Simple quantitative planimetric measurement of nigrosome-1 for clinical settings.

INTRODUCTION: Loss of MRI hyperintense signal in nigrosome-1 (assessed with susceptibility-weighted imaging) is a biomarker for Parkinson's disease (PD). Current clinical practice involves subjectively rating the appearance of nigrosome-1 which is challenging. The study aimed to test and compare a simple method for quantifying nigrosome-1 with the current subjective rating method. METHODS: Two experienced neuroradiologists measured area of hyperintense signal in nigrosome-1 (quantitative method) and rated nigrosome-1 appearance (as normal, attenuated, or absent; subjective method) in 42 patients encompassing the full spectrum of nigrosome-1 integrity (21 patients aged 55.5 ± 20.9 years with Essential tremor (ET) and a subset of 21 patients aged 69.6 ± 8.6 years with PD). Neuroradiologists were blinded to each other's measurements, clinical notes, and patient group. RESULTS: Both methods yielded a significant difference between the groups (PD vs ET; p < 0.001). Pooled (across sides) area of nigrosome-1 hyperintense signal was significantly smaller in the PD group (median = 2.1 mm2, range = 0-15.8 mm2) than ET group (median = 8.3 mm2, range = 0-15.7 mm2; p < 0.001). Inter-rater reliability was high to very high for both methods (subjective: weighted kappa = 0.640, p < 0.001; quantitative: W = 0.733, p = 0.004). Our primary hypothesis that area of nigrosome-1 hyperintense signal exhibits higher inter-rater reliability than subjective rating of nigrosome-1 appearance was not supported. CONCLUSION: The simple quantitative method, used with subjectively rated nigrosome-1 appearance, may improve confidence in longitudinal clinical reporting, when nigrosome-1 is attenuated. However, further work on the incremental diagnostic value of planimetry and bias, repeatability and reproducibility are needed before it can be recommended in clinical practice.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Understanding the Water-in-Salt to Salt-in-Water Characteristics across the Zinc Chloride : Water Phase Diagram.

Using a series of time- and temperature-resolved synchrotron diffraction experiments, the relationship between multiple polymorphs of ZnCl2 and its respective hydrates is established. The δ-phase is found to be the pure anhydrous phase, while the α, ß, and γ phases result from partial hydration. Diffraction, gravimetric, and calorimetric measurements across the entire ZnCl2·R H2O, 0 > R > ∞ composition range using ultrapure, doubly sublimed ZnCl2 establish the ZnCl2 : H2O phase diagram. The results are consistent with the existence of crystalline hydrates at R = 1.33, 3, and 4.5 and identify a mechanistic pathway for hydration. All water is not removed from hydrated ZnCl2 until the system is heated above its melting point. While hydration/dehydration is reversible in concentrated solutions, dehydration from dilute aqueous solutions can result in loss of HCl, the source of hydroxide impurities commonly found in commercial ZnCl2 preparations. The strong interaction between ZnCl2 and water exerts a significant impact on the solvent water such that the system exhibits a deep eutectic at a composition of about R = 7 (87.5 mol %) and a eutectic temperature below -60 °C.

Adults with a history of recreational cannabis use have altered speech production.

Stereotypical depictions of speech in cannabis users often suggest slow, laboured output, yet objective evidence supporting this assumption is extremely limited. We know that depressants or hallucinogenic drugs such as cannabis can cause acute changes in communication and speech rate, but the long-lasting effects of cannabis use on speech are not well described. The aim of this study was to investigate speech in individuals with a history of recreational cannabis use compared to non-drug-using healthy controls. Speech samples were collected from a carefully described cohort of 31 adults with a history of cannabis use (but not use of illicit stimulant drugs) and 40 non-drug-using controls. Subjects completed simple and complex speech tasks including a monologue, a sustained vowel, saying the days of the week, and reading a phonetically balanced passage. Audio samples were analysed objectively using acoustic analysis for measures of timing, vocal control, and quality. Subtle differences in speech timing, vocal effort, and voice quality may exist between cannabis and control groups, however data remain equivocal. After controlling for lifetime alcohol and tobacco use and applying a false discovery rate, only spectral tilt (vocal effort and intensity) differed between groups and appeared to change in line with duration of abstinence from cannabis use. Differences between groups may reflect longer term changes to the underlying neural control of speech. Our digital analysis of speech shows there may be a signal differentiating individuals with a history of recreational cannabis use from healthy controls, in line with similar findings from gait and hand function studies.

