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This paper investigates the effects of shear deformation on the flutter and divergence instabilities of a cantilever beam subjected to a concentrated mass and applied dynamic couple. The beam is modeled using classical and truncated Timoshenko beam theory, accounting for both shear deformation and rotary inertia. The inclusion of rotary inertia is shown to significantly influence the dynamic response, particularly for beams with greater thickness. According to Hamilton’s principle, the equations of motion for the cantilevered beam are derived, applying both classical and truncated Timoshenko beam theories. Auxiliary functions are utilized to solve the resulting system analytically. Various numerical examples are presented, illustrating typical results to demonstrate the effectiveness of the proposed approach. The numerical findings show significant convergence and computational effectiveness. The effect of the location of a concentrated mass and the dynamic couple applied at the free end is analyzed for various beam slenderness ratios and curvature positions, emphasizing their impact on modifying the critical instability limits. To highlight the significance of shear effects, a comparison is made between the outcomes of the Timoshenko model and those of the Euler-Bernoulli beam model, showing notable variations in the anticipated divergence and flutter stability characteristics. All the examples were executed using both classical theory and the truncated Timoshenko theory, and the findings indicated a remarkable level of convergence. Finally, a numerical comparisons with literature papers was performed. The results achieved showed strong alignment.

Background: Oxidative stress is a driver of multiple sclerosis (MS) pathology. We evaluated the effect of coenzyme Q10 (CoQ10) on laboratory markers of oxidative stress and inflammation, and on MS clinical severity. Methods: We included 60 relapsing–remitting patients with MS treated with interferon beta1a 44μg (IFN-β1a) with CoQ10 for 3 months, and with IFN-β1a 44μg alone for 3 more months (in an open-label crossover design). At baseline and at the 3 and 6-month visits, we measured markers of scavenging activity, oxidative damage and inflammation in the peripheral blood, and collected data on disease severity. Results: After 3 months, CoQ10 supplementation was associated with improved scavenging activity (as mediated by uric acid), reduced intracellular reactive oxygen species production, reduced oxidative DNA damage, and a shift towards a more anti-inflammatory milieu in the peripheral blood [with higher interleukin (IL)-4 and IL-13, and lower eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hepatocyte growth factor (HGF), interferon (IFN)-γ, IL-1α, IL-2R, IL-9, IL-17F, macrophage inflammatory proteins (MIP)-1α, regulated on activation-normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF). Also, CoQ10 supplementation was associated with lower Expanded Disability Status Scale, fatigue severity scale, Beck’s depression inventory, and the visual analogue scale for pain. Conclusions: CoQ10 supplementation improved scavenging activity, reduced oxidative damage, and induced a shift towards a more anti-inflammatory milieu, in the peripheral blood of relapsing–remitting MS patients treated with 44μg IFN-β1a 44μg. A possible clinical effect was noted but deserves to be confirmed over longer follow ups.

The variability in the clinical phenotype of Parkinson's disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients. We collected data on demographic, motor, and the whole complex of non-motor symptoms from 100 consecutive newly diagnosed untreated outpatients. Statistical cluster analysis allowed the identification of different subgroups, which have been subsequently explored. The data driven approach identified four distinct groups of patients, we have labeled: 1) Benign Pure Motor; 2) Benign mixed Motor-Non-Motor; 3) Non-Motor Dominant; and 4) Motor Dominant. Our results confirmed the existence of different subgroups of early PD patients. Cluster analysis revealed the presence of distinct subtypes of patients profiled according to the relevance of both motor and non-motor symptoms. Identification of such subtypes may have important implications for generating pathogenetic hypotheses and therapeutic strategies.

