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Spinocerebellar ataxia (SCA) type 1 (SCA1) is a rare autosomal dominant disorder that is characterized by worsening of disordered coordination, ataxia of the trunk, and other neurological symptoms. Physical activity improves both mobility and the daily living activities of patients with SCA. Intervention with daily regular treadmill exercise may slow the deterioration of cerebellar neurons in SCA1. Therefore, the signal changes and performance of cerebellar neurons after exercise in SCA1 was investigated in this study. We employed a transgenic mouse model of SCA1, generated by amplifying the cytosine‐adenine‐guanine trinucleotide repeat expansions, and the mice underwent 1 month of moderate daily treadmill exercise for 1 hour. The rotarod test revealed that the motor function of the SCA1 mice that underwent training was superior to that of the control SCA1 mice, which did not undergo training. Moreover, the cerebellar pathology revealed preserved Purkinje neurons stained by carbindin with an increase of the neuronal Per Arnt Sim domain protein 4, a key regulation in the structural and functional plasticity of neurons, in the excised SCA1 mice relative to the controls. The mechanism was related to an increase of phosphorylation of ribosomal protein S6, a downstream target of the mammalian target of rapamycin pathway, but not to autophagy activation. This study determined that regular treadmill exercise may play a crucial role in the viable support of cerebellar neurons in SCA1.

Background: Clinical and epidemiological studies suggest that two of the most common geriatric diseases, type 2 diabetes and Parkinson’s disease (PD), are linked. These studies notably suggest that treatment of insulin resistance in type 2 diabetes may beneficially modify the pathophysiology of PD and help to maintain motor and nonmotor function. In this meta-analysis, we evaluate the efficacy of new antidiabetic agents in the treatment of PD. Methods: We systematically searched PubMed, Medline, ProQuest, ScienceDirect, ClinicalKey, and Cochrane Library from the date of their inception until 15 March 2020. Multiple efficacy parameters were compared between treatment groups. The results are expressed as mean differences with 95% confidence intervals (CIs) in a random-effects model. Results: A meta-analysis of the data extracted from three randomized control trials revealed that treatment with exenatide yielded significant improvements in scores on the Unified Parkinson’s Disease Rating Scale Part I (UPDRS-I) (−0.438, 95% CI, −0.828 to −0.048, p = 0.028), UPDRS Part IV (UPDRS-IV) (−0.421, 95% CI, −0.811 to −0.032, p = 0.034) and the Mattis Dementia Rating Scale (MDRS) (−0.595, 95% CI, −1.038 to −0.151, p = 0.009). At the 12-month follow-up, the UPDRS Part III (UPDRS-III) scores in the off-medication phase revealed significant improvements in patients using exenatide (−0.729; 95% CI, −1.233 to −0.225, p = 0.005). Treatment with pioglitazone did not yield significant improvements in UPDRS, MDRS, or Parkinson’s Disease Questionnaire scores. Conclusion: This meta-analysis suggests that exenatide use is associated with the alleviation of cognitive, motor and nonmotor symptoms. However, long-term studies with a large sample size of patients with PD of varying severity are required.

Rationale: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset progressive muscle disorder typically characterized by ptosis, difficulty in swallowing, and proximal limb weakness. Underdiagnosis of OPMD is common in Asian countries and results in delayed diagnoses and fatal events. Patient concerns: Here, we report the case of a 53-year-old female who suffered from progressive dysphagia and experienced several choking events involving solid material. An extensive family history of dysphagia was noted, and 2 family members had died as a result of aspiration. Diagnoses: PABPN1 genotyping and DNA sequence analysis revealed a heterozygous (GCG)10(GCA)3GCG mutation that led to the diagnosis of OPMD. Interventions: Rehabilitation exercises, namely, the Shaker exercise and the Masako maneuver, were suggested. Outcomes: Improved swallowing ability with safe food intake was noted after 2 months of training. Surgical intervention will be considered when progression of the disease is noted. Lessons: Underdiagnosis and a lack of awareness of OPMD may lead to choking, aspiration pneumonia, and death in multiple members of affected families. Currently, there is no definitive treatment for OPMD, but rehabilitation exercises and surgical intervention are helpful in relieving dysphagia.

Objective: Previous research has demonstrated that patients with a history of organophosphate poisoning tend to have a higher risk of neurological disorder. However, research on the rate of seizure development in patients after organophosphate poisoning is lacking. This study examined whether individuals with organophosphate poisoning have an increased risk of seizures through several years of follow-up. Patients and Methods: We conducted a retrospective study on a cohort of 45,060 individuals (9012 patients with a history of organophosphate poisoning and 36,048 controls) selected from the Taiwan National Health Insurance Research Database. The individuals were observed for a maximum of 12 years to determine the rate of new-onset seizure disorder. We selected a comparison cohort from the general population that was randomly frequency-matched by age, sex, and index year and further analyzed the risk of seizures using a Cox regression model adjusted for sex, age, and comorbidities. Results: During the study period, the risk of seizure development was 3.57 times greater in patients with organophosphate poisoning compared with individuals without, after adjustments for age, sex, and comorbidities. The absolute incidence of seizures was highest in individuals aged 20 to 34 years in both cohorts (adjusted hazard ratio = 13.0, 95% confidence interval = 5.40&minus, 31.4). A significantly higher seizure risk was also observed in patients with organophosphate poisoning and comorbidities other than cirrhosis. Conclusions: This nationwide retrospective cohort study demonstrates that seizure risk is significantly increased in patients with organophosphate poisoning compared with the general population.

