Understanding the resistance to creating safer ice hockey: essential points for injury prevention.

INTRODUCTION: Despite the known negative health outcomes of concussions in minor level boys' hockey, there has been significant resistance to creating a safer game with less body checking. METHODS: To better understand cultural barriers that prevent making the sport safer for youth and adolescents, semistructured interviews, with 20 ice hockey stakeholders, were conducted and analysed using thematic analysis. RESULTS: Through this analysis, two primary concepts arose from respondents. The first concept is that body checking, despite the harm it can cause, should be done in a respectful sportsmanlike fashion. The second concept is the contradiction that the game of ice hockey is both dynamic and unchangeable. DISCUSSION: Using structural functionalist theory, we propose an argument that the unfortunate perpetuation of violence and body checking in youth ice hockey serves to maintain the social order of the game and its culture. Any strategies aimed at modifying and promoting healthy behaviour in the game should take these concepts into account.

Sleep disruption elevates oxidative stress in parvalbumin-positive cells of the rat cerebral cortex.

We used a novel automated sleep disruption (SD) apparatus to determine the impact of SD on sleep and molecular markers of oxidative stress in parvalbumin (PV) neurons in the rat prefrontal cortex (PFC). Rats were subjected to two 6 hr SD sessions from zeitgeber time (ZT) 0 to ZT6, one by the gentle handling method and the other by an automated agitator running the length of the rat's home cage floor (a novel SD method). The same rats were later subjected to a 12 hr SD session from ZT0 to ZT12. Sleep was disrupted with both methods, although rats slept less during gentle handling than during the automated condition. Immediately after both SD sessions, rats displayed compensatory sleep characterized by elevated slow-wave activity. We measured in the prelimbic prefrontal cortex (prelimbic PFC; 6 and 12 hr SD) and orbital frontal cortex (12 hr SD) the intensity of the oxidative stress marker, 8-oxo-2'-deoxyguanosine (8-oxo-dG) as well as the staining intensity of PV and the PV cell-associated perineuronal net marker, Wisteria floribunda agglutinin (WFA). In the prelimbic PFC, 6 hr SD increased the intensity of 8-oxo-dG, PV, and WFA. After 12 hr SD, the intensity of 8-oxo-dG was elevated in all neurons. PV intensity was elevated only in neurons colabeled with 8-oxo-dG or WFA, and no changes were found in WFA intensity. We conclude that in association with SD-induced sleep drive, PV neurons in the prelimbic PFC exhibit oxidative stress.

Cardiovascular Magnetic Resonance in the Oncology Patient.

Patients with or receiving potentially cardiotoxic treatment for cancer are susceptible to developing decrements in left ventricular mass, diastolic function, or systolic function. They may also experience valvular heart disease, pericardial disease, or intracardiac masses. Cardiovascular magnetic resonance may be used to assess cardiac anatomy, structure, and function and to characterize myocardial tissue. This combination of features facilitates the diagnosis and management of disease processes in patients with or those who have survived cancer. This report outlines and describes prior research involving cardiovascular magnetic resonance for assessing cardiovascular disease in patients with or previously having received treatment for cancer.

Effects of active dry yeast on ruminal pH characteristics and energy partitioning of finishing steers under thermoneutral or heat-stressed environment.

