This pattern of results is inconsistent with a prediction error response. Finally, analyses of cross-correlations between the accumbens and simultaneous recordings of medial frontal cortex suggest a dynamic interaction between these structures. The high spatial and temporal resolution of these recordings provides novel insights into the timing of activity in the human nucleus accumbens, its functions during reward-guided learning and decision-making, and its interactions with medial frontal

cortex. Neuropsychopharmacology (2009) 34, 1649-1658; doi:10.1038/npp.2008.222; published online 17 December 2008″
“Purpose: Afferent nerve firing has been linked to spontaneous bladder contractions Selleckchem 8-Bromo-cAMP in a number of lower urinary

tract pathologies and it may lead to urgency PLX4032 nmr and incontinence. Using optical mapping, single unit recording and tension measurements we investigated the correlation between afferent nerve firing and spontaneous bladder contractions in spinal cord transected mice.

Materials and Methods: Bladder-nerve preparations (bladder sheets and the associated L6-S2 pelvic nerves) were dissected from normal and spinal cord transected mice showing overactivity on cystometry and opened along the ventral aspect from base to dome. Bladder sheets were mounted horizontally in a temperature regulated chamber to simultaneously record Ca(2+) transients across the mucosal surface, single unit afferent nerve firing and whole bladder tension.

Results: Single unit afferent fibers were identified by probing their receptive fields. Fibers showed a graded response to von Frey stimulation and a frequency of afferent firing that increased as a function of the degree of stretch. Optical maps of Ca(2+) transients in control bladders demonstrated multiple initiation sites that resulted in high frequency, low amplitude spontaneous contractions. Selleck HKI 272 Alternatively in maps of the bladders of spinal cord transected mice Ca(2+) transients arose from 1 or 2 focal sites, resulting in low frequency, high amplitude contractions

and concomitant afferent firing.

Conclusions: Large amplitude, spontaneous bladder contractions evoke afferent nerve activity, which may contribute to incontinence.”
“Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic-interacting proteins of these channels are abnormally expressed in some patients with this illness. In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. Here we show that reduced expression of the neuronal RasGAP and NMDAR-associated protein, SynGAP, results in abnormal behaviors strikingly similar to that reported in mice with reduced NMDAR function.

“
“Purpose: The potent immunosuppressive

effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis.

Materials and Methods: A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected AZD1080 solubility dmso intraperitoneally in other rat groups. The Adriamycin molecular weight tacrolimus dose was constant in all formulations at 200 mu g/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II.

Results: The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus

and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC((0-24)) after intravesical administration was significantly higher than in the intraperitoneal group (p < 0.05). Bladder tacrolimus AUC((0-24)) did not differ significantly between the groups.

Conclusions: Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus Electron transport chain may be a promising approach as an orphan drug indication for hemorrhagic cystitis.”
“Staphylococcus aureus is both a prominent cause of nosocomial infections with significant morbidity and mortality and a commensal with nasal carriage in around 30% of the population. The rapid spread of multi-resistant strains necessitates novel therapeutic strategies, a challenging

task because the species S. aureus and the host response against it are highly variable. In a prospective study among 2023 surgical and non-surgical patients, 12 patients developed S. aureus bacteremia. They were analysed in detail using a personalized approach. For each patient, the extracellular proteins of the infecting S. aureus strain were identified and the developing antibody response was assessed on 2-D immunoblots. S. aureus carriers showed clear evidence of strain-specific pre-immunization. In all immune-competent bacteremia patients, antibody binding increased strongly, in most cases already at diagnosis. In endogenous infections, the pattern of antibody binding was similar to the pre-infection pattern. In exogenous infections, in contrast, the pre-infection pattern was radically altered with the acquisition of new specificities.

Analyses

showed higher levels of left-to-right TCI significantly correlated with higher AQ scores. Furthermore, increased left-to-right together with reduced right-to-left TCI was associated with a stronger attentional bias for angry faces. This is the first study to provide a biological mechanism underlying the asymmetry between left and right frontal cortex activity in human aggression. We Mdm2 inhibitor conclude that an aggressive personality style and selective attention to angry faces are positively correlated with functional interhemispheric connectivity.”
“BACKGROUND

Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism.

