Epidemiology, Management, and Outcomes of Accidental Hypothermia: A Multicenter Study of Regional Care.

BACKGROUND: Hypothermia is an uncommon, potentially life-threatening condition. We hypothesized (1) advanced rewarming techniques were more frequent with increased hypothermia severity, (2) active rewarming is increasingly performed with smaller intravascular catheters and decreased cardiopulmonary bypass, and (3) mortality was associated with age, hypothermia severity, and type. METHODS: Trauma patients with temperatures <35°C at 4 ACS-verified trauma centers in Wisconsin and Minnesota from 2006 to 2016 were reviewed. Statistical analysis included chi-square and Fisher's exact tests. A P value < .05 was considered significant. RESULTS: 337 patients met inclusion criteria; primary hypothermia was identified in 127 (38%), secondary in 113 (34%), and mixed primary/secondary in 96 (28%) patients. Hypothermia was mild in 69%, moderate in 26%, and severe in 5% of patients. Intravascular rewarming catheter was the most frequent advanced modality (2%), used increasingly since 2014. Advanced techniques were used for primary (12%) vs. secondary (0%) and mixed (5%) (P = .0002); overall use increased with hypothermia severity but varied by institution. Dysrhythmia, acute kidney injury, and frostbite risk worsened with hypothermia severity (P < .0001, P = .031, and P < .0001, respectively). Mortality was greatest in patients with mixed hypothermia (39%, P = .0002) and age >65 years (33%, P = .03). Thirty-day mortality rates were similar among severe, moderate, and mild hypothermia (P = .44). CONCLUSION: Advanced rewarming techniques were used more frequently in severe and primary hypothermia but varied among institutions. Advanced rewarming was less common in mixed hypothermia; mortality was highest in this subgroup. Reliance on smaller intravascular catheters for advanced rewarming increased over time. Given inconsistencies in management, implementation of guidelines for hypothermia management appears necessary.

Contemporary management of subclavian and axillary artery injuries-A Western Trauma Association multicenter review.

BACKGROUND: Subclavian and axillary artery injuries are uncommon. In addition to many open vascular repairs, endovascular techniques are used for definitive repair or vascular control of these anatomically challenging injuries. The aim of this study was to determine the relative roles of endovascular and open techniques in the management of subclavian and axillary artery injuries comparing hospital outcomes, and long-term limb viability. METHODS: A multicenter, retrospective review of patients with subclavian or axillary artery injuries from January 1, 2004, to December 31, 2014, was completed at 11 participating Western Trauma Association institutions. Statistical analysis included χ, t-tests, and Cochran-Armitage trend tests. A p value less than 0.05 was significant. RESULTS: Two hundred twenty-three patients were included; mean age was 36 years, 84% were men. An increase in computed tomography angiography and decrease in conventional angiography was observed over time (p = 0.018). There were 120 subclavian and 119 axillary artery injuries. Procedure type was associated with injury grade (p < 0.001). Open operations were performed in 135 (61%) patients, including 93% of greater than 50% circumference lacerations and 83% of vessel transections. Endovascular repairs were performed in 38 (17%) patients; most frequently for pseudoaneurysms. Fourteen (6%) patients underwent a hybrid procedure. Use of endovascular versus open procedures did not increase over the duration of the study (p = 0.248). In-hospital mortality rate was 10%. Graft or stent thrombosis occurred in 7% and graft or stent infection occurred in 3% of patients. Mean follow-up was 1.6 ± 2.4 years (n = 150). Limb salvage was achieved in 216 (97%) patients. CONCLUSION: The management of subclavian and axillary artery injuries still requires a wide variety of open exposures and procedures, especially for the control of active hemorrhage from more than 50% vessel lacerations and transections. Endovascular repairs were used most often for pseudoaneurysms. Low early complication rates and limb salvage rates of 97% were observed after open and endovascular repairs. LEVEL OF EVIDENCE: Prognostic/epidemiologic, level IV.

Pharmacological characterisation of the GlyT-1 glycine transporter using two novel radioligands.