The objective of this trial was to determine the effects of supplementing active dried yeast (ADY) in the diets of finishing steers on energy and nitrogen metabolism and ruminal pH characteristics under thermoneutral (TN) or heat-stressed (HS) conditions. Eight British cross steers received 1 of 2 treatments (TRT) [either a control finishing diet (CON) or supplemented with 3 g/d of ADY] under 1 of 2 temperatures [TEMP: TN = 18 ± 0.55 °C and 20 ± 1.2% relative humidity (RH) or HS = 35 ± 0.55 °C and 42 ± 6.1% RH]. Steers were orally administered an indwelling rumen pH and temperature recording bolus. Data collection occurred for 48 consecutive hours inside 2 calorimetry chambers. Data were analyzed as a 4 × 8 Latin rectangle design with fixed effects of TRT and TEMP and random effects of steer and period. There were no TRT × TEMP interactions for metabolism or calorimetric measurements (P ≥ 0.1510). In vivo DM digestibility (DMD) was greater for ADY-fed steers than for CON-fed steers (77.1% vs. 75.3%, respectively; P = 0.0311). No TRT (P = 0.3032) or TEMP (P = 0.1833) effect was observed for nitrogen retention. Energy partitioning suggested DE and ME (Mcal/kg) were greater for ADY-fed steers than for CON-fed steers (P = 0.0097 and P = 0.0377, respectively). Steers under HS had reduced DMI but greater DMD than TN steers (77.1% vs. 75.3%, respectively; P = 0.0316) and greater CH4 per unit of DM (8.53 vs. 6.47 g/kg, respectively; P = 0.0145). Although DE was greater for HS than TN (3.16 vs. 3.06 Mcal/kg, respectively; P = 0.0123), heat production energy (HE) tended to be greater for HS than TN (18.1 vs. 17.0 Mcal/d, respectively; P = 0.0743), resulting in a less retained energy (0.412 vs. 0.100 Mcal/kg; P = 0.0147). There was a tendency for an interaction of mean ruminal pH (P = 0.1279) where pH of ADY-fed steers was greater than pH of CON-fed steers under TN conditions (5.81 vs. 5.57, respectively), but not under HS conditions (5.37 vs. 5.41, respectively). Duration (DUR) and area under the curve (AUC) for pH > 5.6 had similar tendencies; under TN conditions, the DUR and AUC for pH > 5.6 in ADY-fed steers were greater than in CON-fed steers (P = 0.0726 and P = 0.0954, respectively), but under HS conditions, there was no difference between ADY and CON. We conclude that supplementing ADY in the diets of finishing steers improved DMD, DE, ME, and mean ruminal pH under TN conditions, but not in extreme HS conditions likely due to reduced DMI and greater HE requirements.

Understanding the psychiatric effects of concussion on constructed identity in hockey players: Implications for health professionals.

OBJECTIVE: The following study was undertaken to investigate the effect of concussion and psychiatric illness on athletes and their caregivers. METHODS: Semi-structured interviews with 20 ice hockey stakeholders (17 men and 3 women) including minor and professional players, coaches, parents, and physicians were conducted over two years (2012-2014). These interviews were analyzed using grounded theory. RESULTS: From this analysis, a common biographical theme emerged whereby the subject's identity as a hockey player, constructed early in life over many years, was disrupted by concussion. Furthermore, some players underwent a biographical deconstruction when they experienced post-concussive mental illness, which was amplified by isolation, stigma from peers, and lack of a clear life trajectory. Many players obtained support from family and peers and were able to recover, as evidenced by the biographical reconstruction of their identity post-hockey concussion. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Understanding the process of biographical deconstruction and reconstruction has significant psychosocial treatment implications for both healthcare professionals and caregivers of this population. Specifically, the authors suggest that interpersonal psychotherapy (IPT) that focuses on role transitions may create opportunities to facilitate the process of biographical reconstruction and life transition.

Role of perineuronal nets in the anterior dorsal lateral hypothalamic area in the acquisition of cocaine-induced conditioned place preference and self-administration.

