Clinical, Imaging, and Laboratory Markers of Premanifest Spinocerebellar Ataxia 1, 2, 3, and 6: A Systematic Review.

BACKGROUND AND PURPOSE: Premanifest mutation carriers with spinocerebellar ataxia (SCA) can exhibit subtle abnormalities before developing ataxia. We summarized the preataxic manifestations of SCA1, -2, -3, and -6, and their associations with ataxia onset. METHODS: We included studies of the premanifest carriers of SCA published between January 1998 and December 2019 identified in Scopus and PubMed by searching for terms including 'spinocerebellar ataxia' and several synonyms of 'preataxic manifestation'. We systematically reviewed the results obtained in studies categorized based on clinical, imaging, and laboratory markers. RESULTS: We finally performed a qualitative analysis of 48 papers. Common preataxic manifestations appearing in multiple SCA subtypes were muscle cramps, abnormal muscle reflexes, instability in gait and posture, lower Composite Cerebellar Functional Severity scores, abnormalities in video-oculography and transcranial magnetic stimulation, and gray-matter loss and volume reduction in the brainstem and cerebellar structures. Also, decreased sensory amplitudes in nerve conduction studies were observed in SCA2. Eotaxin and neurofilament light-chain levels were revealed as sensitive blood biomarkers in SCA3. Concerning potential predictive markers, hyporeflexia and abnormalities of somatosensory evoked potentials showed correlations with the time to ataxia onset in SCA2 carriers. However, no longitudinal data were found for the other SCA gene carriers. CONCLUSIONS: Our results suggest that preataxic manifestations vary among SCA1, -2, -3, and -6, with some subtypes sharing specific features. Combining various markers into a standardized index for premanifest carriers may be useful for early screening and assessing the risk of disease progression in SCA carriers.

Enhancement of neuroprotection, antioxidant capacity, and water-solubility of crocins by transglucosylation using dextransucrase under high hydrostatic pressure.

Crocin, one of the major carotenoid pigments of Crocus sativus (saffron), is responsible for antioxidant activity, neuroprotection, and the inhibition of tumor cell proliferation. In order to improve the functionality of crocin, α-glucosyl-(1→6)-trans-crocins (C-Gs) were synthesized using sucrose and dextransucrase from Leuconostoc mesenteroides. High hydrostatic pressure (HHP) technique was applied to the synthesis process of C-Gs in order to improve its transglucosylation yield. A 100 MPa HHP condition enhanced the production yield of C-Gs by 1.95 times compared to that of 0.1 MPa atmospheric pressure. Novel C-Gs were purified by HPLC, and their chemical structures were determined using NMR analysis. Novel C-Gs increased water solubility 4.6-5.7 times and antioxidant activity 1.5-2.6 times, respectively, compared to crocin, and their neuroprotections (cell viability 92.5-100.4 %) on HT22 mouse hippocampal neuronal cells were significantly higher than that of crocin (cell viability 84.6 %). This advanced neuroprotection of novel C-Gs could be highly associated with their enhanced antioxidant activity. Thus, the enhanced water solubility and functionality of novel C-Gs can induce better clinical efficacy of neuroprotection than trans-crocin.

Prediction of Suicidal Ideation among Korean Adults Using Machine Learning: A Cross-Sectional Study.

OBJECTIVE: Suicidal ideation (SI) precedes actual suicidal event. Thus, it is important for the prevention of suicide to screen the individuals with SI. This study aimed to identify the factors associated with SI and to build prediction models in Korean adults using machine learning methods. METHODS: The 2010-2013 dataset of the Korea National Health and Nutritional Examination Survey was used as the training dataset (n=16,437), and the subset collected in 2015 was used as the testing dataset (n=3,788). Various machine learning algorithms were applied and compared to the conventional logistic regression (LR)-based model. RESULTS: Common risk factors for SI included stress awareness, experience of continuous depressive mood, EQ-5D score, depressive disorder, household income, educational status, alcohol abuse, and unmet medical service needs. The prediction performances of the machine learning models, as measured by the area under receiver-operating curve, ranged from 0.794 to 0.877, some of which were better than that of the conventional LR model (0.867). The Bayesian network, LogitBoost with LR, and ANN models outperformed the conventional LR model. CONCLUSION: A machine learning-based approach could provide better SI prediction performance compared to a conventional LR-based model. These may help primary care physicians to identify patients at risk of SI and will facilitate the early prevention of suicide.

