Cobalt toxicity in humans-A review of the potential sources and systemic health effects.

Cobalt (Co) and its compounds are widely distributed in nature and are part of numerous anthropogenic activities. Although cobalt has a biologically necessary role as metal constituent of vitamin B12, excessive exposure has been shown to induce various adverse health effects. This review provides an extended overview of the possible Co sources and related intake routes, the detection and quantification methods for Co intake and the interpretation thereof, and the reported health effects. The Co sources were allocated to four exposure settings: occupational, environmental, dietary and medical exposure. Oral intake of Co supplements and internal exposure through metal-on-metal (MoM) hip implants deliver the highest systemic Co concentrations. The systemic health effects are characterized by a complex clinical syndrome, mainly including neurological (e.g. hearing and visual impairment), cardiovascular and endocrine deficits. Recently, a biokinetic model has been proposed to characterize the dose-response relationship and effects of chronic exposure. According to the model, health effects are unlikely to occur at blood Co concentrations under 300µg/l (100µg/l respecting a safety factor of 3) in healthy individuals, hematological and endocrine dysfunctions are the primary health endpoints, and chronic exposure to acceptable doses is not expected to pose considerable health hazards. However, toxic reactions at lower doses have been described in several cases of malfunctioning MoM hip implants, which may be explained by certain underlying pathologies that increase the individual susceptibility for Co-induced systemic toxicity. This may be associated with a decrease in Co bound to serum proteins and an increase in free ionic Co2+. As the latter is believed to be the primary toxic form, monitoring of the free fraction of Co2+ might be advisable for future risk assessment. Furthermore, future research should focus on longitudinal studies in the clinical setting of MoM hip implant patients to further elucidate the dose-response discrepancies.

'Standard' versus 'nose reference' electrode placement for measuring oVEMPs with air-conducted sound: Test-retest reliability and preliminary patient results.

OBJECTIVES: This study compared two electrode placements ('standard' versus 'nose reference' placement) for measuring oVEMPs, elicited by air-conducted 500Hz tone bursts. The test-retest reliability of both positions was evaluated and additionally both electrode placements were applied on a group of vestibular patients. METHODS: Eighteen healthy volunteers (range of 20-25years) participated in the first part and were retested after one week for evaluation of the test-retest reliability. Eleven patients (range of 41-74years) with a variety of vestibular pathologies were tested once. RESULTS: In the normal group, the nose reference electrode placement resulted in significantly larger peak-to-peak amplitudes (p<0.001), shorter n10 (p=0.001) and p15 (p<0.001) latencies and smaller 95% prediction intervals for the Inter-Ocular Ratio (IOR) ([-68, 68] for the standard position versus [-32, 32] for the nose reference position). Furthermore, an excellent amplitude and IOR test-retest reliability was observed with the nose reference configuration, as shown by the intraclass correlation coefficient (ICC), the coefficient of variation of the method error (CVME) and the minimal detectable differences (MDD). In the patient group, the same significant amplitude difference was found. Moreover, three patients presented with absent oVEMPs when recorded with the standard placement, whereas the nose reference placement could evoke a detectable oVEMP response. CONCLUSIONS: This study demonstrated that a nose reference electrode position results in larger oVEMP amplitudes and achieves a better reliability for the most important clinical parameters (amplitude and IOR). Our patient data substantiate the possible clinical benefit of this position, but further systematic patient verification is required. SIGNIFICANCE: The nose reference electrode position facilitates the detection of generally very small oVEMP responses and shows a high test-retest reliability, showing promising potential for future use in the vestibular clinic.

EMBalance - validation of a decision support system in the early diagnostic evaluation and management plan formulation of balance disorders in primary care: study protocol of a feasibility randomised controlled trial.

BACKGROUND: Balance problems are caused by multiple factors and often lead to falls and related fractures, bringing large socio-economic costs. The complexity of balance control mechanisms, the lack of medical expertise, and the absence of specialised equipment contribute to the delayed or incorrect diagnosis and management ofthese patients. Advances in computer science have allowed the development of computer systems that support clinical diagnosis and treatment decisions based on individualised patient data. The aim of the EMBalance decision support system (DSS) is to support doctors facing this clinical challenge, to make a definitive diagnosis and implement an effective management plan. The EMBalance study will determine the accuracy of this supportive tool when used by non-specialist doctors. This study is funded by the European Union's Seventh Framework Programme. METHODS/DESIGN: EMBalance is a proof-of-concept study designed as a non-commercial, international, multi-centre, single-blind, parallel-group randomised controlled trial to be carried out at four clinical sites in the United Kingdom, Germany, Greece and Belgium. The study is comprised of three stages: internal pilot, phase I (diagnosis) and stage II (management). For this purpose, 200 patients presenting with persistent dizziness (>3 months' duration) to primary care services will be randomised to either the intervention group (diagnostic assessment with the DSS) or a control group (diagnostic assessment without the DSS). Patients allocated to the intervention group will be assessed by a doctor with the support of the EMBalance DSS, while patients allocated to the control group will receive a visit as per standard practice. Ultimately, all patients' diagnoses and management plans will be certified by a consultant in neuro-otology. DISCUSSION: EMBalance is the first trial to test the accuracy of a DSS in both the diagnosis of and the management plan for vestibular disorders across the healthcare systems of four different countries. The EMBalance study is the result of a combined effort of engineers and physicians to develop an accurate tool to support non-specialist doctors, with no risk for the patient. This trial will provide reliable information about the benefits of implementing DSSs in primary care while supporting the feasibility of testing the EMBalance algorithms in further research. TRIAL REGISTRATION: ClinicalTrials.gov NCT02704819 . Registered 29 February 2016.

