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A number of factors may contribute to disparities in mental health and suicidality for lesbian, gay, bisexual, and questioning (LGBQ) students, including parental abuse. The Centers for Disease Control and Prevention's (CDC) Adolescent Behaviors and Experiences Survey included a nationally representative sample of US high school students during the COVID-19 pandemic. The current analyses examined experiences of verbal and physical abuse in the home with mental health and suicidality among LGBQ students compared to heterosexual students. The relationship between abuse and mental health and suicidality was significant for all students; however, LGBQ students experienced substantially more abuse and had significantly poorer mental health and greater suicidality than heterosexual students. Experiencing verbal or physical abuse in the home is strongly associated with poor mental health and suicidality among youth, regardless of sexual identity; however, among LGBQ students who experienced abuse, the prevalence of poor mental health and suicidality reached crisis levels. [ABSTRACT FROM AUTHOR]

In vivo imaging methods such as Positron Emission Tomography (PET) can be used to examine the relationship between in vitro binding affinity and in vivo occupancy of binding sites in the brain for new drug candidates. In this study, PET imaging in monkey brain was used to evaluate that correlation for a set of four diastereomers of the compound dihydrotetrabenazine (DTBZ), the pharmacologically active metabolite of the drug tetrabenazine. PET studies of DTBZ diastereomers were completed in a single monkey brain. In vivo occupancies (ED 50) were estimated using multiple drug doses and the vesicular monoamine transporter 2 specific radioligand (+)-α-[11C] DTBZ, employing a test-retest sequence of control PET scan, drug administration and a second PET scan completed on a single day. DTBZ has three chiral carbon centers and eight possible stereoisomers, and in vivo occupancy of the target site VMAT2 was observed only for the four diastereomers of DTBZ having the 11b R absolute configuration. The estimated in vivo occupancies (ED 50 values from 0.023 to >3.15 mg/kg) correlated well (R2 = 0.95) with the in vitro binding affinities (K i values of 4 to 600 nM for the VMAT2), and an even better correlation (R2 = 0.99) was found for the three isomers with in vitro binding affinities <100 nM. If the physiochemical (MW, log P, pKa) or physiological (metabolism, transport, protein binding) properties of a set of drug stereoisomers are considered similar, the binding affinities determined from in vitro assays may predict the in vivo occupancies of the target binding site in the monkey brain. [ABSTRACT FROM AUTHOR]

Objective: To investigate short-term efficacy and safety of a novel lipid ibuprofen formulation 1200 mg/day compared with standard ibuprofen 1200 mg/day and 2400 mg/day in episodic knee arthralgia/flaring pain.Design: Multicentre, randomised, double-blind, 3-arm, non-inferiority trial conducted at 27 primary care centres. Adults with ≥1 knee flare episode within 12 months were recruited within 24 h of new flare with pain severity ≥5 on a 0-10 numerical rating scale (NRS). Primary outcome was change from baseline in WOMAC pain subscale over 5 days. Main secondary outcome was Gastrointestinal Symptom Rating Scale (GSRS) change from baseline. Other endpoints included assessment of WOMAC total subscale scores and self-reported NRS for pain, subject nominated activity, stiffness and swelling.Results: 462 patients were enrolled (58.9% males; mean age 52.2 years). Treatment allocation comprised 148 lipid 1200 mg, 155 soft-gel 1200 mg, 159 soft-gel 2400 mg. WOMAC pain subscale scores decreased in all groups, with lipid 1200 mg being non-inferior to soft-gel 1200 mg (adjusted mean difference -0.26 [95% confidence interval [CI] -0.69, 0.17]) and to soft-gel 2400 mg (difference 0.19 [95% CI -0.24, 0.62]). No differences were seen in mean GSRS total scores. NRS secondary endpoints suggested greater improvements in the lipid 1200 mg group compared to soft-gel 1200 mg, with similar results to soft-gel 2400 mg. The most frequent drug-related adverse events (AEs) were gastrointestinal (GI) disorders, with statistically fewer events for lipid 1200 mg vs soft-gel 2400 mg (P = 0.01, post-hoc analysis).Conclusions: Ibuprofen 1200 mg/day lipid formulation was non-inferior to standard ibuprofen soft-gel capsules 1200 mg and 2400 mg/day in relieving flaring knee pain. NRS endpoints showed lipid 1200 mg was numerically similar to soft-gel 2400 mg.Trial Registration Number: EudraCT number: 2014-004254-33. [ABSTRACT FROM AUTHOR]

