Circumscribing Laser Cuts Attenuate Seizure Propagation in a Mouse Model of Focal Epilepsy.

In partial onset epilepsy, seizures arise focally in the brain and often propagate. Patients frequently become refractory to medical management, leaving neurosurgery, which can cause neurologic deficits, as a primary treatment. In the cortex, focal seizures spread through horizontal connections in layers II/III, suggesting that severing these connections can block seizures while preserving function. Focal neocortical epilepsy is induced in mice, sub-surface cuts are created surrounding the seizure focus using tightly-focused femtosecond laser pulses, and electrophysiological recordings are acquired at multiple locations for 3-12 months. Cuts reduced seizure frequency in most animals by 87%, and only 5% of remaining seizures propagated to the distant electrodes, compared to 80% in control animals. These cuts produced a modest decrease in cortical blood flow that recovered and left a ≈20-µm wide scar with minimal collateral damage. When placed over the motor cortex, cuts do not cause notable deficits in a skilled reaching task, suggesting they hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy.

Ultrasonographic criteria in the diagnosis of polycystic ovary syndrome: a systematic review and diagnostic meta-analysis.

BACKGROUND: Polycystic ovary morphology (PCOM) on ultrasonography is considered as a cardinal feature of polycystic ovarian syndrome (PCOS). Its relevance as a diagnostic criterion for PCOS was reaffirmed in the most recent International Evidence-Based Guideline for the Assessment and Management of PCOS. However, there remains a lack of clarity regarding the best practices and specific ultrasonographic markers to define PCOM. OBJECTIVE AND RATIONALE: The aim of this systematic review and diagnostic meta-analysis was to assess the diagnostic accuracy of various ultrasonographic features of ovarian morphology in the diagnosis of PCOS. SEARCH METHODS: Relevant studies published from 1 January 1990 to 12 June 2023 were identified by a systematic search in PubMed, Web of Science, Scopus, CINAHL, and CENTRAL. Studies that generated diagnostic accuracy measures (e.g. proposed thresholds, sensitivity, specificity) for PCOS using the following ultrasonographic markers met criteria for inclusion: follicle number per ovary (FNPO) or per single cross-section (FNPS), ovarian volume (OV), and stromal features. Studies on pregnant or post-menopausal women were excluded. Risk of bias and applicability assessment for diagnostic test accuracy studies were determined using the QUADAS-2 and QUADAS-C tool for a single index test or between multiple index tests, respectively. Diagnostic meta-analysis was conducted using a bivariate model of pooled sensitivity and specificity, and visualized using forest plots and summary receiver-operating characteristic (SROC) curves. OUTCOMES: From a total of 2197 records initially identified, 31 studies were included. Data from five and two studies were excluded from the meta-analysis due to duplicate study populations or limited data for the index test, leaving 24 studies. Pooled results of 20 adult studies consisted of 3883 control participants and 3859 individuals with PCOS. FNPO was the most accurate diagnostic marker (sensitivity: 84%, CI: 81-87%; specificity: 91%, CI: 86-94%; AUC: 0.905) in adult women. OV and FNPS had similar pooled sensitivities (OV: 81%, CI: 76-86%; FNPS: 81%, CI: 70-89%) but inferior pooled specificities (OV: 81%, CI: 75-86%; FNPS: 83%, CI: 75-88%) and AUCs (OV: 0.856; FNPS: 0.870) compared to FNPO. Pooled results from four adolescent studies consisting of 210 control participants and 268 girls with PCOS suggested that OV may be a robust ultrasonographic marker for PCOS diagnosis albeit the current evidence remains limited. The majority of the studies had high risk of bias for the patient selection (e.g. lack of randomized/consecutive patient selection) and index test (e.g. lack of pre-proposed thresholds for comparison) domains across all ultrasonographic markers. As such, diagnostic meta-analysis was unable to determine the most accurate cutoff for ultrasonographic markers to diagnose PCOS. Subgroup analysis suggested that stratification based on previously proposed diagnostic thresholds, age, BMI, or technology did not account for the heterogeneity in diagnostic accuracy observed across the studies. Studies that diagnosed PCOS using the Rotterdam criteria had improved sensitivity for FNPO. Studies from North America had lower diagnostic accuracy when compared to Asian studies (FNPO: sensitivity) and European studies (OV: specificity, diagnostic odds ratio and positive likelihood ratio). Geographic differences in diagnostic accuracy may potentially be due to differences in age, BMI, and diagnostic criteria of the PCOS group across regions. WIDER IMPLICATIONS: This diagnostic meta-analysis supports the use of FNPO as the gold standard in the ultrasonographic diagnosis of PCOS in adult women. OV and FNPS provide alternatives if total antral follicle counts cannot be accurately obtained. Our findings support the potential for ultrasonographic evidence of PCOM in adolescents as more data becomes available. Subgroup analysis suggests the need to investigate any relative contributions of geographical differences on PCOS phenotypes. These findings may provide the basis for the development of strategies and best practices toward a standardized definition of PCOM and a more accurate ultrasonographic evaluation of PCOS.

