Careful Phenotypic Characterization of Tremor Phenomenology in a Patient with Spinocerebellar Ataxia Type 12-Tremor Features Do Not Match Those of Essential Tremor.

Background: The tremor characteristics of patients with spinocerebellar ataxia 12 (SCA12) are often likened to those in patients with essential tremor (ET); however, data are sparse, and videotaped tremor examinations are rare. Case Report: A 37-year-old woman with progressive hand and head tremors underwent genetic testing after conventional diagnostics failed to explain her symptoms. A PPP2R2B variation confirmed spinocerebellar ataxia type 12 (SCA12), a condition not previously considered because classical cerebellar signs were absent. The tremor characteristics of this patient differed in numerous respects from those seen in patients with ET. Discussion: Although often likened to ET, under careful scrutiny, the tremor characteristics observed in this patient with SCA12 were inconsistent with those typically seen in ET. Such discrepancies highlight the necessity of careful phenotyping for tremor disorders, particularly in familial cases. Recognizing the specific tremor phenomenology of SCA12 and distinguishing it from ET is crucial to avoid misdiagnosis and to guide appropriate management and familial counseling. Highlights: This report characterizes in detail an early-stage SCA12 patient initially misdiagnosed as essential tremor, underscoring the importance of nuanced clinical assessment and genetic testing in atypical tremor cases. Similar patients should be meticulously phenotyped to prevent misclassification and enhance our understanding of tremor pathophysiology.

Generation of Aromatic N-Heterocyclic Radicals for Functionalization of Unactivated Alkenes.

Nitrogen-centered radicals (NCRs) have been widely recognized as versatile synthetic intermediates for the construction of nitrogen containing molecules of high value. As such, there has been a long-standing interest in the field of organic synthesis to develop novel nitrogen-based radicals and explore their inherent reactivity. In this study, we present the generation of aromatic N-heterocyclic radicals and their application in a novel and diverse functionalization of unactivated alkenes. Bench-stable aromatic N-heterocyclic pyridinium salts were employed as crucial NCR precursors, which enabled the efficient conversion of various unactivated alkenes into medicinally relevant alkylated N-heterocyclic amines. This approach offers an unexplored retrosynthetic disconnection for the synthesis of related molecules that commonly possess therapeutic value. Furthermore, this platform can be extended to the synthesis of densely functionalized heterocyclic amines by utilizing disulfides and diethyl bromomalonate as radical quenchers. Mechanistic investigations indicate an energy transfer (EnT) pathway involving the formation of a transient aromatic N-heterocyclic radical, radical addition to unactivated alkenes, and subsequent generation of the amination product through either hydrogen atom transfer (HAT) or radical addition processes.

Vertebral artery dissection induced lateral medullary syndrome characterized with severe bradycardia: a case report and review of the literature.

BACKGROUND: Lateral medullary syndrome is the most common type of brainstem infarction. Lateral medullary syndrome results in damage to the corresponding cranial nerve nuclei and the nucleus tractus solitarius, with vertigo, ipsilateral ataxia, crossed sensory disturbances, Horner's sign, bulbar palsy, and other underlying symptoms or signs. However, cases with cardiac arrhythmia and other autonomic dysfunctions as the primary manifestations are less common. Clinically, sudden death occasionally occurs in patients with lateral medullary syndrome, which may be associated with severe cardiac arrhythmia. These patients may suffer in life-threatening arrhythmia and even cardiac arrest, and vital signs should be closely monitored to prevent sudden death. In younger patients, vertebral artery dissection is the most common cause. CASE DESCRIPTION: Here, we present a case of lateral medullary syndrome caused by vertebral artery dissection with severe bradycardia. The patient was a 49-year-old man who was admitted with "sudden onset of numbness in the left limbs and right side of the face for 1 hour". Electrocardiogram (ECG) monitoring showed a repeated heart rate decrease to as low as 23 beats/min, followed by a gradual increase in heart rate to 35-55 beats/min after 2-3 seconds. Head magnetic resonance imaging (MRI) examination revealed right dorsolateral cerebral infarction of the medulla oblongata. Digital subtraction angiography (DSA) revealed a right vertebral artery dissecting aneurysm. We performed an emergency placement of a temporary pacemaker, followed by conservative treatment with platelet aggregation inhibitors, vascular softening agents and improved collateral circulation. Elective spring coil embolization of the vertebral artery dissecting aneurysm and stent implantation were performed. At outpatient follow-up, the patient had a good prognosis. CONCLUSIONS: Clinical management of patients with lateral medullary syndrome should be prioritized, with close cardiac monitoring at the early stages of observation and pacemaker placement and tracheal intubation as required to prevent adverse events.