Diagnostic accuracy of the appearance of Nigrosome-1 on magnetic resonance imaging in Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: There is currently no definitive diagnostic test for Parkinson's disease (PD) and the current diagnostic procedure primarily relies on clinical manifestations. A hypointense appearance of nigrosome-1 (or absence of the "swallow tail" sign) on magnetic resonance imaging (MRI) has been proposed as a biomarker for PD. This meta-analysis examined the diagnostic accuracy of the appearance of nigrosome-1 on Magnetic Resonance Imaging (MRI) in differentiating idiopathic PD patients from healthy adults. METHODS: Databases (MEDLINE, Embase, Scopus) were searched from 2012 (first publication of nigrosome-1 MRI scans) up until September 2019. Two researchers independently screened all titles and abstracts to identify studies that met the inclusion criteria and extracted relevant articles in a uniform manner. Two authors independently extracted data and assessed the risk of bias using a customized QUADAS-2 tool. Pooled sensitivity and specificity were calculated using a hierarchical summary receiver operating characteristic approach, as were positive and negative likelihood ratios. RESULTS: Nineteen studies containing a total of 1508 participants (903 idiopathic PD patients and 605 healthy controls) were included. The overall sensitivity and specificity were 0.94 (95%CI, 0.93-0.96) and 0.90 (95%CI, 0.88-0.92), respectively. The likelihood ratios for positive and negative test results were 9.72 (95%CI, 5.58-16.04) and 0.08 (95%CI, 0.05-0.12). The pooled area under the receiver operating characteristics curve (AUC) in the diagnosis of idiopathic PD was 0.98. CONCLUSIONS: Visual assessment of the nigrosome-1 appearance, at 3 or 7T, yields excellent diagnostic accuracy for differentiating idiopathic PD from healthy adults.

Prevalence of self-reported movement dysfunction among young adults with a history of ecstasy and methamphetamine use.

BACKGROUND: Illicit stimulant use is associated with long-lasting changes in movement and movement-related brain regions. The aim of our study was to investigate the prevalence of movement dysfunction in this population. We hypothesized that prevalence of self-reported movement dysfunction is higher among stimulant users than non-stimulant users. METHODS: Three groups of adults completed a survey containing questions about demographics, health, drug use, and movement. The groups consisted of ecstasy users with no history of methamphetamine use (ecstasy group, n = 190, 20 ±â€¯3 yrs.), methamphetamine users (methamphetamine group, n = 331, 23 ±â€¯5 yrs.), and non-stimulant users (control group, n = 228, 25 ±â€¯8 yrs.). Movement data was analyzed with logistic regression. RESULTS: In the unadjusted logistic regression model, group had a significant effect on fine hand control, tremor, and voice/speech questions, but not on other movement domain questions. The prevalence of tremor and abnormal fine hand control was significantly higher in the ecstasy and methamphetamine groups than in the control group (p < 0.018), and changes in voice/speech was more prevalent in the ecstasy group than in the control group (p = 0.015). Age and use of cannabis and hallucinogens were confounding variables. However, inspection of chi-square tables suggests that the effect of these parameters on the movement data is likely to be minor. CONCLUSIONS: The prevalence of self-reported tremor and changes in fine hand control and voice/speech is significantly higher in stimulant users than in non-stimulant users. Inclusion of these common and noticeable changes in body function may aid public health campaigns that target prevention or harm minimization.