Impact of periodontitis on oral health-related quality of life of patients with psoriatic arthritis.

BACKGROUND: Since oral health issues can have a negative influence on a person's physical functioning, social status, and wellbeing, oral health-related quality of life (OHRQoL) becomes an indispensable part of overall health. Previous published studies report that periodontitis (PD) and psoriatic arthritis (PsA) have a significant negative impact on OHRQoL. Based on these findings, it would be reasonable to assume that patients with coexisting PsA and PD would see a comparable or maybe synergistic effect on their OHRQoL. Hence, the aim of the present study is to evaluate the OHRQoL and its impact among subjects with concurrent PsA and PD. MATERIAL AND METHODS: The present study was a comparative, cross-sectional investigation. A total of 200 participants were categorized into four groups- PD-PsA (n = 50), PsA (n = 50), PD (n = 50), and healthy controls (n = 50). Demographic data and periodontal parameters-plaque index, sites with gingival bleeding, probing pocket depth, gingival recession, and clinical attachment level were recorded for all the four groups. Number of mobile teeth due to periodontitis was recorded for the PSA-PD and PD groups. OHIP-14 questionnaire was administered to all the four groups. Collected data was then subjected to statistical analysis. RESULTS: The severity of OHIP-14 summary scores was highest in the PsA-PD group (18.06 ± 11.22) followed by the PD group (17.02 ± 9.99) and lowest in the healthy group (6.32 ± 5.59) (p < .0001). The scores of all the domains- oral pain, oral function, orofacial appearance and psychological impact were highest among the PsA-PD group followed by the PD group (p < .0001). The combined interaction of PsA and PD on the OHRQoL was statistically significant (F = 6.33, p = .012). Results of the multiple linear regression analysis indicated that there was a moderate collective significant effect between age, past dental visit, frequency of daily tooth brushing, use of other oral hygiene aids, and OHIP-14 (F(3,196) = 13.08, p < .001, R2  = 0.17, adjusted R2  = 0.15). CONCLUSION: The negative impact on OHRQoL was highest in the patients with concurrent presence of PD with PsA followed by those with PD alone. While the summary scores and dimensional scores of OHIP-14 were insignificant when patients with PsA-PD and PD alone were compared, these scores were significantly higher in patients with PsA-PD than patients with PsA alone.

Biomineralogical signatures of breast microcalcifications.

Microcalcifications, primarily biogenic apatite, occur in cancerous and benign breast pathologies and are key mammographic indicators. Outside the clinic, numerous microcalcification compositional metrics (e.g., carbonate and metal content) are linked to malignancy, yet microcalcification formation is dependent on microenvironmental conditions, which are notoriously heterogeneous in breast cancer. We interrogate multiscale heterogeneity in 93 calcifications from 21 breast cancer patients using an omics-inspired approach: For each microcalcification, we define a "biomineralogical signature" combining metrics derived from Raman microscopy and energy-dispersive spectroscopy. We observe that (i) calcifications cluster into physiologically relevant groups reflecting tissue type and local malignancy; (ii) carbonate content exhibits substantial intratumor heterogeneity; (iii) trace metals including zinc, iron, and aluminum are enhanced in malignant-localized calcifications; and (iv) the lipid-to-protein ratio within calcifications is lower in patients with poor composite outcome, suggesting that there is potential clinical value in expanding research on calcification diagnostic metrics to include "mineral-entrapped" organic matrix.

A randomized trial of iron- and zinc-biofortified pearl millet-based complementary feeding in children aged 12 to 18 months living in urban slums.