Inhibitors of the glycine transporter GlyT-1 are being developed as potential treatments for schizophrenia. Here we report on the use of two novel radioligands, [(3)H]-SB-733993 and [(3)H]-GSK931145, for the characterisation of GlyT-1 in both cells and native tissue. Binding was evaluated in membranes either from HEK293 cells expressing recombinant human GlyT-1 (hGlyT-1) or from rat cerebral cortex. Specific binding of both [(3)H]-SB-733993 and [(3)H]-GSK931145 to hGlyT-1 HEK293 cell membranes and rat cerebral cortex membranes was saturable and comprised >90% of total binding. K(d) and B(max) values for the two radioligands were fairly similar, with K(d) values of 1-2 nM and B(max) values of around 7000 fmol/mg protein in hGlyT-1 membranes and 3000 fmol/mg protein in rat cortex membranes. Association of [(3)H]-SB-733993 was faster, with binding reaching equilibrium within 30 min compared with 90 min for [(3)H]-GSK931145. Dissociation was also much slower for [(3)H]-GSK931145 than for [(3)H]-SB-733993, with 50% of specific binding being dissociated by approximately 40 min and 5 min, respectively. Autoradiography studies with [(3)H]-GSK931145 showed widespread distribution of binding in rat brain, with generally higher binding in caudal compared with rostral areas. Initial studies in human frontal cortex membranes showed clear specific binding of [(3)H]-GSK931145, though with much lower density (B(max) 570 fmol/mg protein) and slightly lower affinity (K(d) 4.5 nM) compared with rat cortex. A human brain autoradiography study showed higher specific binding in cerebellum compared with frontal cortex. All GlyT-1 inhibitors tested, as well as glycine itself, competed fully for the binding of both [(3)H]-SB-733993 and [(3)H]-GSK931145 in both hGlyT-1 and rat cortex membranes. Studies on the effect of varying NaCl concentration showed that [(3)H]-SB-733993 binding was reduced by >90% in the absence of added Na(+) ions, whilst [(3)H]-GSK931145 binding was unaffected. Glycine produced concentration-dependent decreases in binding affinity of both radioligands without major changes in B(max) values, suggesting that both [(3)H]-SB-733993 and [(3)H]-GSK931145 bind to sites on GlyT-1 that are orthosteric to the site at which glycine itself binds. Overall, these results show that both [(3)H]-SB-733993 and [(3)H]-GSK931145 are useful radioligands for studies on GlyT-1 in both cell lines and native tissues, with [(3)H]-GSK931145 being the radioligand of choice for further studies on GlyT-1 expression and pharmacology.

Posttraumatic stress disorder: a primer for trauma surgeons.

In 1980, posttraumatic stress disorder (PTSD) officially became classified as an anxiety disorder in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition. Since then, there has been increasing recognition that PTSD is a prevalent disorder that may have significant impact on the quality of life for survivors of traumatic events. More recently, methodologically sound research has begun to provide important insight into this disorder. The following review serves to provide the trauma surgeons information on PTSD in terms of its diagnosis, prevalence, risk factors, treatment strategies, and outcomes, with the goal of minimizing the sequelae of PTSD and maximizing postinjury quality of life.

11C-GSK189254: a selective radioligand for in vivo central nervous system imaging of histamine H3 receptors by PET.

UNLABELLED: The histamine H(3) receptor is a G-protein-coupled presynaptic auto- and heteroreceptor whose activation leads to a decrease in the release of several neurotransmitters including histamine, acetycholine, noradrenaline, and dopamine. H(3) receptor antagonists such as 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) can increase the release of these neurotransmitters and thus may offer potential therapeutic benefits in diseases characterized by disturbances of neurotransmission. The aim of this study was to synthesize and evaluate (11)C-labeled GSK189254 ((11)C-GSK189254) for imaging the histamine H(3) receptor in vivo by PET. METHODS: GSK189254 exhibits high affinity (0.26 nM) and selectivity for the human histamine H(3) receptor. Autoradiography experiments were performed using (3)H-GSK189254 to evaluate its in vitro binding in porcine brain tissues. GSK189254 was labeled by N-alkylation using (11)C-methyl iodide in good yields, radiochemical purity, and specific activity. A series of PET experiments was conducted to investigate (11)C-GSK189254 binding in the porcine brain. RESULTS: In vitro autoradiography demonstrated specific (3)H-GSK189254 binding in the porcine brain; therefore, (11)C-GSK189254 was evaluated in vivo in pigs and showed good brain penetration and high uptake in regions such as the striatum and cortices, known to contain high densities of the histamine H(3) receptors. The radioligand kinetics were reversible, and quantitative analysis was achieved with a 2-tissue-compartmental model yielding the distribution volume as the outcome measure of interest. The distribution volume was reduced to a homogeneous level in all regions after blocking by the coadministration of either unlabeled GSK189254 or ciproxifan, a structurally distinct histamine H(3) antagonist. Further coadministration studies allowed for the estimation of the radioligand affinity (0.1 nM) and the density of histamine H(3) receptor sites in the cerebellum (0.74 nM), cortex (2.05 nM), and striatum (2.65 nM). CONCLUSION: These findings suggest that (11)C-GSK189254 possesses appropriate characteristics for the in vivo imaging of the histamine H(3) receptor by PET.

