Phase Of Pd Research Articles

MODERN VIEW TO OPTIMIZATION OF DIAGNOSTICS OF PARKINSON'S DISEASE

Parkinsonism is one of the most significant problems of clinical neurology, both due to its high prevalence in the world's populations and due to the significant disability of patients. The work analyzes the diagnosis of Parkinson's disease (as well as other neurodegenerative diseases) at the prodromal stage. A review of methods for preclinical and early clinical diagnosis of PD shows that the study of prodromal markers and criteria for the premotor phase of PD will make it possible in the future to significantly change the course of the disease using neuroprotective therapy at the stage preceding the death of a significant number of dopaminergic neurons of the substantia nigra.

Palladium at high pressure and high temperature: A combined experimental and theoretical study

Palladium is one of the most important technological materials, yet its phase diagram remains poorly understood. At ambient conditions, its solid phase is face-centered cubic (fcc). However, another solid phase of Pd, body-centered cubic (bcc), was very recently predicted in two independent theoretical studies to occur at high pressures and temperatures. In this work, we report an experimental study on the room-temperature equation of state (EOS) of Pd to a pressure of 80 GPa, as well as a theoretical study on the phase diagram of Pd including both fcc-Pd and bcc-Pd. Our theoretical approach consists in ab initio quantum molecular dynamics (QMD) simulations based on the Z methodology which combines both direct Z method for the simulation of melting curves and inverse Z method for the calculation of solid–solid phase transition boundaries. We obtain the melting curves of both fcc-Pd and bcc-Pd and an equation for the fcc–bcc solid–solid phase transition boundary as well as the thermal EOS of Pd which is in agreement with experimental data and QMD simulations. We uncover the presence of another solid phase of Pd on its phase diagram, namely, random hexagonal close-packed (rhcp), and estimate the location of the rhcp-bcc solid–solid phase transition boundary and the rhcp–fcc–bcc triple point. We also discuss the topological similarity of the phase diagrams of palladium and silver, the neighbor of Pd in the periodic table. We argue that Pd is a reliable standard for shock-compression studies and present the analytic model of its principal Hugoniot in a wide pressure range.

(402) Peyronie's Disease Treatment- Active Vs. Stable Phase- Retrospective Review of Cases

Abstract Introduction Peyronie's disease (PD) may be treated with collagenase clostridium histolyticum (CCH) during the stable phase. However, the effectiveness and safety of this treatment during the active phase remain unclear. To address this, we investigated and compared the outcomes of patients receiving treatment in the active phase versus the stable phase of PD. Objective To assess the effectiveness and safety of CCH treatment in patients diagnosed with PD during the active phase. Methods A retrospective review was conducted on men who underwent at least one cycle of CCH injections for PD with a single fellowship-trained urologist between 2017 and 2023. Active PD was defined as occurring within one year from the onset of symptoms. The severity of penile curvature was measured at the point of maximal curvature and assessed at baseline and after each CCH cycle. In addition to the CCH treatment, patients were prescribed daily phosphodiesterase inhibitors (PDEi) and coenzyme-Q10 (CoQ-10). The treatment response was defined as any improvement in curvature from baseline to the final assessment. The characteristics and outcomes of patients were compared between those with active and stable PD. Results Of 107 patients who underwent CCH treatment, 75 were diagnosed with stable PD and 32 with active PD. There were no significant differences observed between the two groups in terms of age (58.1 vs. 57.9 years, p = 0.89), baseline curvature (58.4 vs. 60.5 degrees, p = 0.60), or the number of CCH cycles received (6.6 vs. 6.3 cycles, p = 0.57). Among the active PD patients, 26 (81.2%) experienced an improvement in curvature, which was comparable to the stable PD group (58 (77.3%), p = 0.85). There were no significant differences in the degree of curvature improvement (14.4 vs. 14.0 degrees, p = 0.91) or the percentage of improvement from baseline (22.67% vs. 24.05%, p = 0.86) between the active and stable PD patients. In the subset of patients who showed an improvement in curvature angle, there was no notable distinction in the percentage of improvement from baseline between the stable and active phases (37.4% vs 34.8%, p=0.63). Among the treated patients, we observed two cases of potential penile fractures in the stable phase. All adverse events were conservatively managed. Conclusions Patients treated with CCH during the active phase achieved comparable outcomes to those in the stable phase. There were no additional adverse events in the active phase treatment group. These data suggest that early active phase treatment yields similar effectiveness as treatment administered during the stable phase. Treatment during the active phase could be a disease modifier and may change the course of progression. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Endo, Roman Health.

