Colchicine is not effective for reducing osteoarthritic hand pain compared to placebo: a randomised, placebo-controlled trial (COLAH).

BACKGROUND: Colchicine may offer relief in osteoarthritis. This has never been investigated for hand osteoarthritis. OBJECTIVES: To investigate the effect of 1 mg daily colchicine vs placebo on hand pain and function over 12 weeks in older adults with hand osteoarthritis. METHODS: Community-dwelling adults with diagnosed osteoarthritis of the hand aged 40-80 years were randomised to receive colchicine (0.5 mg twice daily) or matching placebo. Primary outcome measure was VAS hand pain score (0-100 mm). Secondary outcome measures included tender and swollen joint count, grip strength, C-reactive protein, and Michigan Hand Questionnaire total, function and pain scores. In an exploratory assessment, we compared synovial grade and power Doppler. All outcome measures were obtained at baseline and week 12. Stata v16 was used to perform constrained longitudinal data analysis models. RESULTS: 64 adults (54 females, 10 males) aged 48-79 years of age were enrolled. 59 participants completed the study (N = 28 colchicine, N = 31 placebo) (withdrawal rate 8%). Adverse reactions to the study medication occurred in nine patients. VAS score was not significantly different at baseline (61 ± 17 mm in the colchicine, 64 ± 17 mm in the placebo group). Between-group difference for VAS score at week 12 was 7.6 mm (95% CI -3.5-18.7, p-value 0.18). There were no significant differences between groups for any secondary outcomes at baseline or week 12. CONCLUSIONS: 1 mg colchicine daily for 12 weeks was not effective for reducing pain, tender and swollen joint count or increasing grip strength in symptomatic hand osteoarthritis. Our results do not support the use of colchicine in hand osteoarthritis.

Study protocol: families and childhood transitions study (FACTS) - a longitudinal investigation of the role of the family environment in brain development and risk for mental health disorders in community based children.

BACKGROUND: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old. METHODS/DESIGN: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017. DISCUSSION: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population.

Functional brain-imaging correlates of negative affectivity and the onset of first-episode depression.

BACKGROUND: The amygdala and subgenual anterior cingulate cortex (sACC) are key brain regions for the generation of negative affect. In this longitudinal fMRI study of adolescents we investigated how amygdala-sACC connectivity was correlated with negative affectivity (NA) both cross-sectionally and longitudinally, and examined its relationship to the onset of first-episode depression. METHOD: Fifty-six adolescents who were part of a larger longitudinal study of adolescent development were included. They had no history of mental illness at the time of their baseline scan (mean age 16.5 years) and had a follow-up scan 2 years later (mean age 18.8 years). We used resting-state functional-connectivity MRI to investigate whether cross-sectional and change measures of amygdala-sACC connectivity were (i) correlated with NA and its change over time, and (ii) related to the onset of first-episode depression. RESULTS: The magnitude of amygdala connectivity with sACC showed significant positive correlation with NA at both time-points. Further analysis confirmed that change in amygdala-sACC connectivity between assessments was correlated with change in NA. Eight participants developed a first episode of depression between the baseline and follow-up assessments: they showed increased amygdala-sACC connectivity at follow-up. CONCLUSIONS: Amygdala-sACC connectivity is associated with NA in adolescence, with change in connectivity between these regions showing positive correlation with change in NA. Our observation that the onset of depression was associated with an increase in connectivity between the regions provides support for the neurobiological 'scar' hypothesis of depression.

Associations between paternal versus maternal parenting behaviors and child and adolescent internalizing problems: A systematic review and meta-analysis.

There is a large evidence base supporting an important role of parenting behavior in influencing youth mental health; however, this literature often fails to capture the potentially unique and interactive role of mothers and fathers. This systematic review and meta-analysis aimed to investigate the role of maternal and paternal parenting behaviors in relation to child and adolescent internalizing problems. Following PRISMA (2020) guidelines, 88 studies were identified. Of these, 47 studies and upward of 65 parent-behavior and child-outcome combinations were examined. Findings indicated a unique role of maternal overprotection in the prediction of child anxiety symptoms. For other parenting behaviors, largely similar associations were found for maternal and paternal parenting behaviors with child and adolescent anxiety, depressive symptoms and broader internalizing problems. There was preliminary support for the interaction of maternal and paternal parenting being important in predicting youth symptoms. Although findings did not strongly substantiate differences in the effects of maternal and paternal parenting practices, with only one significant difference identified, further research would benefit from stronger representation of fathers, to enable a more rigorous and comprehensive understanding of each parent's role, and their interactive influence on internalizing outcomes of their children.

