Moving to human trials for argon neuroprotection in neurological injury: a narrative review.

Despite the global burden of brain injury, neuroprotective agents remain elusive. There are no clinically effective therapies which reduce mortality or improve long-term cognitive outcome. Ventilation could be an easily modifiable variable in resuscitation; gases are relatively simple to administer. Xenon is the prototypic agent of a new generation of experimental treatments which show promise. However, use is hindered by its prohibitive cost and anaesthetic properties. Argon is an attractive option, being cheaper, easy to transport, non-sedating, and mechanistically distinct from xenon. In vitro and in vivo models provide evidence of argon reducing brain injury, with improvements in neurocognitive, histological, and biomarker metrics, as well as improved survival. Current data suggest that the effect of argon is mediated via the toll-like receptors 2 and 4, the extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3 kinase (PI-3K)-AKT pathways. Ventilation with argon appears to be safe in pigs and preliminary human trials. Given recent evidence that arterial hyperoxia may be harmful, the supplementation of high-concentration argon may not necessitate changes to clinical practice. Given the logistic benefits, and the evidence for argon neuroprotection summarized in this manuscript, we believe that the time has come to consider developing Phase II clinical trials to assess its benefit in acute neurological injury.

Usefulness of Video Review of Possible Concussions in National Youth Rugby League.

A new concussion interchange rule (CIR) was introduced in 2014 for the National Rugby League and National Youth Competition (NYC). The CIR allows a player suspected of having sustained a concussion to be removed from play and assessed without an interchange being tallied against the player's team. Participants included all NYC players who used the CIR during the 2014 season. 2 raters completed video analysis of 131 (of a total of 156 reported) uses of the CIR, describing injury characteristics, situational factors, and concussion signs. The incidence rate was 44.9 (95% CI: 38.5-52.3) uses of the CIR per 1 000 NYC player match hours, or approximately one CIR use every 1.3 games. Apparent loss of consciousness/unresponsiveness was observed in 13% of cases, clutching the head in 65%, unsteadiness of gait in 60%, and a vacant stare in 23%. Most incidences occurred from a hit-up (82%). There appeared to be some instances of video evidence of injury but the athlete was cleared to return to play in the same game. Video review appears to be a useful adjunct for identifying players suffering possible concussion. Further research is required on the usefulness of video review for identifying signs of concussive injury.

Neuroepidemiology of traumatic brain injury.

Traumatic brain injury (TBI) is a significant public-health concern. TBI is defined as an acute brain injury resulting from mechanical energy to the head from external physical forces. Some of the leading causes of TBI include falls, assaults, motor vehicle or traffic accidents, and sport-related concussion. Two of the most common identified risk factors are sex (males are nearly three times more likely to suffer a TBI than females); and a bimodal age pattern (persons 65 years and older, and children under 14 years old). It is estimated that approximately 1.5-2 million Americans suffer from TBI annually. TBIs account for around 1.4 million emergency room visits, 275 000 hospital admissions, and 52 000 deaths in the USA each year. TBI contributes to approximately 30% of all deaths in the USA annually. In Australia, it is estimated that approximately 338 700 individuals (1.9% of the population) suffer from a disability related to TBI. Of these, 160 200 were severely or profoundly affected by acquired brain injury, requiring daily support. In the UK, TBI accounted for 3.4% of all emergency department attendances annually. An overall rate of 453 per 100 000 was found for all TBI severities, of which 40 per 100 000 (10.9%) were moderate to severe. TBI often results in residual symptoms that affect an individual's cognition, movement, sensation, and/or emotional functioning. Recovery and rehabilitation from TBI may require considerable resources and may take years. Some individuals never fully recover, and some require lifetime ongoing care and support. TBI has an enormous social and financial cost, with estimates of the annual financial burden associated with TBI ranging between 9 and 10 billion US dollars.

A Video Analysis of Use of the New 'Concussion Interchange Rule' in the National Rugby League.

The National Rugby League (NRL) in Australia introduced a new 'concussion interchange rule' (CIR) in 2014, whereby a player suspected of having sustained a concussion can be removed from play, and assessed, without an interchange being tallied against the player's team. We conducted a video analysis, describing player and injury characteristics, situational factors, concussion signs, and return to play for each "CIR" event for the 2014 season. There were 167 reported uses of the CIR. Apparent loss of consciousness/unresponsiveness was observed in 32% of cases, loss of muscle tone in 54%, clutching the head in 70%, unsteadiness of gait in 66%, and a vacant stare in 66%. More than half of the players who were removed under the CIR returned to play later in the same match (57%). Most incidences occurred from a hit up (62%) and occurred during a tackle where the initial contact was with the upper body (80%). The new concussion interchange rule has been used frequently during the first season of its implementation. In many cases, there appeared to be video evidence of injury but the athlete was cleared to return to play. More research is needed on the usefulness of video review for identifying signs of concussive injury.

