Dyrk1a Phosphorylation of α-Synuclein Mediating Apoptosis of Dopaminergic Neurons in Parkinson's Disease.

Objective: To investigate the role of aberrant Dyrk1a expression in phosphorylation modification at the α-synuclein serine 129 (Ser129) site to analyze its molecular mechanism in mediating apoptosis of PD. Methods: The protein level of P-α-synuclein (Ser129), α-synuclein, Bcl-2, Bax, active caspase 3, GSK3ß, PI3K, AKT, and cyclinD1 were detected. The mRNA transcript levels of Dyrk1a and DAT and protein levels of IL-1ß, IL-6, COX-2, and TNF-α were detected. Results: P-α-synuclein (Ser129), α-synuclein, Bax, active caspase 3, GSK3ß, and cyclinD1 expressions were decreased in Dyrk1a-AAV-ShRNA (P < 0.05), and Bcl-2, AKT, and PI3K expressions were increased (P < 0.05). Increased TH protein expression was shown in Dyrk1a-AAV-ShRNA (P < 0.05). Dyrk1a mRNA was decreased in the Dyrk1a-AAV-ShRNA group (P < 0.05), and DAT mRNA was increased (P < 0.05). IL-1ß, IL-6, COX-2, and TNF-α protein levels were decreased in Dyrk1al-AAV-Sh-RNA (P < 0.05). Transcriptome sequencing showed that Fam220a, which was expected to activate STAT family protein binding activity and participate in the negative regulation of transcription through RNA polymerase II and protein dephosphorylation showed differentially upregulated expression. The untargeted metabolome showed that the major compounds in the Dyrk1a-AAV-ShRNA group were hormones and transmission mediators and the most metabolism-related pathways. Fam220a showed differentially upregulated expression, and differentially expressed genes were enriched for the neuroactive ligand-receptor interaction, vascular smooth muscle contraction, and melanogenesis-related pathways. Conclusion: Abnormal Dyrk1a expression can affect α-synuclein phosphorylation modifications, and dyrk1a knockdown activates the PI3K/AKT pathway and reduces dopaminergic neuron apoptosis. It provides a theoretical basis for the group to further investigate the molecular mechanism.

Substantia Nigra Echogenicity Signal Correlated with Clinical Features in Patients with Parkinson's Disease in Xinjiang.

Background: Transcranial sonography (TCS) is a noninvasive test that can reveal structural changes in the substantia nigra (SN) in Parkinson's disease (PD). The purpose of this study was to investigate the relationship between SN signatures and clinical features in PD patients in a multiethnic region of China. Methods: A total of 147 patients with PD were included in the study, and all of whom had underwent a TCS examination. Clinical information was collected from PD patients, and motor and nonmotor symptoms were assessed using assessment scales. Results: There were differences in the substantia nigra hyperechogenicity (SNH) area between age of onset, visual hallucinations (VH), and UPDRS3.0 II scores (P < 0.05), patients with late onset PD had a greater SNH area than early onset (0.326 ± 0.352 vs. 0.171 ± 0.194), and PD patients presenting with VH had a greater SNH area than those without hallucinations (0.508 ± 0.670 vs. 0.278 ± 0.659), and further multifactorial analysis showed that a high SNH area was an independent risk factor for development of VH. The area under the ROC curve for predicting VH from the SNH area in PD patients was 0.609 (95% CI: 0.444-0.774). There was a positive correlation between the SNH area and UPDRS3.0-II scores, but further multifactorial analysis showed that SNH was not an independent predictor of the UPDRS3.0-II score. Conclusion: A high SNH area is an independent risk factor for development of VH, there is a positive correlation between the SNH area and UPDRS3.0 II score, and TCS has guiding significance in predicting clinical VH symptoms and activities of daily living in PD patients.

Efficacy of modified EDAS combined with a superficial temporal fascia attachment-dural reversal surgery for the precise treatment of ischemic cerebrovascular disease.