Profiling undergraduates' generic learning skills on entry to medical school; an international study.

BACKGROUND: Medical education faces challenges posed by widening access to training, a demand for globally competent healthcare workers and progress towards harmonisation of standards. AIM: To explore potential challenges arising from variation in diversity and educational background of medical school entrants. METHOD: This study investigated the reported experience and confidence, in a range of 31 generic skills underpinning learning, of 2606 medical undergraduates entering 14 medical schools in England and South Africa, using a validated questionnaire. RESULTS: Responses suggest that there is considerable similarity in prior educational experience and confidence skills profiles on entry to South African and English medical schools. South African entrants reported significantly more experience in 'Technical skills', 'Managing their own Learning', and 'Presentation', while English students reported increased experience in 'IT' skills. South African undergraduates reported more confidence in 'Information Handling', while English students were more confident in 'IT' skills. The most noticeable difference, in 'IT' skills, is probably due to documented differences in access to computer facilities at high school level. Differences between individual schools within each country are noticeable. CONCLUSIONS: Educators need to acquire a good understanding of their incoming cohorts, and ensure necessary tailored support for skills development.

Cerebellar white-matter changes in cannabis users with and without schizophrenia.

BACKGROUND: The cerebellum is rich in cannabinoid receptors and implicated in the neuropathology of schizophrenia. Long-term cannabis use is associated with functional and structural brain changes similar to those evident in schizophrenia, yet its impact on cerebellar structure has not been determined. We examined cerebellar grey and white matter in cannabis users with and without schizophrenia. METHOD: Seventeen patients with schizophrenia and 31 healthy controls were recruited; 48% of the healthy group and 47% of the patients were long-term heavy cannabis users (mean 19.7 and 17.9 years near daily use respectively). Cerebellar measures were extracted from structural 3-T magnetic resonance imaging (MRI) scans using semi-automated methods, and examined using analysis of covariance (ANCOVA) and correlational analyses. RESULTS: Cerebellar white-matter volume was reduced in cannabis users with and without schizophrenia compared to healthy non-users, by 29.7% and 23.9% respectively, and by 17.7% in patients without cannabis use. Healthy cannabis users did not differ in white-matter volume from either of the schizophrenia groups. There were no group differences in cerebellar grey matter or total volumes. Total cerebellar volume decreased as a function of duration of cannabis use in the healthy users. Psychotic symptoms and illness duration correlated with cerebellar measures differentially between patients with and without cannabis use. CONCLUSIONS: Long-term heavy cannabis use in healthy individuals is associated with smaller cerebellar white-matter volume similar to that observed in schizophrenia. Reduced volumes were even more pronounced in patients with schizophrenia who use cannabis. Cannabis use may alter the course of brain maturational processes associated with schizophrenia.

DREEM and beyond; studies of the educational environment as a means for its enhancement.

CONTEXT: Educational environment makes an important contribution to student learning. The DREEM (Dundee Ready Educational Environment Measure) questionnaire is a validated instrument for assessing educational environment, but used alone it has little value for identifying means of remediation of poor aspects of environment. AIMS: This study used qualitative analysis, in association with the DREEM questionnaire, to evaluate the educational environment across all five years of a large undergraduate medical school, and identify areas for change to enhance student experience. METHOD: The DREEM questionnaire was administered to 968 undergraduate students, together with an open question asking for suggested changes to current medical school practices. Items of concern highlighted by this study were further defined through qualitative analysis, using focus groups, email questionnaires and introduction of Stressful Incident reporting. RESULTS: Through responses to the open question, two items with low scores on the DREEM questionnaire were identified as requiring remediation. Focus groups and email questionnaires were used to define the underlying causes of poor scores, which varied by student year group. Stress resulting from experiences on clinical placement was highlighted by some students, but on closer investigation found to be rare. Remedial steps to improve student support are described. CONCLUSIONS: The qualitative data have substantially enhanced questionnaire interpretation, and allowed actions to address common causes for student dissatisfaction to be undertaken. This combined methodology is recommended to other institutions wishing to improve the educational environment, and thus the overall quality of educational provision.

Social connectedness, mental health and the adolescent brain.