As the field of PET has expanded and an ever-increasing number and variety of compounds have been radiolabeled as potential in vivo tracers of biochemistry, transporters have become important primary targets or facilitators of radiotracer uptake and distribution. A transporter can be the primary target through the development of a specific high-affinity radioligand: examples are the multiple high-affinity radioligands for the neuronal membrane neurotransmitter or vesicular transporters, used to image nerve terminals in the brain. The goal of a radiotracer might be to study the function of a transporter through the use of a radiolabeled substrate, such as the application of 3-O-[11C]methyl]glucose to measure rates of glucose transport through the blood-brain barrier. In many cases, transporters are required for radiotracer distributions, but the targeted biochemistries might be unrelated: an example is the use of 2-deoxy-2-[18F]FDG for imaging glucose metabolism, where initial passage of the radiotracer through cell membranes requires the action of specific glucose transporters. Finally, there are transporters such as p-glycoprotein that function to extrude small molecules from tissues, and can effectively work against successful uptake of radiotracers. The diversity of structures and functions of transporters, their importance in human health and disease, and their role in therapeutic drug disposition suggest that in vivo imaging of transporter location and function will continue to be a point of emphasis in PET radiopharmaceutical development. In this review, the variety of transporters and their importance for in vivo PET radiotracer development and application are discussed. Transporters have thus joined the other major protein targets such as G-protein coupled receptors, ligand-gated ion channels, enzymes, and aggregated proteins as of high interest for understanding human health and disease. [ABSTRACT FROM AUTHOR]

Purpose Describe the development and evolution of a primary-care-based, multidisciplinary clinic to support the ongoing care of adult survivors of childhood cancer. Methods A consultative clinic for adult survivors of childhood cancer has been developed that is located in an adult, academic internal medicine setting and is based on a long-term follow-up clinic model available at Children's Hospital Colorado. Results The clinic opened in July 2008. One hundred thirty-five patients have been seen as of April 2014. Referrals and clinic capacity have gradually increased over time, and a template has been developed in the electronic medical record to help facilitate completion of individualized care plan letters. Conclusions A primary care-based, multidisciplinary consultative clinic for adults with a history of childhood cancer survivor is feasible and actively engages adult primary care resources to provide risk-based care for long-term pediatric cancer survivors. This model of care planning can help support adult survivors of pediatric cancer and their primary care providers in non-academic, community settings as well. [ABSTRACT FROM AUTHOR]

Introduction: Neurogenic stress cardiomyopathy (NCM) has been associated with poor outcomes in the setting of aneurysmal subarachnoid hemorrhage (aSAH). Much less is known regarding recovery of cardiac function. The aim of this prospective cohort study was to study the rate of early cardiac recovery after NCM and the potential effect of NCM on short term functional recovery. A secondary aim sought to determine whether certain biomarkers may be associated with the development of NCM. Methods: Patients with confirmed aSAH between November 2012 and October 2013 were prospectively enrolled and received echocardiograms within 48 h of admission. Ejection fraction (%) and regional wall motion abnormality score index (RWMI) were noted. All patients with confirmed aSAH had a troponin and BNP level drawn on admission. Patients with confirmed NCM received a follow up echocardiogram 7-21 days after the initial echocardiogram. Clinical follow up at 3 months evaluated mortality, mRS and mBI scores. Results: 63 patients with confirmed aSAH were enrolled. In this cohort 11 (17%) patients were confirmed to have NCM. The NCM group had higher in-hospital mortality [n = 4(36.4%)] compared to the non-NCM group [n = 5(9.6%)] (p = .021). At 3 months the development of NCM was associated with an unfavorable mRS (p = 0.042) and mBI (p = 0.005). Both an elevated BNP (>100pg/mL) and elevated troponin (>0.3mg/dL) were associated with the development of NCM. Follow-up echocardiograms were performed within 21 days of admission on 8 patients with NCM. An abnormal RWMI of 1.5 or higher was present in 5(71%) patients. Conclusion: NCM is a frequent complication associated with aSAH. The onset of the disease occurs early in the course of aSAH and an elevated BNP and troponin may be associated with the onset of NCM. Cardiac function often remains impaired during the acute recovery phase potentially impeding resuscitation during this period. The routine use of short term follow-up echocardiography may be recommended. [ABSTRACT FROM AUTHOR]