Expanded Utilization of Intralesional Therapies for Treatment of Peyronie's Disease.

In this narrative review we explore additional indications for which intralesional collagenase Clostridium histolyticum (CCH) injection therapy may be used, in addition to those utilized in the IMPRESS trials. The goal is to provide updated assessment of available intralesional therapies and justify whether to expand clinical indications based on advancements over the last decade. Patients receiving CCH in the acute phase of PD have shown significant improvement in penile curvature - which may be even more significant than reported due to progressive curvature over the longitudinal course of injection therapy. Across studies, patients with ventral plaques achieved the greatest curvature improvement (~30°) compared to PD patients with dorsal or lateral plaques. Patients with curvature > 90° have been minimally documented. However, the concept of patients with higher degree of curvature achieving more significant degrees of improvement prevails across studies. Studies including PD patients with volume loss deformities or indentation(s) focus on curvature improvement and do not gauge improvement in these girth loss or indentation features specifically. PD patients with calcification may benefit from CCH, however, critical analysis of included study designs and results compared to placebo do not lend for strong support of CCH in PD at this time. Based on the most recent research, the use of CCH in the acute phase of PD and patients with ventral penile plaques may be effective and safe. The limited available research on the efficacy of CCH on calcified plaque(s) and curvature greater than 90° is promising, however, more research is needed to ensure safety and success in this patient cohort. Finally, the current literature continues to show the use of CCH is not effective in PD patients with volume loss, indentation, or hourglass deformity. When expanding the use of CCH to patients not originally included in the IMPRESS trials, providers must prioritize minimizing chances of potential injury to urethral tissue. Finally, further investigation is required to determine whether CCH has utility for curvature greater than 90° or calcified plaques, although the limited available literature is promising.

(227) Analysis of Gene Expression of Vitamin D in Rats in Experimental Model of Peyronie's Disease and Human Penile Tunica Albuginea

Abstract Introduction Peyronie's disease (PD) is a penile connective tissue disorder that results in an inflammatory process, fibrotic plaque in the tunica albuginea (TA) and penile curvature. The molecular changes of fibrotic plaque formation are complex and include different cellular/protein mechanisms. Vitamin D (vitD) is a steroid hormone that has unconventional pathways of action, and among its effects it has already been described that it plays a role in extracellular matrix remodeling, in the immune response and in fibrosis. The literature regarding the action of vitD in the male genital system is scarce, and the gene expression of its receptors has not yet been demonstrated in penile TA. Objective To identify the gene expression of the vitD receptor in penile TA of rats submitted to the experimental model of PD and human penile TA. Methods The experimental model in rats divided into 2 groups (case and control) described before by Cohen et al. Human penile TA was achieved from Peyronie´s surgery cases and cadaveric controls. The antibody anti vitD (VDR D-6: sc-13133, Santa Cruz Biotechnology®, CA, USA) was used. Immunolabeling was carried out using the avidin-biotin-peroxidase complex method, and 3,3′-diaminobenzidine as liquid chromogen. In each case, the immunolabeling was quantified by computer-assisted digital image analysis following the methodology described by Matos et al. PCR real-time analyses followed the MIQE guideline10. One of the fractions of the tissue samples of the TA was stored in RNAholder. The extraction of total RNA from the samples was carried out using the reagent TRIzol®. The reverse transcription was performed using the reverse transcriptase enzyme ImPromII™ to obtain complementary DNA (cDNA). Messenger RNA expression of vitD was obtained by RT-PCR. Quantitative RT-PCR was carried out using pair of oligonucleotides endogenous RPL13a (human samples) and GAPDH (rat samples), known commercially as forward and reverse primers. It was performed statistical analysis with SPSS® version 17.0 (SPSS® Inc; Illinois, USA). Values were expressed as a mean and standard error with a significance level of 95% (p ≤ 0.05). The tests applied were One-Way ANOVA and unpaired t-test with Welch's correction, confirming the similarity between the variances. Sensitivity and specificity analysis was calculated following the Youden index. Ethical approval local committee number 06/2016. Results The vitD mRNA amplifications demonstrated the presence of its receptors in the penile TA in both the control and the case groups, and the expression of the control group was statistically higher (p < 0,0001) when compared to the case group in rats. In human samples, mRNA amplifications demonstrated the presence of its receptors in the penile TA in both the control and the case groups, and the expression of the control group was statistically lower (p < 0,0001) when compared to the case group. Conclusions The presence of vitD receptors (genic and proteic expression) in penile TA of rats Peyronies´ models and human TA was demonstrated and allows future studies regarding its regulation and modulation according to the evolution and phase of PD and vitD serum levels. Disclosure No