Social relationships promote health and wellbeing. Brain regions regulating social behavior continue to develop throughout adolescence, as teens learn to navigate their social environment with increasing sophistication. Adolescence is also a time of increased risk for the development of psychiatric disorders, many of which are characteristically associated with social dysfunction. In this review, we consider the links between adolescent brain development and the broader social environment. We examine evidence that individual differences in social ability, partly determined by genetic influences on brain structure and function, impact the quality and quantity of social ties during adolescence and that, conversely, the structure of one's social network exerts complex yet profound influences on individual behavior and mental health. In this way, the brain and social environment sculpt each other throughout the teenage years to influence one's social standing amongst peers. Reciprocal interactions between brain maturation and the social environment at this critical developmental stage may augment risk or promote resilience for mental illness and other health outcomes.

Trajectories of adolescent conduct problems in relation to cortical thickness development: a longitudinal MRI study.

Multiple cross-sectional imaging studies have identified structural abnormalities in prefrontal, temporal and limbic regions related to conduct problems (CPs). However, the relationship between development of such neurobiological deficits and developmental pathways of CPs has remained unclear. The current study investigated distinct trajectories of CP and related trajectories of cortical thickness within a community-based sample of adolescents (n=239), age range 12-19, to address this gap. Three trajectory classes were revealed using latent class growth analyses (LCGAs), comprising a 'desisting' CP group, an 'intermediate' CP group and a 'stable low' CP group. Structural magnetic resonance imaging (MRI) scans were collected with a subgroup of 171 adolescents at three waves throughout adolescence (ages 12, 16 and 19). Generalized estimating equation (GEE) analysis-comparing longitudinal changes in cortical thickness and subcortical volume between CP groups for several regions of interest (ROIs)-showed that these CP groups had differential trajectories of cortical thickness in the dorsolateral prefrontal cortex (dl-PFC), and the anterior cingulate cortex (ACC), and volume of the hippocampus. Adolescents in the desisting CP group showed an attenuation of the typical pattern of cortical thinning as present in the intermediate and stable low CP groups, in addition to an exaggeration of the typical pattern of hippocampal volume increase. These findings suggest that a deviant cortical thickness trajectory was related to a desisting CP pathway across adolescence. Such deviant neurodevelopmental growth trajectories may act as an underlying mechanism for developmental CP pathways, and possibly distinguish desisting antisocial adolescents.

Biogenic aldehyde metabolism in rat brain. Differential sensitivity of aldehyde reductase isoenzymes to sodium valproate.

The effects of inhibitors of aldehyde reductase (alcohol:NADP+ oxidoreductase, EC 1.1.1.2) on the formation of 3-methoxy-4-hydroxyphenethylene glycol from normetanephrine have been studied in rat brain homogenates. The reaction pathway was shown to be unaffected by several inhibitors of the major (high Km) form of aldehyde reductase such as sodium valproate. Two isoenzymes of aldehyde reductase have been separated and characterized from rat brain. The minor (low Km) isoenzyme is shown to be relatively insensitive to sodium valproate and exhibits a similar inhibitor-sensitivity profile to that obtained for methoxyhydroxyphenethylene glycol formation. The low Km isoenzyme is therefore implicated in catecholamine metabolism. The metabolism of succinic semialdehyde and xylose by rat brain cytosol has also been examined. Aldose metabolism may also be attributed to the action of the low Km reductase, but the existence of a separate succinic semialdehyde reductase is postulated. The possible roles of aldehyde reductases in brain metabolism and the relationship between these enzymes and aldose reductase (alditol:NADP+ 1-oxidoreductase, EC 1.1.1.21) are discussed.

Dispositional mindfulness is predicted by structural development of the insula during late adolescence.

Adolescence is a critical period of development, in which the increasing social and cognitive demands of independence need to be met by enhanced self-regulatory abilities. The cultivation of mindfulness has been associated with improved self-regulation in adult populations, and it is theorized that one neurodevelopmental mechanism that supports this capacity is the development of the prefrontal cortex. The current study examined the neurodevelopmental mechanisms associated with dispositional mindfulness in adolescence. Using a longitudinal within-persons design, 82 participants underwent structural magnetic resonance imaging (MRI) assessments at approximately ages 16 and 19, and also completed self-reported measurements of mindfulness at age 19. It was hypothesized that adolescents who demonstrated greater thinning of frontal cortical regions between the age of 16 and 19 would exhibit higher dispositional mindfulness levels at age 19. Results indicated that, contrary to predictions, adolescents with higher levels of mindfulness demonstrated less thinning in the left anterior insula. By contrast, higher IQ was associated with greater thinning of the right caudal middle frontal and right superior frontal regions. The involvement of insula development in mindfulness is consistent with a direct role for this structure in managing self-regulation, and in doing so concords with recent models of self-referential interoceptive awareness.