BACKGROUND & AIMS: Biofortification of staple crops with higher levels of micronutrients via traditional breeding methods is a sustainable strategy and can possibly complement fortification and other interventions to target micronutrient deficiencies in low resource settings, particularly among vulnerable populations such as children. We aimed to determine if iron- and zinc-biofortified pearl millet (FeZnPM, Dhanashakti, ICTP-8203Fe)-based complementary feeding improves nutritional status, including iron biomarkers and growth, in children living in urban slums of Mumbai. METHODS: We conducted a randomized controlled trial of FeZnPM among 223 children aged 12-18 months who were not severely anemic at baseline (hemoglobin ≥9.0 g/dL). Children were randomized to receive either FeZnPM or conventional non-biofortified pearl millet (CPM) daily for 9 months. Iron status (hemoglobin, serum ferritin), plasma zinc, and anthropometric indicators (length, weight, mid-upper arm circumference, triceps and subscapular skinfolds) were evaluated at enrollment and throughout the trial. World Health Organization (WHO) anthropometric z-scores were calculated using WHO growth standards. Primary outcomes were hemoglobin and serum ferritin concentrations, and growth, defined as WHO z-scores. An intent to treat approach was used for analyses. We used the Hodges-Lehmann-Sen test to assess the change in primary outcomes between baseline and the last visit and report corresponding 95% confidence intervals. RESULTS: At baseline, 67.7% of children were anemic (hemoglobin <11.0 g/dL) and 59.6% were iron deficient (serum ferritin <12.0 µg/L). FeZnPM did not significantly increase iron biomarkers or improve growth, compared to CPM. In subgroup analyses, FeZnPM improved hemoglobin concentrations in male children, and in children with iron deficiency or iron depletion (serum ferritin <25.0 µg/L) at baseline, relative to CPM. CONCLUSIONS: Daily consumption of FeZnPM-based complementary foods did not significantly impact iron and zinc status or growth in children living in Mumbai's urban slums. However, the intervention significantly improved hemoglobin concentrations among male children and among individuals who were iron-deficient or iron-depleted at baseline. TRIAL REGISTRATION: This trial is registered with Clinicaltrials.gov (ID: NCT02233764), and Clinical Trials Registry of India (ID: REF/2014/10/007731).

Assessment of Periodontal status in Patients with Psoriatic Arthritis: A retrospective, case-control study.

BACKGROUND: Psoriatic arthritis (PsA) and periodontitis both represent chronic inflammatory disorders that share similar pathophysiological processes. However, very few studies have been done to address the link between the two diseases which remains poorly understood. The present study aimed to assess and compare the periodontal status in patients suffering from PsA and systemically healthy subjects to identify whether a possible association exists between PsA and periodontitis. MATERIAL AND METHODS: Periodontal parameters - PI, BOP, mGI, PPD and CAL were recorded in 110 patients with PsA and 110 age- and gender-matched systemically healthy patients. Mean values of the periodontal parameters were calculated for both groups and subjected to statistical analysis. Logistic regression analysis was performed to correlate the demographic data with periodontitis. RESULTS: The frequency of periodontitis and mean values of BOP, mGI, PPD and CAL were found to be significantly higher in patients with PsA than in systemically healthy controls. The number of patients with stage III periodontitis was found to be significantly higher in the PsA group. CONCLUSIONS: A possible link exists between periodontitis and psoriatic arthritis, as exhibited by the results of the present study. Dental and medical health professionals should be aware of this relationship depending on which, they should carry out adequate treatment strategies involving periodic periodontal evaluation and care. Key words:Periodontitis, psoriatic arthritis, chronic inflammation, probing pocket depth, clinical attachment loss.

The Effect of Sagittal and Coronal Balance on Patient-Reported Outcomes Following Mobile-Bearing Total Ankle Replacement.

