Backbone-functionalised ruthenium diphosphine complexes for catalytic upgrading of ethanol and methanol to iso-butanol.

Efficient catalysts for Guerbet-type ethanol/methanol upgrading to iso-butanol have been developed via Michael addition of a variety of amines to ruthenium-coordinated dppen (1,1-bis(diphenylphosphino)ethylene). All catalysts produce over 50% iso-butanol yield with >90% selectivity in 2 h with catalyst 1 showing the best activity (74% yield after this time). The selectivity and turnover number approach 100% and 1000 respectively using catalyst 6. The presence of uncoordinated functionalised donor groups in these complexes results in a more stable catalyst compared to unfunctionalised analogues.

Soluble low affinity nerve growth factor receptor (sLNGFR) may regulate pain in knee osteoarthritis.

OBJECTIVES: Nerve growth factor ß (ß-NGF) is a protein which is important to the development of neurons particularly those involved in the transmission of pain and is central to the experience of pain in osteoarthritis (OA). Direct NGF antagonism has been shown to reduce OA pain but is associated with rapidly progressive OA. The aim of the study is to investigate the ability of soluble neurotrophin receptors in the NGF pathway to modulate pain in OA. METHODS: Synovial fluid (SF) was obtained from the knee joints of 43 subjects who underwent total knee arthroplasty. Visual analogue scale (VAS) pain scores were obtained prior to surgery. Customised-automated-ELISAs and commercial-ELISAs and LEGENDplex™ were used to measure soluble low-affinity nerve growth factor (LNGFR), soluble tropomyosin receptor kinase (TrkA), proNGF, ß-NGF, other neurotrophins (NT) and cytokines including inflammatory marker TNF-α. RESULTS: The VAS score positively correlated with ß-NGF (r=0.34) and there was positive association trend with neurotrophin-3 (NT-3), BDNF and negative association trend with ProNGF. sLNGFR positively correlated with VAS (r=0.33). The ß-NGF/soluble TrkA ratio showed a strong positive correlation with VAS (r=0.80). In contrast, there was no correlation between pain and the ß-NGF/sLNGFR ratio (r=-0.08). TNF-α positively correlated with ß-NGF (r=0.83), NT-3 (r=0.66), and brain-derived neurotrophic factor (BDNF) (r=0.50) and negatively with ProNGF (r= -0.74) and positively correlated with both soluble TrkA (r=0.62), sLNGFR (r=0.26). CONCLUSIONS: This study suggests that endogenous or cleaved sLNGFR, but not soluble TrkA may participate in OA pain modulation thus supporting further research into soluble LNGFR as a therapeutic target in OA.

Improvement in male pelvis magnetic resonance image contouring following radiologist-delivered training.

INTRODUCTION: The magnetic resonance linear accelerator (MRL) combines both magnetic resonance imaging and a linear accelerator, allowing for daily treatment adaptation. This study aimed to assess the impact of radiologist-delivered training in magnetic resonance (MR) contouring of relevant structures within the male pelvis. METHODS: Two radiation oncologists, two radiation oncology registrars and seven radiation therapists completed contouring on 10 male pelvis MR datasets both pre- and post-training. A 2-hour MR anatomy training session was delivered by a radiologist, who also provided the 'gold standard' contours. The pre- and post-training contours were compared against the gold standard with Dice similarity coefficient (DSC) and Hausdorff distances calculated; and the pre- and post-confidence scores and timing were compared. RESULTS: The improvement in DSC were significant in prostate, rectum and seminal vesicles, with a post-training median DSC of 0.87 ± 0.06, 0.92 ± 0.04 and 0.80 ± 0.14, respectively. The median Hausdorff improved with a median of 1.46 ± 0.78 mm, 0.52 ± 0.32 mm and 1.11 ± 0.86 mm for prostate, rectum and seminal vesicles, respectively. Bladder concordance was high both pre- and post-training. Urethra contours improved post-training, however, remained difficult to contour with a median post-DSC of 0.51 ± 0.24. Overall, confidence scoring improved (P < 0.001) and timing decreased by an average of 4.4 ± 16.4 min post-training. CONCLUSION: Radiologist-delivered training improved concordance of male pelvis contouring on MR datasets. Further work is required in the identification of urethra on MRs. These findings are of importance in the MRL adaptive workflow.

Informant Discrepancies in Suicidality Screening Tools Among School Age Youth.