Purpose Cerebellar ataxias are a large and heterogeneous group of disorders. The evaluation of brain parenchyma via MRI plays a central role in the diagnostic assessment of these conditions, being mandatory to exclude the presence of other underlying causes in determining the clinical phenotype. Once these possible causes are ruled out, the diagnosis is usually researched in the wide range of hereditary or sporadic ataxias. Methods We here propose a review of the main clinical and conventional imaging findings of the most common hereditary degenerative ataxias, to help neuroradiologists in the evaluation of these patients. Results Hereditary degenerative ataxias are all usually characterized from a neuroimaging standpoint by the presence, in almost all cases, of cerebellar atrophy. Nevertheless, a proper assessment of imaging data, extending beyond the mere evaluation of cerebellar atrophy, evaluating also the pattern of volume loss as well as concomitant MRI signs, is crucial to achieve a proper diagnosis. Conclusion The integration of typical neuroradiological characteristics, along with patient’s clinical history and laboratory data, could allow the neuroradiologist to identify some conditions and exclude others, addressing the neurologist to the more appropriate genetic testing.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The absence of reliable fluid biomarkers continues to hinder early diagnosis and effective monitoring of disease progression. Circulating microRNAs (cmiRNAs) are potential candidates, given their stability in biofluids and their ability to mirror pathological processes. We conducted a longitudinal study in 30 early-stage levodopa-naive PD patients (22 men, 8 women). Serum samples were collected at baseline (T0) and at a follow-up time point two years later (T2). A panel of MicroRNAs (miRNAs) (miR-146a-5p, miR-34a-5p, miR-155-5p, miR-29a-3p, miR-106a-5p) were quantified by quantitative real-time PCR. Data were expressed as relative expression (2^−ΔCt), and statistical analyses included sex-stratified comparisons and paired tests for longitudinal changes. At baseline, no significant differences were found in the expression of the miRNAs between male and female PD patients. In contrast, longitudinal within-subject analysis revealed a highly significant upregulation in miR-146a-5p expression from T0 to T2 in both sexes (p < 0.0001). No other miRNAs in the panel exhibited significant changes over time. CmiR-146a-5p levels rise markedly over time in PD patients, independent of sex, suggesting that this miRNA could be a dynamic biomarker of disease progression.

Detecting track geometry and rail surface defects using on-board vehicle monitoring systems is a key issue for rail infrastructure managers to increase availability and reliability while reducing the costs associated with monitoring and maintenance. Rail corrugation is one of the most common rail surface defects which grows in almost all metro, conventional and high-speed lines. This paper focuses on the development of a methodology to detect rail corrugation using axle box acceleration measurements acquired on an in-service high-speed vehicle. The main purpose of the proposed methodology is to distinguish the effect of rail corrugation on the accelerations from the other excitations that can be observed in the same wavelength range. For this purpose, the accelerations are analysed by calculating the fast Fourier transform and the spectrogram. Based on the characteristics of each excitation, the effects of modes of vibration, resonances, bridges, switches, and wheel defects are identified. From the remaining effects, which have congruent characteristics, a hypothesis of rail corrugation is formulated. The hypothesis is consolidated with multibody dynamics simulations and by comparing the corrugation indicators provided by the railway infrastructure company.

SYNJ1 has been recently identified by two independent groups as the gene defective in a novel form of autosomal recessive, early-onset atypical parkinsonism (PARK20). Two consanguineous families were initially reported (one of Sicilian and one of Iranian origins), with the same SYNJ1 homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features. Here, we report the identification of the same SYNJ1 homozygous mutation in two affected siblings of a third pedigree. Both siblings had mild developmental psychomotor delay, followed, during the third decade of life, by progressive parkinsonism, dystonia, and mild cognitive impairment. One sibling suffered one episode of generalized seizures. Neuroimaging studies revealed severe nigrostriatal dopaminergic defects, mild striatal and very mild cortical hypometabolism. Treatment with dopamine agonists and anticholinergics resulted in partial improvements. Genetic analyses revealed in both siblings the SYNJ1 homozygous c.773G > A (p.Arg258Gln) mutation. Haplotype analysis suggests that the mutation has arisen independently in this family and the Sicilian PARK20 family previously described by us, in keeping with the hypothesis of a mutational hot spot. This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the SYNJ1 p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. This newly recognized form must be considered in the diagnostic work-up of patients with early-onset atypical parkinsonism. The presence of seizures might represent a red flag to suspect PARK20.

IntroductionPsychosis in Parkinson’s disease (PD) is common and consists of hallucinations, illusions, and delusions. Among the latter, delusional jealousy, also named Othello syndrome (OS), might impair the quality of life of both patients and their partners. We aimed to perform a systematic review and report a series of PD patients presenting with OS.MethodsA systematic review research was performed in PubMed database, excluding non-English articles, single case reports, reviews and neuropathology articles, comments, and articles concerning OS associated with deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel infusion. We also described eleven PD patients (9 M and 2 F) with OS, identified in a cohort of consecutive 153 patients, comparing them with eleven matched no OS (nOS) PD subjects taken from the same cohort.ResultsWe included eight articles (four case series and four cross-sectional studies). OS resulted more common among males than females. We did not find higher levodopa dose and levodopa equivalent dose for dopamine agonists and for all anti-parkinsonian drugs in our OS group. In our case series, OS patients showed visual hallucinations (p=0.001) and a trend to have depression (p=0.080) more frequently than nOS ones.ConclusionsOS is not a rare disorder in PD, probably due not only to abnormal dopaminergic stimulation but also to serotonergic dysfunction in biologically predisposed subjects. Visual hallucinations and other concomitant psychiatric diseases, in particular depression, might represent a risk factor for the OS development.

PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2α/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease.