Aurothiomalate inhibits COX-2 expression in chondrocytes and in human cartilage possibly through its effects on COX-2 mRNA stability

Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with aurothiomalate. The results show that aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for aurothiomalate which may be important in the treatment of arthritis.     

Psychometric properties of the 20-item toronto alexithymia scale and prevalence of alexithymia in a finnish adolescent population

The authors assessed, in an adolescent population sample, the internal consistency, test-retest stability, and factor structure of the Toronto Alexithymia Scale (TAS-20) and established the frequency of alexithymia in this age-group. Pupils (N=882; age-groups: 14-, 15-, and 16-year-olds) from two secondary schools completed the TAS-20 questionnaire twice, with a 5-week interval, in a classroom survey setting. TAS total and subscale scores and proportion of subjects exceeding the cut-point for alexithymia are reported for boys and girls. In confirmatory factor analysis, all estimates except one item were statistically significant; there was no gender difference. The authors conclude that the TAS-20 has good psychometric properties in adolescent samples. Alexithymia rate decreases from early to middle adolescence and remains essentially on a level similar to that among adults.     

Quality of life after hip,vertebral, and distal forearm fragility fractures measured using the EQ-5D-3L,EQ-VAS,and time-trade-off: results from the ICUROS

Introduction

The International Costs and Utilities Related to Osteoporotic fractures Study is a multinational observational study set up to describe the costs and quality of life (QoL) consequences of fragility fracture. This paper aims to estimate and compare QoL after hip, vertebral, and distal forearm fracture using time-trade-off (TTO), the EuroQol (EQ) Visual Analogue Scale (EQ-VAS), and the EQ-5D-3L valued using the hypothetical UK value set.

Methods

Data were collected at four time-points for five QoL point estimates: within 2 weeks after fracture (including pre-fracture recall), and at 4, 12, and 18 months after fracture. Health state utility values (HSUVs) were derived for each fracture type and time-point using the three approaches (TTO, EQ-VAS, EQ-5D-3L). HSUV were used to estimate accumulated QoL loss and QoL multipliers.

Results

In total, 1410 patients (505 with hip, 316 with vertebral, and 589 with distal forearm fracture) were eligible for analysis. Across all time-points for the three fracture types, TTO provided the highest HSUVs, whereas EQ-5D-3L consistently provided the lowest HSUVs directly after fracture. Except for 13–18 months after distal forearm fracture, EQ-5D-3L generated lower QoL multipliers than the other two methods, whereas no equally clear pattern was observed between EQ-VAS and TTO. On average, the most marked differences between the three approaches were observed immediately after the fracture.

Conclusions

The approach to derive QoL markedly influences the estimated QoL impact of fracture. Therefore the choice of approach may be important for the outcome and interpretation of cost-effectiveness analysis of fracture prevention.

     

Botulinum toxin treatment of spastic equinus in cerebral palsy: a randomized trial comparing two injection sites

OBJECTIVE: To explore the clinical relevance of injection site by comparing two different injection techniques in children with cerebral palsy who have spastic equinus gait. DESIGN: A total of 19 children (13 boys, 6 girls; range, 1 yr 6 mos to 7 yrs; nine hemiplegics, eight diplegics, two quadriplegics; levels I to IV with the Gross Motor Function Classification System) participated in the study. The children were randomized into two groups: the proximal group received a botulinum toxin A injection into the proximal part of both heads of the gastrocnemius, and the distal group received a botulinum toxin A injection into the mid-belly of the muscle bulks. A single-point injection of BOTOX, 3 units/kg per site, was used. Assessments of active and passive range of motion, dynamic muscle length (modified Tardieu scale), calf tone (modified Ashworth scale), and video gait analysis (Observational Gait Scale) were performed before treatment and 3, 8, and 16 wks posttreatment. RESULTS: Active and passive dorsiflexion and calf tone in both groups and Observational Gait Scale total scores in the distal group improved at all time points. The median change from baseline values in Observational Gait Scale initial foot contact and total scores at 8 wks showed a significant difference favoring the distal group, but the clinical relevance remained tenuous. CONCLUSIONS: Using the methods described, no major changes in main outcome measures were associated with changing the injection site.     

Cavernous Carotid Aneurysms in the Era of Flow Diversion: A Need to Revisit Treatment Paradigms

BACKGROUND AND PURPOSE:Recent techniques of endoluminal reconstruction with flow-diverting stents have not been incorporated into treatment algorithms for cavernous carotid aneurysms. This study examines the authors'' institutional experience and a systematic review of the literature for outcomes and complications using the Pipeline Embolization Device in unruptured cavernous carotid aneurysms.MATERIALS AND METHODS:A retrospective search for cavernous carotid aneurysms from a prospectively collected data base of aneurysms treated with the Pipeline Embolization Device at our institution was performed. Baseline demographic, clinical, and laboratory values; intrainterventional data; and data at all follow-up visits were collected. A systematic review of the literature for complication data was performed with inquiries sent when clarification of data was needed.RESULTS:Forty-three cavernous carotid aneurysms were included in the study. Our mean radiographic follow-up was 2.05 years. On last follow-up, 88.4% of the aneurysms treated had complete or near-complete occlusion. Aneurysm complete or near-complete occlusion rates at 6 months, 12 months, and 36 months were 81.4%, 89.7%, and 100%, respectively. Of patients with neuro-ophthalmologic deficits on presentation, 84.2% had improvement in their visual symptoms. Overall, we had a 0% mortality rate and a 2.3% major neurologic complication rate. Our systematic review of the literature yielded 227 cavernous carotid aneurysms treated with the Pipeline Embolization Device with mortality and morbidity rates of 0.4% and 3.1%, respectively.CONCLUSIONS:Endoluminal reconstruction with flow diversion for large unruptured cavernous carotid aneurysms can yield high efficacy with low complications. Further long-term data will be helpful in assessing the durability of the cure; however, we advocate a revisiting of current management paradigms for cavernous carotid aneurysms.