METHODS

We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism.

RESULTS

During a median follow-up period of 37.2 months, venous thromboembolism re-curred in

73 of 411 patients assigned to placebo and in 57 of 411 assigned 5-Fluoracil datasheet to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P = 0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% ISRIB (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P = 0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P = 0.01). There was no significant between-group difference in the rates of major or clinically relevant

nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P = 0.22) or serious adverse events.

CONCLUSIONS

In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.

The postoperative survey

was completed by 104 patients. Bladder spasm selleck inhibitor was the only category with less than 86% rate of positive quality of life response.

Conclusions: Vesicoureteral reflux is shown to have little effect on quality of life in pediatric patients. These validated surveys should be applied to compare the effect of different management options on quality of life.”
“Slowness in movement initiation is a cardinal feature of Parkinson’s disease (PD) that is still poorly understood and unsuccessfully alleviated by standard therapies. Here, we raise this major clinical issue within the framework of a novel theoretical model that allows a better understanding of the basic mechanisms involved in movement initiation. This model assumes that movement triggering is inhibited by default to prevent automatic responses to unpredictable events. We investigated

to which extent the top-down control necessary to release this locking state before initiating actions is impaired in PD and restored by standard therapies. We used a cue-target reaction time task to test both the ability to initiate fast responses to targets and the ability to refrain from reacting to cues. Fourteen patients with dopaminergic (DA) medication and 11 with subthalamic nucleus (STN) stimulation were tested on and off treatment, and Z-VAD-FMK nmr compared with 14 healthy controls. We found evidence that patients withdrawn from treatment have trouble voluntarily releasing proactive inhibitory control; while DA medication broadly reduces movement initiation latency, it does not reinstate a normal pattern of movement initiation; and stimulation of the STN specifically C188-9 in vivo re-establishes the efficiency of the top-down control of proactive inhibition. These results suggest that movement initiation disorders that resist DA medication are due to executive, not motor, dysfunctions. This conclusion is discussed with regard to the role the STN may play as an interface between non-DA executive and DA

motor systems in cortico-basal ganglia loops.”
“The resistance of malignant cells to chemotherapy calls for the development of novel anticancer drugs. TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic cytokine, which selectively induces apoptosis in malignant cells. We derived two TRAIL-resistant HL-60 subclones, HL-60/P1 and HL-60/P2, from a TRAIL-sensitive HL-60 acute promyelocytic leukemia cell line. To identify therapeutically exploitable “”weaknesses”" of the TRAIL-resistant leukemia cells that could be used as molecular targets for their elimination, we performed proteomic (2-DE) analysis and compared both TRAIL-resistant subclones with the original TRAIL-sensitive HL-60 cells. We identified over 40 differentially expressed proteins. To significantly narrow the lists of candidate proteins, we excluded proteins that are known to be often differentially expressed, regardless of experiment type and tissue (the so-called “”TOP15″” proteins).

Present data may help to a better understanding of the molecular mechanisms involved in cytoskeletal degradation-induced apoptosis in neurons. (C) 2008 Elsevier Inc. All rights reserved.”
“Objective: To examine the feasibility of using blood-derived smooth muscle cells (BD-SMCs) as a target for to deliver therapeutic proteins. Materials and

Methods: Mononuclear cells (MNC) were isolated from peripheral blood. The outgrowth colonies from MNC culture were differentiated

into BD-SMCs in media containing platelet-derived growth factor BB. Phenotypic PKC412 solubility dmso characterization of BD-SMCs was assessed by immunocytochemistry. Cell proliferation, gene transfer efficiency with a retroviral vector, apoptosis, and the biological activity of the transduced gene product from the BD-SMCs were evaluated Veliparib in vitro and in vivo in comparison with vascular derived SMC (VSMCs).

