Morpho-Functional Changes of Nigral Dopamine Neurons in an α-Synuclein Model of Parkinson's Disease

Background

The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α-syn–dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression.

Objectives

We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons.

Methods

We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA microdialysis measurements in a 12- to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca^+/+) and age-matched wild-type rats.

Results

Aged Snca^+/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/inactivating voltage-gated K⁺ channels and Ca²⁺- and voltage-activated large conductance K⁺ channels. These intrinsic currents underlie the repolarization/afterhyperpolarization phase of action potentials, thus affecting neuronal excitability.

Conclusions

Besides clarifying α-syn–induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

History-based preoperative evaluation of antibiotic-related allergies and design of an easy to use questionnaire

Die Anaesthesiologie - An unconfirmed history of antibiotic allergies may negatively influence prescribing patterns for preoperative antibiotic prophylaxis and increase rates of postoperative wound...     

Ehegattenvertretungsrecht in Angelegenheiten der Gesundheitssorge – praktische Umsetzung einer kontroversen Norm

Die Anaesthesiologie - Die Reichweite des seit dem 01.01.2023 geltenden Ehegattenvertretungsrechts wird derzeit in vielen Aspekten als unsicher, unscharf und nicht hinreichend bestimmt beschrieben....     

Dfree ultrasonic sensor in supporting quality of life and patient satisfaction with bladder dysfunction

Bladder dysfunction is physically and mentally stressful. Long-term catheterization is indicated as conservative therapy for chronic urinary retention as well as urinary incontinence; although an indwelling, transurethral catheter still represents a risk factor for ascending urinary tract infection and urosepsis. The primary outcome of this study was the impact of the DFree ultrasonic sensor on the subjectively perceived quality of life and satisfaction of patients. The secondary outcomes evaluated were usefulness, ease of use (user-friendliness), quality of care, and self-reported degree of autonomy. In this pilot study, 18 urological patients with various kind of bladder dysfunction were treated with an ultrasonic sensor for at least 12 h a day over a 3-month period. Assessment was conducted using the Kings Health Questionnaire (KHQ) and the German version of the Client Satisfaction Questionnaire (ZUF-8) (quantitative data) and guided interviews (qualitative data). Eighteen participants were included in this study. Participants highly appreciated the ideas and concepts of the device. A change in KHQ after treatment could not be statistically confirmed; however, the average value in ZUF-8 showed satisfaction with Dfree. However, no significant improvement was observed in the quantitative data. During the interviews at the end of the testing phase, the participants provided positive feedback with specific suggestions to improve device usability. The application was described as helpful and easy to use. Data triangulation illustrates that an improvement in technical implementation could increase device usefulness. This would imply higher patient satisfaction when using the device for bladder dysfunction.     

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Cerebral multifrequency MR elastography by remote excitation of intracranial shear waves

The aim of this study was to introduce remote wave excitation for high‐resolution cerebral multifrequency MR elastography (mMRE). mMRE of 25–45‐Hz drive frequencies by head rocker stimulation was compared with mMRE by remote wave excitation based on a thorax mat in 12 healthy volunteers. Maps of the magnitude |G*| and phase φ of the complex shear modulus were reconstructed using multifrequency dual elasto‐visco (MDEV) inversion. After the scan, the subjects and three operators assessed the comfort and convenience of cerebral mMRE using two methods of stimulating the brain. Images were acquired in a coronal view in order to identify anatomical regions along the spinothalamic pathway. In mMRE by remote actuation, all subjects and operators appreciated an increased comfort and simplified procedural set‐up. The resulting strain amplitudes in the brain were sufficiently large to analyze using MDEV inversion, and yielded high‐resolution viscoelasticity maps which revealed specific anatomical details of brain mechanical properties: |G*| was lowest in the pons (0.97 ± 0.08 kPa) and decreased within the corticospinal tract in the caudal–cranial direction from the crus cerebri (1.64 ± 0.26 kPa) to the capsula interna (1.29 ± 0.14 kPa). By avoiding onerous mechanical stimulation of the head, remote excitation of intracranial shear waves can be used to measure viscoelastic parameters of the brain with high spatial resolution. Therewith, the new mMRE method is suitable for neuroradiological examinations in the clinic. Copyright © 2015 John Wiley & Sons, Ltd.