Thimerosal-Induced Neuritoxicity: Apoptosis Occurs Through A Mitochondrial-Mediated Pathway Via the JNK Signaling Pathway

Thimerosal is an organic mercurial containing an ethylmercury moiety attached to the sulfur atom of thiosalicylate. Since the 1930s, thimerosal has been used as an antiseptic and a preservative in a wide variety of products, including medicinal preparations administered to children and pregnant women. Past exposures to mercurials have indicated that mercury is a neurotoxin, and can also affect the kidney, skin, eyes, and immune system. Additionally, fetuses exposed to mercurials are more susceptible to toxicity because the nervous system is continuously developing. However, despite its widespread use, thimerosal was only studied on a limited basis until the end of the 1990s. At that time, the use of thimerosal in vaccines began to concern parents and physicians because of its potential neurotoxicity, creating a controversy surrounding the question of safety. Consequently, studies with cell culture and animal models have begun to discern the mechanisms of toxicity of thimerosal. The present study hypothesized that thimerosal-induced toxicity occurs through the cJun N-terminal kinase (JNK)/Activator Protein-1 (AP-1) pathway. We used a human neuroblastoma cell line (SK-N-SH) as a model for neurotoxicity because it has characteristics that resemble the developing nervous system. SK-N-SH cells treated with thimerosal underwent apoptosis in a mitochondrial-dependent manner, as demonstrated by release of cytochrome c, activation of caspases 9 and 3, degradation of poly(ADP)-ribose polymerase (PARP), DNA condensation and fragmentation, along with release of lactate dehydrogenase (LDH), which occurs late in apoptosis. Thimerosal-treated cells also showed activation of the JNK pathway through increases in phosphorylation of JNK and cJun. However, despite increases in AP-1 transcriptional activity, use of a dominant negative to cJun (TAM67) showed that AP-1 activation is not essential to thimerosal- induced apoptosis. Use of a cell permeable JNK inhibitor (SP600125) demonstrated that JNK activation is a necessary component of thimerosal-induced apoptosis. An additional component of thimerosal toxicity is an increase in oxidative stress. Antioxidants were used to determine if the oxidative stress component was connected to the JNK pathway activation. The antioxidant Trolox and the glutathione precursor N- acetylcysteine (NAC) both protected the cells from apoptosis, but served to increase the phosphorylation of JNK, while still decreasing levels of the proapoptotic protein Bim. Additionally, the JNK inhibitor decreased levels of the stress-response protein heme oxygenase-1 (HO-1). These results indicate that while the oxidative stress pathway and the JNK pathway may be affected by the actions of the other, additional intermediates are involved. Taken together, these results present a significant increase in the cumulative information concerning the mechanism of thimerosal-induced neurotoxicity. By increasing the overall knowledge base, we provide targets for the development of methods to attenuate potential neurotoxicity in patients exposed to thimerosal

A randomised feasibility study of serial magnetic resonance imaging to reduce treatment times in Charcot neuroarthropathy in people with diabetes (CADOM): A protocol

Background Charcot neuroarthropathy is a complication of peripheral neuropathy associated with diabetes which most frequently affects the lower limb. It can cause fractures and dislocations within the foot, which may progress to deformity and ulceration. Recommended treatment is immobilisation and offloading, with a below knee non-removable cast or boot. Duration of treatment varies from six months to more than one year. Small observational studies suggest that repeated assessment with Magnetic Resonance Imaging improves decision making about when to stop treatment, but this has not been tested in clinical trials. This study aims to explore the feasibility of using serial Magnetic Resonance Imaging without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot. A nested qualitative study aims to explore participants’ lived experience of Charcot neuroarthropathy and of taking part in the feasibility study. Methods We will undertake a two arm, open study, and randomise 60 people with a suspected or confirmed diagnosis of Charcot neuroarthropathy from five NHS, secondary care multidisciplinary Diabetic Foot Clinics across England. Participants will be randomised 1:1 to receive Magnetic Resonance Imaging at baseline and remission up to 12 months, with repeated foot temperature measurements and x-rays (standard care plus), or standard care plus with additional three-monthly Magnetic Resonance Imaging until remission up to 12 months (intervention). Time to confirmed remission of Charcot neuroarthropathy with off-loading treatment (days) and its variance will be used to inform sample size in a full-scale trial. We will look for opportunities to improve the protocols for monitoring techniques and the clinical, patient centred, and health economic measures used in a future study. For the nested qualitative study, we will invite a purposive sample of 10-14 people able to offer maximally varying experiences from the feasibility study to take part in semi-structured interviews to be analysed using thematic analysis. Discussion The study will inform the decision whether to proceed to a full-scale trial. It will also allow deeper understanding of the lived experience of Charcot neuroarthropathy, and factors that contribute to engagement in management and contribute to the development of more effective patient centred strategies. Trial registration ISRCTN, ISRCTN, 74101606. Registered on 6 November 2017, http://www.isrctn.com/ISRCTN74101606?q=CADom&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-searc

