Dynamic Blood-Brain Barrier Regulation in Mild Traumatic Brain Injury.

Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI.

Liberal Glucose Control in ICU Patients With Diabetes: A Before-and-After Study.

OBJECTIVES: To assess the feasibility, biochemical efficacy, and safety of liberal versus conventional glucose control in ICU patients with diabetes. DESIGN: Prospective, open-label, sequential period study. SETTING: A 22-bed mixed ICU of a tertiary hospital in Australia. PATIENTS: We compared 350 consecutive patients with diabetes admitted over 15 months who received liberal glucose control with a preintervention control population of 350 consecutive patients with diabetes who received conventional glucose control. INTERVENTIONS: Liberal control patients received insulin therapy if glucose was greater than 14 mmol/L (target: 10-14 mmol/L [180-252 mg/dL]). Conventional control patients received insulin therapy if glucose was greater than 10 mmol/L (target: 6-10 mmol/L [108-180 mg/dL]). MEASUREMENTS AND MAIN RESULTS: We assessed separation in blood glucose, insulin requirements, occurrence of hypoglycemia (blood glucose ≤ 3.9 mmol/L [70 mg/dL]), creatinine and white cell count levels, and clinical outcomes. The median (interquartile range) time-weighted average blood glucose concentration was significantly higher in the liberal control group (11.0 mmol/L [8.7-12.0 mmol/L]; 198 mg/dL [157-216 mg/dL]) than in the conventional control group (9.6 mmol/L [8.5-11.0 mmol/L]; 173 mg/dL [153-198 mg/dL]; p < 0.001). Overall, 132 liberal control patients (37.7%) and 188 conventional control patients (53.7%) received insulin in ICU (p < 0.001). Hypoglycemia occurred in 6.6% and 8.6%, respectively (p = 0.32). Among 314 patients with glycated hemoglobin A1c greater than or equal to 7%, hypoglycemia occurred in 4.1% and 9.6%, respectively (p = 0.053). Trajectories of creatinine and white cell count were similar in the groups. In multivariable analyses, we found no independent association between glucose control and mortality, duration of mechanical ventilation, or ICU-free days to day 30. CONCLUSIONS: In ICU patients with diabetes, during a period of liberal glucose control, insulin administration, and among patients with hemoglobin A1c greater than or equal to 7%, the prevalence of hypoglycemia was reduced, without negatively affecting serum creatinine, the white cell count response, or other clinical outcomes. (Trial Registration: Australian New Zealand Clinical Trials Registry; ACTRN12615000216516).

Characteristics and outcome of patients with the ICU Admission diagnosis of status epilepticus in Australia and New Zealand.

OBJECTIVES: Status epilepticus (SE) is a neurological emergency and may lead to Intensive Care Unit (ICU) admission. However, little is known about the characteristics and outcome of patients with the ICU admission diagnosis of SE. METHODS: We performed a retrospective study of patients admitted to ICU with the primary admission diagnosis of SE as recorded in the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database over more than a decade. We examined the ICU and population incidence, physiological and demographic features of such SE patients; compared ventilated and non-ventilated SE patients and assessed their mortality. RESULTS: From 2000-2013, 12,926 patients (1.2% of all ICU admissions) were admitted to ANZ ICUs with SE as the main admission diagnosis. Over the study period, the ICU prevalence (0.93 vs 1.13%), population incidence (30 vs 61 per million population), ICU length of stay (1.45 vs 1.77 days) and the rate of discharge to a rehabilitation facility (2.3 vs 7.1%) of SE increased (P < .0001). In contrast, the use of mechanical ventilation (56.6 vs 47.2%), hospital length of stay (6.64 vs 5.81 days), ICU (2.6 vs 0.75%) and hospital (8.2 vs 4%) mortality decreased (P < .0001). Overall hospital mortality was 613 (4.7%) with 219 (1.7%) patients dying in ICU. Mortality was associated with advancing age, multiple co-morbidities, lower GCS on admission and higher APACHE III scores. From 2000 to 2013 ICU mortality decreased from 2.6% to 0.75%. SIGNIFICANCE: Over a 14-year period in ANZ, there have been major changes in the features, management and outcome of patients admitted to ICU with the primary admission diagnosis of SE such that their ICU mortality is now <1%.

Molecular basis of adaptation to high soil boron in wheat landraces and elite cultivars.