Autoradiographical imaging of PPARgamma agonist effects on PBR/TSPO binding in TASTPM mice.

Chronic inflammation is known to occur in the brains of Alzheimer's Disease (AD) patients, including the presence of activated microglia close to amyloid plaques. We utilised real time autoradiography and immunohistochemistry to investigate microglial activation and the potential anti-inflammatory effects of PPARgamma agonists in the Thy-1 APP695swe/Thy-1 PS-1.M146V (TASTPM) overexpressing transgenic mouse model of AD. An age dependent increase in specific [3H](R)-PK11195 binding to peripheral benzodiazepine receptors (PBR)/translocator protein (18 kDa) (TSPO) was observed in the cortex of TASTPM mice compared to wild type mice, indicative of microglial activation. This was consistent with immunohistochemical data showing age-dependent increases in CD68 immunoreactivity co-localised with amyloid beta (Abeta) deposits. In 10 month old TASTPM mice, pioglitazone (20 mg/kg) and ciglitazone (50 mg/kg) significantly reduced [3H](R)-PK11195 and [3H]DPA-713 binding in cortex and hippocampus, indicative of reduced microglial activation. In AD brain, significant [3H](R)-PK11195 and [3H]DPA-713 binding was observed across all stages of the disease. These results support the use of PBR/TSPO autoradiography in TASTPM mice as a functional readout of microglial activation to assess anti-inflammatory drugs prior to evaluation in AD patients.

Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain.

Several studies have implicated a potential role for histamine H(3) receptors in pain processing, although the data are somewhat conflicting. In the present study we investigated the effects of the novel potent and highly selective H(3) receptor antagonists GSK189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride) and GSK334429 (1-(1-methylethyl)-4-([1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl]carbonyl)hexahydro-1H-1,4-diazepine) in two rat models of neuropathic pain, namely the chronic constriction injury (CCI) model and the varicella-zoster virus (VZV) model. Both GSK189254 (0.3, 3 and/or 10mg/kg p.o.) and GSK334429 (1, 3 and 10mg/kg p.o.) significantly reversed the CCI-induced decrease in paw withdrawal threshold (PWT) measured using an analgesymeter and/or von Frey hairs. In addition, GSK189254 (3mg/kg p.o.) and GSK334429 (10mg/kg p.o.) both reversed the VZV-induced decrease in PWT using von Frey hairs. We also investigated the potential site of action of this analgesic effect of H(3) antagonists using autoradiography. Specific binding to H(3) receptors was demonstrated with [(3)H]-GSK189254 in the dorsal horn of the human and rat spinal cord, and in human dorsal root ganglion (DRG), consistent with the potential involvement of H(3) receptors in pain processing. In conclusion, we have shown for the first time that chronic oral administration of selective H(3) antagonists is effective in reversing neuropathic hypersensitivity in disease-related models, and that specific H(3) receptor binding sites are present in the human DRG and dorsal horn of the spinal cord. These data suggest that H(3) antagonists such as GSK189254 and GSK334429 may be useful for the treatment of neuropathic pain.

GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.

[3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution.