As the rate of death by suicide in youth ages 6 to 12 rises, it is imperative to better understand informant discrepancies when screening for suicidality. Accordingly, this study investigated associations among youth-, caregiver-, and clinician-reports of youth's suicidality and their associations with youth- and caregiver-reports of youth's depressive symptoms. Participants were 161 6- to 12-year-old youth presenting for outpatient psychological services at a Midwest training clinic between 2014 and 2019. More than 1 in 4 youth had at least one informant report some suicidal concerns. Results indicated that all informants' reports of suicidality were correlated with one another, with youth- and clinician-report being most strongly linked and caregiver- and clinician-report having the weakest correlation. Clinician- and youth-reports of suicidality were associated with youth-report, (but not caregiver-report) of depressive symptoms. Caregiver-report of suicidality was not associated with youth- or caregiver-report of depressive symptoms. When youth-report of depressive symptoms was regressed on sex, age, and youth-, caregiver-, and clinician-reports of suicidality, there was a trend that youth-report of suicidality was positively associated with youth-report of depressive symptoms. No informant's report of suicidality was uniquely associated with caregiver-report of depressive symptoms. Findings indicate that youth- and clinician-reports at intake are more strongly linked with one another than with caregiver-reports. Further, youth-reports on suicidality screening tools are more strongly associated with depressive symptoms than caregiver-report, suggesting that caregiver-reports are insufficient to assess concerns of suicidality at intake among school age youth.

Indicators of suicidal outcomes among 6- to 12-year-old treatment seeking youth.

Suicide among elementary school-age youth is vastly understudied despite being a major health concern. This study utilized mediation and moderation models to elucidate the nature of risk factors for suicide by examining the effect emotion dysregulation (of anger, sadness, and worry) has on the relation between ADHD symptoms (hyperactivity/impulsivity and inattention) and suicidal outcomes (suicidal behavior and risk for suicide) in children ages 6 to 12. When accounting for sex, age, depressive symptoms, and emotion dysregulation, hyperactivity/impulsivity was positively associated with suicidal behavior; however, inattention was negatively associated with suicidal behavior. After accounting for the variance associated with sex, age, and depressive symptoms, two interaction effects were evident. At low levels of sadness and worry dysregulation, hyperactivity was positively associated with suicide risk. However, at high levels of sadness and worry dysregulation, hyperactivity was not related to suicide risk. Findings support moderation over mediation.

Varying Experiences of Cyber Victimization among Middle and High School Students.

BACKGROUND: Although cyber victimization (CV) occurs in both middle school (MS) and high school (HS)-and these experiences appear to differ between boys and girls-to our knowledge, no studies have directly examined these differences across specific acts of CV. Further, limited research has examined school environment factors, such as school safety and attachment, as they relate to CV. OBJECTIVES: The current study compared CV experiences reported by boys and girls in both MS and HS as well as examined CV's association with perceived school safety and school attachment. METHOD: Participants were 286 MS and 304 HS students (52% boys) from a small, rural Midwestern community in the United States. Self-reported measures were collected. RESULTS: HS girls reported experiencing more CV than MS girls on 5 of the 6 CV acts examined. Additionally, HS girls reported experiencing more CV on 3 of the acts compared to MS boys. In general, HS boys and HS girls report similar rates of CV, with the exception of HS girls experiencing higher levels of "people saying mean and nasty things about them." Regression analyses indicated that youth who report higher CV feel less connected to school, but their CV experiences do not appear to be related their perceived school safety when also considering traditional forms of victimization. CONCLUSIONS: CV experiences are higher for HS girls for the majority of different types of CV acts compared to MS youth but similar to HS boys, and experiencing these acts is associated with less school connectedness.

Measurement and correlates of irritability in clinically referred youth: Further examination of the Affective Reactivity Index.