Results: BD-SMCs stained positive for SMC markers. No significant difference was observed between BD-SMCs and VSMCs in cell proliferation, migration, adhesiveness, and gene

transfer efficiency. After BD-SMCs were transduced with a retroviral vector carrying the secreted alkaline phosphatase gene (SEAT), 174 +/- 50 mu g biologically active SEAT was produced per 106 cells over 24 hours. After injecting 5 x 106 cells expressing SEAT intravenously into rabbits, SEAT concentration increased

3-deazaneplanocin A clinical trial significantly in the circulation from 0.14 +/- 0.04 mu g/ml to 2.34 +/- 0.16 mu g/ml 3 days after cell injection (P < .01, n = 3). Circulating levels of SEAT decreased to 1.76 mu g/ml 1 week later and remained at this level up to 8 weeks, then declined to pre-cell injection level at 12 weeks. VSMC in vivo gene expression data were equivalent.

Conclusion: BD-SMCs have similar characteristics to mature VSMCs and can be used as a novel target for gene transfer to deliver a therapeutic protein.”
“Many toxic environmental and food agents have been suspected to be potential risk factors in inducing memory disabilities under normal and pathological conditions. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (known as dioxin or TCDD) is a common and prototypical member of a class of noxious environmental and food contaminants called the halogenated aromatic hydrocarbons. Since the role of dioxin in memory processes has not been studied in detail, the present report aims at elucidating the role of this pollutant in the maintenance of cognitive function. We found that TCDD (50 mu g/kg) induced spatial memory deficits in the Morris water maze (MWM) task in female but not male mice. This sex-dependant effect of dioxin seems to be related to the alteration of estrogen pathways, as treatment with 17 beta-estradiol-3-benzoate (E; 5 mu g/day) reversed memory deficits induced by TCDD.

(C) 2008 Elsevier Inc. All rights reserved.”
“The human monoclonal antibody b12 recognizes a conserved epitope on gp120 that overlaps the CD4 binding site. b12 has neutralizing activity against diverse human immunodeficiency virus type 1 (HIV-1) strains. However, we recently reported that b12 sensitivity of HIV-1 envelopes amplified from patient tissues without culture varied considerably. For two subjects, there was clear modulation of b12 sensitivity, with lymph node-derived envelopes being essentially resistant

while those from brain tissue were sensitive. Here, we have mapped envelope determinants of b12 resistance by constructing chimeric envelopes from resistant and sensitive envelopes derived from lymph node and brain tissue, respectively. Residues on the N-terminal flank of the CD4 binding loop conferred partial resistance. However, a potential glycosylation site at residue N386 completely modulated selleck chemicals b12 resistance but required the presence of an arginine

at residue 373. Moreover, the introduction of R373 into b12-sensitive NL4.3 and AD8 envelopes, which carry N386, also conferred b12 resistance. Molecular modeling suggests that R373 and the glycan at N386 may combine to sterically exclude the benzene ring of DAPT b12 W100 from entering a proximal pocket. In summary, we identify residues on either side of the CD4 binding loop that contribute to b12 resistance in immune tissue in vivo. Our data have relevance for the design of vaccines that aim to elicit neutralizing antibodies.”
“Rotavirus infection of cells in culture induces major changes in Ca(2+) homeostasis. These changes include increases in plasma membrane Ca(2+) permeability, cytosolic Ca(2+) concentration, and total cell Ca(2+) content and a reduction in the amount of Ca(2+) released from intracellular pools sensitive to agonists. Various lines of evidence suggest

that the nonstructural glycoprotein NSP4 and possibly the major outer capsid glycoprotein VP7 are responsible for these effects. In order to evaluate the functional roles of for NSP4 and other rotavirus proteins in the changes in Ca(2+) homeostasis observed in infected cells, the expressions of NSP4, VP7, and VP4 were silenced using the short interfering RNA (ARNA) technique. The transfection of specific siRNAs resulted in a strong and specific reduction of the expression of NSP4, VP7, and VP4 and decreased the yield of new viral progeny by more than 90%. Using fura-2 loaded cells, we observed that knocking down the expression of NSP4 totally prevented the increase in Ca(2+) permeability of the plasma membrane and cytosolic Ca(2+) concentration measured in infected cells. A reduction in the levels of VP7 expression partially reduced the effect of infection on plasma membrane Ca(2+) permeability and Ca(2+) pools released by agonist (ATP).