Tailoring of the Tell-us Card communication tool for nurses to increase patient participation using Intervention Mapping

Aims and objectives: To describe the tailoring of the Tell-us Card intervention for enhanced patient participation to the Dutch hospital setting using Intervention Mapping as a systematic approach. Background: Even though patient participation is essential in any patient-to-nurse encounter, care plans often fail to take patients' preferences into account. The Tell-us Card intervention seems promising, but needs to be tailored and tested before implementation in a different setting or on large scale. Design: Description of the Intervention Mapping framework to systematically tailor the Tell-us Card intervention to the Dutch hospital setting. Methods: Intervention Mapping consists of: (i) identification of the problem through needs assessment and determination of fit, based on patients and nurses interviews and focus group interviews; (ii) developing a logic model of change and matrices, based on literature and interviews; (iii) selection of theory-based methods and practical applications; (iv) producing programme components and piloting; (v) planning for adoption, implementation and sustainability; and (vi) preparing for programme evaluation. Results: Knowledge, attitude, outcome expectations, self-efficacy and skills were identified as the main determinants influencing the use of the Tell-us Card. Linking identified determinants and performance objectives with behaviour change techniques from the literature resulted in a well-defined and tailored intervention and evaluation plan. Conclusions: The Tell-us Card intervention was adapted to fit the Dutch hospital setting and prepared for evaluation. The Medical Research Council framework was followed, and the Intervention Mapping approach was used to prepare a pilot study to confirm feasibility and relevant outcomes. Relevance to clinical practice: This article shows how Intervention Mapping is applied within the Medical Research Council framework to adapt the Tell-us Card intervention, which could serve as a guide for the tailoring of similar interventions

Treatment for Vestibular Disorders: How Does Your Physical Therapist Treat Dizziness Related to Vestibular Problems?

Dizziness is very common, but it is never normal. Dizziness can make performing daily activities, work, and walking difficult. Many people get dizzy when they turn their head, which can cause problems with walking and makes people more likely to fall. Most of the time dizziness is not from a life-threatening disease. Often dizziness is because of a disorder of the vestibular (or inner ear balance) system. People can get vestibular disorders from infections in the ear, problems with the immune system, medications that harm the inner ear, and rarely from diabetes or stroke because of a lack of blood flow to the inner ear. Stress, poor sleep, migraines, overdoing some activities, and feeling sad can increase symptoms. New guidelines for the treatment of vestibular disorders were published in the April 2016 issue of the Journal of Neurologic Physical Therapy. The guideline describes which exercises are best to treat the dizziness and balance problems commonly seen with an inner ear disorder

An exploratory, large-scale study of pain and quality of life outcomes in cancer patients with moderate or severe pain, and variables predicting improvement

Background There have been few large-scale, real world studies in Spain to assess change in pain and quality of life (QOL) outcomes in cancer patients with moderate to severe pain. This study aimed to assess changes on both outcomes after 3 months of usual care and to investigate factors associated with change in QoL. Patients and methods Large, multi-centre, observational study in patients with lung, head and neck, colorectal or breast cancer experiencing a first episode of moderate to severe pain while attending one of the participating centres. QoL was assessed using the EuroQol-5D questionnaire and pain using the Brief Pain Inventory (BPI). Instruments were administered at baseline and after 3 months of follow up. Multivariate analyses were used to assess the impact of treatment factors, demographic and clinical variables, pain and other symptoms on QoL scores. Results 1711 patients were included for analysis. After 3 months of usual care, a significant improvement was observed in pain and QoL in all four cancer groups (p<0.001). Effect sizes were medium to large on the BPI and EQ-5D Index and Visual Analogue Scale (VAS). Improvements were seen on the majority of EQ-5D dimensions in all patient groups, though breast cancer patients showed the largest gains. Poorer baseline performance status (ECOG) and the presence of anxiety/depression were associated with significantly poorer QOL outcomes. Improvements in BPI pain scores were associated with improved QoL. Conclusion In the four cancer types studied, pain and QoL outcomes improved considerably after 3 months of usual care. Improvements in pain made a substantial contribution to QoL gains whilst the presence of anxiety and depression and poor baseline performance status significantly constrained improvementFinancial support for this research was provided by Mundipharma Pharmaceuticals S.L