Ginsenoside Rb2 suppresses the glutamate-mediated oxidative stress and neuronal cell death in HT22 cells.

BACKGROUND: The objective of our study was to analyze the neuroprotective effects of ginsenoside derivatives Rb1, Rb2, Rc, Rd, Rg1, and Rg3 against glutamate-mediated neurotoxicity in HT22 hippocampal mouse neuron cells. METHODS: The neuroprotective effect of ginsenosides were evaluated by measuring cell viability. Protein expressions of mitogen-activated protein kinase (MAPK), Bcl2, Bax, and apoptosis-inducing factor (AIF) were determined by Western blot analysis. The occurrence of apoptotic and death cells was determined by flow cytometry. Cellular level of Ca2+ and reactive oxygen species (ROS) levels were evaluated by image analysis using the fluorescent probes Fluor-3 and 2',7'-dichlorodihydrofluorescein diacetate, respectively. In vivo efficacy of neuroprotection was evaluated using the Mongolian gerbil of ischemic brain injury model. RESULT: Reduction of cell viability by glutamate (5 mM) was significantly suppressed by treatment with ginsenoside Rb2. Phosphorylation of MAPKs, Bax, and nuclear AIF was gradually increased by treatment with 5 mM of glutamate and decreased by co-treatment with Rb2. The occurrence of apoptotic cells was decreased by treatment with Rb2 (25.7 µM). Cellular Ca2+ and ROS levels were decreased in the presence of Rb2, and in vivo data indicated that Rb2 treatment (10 mg/kg) significantly diminished the number of degenerated neurons. CONCLUSION: Our results suggest that Rb2 possesses neuroprotective properties that suppress glutamate-induced neurotoxicity. The molecular mechanism of Rb2 is by suppressing the MAPKs activity and AIF translocation.

Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease.

SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2) is a lipid phosphatase that produce phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) from phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), and is involved in many diseases such as neurodegenerative diseases. A recent report demonstrating that SHIP2 inhibition decreased tau hyperphosphorylation induced by amyloid ß and rescued memory impairment in a transgenic Alzheimer's disease mouse model indicates SHIP2 can be a promising therapeutic target for Alzheimer's disease. In the present study, we have developed novel, potent SHIP2 inhibitors by extensive structural elaboration of crizotinib discovered from a high-throughput screening. Our representative compound 43 potently inhibited SHIP2 activity as well as GSK3ß activation in HT22 neuronal cells. It was also shown that 43 has favorable physicochemical properties, especially high brain penetration. Considering SHIP2 is one of key signal mediators for tau hyperphosphorylation, our potent SHIP2 inhibitor 43 may function as a promising lead compound for the treatment of Alzheimer's disease.

A Prediction Model Using Machine Learning Algorithm for Assessing Stone-Free Status after Single Session Shock Wave Lithotripsy to Treat Ureteral Stones.