Addiction involves drug-induced neuroplasticity in the circuitry of motivated behavior, which includes the medial forebrain bundle and the lateral hypothalamic area. Emerging at the forefront of neuroplasticity regulation are specialized extracellular matrix (ECM) structures that form perineuronal nets (PNNs) around certain neurons, mainly parvalbumin positive (PV+), fast-spiking interneurons (FSINs), making them a promising target for the regulation of drug-induced neuroplasticity. Despite the emerging significance of PNNs in drug-induced neuroplasticity and the well-established role of the lateral hypothalamic area (LHA) in reward, reinforcement, and motivation, very little is known about how PNN-expressing neurons control drug-seeking behavior. We found that a discrete region of the anterior dorsal LHA (LHAad) exhibited robust PNN and dense ECM expression. Approximately 87% of parvalbumin positive (PV+) neurons co-expressed the PNN marker Wisteria floribunda agglutinin (WFA), while 62% of WFA positive (WFA+) neurons co-expressed PV in the LHAad of drug naïve rats. Removal of PNNs within this brain region via chrondroitinase ABC (Ch-ABC) administration abolished acquisition of cocaine-induced CPP and significantly attenuated the acquisition of cocaine self-administration (SA). Removal of LHAad PNNs did not affect locomotor activity, sucrose intake, sucrose-induced CPP, or acquisition of sucrose SA in separate groups of cocaine naïve animals. These data suggest that PNN-dependent neuroplasticity within the LHAad is critical for the acquisition of both cocaine-induced CPP and SA but is not general to all rewards, and that PNN degradation may have utility for the management of drug-associated behavioral plasticity and memory in cocaine addicts.

Neuronal metabolomics by ion mobility mass spectrometry in cocaine self-administering rats after early and late withdrawal.

The neuronal metabolomes in rat striatum (STR), prefrontal cortex (PFC), and nucleus accumbens (NAC) were analyzed by Hadamard transform ion mobility mass spectrometry (HT-IMMS) in order to reveal global and specific metabolic changes induced by cocaine self-administration after 1-day or 3-week withdrawal. Metabolite features were comprehensively separated and detected using HPLC-IMMS within minutes. Global metabolic differences were observed by PCA for comparisons between cocaine and saline treatments at 1-day withdrawal time. Metabolite features that were significantly changed were selected using PCA loadings' plot and unpaired LLL test and then tentatively identified by accurate m/z, yielding a complete profile of metabolic changes induced by cocaine self-administration. The majority of these changes were found at the 1-day withdrawal time, but several of them endured even after 3-week withdrawal from cocaine, and these changes were generally brain region specific. Putatively identified metabolites associated with oxidative stress and energy metabolism were also specifically investigated. We discovered that the dysregulation of creatine/creatinine was different between the STR and NAC, demonstrating that metabolic alterations are brain region specific. Glutathione and adenosine were also changed in their abundance, and the results agreed with previous studies. In general, this study provided a high-throughput analytical platform to perform metabolomics analyses with putative identifications for altered metabolite features induced by cocaine treatment, therefore revealing additional metabolic targets of cocaine-induced changes after early and extended withdrawal times.

Removal of perineuronal nets in the medial prefrontal cortex impairs the acquisition and reconsolidation of a cocaine-induced conditioned place preference memory.

Pyramidal neurons in the medial prefrontal cortex (mPFC) critically contribute to cocaine-seeking behavior in humans and rodents. Activity of these neurons is significantly modulated by GABAergic, parvalbumin-containing, fast-spiking interneurons, the majority of which are enveloped by specialized structures of extracellular matrix called perineuronal nets (PNNs), which are integral to the maintenance of many types of plasticity. Using a conditioned place preference (CPP) procedure, we found that removal of PNNs primarily from the prelimbic region of the mPFC of adult, male, Sprague Dawley rats impaired the acquisition and reconsolidation of a cocaine-induced CPP memory. This impairment was accompanied by a decrease in the number of c-Fos-positive cells surrounded by PNNs. Following removal of PNNs, the frequency of inhibitory currents in mPFC pyramidal neurons was decreased; but following cocaine-induced CPP, both frequency and amplitude of inhibitory currents were decreased. Our findings suggest that cocaine-induced plasticity is impaired by removal of prelimbic mPFC PNNs and that PNNs may be a therapeutic target for disruption of cocaine CPP memories.

Anisomycin in the medial prefrontal cortex reduces reconsolidation of cocaine-associated memories in the rat self-administration model.

