Memory-Guided Reaching: Is It Effortful?

We previously showed that perceived effort during visually guided reaching was altered as task demand varied. Further, self-reported subjective fatigue correlated with perceived effort and reach performance under visually guided conditions. Memory-guided reaching often leads to performance deterioration and can provide insights about the planning and control of reach actions. It is unclear how perceived effort changes during memory-guided reaching and whether self-reported subjective fatigue is associated with perceived effort of memory-guided reaching. Twenty-three young adults performed reach actions under visually- and memory-guided conditions. Perceived effort, reaction time, and endpoint error increased significantly from the visually- to the memory-guided condition. Self-reported subjective fatigue was associated with perceived effort and reach distance error during memory-guided reaching; those with higher levels of fatigue reported greater perceived effort and tended to reach farther when visual information was not available. These findings establish a foundation to examine relationships between subjective fatigue, perceived effort, and reach control.

Effect of COVID-19 on presentations of decompensated liver disease in Scotland.

BACKGROUND AND AIMS: SARS-CoV-2 and consequent pandemic has presented unique challenges. Beyond the direct COVID-related mortality in those with liver disease, we sought to determine the effect of lockdown on people with liver disease in Scotland. The effect of lockdown on those with alcohol-related disease is of interest; and whether there were associated implications for a change in alcohol intake and consequent presentations with decompensated disease. METHODS: We performed a retrospective analysis of patients admitted to seven Scottish hospitals with a history of liver disease between 1 April and 30 April 2020 and compared across the same time in 2017, 2018 and 2019. We also repeated an intermediate assessment based on a single centre to examine for delayed effects between 1 April and 31 July 2020. RESULTS: We found that results and outcomes for patients admitted in 2020 were similar to those in previous years in terms of morbidity, mortality, and length of stay. In the Scotland-wide cohort: admission MELD (Model for End-stage Liver Disease) (16 (12-22) vs 15 (12-19); p=0.141), inpatient mortality ((10.9% vs 8.6%); p=0.499) and length of stay (8 days (4-15) vs 7 days (4-13); p=0.140). In the Edinburgh cohort: admission MELD (17 (12-23) vs 17 (13-21); p=0.805), inpatient mortality ((13.7% vs 10.1%; p=0.373) and length of stay (7 days (4-14) vs 7 days (3.5-14); p=0.525)). CONCLUSION: This assessment of immediate and medium-term lockdown impacts on those with chronic liver disease suggested a minimal effect on the presentation of decompensated liver disease to secondary care.

Central Retinal Artery Occlusion Following Prone Transcranial Surgery for Craniosynostosis and Discussion of Risk Factors.

Vision loss is a known rare complication of prone positioning during surgery. Vision loss following prone surgery is most commonly attributed to direct pressure on the eye but can also be caused by central retinal artery occlusion (CRAO) in the absence of pressure on the eye. Central retinal artery occlusion has not been previously described following prone transcranial surgery for craniosynostosis. We present two cases of monocular CRAO following prone calvarial expansion. A multidisciplinary root cause analysis suggested that raised intracranial pressure and intraoperative tranexamic acid may have been risk factors for the development of CRAO in these cases as no conventional risk factors for CRAO following prone surgery were present. Because of this, we retrospectively reviewed all prone transcranial procedures performed at the Oxford Craniofacial Unit for the presence of raised intracranial pressure and intraoperative tranexamic acid use. A total of 662 prone procedures have been performed between 1994 and March, 2019. Tranexamic acid has been used routinely in all transcranial procedures since 2012 and in the last 311 consecutive prone cases. Fifty-one (7.7%) prone procedures were performed for raised intracranial pressure, and tranexamic acid was used in the 33 most recent of these. Since the implementation of standard intraoperative administration of tranexamic acid there have been 2 cases of CRAO following prone surgery. The overall incidence of CRAO was 0.3% but was 6% in the context of raised intracranial pressure and tranexamic acid use. Prone positioning raised intracranial pressure and tranexamic acid use together may represent a potent combination of risk factors for CRAO.

Negative Thermal Expansion of Ni-Doped MnCoGe at Room-Temperature Magnetic Tuning.

