Università degli Studi di Torino
Dipartimento di Scienze cliniche e biologiche
A 57-year-old woman, on dialysis for 6 years because of AA (reactive) amyloidosis (diagnosis based on kidney biopsy), seeks medical attention for malaise, fever (particularly after the dialysis sessions), hypertension and dyspnoea.
Adrenocortical carcinoma is a rare neoplasm characterized by a high risk of recurrence after radical resection. Whether the use of mitotane is beneficial as an adjuvant treatment has been controversial. Our aim was to evaluate the... more
Adrenocortical carcinoma is a rare neoplasm characterized by a high risk of recurrence after radical resection. Whether the use of mitotane is beneficial as an adjuvant treatment has been controversial. Our aim was to evaluate the efficacy of adjuvant mitotane in prolonging recurrence-free survival.
Objective: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey... more
Objective: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. Design: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. Results: A total of 1512 patients, 41% male, mean age: 45G13 years, mean GH: 31G37 mg/l, IGF1: 744 G318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. Conclusions: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.
Acromegaly is an infrequent disease attributable to endogenous excess of GH and IGF-I. Human studies have associated the GH-IGF-I axis with the development of colorectal cancer; however, the question of whether colorectal cancer is a... more
Acromegaly is an infrequent disease attributable to endogenous excess of GH and IGF-I. Human studies have associated the GH-IGF-I axis with the development of colorectal cancer; however, the question of whether colorectal cancer is a problem in acromegaly is currently unresolved. We performed a cross-sectional study to assess the risk of colonic neoplasia in patients with acromegaly. Colonoscopic screening was performed in 235 patients with acromegaly at five tertiary care hospitals in Italy between January 1, 1996, and December 31, 2001. A repeat colonoscopy was performed in 121 patients after a mean interval of 32.1 months. Colonoscopic findings in patients with acromegaly were compared with those of 233 patients with nonspecific abdominal complaints who were referred for endoscopy during the study period. A total of 65 patients (27.7%) and 36 controls (15.5%) had colonic neoplasia.
Corrigendum to "Use of poly(DL-lactide-ε-caprolactone) membranes and mesenchymal stem cells from the Wharton's jelly of the umbilical cord for promoting nerve regeneration in axonotmesis: In vitro and in vivo analysis" [Differentiation 84... more
Corrigendum to "Use of poly(DL-lactide-ε-caprolactone) membranes and mesenchymal stem cells from the Wharton's jelly of the umbilical cord for promoting nerve regeneration in axonotmesis: In vitro and in vivo analysis" [Differentiation 84 (2012) 355-365]
To evaluate information preferences and information seeking behaviour in ALS patients and caregivers. Sixty ALS patients and caregivers couples were interviewed using a structured questionnaire about the content of diagnosis communication... more
To evaluate information preferences and information seeking behaviour in ALS patients and caregivers. Sixty ALS patients and caregivers couples were interviewed using a structured questionnaire about the content of diagnosis communication and their information seeking behaviour. The patients (35 men and 25 women) had a mean age of 63.4 years (SD 9.5). The caregivers (21 men and 39 women) had a mean age of 53.3 years (SD 14.9). The overall satisfaction with bad news communication and the impression that the physician had understood their feelings were higher amongst patients. Both parties indicated that the most important aspects to be informed were current researches, disease-modifying therapies and ALS outcome. Approximately 55% of patients and 83.3% of caregivers searched for information from sources outside the healthcare system. The most frequently checked source was internet, although its reliability was rated low. The caring neurologist should better attune the content of communication to patientsÕ and caregiversÕ preferences, trying to understand what they want to know and encouraging them to make precise questions. Health professionals should be aware that ALS patients and caregivers often use internet to obtain information and should help them to better sort-out and interpret the news they found.