Environmental constraints severely restrict crop yields in most production environments, and expanding the use of variation will underpin future progress in breeding. In semi-arid environments boron toxicity constrains productivity, and genetic improvement is the only effective strategy for addressing the problem. Wheat breeders have sought and used available genetic diversity from landraces to maintain yield in these environments; however, the identity of the genes at the major tolerance loci was unknown. Here we describe the identification of near-identical, root-specific boron transporter genes underlying the two major-effect quantitative trait loci for boron tolerance in wheat, Bo1 and Bo4 (ref. 2). We show that tolerance to a high concentration of boron is associated with multiple genomic changes including tetraploid introgression, dispersed gene duplication, and variation in gene structure and transcript level. An allelic series was identified from a panel of bread and durum wheat cultivars and landraces originating from diverse agronomic zones. Our results demonstrate that, during selection, breeders have matched functionally different boron tolerance alleles to specific environments. The characterization of boron tolerance in wheat illustrates the power of the new wheat genomic resources to define key adaptive processes that have underpinned crop improvement.

Synthesis of a mitochondria-targeted spin trap using a novel Parham-type cyclization.

A new cyclic nitrone spin trap, [4-(3',3'-dibutyl-2'-oxy-3'H-isoindol-5'-yloxy)butyl]triphenylphosphonium bromide (MitoSpin), bearing a lipophilic cation has been prepared by a route that involves a novel Parham-type lithiation-cyclization of an isocyanate to give the isoindolinone core. MitoSpin accumulates in a membrane potential dependent way in energized mitochondria and its oxidation could potentially be used in the study of oxidative stress resulting from reactive oxygen species generated in mitochondria.

Boron-toxicity tolerance in barley arising from efflux transporter amplification.

Both limiting and toxic soil concentrations of the essential micronutrient boron represent major limitations to crop production worldwide. We identified Bot1, a BOR1 ortholog, as the gene responsible for the superior boron-toxicity tolerance of the Algerian barley landrace Sahara 3771 (Sahara). Bot1 was located at the tolerance locus by high-resolution mapping. Compared to intolerant genotypes, Sahara contains about four times as many Bot1 gene copies, produces substantially more Bot1 transcript, and encodes a Bot1 protein with a higher capacity to provide tolerance in yeast. Bot1 transcript levels identified in barley tissues are consistent with a role in limiting the net entry of boron into the root and in the disposal of boron from leaves via hydathode guttation.

Development of a new EPR spin trap, DOD-8C (N-[4-dodecyloxy-2-(7'-carboxyhept-1'-yloxy)benzylidene]-N-tert-butylamine N-oxide), for the trapping of lipid radicals at a predetermined depth within biological membranes.

We report on the development of the first member of a new family of EPR spin-trapping agents designed to trap radicals at a predetermined depth within biological membranes. By analogy to the use of nitroxide spin labels to 'report' on the environment at specific depths within biological membranes, we set out to prepare similar reporter molecules, but with a nitrone in place of the nitroxide function. The prototype compounds were tested in a model system consisting of large unilamellar vesicles exposed to a copper-dependent radical generating system. This entailed the reduction of tert-butylhydroperoxide to the tert-butoxyl radical ((t)BuO(.-)) by a membrane-permeable Cu(I) complex, which was generated in situ by reduction of the Cu(II) complex by ascorbate. To assist in the identification of the radicals detected, preliminary studies were performed in methanolic solution, where the major radical trapped was shown to be (.-)CH(2)OH, resulting from H-atom abstraction from the alcohol by (t)BuO(.-). This conclusion was shown to be in agreement with predictions based on chemical kinetics, which were then used to support the proposal that the primary species trapped in the lipid vesicles were radicals derived from membrane fatty acids. This molecule represents the first of a new generation of spin traps which, through modification, can be used to position the radical-trapping nitrone moiety at chosen depths within biological membranes.

Supplementary nurse prescribing.

AIM: To explore the attitudes of multidisciplinary team members to nurse prescribing and to establish its perceived advantages and disadvantages. METHOD: Five focus groups were conducted with a range of healthcare professionals in one trust. A total of 46 participants took part in the study A structured schedule was used during each discussion to elicit group members' views on supplementary nurse prescribing. The data were analysed thematically and key themes and concepts were identified. FINDINGS: These are summarised under five main headings: what is supplementary prescribing?; why introduce supplementary prescribing?; perceived benefits of supplementary prescribing; concerns about supplementary prescribing; and skills necessary for supplementary prescribing. Analysis of the data suggests that although teams were generally supportive of nurse prescribing they are largely confused about what is being recommended and why. There was concern about how nurse prescribing will be implemented and its potential to disrupt team functioning. CONCLUSION: A considerable amount of preparation will be required to ensure that nurse prescribers have the organisational and team support to adapt to their new roles.