Obesity-related knee osteoarthritis: a role for the rheumatology advanced nurse practitioner in Ireland.

Arthritis is the leading cause of disability in Ireland with knee osteoarthritis the most common presentation. One in five women and one in 10 men over the age of 60 in Ireland are diagnosed with osteoarthritis. The causative factors are multifactorial, but the increasing incidence of obesity is contributing greatly to the occurrence of osteoarthritis of the weight-bearing joints. The rheumatology advanced nurse practitioner is an autonomous clinical practitioner and potential solution to the growing numbers of people needing interventions for osteoarthritis, due to their ability to assess, diagnose, treat, and discharge these patients who ordinarily would be assessed from a medical waiting list. As obesity is becoming increasingly prevalent, it is important to address this with the patient cohort to try to reduce the burden of disease and treat not only the symptomatic knee osteoarthritis but the causative factors and provide patient-centred care.

Hypophosphataemia after ferric carboxymaltose is unrelated to symptoms, intestinal inflammation or vitamin D status.

BACKGROUND: Intravenous iron replacement is recommended for iron-deficient patients with inflammatory bowel disease (IBD), but may be associated with hypophosphataemia, predisposing to osteomalacia and fractures. This study aimed to evaluate the incidence and risk factors for hypophosphataemia following intravenous ferric carboxymaltose (FCM) in patients with IBD. METHODS: This prospective observational study of patients with and without IBD evaluated serum phosphate for 28 days following intravenous FCM, and assessed associations with symptoms, markers of inflammation and vitamin D status. RESULTS: Twenty-four patients with IBD (11 with Crohn's disease [CD], 13 with ulcerative colitis [UC], mean age 45 years [range 19-90], 7 female), and 20 patients without IBD (mean age 56 [22-88] y, 11 female), were included. Overall, serum phosphate declined by a mean of 36% at Day 7, with a mean fall of 42% (SD 19%) at some time point over 28 days (p <  0.001). Twenty-four of 44 (55%) patients developed moderate to severe hypophosphataemia (serum phosphate < 0.6 mmol/L). No differences between patients with and without IBD were seen, but patients with CD had greater decline in phosphate than those with UC. There was no association between hypophosphataemia and symptomatic adverse events, faecal calprotectin, C-reactive protein, albumin, platelet count, 25(OH) vitamin D, or 1,25(di-OH) vitamin D. Serum phosphate < 1.05 mmol/L on Day 2 predicted susceptibility to moderate-severe hypophosphataemia (OR 7.0). CONCLUSIONS: Hypophosphataemia following FCM is common, unrelated to symptomatic adverse events, baseline intestinal or systemic inflammation, or vitamin D status.

A first-level evaluation of a family intervention for adolescent social, emotional and behavioural difficulties in Child and Adolescent Mental Health Services.

UNLABELLED: This study is a first-level evaluation of a family intervention targeted at adolescents with social, emotional and behavioural difficulties (SEBD) attending Child and Adolescent Mental Health Services (CAMHS) in Ireland. It is a combined implementation of the Working Things Out adolescent programme and the Parents Plus Adolescent Programme (WTOPPAP). METHOD: A total of 93 adolescents aged 11-17 years (M = 14.64, SD = 1.31; 39% male) and their parents took part in the study. The study used a quasi-experimental One-Group Pretest-Posttest design to assess change from pre- to post-intervention using the Strengths and Difficulties Questionnaire, the McMaster General Functioning Scale, Goal Attainment, Parent Stress Scale and the Kansas Parenting Satisfaction Scale. Both parent- and adolescent-rated goal attainment and general family functioning improved from pre- to post-intervention. Parents also rated their satisfaction with parenting as having significantly improved. Adolescent-rated emotional difficulties significantly improved for the overall sample and parent-rated child total difficulties for female adolescents significantly improved from pre-test to post-test. Parents of female adolescents also reported a significant drop in parental stress. These findings indicate that the WTOPPAP may be an effective intervention for adolescents with SEBD, particularly females, and their parents. Further implications are discussed.