BACKGROUND: Research on youth irritability has proliferated in recent years, largely facilitated by items from existing measures and by key new instruments like the Affective Reactivity Index (ARI). The present study extends this literature by investigating the psychometric properties of the parent- and youth-report ARI and the correlates of irritability in an independent, clinically referred sample. METHOD: Baseline assessment data were collected from 237 youths (ages 3-18; 36% female) and their parents, seen for outpatient therapy and/or assessment. We examined the ARI in terms of (1) its item, scale, and factor properties; (2) convergent/discriminant validity with internalizing, externalizing, and emotion regulation problems; (3) specificity of associations with reactive aggression, anger, dysregulation, and coping; and (4) robustness of associations after controlling for demographic variables (e.g., age, gender). RESULTS: The ARI's internal consistency and unidimensional factor structure were acceptable or better, with some variation across items and informants. Irritability, as measured by parent- and youth-report, was associated with variables in the externalizing (inattention, hyperactivity, executive dysfunction, aggression), internalizing (anxiety, depression, suicidality), and emotion regulation domains. Associations with reactive aggression, anger, dysregulation, and coping problems were especially pronounced. Irritability's links with internalizing and externalizing problems remained robust after controlling for demographic covariates. LIMITATIONS: The sample was limited in diversity and moderate in size. CONCLUSIONS: Findings support the reliability and validity of the ARI for assessing parent- and youth-rated irritability among clinically referred youth. Future research is needed to understand variations in irritability's manifestations, measurement, and correlates across demographic groups.

Reactive Aggression and Suicidal Behaviors in Children Receiving Outpatient Psychological Services: The Moderating Role of Hyperactivity and Inattention.

The current study examines associations between reactive and proactive aggression and suicidal thoughts and behaviors among youth (N = 115, 62% male), ranging from 6 to 12 years, seeking services in an outpatient psychological clinic. Symptoms of hyperactivity/impulsivity and inattention were evaluated as potential moderators of this link. Children and a caregiver completed self- and parent-report questionnaires on aggression, suicidal behaviors, depressive symptoms, and ADHD-related behaviors during intake. Reactive aggression was more strongly linked to suicidal thoughts and behaviors than proactive aggression. Further, hyperactivity/impulsivity, but not inattention, moderated the association between reactive aggression and suicidal thoughts and behaviors, such that reactive aggression was only associated with suicidal behaviors at high levels of hyperactivity/impulsivity. These findings were evident for reactive, not proactive, aggression and when accounting for the variance associated with depressive symptoms, age, and gender. Hyperactivity/impulsivity is discussed as a potentially important target among reactively aggressive youth for prevention of suicidal behaviors.

Discrimination learning in oxycodone-treated nonhuman primates.

BACKGROUND: Prescription opioid abuse continues to be a public health concern of epidemic proportions. Notwithstanding the extensive literature regarding opioid action, there has been little systematic research regarding the effects of opioid dependence and withdrawal on aspects of cognition-related behavior in laboratory animals. The present studies examined the effects of the prescription opioid oxycodone on learning processes in nonhuman primates. METHODS: The ability of subjects to repeatedly learn novel touchscreen-based visual discriminations was examined during three conditions of opioid exposure. Discrimination learning was examined, first, during oxycodone self-administration (3-hr sessions, 0.1 mg/kg/injection) and, next, during non-contingent chronic treatment with oxycodone (10 mg/kg/day). Finally, discrimination learning was re-examined during antagonist-precipitated opioid withdrawal (0.001-0.1 mg/kg naltrexone) and, subsequently, following abrupt discontinuation of oxycodone treatment. RESULTS: Although motoric behavior was disrupted by oxycodone, neither the development of discrimination learning nor steady-state performance were impaired following oxycodone self-administration or during non-contingent chronic oxycodone treatment. However, discrimination learning was substantially impaired during oxycodone withdrawal, whether elicited by naltrexone or by abrupt oxycodone discontinuation. Moreover, these learning impairments were concordant with autonomic signs of opioid withdrawal. CONCLUSIONS: Taken together, the present studies indicate that impairment of learning processes can accompany the unconditioned signs of opioid withdrawal.

Are Fathering Interventions Acceptable to Veterans? A Needs and Preferences Survey.