Objective: To investigate the potential therapeutic benefits of Modified EDAS combined with superficial temporal fascia attachment-dural reversal surgery for the treatment of ischemic cerebrovascular disease. Methods: Retrospective analysis was made on the clinical data of 33 patients with ischemic cerebrovascular disease, who were admitted to the Neurological Diagnosis and Treatment Center of the Second Affiliated Hospital of Xinjiang Medical University from December 2019 to June 2021. All patients were treated with Modified EDAS combined with superficial temporal fascia attachment-dural reversal surgery. At 3 months after operation, the outpatient department rechecked the patient's head CT perfusion imaging (CTP) to understand the intracranial cerebral blood flow perfusion. The DSA of the patient's head was re-examined 6 months after operation to observe the establishment of collateral circulation. The improved Rankin Rating Scale (mRS) score was used to evaluate the good prognosis rate of patients at 6 months after surgery. The mRS score ≤2 was defined as good prognosis. Results: The preoperative cerebral blood flow (CBF), local blood flow peak time (rTTP), and local mean transit time (rMTT) of 33 patients were 28.235 ml/(100 g·min), 17.702 s, 9.796 s, respectively. At 3 months after surgery, CBF, rTTP, and rMTT were 33.743 ml/(100 g·min), 15.688, and 8.100 s, respectively, with significant differences (P < 0.05). At 6 months after operation, the establishment of extracranial and extracranial collateral circulation was observed in all patients by re-examination of head DSA. At 6 months after operation, the good prognosis rate was 81.8%. Conclusion: The Modified EDAS combined with superficial temporal fascia attachment-dural reversal surgery is safe and effective in the treatment of ischemic cerebrovascular disease, which can significantly increase the establishment of collateral circulation in the operation area and improve the prognosis of patients.

Predicting venous thromboembolism in non-surgical hospitalized patients with type 2 diabetes mellitus: development and validation of a nomogram.

BACKGROUND: Due to confounders like hyperglycemia, patients with type 2 diabetes mellitus (T2DM) have an increased susceptibility to venous thromboembolism (VTE). However, formal risk assessment models, such as using the Padua score, do not include all T2DM-associated risk factors for VTE. Therefore, this study aims to develop and validate a predictive nomogram for VTE in non-surgical inpatients with T2DM. METHODS: We retrospectively analyzed the clinical and biochemical data of 420 non-surgical inpatients with T2DM between 2017 and 2021 from three centers (the PLA 474th hospital, the Second Affiliated Hospital of Xinjiang Medical University and the Fifth Affiliated Hospital of Xinjiang Medical University). A multivariate analysis based on logistic regression model was performed to identify independent risk factors and construct a nomogram. The predictive values were compared by calculating the integrated discrimination improvement (IDI) and net reclassification improvement (NRI), and by decision curve analysis (DCA). RESULTS: Old age, BMI, D-dimer, hypoproteinemia, acute infection, acute myocardial infarction, cerebral ischemic stroke, reduced mobility, and heart/respiratory failure were independent risk factors for VTE in non-surgical inpatients with T2DM, as indicated by the multivariate analysis. The nomogram demonstrated superior discriminative ability compared to the Padua score (area under the curve: 0.923 vs. 0.849). NRI and IDI were also observed, and the DCA identified the greater net benefit and clinical utilization of the new nomogram. CONCLUSIONS: A predictive nomogram for VTE in non-surgical inpatients with T2DM was developed and validated in this study. The nomogram is highly predictive and easy to operate, but external data verification is required before it can be further used.

Upregulation of HSP72 attenuates tendon adhesion by regulating fibroblast proliferation and collagen production via blockade of the STAT3 signaling pathway.

The proliferation of fibroblasts creates an environment favoring post-operative tendon adhesion, but targeted therapy of this pathology remains in its infancy. In this study, we explored the effect of heat shock protein 72 (HSP72), a major inducible member of the heat shock protein family that can protect cells against many cellular stresses including heat shock, on fibroblast proliferation in tendon adhesion, with its underlying mechanisms investigated. HSP72 expression was examined in an established rat model of tendon injury using RT-qPCR and immunoblot analysis. After conducting ectopic expression and depletion experiments in fibroblast NIH3T3 cells, we determined the effects of HSP72 on the expression of α-SMA and STAT3 signaling pathway-related genes, fibroblast proliferation, as well as collagen production. The mRNA (65.46%) and protein (63.65%) expression of HSP72 was downregulated in the rat model of tendon injury. The in vitro experiments revealed that overexpression of HSP72 inhibited fibroblast proliferation (42.57%) and collagen production (45.60%), as well as reducing α-SMA expression (42.49%) and the extent of STAT3 phosphorylation (55.46%). Moreover, we observed that HSP72 overexpression reduced inflammation as well as the number of inflammatory cell infiltration and fibroblasts in vivo. Furthermore, the inhibited extent of STAT3 phosphorylation contributed to the impaired fibroblast proliferation and collagen production evoked by upregulated HSP72. In summary, the present study unveils an inhibitory role of HSP72 in tendon adhesion via inactivation of the STAT3 signaling pathway. This finding may enable the development of new therapeutic strategies for the prevention against tendon adhesion.

