A microtubule stabilizer ameliorates protein pathogenesis and neurodegeneration in mouse models of repetitive traumatic brain injury.

Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and subsequent tau spreading in patient brains are largely unknown, traumatic brain injury (TBI) may be a risk factor for tau-mediated neurodegeneration. Using a repetitive TBI (rTBI) paradigm, we report that rTBI induced somatic accumulation of phosphorylated and misfolded tau, as well as neurodegeneration across multiple brain areas in 7-month-old tau transgenic PS19 mice but not wild-type (WT) mice. rTBI accelerated somatic tau pathology in younger PS19 mice and WT mice only after inoculation with tau preformed fibrils and AD brain-derived pathological tau (AD-tau), respectively, suggesting that tau seeds are needed for rTBI-induced somatic tau pathology. rTBI further disrupted axonal microtubules and induced punctate tau and TAR DNA binding protein 43 (TDP-43) pathology in the optic tracts of WT mice. These changes in the optic tract were associated with a decline of visual function. Treatment with a brain-penetrant microtubule-stabilizing molecule reduced rTBI-induced tau, TDP-43 pathogenesis, and neurodegeneration in the optic tract as well as visual dysfunction. Treatment with the microtubule stabilizer also alleviated rTBI-induced tau pathology in the cortices of AD-tau-inoculated WT mice. These results indicate that rTBI facilitates abnormal microtubule organization, pathological tau formation, and neurodegeneration and suggest microtubule stabilization as a potential therapeutic avenue for TBI-induced neurodegeneration.

Surgical Treatment for Refractory Gastroparesis: Stimulator, Pyloric Surgery, or Both?

BACKGROUND: Several surgical options exist for refractory gastroparesis (Gp) including gastric electric stimulation (GES) and pyloric surgery (PS) such as pyloromyotomy or pyloroplasty. Few studies exist comparing the outcomes of these surgeries. AIM: Compare the clinical outcomes of GES, PS, and simultaneous GES+PS for refractory Gp. METHODS: Patients undergoing surgical intervention at our medical center from January 2016 to April 2019 were given pre- and post-surgery questionnaires to assess their response to intervention: Patient Assessment of Upper Gastrointestinal Symptoms (PAGI-SYM) grading symptoms and Clinical Patient Grading Assessment Scale (CPGAS) grading response to treatment. Results are expressed as mean ± SE. RESULTS: One hundred thirty-two patients underwent surgical intervention; 12 were excluded. Mean CPGAS improvement overall was 2.8 ± 0.2 (p < 0.01): GES+PS had CPGAS score at 3.6 ± 0.5, pyloric interventions 3.1 ± 0.5, and GES 2.5 ± 0.4 (p > 0.05). Mean improvement in Gastroparesis Cardinal Symptom Index (GCSI) total score was 1.0 ± 0.1 (p < 0.01), with improvement of 1.1 ± 0.2 for GES + PS, 0.9 ± 0.2 for GES, and 0.9 ± 0.2 for PS (p > 0.05). GES and GES + PS, but not PS only, significantly improved symptoms of nausea and vomiting (p < 0.01). Among gastroparesis subtypes, patients with diabetic gastroparesis had more improvement on nausea/vomiting subscale compared with idiopathic gastroparesis (p = 0.028). CONCLUSIONS: Patients with refractory symptoms of Gp undergoing GES, PS, or combined GES+PS each had significant improvement of their GCSI total score. GES and combined GES+PS significantly improved nausea/vomiting. These results suggest GES or combined GES+PS appears better for nausea/vomiting predominant refractory Gp.

Factors Associated With Hospital Admissions and Readmissions in Patients With Gastroparesis Using the Nationwide Readmission Database.

BACKGROUND: Gastroparesis can be associated with severe symptoms. Health care utilization for gastroparesis has increased in part due to an increase in hospital admissions. GOALS: To characterize patients admitted for gastroparesis-related symptoms and determine risk factors associated with 30-day readmissions. STUDY: The Nationwide Readmission Database (NRD) for the year 2014 was used to identify patients admitted to hospitals using the International Classification of Diseases (ICD)-9 code for gastroparesis as primary diagnosis or as the secondary diagnosis with first diagnosis code of a gastroparesisrelated symptom. Logistic regression was used to determine risk factors associated with 30-day readmission. RESULTS: There were 5268 gastroparesis patients admitted with the average length of stay (LOS) of 5.4±6.6 days. Age averaged 48.9±18.1 years, 73.8% were female individuals, and 31% had diabetes. Inpatient mortality was 0.4%. The overall 30-day readmission rate was 6.2%. Longer LOS [odds ratio (OR)=1.4; 95% confidence interval (CI), 1.0-1.9], younger age, drug abuse (OR=1.6; 95% CI, 1.2-2.2), and marijuana use (OR=1.7; 95% CI, 1.0-2.7) were associated with increased risk of 30-day readmission. Female gender (P=0.083), opioid use (P=0.057), and admission to larger hospital (P=0.070) showed a trend toward higher readmission rates. Older patients, and patients with hypertension and diabetes showed lower rates of readmission. CONCLUSIONS: Use of the Nationwide Readmission Database (NRD) allows better understanding of gastroparesis admissions and readmissions. Average hospital stay was 5.4 days with 0.4% mortality rate. Overall 30-day readmission rate was 6.2%. Higher LOS, drug abuse, and marijuana use increased the 30-day readmission rate. Diabetes, hypertension, and older age were associated with lower readmissions.

Symptom variability throughout the day in patients with gastroparesis.