Post-conditioning (Post-C) induced cardioprotection involves activation of guanylyl-cyclase. In the ischemic preconditioning scenario, the downstream targets of cGMP include mitochondrial ATP-sensitive K + (mK ATP ) channels and protein... more
Post-conditioning (Post-C) induced cardioprotection involves activation of guanylyl-cyclase. In the ischemic preconditioning scenario, the downstream targets of cGMP include mitochondrial ATP-sensitive K + (mK ATP ) channels and protein kinase C (PKC), which involve reactive oxygen species (ROS) production. This study tests the hypothesis that mK ATP , PKC and ROS are also involved in the Post-C protection. Isolated rat hearts underwent 30 min global ischemia (I) and 120 min reperfusion (R) with or without Post-C (i.e., 5 cycles of 10 s R/I immediately after the 30 min ischemia). In 6 groups (3 with and 3 without Post-C) either mK ATP channel blocker, 5hydroxydecanoate (5-HD), or PKC inhibitor, chelerythrine (CHE) or ROS scavenger, N-acetyl-cysteine (NAC), were given during the entire reperfusion (120 min). In other 6 groups (3 with and 3 without Post-C), 5-HD, CHE or NAC were infused for 117 min only starting after 3 min of reperfusion not to interfere with the early effects of Post-C and/or reperfusion. In an additional group NAC was given during Post-C maneuvers (i.e., 3 min only). Myocardial damage was evaluated using nitro-blue tetrazolium staining and lactate dehydrogenase (LDH) release. Post-C attenuated myocardial infarct size (21 ± 3% vs. 64 ± 5% in control; p < 0.01). Such an effect was abolished by 5-HD or CHE given during either the 120 or 117 min of reperfusion as well as by NAC given during the 120 min or the initial 3 min of reperfusion. However, delayed NAC (i.e., 117 min infusion) did not alter the protective effect of Post-C (infarct size 32 ± 5%; p < 0.01 vs. control, NS vs. Post-C). CHE, 5-HD or NAC given in the absence of Post-C did not alter the effects of I/R. Similar results were obtained in terms of LDH release. Our data show that Post-C induced protection involves an early redox-sensitive mechanism as well as a persistent activation of mK ATP and PKC, suggesting that the mK ATP /ROS/PKC pathway is involved in post-conditioning.
Nitric oxide (NO) donors mimic the early phase of ischemic preconditioning (IPC). The effects of nitroxyl (HNO/NO Ϫ ), the one-electron reduction product of NO, on ischemia/reperfusion (I/R) injury are unknown. Here we investigated... more
Nitric oxide (NO) donors mimic the early phase of ischemic preconditioning (IPC). The effects of nitroxyl (HNO/NO Ϫ ), the one-electron reduction product of NO, on ischemia/reperfusion (I/R) injury are unknown. Here we investigated whether HNO/NO Ϫ , produced by decomposition of Angeli's salt (AS; Na 2 N 2 O 3 ), has a cardioprotective effect in isolated perfused rat hearts. Effects were examined after intracoronary perfusion (19 min) of either AS (1 M), the NO donor diethylamine/NO (DEA/NO, 0.5 M), vehicle (100 nM NaOH) or buffer, followed by global ischemia (30 min) and reperfusion (30 min or 120 min in a subset of hearts). IPC was induced by three cycles of 3 min ischemia followed by 10 min reperfusion prior to I/R. The extent of I/R injury under each intervention was assessed by changes in myocardial contractility as well as lactate dehydrogenase (LDH) release and infarct size. Postischemic contractility, as indexed by developed pressure and dP/dt max , was similarly improved with IPC and pre-exposure to AS, as opposed to control or DEA/NO-treated hearts. Infarct size and LDH release were also significantly reduced in IPC and AS groups, whereas DEA/NO was less effective in limiting necrosis. Co-infusion in the triggering phase of AS and the nitroxyl scavenger, N-acetyl-L-cysteine (4 mM) completely reversed the beneficial effects of AS, both at 30 and 120 min reperfusion. Our data show that HNO/NO Ϫ affords myocardial protection to a degree similar to IPC and greater than NO, suggesting that reactive nitrogen oxide species are not only necessary but also sufficient to trigger myocardial protection against reperfusion through species-dependent, pro-oxidative, and/or nitrosative stress-related mechanisms.