Neonatal overfeeding alters hypothalamic microglial profiles and central responses to immune challenge long-term.

The early life period is one of significant vulnerability to programming effects from the environment. Given the sensitivity of microglial cells to early life programming and to adult diet, we hypothesized overfeeding during the neonatal period would acutely alter microglial profiles within the developing brain, predisposing the individual to a lasting central pro-inflammatory profile that contributes to overactive immune responses long-term. We tested this idea by manipulating litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of 4 (neonatally overfed) or 12 (control). This manipulation induces obesity and susceptibility to lipopolysaccharide (LPS) long-term. We then examined microglial and central pro-inflammatory profiles during development and in adulthood as well as susceptibility to neuroimmune challenge with LPS. Neonatally overfed rats have evidence of microgliosis in the paraventricular nucleus of the hypothalamus (PVN) as early as postnatal day 14. They also show changes in hypothalamic gene expression at this time, with suppressed hypothalamic interleukin 1ß mRNA. These effects persist into adulthood, with basal PVN microgliosis and increased hypothalamic toll-like receptor 4, nuclear factor κB, and interleukin 6 gene expression. These neonatally overfed rats also have dramatically exacerbated microglial activation in the PVN 24h after an adult LPS challenge, coupled with changes in inflammatory gene expression. Thus, it appears neonatal overfeeding sensitizes PVN microglia, contributing to a basal pro-inflammatory profile and an altered response to a neuroimmune challenge throughout life. It remains to be seen if these effects can be reversed with early interventions.

Profile of brief symptom inventory-18 (BSI-18) scores in collegiate athletes: A CARE Consortium study.

Objective: The goal of this study was to characterize normative scores for the Brief Symptom Inventory (BSI-18) in collegiate athletes to inform decision making about the need for psychological health services in this group. Methods: Collegiate student-athletes (N = 20,034) from 25 universities completed the BSI-18 at their preseason baseline assessment. A subgroup (n = 5,387) underwent multiple baseline assessments. Global Severity Index (GSI) scores were compared to community norms and across multiple timepoints. Results: Collegiate athletes reported significantly lower GSI scores than published community norms (p<.001). Published GSI threshold scores for "caseness", identified only 2 per 100 athletes (≥ the 98th percentile) as needing further evaluation. Using a GSI score ≥ than the cohort's 90th percentile, 11.4 per 100 athletes would merit additional evaluation. These individuals were more likely to report a history of psychiatric diagnosis (Odds ratio [95% CI] 2.745 [2.480, 3.039]), as well as ≥ 2 prior concussions (p<.001). GSI scores were not highly correlated across timepoints. Suicidal ideation was rare (n = 230; 1.15%). Conclusions: For collegiate student-athletes, published BSI-18 threshold scores identify only extreme outliers who might benefit from additional behavioral health evaluation. Alternatively, use of threshold scores ≥ the 90th percentile identifies a more realistic 11.4% of the population, with higher likelihood of prior concussion and/or psychiatric disorders.

Endogenous ghrelin's role in hippocampal neuroprotection after global cerebral ischemia: does endogenous ghrelin protect against global stroke?