We tested the hypothesis that infusion of anisomycin into the medial prefrontal cortex (mPFC) disrupts the reconsolidation of a cocaine-associated memory in the rat cocaine self-administration model. Male Sprague-Dawley rats were trained to lever press for cocaine self-administration (0.5 mg/kg/infusion) along with a cue light presentation on an FR1 followed by an FR3 schedule of reinforcement for 2 h/day. Rats were then given extinction sessions or an equivalent forced abstinence period followed by a 5 min memory reactivation session during which time they received an ip cocaine injection (10 mg/kg, ip) and were allowed to press for contingent cue light presentation. Immediately after reactivation, they were administered an intra-mPFC infusion of vehicle or anisomycin. Two additional control groups received extinction and either no memory reactivation and intra-mPFC infusions as above or intra-mPFC infusions 6 h after memory reactivation. A fourth group received forced abstinence and intra-mPFC infusions immediately after memory reactivation. Combined cocaine + cue-induced reinstatement was given 2-3 days (early) and 8-12 days (late) later. Rats given anisomycin in the Extinction + Reactivation demonstrated decreased reinstatement, while anisomycin treatment did not alter behavior in any of the other three groups. These results suggest that extinction training may recruit the mPFC such that it renders the memory susceptible to disruption by anisomycin. These findings have implications for using extinction training prior to or in conjunction with other therapies, including reconsolidation disruption, to enhance prefrontal control over drug-seeking behavior.

Enhanced memory persistence is blocked by a DNA methyltransferase inhibitor in the snail Lymnaea stagnalis.

Lymnaea stagnalis provides an excellent model system for studying memory because these snails have a well-described set of neurons, a single one of which controls expression of long-term memory of operantly conditioned respiratory behavior. We have shown that several different manipulations, including pre-training exposure to serotonin (5-HT) or methamphetamine, submersion of snails after training to prevent memory interference, and exposure to effluent from predatory crayfish (CE), enhance memory persistence. Changes in DNA methylation underlie formation of strong memories in mammals and 5-HT-enhanced long-term facilitation in Aplysia. Here we determined the impact of the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-AZA; 87 µmol l(-1)), on enhanced memory persistence by all four manipulations. We found that 5-HT (100 µmol l(-1)) enhanced memory persistence, which was blocked by 5-AZA pretreatment. Snails pre-exposed to 3.3 µmol l(-1) Meth 4 h prior to training demonstrated memory 72 h later, which was not present in controls. This memory-enhancing effect was blocked by pre-treatment with 87 µmol l(-1) 5-AZA. Similarly, submersion to prevent interference learning as well as training in CE produced memory that was not present in controls, and these effects were blocked by pre-treatment with 87 µmol l(-1) 5-AZA. In contrast, 5-AZA injection did not alter expression of normal (non-enhanced) memory, suggesting that these four stimuli enhance memory persistence by increasing DNA methyltransferase activity, which, in turn, increases expression of memory-enhancing genes and/or inhibits memory suppressor genes. These studies lay important groundwork for delineating gene methylation changes that are common to persistent memory produced by different stimuli.

Consequences of cisplatin binding on nucleosome structure and dynamics.

The effects of cisplatin binding to DNA were explored at the nucleosome level to incorporate key features of the eukaryotic nuclear environment. An X-ray crystal structure of a site-specifically platinated nucleosome carrying a 1,3-cis-{Pt(NH3)2}²+-d(GpTpG) intrastrand cross-link reveals the details of how this adduct dictates the rotational positioning of DNA in the nucleosome. Results from in vitro nucleosome mobility assays indicate that a single platinum adduct interferes with ATP-independent sliding of DNA around the octamer core. Data from in vitro transcription experiments suggest that RNA polymerases can successfully navigate along cisplatin-damaged DNA templates that contain nucleosomes, but stall when the transcription elongation complex physically contacts a platinum cross-link located on the template strand. These results provide information about the effects of cisplatin binding to nuclear DNA and enhance our understanding of the mechanism of transcription inhibition by platinum anticancer compounds.

Structure of duplex DNA containing the cisplatin 1,2-{Pt(NH3)2}2+-d(GpG) cross-link at 1.77 A resolution.