Objective: Postconditioning (PostC) maneuvers allow post-ischemic accumulation of autacoids, which trigger protection. We tested if PostCtriggering includes bradykinin (BK) B 2 receptor activation and its downstream pathway. Methods and... more
Objective: Postconditioning (PostC) maneuvers allow post-ischemic accumulation of autacoids, which trigger protection. We tested if PostCtriggering includes bradykinin (BK) B 2 receptor activation and its downstream pathway. Methods and results: Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Infarct size was evaluated using nitro-blue tetrazolium staining. In Control hearts infarct size was 61 ± 5% of risk area. PostC (5 cycles of 10 s reperfusion/ischemia) reduced infarct size to 22 ± 4% ( p b 0.01). PostC protection was abolished by B 2 BK receptor-antagonists (HOE140 or WIN64338), nitric oxide synthaseinhibitor (L-nitro-arginine-methylester), protein kinase G (PKG)-blocker (8-bromoguanosine-3′,5′-cyclic-monophosphorothioate), and mitochondrial K ATP (mK ATP )-blocker (5-hydroxydecanoate) each given for 3 min only. Since 3 min of BK-infusion (100 nM) did not reproduce PostC protection, protocols with Intermittent-BK infusion were used to mimic PostC: a) 5 cycles of 10 s oxygenated-no-BK/ oxygenated + BK buffer; b) 5 cycles of 10 s oxygenated-no-BK/hypoxic + BK buffer. Both protocols with Intermittent-BK attenuated infarct size (36 ± 5% and 38 ± 4%, respectively; p b 0.05 vs Control and NS vs PostC for both; NS vs each other). Intermittent-BK protection was abolished by the same antagonists used to prevent PostC protection. Intermittence of re-oxygenation only (5 cycles of 10 s oxygenated/ hypoxic buffer) did not reproduce PostC. Yet, cardioprotection was triggered by intermittent mK ATP activation with diazoxide, but not by intermittent reactive oxygen species (ROS) generation with purine/xanthine oxidase. ROS scavengers (N-acetyl-L-cysteine or 2mercaptopropionylglycine), given for 3 min only, abolished PostC-, Intermittent BK-and diazoxide-induced protection. Conclusions: Intermittent targeting of specific cellular sites (i.e. BK B 2 receptors and mK ATP channels) during early reperfusion triggers PostC protection via ROS signaling. Since neither intermittent oxygenation nor exogenous ROS generators can trigger protection, it is likely that intermittent autacoid accumulation and ROS compartmentalization may play a pivotal role in PostC-triggering.
We studied the role of cyclic guanosine monophosphate (cGMP) as a mediator of the reduction of L-type calcium current (/ca) induced by muscarinic receptor stimulation and by nitric oxide in isolated guinea-pig ventricular cells using the... more
We studied the role of cyclic guanosine monophosphate (cGMP) as a mediator of the reduction of L-type calcium current (/ca) induced by muscarinic receptor stimulation and by nitric oxide in isolated guinea-pig ventricular cells using the whole-cell patchclamp technique. Our results show that when the level of cyclic adenosine monophosphate was increased by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), stimulation of a pertussis-toxin (PTX)-sensitive muscarinic receptor by carbachol (1 ~tM) reduced the calcium current increase from 80.6 + 23.5% to 19.8 + 9.6% over the control and this effect was prevented by methylene blue (10 ~M), an inhibitor of the soluble guanylate cyclase. Pipette solution containing 10 pM cGMP reduced the enhancement of Ic, by IBMX from 121.9 + 11.6% to 14.2 + 5.4% above the control. Sodium nitroprusside (10 pM), a spontaneous donor of nitric oxide, and consequently a stimulator of soluble guanylate cyclase, also reduced IBMX-stimulated /ca from 115.2 _+ 13.2% to 32.2 + 6.9% above control and the sodium nitroprusside effect was also suppressed by methylene blue. The latter two reagents were ineffective on basal/ca.