PURPOSE: The aim of this study was to develop and validate a decision support model using a machine learning algorithm to predict treatment success after single session shock wave lithotripsy in ureteral stone cases. MATERIALS AND METHODS: Of the 1,803 patients treated with shock wave lithotripsy we selected those with ureteral stones who had preoperative computerized tomography available. Treatment success after single session shock wave lithotripsy was defined as freedom from stones or residual stone fragments less than 2 mm long on computerized tomography or plain x-ray of the kidneys, ureters and bladder 2 weeks later. Decision tree analysis was done using a machine learning algorithm to identify relevant parameters. A decision support model was developed to calculate the probability of treatment success. RESULTS: A total of 791 patients were enrolled in study. Mean ± SD stone length was 5.9 ± 2.3 mm and mean stone volume was 89.3 ± 140.0 mm3. The overall treatment success rate after SWL was 64.4% (509 cases). The rate for upper, middle and lower ureter stones was 59.8%, 65.5% and 69.6%, respectively. On decision tree analysis the top 3 performance criteria factors were volume, length and HU. Decision models were constructed with all possible combinations of factors. The model with 15 factors had greater than 92% accuracy and an average ROC AUC of 0.951. CONCLUSIONS: We applied a machine learning algorithm, a subfield of artificial intelligence, to predict the outcome after single session shock wave lithotripsy for ureteral stones. A 92.29% accurate decision model was developed with 15 factors and an average ROC AUC of 0.951.

Quantity of Disc Removal and Radiological Outcomes of Percutaneous Endoscopic Lumbar Discectomy.

BACKGROUND: Herniated intervertebral disc disease (HIVD) is a common cause of lower back and leg pain. Percutaneous endoscopic lumbar discectomy (PELD) is indicated when non-surgical treatments such as medication and interventions are intractable. Ruptured discs and loose fragments inside discs are removed during PELD. Nerve root decompression is usually assessed by visualizing the free movement of the traversing nerve root or epidural fat, the free passage of a probe into the epidural space, the depression of the annulus, and the removal of the expected ruptured discs and loose fragments based on preoperative magnetic resonance images (MRI). However, these criteria are subjective, and the quantity of the disc removal necessary for successful outcomes after PELD has not been investigated. OBJECTIVES: The present study investigates the amount of discectomy of PELD and its clinical and radiological outcomes. STUDY DESIGN: A retrospective case study (IRB Number H-1611-015-803). SETTING: University Medical Center, Seoul, Korea. METHODS: PELD was performed in 109 consecutive patients (M:F = 53:56; mean age, 37.4 years) using the transforaminal or interlaminar route. Ruptured disc fragments were first removed in all patients, and the graspable loose fragments under the disc were removed. After surgery, all removed disc fragments were placed into disposable syringes and manually compressed to measure their volume. The volume of herniated disc outside the disc boundary was calculated in MRI. The measured and calculated disc volumes were retrospectively compared. Clinical success was defined as an improvement in both the Oswestry Disability Index (ODI) and leg pain, as well as no recurrent symptoms. Radiological success was defined as the disappearance of herniated disc material outside the disc boundary based on postoperative MRI taken within one day after surgery. The follow-up period was 7.2 ± 5.2 months. RESULTS: Successful clinical outcomes were obtained in 96/109 (88.1%) patients in a median time of 3 months. Re-operation was performed in 3 patients due to recurrent discs in 2 patients and a residual disc in one patient. Predictors of clinical success were not identified, and the quantity of the removed disc was not associated with the clinical outcome. Radiological success was achieved in 93/109 (85.3%) patients. Of 13 patients with radiological failure, 2 patients showed clinical failure. A logistic regression analysis showed that the relative volume of the removed disc (%) compared with the volume of preoperative herniated disc based on the MRI was the only significant predictor (P < 0.001; OR = 0.96). When 100% of the calculated disc amount was removed during the operation, the probability of residual disc was 30%. When 131% of the calculated disc amount was removed, the probability of residual disc was 10%. LIMITATIONS: This study employed a retrospective design, and its inherent selection bias and limited statistical power should be considered. CONCLUSIONS: The amount of disc removal during PELD was not a significant predictor of clinical success after the primary ruptured fragments were removed. The relative volume of the removed disc based on the preoperative MRI might predict the postoperative MRI. KEY WORDS: Disc, lumbar vertebra, discectomy, surgery, endoscopy, volume.