(481) Experience with Plaque Excision and Dermal Grafting in the Surgical Treatment of Peyronie's Disease

Abstract Introduction Plaque incision and grafting (PIG) is indicated for men with complex or severe penile curvature, several surgical options to treat PD have been performed. Surgical treatment use graft, as these procedures aim to maintain penile length. Objective To assess outcomes following plaque excision and dermal grafting in the surgical treatment of Peyronie's disease. Methods A prospective study, was performed at Binh Dan Hospital (Ho Chi Minh City – VietNam), from 1/2016 – 12/2020. Surgical correction for curvature is indicated when the PD duration is >12 months, and when the stable phase of PD is >6 months, all case use plaque excision and dermal grafting technique. Results our study have 52 patients, - History illnes: 42.1% diabetes, 26.3% hypertension, 36.84% hyperlipid. - Age mean: 58.31 ± 8.5 years (min: 48 – max 72). - Chief complaine: penile deformities (36.8%), pain (31.6%), palpable lumps (26.3%). - 52.6% have psychological effects. - Fibrous plaque on corpus: Anterior (5.2%), Mid (47.37%), Posterior (47.37%). - Plaque size: 72.59 ± 75.78mm2 (15.51 mm2 – 207 mm2). + Primary outcome measures - Complications (follow one month): alter sensation (16.7%), edema (21.05%), infection (1.9%), pain (10.53%) - Penile straightening: 89%. - Penile length: no changes (82.7%), shorter (17.3%). + Secondary outcome measures - Recurrent curvature: 3 cases – 01 case need operation second time. - Post-operative erectile dysfunction: 7 cases (13.46%). - Patient satisfaction: 82.3% Conclusions Surgical correction of penile curvature is the mainstay for PD treatment. Dermal graft: effectiveness in terms of satisfaction, length change, straightening, economic efficiency and complications. Suitable for patients with underlying medical conditions. Adequate preoperative patient counseling. Disclosure No

Fine-tuning of Pd–CeO2/rGO nanocomposite: A facile synergetic strategy for effective electrochemical detection of dopamine in pharmaceutical and biological samples

A facile, sensitive, and rapid electrochemical sensor based on reduced graphene oxide (rGO) supported palladium–cerium oxide nanocomposite on the surface of a glassy carbon electrode (Pd–CeO2/rGO/GCE) was prepared by a two-step process. The Pd–CeO2/rGO nanocomposite was synthesized by the polyol method, and the as-synthesized nanocomposite was then drop-cast onto the surface of the electrode; Pd–CeO2/rGO/GCE. The microstructural and morphological properties of the as-prepared electrocatalysts were investigated using powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), and electron microscopy techniques. These results show that rGO sheets are embellished with a face-centred cubic phase of Pd and a cubic fluorite structure of CeO2, resulting in an electrode material with a well-connected conducting network. The synergy of Pd–CeO2 composite with the support of rGO results in a significant increase in the electrocatalytic activity and active surface area of the electrode, which enables the excellent detection of dopamine (DA) with remaining paracetamol (PC), and tyrosine (TY). The optimized electrode demonstrated a good linear range of 5–240 µM, a low limit of detection (LOD) of 0.69 µM, and a sensitivity of 0.894 µM−1 cm−2. Additionally, the selectivity of the sensor was also successfully accomplished in the presence of several interfering substances. Some inherent properties of the produced sensor, such as reproducibility and stability, were also investigated. The developed sensor was also effectively used for DA sensing in human serum samples and pharmaceutical drug injection samples with satisfactory recoveries.