Management of displaced inferior patellar pole fractures with modified tension band technique combined with cable cerclage using Cable Grip System.

INTRODUCTION: We present a modified tension band technique combined with cable cerclage using Cable Grip System for the treatment of displaced inferior patellar pole fractures and report the knee functional outcome. PATIENTS AND METHODS: The patients who had had operative treatment of a displaced inferior patellar pole fracture (AO/OTA 34-A1) between December 2013 and December 2015 were studied retrospectively. Eleven consecutive patients had had open reduction and internal fixation with the modified technique using Cable Grip System, of whom, five males and six females with an average age of 60.9 years (range, 29-81 years). All fractures occurred from direct fall onto the knee. The average time from injury to surgery was 6.1days (range, 2-12days). The range of motion (ROM) was measured in degrees by goniometry at postoperative intervals of 1, 2, 4, 12, and 48 weeks; Knee function was evaluated using the Rasmussen scores at final follow-up. RESULTS: No patients had nonunion, loss of reduction, migration of wire, irritation from the implant and fixation breakage during the follow-up period. Recovery of ROM was achieved at 12 weeks, with the average ROM at 1 week was 72° (range, 65°-78°), 86.4° (range, 78°-92°) at 2 weeks, 115.5° (range, 103°-122°) at 4 weeks, 129.6° (range, 122°-133°) at 12 weeks, 134.5° (range, 129°-139°) at 48 weeks after the operation. Concerning the knee function outcome assessment, all patients showed excellent results at final follow-up. The average Rasmussen scores was 27.9 out of 30 (range, 27-29). CONCLUSIONS: The modified tension band technique combined with cable cerclage using Cable Grip System for displaced inferior patellar pole fractures can provide stable fixation with excellent results in knee function, allows for immediate mobilization and early weight-bearing, which is a simple and valuable technique in routine clinical practice.

Thermal Preconditioning May Prevent Tendon Adhesion by Up-Regulating HSP72 in Rats.

BACKGROUND/AIMS: The study aims to determine the effects of thermal preconditioning on tendon adhesion by regulating the expression of heat shock protein 72 (HSP72) in rat models. METHODS: Sixty male Wistar rats were collected and randomly assigned into the thermal preconditioning and control groups. During the 4th and 8th weeks following surgery, 15 rats were sacrificed in each period respectively, and their tendon adhesion was observed and evaluated. Biomechanical testing was performed to measure the tensile strength and gliding distance of tendons. Hematoxylin-eosin (HE) was used to observe the morphological structure of the tendons. Immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the HSP72, fibroblast growth factor-2 (FGF-2), fibroblast growth factor receptor-1 (FGFR-1), ß-catenin, epithelial cell adhesion molecule (EPCAM), Tenomodulin and scleraxis protein expressions. Pearson correlation analysis was applied to analyze the correlation between HSP72 expression and tendon adhesion. RESULTS: At the 4th week after surgery, we found no differences in the tendon adhesion scores or mRNA and protein expressions of HSP72 between the thermal preconditioning and control groups. However, after the 8th week after surgery, the thermal preconditioning group had a lower tendon adhesion score and higher mRNA and protein expressions of HSP72 than the control group. During the same period, we found longer gliding distance and higher expression levels of FGF-2, FGFR-1, ß-catenin, Tenomodulin and scleraxis, but lower EPCAM expression in the thermal preconditioning group. Pearson correlation analysis indicated that HSP72 mRNA and protein expression levels were negatively correlated with tendon adhesion. CONCLUSIONS: These findings provide evidence that thermal preconditioning may alleviate tendon adhesions via upregulation of HSP72 expression.