Ghrelin is a gastrointestinal hormone with a well-characterized role in feeding and metabolism. Recent evidence suggests that ghrelin may also be neuroprotective after injury in animal models of cerebral ischemia. Thus exogenous ghrelin treatment can improve cell survival, reduce infarct size, and rescue memory deficits in focal ischemia models, doing so by suppressing inflammation and apoptosis. Endogenous ghrelin plays a key a role in a number of physiological processes, including feeding, metabolism, stress, and anxiety. However, no study has examined whether endogenous ghrelin also contributes to neuroprotection after cerebral ischemia. Here, we aimed to determine whether endogenous ghrelin normally protects against neuronal cell death and cognitive impairments after global cerebral ischemia and whether such changes are linked with inflammation or apoptosis. We used a two-vessel occlusion (2VO) model of global cerebral ischemia in wild-type (wt) and ghrelin knockout (ghr-/-) C57/Bl6J mice. ghr-/- mice had improved cell survival in the Cornu Ammonis(CA)-2/3 region of the hippocampus-a region of significant growth hormone secretagogue receptor expression. They also displayed less cellular degeneration than wt mice after the 2VO (Fluoro-Jade) and had less cognitive impairment in the novel object-recognition test. These outcomes were despite evidence of more neuroinflammation and apoptosis in the ghr-/- and less of a postsurgery hypothermia. Finally, we found that mortality in the week following the 2VO was reduced more in ghr-/- mice than in wt. Overall, these experiments point to a neurodegenerative but antiapoptotic effect of endogenous ghrelin in this model of global ischemia, highlighting that further research is essential before we can apply ghrelin treatments to neurodegenerative insults in the clinic.

Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation.

Multiple sclerosis involves demyelination and axonal degeneration of the central nervous system. The molecular mechanisms of axonal degeneration are relatively unexplored in both multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis. We previously reported that targeting the axonal growth inhibitor, Nogo-A, may protect against neurodegeneration in experimental autoimmune encephalomyelitis; however, the mechanism by which this occurs is unclear. We now show that the collapsin response mediator protein 2 (CRMP-2), an important tubulin-associated protein that regulates axonal growth, is phosphorylated and hence inhibited during the progression of experimental autoimmune encephalomyelitis in degenerating axons. The phosphorylated form of CRMP-2 (pThr555CRMP-2) is localized to spinal cord neurons and axons in chronic-active multiple sclerosis lesions. Specifically, pThr555CRMP-2 is implicated to be Nogo-66 receptor 1 (NgR1)-dependent, since myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced NgR1 knock-out (ngr1(-)(/)(-)) mice display a reduced experimental autoimmune encephalomyelitis disease progression, without a deregulation of ngr1(-)(/)(-) MOG(35-55)-reactive lymphocytes and monocytes. The limitation of axonal degeneration/loss in experimental autoimmune encephalomyelitis-induced ngr1(-)(/)(-) mice is associated with lower levels of pThr555CRMP-2 in the spinal cord and optic nerve during experimental autoimmune encephalomyelitis. Furthermore, transduction of retinal ganglion cells with an adeno-associated viral vector encoding a site-specific mutant T555ACRMP-2 construct, limits optic nerve axonal degeneration occurring at peak stage of experimental autoimmune encephalomyelitis. Therapeutic administration of the anti-Nogo(623-640) antibody during the course of experimental autoimmune encephalomyelitis, associated with an improved clinical outcome, is demonstrated to abrogate the protein levels of pThr555CRMP-2 in the spinal cord and improve pathological outcome. We conclude that phosphorylation of CRMP-2 may be downstream of NgR1 activation and play a role in axonal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Blockade of Nogo-A/NgR1 interaction may serve as a viable therapeutic target in multiple sclerosis.

Interpersonal relationships and emotional distress in adolescence.

The aim of this study was to examine positive and negative qualities in adolescents' interpersonal relationships and their relative importance in predicting emotional distress. Participants were 260 students from three schools in the Dublin area (119 girls; 141 boys), aged 12-18 years (M = 15.32, SD = 1.91). Students completed questionnaires assessing qualities in important interpersonal relationships in their lives and emotional distress. Girls reported more positive qualities in their relationships with mothers and best friends than boys. Younger students reported more positive qualities in their relationships with parents than older students. Stepwise multiple regression analysis revealed high levels of satisfaction in interpersonal relationships were predictive of low levels of emotional distress whereas high levels of criticism and exclusion were predictive of high levels of distress. High levels of support and disclosure were also linked to emotional distress. These findings and their implications are discussed in detail.