Post-conditioning reduces infarct size in the isolated rat heart: Role of coronary flow and pressure and the nitric oxide/cGMP pathway Abstract We aimed to assess the role of the nitric oxide (NO)-cGMP pathway in cardioprotection by brief... more
Post-conditioning reduces infarct size in the isolated rat heart: Role of coronary flow and pressure and the nitric oxide/cGMP pathway Abstract We aimed to assess the role of the nitric oxide (NO)-cGMP pathway in cardioprotection by brief intermittent ischemias at the onset of reperfusion (i.e., post-conditioning (Post-con)). We also evaluated the role of coronary flow and pressure in Post-con. Rat isolated hearts perfused at constantflow or -pressure underwent 30 min global ischemia and 120 min reperfusion. Post-con obtained with brief ischemias of different duration (modified, M-Post-con) was compared with Post-con obtained with ischemias of identical duration (classical, C-Post-con) and with ischemic preconditioning (IP). Infarct size was evaluated using nitro-blue tetrazolium staining and lactate dehydrogenase (LDH) release. In the groups, NO synthase (NOS) or guanylyl-cyclase (GC) was inhibited with LNAME and ODQ, respectively. In the subgroups, the enzyme immunoassay technique was used to quantify cGMP release. In the constant-flow model, M-Post-con and C-Post-con were equally effective, but more effective than IP in reducing infarct size. The cardioprotection by M-Post-con was only blunted by the NOS-inhibitor, but was abolished by the GC-antagonist. Post-ischemic cGMP release was enhanced by M-Post-con. In the constant-pressure model IP, M-Post-con and C-Post-con were equally effective in reducing infarct size. Post-con protocols were more effective in the constant-flow than in the constant-pressure model. In all groups, LDH release during reperfusion was proportional to infarct size. In conclusion, Post-con depends upon GC activation, which can be achieved by NOS-dependent and NOS-independent pathways. The benefits of M-and C-Post-con are similar. However, protection by Post-con is greater in the constant-flow than in the constant-pressure model.
A series of brief (a few minutes) ischemia/reperfusion cycles (ischemic preconditioning, IP) limits myocardial injury produced by a subsequent prolonged period of coronary artery occlusion and reperfusion. Postconditioning (PostC), which... more
A series of brief (a few minutes) ischemia/reperfusion cycles (ischemic preconditioning, IP) limits myocardial injury produced by a subsequent prolonged period of coronary artery occlusion and reperfusion. Postconditioning (PostC), which is a series of brief (a few seconds) reperfusion/ischemia cycles at reperfusion onset, attenuates also ischemia/reperfusion injury. In recent years the main idea has been that reactive oxygen species (ROS) play an essential, though double-edged, role in cardioprotection: they may participate in reperfusion injury or may play a role as signaling elements of protection in the preischemic phase. It has been demonstrated that preconditioning triggering is redox-sensitive, using either ROS scavengers or ROS generators. We have shown that nitroxyl triggers preconditioning via pro-oxidative, and/or nitrosative stress-related mechanism(s). Several metabolites, including acetylcholine, bradykinin, opioids and phenylephrine, trigger preconditioning-like protection via a mitochondrial K ATP -ROSdependent mechanism. Intriguingly, and contradictory to the above mentioned theory of ROS as an obligatory part of reperfusion-induced damage, some studies suggest the possibility that some ROS at low concentrations could protect ischemic hearts against reperfusion injury. Yet, we demonstrated that ischemic PostC is also a cardioprotective phenomenon that requires the intervention of redox signaling to be protective. Emerging evidence suggests that in a preconditioning scenario a redox signal is required during the first few minutes of myocardial reperfusion following the index ischemic period. Intriguingly, the ROS signaling in the early reperfusion appear crucial to both preconditioning-and postconditioninginduced protection. Therefore, our and others' results suggest that the role of ROS in reperfusion may be reconsidered as they are not only deleterious.