Cavernous carotid aneurysms (CCAs) are a distinct form of extradural intracranial aneurysms. The natural history of CCAs has been studied, with the conclusion that these aneurysms have a low risk of causing major morbidity and mortality.^1–4 However, once they reach the size at which they penetrate or protrude through the dura, they, like other intradural aneurysms, carry the risk of subarachnoid hemorrhage. The overall relatively benign natural history has been weighed against traditional treatment options, including surgical clipping, parent artery occlusion with or without bypass, and endovascular coiling, all of which carry varying risks of major morbidity and mortality. The result has shown that expectant management for most CCAs carries a significantly lower risk than treatment, and this has been the standard of care for most CCAs for the past several decades.The consensus among practitioners has been that CCAs merit treatment only in narrowly defined circumstances (1–3 Underlying reasons to pursue conservative management also include the low annual rupture rate of CCAs and their tendency to rupture into the cavernous sinus, leading to carotid cavernous fistula formation rather than subarachnoid hemorrhage.Table 1:Generally accepted indications to treat CCAs

Mammography use and mode of detection among breast cancer patients in Estonia

ABSTRACT

The aim of this study was to examine past mammography use and mode of detection among breast cancer (BC) patients in Estonia, a country that has low screening coverage and high BC mortality. Women newly diagnosed with primary BC in Estonia in 2008–2010 were interviewed. Determinants of past mammography use and the detection of BC by mammography were studied using multivariate logistic regression. Among 977 participants, almost half reported no mammograms prior to the detection of BC. Overall, 22% of the cases were detected by mammography (16% by screening mammography). Detection by mammography was strongly related to age, past mammography use, and obesity. Among cases detected by mammography, 10% were stage III/IV at diagnosis (32% among cases detected by other modes). This study showed low mammography utilization and high rate of self-detection of BC in Estonia. Increased detection by mammography would help diagnose the disease at an earlier stage and consequently avoid premature BC deaths. Efforts should be undertaken to increase participation in screening and improve the availability of mammography among older and high-risk women. The results are likely to be relevant for other countries and population groups with low screening coverage.     

Azole Antifungal Resistance Today: Focus on <Emphasis Type="Italic">Aspergillus</Emphasis>

Oral triazole therapy is well established for the treatment of invasive aspergillosis (IPA), allergic aspergillosis (ABPA), and chronic pulmonary aspergillosis (CPA), and is often long-term. Resistance to triazole azole antifungal drugs in Aspergillus fumigatus is now a major clinical problem in a number of European locations, in China, Canada and the USA with particularly high frequencies from the north-west of the UK, and The Netherlands. A number of centers are reporting the continuing increasing frequency and evolution of resistance mechanisms in A. fumigatus, in both azole-naïve and patients treated with azoles. The increasing rate of resistance is of concern. A number of resistance mechanisms have been found. The biofilm modality of Aspergillus growth may have a number of therapeutic implications for aspergillosis, including antifungal resistance. Microbiological diagnosis of aspergillosis is limited by poor culture yield, leading to uncertainty about the frequency of triazole resistance. Direct resistance testing in culture-negative clinical samples may add additional insights into the prevalence of azole resistance in A. fumigatus.     

Neurocognitive development and behavioral outcome of 2-year-old children with univentricular heart

Recent advances in the treatment of children with severe congenital heart defects, such as hypoplastic left heart syndrome (HLHS) and other forms of univentricular heart (UVH), have significantly improved their survival rates. However, these children are at risk for various neurodevelopmental deficits. The aim of the present study was to assess cognitive development, expressive language, and behavior in 30-month-old children with univentricular heart. The participants were 22 children with HLHS, 14 with UVH, and 41 healthy control subjects. The Bayley Scales of Infant Development II, MacArthur Communicative Development Inventories, and Child Behavior Checklist were used for assessments. The results revealed that children with HLHS exhibited a significantly lower mean mental development index, more delays in expressive language functions, and more behavioral problems than did the control children. Two children with HLHS (9%) had mental development indexes below 50, indicating significantly delayed performance. The children with UVH differed from the control children with respect to their lower mean mental development index. These findings suggest that at the age of 30 months, neurodevelopmental deficits are especially prevalent in children with HLHS. Thus, early developmental screening, intervention, and neuropsychological follow-up until school age is recommended particularly for the children with HLHS.     

Endovascular management of spinal dural arteriovenous fistulas

Spinal dural arteriovenous fistulas (SDAVFs) represent the most frequent spinal arteriovenous malformation and have an ominous natural history if left untreated. In the present review, we describe the spinal vascular anatomy, pathophysiology and clinical manifestations of SDAVFs, and the current role of endovascular embolization in this type of lesion.