Differential Effects of Pergolide and Bromocriptine on Working Memory Performance and Brain Activation after Mild Traumatic Brain Injury.

Dopamine D1 and D2 receptors differ with respect to patterns of regional brain distribution and behavioral effects. Pre-clinical work suggests that D1 agonists enhance working memory, but the absence of selective D1 agonists has constrained using this approach in humans. This study examines working memory performance in mild traumatic brain injury (mTBI) patients when given pergolide, a mixed D1/D2 agonist, compared with bromocriptine, a selective D2 agonist. Fifteen individuals were studied 1 month after mTBI and compared with 17 healthy controls. At separate visits, participants were administered 1.25 mg bromocriptine or 0.05 mg pergolide prior to functional magnetic resonance imaging (MRI) using a working memory task (visual-verbal n-back). Results indicated a significant group-by-drug interaction for mean performance across n-back task conditions, where the mTBI group showed better performance on pergolide relative to bromocriptine, whereas controls showed the opposite pattern. There was also a significant effect of diagnosis, where mTBI patients performed worse than controls, particularly while on bromocriptine, as shown in our prior work. Functional MRI activation during the most challenging task condition (3-back > 0-back contrast) showed a significant group-by-drug interaction, with the mTBI group showing increased activation relative to controls in working memory circuitry while on pergolide, including in the left inferior frontal gyrus. Across participants there was a positive correlation between change in activation in this region and change in performance between drug conditions. Results suggest that activation of the D1 receptor may improve working memory performance after mTBI. This has implications for the development of pharmacological strategies to treat cognitive deficits after mTBI.

Is there an app for that? A cluster randomised controlled trial of a mobile app-based mental health intervention.

Demand for the use of mobile apps in mental health interventions has grown in recent years, particularly among adolescents who experience elevated levels of distress. However, there is a scarcity of evidence for the effectiveness of these tools within this population. The aim of this study was to test the effectiveness of CopeSmart, a mental health mobile app, using a multicentre cluster randomised controlled trial design. Participants were 15-18-years-olds (N = 560) recruited from 10 schools randomly assigned to an intervention or control condition. Intervention participants used the app over a 4-week period. Multi-level modelling analyses revealed no significant changes in the intervention group from pre-test to post-test, when compared to the control group, in terms of emotional distress, well-being, emotional self-awareness or coping strategies. Findings suggest that a 4-week app-based intervention may not be enough to elicit intra-personal changes in mental health outcomes in a general adolescent population.

Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles. Prior to the development of these characteristic pathological hallmarks of AD, anterograde axonal transport is impaired. However, the key proteins that initiate these intracellular impairments remain elusive. The collapsin response mediator protein-2 (CRMP-2) plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2 releases kinesin-1. Here, we tested the hypothesis that amyloid-beta (Aß)-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1 (an anterograde axonal motor transport protein) in AD. We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site. Additionally, in the transgenic Tg2576 mouse model of familial AD (FAD) that exhibits Aß accumulation in the brain with age, we found substantial co-localization of pT555CRMP-2 and dystrophic neurites. In SH-SY5Y differentiated neuronal cultures, Aß-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1. The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation. These data suggest that Aß-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function, leading to neuronal defects.

Developing mental health mobile apps: Exploring adolescents' perspectives.

Mobile applications or 'apps' have significant potential for use in mental health interventions with adolescents. However, there is a lack of research exploring end users' needs from such technologies. The aim of this study was to explore adolescents' needs and concerns in relation to mental health mobile apps. Five focus groups were conducted with young people aged 15-16 years (N = 34, 60% male). Participants were asked about their views in relation to the use of mental health mobile technologies and were asked to give their responses to a mental health app prototype. Participants identified (1) safety, (2) engagement, (3) functionality, (4) social interaction, (5) awareness, (6) accessibility, (7) gender and (8) young people in control as important factors. Understanding end users' needs and concerns in relation to this topic will inform the future development of youth-oriented mental health apps that are acceptable to young people.