Dealing with the health state ‘dead’ when using discrete choice experiments to obtain values for EQ-5D-5L heath states - Springer

__Abstract__ __Objective__ : To evaluate two different methods to obtain a dead (0)—full health (1) scale for EQ-5D-5L valuation studies when using discrete choice (DC) modeling. __Method__ : The study was carried out among 400 respondents from Barcelona who were representative of the Spanish population in terms of age, sex, and level of education. The DC design included 50 pairs of health states in five blocks. Participants were forced to choose between two EQ-5D-5L states (A and B). Two extra questions concerned whether A and B were considered worse than dead. Each participant performed ten choice exercises. In addition, values were collected using lead-time trade-off (lead-time TTO), for which 100 states in ten blocks were selected. Each participant performed five lead-time TTO exercises. These consisted of DC models offering the health state ‘dead’ as one of the choices—for which all participants’ responses were used (DCdead)—and a model that included only the responses of participants who chose at least one state as worse than dead (WTD) (DCWTD). The study also estimated DC models rescaled with lead-time TTO data and a lead-time TTO linear model. __Results__ : The DCdead and DCWTD models produced relatively similar results, although the coefficients in the DCdead model were slightly lower. The DC model rescaled with lead-time TTO data produced higher utility decrements. Lead-time TTO produced the highest utility decrements. __Conclusions__: The incorporation of the state ‘dead’ in the DC models produces results in concordance with DC models that do not include ‘dead’

Telephone conversation impairs sustained visual attention via a central bottleneck

Recent research has shown that holding telephone conversations disrupts one's driving ability. We asked whether this effect could be attributed to a visual attention impairment. In Experiment 1, participants conversed on a telephone or listened to a narrative while engaged in multiple object tracking (MOT), a task requiring sustained visual attention. We found that MOT was disrupted in the telephone conversation condition, relative to single-task MOT performance, but that listening to a narrative had no effect. In Experiment 2, we asked which component of conversation might be interfering with MOT performance. We replicated the conversation and single-task conditions of Experiment 1 and added two conditions in which participants heard a sequence of words over a telephone. In the shadowing condition, participants simply repeated each word in the sequence. In the generation condition, participants were asked to generate a new word based on each word in the sequence. Word generation interfered with MOT performance, but shadowing did not. The data indicate that telephone conversation disrupts attention at a central stage, the act of generating verbal stimuli, rather than at a peripheral stage, such as listening or speaking

EQ-5D in skin conditions: an assessment of validity and responsiveness

Aims and objectives This systematic literature review aims to assess the reliability, validity and responsiveness of three widely used generic preference-based measures of health-related quality of life (HRQL), i.e., EQ-5D, Health Utility Index 3 (HUI3) and SF-6D in patients with skin conditions. Methods A systematic search was conducted to identify studies reporting health state utility values obtained using EQ-5D, SF-6D, or HUI3 alongside other HRQL measures or clinical indices for patients with skin conditions. Data on test-retest analysis for reliability, known group differences or correlation and regression analyses for validity, and change over time or responsiveness indices analysis were extracted and reviewed. Results A total of 16 papers reporting EQ-5D utilities in people with skin conditions were included in the final review. No papers for SF-6D and HUI3 were found. Evidence of reliability was not found for any of these measures. The majority of studies included in the review (12 out of 16) examined patients with plaque psoriasis or psoriatic arthritis and the remaining four studies examined patients with either acne, hidradenitis suppurativa, hand eczema, or venous leg ulcers. The findings were generally positive in terms of performance of EQ-5D. Six studies showed that EQ-5D was able to reflect differences between severity groups and only one reported differences that were not statistically significant. Four studies found that EQ-5D detected differences between patients and the general population, and differences were statistically different for three of them. Further, moderate-to-strong correlation coefficients were found between EQ-5D and other skin-specific HRQL measures in four studies. Eight studies showed that EQ-5D was able to detect change in HRQL appropriately over time and the changes were statistically significant in seven studies. Conclusions Overall, the validity and responsiveness of the EQ-5D was found to be good in people with skin diseases, especially plaque psoriasis or psoriatic arthritis. No evidence on SF-6D and HUI3 was available to enable any judgments to be made on their performance