Overlapping stimulation of subthalamic nucleus and dentato-rubro-thalamic tract in Parkinson's disease after deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces tremor, rigidity, and akinesia. According to the literature, the dentato-rubro-thalamic tract (DRTt) is verified target for DBS in essential tremor; however, its role in the treatment of Parkinson's disease is only vaguely described. The aim of our study was to identify the relationship between symptom alleviation in PD patients and the distance of the DBS electrode electric field (EF) to the DRTt. METHODS: A single-center retrospective analysis of patients (N = 30) with idiopathic Parkinson's disease (PD) who underwent DBS between November 2018 and January 2020 was performed. DRTt and STN were visualized using diffusion-weighted imaging (DWI) and tractography protocol of magnetic resonance (MR). The EF was calculated and compared with STN and course of DRTt. Evaluation of patients before and after surgery was performed with use of UPDRS-III scale. The association between distance from EF to DRTt and clinical outcomes was examined. To confirm the anatomical variation between DRTt and STN observed in tractography, white matter dissection was performed with the Klingler technique on ten human brains. RESULTS: Patients with EF overlapping STN and DRTt benefited from significant motor symptoms improvement. Anatomical findings confirmed the presence of population differences in variability of the DRTt course and were consistent with the DRTt visualized by MR. CONCLUSIONS: DRTt proximity to STN, the main target in PD DBS surgery, confirmed by DWI with tractography protocol of MR combined with proper predefined stimulation parameters may improve efficacy of DBS-STN.

Normalization of clonal diversity in gene therapy studies using shape constrained splines.

Viral vectors are used to insert genetic material into semirandom genomic positions of hematopoietic stem cells which, after reinfusion into patients, regenerate the entire hematopoietic system. Hematopoietic cells originating from genetically modified stem cells will harbor insertions in specific genomic positions called integration sites, which represent unique genetic marks of clonal identity. Therefore, the analysis of vector integration sites present in the genomic DNA of circulating cells allows to determine the number of clones in the blood ecosystem. Shannon diversity index is adopted to evaluate the heterogeneity of the transduced population of gene corrected cells. However, this measure can be affected by several technical variables such as the DNA amount used and the sequencing depth of the library analyzed and therefore the comparison across samples may be affected by these confounding factors. We developed an advanced spline-regression approach that leverages on confounding effects to provide a normalized entropy index. Our proposed method was first validated and compared with two state of the art approaches in a specifically designed in vitro assay. Subsequently our approach allowed to observe the expected impact of vector genotoxicity on entropy level decay in an in vivo model of hematopoietic stem cell gene therapy based on tumor prone mice.

The strategies for the modelling of the passive mass transport through porous membranes: Applicability to transdermal delivery systems.

The paper concerns the modelling of the passive solute transport through porous membranes. A general scheme for the mass transport has been developed upon the mixed diffusion-advection-reaction model. The passive advection has been introduced as a certain simplification of the Navier-Stokes problem, involving a pressure gradient-induced creeping flow of an incompressible Newtonian fluid. Nine scenarios for the drug transport process have been tested versus two experimental datasets acquired earlier (photoacoustic depth-profiling and contact angle surface wettability techniques) for the characterization of bulk and interfacial processes in a model pharmaceutical system: the synthetic dodecanol-collodion porous membrane in contact with a photodegradable pigment dithranol. The scenarios considered include three mass transport models (the diffusion-advection-reaction, diffusion-advection and diffusion-reaction models) under three distinct types of the lower (the donor/acceptor interface) boundary conditions: the Dirichlet-type instantaneous source, the Dirichlet-type interface relaxation, and the Neumann-type concentration gradient. The results obtained indicate a considerable agreement between the experimental data and predictions of the diffusion-reaction and the general models for long times, however, some deviations were exhibited at the initial stages of the permeation process. It is considered, that the discrepancies originate from a specific penetrant behaviour at the interfaces, which violates boundary transfer schemes classically employed for the mass transport phenomena quantification. Moreover, an additional mixing process taking place close to the interface related to the liquid flow driven by the surface tension gradients (so-called classic and thermal Marangoni effect) could play a still underestimated role in the trans-interfacial mass transport.

A wettability-based approach for the monitoring of drug transport through biological membranes.

The aim of the work was to exploit a methodology based on contact angle measurements for the purpose of membrane transport studies. Special attention has been paid to a model system of pharmacological relevance, consisting of the drug dithranol (from semisolid Vaseline suspension) in contact with an artificial skin barrier. The drug permeation has been monitored by the surface wettability evolution during the drug transport process. The surface wettability parameters, such as: surface free energy, 2D film pressure, contact angle hysteresis (CAH) and surface excess for long and short adsorption time intervals, have been derived from dynamic contact angle measurements of the probe liquid drops deposited on the outermost membrane layer. The analysis has allowed the apparent Arrhenius-type energy barrier for the drug surface adsorption (Ea/RgT = -8.04 ±â€¯0.84 at 295 K), the characteristic lag-time of the transport process (tlag = 20 ±â€¯1.9 min) and the diffusion coefficient of the drug through the membrane (D = 1.25 ±â€¯0.24·10-9 cm2 s-1) to be determined. The latter one remains in a good agreement with literature data for the same system investigated by means of spectroscopic methods.

Evidence for weakly bound electrons in non-irradiated alkane crystals: The electrons as a probe of structural differences in crystals.

It is generally assumed that weakly bound (trapped) electrons in organic solids come only from radiolytical (or photochemical) processes like ionization caused by an excited positron entering the sample. This paper presents evidence for the presence of these electrons in non-irradiated samples of docosane. This can be due to the triboelectrification process. We argue that these electrons can be located (trapped) either in interlamellar gaps or in spaces made by non-planar conformers. Electrons from the former ones are bound more weakly than electrons from the latter ones. The origin of Vis absorption for the samples is explained. These spectra can be used as a probe indicating differences in the solid structures of hydrocarbons.

Absolute beta-catenin concentrations in Wnt pathway-stimulated and non-stimulated cells.

The intracellular level of the proto-oncoprotein beta-catenin is a parameter for the activity of the Wnt pathway, which has been linked to carcinogenesis. The paper introduces a novel sandwich-based ELISA for the determination of the beta-catenin concentration in lysates from cells or tissues. The advantages of the method were proven by determining beta-catenin levels in cell lines and in cells after activation of the Wnt pathway. Analysis revealed high beta-catenin concentrations in the cell lines HeLa, KB, HT1080, MCF-7, U-87 and U-373, which had not been described before. Beta-catenin concentrations were compared in HEK293 and C57MG cells after activation of the Wnt pathway. The beta-catenin concentrations increased by different factors depending on whether the Wnt pathway was activated by incubation with LiCl or with Wnt-3a-conditioned medium. This finding indicated that the beta-catenin level depends on the way and level of Wnt pathway activation. The quantitative analysis of beta-catenin in colorectal tumours revealed high beta-catenin levels in tumours with truncating mutations in the APC gene.