Ecological Momentary Assessment of Adolescent Problems, Coping Efficacy, and Mood States Using a Mobile Phone App: An Exploratory Study.

BACKGROUND: Mobile technologies have the potential to be used as innovative tools for conducting research on the mental health and well-being of young people. In particular, they have utility for carrying out ecological momentary assessment (EMA) research by capturing data from participants in real time as they go about their daily lives. OBJECTIVE: The aim of this study was to explore the utility of a mobile phone app as a means of collecting EMA data pertaining to mood, problems, and coping efficacy in a school-based sample of Irish young people. METHODS: The study included a total of 208 participants who were aged 15-18 years, 64% female (113/208), recruited from second-level schools in Ireland, and who downloaded the CopeSmart mobile phone app as part of a randomized controlled trial. On the app, participants initially responded to 5 single-item measures of key protective factors in youth mental health (formal help-seeking, informal help-seeking, sleep, exercise, and sense of belonging). They were then encouraged to use the app daily to input data relating to mood states (happiness, sadness, anger, stress, and worry), daily problems, and coping self-efficacy. The app automatically collected data pertaining to user engagement over the course of the 28-day intervention period. Students also completed pen and paper questionnaires containing standardized measures of emotional distress (Depression, Anxiety, and Stress Scale; DASS-21), well-being (World Health Organization Well-Being Index; WHO-5), and coping (Coping Strategies Inventory; CSI). RESULTS: On average the participants completed 18% (5/28) of daily ratings, and engagement levels did not differ across gender, age, school, socioeconomic status, ethnicity, or nationality. On a scale of 1 to 10, happiness was consistently the highest rated mood state (overall mean 6.56), and anger was consistently the lowest (overall mean 2.11). Pearson correlations revealed that average daily ratings of emotional states were associated with standardized measures of emotional distress (rhappiness=-.45, rsadness=.51, ranger=.32, rstress=.41, rworry=.48) and well-being (rhappiness=.39, rsadness =-.43, ranger=-.27, rstress=-.35, rworry=-.33). Inferential statistics indicated that single-item indicators of key protective factors were related to emotional distress, well-being, and average daily mood states, as measured by EMA ratings. Hierarchical regressions revealed that greater daily problems were associated with more negative daily mood ratings (all at the P<.001 level); however, when coping efficacy was taken into account, the relationship between problems and happiness, sadness, and anger became negligible. CONCLUSIONS: While engagement with the app was low, overall the EMA data collected in this exploratory study appeared valid and provided useful insights into the relationships between daily problems, coping efficacy, and mood states. Future research should explore ways to increase engagement with EMA mobile phone apps in adolescent populations to maximize the amount of data captured by these tools. TRIAL REGISTRATION: Clinicaltrials.gov NCT02265978; http://clinicaltrials.gov/ct2/show/NCT02265978 (Archived by WebCite at http://www.webcitation.org/6mMeYqseA).

Early Postnatal Hyperoxia in Mice Leads to Severe Persistent Vitreoretinopathy.

