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.

Influence of phosphate chelators on white efflorescence formation in dry fermented sausages with co-extruded alginate casings.

The aim of the study was to investigate the effect of different condensed phosphates on the white efflorescence formation on dry fermented sausages with calcium alginate casings. The efflorescence formation is induced by the complexation of the divalent cations magnesium and calcium with lactate on the surface of the product. Phosphates are known to complex divalent cations like magnesium and calcium, which are responsible for the efflorescence formation with lactate. To treat the surface of the raw fermented sausages a mixture of di- and polyphosphates and a polyphosphate were used. The sausages were dipped in 5% solutions of the phosphates. The mixture of di- and polyphosphate showed the best results in reducing the white efflorescence formation, the amount of efflorescences on the surface was 18.12% after 8 weeks of storage. The diffusion of magnesium was significantly reduced by ~40% after 8 weeks of storage compared to the control for both phosphates. However, the crystals formed during storage had a different structure and size compared to the control. Isothermal titration calorimetry measurements showed that the divalent calcium ions and the polyphosphates from aggregates caused the crystal formation on the surface, whereas this effect was not seen in combination with magnesium. The surface treatment with the phosphates did not inhibit the white efflorescence formation. However, the extent was reduced but different kind of crystals were formed on the surface during the storage.

Paediatric case of prolonged COVID-19 manifesting as PMIS-TS and atypical Kawasaki.

The COVID-19 pandemic has created an unprecedented disease burden worldwide, affecting patients of all ages. Recently, there has been a rise in a new inflammatory condition termed paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PMIS-TS). We are yet to understand significant risk factors, disease progression and prognosis in children affected. We describe a case of a 9-year-old boy who tested positive concurrently for the SARS-CoV-2 virus 4 weeks apart. He presented with a 2-day history of fever, abdominal pain, headache and diarrhoea. Initial investigations supported PMIS-TS and he went on to develop atypical Kawasaki disease. With no results to differentiate between his positive results, we question whether he remained positive throughout or recovered with reactivation of the virus. There are reports of reactivation in adults but none in children. There are also no reports of children remaining positive for such a prolonged period, which raises public health concerns.

Ursodeoxycholic acid as a novel disease-modifying treatment for Parkinson's disease: protocol for a two-centre, randomised, double-blind, placebo-controlled trial, The 'UP' study.

INTRODUCTION: There are no disease-modifying treatments for Parkinson's disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of UDCA, apply a novel motion sensor-based approach to quantify disease progression objectively, and estimate the mean effect size and its variance on the change in motor severity. METHODS AND ANALYSIS: This is a phase II, two-centre, double-blind, randomised, placebo-controlled trial of UDCA at a dose of 30 mg/kg in 30 participants with early PD. Treatment duration is 48 weeks, followed by an 8-week washout phase. Randomisation is 2:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48 and 56. The primary outcome is safety and tolerability. Secondary outcomes will compare the change between baseline and week 48 using the following three approaches: the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part 3 in the practically defined 'OFF' medication state; confirmation of target engagement, applying 31Phosphorus MR Spectroscopy to assess the levels of ATP and relevant metabolites in the brain; and objective quantification of motor impairment, using a validated, motion sensor-based approach. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups. For each secondary outcome, the change from baseline will be summarised within treatment groups using summary statistics and appropriate statistical tests assessing for significant differences. All outcomes will use an intention-to-treat analysis population. ETHICS AND DISSEMINATION: This trial has been approved by the East of England - Cambridgeshire and Hertfordshire Research Ethics committee. Results will be disseminated in peer-reviewed journals, presentations at scientific meetings and to patients in a lay-summary format. TRIAL REGISTRATION NUMBER: NCT03840005.

Community Participation and Strengthening in a Reconstruction Context After a Natural Disaster.