Use of illicit amphetamines is associated with long-lasting changes in hand circuitry and control.

OBJECTIVE: The study aim was to determine if use of illicit amphetamines or ecstasy is associated with abnormal excitability of the corticomotoneuronal pathway and manipulation of novel objects with the hand. METHODS: Three groups of adults aged 18-50 years were investigated: individuals with a history of illicit amphetamine use, individuals with a history of ecstasy use but minimal use of other stimulants, and non-drug users. Transcranial magnetic stimulation was delivered to the motor cortex and the electromyographic response (motor evoked potential; MEP) was recorded from a contralateral hand muscle. Participants also gripped and lifted a novel experimental object consisting of two strain gauges and an accelerometer. RESULTS: Resting MEP amplitude was larger in the amphetamine group (6M, 6F) than the non-drug and ecstasy groups (p < 0.005) in males but not females. Overestimation of grip force during manipulation of a novel object was observed in the amphetamine group (p = 0.020) but not the ecstasy group. CONCLUSIONS: History of illicit amphetamine use, in particular methamphetamine, is associated with abnormal motor cortical and/or corticomotoneuronal excitability in males and abnormal manipulation of novel objects in both males and females. SIGNIFICANCE: Abnormal excitability and hand function is evident months to years after cessation of illicit amphetamine use.

History of cannabis use is associated with altered gait.

BACKGROUND: Despite evidence that cannabinoid receptors are located in movement-related brain regions (e.g., basal ganglia, cerebral cortex, and cerebellum), and that chronic cannabis use is associated with structural and functional brain changes, little is known about the long-term effect of cannabis use on human movement. The aim of the current study was to investigate balance and walking gait in adults with a history of cannabis use. We hypothesised that cannabis use is associated with subtle changes in gait and balance that are insufficient in magnitude for detection in a clinical setting. METHODS: Cannabis users (n=22, 24±6years) and non-drug using controls (n=22, 25±8years) completed screening tests, a gait and balance test (with a motion capture system and in-built force platforms), and a clinical neurological examination of movement. RESULTS: Compared to controls, cannabis users exhibited significantly greater peak angular velocity of the knee (396±30 versus 426±50°/second, P=0.039), greater peak elbow flexion (53±12 versus 57±7°, P=0.038) and elbow range of motion (33±13 versus 36±10°, P=0.044), and reduced shoulder flexion (41±19 versus 26±16°, P=0.007) during walking gait. However, balance and neurological parameters did not significantly differ between the groups. CONCLUSIONS: The results suggest that history of cannabis use is associated with long-lasting changes in open-chain elements of walking gait, but the magnitude of change is not clinically detectable. Further research is required to investigate if the subtle gait changes observed in this population become more apparent with aging and increased cannabis use.

ß-Blockers, heart disease and COPD: current controversies and uncertainties.

Treating people with cardiovascular disease and COPD causes significant clinician anxiety. ß-Blockers save lives in people with heart disease, specifically postinfarction and heart failure. COPD and heart disease frequently coexist and people with both disorders have particularly high cardiovascular mortality. There are concerns about giving ß-blockers to people with concomitant COPD that include reduced basal lung function, diminished effectiveness of emergency ß-agonist treatments, reduced benefit of long-acting ß-agonist treatment and difficulty in discriminating between asthma and COPD. ß-Blockers appear to reduce lung function in both the general population and those with COPD because they are poorly selective for cardiac ß1-adrenoceptors over respiratory ß2-adrenoceptors, and studies have shown that higher ß-agonist doses are required to overcome the ß-blockade. COPD and cardiovascular disease share similar environmental risks and both disease states have high adrenergic and inflammatory activation. ß-Blockers may therefore be particularly helpful in reducing cardiovascular events in this high-risk group. They may reduce the background inflammatory state, and inhibit the tachycardia and hypertension associated with both the endogenous adrenaline and high-dose ß-agonist treatment associated with acute exacerbations of COPD. Some studies have suggested no increased and, at times, reduced mortality in patients with COPD taking ß-blockers for heart disease. However, these are all observational studies and there are no randomised controlled trials. Potential ways to improve this dilemma include the development of highly ß1-selective ß-blockers or the use of non-ß-blocking heart rate reducing agents, such as ivabridine, if these are proven to be beneficial in randomised controlled trials.

