Microcystins (MCs) comprise a group of cyanobacterial toxins with hepatotoxic, nephrotoxic and, possibly, neurotoxic activity in mammals. In order to understand the development of their neurotoxicity we investigated the toxic effects of MC variants, MC-LR, MC-LW and MC-LF, in astrocytes that play a central role in maintaining brain homeostasis. 24 h exposure of cultured rat cortical astrocytes to MCs revealed dose-dependent toxicity of MC-LF and MC-LW, but not of MC-LR, observed by significant reduction in cell number, declined viability monitored by MTT test and an increased percentage of apoptotic cells, confirmed by Annexin-V labelling. The cultured astrocytes expressed organic anion-transporting polypeptides (Oatp) Oatp1a4, Oatp1c1 and Oatp1a5, but not Oatp1b2. Intracellular localisation of MC-LF and MC-LW, proven by anti-Adda primary antibody, demonstrated transport of tested MCs into cultured astrocytes. Acute MC-LW and MC-LF intoxication induced cytoskeletal disruption as seen by the degradation of glial fibrillary acid protein (GFAP), actin and the tubulin network. In this in vitro study, MC-LF and MC-LW, but not MC-LR, are shown to cause the dysfunction of astrocytic homeostatic capabilities, already at low concentrations, suggesting that astrocyte atrophy, with loss of function, could be expected in the brain response to the toxic insult.
COBISS.SI-ID: 32931545
We sought to evaluate the physiological background and the effects of CD34(+) cell transplantation on diastolic parameters in nonischemic dilated cardiomyopathy patients (DCM). We enrolled 38 DCM patients with NYHA class III and LVEF ( 40% who underwent transendocardial CD34(+) cell transplantation. Peripheral blood CD34(+) cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially in the areas of myocardial hibernation. Patients were followed for 1 year. At baseline, estimated filling pressures were significantly elevated (E/e' ≥ 15) in 18 patients (Group A), and moderately elevated (E/e '( 15) in 20 patients (Group B). The groups did not differ in age (54 ± 9 years vs. 52 ± 10 years; p = .62), gender (male: 85% vs. 78%; p = .57), or LVEF (31 ± 7% vs. 34 ± 6%; p = .37). When compared to Group B patients in Group A had more segments with myocardial scar (4.9 ± 2.7 vs. 2.7 ± 2.9; p = .03), myocardial hibernation (2.2 ± 1.6 vs. 0.9 ± 1.1; p = .02), and longer average local relaxation time on electroanatomical mapping (378 ± 41 ms vs. 333 ± 34 ms, p = .01). During follow-up there was an improvement in diastolic parameters in Group A (E/e': from 24.3 ± 12.1 to 16.3 ± 8.0; p = .005), but not in Group B (E/e': from 10.2 ± 3.7 to 13.2 ± 9.1; p = .19). Accordingly, in Group A, we found an increase in 6-minute walk distance (from 463 ± 83 m to 546 ± 91 m;p = .03), and a decrease in NTproBNP (from 2140 ± 1743 pg/ml to 863 ± 836 pg/ml;p = .02). In nonischemic DCM, diastolic dysfunction appears to correlate with areas of myocardial scar and hibernation. Transendocardial CD34(+) cell transplantation may improve diastolic parameters in this patient cohort.
