phosphatidylinositol 3-kinase (PI3K) dependent pathway. LPS induces extracellular signal-regulated kinases (ERK1/2) phosphorylation through PKCdelta and blockade of ERK1/2 activation abolishes upregulation of CHL1 expression.
LPS-triggered upregulation of CHL1 expression mediated through translocation of nuclear factor kappaB (NF-kappaB) to the nucleus is blocked by a specific NF-kappaB inhibitor and by inhibition of PI3K, PKCdelta, and ERK1/2 activities, implicating NF-kappaB as a downstream target for upregulation of CHL1 expression. Furthermore, the LPS-mediated upregulation of CHL1 expression by reactive astrocytes is inhibitory for hippocampal neurite outgrowth in cocultures.
Although the LPS-triggered NO-guanylate cyclase-cGMP pathway upregulates glial fibrillary acid protein expression in cultured astrocytes, we did not observe this pathway to mediate LPS-induced upregulation of CHL1 expression.
Our results indicate that elevated CHL1 expression by reactive astrocytes requires activation of PI3K/PKCdelta-dependent pathways and suggest that reduction of PI3K/PKCdelta activity represents a therapeutic target to downregulate CHL1 expression and thus benefit axonal regeneration after SCI. (c) 2009 Wiley-Liss, Inc.
"Phosphatidylinositol 3-kinase/protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes"
Glia. 2009 Aug 11; Wu J, Wrathall JR, Schachner MUp
Here, we investigate the molecular mechanisms underlying upregulation of CHL1 expression by analyzing the signal transduction pathways in vitro. We show that astrogliosis stimulated by bacterial lipopolysaccharide (LPS) upregulates CHL1 expression in primary cultures of mouse cerebral astrocytes, coinciding with elevated protein synthesis and translocation of protein kinase delta (PKCdelta) from cytosol to the membrane fraction.
Blocking PKCdelta activity pharmacologically and genetically attenuates LPS-induced elevation of CHL1 protein expression through a phosphatidylinositol 3-kinase (PI3K) dependent pathway. LPS induces extracellular signal-regulated kinases (ERK1/2) phosphorylation through PKCdelta and blockade of ERK1/2 activation abolishes upregulation of CHL1 expression.
LPS-triggered upregulation of CHL1 expression mediated through translocation of nuclear factor kappaB (NF-kappaB) to the nucleus is blocked by a specific NF-kappaB inhibitor and by inhibition of PI3K, PKCdelta, and ERK1/2 activities, implicating NF-kappaB as a downstream target for upregulation of CHL1 expression. Furthermore, the LPS-mediated upregulation of CHL1 expression by reactive astrocytes is inhibitory for hippocampal neurite outgrowth in cocultures.
Although the LPS-triggered NO-guanylate cyclase-cGMP pathway upregulates glial fibrillary acid protein expression in cultured astrocytes, we did not observe this pathway to mediate LPS-induced upregulation of CHL1 expression.
Our results indicate that elevated CHL1 expression by reactive astrocytes requires activation of PI3K/PKCdelta-dependent pathways and suggest that reduction of PI3K/PKCdelta activity represents a therapeutic target to downregulate CHL1 expression and thus benefit axonal regeneration after SCI. (c) 2009 Wiley-Liss, Inc.
"Phosphatidylinositol 3-kinase/protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes"
Glia. 2009 Aug 11; Wu J, Wrathall JR, Schachner MUp
Severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs) are associated with over 200 medicines including lamotrigine, an antiepileptic drug. Previous studies have suggested the involvement of immune mechanisms in the development of drug-induced SCARs.
High-resolution HLA genotyping was performed for 65 patients of European ancestry treated with lamotrigine (22 cases with lamotrigine-induced SCARs and 43 controls on lamotrigine without SCAR-related symptoms). Association of HLA genetic variants with SCARs in these patients were evaluated by contrasting allele frequencies between the cases and the controls for each of 112 HLA four-digit alleles.
RESULTS:
Five alleles were observed with higher frequencies in the cases compared with the treated controls with exact P values less than 0.05.
In contrast to the study of carbamazepine-induced Stevens-Johnson syndrome in Han Chinese patients, none of the cases carried B*1502. Accounting for the large number of hypothesis tests conducted, none of the associations identified were statistically significant.