Strategies to attenuate micro-vascular obstruction during P-PCI: the randomized reperfusion facilitated by local adjunctive therapy in ST-elevation myocardial infarction trial.

BACKGROUND: Microvascular obstruction (MVO) following primary percutaneous coronary intervention (PPCI) treatment of ST-segment elevation myocardial infarction (STEMI) contributes to infarct expansion, left ventricular (LV) remodelling, and worse clinical outcomes. The REFLO-STEMI trial tested whether intra-coronary (IC) high-dose adenosine or sodium nitroprusside (SNP) reduce infarct size and/or MVO determined by cardiac magnetic resonance (CMR). METHODS AND RESULTS: REFLO-STEMI, a prospective, open-label, multi-centre trial with blinded endpoints, randomized (1:1:1) 247 STEMI patients with single vessel disease presenting within 6 h of symptom onset to IC adenosine (2-3 mg total) or SNP (500 µg total) immediately following thrombectomy and again following stenting, or to standard PPCI. The primary endpoint was infarct size % LV mass (%LVM) on CMR undertaken 24-96 h after PPCI (n = 197). Clinical follow-up was to 6 months. There was no significant difference in infarct size (%LVM, median, interquartile range, IQR) between adenosine (10.1, 4.7-16.2), SNP (10.0, 4.2-15.8), and control (8.3, 1.9-14.0), P = 0.062 and P = 0.160, respectively, vs. CONTROL: MVO (% LVM, median, IQR) was similar across groups (1.0, 0.0-3.7, P = 0.205 and 0.6, 0.0-2.4, P = 0.244 for adenosine and SNP, respectively, vs. control 0.3, 0.0-2.8). On per-protocol analysis, infarct size (%LV mass, 12.0 vs. 8.3, P = 0.031), major adverse cardiac events (hazard ratio, HR, 5.39 [1.18-24.60], P = 0.04) at 30 days and 6 months (HR 6.53 [1.46-29.2], P = 0.01) were increased and ejection fraction reduced (42.5 ± 7.2% vs. 45.7 ± 8.0%, P = 0.027) in adenosine-treated patients compared with control. CONCLUSIONS: High-dose IC adenosine and SNP during PPCI did not reduce infarct size or MVO measured by CMR. Furthermore, adenosine may adversely affect mid-term clinical outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01747174; https://clinicaltrials.gov/ct2/show/NCT01747174.

Adults with a history of illicit amphetamine use exhibit abnormal substantia nigra morphology and parkinsonism.

INTRODUCTION: The sonographic appearance of the substantia nigra is abnormally bright and enlarged (hyperechogenic) in young adults with a history of illicit stimulant use. The abnormality is a risk factor for Parkinson's disease. The aim of the current study was to identify the type of illicit stimulant drug associated with substantia nigra hyperechogenicity and to determine if individuals with a history of illicit stimulant use exhibit clinical signs of parkinsonism. We hypothesised that use of amphetamines (primarily methamphetamine) is associated with substantia nigra hyperechogenicity and clinical signs of parkinsonism. METHODS: The area of echogenic signal in the substantia nigra was measured in abstinent human amphetamine users (n = 27; 33 ± 8 years) and in three control groups comprising a) 'ecstasy' users (n = 19; 23 ± 3 years), b) cannabis users (n = 30; 26 ± 8 years), and c) non-drug users (n = 37; 25 ± 7 years). A subset of subjects (n = 55) also underwent a neurological examination comprising the third and fifth part of the Unified Parkinson's Disease Rating Scale. RESULTS: Area of substantia nigra echogenicity was significantly larger in the amphetamine group (0.276 ± 0.080 cm(2)) than in the control groups (0.200 ± 0.075, 0.190 ± 0.049, 0.191 ± 0.055 cm(2), respectively; P < 0.002). The score on the clinical rating scale was also significantly higher in the amphetamine group (8.4 ± 8.1) than in pooled controls (3.3 ± 2.8; P = 0.002). CONCLUSION: Illicit use of amphetamines is associated with abnormal substantia nigra morphology and subtle clinical signs of parkinsonism. The results support epidemiological findings linking use of amphetamines, particularly methamphetamine, with increased risk of developing Parkinson's disease later in life.