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is an often devastating form of stroke. Aside from the initial hemorrhage, cardiac complications can occur resulting in neurogenic stress cardiomyopathy (NCM), leading to impaired cardiac function. We investigated whether aSAH patients with NCM had poorer long term functional outcomes than patients without NCM. Mortality, vasospasm, and delayed ischemic complications were also evaluated. Methods: A retrospective study of all patients admitted for aneurysmal subarachnoid hemorrhage (aSAH) from January 2006 to June 2011 (n = 299) was conducted. Those patients who underwent an echocardiogram were identified (n = 120) and were assigned to the NCM (n = 49) category based on echocardiographic findings defined by a depressed ejection fraction (EF%) along with a regional wall motion abnormality (RWMA) in a non-vascular pattern. Primary outcome measures included in-hospital mortality and functional outcomes as measured by the Modified Barthel Index (mBI) at 3 months and one year. Secondary analysis determined if there was an association between NCM, cerebral vasospasm and delayed cerebral ischemia. Results: 16% of aSAH patients developed NCM. Mortality was higher (p < .001) in the NCM group (n = 23[46.9%]) than in the non-CM group (n = 28[11.2%]). Patients with NCM had poorer functional outcomes as measured by the mBI at both 3 months (p = .002) and 12 months (p = .014). The Hunt--Hess score was predictive of functional outcome as measured by the mBI at both 3 months (p = .002) as well as at 1 year (p = .014). NCM was associated with both death (p = .047 CI, 1.012-7.288) and vasospasm (p = .008 CI, 1.34-6.66) after correction for Hunt--Hess grade. Tobacco use (p < .001) and a history of diabetes mellitus (p < .009) were also associated with vasospasm. NCM was associated with higher in-hospital mortality (p = .047) in multivariate analysis. Conclusion: NCM is seen in a substantial number of aSAH patients and when present, it is associated with higher mortality and poorer long-term functional outcomes. This finding may guide further prospective studies in order to determine if early recognition of NCM as well as optimization of cardiac output would improve mortality. [ABSTRACT FROM AUTHOR]

Abstract: The hypothesis that repeated daily doses of amphetamine increases the number of available dopamine D2 receptors in vivo in rat striatum, and may enhance the response to subsequent amphetamine challenge doses, was examined. The in vivo binding potentials of [11C]raclopride, a D2 receptor antagonist, were determined in male CD-1 rats under five conditions: (1) drug-naïve with saline challenge, (2) drug naïve with 5mg/kg amphetamine challenge, (3) amphetamine-dosed (five daily repeated s.c. doses of 5mg/kg amphetamine) and saline challenge, (4) amphetamine-dosed and amphetamine challenge, and (5) saline treated (five daily repeated s.c. doses) and saline challenged. Radiotracer studies in amphetamine-dosed animals were done after a 10-day drug free interval. In the amphetamine-dosed group the baseline [11C]raclopride binding was increased by 63% compared to saline-treated controls. The response to an amphetamine challenge, evidenced by a reduction of [11C]raclopride binding, was doubled in amphetamine-dosed animals (40%) compared to drug-naïve controls (20%). These results support increased baseline in vivo dopamine D2 receptor antagonist radioligand binding after repeated amphetamine administration in rats. [Copyright &y& Elsevier]