This study compared the influences of mu-opioid receptor (MOR) activation in the central nucleus of the amygdala

(CEA) on unconditioned fear or anxiety-like responses in two models, the elevated plus maze, and the defensive burying test. The role of MORs in the anxiolytic actions of the benzodiazepine agonist diazepam this website was also examined using both models. Either the MOR agonist [D-Ala(2), NMe-Ph (4), Gly-ol(5)]-enkephalin (DAMGO), or the MOR antagonists Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) or beta-funaltrexamine (FNA) were bilaterally infused into the CEA of rats before testing. The results show that microinjection of DAMGO in the CEA decreased open-arm time in the plus maze, whereas CTAP increased open-arm behaviors. In contrast, DAMGO injections in the CEA reduced burying behaviors and increased rearing following exposure to a predator odor, suggesting a shift in the behavioral response in this context. Amygdala injections of the MOR agonist DAMGO or

the MOR antagonist CTAP failed to change the anxiolytic effects of diazepam in either test. Our results demonstrate that MOR activation in the central amygdala exerts distinctive effects in two different models of unconditioned fear or anxiety-like responses, and suggest that opioids may exert context-specific regulation of amygdalar output circuits and behavioral responses https://www.selleckchem.com/products/ink128.html during exposure to potential threats (open arms of the maze) vs discrete threats (predator odor).”
“There is click here consensus that ischemia/reperfusion injury associated with preeclampsia (PE) promotes both placental damage and the release of factors leading to maternal endothelium dysfunction, a hallmark of this potentially life-threatening syndrome. These factors include plasminogen activator inhibitor-1 (PAI-1) and soluble fms-like tyrosine kinase-1 (sFlt-1). The goal of this study was to further characterize placental factors involved in the pathophysiology of PE. Thus, DNA microarray gene profiling was utilized to identify

mRNA differentially regulated in placentas from women with severe PE compared to both preterm (PC) and term control (TC) groups. Microarray studies detected an upregulation of mRNA for ceruloplasmin, a copper-containing iron transport protein with antioxidant ferroxidase properties, in PE compared to PC and TC placentas, respectively. Quantitative real-time PCR confirmed these results by demonstrating significant increases in ceruloplasmin mRNA in PE vs PC and TC placentas. Supporting previous reports, the expression of sFlt-1 and PAI-1 were also upregulated in PE placentas. Immunohistochemistry localized ceruloplasmin to the intervillous space in PE and PC placentas, whereas stronger syncytial staining was noted in PE. Western blotting confirmed a significant increase in ceruloplasmin levels in placental tissue in PE compared to PC groups.

Haptic processing consists of the integration of data from multiple sources to form a single percept. Previous research provides strong support for a hierarchical and functional distribution within haptic processing. We investigated hemispheric asymmetry in haptic discrimination of objects with differing textures and centres of mass. By analogy with vision it was hypothesised that participants would demonstrate

a left-hand advantage for centre of mass discrimination (a ‘global’, presumed right hemisphere, judgement) and a right-hand advantage for surface texture judgements (a ‘local’, presumed left hemisphere discrimination). We found that left-handed participants showed these effects to a lesser degree than did the right-handers, consistent with the C646 datasheet notion that left-handed people generally selleckchem show weaker asymmetries in bimanual tasks. In a second experiment the effect

of conflicting information on haptic percept formation was investigated. Following from the previous hypotheses it was predicted that participants would be more accurate with their right hands at judging conflicting surfaces. Contrary to predictions an advantage was demonstrated for the left hand for texture discrimination and for the right hand for centre of mass judgement. (C) 2011 Elsevier Ltd. All rights reserved.”
“Background: The endothelial cell (EC) protein C receptor (EPCR) negatively regulates coagulation and inflammation. Factors and mechanisms regulating the expression of cell-bound EPCR and the release of soluble (s) EPCR are still unclear. Methods: We investigated the reciprocal regulation of membrane-bound and sEPCR upon inflammation using primary cultures of vascular EC. The impact of 2 parameters, gender and EPCR gene A3 haplotype, on sEPCR plasma basal level and endothelial click here expression was examined by Elisa and flow cytometry. Results: Exposure of EC to tumor necrosis factor alpha causes a rapid downregulation of membrane-associated EPCR expression without affecting markedly the spontaneous release of sEPCR