Aging of the Peritoneal Dialysis Membrane.

Long-term peritoneal dialysis as currently performed, causes structural and functional alterations of the peritoneal dialysis membrane. This decay is brought about by the continuous exposure to commercially available glucose-based dialysis solutions. This review summarizes our knowledge on the peritoneum in the initial phase of PD, during the first 2 years and the alterations in function and morphology in long-term PD patients. The pseudohypoxia hypothesis is discussed and how this glucose-induced condition can be used to explain all peritoneal alterations in long-term PD patients. Special attention is paid to the upregulation of hypoxia inducing factor-1 and the subsequent stimulation of the genes coding for glucose transporter-1 (GLUT-1) and the growth factors transforming growth factor-β (TGFβ), vascular endothelial growth factor (VEGF), plasminogen growth factor activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF). It is argued that increased pseudohypoxia-induced expression of GLUT-1 in interstitial fibroblasts is the key factor in a vicious circle that augments ultrafiltration failure. The practical use of the protein transcripts of the upregulated growth factors in peritoneal dialysis effluent is considered. The available and developing options for prevention and treatment are examined. It is concluded that low glucose degradation products/neutral pH, bicarbonate buffered solutions with a combination of various osmotic agents all in low concentration, are currently the best achievable options, while other accompanying measures like the use of RAAS inhibitors and tamoxifen may be valuable. Emerging developments include the addition of alanyl glutamine to the dialysis solution and perhaps the use of nicotinamide mononucleotide, available as nutritional supplement.

Palladium selenide as cathode for dye-sensitized solar cell: Effect of palladium content

This work is concerned with the preparation of PalladiumSelenide (PdSe) via a simple technique that is dip coating based multilayer deposition technique as cathode for dye-sensitized solar cell (DSSC). The influence of Pd content at the fixed content of Se on the performance of the device has been investigated. The XRD analysis reveals that the dominant phase of Pd and minor phase of Se exist in the sample. The photovoltaic measurement results reveals that the DSSC based PdSe CE demonstrates comparable power conversion efficiency (η) compared with that of the Pt based device. The highest η of the device utilizing PdSe cathode with the Se:Pd ratio of 1:6 was 3.14 %, while that of the device with Pt cathode was 4.83%. The PdSe CE based device with the ratio of 1:6 owns the highest η due to the highest IPCE in the visible region. In conclusion, the performance of the device is found to be significantly affected by Pd content.

Regulation of the surface micro-structure and crystal phase of Pd2B mesoporous nanoparticles for enhanced hydrogen evolution electrocatalysis

Polyethylenimine-modified Pd2B nanoparticles were fabricated and demonstrated improved electrocatalytic performance for hydrogen evolution.

Separation of Pt(IV), Pd(II), and Rh(III) from Chloride Solutions by Multistage Extraction Using Nitrogen-Containing Extractants