Postconditioning (PostC) may limit mitochondrial damage and apoptotic signaling. We studied markers of apoptosis and mitochondrial protection in isolated rat hearts, which underwent a) perfusion without ischemia (Sham), b) 30-min ischemia... more
Postconditioning (PostC) may limit mitochondrial damage and apoptotic signaling. We studied markers of apoptosis and mitochondrial protection in isolated rat hearts, which underwent a) perfusion without ischemia (Sham), b) 30-min ischemia (I) plus 2-hour reperfusion (R), or c) PostC protocol (5 intermittent cycles of 10-s reperfusion and 10-s ischemia immediately after the 30-min ischemia). Markers were studied in cytosolic (CF) and/or mitochondrial (MF) fractions. In CF, while pro-apoptotic factors (cytochrome c and caspase-3) were reduced, the anti-apoptotic markers (Bcl-2 and Pim-1) were increased by PostC, compared to the I/R group. Accordingly, phospho-GSK-3β and Bcl-2 levels increased in mitochondria of PostC group. Moreover, I/R reduced the level of mitochondrial structural protein (HSP-60) in MF and increased in CF, thus suggesting mitochondrial damage and HSP-60 release in cytosol, which were prevented by PostC. Electron microscopy confirmed that I/R markedly damaged cristae and mitochondrial membranes; damage was markedly reduced by PostC. Finally, total connexin-43 (Cx43) levels were reduced in the CF of the I/R group, whereas phospho-Cx43 level resulted in higher levels in the MF of the I/R group than the Sham group. PostC limited the I/R-induced increase of mitochondrial phospho-Cx43. Data suggest that PostC i) increases the levels of anti-apoptotic markers, including the cardioprotective kinase Pim-1, ii) decreases the pro-apoptotic markers, e.g. cytochrome c, iii) preserves the mitochondrial structure, and iv) limits the migration of phospho-Cx43 to mitochondria.
Angiotensin-converting enzyme (ACE) plays a pivotal role in the renin-angiotensin system (RAS) and ACE-inhibitors are widely used in several clinical conditions, including hypertension and heart failure. Recently, a homologue of ACE, ACE... more
Angiotensin-converting enzyme (ACE) plays a pivotal role in the renin-angiotensin system (RAS) and ACE-inhibitors are widely used in several clinical conditions, including hypertension and heart failure. Recently, a homologue of ACE, ACE 2 has been discovered. Both ACE and ACE 2 are emerging as key enzymes of the RAS, where ACE 2 may play a role as negative regulator of ACE. Moreover, ACE 2 appears to be an important enzyme outside the classical RAS, as it hydrolyzes apelins, dynorphin A 1-13, des-Arg-bradykinin and other peptide substrates. The precise interplay between tissue ACE, ACE 2 , and their substrates and by-products are presently still unclear.
Nitric oxide (NO) participates in the control of contractility and heart rate, limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre- and postconditioning. Low concentrations of NO, with... more
Nitric oxide (NO) participates in the control of contractility and heart rate, limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre- and postconditioning. Low concentrations of NO, with production of small amounts of cGMP, inhibit phosphodiesterase III, thus preventing the hydrolysis of cAMP. The subsequent activation of a protein-kinase A causes the opening of sarcolemmal voltage-operated and sarcoplasmic ryanodin receptor Ca2+ channels, thus increasing myocardial contractility. High concentrations of NO induce the production of larger amounts of cGMP which are responsible for a cardiodepression in response to an activation of protein kinase G (PKG) with blockade of sarcolemmal Ca2+ channels. NO is also involved in reduced contractile response to adrenergic stimulation in heart failure. A reduction of heart rate is an evident effect of NO-synthase (NOS) inhibition. It is noteworthy that the direct effect of NOS inhibition can be altered if baroreceptors are stimulated by increases in blood pressure. Finally, NO can limit the deleterious effects of cardiac remodeling after myocardial infarction possibly via the cGMP pathway. The protective effect of NO is mainly mediated by the guanylyl cyclase–cGMP pathway resulting in activation of PKG with opening of mitochondrial ATP-sensitive potassium channels and inhibition of the mitochondrial permeability transition pores. NO acting on heart is produced by vascular and endocardial endothelial NOS, as well as neuronal and inducible synthases. In particular, while in the basal control of contractility, endothelial synthase has a predominant role, the inducible isoform is mainly responsible for the cardiodepression in septic shock.
- by claudia penna and +2
- •
- Life Sciences, Heart Failure, Septic Shock, Blood Pressure
1. Electrophysiological (whole-cell clamp) techniques were used to study the effect of NO synthase (NOS) inhibitors on guinea-pig ventricular calcium current (ICa), and biochemical measurements (Western blot and citrulline synthesis) were... more
1. Electrophysiological (whole-cell clamp) techniques were used to study the effect of NO synthase (NOS) inhibitors on guinea-pig ventricular calcium current (ICa), and biochemical measurements (Western blot and citrulline synthesis) were made to investigate the possible mechanisms of action. 2. The two NOS inhibitors, N G -monomethyl-¬-arginine (¬_NMMA, 1 mÒ) and N G -nitro-¬arginine (¬_NNA, 1 mÒ), induced a rapid increase in ICa when applied to the external solution. ª_NMMA (1 mÒ), the stereoisomer of ¬_NMMA, which has no effect on NOS, did not enhance ICa.