INTRODUCTION: Military deployments cause stress for both service members and their families. Returning Veterans often report significant trauma exposure, and experience increased stress and mental health problems following deployment. These factors can in turn increase family problems and parenting strain among Veterans who are parents, exacerbating mental health symptoms. Men are generally less likely to seek treatment for mental health problems, and male Veterans, in particular, report lower rates of mental health treatment use. Interventions that target fathering or parenting skills may be more acceptable and less stigmatizing to male Veterans while serving the dual function of improving parental relationships and reducing mental health symptoms. However, it is unclear whether Veteran fathers will engage in these services. MATERIALS AND METHODS: As a preliminary evaluation of the acceptability of fathering interventions, 50 returning Veteran fathers completed an anonymous survey designed to assess their needs and preferences regarding this type of service. All procedures were approved by the local Institutional Review Board and Research and Development Committee. RESULTS: Ninety-eight percent of participants reported experiencing at least one parenting issue either that started postdeployment or that got noticeably worse following postdeployment. The majority (86%) stated that they would be open to participating in a fathering program if offered. CONCLUSIONS: Returning Veteran fathers demonstrate interest in and willingness to participate in fathering programs suggesting that parenting programs may be a way to engage Veterans in mental health care following deployment.

Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates.

RATIONALE: Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. OBJECTIVES: The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. METHODS: First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. RESULTS: Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. CONCLUSIONS: The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

Calculation and experimental measurement of paramagnetic NMR parameters of phenolic oximate Cu(ii) complexes.

We present a strategy for predicting the unusual 1H and 13C shifts in NMR spectra of paramagnetic bisoximato copper(ii) complexes using DFT. We demonstrate good agreement with experimental measurements, although 1H-13C correlation spectra show that a combined experimental and theoretical approach remains necessary for full assignment.

A comparison of service organisation and guideline compliance between two adjacent European health services.

INTRODUCTION: Outcomes in stroke patients are improved by a co-ordinated organisation of stroke services and provision of evidence-based care. We studied the organisation of care and application of guidelines in two neighbouring health care systems with similar characteristics. METHODS: Organisational elements of the 2015 National Stroke Audit (NSA) from the Republic of Ireland (ROI) were compared with the Sentinel Stroke National Audit Programme (SSNAP) in Northern Ireland (NI) and the United Kingdom (UK). Compliance was compared with UK and European guidelines. RESULTS: Twenty-one of 28 ROI hospitals (78%) reported having a stroke unit (SU) compared with all 10 in NI. Average SU size was smaller in ROI (6 beds vs. 15 beds) and bed availability per head of population was lower (1:30,633 vs. 1:12,037 p < 0.0001 Chi Sq). Fifty-four percent of ROI patients were admitted to SU care compared with 96% of UK patients (p < 0.0001). Twenty-four-hour physiological monitoring was available in 54% of ROI SUs compared to 91% of UK units (p < 0.0001). There was no significant difference between ROI and NI in access to senior specialist physicians or nurses or in SU nurse staffing (3.9/10 beds weekday mornings) but there was a higher proportion of trained nurses in ROI units (2.9/10 beds vs. 2.3/10 beds (p = 0.02 Chi Sq). CONCLUSION: Whilst the majority of hospitals in both jurisdictions met key criteria for organised stroke care the small size and underdevelopment of the ROI units meant a substantial proportion of patients were unable to access this specialised care.

Paramagnetic NMR of Phenolic Oxime Copper Complexes: A Joint Experimental and Density Functional Study.

1 H and 13 C pNMR properties of bis(salicylaldoximato)copper(II) were studied in the solid state using magic-angle-spinning NMR spectroscopy and, for the isolated complex and selected oligomers, using density-functional theory at the PBE0-1/3 //PBE0-D3 level. Large paramagnetic shifts are observed, up to δ(1 H)=272 ppm and δ(13 C)=1006 ppm (at 298 K), which are rationalised through spin delocalisation from the metal onto the organic ligand and the resulting contact shifts arising from hyperfine coupling. The observed shift ranges are best reproduced computationally using exchange-correlation functionals with a high fraction of exact exchange (such as PBE0-1/3 ). Through a combination of experimental techniques and first-principles computation, a near-complete assignment of the observed signals is possible. Intermolecular effects on the pNMR shifts, modelled computationally in the dimers and trimers through effective decoupling between the local spins via A-tensor and total spin rescaling in the pNMR expression, are indicated to be small. Addition of electron-donating substituents and benzannelation of the organic ligand is predicted computationally to induce notable changes in the NMR signal pattern, which suggests that pNMR spectroscopy can be a sensitive probe for the spin distribution in paramagnetic phenolic oxime copper complexes.

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.

'Preconditioning' with low dose lipopolysaccharide aggravates the organ injury / dysfunction caused by hemorrhagic shock in rats.