This article demonstrates possible separation of Pd(II), Pt(IV), and Rh(III) ions from chloride solutions by solvent extraction in rotating coiled columns (RCC). The most common reagents used for extraction of platinum metals were selected as extractants: trioctylamine (TOA), methyltrialkylammonium chloride (MTAA), tributyl phosphate (TBP), and relatively new reagent—N,N,N',N'-tetra-n-octyldiglycolamide (TODGA). The completeness of extraction of platinum metals from individual and mixed hydrochloric acid and chloride solutions has been analyzed as a function of the essence and concentration of extractant, acidity of the analyzed solutions, and other factors. Optimum conditions of quantitative extraction of the metals from model hydrochloric acid and chloride solutions into the extractant phase have been determined, including subsequent selective separation at the re-extraction stage. A flowchart has been proposed for multistage extraction of Pd(II), Pt(IV), and Rh(III) using 0.05 M MTAA solution in toluene as a stationary phase in RCC. The flowchart includes extraction of Pd(II) and Pt(IV) ions from the solution (0.1 M HCl + 30 g/L Cl–) into the organic phase upon simultaneous separation of Rh(III) remaining in the aqueous phase and consecutive re-extraction of Pd(II) and Pt(IV) from the organic phase using 0.01 M solution of thiourea in 0.1 M HCl and 1 M solution of thiourea in 0.5 M HCl, respectively. The flowchart has been verified for separation of platinum metals in the production process of preset composition. The degree of metal extraction after processing by 0.05 M solution of MTAA in in toluene and consecutive re-extraction by solutions of thiourea is 99.5% for rhodium(III), 99.9% for palladium(II), and 97.4% for platinum(IV). The extracted aqueous phases of rhodium and platinum after output from the column did not contain impurities of other platinum metals. In the aqueous fraction of palladium, the platinum content was 0.5%.

The role of alpha-synuclein as ferrireductase in neurodegeneration associated with Parkinson's disease.

Misfolding of the protein α-synuclein contributes to the formation of the intracellular inclusion, Lewy bodies. Although these structures are not exclusive to Parkinson's disease, nevertheless, their presence in the substantia nigra is mandatory for the pathological diagnosis of the disorder. Therefore, there must be a focus on the pathological mechanisms responsible for Lewy body generation. Recent studies have suggested that α-synuclein has the potential to operate as the enzyme ferrireductase. Perhaps in the early diseased state, overexpression or mutation of alpha-synuclein/ferrireductase invokes the dyshomeostasis of iron (III)/(II) only, while in advanced stages, accumulation of iron in particular areas of the brain follows. Furthermore, the loss of an important iron chelator, neuromelanin (due to dopaminergic neuronal death), may then result in the release and increase in unbound free iron. Iron could generate reactive oxygen species, which could instigate a torrent of cellular deleterious processes. In addition, loss of energy supply may contribute to the alteration in activity of enzymes involved in the mitochondrial respiratory chain and would, therefore, confer a vulnerability to the dopaminergic neurons in the substantia nigra. Therefore, the ferrireductase alpha-synuclein may hold the key for major pathology of Parkinson's disease. In conclusion, we hypothesize that environmentally or genetically overexpressed and/or mutated α-synuclein/ferrireductase causes iron dyshomeostasis without increase of free iron concentration in the early phases of PD, while increased iron concentration accompanied by iron dyshomeostasis is a marker for progressed PD stages. It is essential to elucidate these degenerative mechanisms, so as to provide effective therapeutic treatment to halt or delay the progression of the illness already in the early phase of PD. The development of iron chelators seems to be a reasonable approach.

New awakenings: current understanding of sleep dysfunction and its treatment in Parkinson\u2019s disease

The non-motor features of Parkinson’s disease (PD) are increasingly being recognised. This review deals with the spectrum of sleep disorders associated with PD, which have a multifactorial aetiology and can significantly have an impact on the quality of life of patients and their carers. Some sleep disorders represent a prodromal phase of PD, with REM sleep behaviour disorder (RBD) being of particular interest in this regard, whereas others become more common as the disease advances. Understanding the pathophysiology of these sleep disturbances will hopefully lead to new treatment opportunities in the future. The recent discovery of the glymphatic system for removal of waste products from the brain has also raised the possibility that sleep disruption may cause or accelerate the underlying disease process.