CONCLUSION:
No single major HLA-related genetic risk factor was identified for lamotrigine-induced SCARs in patients of European origin. Only suggestive evidence was obtained for B*5801, A*6801, Cw*0718, DQB1*0609, and DRB1*1301.
Confirmation of these results in a larger, independent sample is needed to determine whether any of the HLA alleles identified are truly associated with the development of lamotrigine-induced SCARs.
"High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients."
Pharmacogenet Genomics. 2009 Aug 6; Kazeem GR, Cox C, Aponte J, Messenheimer J, Brazell C, Nelsen AC, Nelson MR, Foot E
Related:
High-resolution HLA genotyping and severe cutaneous adverse
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High-resolution HLA genotyping was performed for 65 patients of European ancestry treated with lamotrigine (22 cases with lamotrigine-induced SCARs and 43 controls on lamotrigine without SCAR-related symptoms). Association of HLA genetic variants with SCARs in these patients were evaluated by contrasting allele frequencies between the cases and the controls for each of 112 HLA four-digit alleles.
RESULTS:
Five alleles were observed with higher frequencies in the cases compared with the treated controls with exact P values less than 0.05.
In contrast to the study of carbamazepine-induced Stevens-Johnson syndrome in Han Chinese patients, none of the cases carried B*1502. Accounting for the large number of hypothesis tests conducted, none of the associations identified were statistically significant.
CONCLUSION:
No single major HLA-related genetic risk factor was identified for lamotrigine-induced SCARs in patients of European origin. Only suggestive evidence was obtained for B*5801, A*6801, Cw*0718, DQB1*0609, and DRB1*1301.
Confirmation of these results in a larger, independent sample is needed to determine whether any of the HLA alleles identified are truly associated with the development of lamotrigine-induced SCARs.
"High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients."
Pharmacogenet Genomics. 2009 Aug 6; Kazeem GR, Cox C, Aponte J, Messenheimer J, Brazell C, Nelsen AC, Nelson MR, Foot E
Related:
High-resolution HLA genotyping and severe cutaneous adverse
Cutaneous Adverse Reactions: Stevens-Johnson Syndrome
Review: severe cutaneous adverse reactions to drugs
In the pursuit of classifying severe cutaneous adverse reactions
Cutaneous adverse reactions to valdecoxib distinct from stevens ...
Study: cutaneous adverse reactions to valdecoxib distinct from ...
Submucosal tunneling using endoscopic submucosal dissection for peritoneal access and closure in natural orifice transluminal endoscopic surgery: a porcine survival study.
Endoscopy. 2009 Aug; 41(8): 707-11Yoshizumi F, Yasuda K, Kawaguchi K, Suzuki K, Shiraishi N, Kitano SBACKGROUND AND STUDY AIMS: Safe peritoneal access and gastric closure are the most important concerns in the clinical application of natural orifice transluminal endoscopic surgery (NOTES). We aimed to clarify the feasibility of a submucosal tunnel technique using endoscopic submucosal dissection (ESD) for transgastric peritoneal access and subsequent closure for NOTES. METHODS: Seven female pigs, each weighing about 40 kg were included in the study. The following procedures were performed: (i) after injection of normal saline into the submucosa, the mucosa was cut with a flex knife; (ii) the submucosal layer was dissected using an insulation-tipped electrosurgical knife to make a narrow longitudinal 50-mm submucosal tunnel; (iii) a small incision was made at the end of the tunnel and enlarged with a dilation balloon. After transgastric peritoneoscopy, the mucosal incision site was closed with clips. The following outcome measures were used: (a) evaluation of the technical feasibility of making a submucosal tunnel; (b) clinical monitoring for 7 days; (c) follow-up endoscopy and necropsy; and (d) peritoneal fluid culture. RESULTS: Natural orifice transluminal endoscopic peritoneoscopy with a submucosal tunnel was successfully carried out in all pigs. The pigs recovered well, without signs of peritonitis. Follow-up endoscopy showed healing of mucosal incision sites without open defects. Necropsy revealed no findings of peritonitis, confirming completeness of gastric closure; there was a thin scar in one pig and adhesion of the omentum in six pigs. Peritoneal fluid culture demonstrated no bacterial growth. CONCLUSIONS: The submucosal tunnel technique is feasible and effective for transgastric peritoneal access and closure.