Total ankle replacement (TAR) is an established technique for the treatment of end-stage ankle arthritis. The aims of TAR include pain relief, preservation of tibiotalar movement, protection of adjacent joints, and restoration of anatomic alignment in the coronal and sagittal planes. The aims of this study were to determine the relative importance of pre- and post-TAR coronal and sagittal balance on postoperative patient-reported outcome measures (PROMs). A total of 101 ankles in 99 patients were included in this retrospective cohort study. Patients were scored preoperatively and at a minimum of 2 years by using the Foot and Ankle Outcome Score (FAOS), the American Orthopedic Foot and Ankle Society (AOFAS) hindfoot-ankle score, the Short Form-36 measures, and a set of radiographic measurements to define the sagittal and coronal alignment. There was no significant difference between the groups regarding the anterior or posterior translation of the talus preoperatively. There were no statistically significant correlations between any preoperative measure and any domain of the PROM data. Significant correlations were observed between postoperative medial distal tibial angle and the function domain of the FAOS and the AOFAS hindfoot-ankle score. Preoperative coronal and sagittal plane deformity are not markedly different, depending on the diagnosis. Preoperative deformity does not appear to correlate significantly with postoperative function, as measured by the PROM scores. Postoperative sagittal plane alignment does not correlate significantly with postoperative function, as measured by PROMs. Coronal plane alignment, as measured by the medial distal tibial angle, may be associated with postoperative function, as measured on the AOFAS hindfoot-ankle and FAOS function subscales.

Retinoic acid and 6-formylindolo(3,2-b)carbazole (FICZ) combination therapy reveals putative targets for enhancing response in non-APL AML.

In non-acute promyelotic leukemia (APL)- non myelocytic leukemia (AML), identification of a signaling signature would predict potentially actionable targets to enhance differentiation effects of all-trans-retinoic acid (RA) and make combination differentiation therapy realizable. Components of such a signaling machine/signalsome found to drive RA-induced differentiation discerned in a FAB M2 cell line/model (HL-60) were further characterized and then compared against AML patient expression profiles. FICZ, known to enhance RA-induced differentiation, was used to experimentally augment signaling for analysis. FRET revealed novel signalsome protein associations: CD38 with pS376SLP76 and caveolin-1 with CD38 and AhR. The signaling molecules driving differentiation in HL-60 cluster in non-APL AML de novo samples, too. Pearson correlation coefficients for this molecular ensemble are nearer 1 in the FAB M2 subtype than in non-APL AML. SLP76 correlation to RXRα and p47phox were conserved in FAB M2 model and patient subtype but not in general non-APL AML. The signalsome ergo identifies potential actionable targets in AML.

The effect of patient age and diagnosis on the 5-year outcomes of mobile-bearing total ankle replacement.

Total Ankle Replacement is an established technique for the management of end-stage ankle arthritis. However, there are few studies focussing on patient-reported outcomes in the medium and long term related to age or arthritis type. We compared demographic data and patient-reported outcomes preoperatively and at five years postoperatively for patients who underwent total ankle replacement with the aim of establishing whether differences exist in outcome depending on patient age or diagnosis. The Foot and Ankle Score (FAOS) and 36-item Short-Form (SF-36) Health Survey were analysed by diagnosis (osteoarthritis, rheumatoid arthritis, post-traumatic arthritis) and age (under or over 60 years). At 5 years, the post-traumatic arthritis group had a significantly higher composite score than the osteoarthritis (p<0.0001) or rheumatoid arthritis groups (p<0.0001). Only the post-traumatic arthritis group experienced a significant increase in composite SF-36 score from baseline (p<0.0001). There was a significant improvement from pre-operatively to 5 years in all three domains of the FAOS and in total scores in both groups (over 60 p<0.0001; 60 and under p=0.0002). There was a significant improvement in composite SF-36 score from pre-operative to 5 years in the patients 60 years or younger at the time of surgery (p=0.0006), but not for the patients over 60. Three patients have been revised (4%), at a mean of 4.8 years following surgery with one patient awaiting revision.

Neuroarthropathy in diabetes: pathogenesis of Charcot arthropathy.

Charcot neuroarthropathy is a rare but serious complication of diabetes, causing progressive destruction of the bones and joints of the foot leading to deformity, altered biomechanics and an increased risk of ulceration. Management is complicated by a lack of consensus on diagnostic criteria and an incomplete understanding of the pathogenesis. In this review, we consider recent insights into the development of Charcot neuroarthropathy. It is likely to be dependent on several interrelated factors which may include a genetic pre-disposition in combination with diabetic neuropathy. This leads to decreased neuropeptides (nitric oxide and calcitonin gene-related peptide), which may affect the normal coupling of bone formation and resorption, and increased levels of Receptor activator of nuclear factor kappa-B ligand, potentiating osteoclastogenesis. Repetitive unrecognized trauma due to neuropathy increases levels of pro-inflammatory cytokines (interleukin-1ß, interleukin-6, tumour necrosis factor α) which could also contribute to increased bone resorption, in combination with a pre-inflammatory state, with increased autoimmune reactivity and a profile of monocytes primed to transform into osteoclasts - cluster of differentiation 14 (CD14). Increased blood glucose and loss of circulating Receptor for Advanced Glycation End-Products (AGLEPs), leading to increased non-enzymatic glycation of collagen and accumulation of AGLEPs in the tissues of the foot, may also contribute to the pathological process. An understanding of the relative contributions of each of these mechanisms and a final common pathway for the development of Charcot neuroarthropathy are still lacking. Cite this article: S. E. Johnson-Lynn, A. W. McCaskie, A. P. Coll, A. H. N. Robinson. Neuroarthropathy in diabetes: pathogenesis of Charcot arthropathy. Bone Joint Res 2018;7:373-378. DOI: 10.1302/2046-3758.75.BJR-2017-0334.R1.