Knowledge of the distribution and function of the vanilloid receptor (VR-1 or TRPV1) in the CNS lacks the detailed appreciation of its role in the peripheral nervous system. The radiolabelled vanilloid agonist [3H]resiniferatoxin (RTX) has been used to indicate the presence of TRPV1 receptor protein in the brain but low specific binding has complicated interpretation of this data. Recently, support for a more widespread CNS distribution of TRPV1 mRNA and protein has been provided by RT-PCR and antibody data. We have exploited the availability of TRPV1 null mice and used [3H]RTX autoradiography in the CNS of TRPV1 wild-type and TRPV1 null mice to identify the component of [3H]RTX binding to TRPV1 receptor protein. In the brains of TRPV1+/+ mice, specific [3H]RTX binding was broadly localised with the greatest binding in the olfactory nuclei, the cerebral cortex, dentate gyrus, thalamus, hypothalamus, periaqueductal grey, superior colliculus, locus coeruleus and cerebellar cortex. Specific binding was also seen in the spinal cord and sensory (dorsal root and trigeminal) ganglia. This binding was much lower but not abolished in most regions in the TRPV1-/- mice. Nonspecific binding was low in all cases. The present study unequivocally demonstrates a widespread and discrete distribution pattern of the TRPV1 receptor protein in the rat central nervous system. The presence of TRPV1 receptors in several brain regions suggests that it may function as a cannabinoid-gated channel in the CNS.

5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585.

The 5-hydroxytryptamine (5-HT; serotonin)-6 receptor (5-HT6R) is a putative target of atypical antipsychotic drugs and its mRNA expression is altered in schizophrenia. [125I]SB-258585 is a selective 5-HT6R antagonist which has been well characterized for use in the rat brain. The present study evaluated its suitability for receptor autoradiography in the human brain and its application to quantitative studies. The affinity (K(d) approximately 1.2 nM) and relative distribution of binding sites (striatum >> cortex approximately hippocampus) were similar to the rat. The distribution of [125I]SB-258585 binding in these regions was also consistent with that of 5-HT6R mRNA, determined in parallel using in situ hybridization. [125I]SB-258585 binding site densities were measured in dorsolateral prefrontal cortex of 20 patients with chronic schizophrenia and compared with 17 normal subjects. No differences were seen between groups. Neither were [125I]SB-258585 binding site densities affected in the frontal cortex or striatum of rats following 2 weeks' administration of the antipsychotic drugs haloperidol, chlorpromazine, olanzapine, risperidone, or clozapine. In summary, [125I]SB-258585 is a suitable radioligand for studies of human brain 5-HT6R binding sites and shows that their distribution is broadly similar to that of the rodent. The lack of effect of schizophrenia or antipsychotic drug administration on [125I]SB-258585 binding suggests that an altered receptor density does not contribute to any involvement which the 5-HT6R may have in the disease or its treatment.

The distribution of 5-HT(6) receptors in rat brain: an autoradiographic binding study using the radiolabelled 5-HT(6) receptor antagonist [(125)I]SB-258585.

We used the highly selective 5-HT(6) receptor radioligand [(125)I]SB-258585 (4-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide) to perform autoradiographic binding studies on the rat brain. High levels of specific binding occurred in the corpus striatum, nucleus accumbens, Islands of Calleja and the olfactory tubercle. A high level of binding also appeared in the choroid plexus. Moderate levels occurred in several regions of the hippocampal formation and in certain regions of the cerebral cortex, thalamus, hypothalamus, and substantia nigra; and very low levels in the globus pallidus, cerebellum, other mesencephalic regions, and the rhombencephalon. Displacement of total binding with 10 microM unlabelled SB-214111 (4-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), another selective 5-HT(6) receptor antagonist, or 10 microM unlabelled methiothepin, reduced binding to barely discernible levels. Some animals received unilateral injections of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle to lesion the nigro-striatal pathway before autoradiographic examination. Effectiveness of the 6-OHDA lesions in the substantia nigra and striatum was confirmed with tyrosine hydroxylase immunohistochemistry. Such lesions resulted in no significant changes in [(125)I]SB-SB258585 binding in any brain region examined, suggesting that 5-HT(6) receptors in the striatum are not located on dendritic, somatic or terminal elements of dopaminergic neurones. Thus, the striatal binding sites seen in this study may be on intrinsic GABAergic or cholinergic neurones, or on terminals of projection neurones from the thalamus or cerebral cortex. The 5-HT(6) receptor ligand binding seen here in the striatum, accumbens, olfactory tubercle, Islands of Calleja, cerebral cortex and hippocampus are in concordance with previous immunohistochemical studies, and suggest a possible involvement of 5-HT(6) receptors in locomotor control, cognition, memory, and control of affect. The high levels of binding observed in the choroid plexus in this study have not been reported before. This finding suggests that 5-HT(6) receptors could play a role in the control of cerebrospinal fluid dynamics.