The Predisposition for Type 2 Diabetes Mellitus and Metabolic Syndrome.

Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are diseases caused by the interaction of genetic and non-genetic factors. Therefore, the aim of our study was to investigate the association between six common genetic polymorphisms and T2DM and MetS in males. A total of 120 T2DM, 75 MetS, and 120 healthy controls (HC) were included in the study. ACE ID, eNOS 4a/b, ATR1 A1166C, OXTR (A>G), SOD1 +35A/C, CAT-21A/T gene polymorphisms were genotyped by PCR or PCR-RFLP techniques. T2DM was diagnosed at an earlier age compared to MetS (54 vs 55 years old, p=0.0003) and the difference was greater in carriers of the OXTR G allele (54 vs 56 years old, p=0.0002) or both OXTR G and eNOS b alleles (54 vs 56, p=0.00016). The SOD1 AA genotype (O.R.=0.11, p=0.0006) and the presence of both ACE I and OXTR1 A (O.R.=0.39, p=0.0005) alleles revealed to be protective for T2DM. SOD1 AA and AC genotypes were protective factors for triglyceride (p=0.0002 and p=0.0005, respectively) and HDL cholesterol (p=0.0002 and p=0.0004, respectively) levels in T2DM patients. ACE DD was identified more frequently in hypertensive T2DM patients (O.R.=3.77, p=0.0005) and in those who reported drinking alcohol (p=0.0001) comparing to HC and T2DM patients who did not drink alcohol, respectively. We observed that T2DM patients who reported drinking alcohol had an increased frequency of ACE DD and eNOS bb (p<0.0001), or ACE DD and OXTR G (p<0.0001) compared to non-drinkers. No gene polymorphisms were associated with MetS.

PROSPECT guideline for rotator cuff repair surgery: systematic review and procedure-specific postoperative pain management recommendations.

Rotator cuff repair can be associated with significant and difficult to treat postoperative pain. We aimed to evaluate the available literature and develop recommendations for optimal pain management after rotator cuff repair. A systematic review using procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in English from 1 January 2006 to 15 April 2019 assessing postoperative pain after rotator cuff repair using analgesic, anaesthetic or surgical interventions were identified from MEDLINE, Embase and Cochrane Databases. Out of 322 eligible studies identified, 59 randomised controlled trials and one systematic review met the inclusion criteria. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol, cyclo-oxygenase-2 inhibitors, intravenous dexamethasone, regional analgesia techniques including interscalene block or suprascapular nerve block (with or without axillary nerve block) and arthroscopic surgical technique. Limited evidence was found for pre-operative gabapentin, perineural adjuncts (opioids, glucocorticoids, or α-2-adrenoceptor agonists added to the local anaesthetic solution) or postoperative transcutaneous electrical nerve stimulation. Inconsistent evidence was found for subacromial/intra-articular injection, and for surgical technique-linked interventions, such as platelet-rich plasma. No evidence was found for stellate ganglion block, cervical epidural block, specific postoperative rehabilitation protocols or postoperative compressive cryotherapy. The analgesic regimen for rotator cuff repair should include an arthroscopic approach, paracetamol, non-steroidal anti-inflammatory drugs, dexamethasone and a regional analgesic technique (either interscalene block or suprascapular nerve block with or without axillary nerve block), with opioids as rescue analgesics. Further randomised controlled trials are required to confirm the influence of the recommended analgesic regimen on postoperative pain relief.

Ischemic preconditioning phosphorylates mitogen-activated kinases and heat shock protein 27 in the diabetic rat heart.

Diabetes mellitus blocks protection by ischemic preconditioning (IPC), but the mechanism is not known. We investigated the effect of ischemic preconditioning on mitogen-activated protein kinases (extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases, p38 mitogen-activated kinase) and heat shock protein 27 phosphorylation in diabetic and nondiabetic rat hearts in vivo. Two groups of anaesthetized nondiabetic and diabetic rats underwent a preconditioning protocol (3 cycles of 3 min coronary artery occlusion and 5 min of reperfusion). Two further groups served as untreated controls. Hearts were excised for protein measurements by Western blot. Four additional groups underwent 25 min of coronary occlusion followed by 2 h of reperfusion to induce myocardial infarction. In these animals, infarct size was measured. IPC reduced infarct size in the nondiabetic rats but not in the diabetic animals. In diabetic rats, IPC induced phosphorylation of the mitogen-activated protein kinases and of heat shock protein 27. We conclude that protection by IPC is blocked by diabetes mellitus in the rat heart in vivo without affecting phosphorylation of mitogen-activated protein kinases or heat shock protein 27. Therefore, the blockade mechanism of diabetes mellitus is downstream of mitogen-activated kinases and heat shock protein 27.