• Introduction• Reperfusion injury- Causes of reperfusion injury- Effects of reperfusion injury• Definition of postconditioning- Postconditioning algorithm• Protective effects of postconditioning- Infarct size reduction- Reduction of... more
• Introduction• Reperfusion injury- Causes of reperfusion injury- Effects of reperfusion injury• Definition of postconditioning- Postconditioning algorithm• Protective effects of postconditioning- Infarct size reduction- Reduction of apoptosis- Reduction in endothelial dysfunction- Reduction in endothelial activation, and neutrophil adherence- Reduction of stunning- Anti-arrhythmic effects• Potentiality of postconditioning- Remote postconditioning- Pharmacological postconditioning- Postconditioning the human heart- Postconditioning in diseased hearts• Mechanisms involved in postconditioning- Passive mechanisms- Mechanical mechanisms- Cellular mechanisms- Active mechanisms (intramyocardiocyte mechanisms)- Triggers- Mediators- End effectors- Cardioprotection by pre- and post-conditioning is redox-sensitive• Conclusions• Introduction• Reperfusion injury- Causes of reperfusion injury- Effects of reperfusion injury• Definition of postconditioning- Postconditioning algorithm• Protective effects of postconditioning- Infarct size reduction- Reduction of apoptosis- Reduction in endothelial dysfunction- Reduction in endothelial activation, and neutrophil adherence- Reduction of stunning- Anti-arrhythmic effects• Potentiality of postconditioning- Remote postconditioning- Pharmacological postconditioning- Postconditioning the human heart- Postconditioning in diseased hearts• Mechanisms involved in postconditioning- Passive mechanisms- Mechanical mechanisms- Cellular mechanisms- Active mechanisms (intramyocardiocyte mechanisms)- Triggers- Mediators- End effectors- Cardioprotection by pre- and post-conditioning is redox-sensitive• ConclusionsIntroductionReperfusion injury- Causes of reperfusion injury- Effects of reperfusion injuryCauses of reperfusion injuryEffects of reperfusion injuryDefinition of postconditioning- Postconditioning algorithmPostconditioning algorithmProtective effects of postconditioning- Infarct size reduction- Reduction of apoptosis- Reduction in endothelial dysfunction- Reduction in endothelial activation, and neutrophil adherence- Reduction of stunning- Anti-arrhythmic effectsInfarct size reductionReduction of apoptosisReduction in endothelial dysfunctionReduction in endothelial activation, and neutrophil adherenceReduction of stunningAnti-arrhythmic effectsPotentiality of postconditioning- Remote postconditioning- Pharmacological postconditioning- Postconditioning the human heart- Postconditioning in diseased heartsRemote postconditioningPharmacological postconditioningPostconditioning the human heartPostconditioning in diseased heartsMechanisms involved in postconditioning- Passive mechanisms- Mechanical mechanisms- Cellular mechanisms- Active mechanisms (intramyocardiocyte mechanisms)- Triggers- Mediators- End effectors- Cardioprotection by pre- and post-conditioning is redox-sensitivePassive mechanismsMechanical mechanismsCellular mechanismsActive mechanisms (intramyocardiocyte mechanisms)TriggersMediatorsEnd effectorsCardioprotection by pre- and post-conditioning is redox-sensitiveConclusionsAbstractIschaemic preconditioning limits the damage induced by subsequent ischaemia/reperfusion (I/R). However, preconditioning is of little practical use as the onset of an infarction is usually unpredictable. Recently, it has been shown that the heart can be protected against the extension of I/R injury if brief (10–30 sec.) coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called postconditioning (PostC). It can also be elicited at a distant organ, termed remote PostC, by intermittent pacing (dyssynchrony-induced PostC) and by pharmacological interventions, that is pharmacological PostC. In particular, brief applications of intermittent bradykinin or diazoxide at the beginning of reperfusion reproduce PostC protection. PostC reduces the reperfusion-induced injury, blunts oxidant-mediated damages and attenuates the local inflammatory response to reperfusion. PostC induces a reduction of infarct size, apoptosis, endothelial dysfunction and activation, neutrophil adherence and arrhythmias. Whether it reduces stunning is not clear yet. Similar to preconditioning, PostC triggers signalling pathways and activates effectors implicated in other cardioprotective manoeuvres. Adenosine and bradykinin are involved in