We report the 1.77-A resolution X-ray crystal structure of a dodecamer DNA duplex with the sequence 5'-CCTCTGGTCTCC-3' that has been modified to contain a single engineered 1,2-cis-{Pt(NH(3))(2)}(2+)-d(GpG) cross-link, the major DNA adduct of cisplatin. These data represent a significant improvement in resolution over the previously published 2.6-A structure. The ammine ligands in this structure are clearly resolved, leading to improved visualization of the cross-link geometry with respect to both the platinum center and to the nucleobases, which adopt a higher energy conformation. Also better resolved are the deoxyribose sugar puckers, which allow us to re-examine the global structure of platinum-modified DNA. Another new feature of this model is the location of four octahedral [Mg(H(2)O)(6)](2+) ions associated with bases in the DNA major groove and the identification of 124 ordered water molecules that participate in hydrogen-bonding interactions with either the nucleic acid or the diammineplatinum(II) moiety.

Inhibition of transcription by platinum antitumor compounds.

Cisplatin, carboplatin, and oxaliplatin are three FDA-approved members of the platinum anticancer drug family. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of structural adducts and triggering cellular responses, one of which is the inhibition of transcription. In this report we present (i) a detailed review of the structural investigations of various Pt-DNA adducts and the effects of these lesions on global DNA geometry; (ii) research detailing inhibition of cellular transcription by Pt-DNA adducts; and (iii) a mechanistic analysis of how DNA structural distortions induced by platinum damage may inhibit RNA synthesis in vivo. A thorough understanding of the molecular mechanism of action of platinum antitumor agents will aid in the development of new compounds in the family.

cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects.

We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH(3))(2)(py)Cl](+) or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH = trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH(3))(2)(py)}(2+) bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5' side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)}(2+). cDPCP-DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum-DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.

Catalytic sulfoxidation and epoxidation with a Mn(III) triazacorrole: evidence for a "third oxidant" in high-valent porphyrinoid oxidations.

The reaction between (TBP)8(Cz)Mn(III) (1) and the oxygen atom donors iodosylbenzene (PhIO) or p-cyanodimethylaniline-N-oxide (CDMANO) leads to the manganese(V)-oxo complex (TBP)8(Cz)Mn(V)O (2), which has been isolated and characterized previously. Under catalytic conditions with 1 as added catalyst and PhIO as oxidant, both sulfoxidation of PhSMe and epoxidation of cis-stilbene is observed, whereas with CDMANO no sulfoxidation takes place, suggesting that 2 is not the active oxidant. Examination of the independent reactivity of isolated 2 toward PhSMe and cis-stilbene supports this conclusion. A mechanism which relies on a novel type of oxidant involving Lewis acid activation of PhIO by the Mn(V)-oxo complex 2 accounts for these observations and is confirmed by 18O-labeling experiments.

A stable manganese(V)-oxo corrolazine complex.

The synthesis and characterization of an oxomanganese(V) corrolazine, (TBP)8(Cz)Mn(V)O (2), are reported. This remarkably stable high-valent complex is obtained from the stoichiometric reaction of (TBP)8(Cz)Mn(III) (1) with m-CPBA and is easily purified by standard chromatographic methods on silica gel at room temperature. Complex 2 exhibits a diamagnetic 1H NMR spectrum indicative of a low-spin d2 Mn(V)O species. LDI-TOFMS of 2 shows the predicted isotopic envelope at m/z 1426.8. This envelope shifts to higher mass as expected after the facile exchange of the terminal oxo group with H218O. The resonance Raman spectrum of 2 either in solution or in the solid state shows a strongly enhanced Raman band for the stretching mode of the Mn-oxo bond, which also shifts as expected upon 18O substitution: 2(16O), 979 cm-1; 2(18O), 938 cm-1 (in CH2Cl2). Initial reactivity studies show that 2 rapidly transfers the terminal oxo ligand to PPh3, resulting in the quantitative formation of OPPh3 and concomitant reduction of 2 back to 1. Complex 2 is the first example of an oxomanganese(V)-porphyrinoid complex that can be isolated at room temperature.