Identification of glomerular lesions and intrinsic glomerular cell types in kidney diseases via deep learning.

Identification of glomerular lesions and structures is a key point for pathological diagnosis, treatment instructions, and prognosis evaluation in kidney diseases. These time-consuming tasks require a more accurate and reproducible quantitative analysis method. We established derivation and validation cohorts composed of 400 Chinese patients with immunoglobulin A nephropathy (IgAN) retrospectively. Deep convolutional neural networks and biomedical image processing algorithms were implemented to locate glomeruli, identify glomerular lesions (global and segmental glomerular sclerosis, crescent, and none of the above), identify and quantify different intrinsic glomerular cells, and assess a network-based mesangial hypercellularity score in periodic acid-Schiff (PAS)-stained slides. Our framework achieved 93.1% average precision and 94.9% average recall for location of glomeruli, and a total Cohen's kappa of 0.912 [95% confidence interval (CI), 0.892-0.932] for glomerular lesion classification. The evaluation of global, segmental glomerular sclerosis, and crescents achieved Cohen's kappa values of 1.0, 0.776, 0.861, and 95% CI of (1.0, 1.0), (0.727, 0.825), (0.824, 0.898), respectively. The well-designed neural network can identify three kinds of intrinsic glomerular cells with 92.2% accuracy, surpassing the about 5-11% average accuracy of junior pathologists. Statistical interpretation shows that there was a significant difference (P value < 0.0001) between this analytic renal pathology system (ARPS) and four junior pathologists for identifying mesangial and endothelial cells, while that for podocytes was similar, with P value = 0.0602. In addition, this study indicated that the ratio of mesangial cells, endothelial cells, and podocytes within glomeruli from IgAN was 0.41:0.36:0.23, and the performance of mesangial score assessment reached a Cohen's kappa of 0.42 and 95% CI (0.18, 0.69). The proposed computer-aided diagnosis system has feasibility for quantitative analysis and auxiliary recognition of glomerular pathological features. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Development and In Situ Application of Deformation Monitoring System for Concrete-Face Rockfill Dam Using Fiber Optic Gyroscope.

Deformation monitoring is of importance to ensure the operation status of concrete-face rockfill dams (CFRD). This paper reported a novel fiber optic gyroscope (FOG) monitoring system for continuously monitoring face slab deformation of CFRD, which consisted of a permanent monitoring pipeline and a sensing vehicle. The monitoring pipeline was made of steel pipes and polyvinyl chloride polymer connectors, which was embedded in a slot of the crushing-type sidewall beneath the concrete face slab of CFRD, forming a permanent monitoring channel. The sensing vehicle was equipped with a high-precision FOG sensor. A low-pass filter was designed to eliminate the vibration noise of the angular velocities of the sensing vehicle during the monitoring process. An in situ test was carried out on the Shuibuya dam, the highest CFRD in the world. The measurements of the FOG monitoring system agreed well with traditional instrument measurements, serving as validation of the system. The FOG monitoring system has the advantages of excellent repeatability, long service life, distributed monitoring, and automatic measurement.

An Enhanced Lightning Attachment Procedure Optimization with Quasi-Opposition-Based Learning and Dimensional Search Strategies.

Lightning attachment procedure optimization (LAPO) is a new global optimization algorithm inspired by the attachment procedure of lightning in nature. However, similar to other metaheuristic algorithms, LAPO also has its own disadvantages. To obtain better global searching ability, an enhanced version of LAPO called ELAPO has been proposed in this paper. A quasi-opposition-based learning strategy is incorporated to improve both exploration and exploitation abilities by considering an estimate and its opposite simultaneously. Moreover, a dimensional search enhancement strategy is proposed to intensify the exploitation ability of the algorithm. 32 benchmark functions including unimodal, multimodal, and CEC 2014 functions are utilized to test the effectiveness of the proposed algorithm. Numerical results indicate that ELAPO can provide better or competitive performance compared with the basic LAPO and other five state-of-the-art optimization algorithms.