Infarct Size, Shock, and Heart Failure: Does Reperfusion Strategy Matter in Early Presenting Patients With ST-Segment Elevation Myocardial Infarction?

BACKGROUND: A pharmacoinvasive (PI) strategy for early presenting ST-segment elevation myocardial infarction nominally reduced 30-day cardiogenic shock and congestive heart failure compared with primary percutaneous coronary intervention (PPCI). We evaluated whether infarct size (IS) was related to this finding. METHODS AND RESULTS: Using the peak cardiac biomarker in patients randomized to PI versus PPCI within the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial, IS was divided into 3 groups: small (≤2 times the upper limit normal [ULN]), medium (>2 to ≤5 times the upper limit normal) and large (>5 times the upper limit normal). The association between IS and 30-day shock and congestive heart failure was subsequently examined. Data on 1701 of 1892 (89.9%) patients randomized to PI (n=853, 50.1%) versus PPCI (n=848, 49.9%) within STREAM were evaluated. A higher proportion of PPCI patients had a large IS (PI versus PPCI: small, 49.8% versus 50.2%; medium, 56.9% versus 43.1%; large, 48.4% versus 51.6%; P=0.035), despite comparable intergroup ischemic times for each reperfusion strategy. As IS increased, a parallel increment in shock and congestive heart failure occurred in both treatment arms, except for the small IS group. The difference in shock and congestive heart failure in the small IS group (4.4% versus 11.6%, P=0.026) in favor of PI likely relates to higher rates of aborted myocardial infarction with the PI strategy (72.7% versus 54.3%, P=0.005). After adjustment, a trend favoring PI persisted in this subgroup (relative risk 0.40, 95% CI 0.15 to 1.06, P=0.064); no difference in treatment-related outcomes was evident in the other 2 groups. CONCLUSION: A PI strategy appears to alter the pattern of IS after ST-segment elevation myocardial infarction, resulting in more medium and fewer large infarcts compared with PPCI. Despite a comparable number of small infarcts, PI patients in this group had more aborted myocardial infarctions and less 30-day shock and congestive heart failure. CLINICAL TRIAL REGISTRATION: URL: http://ClinicalTrials.gov. Unique identifier: NCT00623623.

Impact of a pharmacoinvasive strategy when delays to primary PCI are prolonged.

OBJECTIVES: Primary percutaneous coronary intervention (P-PCI) is the preferred reperfusion option in ST-elevation myocardial infarction, but its benefits become attenuated as time to its potential delivery becomes prolonged. Based on the STrategic Reperfusion Early After Myocardial Infarction trial, we assessed the impact of increasing time delay on outcomes in patients randomised to a pharmacoinvasive strategy (PI) or P-PCI. METHODS: Thirty-day clinical outcomes were examined according to PCI-related delay (P-RD). Data from hospitals that enrolled >10 randomised patients were used and P-RD categorised as ≤55 min, >55-97 min and >97 min. RESULTS: Composite of death/congestive heart failure/cardiogenic shock/myocardial infarction in PI and P-PCI arms occurred in 10.6% versus 10.3% (≤55 min, p=0.910); 13.9% versus 17.9% (>55-97 min, p=0.148) and 13.5% versus 16.2% (>97 min, p=0.470), respectively. While there was no worsening of outcomes for PI across the P-RD spectrum, this occurred in the P-PCI arm (p(trend)=0.038). For P-RD ≤55 min, fewer events tended to occur with P-PCI than PI. Conversely, as P-RD increased to >55 min, PI-assigned patients had better outcomes than P-PCI, suggesting an event-free advantage with PI as P-RD increased (p(interaction)=0.094). Analysing P-RD continuously showed that for every 10-min increment there was an increasing trend towards benefit among PI-assigned patients (p(interaction)=0.073). CONCLUSIONS: As P-RD increased, PI outcomes became superior to P-PCI when P-RD is prolonged and exceeds guideline-mandated times. In such circumstances, a PI strategy may provide an alternative reperfusion option. Adverse time delays for delivery of P-PCI should be considered when evaluating reperfusion strategies. TRIAL REGISTRATION NUMBER: NCT00623623.