Potential for subsets of wt-NPM1 primary AML blasts to respond to retinoic acid treatment.

Acute myeloid leukemia (AML) has high mortality rates, perhaps reflecting a lack of understanding of the molecular diversity in various subtypes and a lack of known actionable targets. There are currently 12 open clinical trials for AML using combination therapeutic modalities including all-trans retinoic acid (RA). Mutant nucleophosmin-1, proposed as a possible marker for RA response, is the criterion for recruiting patients in three active RA phase 3 clinical trials. We tested the ability of RA alone or in combination with either bosutinib (B) or 6-formylindolo(3,2-b) carbazole (F) to induce conversion of 12 de novo AML samples toward a more differentiated phenotype. We assessed levels of expression of cell surface markers associated with differentiation, aldehyde dehydrogenase activity, and glucose uptake activity. Colony formation capacity was reduced with the combined treatment of RA and B or F, and correlated with modulation of a c-Cbl/Lyn/c-Raf-centered signalsome. Combination treatment was in most cases more effective than RA alone. Based on their responses to the treatments, some primary leukemic samples cluster closer to HL-60 cells than to other primary samples, suggesting that they may represent a hitherto undefined AML subtype that is potentially responsive to RA in a combination differentiation therapy.

Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation.

The aim of the trial was to assess whether extending plasma levels of the alpha7-nicotinic acetylcholine receptor (nAChR) agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) over time enhances its cognitive effects in schizophrenia. Both smoking and non-smoking patients were studied, to determine whether effects differ between these two groups. Forty-three smokers and thirty-seven non-smokers who met DSM-IV criteria for schizophrenia were enrolled in a double-blind, randomized, placebo-controlled 1 month trial. DMXB-A 150 mg was formulated with hypromellose to produce extended release over 4 h and administered four times daily. The primary outcome (the Neurocognitive Composite of the MATRICS Consensus Cognitive Battery) and secondary outcomes (the MATRICS Attention-Vigilance Domain and P50 gating), showed no significant effect. Plasma levels were obtained 2.5 h post administration. In non-smokers, levels were similar to those reached transiently with 75-150 mg DMXB-A immediate-release formulations twice daily, which were earlier shown to be effective doses. However, the extended-release formulation produced no cognitive or clinical effect either in non-smokers or smokers. The 10-fold lower DMXB-A plasma levels in smokers suggest that chronic smoking enhances DMXB-A metabolism. Pro-cognitive effects of DMXB-A may result from transient increases in cell signaling that are limited by receptor tachyphylaxis. Future efforts to improve cognition in schizophrenia by enhancing alpha7 nAChR function may require consideration of these pharmacokinetic limitations.

First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288.

Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.

How Knowledge Relates to Confidence in Orthopedics and Emergency Medicine Regarding Return to Sport and Rehabilitation in Foot and Ankle Trauma.