Kidney injury molecule-1 expression predicts structural damage and outcome in histological acute tubular injury.

BACKGROUND: A few studies have shown that urinary kidney injury molecule-1 (uKIM-1) levels are increased in acute kidney injury (AKI); however, the correlation between uKIM-1 and histological tubular injury, which is considered to be the gold standard for evaluating renal damage and predicting prognosis, is still unclear. We performed this study to determine whether the predicted value of uKIM-1 is correlated with renal KIM-1 (tKIM-1) expression and tissue damage in AKI patients. METHODS: This retrospective study recruited 14 healthy individuals and 27 biopsy-proven acute tubular injury (ATI) patients. uKIM-1 and plasma KIM-1 (sKIM-1) levels were measured by ELISA, and tKIM-1 expression was evaluated by immunohistochemistry. RESULTS: Elevated levels of urinary, plasma, and renal KIM-1 were found in ATI patients. The uKIM-1 concentration was positively correlated with tKIM-1 expression and reflected the severity of renal histological injury. The outcome of ATI was associated with uKIM-1 expression: the ATI patients with higher uKIM-1 levels had an increased potential for an incomplete recovery of renal function during follow-up. Additionally, the level of KIM-1, regardless of source, was negatively related to the eGFR, and ROC curve analysis revealed that the ROC-AUC was 0.923 (p = 0.000) for the diagnosis of ATI based on a combination of high uKIM-1 and sKIM-1 levels. CONCLUSION: The uKIM-1 level corresponds with the severity of renal histological damage and can be a potential reliable predictor of adverse renal outcomes in ATI patients. Moreover, combining uKIM-1 and sKIM-1 can increase the sensitivity and specificity of the diagnosis of severe ATI.

Reversing the thermal equilibration by differential magneto-thermal force.

A special magnetic body force, the differential magneto-thermal (DMT) force, was proposed to reverse thermal equilibration by 'pushing' a fluid element colder than its surroundings to a colder region, and a fluid element hotter than its surroundings to a hotter region [1]. In this work, we discuss the fulfilment of the requirements for this force and the experiment to verify it. We present experimental and analytical results that clearly demonstrate: (1) approaching thermal equilibrium in our magnetic fluid sample was indeed 'reversed' as the magnetic body force introduces the localized flows that stop the conventional convective heat transfer; (2) the DMT force density calculated with experimental parameters agrees with the design principle. These results prove the feasibility of the predicted mechanism for a new generation of heat transfer apparatus that can transfer heat energy with higher efficiency than the ones discussed in textbooks, such as heat engines.

Role of miR­21 on vascular endothelial cells in the protective effect of renal delayed ischemic preconditioning.

Vascular endothelial cells may serve crucial roles in the development of acute kidney injury (AKI). microRNA (miR)­21, which possesses a renal protective function has been found on vascular endothelial cells. The present study aimed to test the hypothesis that miR­21 may protect vascular endothelial cells against injury, which may contribute to the protective effects of renal delayed ischemic preconditioning (IPC). Preconditioned (15 min ischemia) or Sham mice (not clamped) were subjected to 35 min occlusion of bilateral renal pedicles 4 days following preconditioning or Sham treatment. Human umbilical vein endothelial cells (HUVECs) were treated with cobalt(II) chloride (CoCl2) to establish an in vitro hypoxia model. Locked nucleic acid­modified anti­miR­21 or scrambled control oligonucleotides were transfected into cells or delivered into mice via tail vein injection <1 h prior to IPC. Following 24 h of reperfusion or hypoxia, morphological and functional parameters, apoptosis and miR­21 and programmed cell death 4 (PDCD4) expression were assessed in vivo and in vitro. Treatment of HUVECs with CoCl2 led to an upregulation of miR­21 expression, a downregulation of PDCD4 protein expression and attenuation of apoptosis. Inhibition of miR­21 expression led to increased expression levels of PDCD4 protein and apoptosis in HUVECs. IPC attenuated renal IR injury in mice. The protective effect of IPC appeared to be dependent on upregulated miR­21 expression. IPC­induced upregulation of miR­21 expression also occurred in HUVECs, and IPC also led to reduced PDCD4 expression and vascular permeability in mouse kidneys. The effects of IPC were attenuated by the inhibition of miR­21; miR­21 expression attenuated damage in vascular endothelial cells, which may contribute to the protective effects of delayed IPC on renal IR injury. The present study suggested a novel target for the prevention and repair of AKI in the future.