PostC triggering. PostC triggers survival kinases (RISK), including A t and extracellular signal-regulated kinase (ERK). Nitric oxide, via nitric oxide synthase and non-enzymatic production, cyclic guanosine monophosphate (cGMP) and protein kinases G (PKG) participate in PostC. PostC-induced protection also involves an early redox-sensitive mechanism, and mitochondrial adenosine-5′ -triphosphate (ATP)-sensitive K+ and PKC activation. Protective pathways activated by PostC appear to converge on mitochondrial permeability transition pores, which are inhibited by acidosis and glycogen synthase kinase-3β (GSK-3β). In conclusion, the first minutes of reperfusion represent a window of opportunity for triggering the aforementioned mediators which will in concert lead to protection against reperfusion injury. Pharmacological PostC and possibly remote PostC may have a promising future in clinical scenario.Ischaemic preconditioning limits the damage induced by subsequent ischaemia/reperfusion (I/R). However, preconditioning is of little practical use as the onset of an infarction is usually unpredictable. Recently, it has been shown that the heart can be protected against the extension of I/R injury if brief (10–30 sec.) coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called postconditioning (PostC). It can also be elicited at a distant organ, termed remote PostC, by intermittent pacing (dyssynchrony-induced PostC) and by pharmacological interventions, that is pharmacological PostC. In particular, brief applications of intermittent bradykinin or diazoxide at the beginning of reperfusion reproduce PostC protection. PostC reduces the reperfusion-induced injury, blunts oxidant-mediated damages and attenuates the local inflammatory response to reperfusion. PostC induces a reduction of infarct size, apoptosis, endothelial dysfunction and activation, neutrophil adherence and arrhythmias. Whether it reduces stunning is not clear yet. Similar to preconditioning, PostC triggers signalling pathways and activates effectors implicated in other cardioprotective manoeuvres. Adenosine and bradykinin are involved in PostC triggering. PostC triggers survival kinases (RISK), including A t and extracellular signal-regulated kinase (ERK). Nitric oxide, via nitric oxide synthase and non-enzymatic production, cyclic guanosine monophosphate (cGMP) and protein kinases G (PKG) participate in PostC. PostC-induced protection also involves an early redox-sensitive mechanism, and mitochondrial adenosine-5′ -triphosphate (ATP)-sensitive K+ and PKC activation. Protective pathways activated by PostC appear to converge on mitochondrial permeability transition pores, which are inhibited by acidosis and glycogen synthase kinase-3β (GSK-3β). In conclusion, the first minutes of reperfusion represent a window of opportunity for triggering the aforementioned mediators which will in concert lead to protection against reperfusion injury. Pharmacological PostC and possibly remote PostC may have a promising future in clinical scenario.
Increasing attention is being given to the use of adult rather than embryonic stem cells, both for research and for the development of transplantation treatments for human disease. In particular, mesenchymal bone marrow stem cells have... more
Increasing attention is being given to the use of adult rather than embryonic stem cells, both for research and for the development of transplantation treatments for human disease. In particular, mesenchymal bone marrow stem cells have been studied extensively because of their ability to self-renew and to give rise to various differentiated cell types, and because of the relative ease with which they can be obtained and cultured. In addition, the possibility of labelling stem cells with green fluorescent protein before transplantation has opened new and promising perspectives for their use in basic research. Because no structural or ultrastructural description of adult mesenchymal stem cells is available in the literature, this paper describes their morphology as revealed by light, confocal and electron microscopy, focusing on cells that are particularly suitable for transplantation studies, i.e. those derived from rat bone marrow transfected with green fluorescent protein. The results provide a basis for experimental studies of the differentiation of these cells in normal and pathological tissues. Morphology of mesenchymal bone marrow stem cells, S. Raimondo et al. Morphology of mesenchymal bone marrow stem cells, S. Raimondo et al.