METHODS: Male rats were 'pretreated' with phosphate-buffered saline (PBS; i.p.) or LPS (1 mg/kg; i.p.) 24 h prior to HS. Mean arterial pressure (MAP) was maintained at 30 ± 2 mmHg for 90 min or until 25% of the shed blood had to be re-injected to sustain MAP. This was followed by resuscitation with the remaining shed blood. Four hours after resuscitation, parameters of organ dysfunction and systemic inflammation were assessed. RESULTS: HS resulted in renal dysfunction, and liver and muscular injury. At a first glance, LPS preconditioning attenuated organ dysfunction. However, we discovered that HS-rats that had been preconditioned with LPS (a) were not able to sustain a MAP at 30 mmHg for more than 50 min and (b) the volume of blood withdrawn in these animals was significantly less than in the PBS-control group. This effect was associated with an enhanced formation of the nitric oxide (NO) derived from inducible NO synthase (iNOS). Thus, a further control group in which all animals were resuscitated after 50 min of hemorrhage was performed. Then, LPS preconditioning aggravated both circulatory failure and organ dysfunction. Most notably, HS-rats pretreated with LPS exhibited a dramatic increase in NF-κB activation and pro-inflammatory cytokines. CONCLUSION: In conclusion, LPS preconditioning predisposed animals to an earlier vascular decompensation, which may be mediated by an excess of NO production secondary to induction of iNOS and activation of NF-κB. Moreover, LPS preconditioning increased the formation of pro-inflammatory cytokines, which is likely to have contributed to the observed aggravation of organ injury/dysfunction caused by HS.

Intentional insulin overdose associated with minimal hypoglycemic symptoms in a non-diabetic patient.

ABSTRACT: Non-accidental suicidal insulin overdose is a rare presentation among non-diabetic patients. It seems to be more common among working medical professionals. OBJECTIVES: To present the case of a young patient, who despite injecting a large dose of rapid-acting insulin presented with only mild symptoms, and to familiarize the medical professionals involved in managing this condition with the recognition, pathophysiology and appropriate therapeutic interventions. MATERIALS AND METHODS: We report the case of a previously healthy non-diabetic young medical professional who presented with a rapid-acting insulin overdose. On initial assessment the patient was alert and oriented, and glucose measurement was 1.4 mmol/L. The oral glucose gel and intramuscular glucagon failed to raise the glucose. Hypokalaemia, hypomagnesaemia, hypophosphataemia, lactic acidosis and ECG changes completed the presentation. OUTCOMES: The treatment consisted of dextrose infusion and appropriate electrolytes replacement. An uneventful recovery was made, so 36 hours later the patient was discharged with psychiatric follow-up. CONCLUSIONS: Insulin overdose should be considered as a differential diagnosis in hypoglycaemic patients when blood glucose fails to correct as expected. Improper management carries a significant risk of hypoglycaemic encephalopathy, which can cause lifelong cerebral changes.

In vitro and in vivo pharmacological characterisation of the potent and selective vasopressin V(1A) receptor antagonist 4-[4-(4-Chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl-(3,5-difluoro-phenyl) methanone (PF-00738245).

The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin receptors plays an important role in disease conditions including polycystic kidney disease, congestive heart failure and dysmenorrhoea. The development of potent and selective vasopressin receptor ligands is needed to help dissect the function of the specific subtypes in disease pathogenesis. Here we report the pharmacological characterisation of PF-00738245 in in vitro binding and functional assays using cells expressing vasopressin V(1A), V(1B) or V2 receptors. PF-00738245 inhibited AVP binding to the recombinant human vasopressin V(1A) receptor (K(i)=2.85 nM) and blocked AVP-induced rat aortic ring and human myometrial contraction (pK(B)=7.35 and 8.62 respectively). PF-00738245 was selective for the vasopressin V(1A) receptor by demonstrating minimal binding to vasopressin V(1B) (3.6% inhibition at 10 µM) or functional activity at vasopressin V2 receptors (8.1% agonist and -8.4% antagonist activity at 10 µM) as well as the oxytocin receptor (46.3% antagonist activity at 10 µM). The in vivo pharmacological properties were tested orally in the rat and PF-00738245 dose dependently blocked the effect of AVP on a capsaicin-induced cutaneous flare response. Taken together the data support the use of PF-00738245 as a potent and selective vasopressin V(1A) receptor antagonist which may have utility in the treatment of disease conditions which are propagated by elevation in vasopressin V(1A) receptor signalling.