Usp2-69 overexpression slows down the progression of rat anti-Thy1.1 nephritis.

Mesangial proliferative glomerulonephritis is characterized by proliferation of mesangial cells (MCs) and transforming growth factor-ß (TGF-ß)-dependent stimulation of abnormal extracellular matrix (ECM) accumulation. We previously showed that Decorin--a leucine-rich proteoglycan inhibiting the progression of glomerulonephritis and glomerular sclerosis--can be degraded by the ubiquitin-proteasome pathway and deubiquitinated and stabilized by ubiquitin-specific processing protease 2-69(Usp2-69). Usp2-69 is highly expressed in the kidney and has been implicated in the regulation of cell proliferation and apoptosis. However, its role in mesangial proliferative glomerulonephritis remains unclear. Here, we explored the effect of Usp2-69 on MC proliferation and ECM deposition by transfecting Usp2-69 plasmid into rat anti-Thy1.1 nephritis model and into cultured MCs, as well as detected Usp2-69 and Decorin in rat anti-Thy1.1 nephritis model by western blot. Overexpressing Usp2-69 at the early stage, but not advanced stage, of anti-Thy1.1 nephritis alleviated cell proliferation and ECM deposition, which was shown by decreased Ki-67, Collagen IV and Fibronectin detected by immunohistochemistry. Overexpression also increased Decorin and decreased TGF-ß1 and Collagen IV both in vitro and in vivo. In conclusion, our findings suggest that Usp2-69 overexpression alleviates the progression of rat anti-Thy1.1 nephritis and, therefore, that exogenous plasmid injection via the renal artery enhanced by electrotransfer technology could be a promising avenue for glomerular disease research.

Wnt/ß-Catenin Signaling Mediated-UCH-L1 Expression in Podocytes of Diabetic Nephropathy.

Increasing studies identified podocyte injury as a key early risk factor resulting in diabetic nephropathy (DN). The ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) participates in podocyte differentiation and injury, which is elevated in the podocytes of a variety of nephritis. Whether UCH-L1 expression is positively related to podocyte injury of DN remains unclear. In this study, elevated expression of UCH-L1 and its intrinsic mechanism in high glucose (HG)-stimulated murine podocytes were investigated using western blot and real-time quantitative PCR. Kidney biopsies of DN patients and health individuals were stained by immunofluorescence (IF) method. The morphological and functional changes of podocytes were tested by F-actin staining and cell migration assay. Results demonstrated that HG induced upregulation of UCH-L1 and activation of the Wnt/ß-catenin signaling pathway in podocytes. However, blocking of the Wnt pathway by dickkopf related protein 1 (DKK1) eliminated the above changes. Furthermore, IF staining confirmed that, compared with healthy individuals, the expression of UCH-L1 and ß-catenin were obviously increased in kidney biopsy of DN patients. Overexpression of UCH-L1 remodeled its actin cytoskeleton, increased its cell migration and impacted its important proteins. All the findings manifested that Wnt/ß-catenin/UCH-L1 may be a new potential therapy method in the treatment of DN in future.

NF-κB upregulates ubiquitin C-terminal hydrolase 1 in diseased podocytes in glomerulonephritis.