Crystalline and liquid structure of zinc chloride trihydrate: a unique ionic liquid.

The water/ZnCl(2) phase diagram in the vicinity of the 75 mol % water composition is reported, demonstrating the existence of a congruently melting phase. Single crystals of this 3-equiv hydrate were grown, and the crystal structure of [Zn(OH(2))(6)][ZnCl(4)] was determined. Synchrotron X-ray and neutron diffraction and IR and Raman spectroscopy along with reverse Monte Carlo modeling demonstrate that a CsCl-type packing of the molecular ions persists into the liquid state. Consistent with the crystalline and liquid structural data, IR spectroscopy demonstrates that the O-H bonds of coordinated water do not exhibit strong intermolecular hydrogen ion bonding but are significantly weakened because of the water's coordination to Lewis acidic zinc ions. The O-H bond weakening makes this system a very strong hydrogen-bond donor, whereas the ionic packing along with the nonpolar geometry of the molecular ions makes this system a novel nonpolar, hydrogen-bonding, ionic liquid solvent.

Genome sequencing identifies a novel mutation in ATP1A3 in a family with dystonia in females only.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Several genetic causes of dystonia have been elucidated but genetic causes of dystonia specifically affecting females have not yet been described. In the present study, we investigated a large dystonia family from New Zealand in which only females were affected. They presented with a generalized form of the disorder including laryngeal, cervical, and arm dystonia. We found a novel, likely disease-causing, three base-pair deletion (c.443_445delGAG, p.Ser148del) in ATP1A3 in this family by combining genome and exome sequencing. Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome. Therefore, we re-examined our patients with a specific focus on typical symptoms of these conditions. It turned out that all patients reported a rapid onset of dystonic symptoms following a trigger suggesting a diagnosis of RDP. Notably, none of the patients showed clear symptoms of parkinsonism or symptoms specific for AHC or CAPOS. The ATP1A3 gene is located on chromosome 19q13.2, thus, providing no obvious explanation for the preponderance to affect females. Interestingly, we also identified one unaffected male offspring carrying the p.Ser148del mutation suggesting reduced penetrance of this mutation, a phenomenon that has also been observed for other RDP-causing mutations in ATP1A3. Although phenotypic information in this family was initially incomplete, the identification of the p.Ser148del ATP1A3 mutation elicited clinical re-examination of patients subsequently allowing establishing the correct diagnosis, a phenomenon known as "reverse phenotyping".

Upper limb function is normal in patients with restless legs syndrome (Willis-Ekbom Disease).

OBJECTIVE: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor amplitude but normal dexterity and movement speed and rhythmicity compared to healthy controls. METHODS: RLS/WED patients (n=17, 59 ± 7 years) with moderate disease and healthy controls (n=17, 58 ± 6 years) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. RESULTS: Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. CONCLUSIONS: Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. SIGNIFICANCE: Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology.

Hand function is altered in individuals with a history of illicit stimulant use.