During the first academic term of 2010, participatory action investigation processes were conducted in three communities affected by the 2007 high magnitude earthquake that occurred in the province of Chincha (Ica, Peru). In the process, members of the communities identified, as core problems, aspects related to the community coexistence, emphasizing the attention of the most vulnerable segments (children and adolescents) in the context of economic constraints and problems aggravated by the earthquake. Results include an analysis of the needs and reactions following the earthquake, the leadership and the power relations visible in the post disaster context and, finally, the community participation throughout the reconstruction process. This article also proposes some topics resulting from the analysis, aiming to contribute to interventions focused on community participation and strengthening of local resources in contexts of great vulnerability to natural disasters.

Epidermal growth factor rescues trophoblast apoptosis induced by reactive oxygen species.

Pre-eclampsia and intrauterine growth restriction are associated with increased apoptosis of placental villous trophoblast. This may result from placental hypoperfusion, leading to the generation of reactive oxygen species (ROS). Apoptosis can be induced in villous trophoblast following exposure to oxidative stress. Epidermal growth factor (EGF) reduces trophoblast apoptosis resulting from exposure to hypoxia. We hypothesised that exposure to hydrogen peroxide, a potent generator of ROS, would induce apoptosis in term placental villous explants and that this could be reduced by treatment with EGF. Placental explants were taken from normal term pregnancies and exposed to increasing doses of hydrogen peroxide (0-1,000 microM) or to a combination of increasing doses of hydrogen peroxide and EGF (0-100 ng/ml) for either 6 or 48 h. Apoptosis was assessed by TUNEL, proliferation by Ki-67 immunostaining, necrosis by lactate dehydrogenase activity and trophoblast differentiation by human chorionic gonadotrophin (hCG) secretion in conditioned culture media. Immunoperoxidase staining was performed to identify phosphorylated-AKT (p-AKT) and phosphorylated-PI3 kinase (p-PI3k). Exposure to 1,000 microM hydrogen peroxide for 48 h induced apoptosis in placental explants. The increase in TUNEL positive nuclei predominantly localised to syncytiotrophoblast. The amount of apoptosis was reduced to control levels by treatment with 10 and 100 ng/ml EGF. Proliferation of cytotrophoblasts within villous explants was significantly reduced following exposure to 1,000 microM hydrogen peroxide, this was restored to control levels by simultaneous treatment with 10 or 100 ng/ml EGF. Neither exposure to hydrogen peroxide or EGF altered the amount of necrosis. There was increased immunostaining for pPI3K following treatment with EGF. This study shows that apoptosis may be induced in villous trophoblast following exposure to ROS, and demonstrates the anti-apoptotic effect of EGF in trophoblast, the maintenance of which is essential for normal pregnancy.

Identification and validation of a novel cell-recognition site (KNEED) on the 8th type III domain of fibronectin.

Interactions between cell-surface integrins and extracellular matrix proteins underlie a versatile recognition system providing cells with anchorage, traction for migration or matrix remodeling, as well as signals for polarity, differentiation and growth. Short peptide sequences of fibronectin (FN), most notably RGD found on a loop in the 10th type III domain, are effective in promoting cell adhesion when immobilized to a biomaterial scaffold. Additional sequences (e.g. PHSRN) have been shown to act synergistically to enhance cell adhesion and other cellular processes. Using bioinformatics, we identified a candidate cell-binding peptide sequence, KNEED, located on the loop region of the 8th domain of FN that from in vitro studies appears to participate in cell attachment and spreading. Computational analysis revealed that KNEED exhibits both high solvent accessibility and sequence conservation values across FN sequences from seven species. We demonstrate the importance of the KNEED sequence using a solution-phase competitive inhibition assay utilizing soluble peptides. Results indicate that the presence of soluble KNEED peptides inhibits the attachment and spreading of 3T3 balb/c fibroblasts on FN-coated surfaces in a concentration-dependent manner. As more sequence and crystallographic data become available, computational approaches may aid in the identification of new targets for applications where biorecognition plays a key role.