Methotrexate (MTX) is a widely used anticancer and antirheumatic drug that has been postulated to protect against metabolic risk factors associated with type 2 diabetes, although the mechanism remains unknown. MTX inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) and thereby slows the metabolism of 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranosyl-5'-monophosphate (ZMP) and its precursor AICAR, which is a pharmacological AMPK activator. We explored whether MTX promotes AMPK activation in cultured myotubes and isolated skeletal muscle. We found MTX markedly reduced the threshold for AICAR-induced AMPK activation and potentiated glucose uptake and lipid oxidation. Gene silencing of the MTX target ATIC activated AMPK and stimulated lipid oxidation in cultured myotubes. Furthermore, MTX activated AMPK in wild-type HEK-293 cells. These effects were abolished in skeletal muscle lacking the muscle-specific, ZMP-sensitive AMPK-gamma3 subunit and in HEK-293 cells expressing a ZMP-insensitive mutant AMPK-gamma2 subunit. Collectively, our findings underscore a role for AMPK as a direct molecular link between MTX and energy metabolism in skeletal muscle. Cotherapy with AICAR and MTX could represent a novel strategy to treat metabolic disorders and overcome current limitations of AICAR monotherapy.
COBISS.SI-ID: 31657689
Liposomal bupivacaine is a prolonged-release local anaesthetic, the neurotoxicity of which has not yet been determined. We used quantitative histomorphometric and immunohistochemical analyses to evaluate the neurotoxic effect of liposomal bupivacaine after perineural and intraneural (extrafascicular) injection of the sciatic nerve in pigs. In this double-blind prospective randomised trial, 4 ml liposomal bupivacaine 1.3% was injected either perineurally (n = 5) or intraneurally extrafascicularly (n = 5). Intraneural extrafascicular injection of saline (n = 5) was used as a control. After emergence from anaesthesia, neurological examinations were conducted over two weeks. After harvesting the sciatic nerves, no changes in nerve fibre density or myelin width indicative of nerve injury were observed in any of the groups. Intraneural injections resulted in longer sensory blockade than perineural (p ( 0.003) without persistent motor or sensory deficit. Sciatic nerve block with liposomal bupivacaine in pigs did not result in histological evidence of nerve injury.
COBISS.SI-ID: 32164313
Aim of the study This study aimed to establish the incidence, number and location of CPR-related skeletal chest injuries (SCI) and to investigate the influence of age, gender, changes in resuscitation guidelines and technique of resuscitation. Methods We analysed SCI in 2148 patients who had undergone resuscitation for non-traumatic cardiac arrest, as shown by autopsies performed at the Institute of Forensic Medicine in Ljubljana in the period 2004-2013. Results External cardiac massage caused SCI in 86% of males and in 91% of females; sternum fractures occurred in 59% of males and 79% of females, rib fractures in 77% of males and 85% of females and sternocostal separations in 33% of males and 12% of females. The average number of all SCI per person was thus almost the same in males and females: 10.95 vs. 10.96. The percentage of patients injured and the number of SCI increased with age. Changes in resuscitation guidelines were also identified as a factor contributing to the incidence and number of SCI. No adverse effect of the use of LUCAS was found. Conclusion It is generally considered that at least 1/3 of resuscitated patients sustain rib fractures and at least 1/5 sustains sternum fractures. However, our study showed that these injuries are much more frequent and that increased compression rate and depth cause more SCI. Since in the period 2011-2013 accompanying severe injuries occurred in only 1.85% of cases, the resuscitation technique has not yet jeopardised patient's safety, but further close monitoring is needed.
COBISS.SI-ID: 32159449
In this mini-review, we briefly present the data regarding the effect of extrinsic factors, i.e., innervation and thyroid hormones (TH) on myosin heavy chain genes and isoforms expression and consequently on muscle fiber type transitions. It has been well known that reduced neuromuscular activity, hyperthyroidism or mechanical unloading stimulate slow-to-fast fiber type transitions, while increased neuromuscular activity, hypothyroidism and higher mechanical loading result in fast to slow fiber type transitions. As there is a plethora of results on these topics, we focus mostly on data relevant to our experimental model of slow-to-fast muscle transformation following heterochronous intramuscular isotransplantation in rats with altered TH status.
COBISS.SI-ID: 31712985
The examination of nerve microarchitecture has hitherto been limited solely to two-dimensional imaging techniques. The objective of this study was to evaluate the ability of optical projection tomography to discern the nerve microarchitecture and injection injury in three dimensions. Five piglets were studied, whose median and lingual nerves were unilaterally injected post mortem with preset volumes of local anaesthetic, excised and subsequently made transparent with benzyl alcohol benzyl benzoate. Images were captured in three dimensions. The same contralateral nerves were used as controls. Using optical projection tomography, we observed differences between the internal organisation of the median and the lingual nerves, which potentially explain the variations in their susceptibility to injury. This was demonstrated in three dimensions as a disruption to the fascicles in the lingual nerve, and their displacement in the median nerve. This new technology offers potential for studying nerve microarchitecture topography and its tolerance to injection injury.
COBISS.SI-ID: 31918809