Xenon preconditioning differently regulates p44/42 MAPK (ERK 1/2) and p46/54 MAPK (JNK 1/2 and 3) in vivo.

BACKGROUND: Xenon (Xe) induces preconditioning (PC) of the rat heart in vivo via activation of p38 mitogen-activated protein kinase (MAPK). The role of ERK 1/2 and JNK 1/2 and 3 in Xe-PC has yet not been determined. METHODS: For infarct size measurements, anaesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Animals received Xe 70% during three 5 min periods with and without the ERK inhibitor PD 98059 (1 mg kg(-1), PD) or the JNK inhibitor SP 600125 (6 mg kg(-1), SP) (n=10 per group). Additional hearts were excised for western blot and kinase activity assay: without further treatment, after the first, the second and the third period of Xe-PC or at the end of the last washout phase (n=4 each). RESULTS: Infarct size (% of area at risk) was reduced from 46.2 (8.1)% to 28.4 (11.3)% after Xe-PC (P<0.01). PD completely abolished this effect [49.7 (11.4)%, P<0.01 vs Xe-PC]. The ratio of particulate/cytosolic phospho ERK 1/2 was time dependently increased during the PC protocol [ERK 1: 15 min: 2.4 (1.2), 25 min: 1.5 (0.3), 35 min: 1.6 (0.7), 45 min: 1.5 (0.5) vs Con 1.0 (0.5) and ERK 2: 15 min: 3.3 (1.8), 25 min: 2.0 (1.5), 35 min: 1.8 (1.7), 45 min: 0.9 (0.6) vs Con 0.8 (0.4)]. This finding was confirmed by a non-radioactive MAPK activity assay. In contrast SP had no effect on Xe-PC and the phosphorylation state of JNK was not influenced by Xe-PC. CONCLUSION: Besides the p38 MAPK, ERK 1/2 also is a mediator of Xe-PC. However, JNK is not involved, demonstrating a highly specific regulation of different kinases during Xe-PC.

Role of protein kinase C-epsilon (PKCepsilon) in isoflurane-induced cardioprotection.

BACKGROUND: Volatile anaesthetics precondition the heart against infarction, an effect partly mediated by activation of the epsilon isoform of protein kinase C (PKCepsilon). We investigated whether cardioprotection by activation of PKCepsilon depends on the isoflurane concentration. METHODS: Anaesthetized rats underwent 25 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups (n=10 in each group): isoflurane preconditioning induced by 15 min administration of 0.4 minimal alveolar concentration (MAC) (0.4MAC), 1 MAC (1MAC) or 1.75 MAC (1.75MAC) followed by 10 min washout before ischaemia. Each protocol was repeated in the presence of the PKC inhibitor staurosporine (10 microg kg(-1)): 0.4MAC+S, 1MAC+S and 1.75MAC+S. Controls were untreated (CON) and additional hearts received staurosporine without isoflurane (S). In a second set of experiments (n=6 in each group) hearts were excised before the infarct inducing ischaemia, and phosphorylation and translocation of PKCepsilon were determined by western blot analysis. RESULTS: Isoflurane reduced infarct size from a mean of 61(SEM 2)% of the area at risk in controls to 20(1)% (0.4MAC), 26(3)% (1MAC) and 30(1)% (1.75MAC) (all P<0.01 vs CON or S). This protection was partially reversed by administration of staurosporine in the 0.4MAC+S group (30[2]%; P<0.05 vs 0.4MAC) group, but not after administration of 1 MAC or 1.75 MAC isoflurane (26[2]% and 31[2]%, respectively). Thus 0.4MAC increased PKCepsilon phosphorylation, and this effect was blocked by staurosporine. Higher concentrations of isoflurane did not change PKCepsilon phosphorylation. PKCepsilon was translocated to the membrane fraction after administration of 0.4 MAC isoflurane, but not after 1.0 or 1.75 MAC. CONCLUSIONS: Although isoflurane preconditioning resulted in a reduction in infarct size at all concentrations used, the protection was mediated by phosphorylation and translocation of PKCepsilon only at 0.4 MAC.