A systematic review of optical coherence tomography findings in adults with mild traumatic brain injury

Mild traumatic brain injury (mTBI) is common with many patients suffering disabling long-term sequelae, with visual symptoms frequently reported. There are no objective biomarkers of mTBI that are routinely used in clinical practice. Optical coherence tomography (OCT) has been used in mTBI research, as it enables visualisation of the neuroretina, allowing measurement of the retinal nerve fibre layer and ganglion cell layer. This systematic review aims to appraise the available literature and assess whether there are significant changes within the retinal nerve fibre layer and ganglion cell layer in subjects after mTBI. A systematic review was carried out in accordance with PRISMA guidelines and registered with PROSPERO (Number: CRD42022360498). Four databases were searched for relevant literature published from inception until 1 September 2022. Abstracts and full texts were screened by three independent reviewers. Initial screening of databases yielded 341 publications, of these, three fulfilled all the criteria for inclusion. All three studies showed thinning of the retinal nerve fibre layer, whereas there were no significant changes in the ganglion cell layer. This systematic review demonstrated that thinning of the retinal nerve fibre layer (but not of the ganglion cell layer) is associated with mTBI. It provides preliminary evidence for the use of the retinal nerve fibre layer as a potential biomarker of damage to the visual system in mTBI. Further prospective longitudinal studies ensuring uniform diagnosis and accurate phenotyping of mTBI are needed to understand the effects on the visual system and potential of OCT as a prognostic biomarker

Remote ischaemic conditioning for fatigue after stroke (RICFAST): a pilot randomised controlled trial.

Post stroke fatigue (PSF) affects 50 % of stroke survivors and can be disabling. Remote ischaemic conditioning (RIC) can preserve mitochondrial function, improve tissue perfusion and may mitigate PSF. This pilot randomised controlled trial evaluates the safety and feasibility of using RIC for PSF and evaluated measures of cellular bioenergetics. 24 people with debilitating PSF (7 item Fatigue Severity Score, FSS-7 > 4) were randomised (1:1) in this single-centre phase 2 study to RIC (blood pressure cuff inflation around the upper arm 200 mmHg for 5 min followed by 5 min of deflation), or sham (inflation pressure 20 mmHg), repeated 4 cycles, 3 times per week for 6 weeks. Primary outcomes were safety, acceptability and compliance. Secondary outcomes included FSS-7, 6 min walking test (6MWT), peak oxygen consumption (V̇O2peak), ventilatory anaerobic threshold (VAT), and muscle adenosine triphosphate (ATP) content measured using 31-phosphorous magnetic resonance spectroscopy of tibialis anterior. RIC was safe (no serious adverse events, adverse events mild) and adherence excellent (91 % sessions completed). Exploratory analysis revealed lower FSS-7 scores in the RIC group compared to sham at 6 weeks (between group difference FSS-7 -0.7, 95 %CI -2.0 to 0.6), 3 months (-1.0, 95 %CI -2.2 to 0.2) and 6 months (-0.9, 95 %CI -2.0 to 0.2). There were trends towards increased VAT, increased muscle ATP content and improved 6MWT in the RIC group. RIC is safe and acceptable for people with PSF and may result in clinically meaningful improvements in fatigue and muscle bioenergetics that require further investigation in larger studies

Remote ischaemic conditioning for fatigue after stroke (RICFAST): A pilot randomised controlled trial

Background Post stroke fatigue (PSF) affects 50 % of stroke survivors, and can be disabling. Remote ischaemic conditioning (RIC), can preserve mitochondrial function, improve tissue perfusion and may mitigate PSF. This pilot randomised controlled trial evaluates the safety and feasibility of using RIC for PSF and evaluated measures of cellular bioenergetics. Methods 24 people with debilitating PSF (7 item Fatigue Severity Score, FSS-7 > 4) were randomised (1:1) in this single-centre phase 2 study to RIC (blood pressure cuff inflation around the upper arm 200 mmHg for 5 min followed by 5 min of deflation), or sham (inflation pressure 20 mmHg), repeated 4 cycles, 3 times per week for 6 weeks. Primary outcomes were safety, acceptability, and compliance. Secondary outcomes included FSS-7, 6 min walking test (6MWT), peak oxygen consumption (V̇O2peak), ventilatory anaerobic threshold (VAT), and muscle adenosine triphosphate (ATP) content measured using 31-phosphorous magnetic resonance spectroscopy of tibialis anterior. Results RIC was safe (no serious adverse events, adverse events mild) and adherence excellent (91 % sessions completed). Exploratory analysis revealed lower FSS-7 scores in the RIC group compared to sham at 6 weeks (between group difference FSS-7 -0.7, 95 %CI -2.0 to 0.6), 3 months (-1.0, 95 %CI -2.2 to 0.2) and 6 months (-0.9, 95 %CI -2.0 to 0.2). There were trends towards increased VAT, increased muscle ATP content and improved 6MWT in the RIC group. Discussion RIC is safe and acceptable for people with PSF and may result in clinically meaningful improvements in fatigue and muscle bioenergetics that require further investigation in larger studies

The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS)

Background Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS. Main body The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications. Conclusion Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance

A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease

BACKGROUND: Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD. OBJECTIVES: To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement. METHODS: The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (31 P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment. RESULTS: UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31 P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups. CONCLUSIONS: High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Membrane potential and delta pH dependency of reverse electron transport-associated hydrogen peroxide production in brain and heart mitochondria

Succinate-driven reverse electron transport (RET) is one of the main sources of mitochondrial reactive oxygen species (mtROS) in ischemia-reperfusion injury. RET is dependent on mitochondrial membrane potential (Δψm) and transmembrane pH difference (ΔpH), components of the proton motive force (pmf); a decrease in Δψm and/or ΔpH inhibits RET. In this study we aimed to determine which component of the pmf displays the more dominant effect on RET-provoked ROS generation in isolated guinea pig brain and heart mitochondria respiring on succinate or α-glycerophosphate (α-GP). Δψm was detected via safranin fluorescence and a TPP+ electrode, the rate of H2O2 formation was measured by Amplex UltraRed, the intramitochondrial pH (pHin) was assessed via BCECF fluorescence. Ionophores were used to dissect the effects of the two components of pmf. The K+/H+ exchanger, nigericin lowered pHin and ΔpH, followed by a compensatory increase in Δψm that led to an augmented H2O2 production. Valinomycin, a K+ ionophore, at low [K+] increased ΔpH and pHin, decreased Δψm, which resulted in a decline in H2O2 formation. It was concluded that Δψm is dominant over ∆pH in modulating the succinate- and α-GP-evoked RET. The elevation of extramitochondrial pH was accompanied by an enhanced H2O2 release and a decreased ∆pH. This phenomenon reveals that from the pH component not ∆pH, but rather absolute value of pH has higher impact on the rate of mtROS formation. Minor decrease of Δψm might be applied as a therapeutic strategy to attenuate RET-driven ROS generation in ischemia-reperfusion injury

Medically assisted suicide in Italy: Recent legal developments on a controversial topic

: On 16th June 2022, the first case of lawful 'medically assisted suicide' took place on Italian soil. This event is a result of decade-long debates on informed consent and end-of-life care stimulated by medical jurisprudence. The authors first retrace the crucial moments that allowed this to happen and underline the problems still to be solved. The cases of DJ Fabo, Davide Trentin, Mario and Fabio Ridolfi are discussed, signalling how they influenced the path implemented by Italian jurisprudence