Differential effects of sedative and anticonvulsant barbiturates on specific [3H]GABA binding to membrane preparations from rat brain cortex.

The sensitivity to barbiturates of [3H]GABA binding to synaptosomal membrane fractions from rat cortex has been examined. We show that a range of anaesthetic/sedative barbiturates enhance GABA binding in the presence of chloride or other ions that interact with the associated ionophore. Furthermore, picrotoxinin and the anticonvulsant barbiturate phenobarbital antagonise the enhancement produced by pentobarbital. These effects are therefore comparable to those observed at benzodiazepine receptors and may be mediated through the chloride ionophore component of the receptor complex. Other classes of anticonvulsants failed to antagonise pentobarbital activation, suggesting that these interactions may occur at a specific barbiturate site in the membrane.

Human placental tissue factor: protease susceptibility of extracellular and cytoplasmic domains.

We have examined the effects of seven proteases on human placental tissue factor in Triton X-100, focusing on extracellular and cytoplasmic domains recognized by monoclonal antibodies HTF1, C28 1.1, and C28 2.1. Plasmin produced peptides recognized on Western blots by C281.1 but not HTF1. None of the other proteases destroyed the extracellular epitope without also removing the cytoplasmic epitope, and both trypsin and chymotrypsin removed the cytoplasmic epitope with little effect on the extracellular domain. Proteinase K destroyed both epitopes, as did neutrophil elastase when used at a relatively high concentration. When digests were sampled over time and reconstituted with lipids for determination of tissue factor activity, only proteinase K consistently produced a loss in tissue factor activity at four hours. After 24 hr, other enzymes also decreased the recovered activity, with the order of effectiveness elastase > trypsin > chymotrypsin.

Radiographic changes in the knee after meniscal transplantation. An experimental study in a sheep model.

Meniscal transplantation has been suggested as an alternative to total meniscectomy, which is now known to lead to long-term osteoarthritic degeneration of the knee joint. To evaluate the success of meniscal transplantation, we divided 28 sheep knees into 4 groups: total meniscectomy, allograft, autograft, and control. After a mean postoperative time of 21.4 months, we radiographed the excised knee joints in a loaded state and graded the radiographs for osteoarthritic changes. The knees with meniscectomies, allografts, and autografts showed significantly more degenerative changes than the control knees. However, there were no statistically significant differences between these three groups. The results of this study suggest that meniscal allograft transplantation does not protect the knee against degenerative changes.

Lipids of hamster cheek pouch epithelium.

The hamster cheek pouch is a much used but incompletely understood experimental model. In particular, the cheek pouch epithelial lipids, which are important for permeability barrier function as well as other aspects of epithelial biology, have not been completely characterized. In the present study, the complete lipid class composition has been determined by thin-layer chromatography in conjunction with photodensitometry. The major lipid classes were phospholipids, free sterols, and ceramides. Minor amounts of monohexosylceramides, sterol esters, fatty acids, and triglycerides were also present. Significant amounts of covalently bound omega-hydroxyceramide was also detected. Transmission electron micrographs reveal extensive, largely paired, lipid bilayers in the intercellular spaces of the stratum corneum.

Topical use of papaya in chronic skin ulcer therapy in Jamaica.

The objective of the study was to determine the prevalence of the use of the fruit (papaya) of Carica papaya as topical ulcer dressings by registered nurses in the Spanish Town Hospital (STH), Kingston Public Hospital (KPH) and the University Hospital of the West Indies (UHWI), Jamaica. A ten-item pretested self-administered questionnaire was distributed to 285 randomly selected registered nurses at the UHWI, KPH and STH. There was a 72% response rate. The prevalence of topical papaya use among the respondents was 75%. Comments from the users of papaya suggested that topical application of the unripe fruit promoted desloughing, granulation and healing and reduced odour in chronic skin ulcers. It was cost effective. Papaya was considered to be more effective than other topical applications in the treatment of chronic ulcers. There was some difficulty in preparation of the fruit and occasionally a sensation of burning was reported by the patients. There was concern about the use of a non-sterile, non-standardised procedure but there were no reports of wound infection from its use. Papaya is widely used by nurses as a form of dressing for chronic ulcers and there is need for standardisation of its preparation and application.