Compounds that exhibit the unique behavior of negative thermal expansion (NTE)-the physical property of contraction of the lattice parameters on warming-can be applied widely in modern technologies. Consequently, the search for and design of an NTE material with operational and controllable qualities at room temperature are important topics in both physics and materials science. In this work, we demonstrate a new route to achieve magnetic manipulation of a giant NTE in (Mn0.95Ni0.05)CoGe via strong magnetostructural (MS) coupling around room temperature (∼275 to ∼345 K). The MS coupling is realized through the weak bonding between the nonmagnetic CoGe-network and the magnetic Mn-sublattice. Application of a magnetic field changes the NTE in (Mn0.95Ni0.05)CoGe significantly: in particular, a change of Δ L/ L along the a axis of absolute value 15290(60) × 10-6-equivalent to a -31% reduction in NTE-is obtained at 295 K in response to a magnetic field of 8 T.

Opioid suppression of conditioned anticipatory brain responses to breathlessness.

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.

Influence of age on the prevalence and components of the metabolic syndrome and the association with cardiovascular disease.

OBJECTIVE: The significance of the metabolic syndrome (MS) is debated. We investigated whether MS component (by ATPIII and IDF definitions) clustering and any association between MS and prevalent cardiovascular disease (CVD) varied with age. RESEARCH DESIGN AND METHODS: In all, 1429 adults (≥25 years) from randomly selected households in rural Victoria, Australia, were assessed for components of MS and prevalent CVD. The expected prevalence of MS was calculated following a simple probabilistic model using the prevalence of each MS component. RESULTS: The observed prevalence of MS was greater than expected: 27.0% vs 21.2% (ATPIII) and 36.0% vs 30.1% (IDF; p<0.0001), based on the prevalence of individual components. There was significant clustering of 4 and 5 MS components in participants <65 years (p<0.0001). CVD was more prevalent in MS participants, 13.5% (IDF), 14.5% (ATPIII) versus 5.3% (no MS) p<0.0001. The OR for CVD in MS participants was greatest in those <45 years OR (95% CI): IDF 17.5 (1.8 to 172); ATPIII 24.3(2.4 to 241), p<0.001 for both, and was not significant in those >65 years. The prevalence of MS (ATPIII) with normal waist circumference (WC) was less than expected (4.8% vs 7.9%, p<0.002). Low levels of high-density lipoprotein and high triglyceride were less common in older MS participants. CONCLUSIONS: ATPIII MS is rare among those with a normal WC. MS components cluster most markedly among those aged <65 years, who also experience substantially greater rates of CVD. Younger patients with MS may warrant more aggressive CVD preventative treatment than suggested by the summation of their individual risk factors.

ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration.

Age is a major risk factor in age-related macular degeneration (AMD), but the underlying cause is unknown. We find increased Rho-associated kinase (ROCK) signaling and M2 characteristics in eyes of aged mice, revealing immune changes in aging. ROCK isoforms determine macrophage polarization into M1 and M2 subtypes. M2-like macrophages accumulated in AMD, but not in normal eyes, suggesting that these macrophages may be linked to macular degeneration. M2 macrophages injected into the mouse eye exacerbated choroidal neovascular lesions, while M1 macrophages ameliorated them, supporting a causal role for macrophage subtypes in AMD. Selective ROCK2 inhibition with a small molecule decreased M2-like macrophages and choroidal neovascularization. ROCK2 inhibition upregulated M1 markers without affecting macrophage recruitment, underlining the plasticity of these macrophages. These results reveal age-induced innate immune imbalance as underlying AMD pathogenesis. Targeting macrophage plasticity opens up new possibilities for more effective AMD treatment.

Motor imagery during movement activates the brain more than movement alone after stroke: a pilot study.

OBJECTIVE: To examine the neural correlates of motor imagery performed in conjunction with movement of the paretic arm after stroke. DESIGN: Cross-sectional, cohort study. SUBJECTS: Seven individuals in the chronic phase of stroke recovery (median (range): age: 58 years (37-73); time post-stroke: 9 months (4-42); upper extremity Fugl-Meyer motor score: 48 (36-64)). METHODS: Participants actively moved the paretic/right arm under two conditions while undergoing functional magnetic resonance imaging. In the motor condition, pronation/supination movements were made in response to a visual cue. In the motor + imagery condition, the same movements were performed in response to a visual cue but the participants were instructed to imagine opening and closing a doorknob during performance of the movement. RESULTS: For the motor condition, the anticipated motor network was activated and included left sensorimotor cortex and right cerebellum. For performance of the same movements during the motor + imagery condition, additional brain regions were significantly engaged including the left inferior parietal lobule and right dorsolateral prefrontal cortex. CONCLUSIONS: The addition of motor imagery to movement may provide a practical, accessible way to modulate activity in both the planning and execution components of the motor network after stroke.