Background aims The feasibility of delivering mitochondria using the cell-penetrating peptide Pep-1 for the treatment of MERRF (myoclonic epilepsy with ragged red fibers) syndrome, which is caused by point mutations in the transfer RNA genes of mitochondrial DNA, is examined further using cellular models derived from patients with MERRF syndrome. Methods Homogenesis of mitochondria (wild-type mitochondria) isolated from normal donor cells with about 83.5% preserved activity were delivered into MERRF fibroblasts by Pep-1 conjugation (Pep-1-Mito). Results Delivered doses of 52.5 μg and 105 μg Pep-1-Mito had better delivered efficiency and mitochondrial biogenesis after 15 days of treatment. The recovery of mitochondrial function in deficient cells receiving 3 days of treatment with peptide-mediated mitochondrial delivery was comprehensively demonstrated by restoration of oxidative phosphorylation subunits (complex I, III and IV), mitochondrial membrane potential, adenosine triphosphate synthesis and reduction of reactive oxygen species production. The benefits of enhanced mitochondrial regulation depended on the function of foreign mitochondria and not the existence of mitochondrial DNA and can be maintained for at least 21 days with dramatically elongated mitochondrial morphology. In contrast to delivery of wild-type mitochondria, the specific regulation of Pep-1-Mito during MERRF syndrome progression in cells treated with mutant mitochondria was reflected by the opposite performance, with increase in reactive oxygen species production and matrix metalloproteinase activity. Conclusions The present study further illustrates the feasibility of mitochondrial intervention therapy using the novel approach of peptide-mediated mitochondrial delivery and the benefit resulting from mitochondria-organelle manipulation.

Dyslipidemia is a major risk factor for cardiovascular complications in people with diabetes. Lowering low-density lipoprotein cholesterol (LDL-C) levels is effective in the primary and secondary prevention of diabetic vascular complications. However, LDL-C levels do not reflect all aspects of diabetic dyslipidemia, which is characterized by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). Statins, nicotinic acid, and fibrates play a role in treating diabetic dyslipidemia. Atherosclerosis is a major disorder of the blood vessel wall in patients with diabetes. A number of antihyperlipidemic agents may be beneficial and exhibit effects at the actual site of vascular disease and not only on plasma lipoprotein concentrations. Several novel therapeutic compounds are currently being developed. These include additional therapeutics for LDL-C, triglycerides, HDL-C, and modulators of inflammation that can be used as possible synergic agents for the treatment of atherosclerosis and irregularities in plasma lipoprotein concentrations.

Pneumoconiosis is a parenchymal lung disease that develops through the inhalation of inorganic dust at work. Cerebrovascular and cardiovascular events are leading causes of mortality and adult disability worldwide. This retrospective cohort study investigated the association between pneumoconiosis, and cerebrovascular and cardiovascular events by using a nationwide population-based database in Taiwan. The data analyzed in this study was retrieved from the Taiwan National Health Insurance Research Database. We selected 6940 patients with pneumoconiosis from the database as our study cohort. Another 27,760 patients without pneumoconiosis were selected and matched with those with pneumoconiosis according to age and sex as the comparison cohort. We used univariate and multivariate Cox proportional-hazard regression analyses to determine the association between pneumoconiosis and the risk of cerebrovascular and cardiovascular events after adjusting for medical comorbidities. After adjustment for age, sex, and comorbidities, the patients with pneumoconiosis exhibited a significantly higher incidence of ischemic stroke (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.05-1.24) than did those without pneumoconiosis. The incidence of hemorrhagic stroke was higher, but not significant, in the pneumoconiosis patients (HR 1.20, 95% CI 0.99-1.46). No statistically significant differences were observed between the pneumoconiosis and nonpneumoconiosis groups in acute coronary syndrome (HR 1.10, 95% CI 0.95-1.26). The findings of this study reveal an association between pneumoconiosis and a higher risk of cerebrovascular events after adjustment for comorbidities. Healthcare providers should control the related risk factors for primary prevention of stroke in pneumoconiosis patients.