COBISS.SI-ID: 3772588
Background: After neonatal asphyxia, therapeutic hypothermia (HT) is the only proven treatment option. Although established as a neuroprotective therapy, benefit from HT has been questioned when infection is a comorbidity to hypoxic-ischaemic (HI) brain injury. Gram-negative and gram-positive species activate the immune system through different pathogen recognition receptors and subsequent immunological systems. In rodent models, gram-negative (lipopolysaccharide [LPS]) and gram-positive (PAM3CSK4 [PAM]) inflammation similarly increase neuronal vulnerability to HI. Interestingly, while LPS pre-sensitisation negates the neuroprotective effect of HT, HT is highly beneficial after PAM-sensitised HI brain injury. Objective: We aimed to examine whether systemic gram-positive or gram-negative inflammatory sensitisation affects juvenile rat pups per se, without an HI insult. Methods: Neonatal 7-day-old rats (n = 215) received intraperitoneal injections of vehicle (0.9% NaCl), LPS (0.1 mg/kg), or PAM (1 mg/kg). Core temperature and weight gain were monitored. Brain cytokine expression (IL-6, IL-1%, TNF-%, and IL-10, via PCR), apoptosis (cleaved caspase 3, via Western blots), and microglial activation (Iba1, via immunohistochemistry) were examined. Results: LPS induced an immediate drop in core temperature followed by poor weight gain, none of which were seen after PAM. Furthermore, LPS induced brain apoptosis, while PAM did not. The magnitude and temporal profile of brain cytokine expression differed between LPS- and PAM-injected animals. Conclusion: These findings reveal sepsis-like conditions and neuroinflammation specific to the inflammatory stimulus (gram-positive vs. gram-negative) in the neonatal rat. They emphasise the importance of pre-clinical models being pathogen dependent, and should always be carefully tailored to their clinical scenario.
COBISS.SI-ID: 33568985
Context: Synthetic cannabinoids are getting more popular among young people and illicit manufacturers. We report a case series of occupational transdermal poisoning with synthetic cannabinoids. Case details: Three customs inspectors got in contact with a sticky substance with their fingertips because they were not wearing protection gloves and the delivered package was damaged. Despite washing their hands with water, signs of synthetic cannabinoids intoxication started occurring half an hour after exposure. On arrival at the Emergency Department six hours later, they were somnolent, lethargic and confused. They showed signs of mydriasis, blurred vision, ataxia, weakness, numbness, tachycardia and one of them had orthostatic hypotension. Two days later, they were feeling much better and reported amnesia and slowed perception of time after exposure. Toxicology analysis by LC-MS/MS revealed synthetic cannabinoid cumyl-PINACA (SGT-24) in their blood samples taken on admission. cumyl-PINACA was also confirmed with NMR method in liquid samples seized at the airport. It was 98% pure substance with the purpose of being diluted and sold further in the drug market by drug dealer. Discussion: This case series highlights the possible transdermal exposure to synthetic cannabinoids oil resulting in prolonged cannabinoid syndrome.
COBISS.SI-ID: 33123033
Context:In clinical practice it is difficult to differentiate between V. berus and V. ammodytes venomous bites. In the past this was not a concern, but due to the current shortage in Viperfav™ and European viper venom antiserum availability, V. a. ammodytes venomous bites have recently been treated with ViperaTAb®, which is a pharmaceutical formulation containing a monospecific ovine Fab fragments against the venom of V. berus. Objective:To evaluate ViperaTAb® in V. a. ammodytes envenomations. Materials and metds: This is a prospective case series of three consecutive patients envenomed by V. a. ammodytes snakebite treated with ViperaTAb®. V. ammodytes venom, neurotoxic ammodytoxins, and Fab fragment levels were determined in serum samples and a pharmacokinetic analysis of the antivenom Fab fragments was carried out. Results:Three patients bitten by V. a. ammodytes with extensive local swelling, neurological symptoms and recurrent thrombocytopenia were treated with ViperaTAb®. V. ammodytes venom was detected in serum of all three patients. Ammodytoxins were detected in the serum of only the most severely envenomed patient who developed neurological symptoms. In the presented moderate cases, a dose of 8 mL of ViperaTAb® reduced swelling and improved systemic effects, such as thrombocytopenia. However, this dose of ViperaTAb® was not effective in the most severely envenomed patient with the highest serum values of V. ammodytes venom. In this case ViperaTAb® did not stop local swelling and it had no effect on neurological signs. ViperaTAb®'s systemic clearance, distribution and elimination half-lives were 4.3-13.4 mL/h/kg, 1.2-3.2 h and 14.1-55.4 h, respectively. Conclusions: In patients envenomed by V. a. ammodytes venom, ViperaTAb® reduces moderate swelling and temporarily improves systemic effects, except neurological symptoms. ViperaTAb® application induces a decrement of V. ammodytes venom level in the blood, but did not affect serum concentration of neurotoxic ammodytoxins in the one patient with measurable concentrations.
COBISS.SI-ID: 30174759