Complex cases in primary care: report of a CME-certified series addressing patients with multiple comorbidities.

AIM: To assess whether participation in a series of continuing medical education-certified activities presenting complicated case scenarios resulted in evidence-based decision making for patients with chronic comorbid conditions. METHODS: A series of interactive live workshops and online case studies presented evidence-based, practical information addressing the care of patients with multiple chronic diseases to primary care physicians. Clinical case vignettes were used to assess workshop participant knowledge and competence. Results were compared with those of matched non-participant controls. Online participants were surveyed to evaluate immediate knowledge gains from the activity. RESULTS: Overall, physician workshop participants were 27% more knowledgeable of evidence-based treatment decisions. Participants were more likely to refer a patient with rheumatoid arthritis to a rheumatologist (57% vs. 36%; p = 0.035) and showed better recognition of medications that can contribute to overactive bladder symptoms (36% vs. 18%; p = 0.043) compared with non-participant controls. Non-significant differences in favour of participants included evidence-based decisions regarding the management of osteoporosis, attention deficit hyperactivity disorder in adults and type 2 diabetes mellitus in adolescents. Online participants demonstrated significant knowledge gains (p < 0.001) on 17 of 18 assessment questions across all therapeutic areas. DISCUSSION: Chronic comorbid conditions afflict a sizable minority of patients. However, specific recommendations and education surrounding patient management are often overlooked because of the inherent difficulty of treating this group. Highly interactive educational activities can improve participant knowledge and competency in treating these patients by providing an opportunity to interact with faculty experts, receive immediate feedback and practice new skills. CONCLUSION: Interactive educational activities that discuss complicated case scenarios can improve participant application of evidence-based medicine for patients with multiple chronic comorbidities.

Synthesis and in vitro biological activity of 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha,12 alpha-diol, a 12alpha-hydroxyl analog of 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol: the latter is a potent activator of the low-density lipoprotein receptor promoter.

4alpha-(2-Propenyl)-5alpha-cholest-24-en-3alpha-ol (3) was shown recently in a Chinese hamster ovary (CHO) cell-based low-density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. Because of the involvement of 12alpha-hydroxylation in the metabolism of cholesterol, we are interested in investigating the effect of introducing a 12alpha-hydroxyl group to 3 on the transcriptional activity of the LDL receptor promoter. Thus 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha,12a lpha-diol (14), a 12alpha-hydroxyl analog of 3, was synthesized from deoxycholic acid via the formation of 12alpha-[[(tertbutyl)dimethylsilyl]oxy]-4alpha-( 2-propenyl)-5alpha-cholest-24-en-3-one (11). Test results show that 14 is inactive at concentrations of up to 20 microg/ml, compared to 3 with an EC30 value of 2.6 microM, in the CHO cell-based LDLR/Luc assay. Apparently introduction of a 12alpha-hydroxyl group abolishes the capability of 3alpha-sterol 14 to activate the transcription of the LDL receptor promoter. However, in the [1-14C-acetate]cholesterol biosynthesis inhibition assay in CHO cells, 14 at 10 microg/ml (23 microM) is shown to inhibit the cholesterol biosynthesis by 51% relative to the control cells. Our previous studies indicated that 3 showed a 38% inhibition, but 4alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (1) exhibited no inhibition in the same assay at 10 microg/ml. In summary the results indicate that, in addition to the 24,25-unsaturation, the 12alpha-hydroxyl group in 14 has also conferred an inhibitory effect on cholesterol biosynthesis in CHO cells; however, the inhibition of cholesterol biosynthesis by 14 does not lead to the transcriptional activation of the LDL receptor promoter.

Synthesis and in vitro biological activity of 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol: a 24,25-dehydro analog of the hypocholesterolemic agent 4alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol.

4Alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (LY295427) was previously identified from a Chinese hamster ovary (CHO) cell-based low density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. To investigate the effect of the 24,25-unsaturation in the D-ring side chain (desmosterol D-ring side chain) on antagonizing the repressing effect of 25-hydroxycholesterol, 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol (17), a 24,25-dehydro analog of LY295427, was thus synthesized from lithocholic acid via the formation of 3alpha-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4alpha- (2-propenyl)-5alpha-cholan-24-al (15). Test results showed that 17 had an EC30 value of 2.6 microM, comparable to 2.9 microM of LY295427, in the CHO cell-based LDLR/Luc assay in the presence of 25-hydroxycholesterol. Apparently, the built-in 24,25-unsaturation in the D-ring side chain of 17 had added little effect to antagonizing the repressing effect of 25-hydroxycholesterol. In the [1-14C-acetate]cholesterol biosynthesis inhibition assay, 17 at 10 microg/ml (23 microM) has been shown to inhibit the cholesterol biosynthesis in CHO cells by 38% relative to the vehicle control; whereas LY295427 showed no inhibition in the same assay in our previous studies. In contrast to LY295427, the built-in 24,25-unsaturation in the D-ring side chain of 17 has conferred an inhibitory effect on cholesterol biosynthesis in CHO cells. In summary, the observed LDL receptor promoter activity of 17 is related to its ability to prevent 25-hydroxycholesterol from exerting the repressing effect via an undetermined mechanism and, in part, to inhibit the cholesterol biosynthesis.

Outpatient transesophageal echocardiography with intravenous propofol anesthesia in children and adolescents.

Outpatient transesophageal echocardiography (TEE) was performed in 10 children and adolescents (aged 3 to 19.5 years, mean 13.5 years; weight 12 to 91 kg, mean 49 kg), including two with Down's syndrome and one with autism, for diagnostic evaluation of issues unresolved by transthoracic echo examination (TTE). Issues for TEE: evaluation for atrial septal defect (two patients); anatomy of left ventricular outflow tract obstruction (one patient); aortic valve anatomy before valvuloplasty for insufficiency (one patient); evaluation for cause of cyanosis after Fontan operation (one patient); determination of source of high-velocity intracardiac turbulence after atrioventricular septal defect repair (one patient); rule out cardiac embolic source in patient with stroke (one patient); evaluate prosthetic valve function and rule out thrombus (one patient); determination of anatomic relationship of mitral valve to a ventricular septal defect before surgery for complex cyanotic heart disease (one patient); and evaluation for aortic dissection in Marfan's syndrome (one patient). Intravenous propofol anesthesia administered without endotracheal intubation by an anesthesiologist allowed successful outpatient TEE in nine patients; midazolam-conscious sedation was used in one. Outpatient TEE resolved diagnostic issues in all patients without complication, thereby avoiding cardiac catheterization in six patients and supplementing catheterization for preoperative planning in four patients. TEE can be performed safely and effectively with propofol anesthesia in the outpatient setting in carefully selected children and adolescents to provide vital diagnostic information. However, given the invasive nature of the procedure and the use of anesthesia, outpatient pediatric TEE should be used judiciously.

Sinusoidal fetal heart rate pattern associated with alphaprodine administration.

Sinusoidal fetal heart rate patterns were observed in 42.5% of a group of 40 women who had received alphaprodine (Nisentil) for relief of labor pain. Analysis showed that the pattern appeared approximately 19 minutes following alphaprodine administration and persisted for approximately 60 minutes. In a control group of 18 patients who did not receive narcotic analgesia, and intermittent sinusoidal pattern was observed in one patient. All babies with sinusoidal heart rate during labor had 1-minute Apgar scores of 7 or greater except two in the study group. Both these neonates had low Apgar scores directly associated with complications at delivery. All 5-minute Apgar scores were 7 or greater, and there were no perinatal deaths.

Self-mutilation, obsessionality and narcissism.

A controlled study of the clinical and biographical features of 22 female repeated self-cutters is described. The results of the assessment of these patients, using the Middlesex Hospital Questionnaire and the Obsessive-Compulsive section of the Tavistock Inventory, is presented. The marked obsessionality of these patients is emphasized and the possible implications of these findings for treatment is discussed.

Neuropathy after alcohol withdrawal.

Three probable cases of neuropathy in alcoholics are described. They are very atypical for three reasons. First, each developed an acute asymmetrical neuropathy for the first time well after ceasing to drink, and after routine saturation with the vitamin B group. Secondly, none had previously suffered from neuropathy while still drinking. If this puzzling reversal of the usual order of clinical events has been noticed before, no record has been found in the literature. Further study by psychiatrists treating alcoholics aided by their neurological colleagues is suggested.