Although gait change is considered a useful indicator of severity in animal models of Parkinson's disease, systematic and extensive gait analysis in animal models of neurological deficits is not well established. The CatWalk-assisted automated gait analysis system provides a comprehensive way to assess a number of dynamic and static gait parameters simultaneously. In this study, we used the Catwalk system to investigate changes in gait parameters in adult rats with unilateral 6-OHDA-induced lesions and the rescue effect of dopaminergic neuron transplantation on gait function. Four weeks after 6-OHDA injection, the intensity and maximal area of contact were significantly decreased in the affected paws and the swing speed significantly decreased in all four paws. The relative distance between the hind paws also increased, suggesting that animals with unilateral 6-OHDA-induced lesions required all four paws to compensate for loss of balance function. At 8 weeks post-transplantation, engrafted dopaminergic neurons expressed tyrosine hydroxylase. In addition, the intensity, contact area, and swing speed of the four limbs increased and the distance between the hind paws decreased. Partial recovery of methamphetamine-induced rotational response was also noted.

Diabetes is associated with an increased risk of various forms of cancer, such as cancer of the liver, colon, pancreas, breast, bladder, and kidney. Metformin, widely given to patients with type 2 diabetes, works by inhibiting hepatic glucose production through an LKB1 (serine-threonine liver kinase B1)/AMP-activated protein kinase (AMPK)–mediated mechanism. LKB1 is a well-recognized tumor suppressor. Activation of AMPK by LKB1 plays an important role in inhibiting cell growth. It has been suggested that metformin use in patients with diabetes may reduce their risk of cancer (1). Some studies have reported that diabetic patients taking metformin showed decreased cancer risk (2,3). However, several studies have shown that metformin does not reduce the risk of cancer in patients with diabetes (4,5). Little information is available on the subject considering non-Caucasian ethnicity. We used representative National Health Insurance datasets for Taiwan to form a cohort to …

Dementia is among various diseases affecting the elderly, who is also at a high risk for fractures. This study aimed to evaluate the association between fracture history and sequential risk of dementia in Taiwan. A retrospective cohort study was designed using the claims data of the entire insured residents covered by Taiwan's universal health insurance from 1998 to 2010. A total of 66,797 patients with fractures and 133,594 control subjects without fractures were matched in terms of age (±5 years), sex, and index year and then recruited. Fractures and dementia were defined in accordance with the International Classification of Diseases, 9th Revision, Clinical Modification. The influence of fractures on the risk of dementia was analyzed using a Cox proportional hazards model. After a 12-year follow-up period, 2775 and 3991 incident cases of dementia were reported in exposed and unexposed cohorts, respectively. The overall incidence rate of dementia in individuals with fractures was 41% higher than that in individuals without fractures (6.05 vs 4.30 per 1000 person-years) at an adjusted hazard ratio of 1.38 (95% confidence interval 1.32–1.45) after age, sex, urbanization, and individual disorders or comorbidities were adjusted. Considering fracture location, we found that patients with hip fractures were at a slightly high risk for dementia. The occurrence of multiple fractures at a single visit was also significantly associated with an increased risk of dementia. Fracture history is regarded as an independent risk factor of dementia in individuals aged ≥65 years, particularly those who suffered from multiple fractures and/or fractures located in the hip. Further studies are needed to support an independent role of fracture in dementia considering the clinical information and other comorbidities.

ntroduction: Pituitary apoplexy is a rare but life-threatening disorder. The clinical presentation includes severe headache, impaired consciousness, fever, visual disturbances, variable ocular paresis and hypoadrenalism. It usually results from sudden hemorrhage or infarction-induced swelling in a pituitary adenoma. Signs of meningeal irritation are very rare. The presentation of headache, fever, pleocytosis and meningism might lead to a misdiagnosis of septic meningitis. Case Report: We described a 71-year-old man who suffered from acute headache, fever, chills, dizziness and photophobia. Stiffness in the neck was notable and the cerebrospinal fluid study revealed neutrophilic pleocytosis. Empiric antibiotic therapy was administered for suspected septic meningitis but the symptoms persisted. Further brain imaging study showed pituitary adenoma with recent hemorrhage and the endocrine survey revealed a low cortisol level. Corticosteroid was added for pituitary apoplexy, and the patient recovered without surgical management. Conclusion: When a patient presents with fever, headache and meningeal irritation, it is important to include pituitary apoplexy in the differential diagnosis of infectious meningitis. Early treatment of pituitary apoplexy allows for aggressive endocrine management or neurosurgical decompression when required.

Abnormal magnetic resonance spectroscopic (MRS) signals in the basal ganglia may be one of the characteristics in mitochondrial disease. We report MRS study in a family with myoclonic epilepsy with ragged-red fibers (MERRF). Their MRS studies over the basal ganglia revealed decreased N-acetylaspartate/creatine ratio and increased choline/creatine ratio in the four symptomatic members, but normal in the two asymptomatic members. However, negative MRI study was found in all members of this family. Our report suggests that the increased choline/creatine ratio in basal ganglia MRS may be one of the early information to suspect MERRF disease.