OBJECTIVE: The aim of this study was to survey the knowledge of registrars in emergency medicine and orthopedics on 5 common injuries to the foot and ankle and compare this knowledge, and self-reported confidence in giving it, with that of consultants and physiotherapists of various levels of experience. DESIGN: An online survey was used to gather the information using scenario-based open and closed questions. PARTICIPANTS: A total of 102 health care professionals, who regularly deal with sports injuries, were recruited. These included consultant orthopedic surgeons with a subspecialty interest in foot and ankle surgery, orthopedic surgeons in other specialties, extended scope physiotherapy practitioners (ESPs) in foot and ankle and general musculoskeletal practice, emergency medicine consultants, emergency medicine registrars, orthopedic registrars, senior physiotherapists, and junior physiotherapists. SETTING: The participants were drawn from various health care institutions in the North East of England. RESULTS: Consultant foot and ankle surgeons and extended scope practitioners in foot and ankle both scored significantly on knowledge of rehabilitation program design than either set of registrars. For 2 of the case scenarios, there was a significant difference in scores between either orthopedic consultants or ESPs and registrars (p < 0.05). For total score, there was a trend for extended scope practitioners to score higher than both sets of registrars, but this did not reach significance. Correlation coefficients for knowledge and self-reported confidence ranged between 0.009 and 0.33, demonstrating only weak positive linear correlation between scenario score and reported confidence in advice given. CONCLUSIONS: The most significant area of gaps in knowledge among the 2 groups of registrars was in the specifics of rehabilitation programs. There was markedly higher confidence with greater seniority. Registrars in emergency medicine and orthopedics are likely to benefit from case-based teaching in sports injury rehabilitation.

The effect of delay to surgery on morbidity, mortality and length of stay following periprosthetic fracture around the hip.

With the increasing prevalence of total hip arthroplasty and the increasing longevity of patients with implants in situ, periprosthetic fractures of the proximal femur are seen with greater frequency. They represent a challenging surgical problem, requiring combined arthroplasty and trauma skills in a potentially compromised surgical bed. We present data from the 82 consecutive patients with periprosthetic fractures around the hip presenting to two NHS Foundation Trusts in the period January 2009 to February 2014. Inpatient mortality across all sites was 11.0%. This increased to 17.1% at 1 year. There was no association between delay to surgery and either inpatient or 1 year mortality. Mean delay to surgery was 4.1 days in those without inpatient mortality, 5.2 days in those with (p=0.3075). Mean delay to surgery was 4.5 days in those with 1 year mortality, 4.16 days in those without (p=0.6203). The number of post-operative complications was not significantly positively correlated with increasing delay to surgery (Pearson correlation coefficient -0.04437). It would appear that a delay to order necessary equipment and obtain relevant surgical expertise for the treatment of these complex fractures is safe and not associated with increased mortality or post-operative complications.

An unusual complication of the Mackenzie approach for a Copeland hemiarthroplasty.

We report the case of a patient with end-stage osteoarthritis who received a successful Copeland resurfacing hemiarthroplasty through a Mackenzie anterosuperior approach, which involves taking the anterior portion of the deltoid attachment from the acromion along with an osteo-periosteal sleeve. The patient went on to develop severe subacromial impingement symptoms 4 months postoperatively. X-rays revealed a large anteroinferior acromial osteophyte that had not been present preoperatively and was deemed to represent a malunited osteo-periosteal sleeve from the Mackenzie approach.

Juvenile idiopathic arthritis in adulthood and orthopaedic intervention.

There have been marked changes in the management of juvenile idiopathic arthritis (JIA) over recent decades, mainly with earlier use of methotrexate (MTX). Our aim was to describe orthopaedic interventions in a large group of adults with JIA followed up over several decades. This was a retrospective observational study of adult JIA patients attending a teaching hospital clinic, with information collated on JIA subtype, disease duration, orthopaedic interventions, and exposure to MTX. The study included 144 patients with median disease duration of 19 years. Survival analysis showed that joint surgery was observed in the majority (75%) of patients with disease duration over 40 years with a trend for less joint surgery in patients with oligoarticular JIA. In total, 41 patients (28.5%) had received joint surgery, and 17/41 (41%) have required multiple procedures. Of those who have required joint surgery, 20/41 (48%) had started MTX in their adult years, with only 5/41 (12%), starting MTX prior to first joint replacement and none within 5 years of disease onset. Of the patients who have not had joint surgery to date, most (46/103, 45%) were receiving MTX or another immunosuppressive agent; in the majority of cases, MTX was started within 2 years of disease onset. Many adults with JIA require joint replacement surgery and ongoing immunosuppressive treatments, emphasising that JIA is not a benign disease. Many patients who have had joint replacement surgery have had exposure to MTX albeit after many years after disease onset; it remains to be seen whether patients who have received MTX therapy early in their disease course will ultimately have less requirement for joint surgery.

Initial phase 2 trial of a nicotinic agonist in schizophrenia.

OBJECTIVE: Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia. METHOD: Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers. RESULTS: There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A. CONCLUSION: DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.