PROXIMO-DISTAL INCREASE OF ENZYMIC ACTIVITY IN THE DORSAL SPINAL TRACTS *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65919/1/j.1471-4159.1964.tb06151.x.pd

A COMPARATIVE MAPPING OF ENZYMES INVOLVED IN HEXOSEMONOPHOSPHATE SHUNT AND CITRIC ACID CYCLE IN THE BRAIN *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66082/1/j.1471-4159.1963.tb05042.x.pd

Rekindling the love of books - a pilot project exploring whether e-readers help people to read again after a stroke

Background E-readers may facilitate reading in aphasia through “aphasia-friendly” features such as altering text size and formatting (Worrall et al, 2005), and text-to-speech functions. However, no previous research has examined whether e-readers help people with aphasia to read. Aims This project explored: • whether people with aphasia can learn to use e-readers following a brief period of training • whether e-reader training improves reading comprehension • whether e-readers increase participation in and enjoyment of reading activities Method and procedures In phase one, available e-readers were compared using an expert evaluation against a set of criteria, to identify the model with optimum accessibility features and fewest potential barriers. The Kindle Keyboard 3G TM (Amazon) was selected for trialling in phase two. Four people with self-reported reading difficulties post-stroke participated in phase two. All had mild or mild-moderate aphasia. Four one-hour training sessions aimed to trial accessibility features, identify helpful features, and teach independent operation of these. A repeated measures design was used. Outcome measures assessed reading comprehension (Gray Oral Reading Tests, Bryant & Wiederholt, 2001) and confidence and emotions associated with reading (Reading Confidence and Emotions Questionnaire, Cocks et al., 2013). Matched texts were used to compare reading comprehension using printed texts and the e-reader. Usability evaluations explored independence in e-reader use and acceptability of the technology. Participation in reading activities and reading enjoyment were explored using qualitative exit interviews. Outcomes and results Participants’ reading comprehension on the Kindle, as measured by the GORT-4, did not improve following training and did not exceed comprehension of printed texts. However, reading confidence improved significantly for three of the participants (RCEQ: p<.05, p<.01 and p<.005). Analysis of exit interviews and usability evaluations indicates that three out of four participants preferred reading on the Kindle to printed texts. These participants read more frequently on the Kindle than they had done before the training, and the technology enabled them to access more challenging texts (e.g. novels). They appreciated different features of the Kindle. Two participants experienced difficulties operating the technology, one of whom would have benefited from a longer training period. Conclusions This pilot study suggests that a short block of e-reader training led to improvements in reading confidence, participation and enjoyment. E-readers were not shown to enhance reading comprehension. Larger-scale investigations are warranted to further investigate whether and how e-readers facilitate reading for people with aphasia

A QUANTITATIVE MAPPING OF ALKALINE PHOSPHATASE IN THE BRAIN OF THE RHESUS MONKEY *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65477/1/j.1471-4159.1966.tb07513.x.pd

A COMPARISON OF CHOLINESTERASE DISTRIBUTION IN THE CEREBELLUM OF SEVERAL SPECIES *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65142/1/j.1471-4159.1964.tb06717.x.pd

Thermal aspects of the smelting of iron ore in reconstructed South African Iron Age furnaces

