Incidence and characteristics of severe exercise-associated collapse at the world's largest half-marathon

Background Whilst many health benefits are associated with regular exercise, medical complications may occur during higher-intensity activities, such as long distance running contests. The most common complication is collapse. However, the incidence and characteristics of these collapses are not very well studied. Method This is a retrospective study of severe collapse, defined as a patient in need of advanced medical care after a collapse, during the large Gothenburg's half marathon, Goteborgsvarvet. The study included 230,501 competitors during the study-period of 5 years (20132017) with data being collected from medical race tents and using ambulance data. Vital signs, treatment and blood gas samples were noted and analyzed. Results The incidence of severe collapse was 1.53 per 1000 starting runners. The average age for patients was 34 years old and no difference in incidence were seen between male and female runners. The typical collapsed runner presented with tachycardia, normal systolic blood pressure, elevated body temperature and metabolic acidosis. The most common medical encounter was exercise-associated collapse. Conclusion The incidence of severe collapse was similar to findings in other studies, even though this study was set in different part of the world. Typical characteristics of a collapsed runner were identified providing new information which could be beneficial in the medical planning of larger running competitions and future preventative interventions. Importantly, life threatening conditions seem uncommon; no case of hyponatremia and only two cases of hypoglycemia were seen

Efficacy and safety of dexanabinol in severe traumatic brain injury : results of a phase III randomised, placebo-controlled, clinical trial

Background Traumatic brain injury is a major cause of death and disability. We sought to assess the safety and efficacy of dexanabinol, a synthetic cannabinoid analogue devoid of psychotropic activity, in severe traumatic brain injury. Methods 861 patients with severe traumatic brain injury admitted to 86 specialist centres from 15 countries were included in a multi-centre, placebo-controlled, phase III trial. Patients were randomised to receive a single intravenous 150 mg dose of dexanabinol or placebo within 6 h of injury. The primary outcome was the extended Glasgow outcome scale assessed at 6 months, with the point of dichotomisation into unfavourable versus favourable outcome differentiated by baseline prognostic risk. Prespecified subgroup analyses were defined by injury severity, recruitment rate, and time to dosing. Secondary analysis included control of intracranial pressure and quality of life. Analysis were prespecified in the protocol and the statistical analysis plan. This study is registered with ClinicalTrials.gov, number NCT00129857. Findings 846 patients were included in the efficacy analysis. The extended Glasgow outcome scale at 6 months did not differ between groups; 215 (50%) patients in the dexanabinol group and 214 (51%) patients in the placebo group had an unfavourable outcome (odds ratio for a favourable response 1.04; 95% CI 0.79-1.36). Improvements in the control of intracranial pressure or quality of life were not recorded and subgroup analysis showed no indication of differential treatment effects. Dexanabinol was not associated with hepatic, renal, or cardiac toxic effects. Interpretation Dexanabinol is safe, but is not efficacious in the treatment of traumatic brain injury

Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ET(B) receptor, NADPH oxidase and caveolin-1

1. Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, participates in the regulation of endothelial function through mechanisms that are not fully elucidated. This study examined the impact of ET-1 on oxidative stress, apoptosis and cell proliferation in human umbilical vein endothelial cells (HUVEC). HUVECs were challenged for 24 h with ET-1 (10 pM–10 nM) in the absence or presence of the ET(B) receptor antagonist BQ788 (1 μM) or the NADPH oxidase inhibitor apocynin (1 μM). Reactive oxygen species (ROS) were detected using chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated with 4′,6′-diamidino-2′-phenylindoladihydrochloride staining and by the caspase-3 assay. Cell proliferation was measured by a colorimetric assay. Expression of NADPH oxidase, Akt, pAkt, Bcl-2, Bax, IκB, caveolin-1 and eNOS was evaluated by Western blot analysis. 2. ET-1 significantly enhanced ROS generation and cell proliferation following 24-h incubation, both of which were prevented by BQ788 or apocynin, consistent with the ability of ET-1 to directly upregulate NADPH oxidase. ET-1 itself did not affect apoptosis but attenuated homocysteine-induced apoptosis through an ET(B) receptor-mediated mechanism. Western blot analysis indicated that ET-1 alleviated homocysteine (Hcy)-induced apoptosis, likely acting by antagonizing the Hcy-induced decreases in Akt, pAkt, pAkt-to-Akt, Bcl-2-to-Bax ratios and increases in Bax and caveolin-1 expression. Furthermore, ET-1 downregulated expression of caveolin-1 and eNOS, which was attenuated by BQ788 or apocynin. 3. In summary, our results suggest that ET-1 affects oxidative stress, proliferation and apoptosis possibly through ET(B), NADPH oxidase, Akt, Bax and caveolin-1-mediated mechanisms

Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-κB at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death

As the origin of a ‘life-and-death’ signal that reflects central cardiovascular regulatory failure during brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this vital phenomenon. Using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult, we evaluated the hypothesis that transcriptional up-regulation of nitric oxide synthase I or II (NOS I or II) gene expression by nuclear factor-κB (NF-κB) on activation of muscarinic receptors in the RVLM underlies brain stem death. In Sprague-Dawley rats maintained under propofol anaesthesia, co-microinjection of muscarinic M2R (methoctramine) or M4R (tropicamide), but not M1R (pirenzepine) or M3R (4-diphenylacetoxy-N-dimethylpiperidinium) antagonist significantly reduced the enhanced NOS I–protein kinase G signalling (‘pro-life’ phase) or augmented NOS II–peroxynitrite cascade (‘pro-death’ phase) in ventrolateral medulla, blunted the biphasic increase and decrease in baroreceptor reflex-mediated sympathetic vasomotor tone that reflect the transition from life to death, and diminished the elevated DNA binding activity or nucleus-bound translocation of NF-κB in RVLM neurons induced by microinjection of Mev into the bilateral RVLM. However, NF-κB inhibitors (diethyldithiocarbamate or pyrrolidine dithiocarbamate) or double-stranded κB decoy DNA preferentially antagonized the augmented NOS II–peroxynitrite cascade and the associated cardiovascular depression exhibited during the ‘pro-death’ phase. We conclude that transcriptional up-regulation of NOS II gene expression by activation of NF-κB on selective stimulation of muscarinic M2 or M4 subtype receptors in the RVLM underlies the elicited cardiovascular depression during the ‘pro-death’ phase in our Mev intoxication model of brain stem death

A Novel Mitogen-Activated Protein Kinase Phosphatase Is an Important Negative Regulator of Lipopolysaccharide-Mediated c-Jun N-Terminal Kinase Activation in Mouse Macrophage Cell Lines

We have isolated a cDNA homologous to known dual-specificity phosphatases from a mouse macrophage cDNA library and termed it MKP-M (for mitogen-activated protein kinase phosphatase isolated from macrophages). Three other presumed splice variant isoforms have also been identified for MKP-M. The longest and most abundant mRNA contains an open reading frame corresponding to 677 amino acids and produces an 80-kDa protein. The deduced amino acid sequence of MKP-M is most similar to those of hVH-5 (or mouse M3/6) and VHP1, a Caenorhabditis elegans tyrosine phosphatase. It includes an N-terminal rhodanase homology domain, the extended active-site sequence motif (V/L)X(V/I)HCXAG(I/V)SRSXT(I/V)XXAY(L/I)M (where X is any amino acid), and a C-terminal PEST sequence. Northern blot analysis revealed a dominant MKP-M mRNA species of approximately 5.5 kb detected ubiquitously among all tissues examined. MKP-M was constitutively expressed in mouse macrophage cell lines, and its expression levels were rapidly increased by lipopolysaccharide (LPS) stimulation but not by tumor necrosis factor alpha (TNF-α), gamma interferon, interleukin-2 (IL-2), or IL-15 stimulation. Immunocytochemical analysis showed MKP-M to be present within cytosol. When expressed in COS7 cells, MKP-M blocks activation of mitogen-activated protein kinases with the selectivity c-Jun N-terminal kinase (JNK) ≫ p38 = extracellular signal-regulated kinase. Furthermore, expression of a catalytically inactive form of MKP-M in a mouse macrophage cell line increased the intensity and duration of JNK activation and TNF-α secretion after LPS stimulation, suggesting that MKP-M is at least partially responsible for the desensitization of LPS-mediated JNK activation and cytokine secretion in macrophages