Abstract: Introduction: The sensitivity of the in vivo binding of [11C]dihydrotetrabenazine ([11C]DTBZ) and [11C]methylphenidate ([11C]MPH) to their respective targets — vesicular monoamine transporter type 2 (VMAT2) and neuronal membrane dopamine transporter — after alterations in endogenous levels of dopamine was examined in the rat brain. Methods: In vivo binding of [11C]DTBZ and [11C]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography. Results: Repeated dosing with α-methyl-p-tyrosine (AMPT) at doses that significantly (−75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [11C]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed via treatment with l-DOPA/benserazide to restore dopamine levels. There were no changes in the total number of VMAT2 binding sites, as measured using in vitro autoradiography. No changes were observed for in vivo [11C]MPH binding to the dopamine transporter in the striatum following AMPT pretreatment. Conclusion: These results indicate that large reductions in dopamine concentrations in the rat brain can produce modest but significant changes in the binding of radioligands to VMAT2, which can be reversed by replenishment of dopamine using exogenous l-DOPA. [Copyright &y& Elsevier]

Abstract: Introduction: The regional brain distribution of (2R,3R)-5-[18F]fluoroethoxy-benzovesamicol ((−)-[18F]FEOBV), a radioligand for the vesicular acetylcholine transporter (VAChT), was examined in vivo in mice, rats and rhesus monkeys. Methods: Regional brain distributions of (−)-[18F]FEOBV in mice were determined using ex vivo dissection. MicroPET imaging was used to determine the regional brain pharmacokinetics of the radioligand in rat and rhesus monkey brains. Results: In all three species, clear heterogeneous regional brain distributions were obtained, with the rank order of brain tissues (striatum>thalamus>cortex>cerebellum) consistent with the distribution of cholinergic nerve terminals containing the VAChT. Conclusions: (−)-[18F]FEOBV remains a viable candidate for further development as an in vivo imaging agent for positron emission tomography (PET) studies of the VAChT in the human brain. [Copyright &y& Elsevier]

Abstract: A simple modification of the GE Tracerlab FX C Pro system which enabled performance of both solvent capture (loop method) and conventional solution phase [11C]methylation in the same module is described. By the quick setup and automated method, [11C]carfentanil and [11C]raclopride could be prepared in rapid succession without opening the hot cell. The radiochemical yields were over 40% and 30% (decay-corrected and based on [11C]methyl iodide) for [11C]carfentanil and [11C]raclopride, respectively. The radiochemical purities were greater than 95% and specific activities over 5Ci/mmol for both tracers. The modification is extremely easy and can be utilized for multiple syntheses of other 11C-labeled radiopharmaceuticals in a fast and reliable manner. [Copyright &y& Elsevier]

Abstract: This paper argues for understanding ICT from the standpoint of philosophical world views. We present a framework, based on Pepper’s root-metaphors (Formism, Contextualism, Mechanism, Organicism, and Animism/Mysticism) and we illustrate the use of the framework by looking at a common example of ICT: e-mail. It is argued that such a framework is potentially helpful to ICT teachers, especially when they work with pre-service education students who are struggling with how to integrate ICT critically into their future classrooms. [Copyright &y& Elsevier]

Abstract: 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix® 2.2.2) is used in the routine preparation of [18F]-labeled tracers employed in positron emission tomography (PET) imaging. Confirming the absence of Kryptofix® in radiopharmaceuticals is a quality control criterion required before they can be released for human use. Analysis of Kryptofix® levels using the iodoplatinate spot-test can be complicated by false-positive results due to nitrogen containing tracers and/or false-negative results caused by added stabilizers. To overcome this issue, we have developed a universal TLC method for the rapid and reliable determination of Kryptofix® levels in the wide range of fluorine-18 radiopharmaceuticals we prepare, including complex multi-component formulations. [Copyright &y& Elsevier]