Use of illicit stimulant drugs such as methamphetamine, cocaine, and ecstasy are a significant worldwide problem. However, little is known about the effect of these drugs on movement. The aim of the current study was to investigate hand function in adults with a history of illicit stimulant use. We hypothesized that prior use of illicit stimulant drugs is associated with abnormal manipulation of objects. The study involved 22 subjects with a history of illicit stimulant use (aged 29±8 yrs; time since last use: 1.8±4.0 yrs) and two control groups comprising 27 non-drug users (aged 25±8 yrs) and 17 cannabis users with no history of stimulant use (aged 22±5 yrs). Each subject completed screening tests (neuropsychological assessment, medical history questionnaire, lifetime drug history questionnaire, and urine drug screen) prior to gripping and lifting a light-weight object with the dominant right hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus electromyographic (EMG) activity were recorded during three trials. In trial one, peak grip force was significantly greater in the stimulant group (12.8±3.9 N) than in the control groups (non-drug: 10.3±4.6 N; cannabis: 9.4±2.9 N, P<0.022). However, peak grip force did not differ between groups in trials two and three. The results suggest that individuals with a history of stimulant use overestimate the grip force required to manipulate a novel object but, are able to adapt grip force in subsequent lifts. The results suggest that movement dysfunction may be an unrecognized consequence of illicit stimulant use.

The REFLO-STEMI trial comparing intracoronary adenosine, sodium nitroprusside and standard therapy for the attenuation of infarct size and microvascular obstruction during primary percutaneous coronary intervention: study protocol for a randomised controlled trial.

BACKGROUND: Microvascular obstruction (MVO) secondary to ischaemic-reperfusion injury is an important but underappreciated determinant of short- and longer-term outcome following percutaneous coronary intervention (PCI) treatment of ST-elevation myocardial infarction (STEMI). Several small studies have demonstrated a reduction in the degree of MVO utilising a variety of vasoactive agents, with adenosine and sodium nitroprusside (SNP) being most evaluated. However, the evidence base remains weak as the trials have had variable endpoints, differing drug doses and delivery. As such, the results regarding benefit are conflicting. METHODS: The REperfusion Facilitated by LOcal adjunctive therapy in STEMI (REFLO-STEMI) trial is a multicentre, prospective, randomised, controlled, open label, study with blinded endpoint analysis: Patients presenting within 6 h of onset of STEMI and undergoing planned primary PCI (P-PCI) with TIMI 0/1 flow in the infarct-related artery (IRA) and no significant bystander coronary artery disease on angiography, are randomised into one of three groups: PCI with adjunctive pharmacotherapy (intracoronary adenosine or SNP) or control (standard PCI). All receive Bivalirudin anticoagulation and thrombus aspiration. The primary outcome is infarct size (IS) (determined as a percentage of total left ventricular mass) measured by cardiac magnetic resonance imaging (CMRI) undertaken at 48 to 72 h post P-PCI. Secondary outcome measures include MVO (hypoenhancement within infarct core) on CMRI, angiographic markers of microvascular perfusion and MACE during 1-month follow-up. The study aims to recruit 240 patients (powered at 80% to detect a 5% absolute reduction in IS). DISCUSSION: The REFLO-STEMI study has been designed to address the weaknesses of previous trials, which have collectively failed to demonstrate whether adjunctive pharmacotherapy with adenosine and/or SNP can reduce measures of myocardial injury (infarct size and MVO) and improve clinical outcome, despite good basic evidence that they have the potential to attenuate this process. The REFLO-STEMI study will be the most scientifically robust trial to date evaluating whether adjunctive therapy (intracoronary adenosine or SNP following thrombus aspiration) reduces CMRI measured IS and MVO in patients undergoing P-PCI within 6 h of onset of STEMI. TRIAL REGISTRATION: Trial registered 20th November 2012: ClinicalTrials.gov Identifier NCT01747174.

ST-segment-elevation myocardial infarction patients randomized to a pharmaco-invasive strategy or primary percutaneous coronary intervention: Strategic Reperfusion Early After Myocardial Infarction (STREAM) 1-year mortality follow-up.

BACKGROUND: In the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial, a pharmaco-invasive (PI) strategy was compared with primary percutaneous coronary intervention (pPCI) in ST-segment-elevation myocardial infarction patients presenting within 3 hours after symptom onset but unable to undergo pPCI within 1 hour. At 30 days, the PI approach was associated with a nominally but nonstatistically significant lower incidence of the composite primary end point of death, shock, congestive heart failure, and reinfarction when compared with pPCI. The aim of the present study was to determine the effect of these strategies on 1-year mortality. METHODS AND RESULTS: Vital status at 1 year was available in 936 of 944 (99.2%) and 941 of 948 (99.3%) patients in the PI and pPCI arm, respectively. At 1 year, all-cause mortality rates (6.7% versus 5.9%) were similar for PI and pPCI-treated patients (P=0.49; risk ratio, 1.13; 95% confidence interval, 0.79-1.62). Cardiac mortality rates were similar as well (4.0% versus 4.1%, P=0.93; risk ratio, 0.98; 95% confidence interval, 0.62-1.54). Overall, only 34 patients died between day 30 and 1 year, 20 in the PI arm and 14 in the pPCI arm, of whom 20 died of noncardiac reasons (13 in the PI and 7 in the pPCI arm). There was no significant difference in 1-year all-cause mortality between the 2 groups among the prespecified key subgroups. CONCLUSIONS: At 1 year, mortality rates in the PI and pPCI arms were similar in ST-segment-elevation myocardial infarction patients presenting within 3 hours after symptom onset and unable to undergo pPCI within 1 hour. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00623623.

Outcomes of a pharmacoinvasive strategy for successful versus failed fibrinolysis and primary percutaneous intervention in acute myocardial infarction (from the STrategic Reperfusion Early After Myocardial Infarction [STREAM] study).

Although a fibrinolytic pharmacoinvasive strategy is recommended for patients with ST elevation myocardial infarction (STEMI) unable to undergo timely primary percutaneous coronary intervention (PCI), there are limited data addressing outcomes specific to those with successful or unsuccessful pharmacologic reperfusions. Accordingly, we evaluated a contemporary pharmacoinvasive strategy for failed and successful reperfusions within the STrategic Reperfusion Early After Myocardial infarction study. Of 1,823 per-protocol-treated patients with STEMI, we examined clinical outcomes and angiographic and electrocardiographic metrics in 3 groups as follows: fibrinolysis requiring rescue (rescue, n = 348), fibrinolysis with scheduled angiography (scheduled, n = 516), and primary PCI (n = 927). Compared with pharmacoinvasive patients undergoing scheduled angiography, rescue patients were more likely to have anterior wall myocardial infarction, more baseline ST-segment elevation and deviation, as well as Q waves in the distribution of their ST elevation. Residual ST elevation ≥ 2 mm 30 minutes after angiography occurred in 27.9%, 7.9%, and 24.8% of patients who underwent rescue, scheduled, and primary PCI, respectively. Thirty-day composite event rates (all-cause death, cardiogenic shock, heart failure, and reinfarction) were 18.7%, 5.5%, and 13.9%; all-cause death: 6.1%, 2.1%, and 3.9%; cardiogenic shock: 7.5%, 2.0%, and 5.4%; heart failure: 11.8%, 2.3%, and 7.6%; and reinfarction: 1.5%, 1.4%, and 2.2%, for rescue, scheduled, and primary PCI, respectively. Compared with successfully reperfused patients undergoing scheduled angiography, the adjusted relative risk of the primary outcome was 2.92 (95% confidence interval 1.92 to 4.45) in rescue patients. In conclusion, pharmacoinvasive-treated patients requiring rescue angiography had greater baseline risk with more co-morbidities and worse 30-day outcomes compared with successful fibrinolytic-treated patients. Residual ST elevation after reperfusion assists in defining prognosis.