by EC. In a cohort of 100 healthy donors, we show that males express significantly higher basal sEPCR in plasma than females (194 +/- 12 vs. 145 +/- 9 ng/ml, respectively, p < 0.01). Both gender and EPCR A3 haplotype affect sEPCR plasma levels but have no apparent effect on EPCR expression by EC. No quantitative correlation between cellular expression and circulating blood sEPCR was observed, suggesting that endothelial expression may not reflect the plasma level. Conclusion: Male gender is another parameter with A3 haplotype associated with elevated sEPCR levels in blood, and both parameters may contribute to selective regulatory mechanisms of EPCR release upon inflammation. Copyright (C) 2011 S. Karger AG, Basel”
“It is well known that viewing graspable tools (but not other objects) activates motor-related brain regions, but the time course of affordance processing has remained relatively unexplored.

In vitro release assays using rat

brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of Capmatinib in vitro effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with 4SC-202 in vivo MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity

comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study. Neuropsychopharmacology (2012) 37, 1192-1203; doi:10.1038/npp.2011.304; published online 14 December 2011″
“Striatal dopamine activity declines with normal aging. Age-related striatal dopaminergic denervation (SDD) has been implicated in standing balance and unperturbed gait. The goal of this

study was to analyze the association between the degree of SDD and the magnitude of an unexpected slip perturbation induced during gait.

Fifty healthy participants aged 20-86 years old underwent dopamine transporter positron emission tomography to classify SDD severity as mild, moderate, or severe. Participants also walked on a floor that was unexpectedly contaminated with a glycerol solution for gait testing. The magnitude of a slip was quantified using the peak slip velocity (PSV), measured at the slipping foot. Data were analyzed for before both fast (greater than 1.2 m/s) and slow walkers as gait speed correlated with slip severity. All data analyses were age adjusted.

Greater severity of dopaminergic denervation in the caudate nucleus was correlated with higher PSV (p < .01) but only in the fast speed walking group. The relationship between SDD in the putamen and slip severity was not statistically significant in fast and slow walkers.

Age-related SDD may impact the ability to recover from large perturbations during walking in individuals who typically walk fast. This effect, prominent in the caudate nucleus, may implicate a role of cognitive frontostriatal pathways in the executive control of gait when balance is challenged by large perturbations.

The keys for hepatitis C virus identification Belnacasan have been determined at the genus, species, genotype and subtype levels. Secondary structure nucleotide substitutions were characteristics to the genus included in a complex stem-loop structure composed of 112-115 nucleotides. Due

to the worldwide importance of hepatitis C virus, and the difficulties encountered in the control of the disease, it is, therefore, important to understand the genetic aspects of the virus. The application of the PNS method might represent an additional useful tool for determining the genetic variations among hepatitis C virus strains. The identification of viral types or subtypes based on genetic changes should improve our understanding of hepatitis C virus and might provide markers for biological differences, such as virulence, and improve understanding of the

evolution of the virus. (C) 2008 Elsevier B.V. All rights reserved.”
“Although the concepts of secondary injury and neuroprotection after neurotrauma are experimentally buy DMH1 well supported, clinical trials of neuroprotective agents in traumatic brain injury or spinal cord injury have been disappointing. Most strategies to date have used drugs directed toward a single pathophysiological mechanism that contributes to early necrotic cell death. Given these failures, recent research has increasingly focused on multifunctional (i.e., multipotential, pluripotential) agents that target multiple injury mechanisms, particularly those that occur later after the insult. Here we review two such approaches that show particular promise in experimental neurotrauma: cell cycle

inhibitors and small selleck cyclized peptides. Both show extended therapeutic windows for treatment and appear to share at least one important target.”
“Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome.