Infectious Agents as Potential Drivers of α-Synucleinopathies

α-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society     

Nicotine improves probabilistic reward learning in wildtype but not alpha7 nAChR null mutants,yet alpha7 nAChR agonists do not improve probabilistic learning

Cognitive impairments, e.g., reward learning, are present in various psychiatric disorders and warrant treatment. Improving reward-related learning could synergistically enhance psychosocial treatments and cognition generally. A critical first step is to understand the mechanisms underlying reward learning. The dopamine system has been implicated in such learning, but less known is how indirect activation of this system may affect reward learning. We determined the role of alpha7 nicotinic acetylcholine receptors (nAChR) on a probabilistic reversal learning task (PRLT) in mice that includes reward and punishment. Male alpha7 knockout (KO), heterozygous (HT), and wildtype (WT) littermate mice (n?=?84) were treated with vehicle, 0.03, or 0.3?mg/kg nicotine. Two cohorts of C57BL/6NJ male mice were treated with various alpha7 nAChR ligands, including the full agonists PNU282877 and AR-R-17779, the positive allosteric modulator CCMI, the partial agonist SSR180711, and the antagonist methyllycaconitine. All mice were then tested in the PRLT. Nicotine (0.3?mg/kg) significantly improved initial reward learning in alpha7 WT and HT mice but did not improve learning in KO mice, suggesting an involvement of the alpha7 nAChR in the pro-learning effects of nicotine. Neither alpha7 nAChR treatments (PNU282987, AR-R-17779, CCMI, SSR180711, nor methyllycaconitine) affected mouse PRLT performance however. Nicotine improved reward learning via a mechanism that may include alpha7 nAChRs. This improvement unlikely relied solely on alpha7 nAChRs however, since no alpha7 nAChR ligand improved reward learning in normal mice. Future assessments of the effects of other nAChR subtypes on reward learning are needed.     

Integrating functional and anatomical information to facilitate cardiac resynchronization therapy

Multiple imaging modalities are required in patients receiving cardiac resynchronization therapy. We have developed a strategy to integrate echocardiographic and angiographic information to facilitate left ventricle (LV) lead position. Full three-dimensional LV-volumes (3DLVV) and dyssynchrony maps were acquired before and after resynchronization. At the time of device implantation, 3D-rotational coronary venous angiography was performed. 3D-models of the veins were then integrated with the pre- and post-3DLVV. In the case displayed, prior to implantation, the lateral wall was delayed compared to the septum. The LV lead was positioned into the vein over the most delayed region, resulting in improved LV synchrony.     

Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: A randomized double‐blinded controlled trial

The healing process in diabetic foot ulcer (DFU) is hindered by factors such as chronic inflammation, defects in fibroblast function, poor angiogenesis, and lack of cell migration. Recombinant human epidermal growth factor (rhEGF) has been shown to enhance extracellular matrix formation, cellular proliferation, and angiogenesis. Therefore, intralesional application of rhEGF in DFU could accelerate wound healing. Our objective was to determine the efficacy and safety of rhEGF in patients with DFU. A randomized, double‐blinded, placebo‐controlled study was conducted comparing a thrice‐per‐week intralesional application of rhEGF (75 μg) or placebo in patients with DFU for 8 weeks. The number of completely healed ulcers, size, and wound bed characteristics were evaluated to determine the efficacy of rhEGF. Adverse events were recorded and analyzed to establish its safety. A total of 34 patients were recruited for the study. After three dropouts, we were able to follow and analyze 16 patients in the placebo group and 15 patients in the rhEGF study to the end of the trial. Baseline testing showed that both groups were similar. Compared to the placebo group, more ulcers achieved complete healing in the rhEGF group (rhEGF, n = 4; placebo, n = 0; p = 0.033); ulcers in the rhEGF group decreased in area size (12.5 cm2 [rhEGF] vs. 5.2 cm2 [placebo]; p = 0.049); and more epithelial islands in the wound bed were present (28% vs. 3%; p = 0.025). Mild transitory dizziness was the only side effect that was more frequently noted in the rhEGF group. Our results showed that in patients with DFU who received standard care, intralesional rhEGF application resulted in complete healing in more patients, promoted the epithelialization of the wound bed, and significantly reduced the area of the DFU treated. Therefore, rhEGF resulted in better outcomes for patients suffering from DFU.     

Hepatic artery stenosis after liver transplant, managed with percutaneous angioplasty and stent placement.

Hepatic artery stenosis is a recognized vascular complication of orthotopic liver transplant that carries significant morbidity and mortality. The authors present a case of hepatic artery stenosis in a 50-year-old female successfully treated with balloon angioplasty and stent. This case report highlights the importance of percutaneous intervention as a preferred treatment option in patients with hepatic artery stenosis post-orthotopic liver transplant.     

The Relationship Between Diabetes Attitudes and Treatment Among Free Clinic Patients and Volunteers

Free clinics provide free primary care to the under or uninsured and have been playing an important role in serving the socio-economically disadvantaged. Free clinic patients represent a group of people who experience significant barriers to receiving diabetes prevention and intervention. This study examined diabetes attitudes among free clinic patients and volunteers. English or Spanish speaking patients and volunteers (N = 384), aged 18 years or older completed a self-administered survey. Diabetic patients and volunteers shared similar levels of diabetes attitudes compared to non-diabetic patients. Among patients, ethnicity, education level, diabetes education, and family history affected diabetes attitudes. Among volunteers, diabetes education was an important factor associated with positive diabetes attitudes. Whether the volunteer is a healthcare professional or student was related only to one aspect of diabetes attitudes, seriousness of type 2 diabetes. The results, indicating free clinic diabetic patients and volunteers shared similar levels of diabetes attitudes, were positive for maintaining and developing diabetes education programs at a free clinic. Unfortunately, the average length of volunteering at this free clinic was short and student volunteers likely leave the clinic upon graduation. Future research should examine issues of volunteer retention in free clinics. Diabetes education for patients may need to be diversified according to ethnicity, family history of diabetes, and educational level. Finally, non-healthcare professional volunteers could potentially be involved in diabetes education at a free clinic.     

Evaluation of Mechanical and Electrical Performance of Aging Resistance ZTA Composites Reinforced with Graphene Oxide Consolidated by SPS

This paper presents a study of Al₂O₃–ZrO₂ (ZTA) nanocomposites with different contents of reduced graphene oxide (rGO). The influence of the rGO content on the physico-mechanical properties of the oxide composite was revealed. Graphene oxide was obtained using a modified Hummers method. Well-dispersed ZTA-GO nanopowders were produced using the colloidal processing method. Using spark plasma sintering technology (SPS), theoretically dense composites were obtained, which also reduced GO during SPS. The microstructure, phase composition, and physico-mechanical properties of the sintered composites were studied. The sintered ZTA composite with an in situ reduced graphene content of 0.28 wt.% after the characterization showed improved mechanical properties: bending strength was 876 ± 43 MPa, fracture toughness—6.8 ± 0.3 MPa·m^1/2 and hardness—17.6 ± 0.3 GPa. Microstructure studies showed a uniform zirconia distribution in the ZTA ceramics. The study of the electrical conductivity of reduced graphene oxide-containing composites showed electrical conductivity above the percolation threshold with a small content of graphene oxide (0.28 wt.%). This electrical conductivity makes it possible to produce sintered ceramics by electrical discharge machining (EDM), which significantly reduces the cost of manufacturing complex-shaped products. Besides improved mechanical properties and EDM machinability, 0.28 wt.% rGO composites demonstrated high resistance to hydrothermal degradation.     

Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease

The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved in the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, Parkinson's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based". There are five known muscarinic receptor subtypes (M(1) to M(5)). Due to their overlapping expression patterns and the lack of receptor subtype-specific ligands, the roles of the individual muscarinic receptors have long remained elusive. During the past decade, studies with knock-out mice lacking specific muscarinic receptor subtypes have greatly advanced our knowledge of the physiological roles of the M(1)-M(5) receptors. Recently, new ligands have been developed that can interact with allosteric sites on different muscarinic receptor subtypes, rather than the conventional (orthosteric) acetylcholine binding site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess the roles of M(1), M(4), and M(5) receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the CNS.