SYNOPSIS A study was made of the smelting process in two experimental furnaces patterned on Iron Age furnaces excavated at Melville Koppies Nature Reserve, Johannesburg. In a number of smelting experiments, the influences of air supply, temperature, time of operation, fuel consumption, and other operational factors were investigated. Metallurgical and metallographic aspects of the furnace operation and smelting products are discussed, and the experiments are compared with similar research work conducted in Europe and Africa. SAMEVATTING Daar is &apos;n studie gemaak van die smeltproses in twee eksperimentele oonde wat gebou is volgens die patroon van oonde uit die Ystertydperk wat in die Natuurreservaat Melville Koppies, Johannesburg, uitgegrawe is. Die invloed van die lugtoevoer, temperatuur, bewerktyd, brandstofverbruik en ander bedryfsaspekte is in &apos;n aantal smelteksperimente ondersoek. Die metallurgiese en metallografiese aspekte van die oondbedryf en smeltprodukte word bespreek, en die eksperimente word vergelyk met deeglike navorsingswerk wat in Europa en Afrika gedoen is. Introduction The work described in this paper is a continuation of the archaeo-metallurgical investigations undertaken over the past ten years at the Archaeological Research Unit of the University of the Witwatersrandl-3. One of the previous studies on the correlation of slag characteristics and operational furnace temperatures had led to the conclusion that further work in this field, based on smelting experiments, would be desirable3. The present paper reports on such experiments, and on the results obtained by temperature measurements in furnaces and by the construction of temperature profiles. Since slag is the principal, and often the only, preserved material from ancient smelting sites, various methods were investigated by which information on the thermal characteristics of the smelting process could be obtained from samples of slag: chemical/physical analysis, phase-diagram studies, determination of liquidus temperatures, and metallographic examinations. In addition, the problem of preheating ofthe air injected into such furnaces was investigated

dfpk : An R-package for Bayesian dose-finding designs using Pharmacokinetics (PK) for phase I clinical trials

Background and objective Dose-finding, aiming at finding the maximum tolerated dose, and pharmacokinetics studies are the first in human studies in the development process of a new pharmacological treatment. In the literature, to date only few attempts have been made to combine pharmacokinetics and dose-finding and to our knowledge no software implementation is generally available. In previous papers, we proposed several Bayesian adaptive pharmacokinetics-based dose-finding designs in small populations. The objective of this work is to implement these dose-finding methods in an R package, called dfpk. Methods All methods were developed in a sequential Bayesian setting and Bayesian parameter estimation is carried out using the rstan package. All available pharmacokinetics and toxicity data are used to suggest the dose of the next cohort with a constraint regarding the probability of toxicity. Stopping rules are also considered for each method. The ggplot2 package is used to create summary plots of toxicities or concentration curves. Results For all implemented methods, dfpk provides a function (nextDose) to estimate the probability of efficacy and to suggest the dose to give to the next cohort, and a function to run trial simulations to design a trial (nsim). The sim.data function generates at each dose the toxicity value related to a pharmacokinetic measure of exposure, the AUC, with an underlying pharmacokinetic one compartmental model with linear absorption. It is included as an example since similar data-frames can be generated directly by the user and passed to nsim. Conclusion The developed user-friendly R package dfpk, available on the CRAN repository, supports the design of innovative dose-finding studies using PK information

Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project)