Cortical reorganization in an astronaut's brain after long-duration spaceflight.

To date, hampered physiological function after exposure to microgravity has been primarily attributed to deprived peripheral neuro-sensory systems. For the first time, this study elucidates alterations in human brain function after long-duration spaceflight. More specifically, we found significant differences in resting-state functional connectivity between motor cortex and cerebellum, as well as changes within the default mode network. In addition, the cosmonaut showed changes in the supplementary motor areas during a motor imagery task. These results highlight the underlying neural basis for the observed physiological deconditioning due to spaceflight and are relevant for future interplanetary missions and vestibular patients.

The treatment of muscle tension dysphonia: a comparison of two treatment techniques by means of an objective multiparameter approach.

The purpose of the present study is to measure the effectiveness of two treatment techniques--vocalization with abdominal breath support and manual circumlaryngeal therapy (MCT)--in patients with muscle tension dysphonia (MTD). The vocal quality before and after the two treatment techniques was measured by means of the dysphonia severity index (DSI), which is designed to establish an objective and quantitative correlate of the perceived vocal quality. The DSI is based on the weighted combination of the following set of voice measurements: maximum phonation time (MPT), highest frequency, lowest intensity, and jitter. The repeated-measures analysis of variance (ANOVA) revealed a significant difference between the objective overall vocal quality before and after MCT. No significant differences were measured between the objective overall vocal quality before and after vocalization with abdominal breath support. This study showed evidence that MCT is an effective treatment technique for patients with elevated laryngeal position, increased laryngeal muscle tension, and MTD. The precise way in which MCT has an effect on vocal quality has not been addressed in this experiment, but merits study. Further research into this topic could focus on electromyography (EMG) recordings in relation to vocal improvements with larger sample of subjects.

High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury.

BACKGROUND: The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury. METHODS AND RESULTS: Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5x10(-6) mol/L i.c.) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (Delta dP/dtmax, -878+/-586 versus -1956+/-351 mm Hg/s placebo; P=0.03), and regional thickening was better preserved (37.3+/-5.3% versus 5.1+/-0.6% placebo; P=0.004). Anterior wall perfusion fell similarly (-78.4+/-9.3% versus -71.2+/-13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740+/-58 nmol/g; ischemia, 947+/-55 nmol/g; ischemia plus FA, 1332+/-101 nmol/g; P=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124+/-280 cpm/mg FA versus 5898+/-474 cpm/mg placebo; P=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8+/-1.2% versus 60.3+/-4.1% placebo area at risk; P<0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA. CONCLUSIONS: FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.

Effect of folic acid on endothelial function following acute myocardial infarction.

The aim of this study was to test the influence of high-dose folic acid (10 mg/d) on endothelial function in patients referred for coronary intervention after an acute myocardial infarction (AMI) and determine its relation to homocysteine levels. Flow-mediated dilation (FMD) of the brachial artery was performed in 40 patients after AMI (16 with normal homocysteine levels and 24 patients with elevated levels [>11 micromol/L]). Subjects were randomized to receive first folic acid (10 mg/day; group A) or placebo (group B) for 6 weeks in a double-blind crossover trial with a 2-week washout. Plasma folate, total homocysteine and its subtypes (oxidized, reduced, and protein-bound), FMD, and nitroglycerin-mediated dilation were assessed at baseline and at 6 and 14 weeks. In group A, folic acid improved FMD from 3.98 +/- 0.35% to 6.44 +/- 0.56% (p <0.001). This effect persisted after the crossover with placebo (5.42 +/- 0.59, p = 0.13). In group B, placebo did not increase FMD (4.01 +/- 0.34% vs 4.46 +/- 0.38, p = 0.38); however, a significant increase was observed in the second active treatment period (6.49 +/- 0.56%, p = 0.005). In both groups, improved FMD neither correlated with basal levels of homocysteine and its subtypes nor with changes induced during the folate treatment. Nitroglycerin-mediated dilation did not change significantly in either group. Folic acid increased FMD in both normo- and hyperhomocysteinanemic groups (p = 0.006 and p <0.001). In conclusion, 6-week treatment with high-dose folic acid improves endothelial function in post-AMI patients, independent from homocysteine status. Folic acid can be recommended to improve postinfarction endothelial dysfunction in patients with normo- and hyperhomocysteinemia.

Improving vestibular evoked myogenic potential reliability by using a blood pressure manometer.

OBJECTIVE/HYPOTHESIS: To improve the reliability of vestibular evoked myogenic potentials (VEMP), we propose a feedback method making use of a readily available blood pressure manometer with inflatable cuff to control the sternocleidomastoid muscle (SCM) contraction. STUDY DESIGN: Prospective study. MATERIALS AND METHODS: The feedback method for SCM contraction consisted of subjects pushing with their jaw against the hand-held inflated cuff to generate a specified cuff pressure. This pressure level was monitored by subject and investigator. First, we tested in a group of healthy subjects whether there was a learning or fatigue effect during four successive SCM contraction runs when making use of the feedback method. Then, we investigated the mean rectified voltage (MRV) values of the SCM. Next, we examined the hypothesis that the MRV values of the SCM contraction measured before and simultaneously with the VEMP test were equal when using this feedback method. Finally, we compared the VEMP amplitude variability in two circumstances: with and without the feedback method. RESULTS: There was no learning or fatigue effect, and the MRV values measured before the VEMP were not significantly different from those measured during the VEMP test. The VEMP amplitude variability was significantly lower when applying the feedback method than when no feedback method was used. CONCLUSION: This feedback method improves significantly the VEMP amplitude reliability.