Purpose: To describe a mouse model of hyperoxia-induced vitreoretinopathy that replicated some of the clinical and pathologic features encountered in infants with severe retinopathy of prematurity and congenital ocular conditions such as persistent hyperplastic primary vitreous. Methods: Experimental mice (C57BL/6J) were exposed to 65% oxygen between postnatal days (P)0 to P7 and studied at P10, P14, and 3, 5, 8, 20, and 40 weeks. Controls were exposed to normoxic conditions. Fundus imaging and fluorescein angiography were performed at all time points, and spectral-domain optical coherence tomography (SD-OCT) and electroretinography were performed at 8- and 20-week time points. Eyes were processed for resin histology, frozen sections, and retinal whole mounts. Immunostaining was performed to visualize vasculature isolectin B4 (Ib4), collagen type IV, glial fibrillary acidic protein, and α-smooth muscle actin. Results: Early exposure to hyperoxia resulted in bilateral vitreous hemorrhages at 3 weeks. From 5 weeks onward there were extensive zones of retinal degeneration, scarring or gliosis, retinal folding, and detachments caused by traction of α-smooth muscle actin-positive vitreous membranes. Tortuous retinal vessels, together with hyperplastic and persistence of hyaloid vessels are evident into adulthood. In the early stages (P10-3 weeks), branches from the tunica vasculosa lentis (TVL) supplied the marginal retina until retinal vessels were established. The peripheral retina remained poorly vascularized into adulthood. Electroretinography revealed 50% to 60% diminution in retinal function in adult mice that strongly correlated with vitreal changes identified using SD-OCT. Conclusions: This animal model displays a mixture of vitreoretinal pathologic changes that persist into adulthood. The model may prove valuable in experimental investigations of therapeutic approaches to blinding conditions caused by vitreous and retinal abnormalities.

Feasibility of "CopeSmart": A Telemental Health App for Adolescents.

BACKGROUND: Early intervention is important in order to improve mental health outcomes for young people. Given the recent rise in mobile phone ownership among adolescents, an innovative means of delivering such intervention is through the use of mobile phone applications (apps). OBJECTIVE: The aim of this study was to evaluate the feasibility of "CopeSmart", a telemental health app developed to foster positive mental health in adolescents through emotional self-monitoring and the promotion of positive coping strategies. METHODS: Forty-three adolescents (88% female) aged 15-17 years downloaded the app and used it over a one-week period. They then completed self-report questionnaires containing both open-ended and closed-ended questions about their experiences of using the app. The app itself captured data related to user engagement. RESULTS: On average participants engaged with the app on 4 of the 7 days within the intervention period. Feedback from users was reasonably positive, with 70% of participants reporting that they would use the app again and 70% reporting that they would recommend it to a friend. Thematic analysis of qualitative data identified themes pertaining to users' experiences of the app, which were both positive (eg, easy to use, attractive layout, emotional self-monitoring, helpful information, notifications, unique) and negative (eg, content issues, did not make user feel better, mood rating issues, password entry, interface issues, engagement issues, technical fixes). CONCLUSIONS: Overall findings suggest that telemental health apps have potential as a feasible medium for promoting positive mental health, with the majority of young people identifying such technologies as at least somewhat useful and displaying a moderate level of engagement with them. Future research should aim to evaluate the efficacy of such technologies as tools for improving mental health outcomes in young people.

Effects of mild calorie restriction on anxiety and hypothalamic-pituitary-adrenal axis responses to stress in the male rat.

Abstract Chronic calorie restriction (CR) is one of the few interventions to improve longevity and quality of life in a variety of species. It also reduces behavioral indices of anxiety and influences some stress hormones under basal conditions. However, it is not known how CR influences hypothalamic-pituitary-adrenal (HPA) axis function or if those on a CR diet have heightened HPA axis responses to stress. We hypothesized elevated basal glucocorticoid levels induced by CR would lead to exacerbated HPA axis responses to the psychological stress, restraint, in the male rat. We first confirmed rats fed 75% of their normal calorie intake for 3 weeks were less anxious than ad libitum-fed (AD) rats in the elevated plus maze test for anxiety. The anxiolytic effect was mild, with only grooming significantly attenuated in the open field and no measured behavior affected in the light/dark box. Despite elevated basal glucocorticoids, CR rats had very similar hormonal and central responses to 15-min restraint to the AD rats. Both CR and AD rats responded to restraint stress with a robust increase in glucocorticoids that was resolved by 60 min. Both groups also showed robust neuronal activation in the paraventricular nucleus of the hypothalamus and in other stress- and feeding-sensitive brain regions that was not substantially affected by calorie intake. Our findings thus demonstrate chronic mild CR is subtly anxiolytic and is not likely to affect HPA axis responses to psychological stress. These findings support research suggesting a beneficial effect of mild CR.