A small-molecule inhibitor of enterocytic microsomal triglyceride transfer protein, SLx-4090: biochemical, pharmacodynamic, pharmacokinetic, and safety profile.

First-generation microsomal triglyceride transfer protein (MTP) inhibitors were designed to inhibit hepatic MTP and provide a novel treatment of dyslipidemia. Effective at lowering low-density lipoprotein-cholesterol (LDL-C), these inhibitors also elevate liver enzymes and induce hepatic steatosis in animals and humans. MTP is highly expressed in the enterocytes, lining the lumen of the jejunum, and is critical in the production of chylomicrons assembled from lipid/cholesterol and their transfer into systemic circulation. 6-(4'-Trifluoromethyl-6-methoxy-biphenyl-2-ylcarboxamido)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid phenyl ester (SLx-4090) (IC(50) value ∼8 nM) was designed to inhibit only MTP localized to enterocytes. In Caco-2 cells SLx-4090 inhibited apolipoprotein B (IC(50) value ∼9.6 nM) but not apolipoprotein A1 secretion. Administered orally to rats SLx-4090 reduced postprandial lipids by >50% with an ED(50) value ∼7 mg/kg. SLx-4090 was not detected in the systemic or portal vein serum of the animals (lower limit of quantitation ∼5 ng/ml) after single or multiple oral doses in fasted rodents. When coadministered with tyloxapol, SLx-4090 did not inhibit the secretion of hepatic triglycerides (TG), consistent with the absence of systemic exposure. Chronic treatment with SLx-4090 in mice maintained on a high-fat diet decreased LDL-C and TG and resulted in weight loss without the elevation of liver enzymes or an increase in hepatic fat. The compound did not result in toxicity when administered to rats for 90 days at a dose of 1000 mg/kg per day. These data support the concept that the inhibition of enterocytic MTP could serve as a useful strategy in the treatment of metabolic disorders.

Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series.

AIMS: Nodular regenerative hyperplasia (NRH) is a rarely identified liver disorder. It is characterized histologically by nodular hepatocyte regeneration without significant fibrosis, and clinically by portal hypertension and abnormal liver function tests (LFTs). Survival data in an unselected cohort after diagnosis of NRH have not been previously described. This study aims to identify a regional cohort with NRH, to determine survival after diagnosis and to assess the relative frequency of associated conditions. METHODS: Patients were identified retrospectively from liver biopsy reports within pathology databases, over a 13-year period from Glasgow, Scotland, UK. Case notes were retrieved, clinical information extracted and survival was determined. RESULTS: Forty-two patients were identified (19 males). Common presenting features were abnormal LFTs (predominantly cholestatic) (76%) and portal hypertension (9.5%). None had severe liver dysfunction (Child-Pugh score A: 81%, B: 19%, C: 0%). Varices were detected in 26%, and portal hypertension was detected in 31%. There were five (12%) variceal bleeds, one fatal. The patients were subdivided into four groups according to associated clinical conditions: malignancy (29%), prothrombotic (21%), rheumatological (24%) and idiopathic/other (26%). Mean survival was 8.1 years, although survival was highly variable, and was associated with age and associated disease, but not with portal hypertension or varices. No patients in the rheumatological subgroup died. CONCLUSION: NRH is usually associated with malignant, prothrombotic or rheumatological conditions. Survival is highly variable and related to age and the underlying disease process, but not to portal hypertension overall. Liver function remains well preserved.

Dynamics and supramolecular organization of the 1D spin transition polymeric chain compound [Fe(NH2trz)3](NO3)2. Muon spin relaxation.