Catalytic CO Methanation over Mesoporous ZSM5 with Different Metal Promoters

The carbon monoxide methanation has possessed huge potential as an effective method to produce synthetic natural gas (SNG). The basic requirements such as high catalytic activity at low temperatures (<500 °C) and high stability throughout all temperatures is needed for an ideal methanation catalysts. The ultimate goal of the study is to examine the influential of different metal promoters towards catalytic properties and catalytic CO methanation performance. A series of metal promoters (Rh, Co, Pd and Zn) mesoporous ZSM5 were synthesized using an incipient-wetness impregnation method and evaluated for catalytic CO methanation. XRD analysis showed that only metal oxides and no metallic phase of Rh, Co, Pd, and Zn were observed. The nitrogen physisorption analysis showed that mZSM5 possessed high surface area and micro-mesoporosity with intra- and interparticle pores. FESEM analysis illustrated that mZSM5 had typical coffin-type morphology and Rh metal dispersed on the surface of the support was confirmed by EDX analysis. Moreover, Rh (CO conversion = 95%, CH4 yield = 82%) and Co (CO conversion = 91%, CH4 yield = 71%) promoters showed significant improvement in CO methanation. On the other hand, Pd (CO conversion = 18%, CH4 yield = 12%) and Zn (CO conversion = 10%, CH4 yield = 9%) promoters had only low benefit to the CO methanation. This study affirmed that the catalytic activity of CO methanation was influenced by the variation in the type of metal loading due to different nature of metallic phases and their synergistic interaction with the supporting material.

Constipation, deficit in colon contractions and alpha-synuclein inclusions within the colon precede motor abnormalities and neurodegeneration in the central nervous system in a mouse model of alpha-synucleinopathy

BackgroundGastrointestinal dysfunction can affect Parkinson’s disease (PD) patients long before the onset of motor symptoms. However, little is known about the relationship between gastrointestinal abnormalities and the development of PD. Contrary to other animal models, the human A53T alpha-synuclein (αS) transgenic mice, Line G2–3, develops αS-driven neurological and motor impairments after 9 months of age, displaying a long presymptomatic phase free of central nervous system (CNS) dysfunction.MethodsTo determine whether this line can be suitable to study constipation as it occurs in prodromal PD, gastrointestinal functionality was assessed in young mice through a multidisciplinary approach, based on behavioral and biochemical analysis combined with electrophysiological recordings of mouse intestinal preparations.ResultsWe found that the A53T αS mice display remarkable signs of gastrointestinal dysfunction that precede motor abnormalities and αS pathology in the CNS by at least 6 months. Young αS mice show a drastic delay in food transit along the gastrointestinal tract, of almost 2 h in 3 months old mice that increased to more than 3 h at 6 months. Such impairment was associated with abnormal formation of stools that resulted in less abundant but longer pellets excreted, suggesting a deficit in the intestinal peristalsis. In agreement with this, electrically evoked contractions of the colon, but not of the ileum, showed a reduced motor response in both longitudinal and circular muscle layers in αS mice already at 3 months of age, that was mainly due to an impaired cholinergic transmission of the underlying enteric nervous system. Interestingly, the presence of insoluble and aggregated αS was found in enteric neurons in both myenteric and submucosal plexi only in the colon of 3 months old αS mice, but not in the small intestine, and exacerbated with age, mimicking the increase in transit delay and the contraction deficit showed by behavioral and electrical recordings data.ConclusionsGastrointestinal dysfunction in A53T αS mice represents an early sign of αS-driven pathology without concomitant CNS involvement. We believe that this model can be very useful to study disease-modifying strategies that could extend the prodromal phase of PD and halt αS pathology from reaching the brain.

H2 gas sensor based on PdOx-doped In2O3 nanoparticles synthesized by flame spray pyrolysis