Podocyte injury is a pivotal factor during the progression of glomerular diseases. It has been demonstrated that the expression of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in injured podocytes in a number of types of glomerulonephritis. However, its mechanism of regulation remains to be elucidated. A previous study by our group suggested that UCH-L1 is a downstream protein of nuclear factor (NF)-κB signaling. In the present study, the involvement of NF-κB in the regulation of the expression of UCH-L1 was investigated in diseased podocytes in vivo and in vitro. Increases in the expression of phosphorylated NF-κB at p65 and UCH-L1 were detected using immunohistochemical analysis of kidney biopsy tissues from 56 cases of nephritis, including immunoglobulin A nephropathy, membranous glomerulonephritis and lupus nephritis. The two indicators were also analyzed using western blot analysis in cultured murine podocytes stimulated by inflammatory factors. The results of the present study demonstrated that in human renal biopsies of several cases of immune complex-mediated glomerulonephritis, the increases of NF-κB and UCH-L1 were positively correlated with the number of diseased podocytes. By contrast, in non-immune complex-mediated glomerulonephritis, no clear activation of NF-κB and increase of UCH-L1 expression was observed. In vitro, immune stimulation also led to the upregulation of UCH-L1 through the NF-κB signaling pathway in mouse podocytes. In conclusion, the results of the present study suggested that the activation of NF-κB and upregulation of UCH-L1 in podocytes may be vital in podocyte injury associated with immune complex-mediated glomerulonephritis.

A novel contrast-induced acute kidney injury model based on the 5/6-nephrectomy rat and nephrotoxicological evaluation of iohexol and iodixanol in vivo.

Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Proper animal models of CI-AKI can help understand the mechanisms involved and prevent the disorder. We used the 5/6-nephrectomized (NE) rat to develop a CI-AKI model and to evaluate differences in the toxic effects on the kidney between iohexol and iodixanol. We found that six weeks after ablative surgery was the preferred time to induce CI-AKI. We compared multiple pretreatment plans and found that dehydration for 48 hours before iodixanol (320, 10 mL/kg) administration was optimal to induce CI-AKI in the 5/6 NE rats. Compared with iodixanol, iohexol induced a significantly greater reduction in renal function, severe renal tissue damage, intrarenal hypoxia, and apoptotic tubular cells. Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress. In summary, the 5/6 NE rat combined with dehydration for 48 hours is a useful pretreatment to establish a novel and reliable CI-AKI model. Iohexol induced more severe CI-AKI than iodixanol in this model.

The regulation of the UCH-L1 gene by transcription factor NF-κB in podocytes.

In kidney, the ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) is involved in podocyte injury and proteinuria but details of the mechanism underlying its regulation are not known. Activation of NF-κB is thought to be the predominant risk factor for kidney disease; therefore, it is postulated that UCH-L1 may be one of the NF-κB target genes. In this study, we investigated the involvement of NF-κB activation in the regulation of UCH-L1 expression and the function of murine podocytes. Stimulation of podocytes with the cytokines TNF-α and IL-1ß up-regulated UCH-L1 expression rapidly at the mRNA and protein levels and the NF-κB-specific inhibitor pyrrolidine dithiocarbamate resulted in down-regulation. NF-κB up-regulates UCH-L1 via binding the --300 bp and --109 bp sites of its promoter, which was confirmed by the electrophoretic mobility shift assay of DNA-nuclear protein binding. In the renal biopsy from lupus nephritis patients, the expressions of NF-κB and UCH-L1 increased in immunohistochestry staining and were positively correlated. Activation of NF-κB up-regulates UCH-L1 expression following changing of other podocytes molecules, such as nephrin and snail. These results suggest that activation of the NF-κB signaling pathway could be the major pathogenesis to up-regulate UCH-L1 in podocyte injury, followed by the turnover of other molecules, which might result in morphological changes and dysfunction of podocytes. This work help us to understand the effect of NF-κB on specific target molecules of podocytes, and suggest that targeting the NF-κB-UCH-L1 interaction could be a novel therapeutic strategy for the treatment of podocyte lesions and proteinuria.

Thermodynamic model of electric-field-induced pattern formation in binary dielectric fluids.

An electric-field-induced phase transition and pattern formation in a binary dielectric fluid layer are studied using a coarse-grained free-energy functional. The electrostatic part of the free energy is a nonlinear functional of the dielectric function, which depends in turn on the local colloidal concentration. We determine the phase coexistence curve and find that beyond a critical electric field the system phase separates. Accompanying the phase separation are patterns similar to those observed in a spinodal decomposition of an ordinary binary fluid. The temporal evolution of the phase separating patterns are discussed both analytically and numerically by integrating a Cahn-Hilliard type of equation.