The thermal spin transition that occurs in the polymeric chain compound [Fe(NH(2)trz)3](NO3)2 above room temperature has been investigated by zero-field muon spin relaxation (microSR) over the temperature range approximately 8-402 K. The depolarization curves are best described by a Lorentzian and a Gaussian line that represent fast and slow components, respectively. The spin transition is associated with a hysteresis loop of width DeltaT = 34 K (T1/2 upward arrow = 346 K and T1/2 downward arrow = 312 K) that has been delineated by the temperature variation of the initial asymmetry parameter, in good agreement with previously published magnetic measurements. Zero-field and applied field (20-2000 Oe) microSR measurements show the presence of diamagnetic muon species and paramagnetic muonium radical species (A = 753 +/- 77 MHz) over the entire temperature range. Fast dynamics have been revealed in the high-spin state of [Fe(NH(2)trz)3](NO3)2 with the presence of a Gaussian relaxation mode that is mostly due to the dipolar interaction with static nuclear moments. This situation, where the muonium radicals are totally decoupled and not able to sense paramagnetic fluctuations, implies that the high-spin dynamics fall outside the muon time scale. Insights to the origin of the cooperative effects associated with the spin transition of [Fe(NH(2)trz)3](NO3)2 through muon implantation are presented.

Modifications to advanced life support in renal failure.

The outcome of cardiopulmonary resuscitation (CPR) has been reported to be worse in patients with renal failure compared with those with normal renal function. It is likely that this increased mortality may be at least partly attributable to sub-optimal and highly variable treatment strategies used in cardiac arrest in patients with renal failure, but this issue has not previously been explored. Such patients undoubtedly pose a challenge to advanced life support (ALS) providers, and renal unit staff are not trained to provide specialist advice after a patient has sustained a cardiac arrest. There are few studies investigating the epidemiology, safety or outcome of cardiac arrest in patients with renal failure and there are no generally accepted resuscitation guidelines for this special circumstance. In this article we discuss the unique problems of resuscitating patients with renal failure and propose a suitable management strategy.

A sensitive, colorimetric, microtitre assay for alcohol dehydrogenase in standard endoscopic gastric biopsies.

Traditional assays of alcohol dehydrogenase (ADH) activity in gastric mucosa use spectrophotometry of tissue homogenates, which are based on the reduction of nicotinamide adenine dinucleotide (NAD). We describe a colorimetric method using the coupled reduction of N,N-dimethyl-4-nitrosoaniline. This method has increased sensitivity, allowing activity to readily be determined in standard endoscopic biopsies. Tissue homogenisation has been replaced by an incubation stage, and the method has been optimised for a 96-well plate reader, allowing rapid processing of large numbers of samples. We found that Helicobacter pylori infection and age have a significant effect on gastric ADH activity.

Plasma tissue inhibitor of metalloproteinase-1 levels are elevated in essential hypertension and related to left ventricular hypertrophy.

BACKGROUND: Essential hypertensive patients have an increased heart and arterial collagen concentration. Increased collagen synthesis can be assessed using procollagen III N peptide (PIIINP) and reduced collagen degradation measured using tissue inhibitor of metalloproteinase-1 (TIMP-1). METHODS: Plasma TIMP-1 and PIIINP levels were measured in 31 patients with essential hypertension and in 17 normotensive control subjects. The hypertensive patients were either treatment naive (n = 18) or had been without treatment for 1 month (n = 13). Both groups of patients were screened to exclude other fibrotic diseases. RESULTS: In the hypertensive patients, TIMP-1 levels were significantly (P < .0002) elevated (median 380 ng/ mL, range 160 to 1,560 ng/mL) compared with those of the normotensive control subjects (median 178 ng/mL, range 99 to 330 ng/mL). In hypertensive subjects who had never received antihypertensive therapy there were significant correlations between TIMP-1 and left ventricular posterior wall thickness in diastole (LVPWd) (r = 0.58) (P < .02) and left ventricular mass index (r = 0.58) (P < .02). There was no difference in PIIINP levels (mean +/- 2 SD) between the hypertensive (0.56 U/mL +/- 0.3) and normotensive groups (0.52 U/mL +/- 0.2). CONCLUSIONS: The increased tissue collagen III levels found in the heart and vessels of hypertensive patients is due to a reduction in collagen degradation because of high TIMP-1 levels, rather than an increase in synthesis of collagen type III. The tissue source of this TIMP-1 is unclear.