Abstract: The in vivo binding of N-[18F]fluoroethyl-piperidinyl benzilate ([18F]FEPB) to the muscarinic cholinergic receptor was measured in awake and anesthetized rats. Studies were done using an equilibrium infusion technique to provide estimates of specific binding as distribution volume ratios. Anesthesia with either isoflurane or sodium pentobarbital produced a significant (65–90%) increase of radiotracer binding in receptor-rich brain regions (striatum, cortex, hippocampus) relative to awake controls. Pretreatment of anesthetized animals with the acetylcholinesterase inhibitor phenserine produced no further increases in radioligand binding, in contrast to the large (>70%) increases previously observed in awake animals following drug treatment. These studies demonstrate that anesthesia can produce significant changes in baseline biochemical measures that can obscure even very large effects of pharmacological challenges. [Copyright &y& Elsevier]

Abstract: The specific binding and regional brain pharmacokinetics of new fluorine-18 ([18F])-labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-[18F]fluoropropyl-(±)-9-O-desmethyldihydrotetrabenazine ([18F]FP-(±)-DTBZ) showed better specific binding in the striatum than either (+)-[11C]dihydrotetrabenazine ((+)-[11C]DTBZ) or 9-[18F]fluoroethyl-(±)-9-O-desmethyldihydrotetrabenazine ([18F]FE-(±)-DTBZ). Using microPET, the regional brain pharmacokinetics of [18F]FE-(±)-DTBZ, [18F]FP-(±)-DTBZ and (+)-[11C]DTBZ were examined in the same monkey brain. (+)-[11C]DTBZ and [18F]FP-(±)-DTBZ showed similar brain uptakes and pharmacokinetics, with similar maximum striatum-to-cerebellum ratios (STR/CBL=5.24 and 5.15, respectively) that were significantly better than obtained for [18F]FE-(±)-DTBZ (STR/CBL=2.55). Striatal distribution volume ratios calculated using Logan plot analysis confirmed the better specific binding for the fluoropropyl compound [distribution volume ratio (DVR)=3.32] vs. the fluoroethyl compound (DVR=2.37). Using the resolved single active isomer of the fluoropropyl compound, [18F]FP-(+)-DTBZ, even better specific to nonspecific distribution was obtained, yielding the highest distribution volume ratio (DVR=6.2) yet obtained for a VMAT2 ligand in any species. The binding of [18F]FP-(+)-DTBZ to the VMAT2 was shown to be reversible by administration of a competing dose of unlabeled tetrabenazine. Metabolic defluorination was slow and minor for the [18F]fluoroalkyl-DTBZ ligands. The characteristics of high specific binding ratio, reversibility, metabolic stability and longer half-life of the radionuclide make [18F]FP-(+)-DTBZ a promising alternative VMAT2 radioligand suitable for widespread use in human positron emission tomography studies of monoaminergic innervation of the brain. [Copyright &y& Elsevier]

Abstract: The effects of limestone dust deposition on vegetation in desert ecosystems have not yet been reported. We investigated these effects in a succulent shrub from the Namib Desert at a limestone quarry near Skorpion Zinc mine (Namibia). Effects of limestone dust were determined in Zygophyllum prismatocarpum (dollar bush) plants with heavy, moderate and no visible foliar dust cover by means of chlorophyll a fluorescence measurements. Limestone dust deposition decreased overall plant performance through loss of chlorophyll content, inhibition of CO2 assimilation, uncoupling of the oxygen-evolving complex and decreased electron transport. Importantly, dynamic recovery occurred after termination of limestone extraction at the quarry. Recovery was accelerated by rainfall, mainly because of dust removal from leaves and stimulation of new growth. These results indicate that limestone dust has severe effects on photosynthesis in desert shrubs, but that recovery is possible and that, in arid environments, this process is modulated by rainfall. [Copyright &y& Elsevier]