In this work, 0–1.0 wt% PdOx-doped In2O3 nanoparticles were successfully synthesized by flame spray pyrolysis (FSP) in a single step for the first time and investigated for gas-sensing applications. The sensing films were fabricated by spin coating and tested towards hydrogen (H2) at various temperatures ranging from 150 to 350 °C in dry air. The powder and sensing film properties were analyzed by X-ray analyses, nitrogen adsorption and electron microscopy. The spherical and cubic In2O3 nanoparticles with diameters ranging from 2 to 20 nm were observed with no apparent secondary phase of Pd or PdOx. Detailed analyses suggested that Pd species might be in the form of PdOx crystallites embedded in and on grain boundaries of In2O3 nanoparticles. From gas-sensing measurements, hydrogen-sensing characteristics of In2O3 nanoparticles were significantly improved by PdOx doping particularly at the optimal Pd content of 0.50 wt%. The optimal PdOx-doped In2O3 sensing film showed a high response of 3526 towards 10,000 ppm H2 at the optimal working temperature of 250 °C. In addition, PdOx doped In2O3 sensing films displayed good stability and high H2 selectivity against various toxic and flammable gases including H2S, NO2, C2H4O, C2H4, C2H5OH and C2H2.

Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models

BackgroundPeyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option. ObjectiveTo identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD. Design, setting, and participantsWe have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD. Results and limitationsThe new assay was able to detect transforming growth factor-β1–induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy. ConclusionsThis is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models. Patient summaryThis report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.

N-acetylcysteine protects against motor, optomotor and morphological deficits induced by 6-OHDA in zebrafish larvae.

BackgroundParkinson’s disease (PD) is the second most common neurodegenerative disorder. In addition to its highly debilitating motor symptoms, non-motor symptoms may precede their motor counterparts by many years, which may characterize a prodromal phase of PD. A potential pharmacological strategy is to introduce neuroprotective agents at an earlier stage in order to prevent further neuronal death. N-acetylcysteine (NAC) has been used against paracetamol overdose hepatotoxicity by restoring hepatic concentrations of glutathione (GSH), and as a mucolytic in chronic obstructive pulmonary disease by reducing disulfide bonds in mucoproteins. It has been shown to be safe for humans at high doses. More recently, several studies have evidenced that NAC has a multifaceted mechanism of action, presenting indirect antioxidant effect by acting as a GSH precursor, besides its anti-inflammatory and neurotrophic effects. Moreover, NAC modulates glutamate release through activation of the cystine-glutamate antiporter in extra-synaptic astrocytes. Its therapeutic benefits have been demonstrated in clinical trials for several neuropsychiatric conditions but has not been tested in PD models yet.MethodsIn this study, we evaluated the potential of NAC to prevent the damage induced by 6-hydroxydopamine (6-OHDA) on motor, optomotor and morphological parameters in a PD model in larval zebrafish.ResultsNAC was able to prevent the motor deficits (total distance, mean speed, maximum acceleration, absolute turn angle and immobility time), optomotor response impairment and morphological alterations (total length and head length) caused by exposure to 6-OHDA, which reinforce and broaden the relevance of its neuroprotective effects.DiscussionNAC acts in different targets relevant to PD pathophysiology. Further studies and clinical trials are needed to assess this agent as a candidate for prevention and adjunctive treatment of PD.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder

BackgroundThe majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. MethodsWe studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. ResultsRegions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = −0.00026, 95% confidence interval [−0.00050 to −0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. ConclusionThalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Hydrogen absorption of Pd/ZrO2 composites prepared from Zr65Pd35 and Zr60Pd35Pt5 amorphous alloys

Metal-dispersed composites were derived from amorphous Zr65Pd35 and Zr65Pd30Pt5 alloys and their hydrogen absorption behavior was studied. X-ray diffractograms and scanning electron micrographs indicated that mixtures containing ZrO2, the metallic phase of Pd, and PdO were formed for both amorphous alloys heat-treated in air. In the composites, micron-sized Pd-based metal precipitates were embedded in a ZrO2 matrix after heat treatment at 800 °C in air. The hydrogen temperature-programmed reduction was applied to study the reactivity of hydrogen gas with the oxidized Zr65Pd35 and Zr65Pd30Pt5 materials. Rapid hydrogen absorption and release were observed on the composite derived from the amorphous alloy below 100 °C. The hydrogen pressure–concentration isotherm showed that the absorbed amount of hydrogen in materials depended on the formation of the Pd or Pt-doped Pd phase and its large interface area to the matrix in the nanocomposites. The results indicate the importance of the composite structure for the fabrication of a new type of hydrogen storage material prepared from amorphous alloys.