Profile of uncontrolled hypertensive patients attending the Specialist Hypertension Clinic, University Hospital of the West Indies.

The purpose of this study was to describe the knowledge of hypertension, its management, anthropometric measurements, blood pressure (BP), medication use, and current lifestyles of patients with persistent hypertension. Patients (n = 80) attending the Specialist Hypertension Clinic at the University Hospital of the West Indies (UHWI) who had a baseline systolic BP > 140 mmHg and/or a diastolic BP > 90 mmHg were invited to participate in the study. Blood pressure, height, weight, waist and hip circumferences were measured. Body mass index (BMI) and waist/hip ratio (WHR) were calculated. A pretested questionnaire with 40 items eliciting demographic data, level of activity, dietary habits, knowledge of hypertension, medication compliance, use of alternative medicines, and substance use was administered to each participant. Mean BMI for men was 27.65 (95% CI 25.7-29.6); mean BMI for women was 30.89 (95% CI 26.1-35.7). In men, there was an association between BMI and WHR, r = 0.62, p < 0.05, an association between BMI and diastolic BP and a negative association between BMI and activity level (r = -0.42, p < 0.05). There was also an association between systolic BP and substance use (r = 0.41, p < 0.05). Although the majority of both men and women were classified as obese, only 12% of men and 7% of women recognized diet and overweight as contributing to high blood pressure. Reported diets tended to be high in fat, salt and meats and low in vegetables and fruits; the majority of the participants were sedentary. Medication compliance was good, with a mean of only four days of medications missed per month. These findings suggest that to lower blood pressures in this population, the use of nonpharmacologic therapy involving lifestyle changes such as improved diet, weight loss and increased physical activity will be important.

Impact on blood pressure control of a six-month intervention project.

The aim of this study is to evaluate the impact of a six-month structured education programme on blood pressure (BP) control in patients with uncontrolled hypertension. All patients attending the Specialist Hypertension Clinic, University Hospital of the West Indies (UHWI), between January 4 and March 29, 1999, with blood pressure > 140/90 mmHg (n = 80), were randomly divided into Group 1, cases (n = 42) and Group 2, controls (n = 38). A 40-item pretested questionnaire, administered at the baseline and final visits of both groups, elicited demographic, lifestyle and knowledge data. Group 1 attended monthly structured interventions for six months. Except for diastolic blood pressure among male controls, diastolic blood pressure and systolic blood pressure were significantly reduced at the end of the intervention period (p < 0.01). Knowledge improved among the male patients (p < 0.01). Among the female patients, activity scores were significantly increased (p < 0.01), weight (p < 0.05) and BMI (p < 0.05) were significantly reduced. There were no differences in these variables among the controls. This intervention had a benefit in blood pressure control.

Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study.

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13-19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.

The accuracy of methods for urate crystal detection in synovial fluid and the effect of sample handling: a systematic review.

This study aims to compare different methods of monosodium urate crystal (MSU) detection in synovial fluid (SF) and the effect of sample storage and handling on crystal detection. A systematic literature search was performed in MEDLINE, EMBASE, the Cochrane Library and the American College of Rheumatology/European League Against Rheumatism conference abstracts of 2010 and 2011. Studies that compared a method for detecting MSU crystals in SF with polarised light microscopy (PLM) or compared various SF storage and handling factors with the detection of MSU crystals as an outcome were included. Twelve studies out of 247 identified references were included in the review. Seven studies compared different methods of MSU crystal detection in SF with PLM. Due to study heterogeneity, methodological limitations and risk of bias, no firm conclusions could be drawn from the available data. Five studies examining SF storage and handling factors were identified. A reduction in MSU crystal concentration was observed over time at room temperature that was not seen in refrigerated samples. The use of anticoagulation as a storage medium provided no benefit. Dried cytospin preparations appeared to be a suitable medium for long-term storage and delayed crystal analysis for at least 12 months. The existing data do not provide a compelling argument for the replacement of PLM as the current standard. SF sample storage and handling have an effect on MSU crystals and may impact on the reliability of analysis.