Objective: To determine whether a multicomponent intervention based on physical activity with technological support and nutritional counselling prevents mobility disability in older adults with physical frailty and sarcopenia. Design: Evaluator blinded, randomised controlled trial. Setting: 16 clinical sites across 11 European countries, January 2016 to 31 October 2019. Participants: 1519 community dwelling men and women aged 70 years or older with physical frailty and sarcopenia, operationalised as the co-occurrence of low functional status, defined as a short physical performance battery (SPPB) score of 3 to 9, low appendicular lean mass, and ability to independently walk 400 m. 760 participants were randomised to a multicomponent intervention and 759 received education on healthy ageing (controls). Interventions: The multicomponent intervention comprised moderate intensity physical activity twice weekly at a centre and up to four times weekly at home. Actimetry data were used to tailor the intervention. Participants also received personalised nutritional counselling. Control participants received education on healthy ageing once a month. Interventions and follow-up lasted for up to 36 months. Main outcome measures: The primary outcome was mobility disability (inability to independently walk 400 m in &lt;15 minutes). Persistent mobility disability (inability to walk 400 m on two consecutive occasions) and changes from baseline to 24 and 36 months in physical performance, muscle strength, and appendicular lean mass were analysed as pre-planned secondary outcomes. Primary comparisons were conducted in participants with baseline SPPB scores of 3-7 (n=1205). Those with SPPB scores of 8 or 9 (n=314) were analysed separately for exploratory purposes. Results: Mean age of the 1519 participants (1088 women) was 78.9 (standard deviation 5.8) years. The average follow-up was 26.4 (SD 9.5) months. Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005). Persistent mobility disability occurred in 127/605 (21.0%) participants assigned to the multicomponent intervention and 150/600 (25.0%) controls (0.79, 0.62 to 1.01; P=0.06). The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P&lt;0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P&lt;0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively. The decline in handgrip strength at 24 months was smaller in women assigned to the multicomponent intervention than to control (0.9 kg, 95% confidence interval 0.1 to 1.6 kg; P=0.028). Women in the multicomponent intervention arm lost 0.24 kg and 0.49 kg less appendicular lean mass than controls at 24 months (95% confidence interval 0.10 to 0.39 kg; P&lt;0.001) and 36 months (0.26 to 0.73 kg; P&lt;0.001), respectively. Serious adverse events occurred in 237/605 (39.2%) participants assigned to the multicomponent intervention and 216/600 (36.0%) controls (risk ratio 1.09, 95% confidence interval 0.94 to 1.26). In participants with SPPB scores of 8 or 9, mobility disability occurred in 46/155 (29.7%) in the multicomponent intervention and 38/159 (23.9%) controls (hazard ratio 1.25, 95% confidence interval 0.79 to 1.95; P=0.34). Conclusions: A multicomponent intervention was associated with a reduction in the incidence of mobility disability in older adults with physical frailty and sarcopenia and SPPB scores of 3-7. Physical frailty and sarcopenia may be targeted to preserve mobility in vulnerable older people

Longitudinal assessment of multiple sclerosis with the brain-age paradigm

OBJECTIVE: During the natural course of MS, the brain is exposed to ageing as well as disease effects. Brain ageing can be modelled statistically; the so-called 'brain-age' paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression and future outcomes. METHODS: In a longitudinal, multi-centre sample of 3,565 MRI scans, in 1,204 MS and clinically-isolated syndrome (CIS) patients and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured 'brain-predicted age' using T1-weighted MRI. We compared brain-PAD between MS and CIS patients and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored. RESULTS: MS patients had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years [95% CI 8.5, 12.1] versus 4.3 years [-2.1, 6.4], p < 0.001). The highest brain-PADs were in secondary-progressive MS (+19.4 years [17.1, 21.9]). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02 [1.01, 1.03], p < 0.001); though normalised brain volume was a stronger predictor. Greater annualised brain-PAD increases were associated with greater annualised EDSS score (r = 0.26, p < 0.001). INTERPRETATION: The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, 'brain-age' could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrolment. This article is protected by copyright. All rights reserved

Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis

The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to identify unique protein expression profiles and subtype-specific AS mechanisms. Left-ventricular endomyocardial biopsies were harvested from patients during transcatheter AVR, and inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification: 1) normal ejection fraction (EF)/high-gradient; 2) low EF/high-gradient; 3) low EF/low-gradient; and 4) paradoxical low-flow/low-gradient AS. Samples from non-failing donor hearts served as control. We analyzed 25 individual left-ventricular biopsies by data-independent acquisition mass spectrometry (DIA-MS), and 26 biopsies by histomorphology and cardiomyocytes by STimulated Emission Depletion (STED) superresolution microscopy. Notably, DIA-MS reliably detected 2273 proteins throughout each individual left-ventricular biopsy, of which 160 proteins showed significant abundance changes between AS-subtype and non-failing samples including the cardiac ryanodine receptor (RyR2). Hierarchical clustering segregated unique proteotypes that identified three hemodynamic AS-subtypes. Additionally, distinct proteotypes were linked with AS-subtype specific differences in cardiomyocyte hypertrophy. Furthermore, superresolution microscopy of immunolabeled biopsy sections showed subcellular RyR2-cluster fragmentation and disruption of the functionally important association with transverse tubules, which occurred specifically in patients with systolic dysfunction and may hence contribute to depressed left-ventricular function in AS