The long-term reproducibility of measures of in vivo specific binding of radiolabeled forms of (+)-α-dihydrotetrabenazine (DTBZ) and d-threo-methylphenidate (MPH) in rat brain was examined. All studies were done using a consistent bolus plus infusion protocol and calculation of equilibrium distribution volume ratios (DVR). Over a period of eight years striatal DVR values for DTBZ binding to the vesicular monoamine transporter 2 (VMAT2) in young adult (8-10 wks old) rats showed very good reproducibility (3.62±0.33, N=35). Equivalent values were obtained using either tritiated or carbon-11 labeled DTBZ, and were irrespective of sex of animals. Older animals (78 wks old) showed losses (-45%) of specific binding. Striatal binding of MPH to the dopamine transporter (DAT) showed a similar reproducibility over a five year period (DVR=2.17±0.39, N=52), again irrespective of radionuclide or sex. These studies demonstrate that use of a consistent in vivo technique can provide reliable measures of specific binding of radioligands to high affinity sites in the rat brain. [Copyright &y& Elsevier]

Eight derivatives of [11C]carfentanil were evaluated as alternative mu opioid receptor radioligands with the potential for lower pharmacological activity, faster pharmacokinetics, and/or lower non-specific binding. Derivatives with aryl ring substituents or alkyl group substitutions were prepared in carbon-11 labeled form and examined for initial brain uptake and regional brain tissue pharmacokinetics in mouse brain. Promising derivatives with chloro, methoxy and methyl substituents on one aryl ring were then evaluated for specific binding in an equilibrium infusion rat model of regional brain distributions. Although no derivatives were identified with improved pharmacokinetics or lower non-specific binding, several derivatives show acceptable in vivo specific binding properties and may deserve further evaluation as less potent and thus safer compounds for in vivo imaging studies. [Copyright &y& Elsevier]

Abstract: (+)-α-[11C]Dihydrotetrabenazine ((+)-[11C]DTBZ), a radioligand for the vesicular monoamine transporter type 2 (VMAT2), has been previously proposed as an in vivo marker of beta-cell degeneration in the pancreas. The stereospecificity of uptake of [11C]DTBZ into rat pancreas was examined here using radiolabeled forms of the (+)- and (−)-isomers. Pancreas localization of (+)-[11C]DTBZ could be partially blocked by prior administration of unlabeled (+)-DTBZ. Pancreatic uptake of the (−)-isomer was unexpectedly high and could not be blocked by pretreatment with (+)-DTBZ, but could be significantly reduced by treatment with racemic tetrabenazine, an in vivo source of (−)-DTBZ. These studies indicate that the inactive isomer of DTBZ does not provide a mechanism for defining the nonspecific binding of (+)-DTBZ in rat pancreas. [Copyright &y& Elsevier]

Background Dual antiplatelet therapy is associated with increased rates of intracerebral hemorrhage, especially in the context of subarachnoid hemorrhage. We present a case of a spontaneous hemorrhage in a patient treated with a Pipeline stent for a ruptured dissecting vertebrobasilar aneurysm and the novel use of direct application of platelets during surgery to control bleeding. Case Description A 54-year-old previously healthy woman presented with an intradural right vertebral artery dissection with a ruptured 6-mm pseudoaneurysm. The patient was started on aspirin and clopidogrel and the vessel was reconstructed with 2 Pipeline Embolization Devices. On postbleed day number 14, she became obtunded with a blown right pupil; computed tomography of the head demonstrated a large right temporal intracerebral hematoma. The patient was taken emergently to the operating room for evacuation of the clot. Intraoperatively, satisfactory control of bleeding was not achieved despite transfusing several units of platelets intravenously. Ultimately, a mixture of Floseal and platelets applied directly to the hematoma wall allowed prompt hemostasis. At 3 months the patient was doing extremely well clinically and angiography demonstrated occlusion of the aneurysm. Conclusions This is the first reported description of direct application of platelets to achieve intraoperative hemostasis. Platelets are activated by thrombin and collagen and the use of Floseal (a bovine-derived, gelatin matrix and human-derived thrombin) further potentiated the effectiveness of this strategy. With the increased incidence of intracerebral hemorrhage associated with dual antiplatelet therapy, this technique may provide a useful tool in the neurosurgical armamentarium. [ABSTRACT FROM AUTHOR]