BACKGROUND: Symptoms of gastroparesis (Gp) can fluctuate at different times of the day. Our aims are (1) To characterize Gp symptom variability throughout the day and in relation to meals and (2) to compare the daily symptom variability in subtypes of Gp-diabetic gastroparesis (DGp) and idiopathic gastroparesis (IGp). METHODS: Patients with Gp filled Patient Assessment of Gastrointestinal Symptoms (PAGI-SYM) and completed a modified GCSI-DD seven times a day (GCSI-Throughout the Day [GCSI-TTD]; before and after meals, and before going to bed) over a 2-week period. KEY RESULTS: A total of 44 patients participated (86% females), including 29 (66%) with IGp, 13 (30%) with DGp, and 2 (4%) with postsurgical Gp. Using the GCSI-TTD, patients with Gp reported significant postprandial worsening of overall symptom severity, as well as severities of nausea, early satiety, stomach fullness, and abdominal pain. Patients also had progressive worsening of the overall symptom severity, early satiety, stomach fullness, and abdominal pain during the day; however, nausea severity did not differ during the day. Number of vomiting and retching episodes did not show significant variations postprandially or during the day. Patients with IGp had greater symptom severity throughout the day and greater postprandial increase in symptoms compared to patients with DGp. CONCLUSIONS AND INFERENCES: Patients with Gp experience postprandial worsening of overall symptom severity, as well as severities of nausea, early satiety, stomach fullness, and abdominal pain. These symptoms also progressively worsen during the day, except for the severity of nausea which persists throughout the day. Understanding the symptom variability in patients with Gp throughout the day and postprandially may be useful in treatment of patients with Gp.

Gastric Electric Stimulation for Refractory Gastroparesis.

OBJECTIVE: To outline the use and utility of gastric electric stimulation (GES) as a therapeutic intervention for gastroparesis. METHODS: Review of the literature. RESULTS: Gastroparesis is characterized by delayed gastric emptying, with symptoms of nausea, vomiting, early satiety, postprandial fullness, and abdominal pain. Some patients with gastroparesis do not respond to medical intervention, and for these patients surgical intervention may be warranted. GES utilizes high-frequency gastric neurostimulation to facilitate gastric emptying and reduce symptoms of gastroparesis. It is indicated for patients with idiopathic and diabetic gastroparesis who have nausea and vomiting as their primary symptoms and who have not responded to medical therapy. GES has also been used in postsurgical and pediatric gastroparesis patients. Optimizing the outcome of this surgical treatment through proper patient selection and meticulous surgical technique is essential as there are inherent risks to the procedure. Nonblinded studies of GES for medically refractory gastroparesis have demonstrated therapeutic symptomatic benefit, whereas randomized controlled trials have not. New interventions such as pyloromyotomy and pyloroplasty are reasonable alternatives or addendums to GES. CONCLUSION: GES may be considered among the therapies available for treating patients with refractory symptoms of gastroparesis. More studies, specifically those comparing GES, pyloromyotomy, GES combined with pyloromyotomy, and placebo, are needed to help guide therapy selection for refractory gastroparesis.

De novo coronary artery disease in graves' disease. coincidence?

Hyperthyroidism is associated with increased risk of cardiovascular conditions. We report a case of a 50-year-old woman with no prior cardiac history who presented to the emergency department with shortness of breath, chest pain, lower extremity swelling, and generalized fatigue. She was found to have Graves' Disease (GD) and extensive coronary artery disease (CAD), suggesting the possibility of increased risk of de novo CAD in patients with GD in the absence of other risk factors.

Outcomes of surgical intervention for refractory gastroparesis: a systematic review.

BACKGROUND: Gastroparesis (GP) is characterized by delayed gastric emptying with symptoms of nausea, vomiting, early satiety, postprandial fullness, and abdominal pain. Various surgical options exist to treat GP not responding to medical treatments (refractory GP), including gastric electric stimulation (GES), gastrectomy (GTx), and pyloric interventions (PI), whereas the outcomes of these procedures have been published; few comparison studies exist. METHODS: PubMed literature review for articles from September 1988 to October 2017 was performed for prospective and retrospective analyses reporting >5 patients. Unweighted (per study) and weighted (per patient) overall improvement and improvement in symptoms of nausea, vomiting, and abdominal pain were calculated and compared for the different procedures. RESULTS: Of 325 studies satisfying search criteria, 38 met the study criteria and were included for analysis. Total response to intervention, both weighted and unweighted, was greater with PIs compared to GES (P < 0.05). For unweighted symptom improvements, nausea improved more with PI than with GES (P < 0.05). GES improved vomiting more than epigastric pain (P < 0.05). For weighted symptom improvements, pyloric surgery and GTx improved vomiting compared to GES (P < 0.05). CONCLUSIONS: Published outcomes of GES, pyloric surgery, and GTx for refractory GP are compared. Pyloromyotomy/pyloroplasty improves patient response greater than with GES. Weighing by number of studies, pyloric surgery improves nausea and abdominal pain greater than GES. For GES, vomiting is more likely to improve than abdominal pain. Weighing by number of patients, pyloric surgery and GTx improved vomiting compared to GES.

The Dynamics and Turnover of Tau Aggregates in Cultured Cells: INSIGHTS INTO THERAPIES FOR TAUOPATHIES.

Filamentous tau aggregates, the hallmark lesions of Alzheimer disease (AD), play key roles in neurodegeneration. Activation of protein degradation systems has been proposed to be a potential strategy for removing pathological tau, but it remains unclear how effectively tau aggregates can be degraded by these systems. By applying our previously established cellular model system of AD-like tau aggregate induction using preformed tau fibrils, we demonstrate that tau aggregates induced in cells with regulated expression of full-length mutant tau can be gradually cleared when soluble tau expression is suppressed. This clearance is at least partially mediated by the autophagy-lysosome pathway, although both the ubiquitin-proteasome system and the autophagy-lysosome pathway are deficient in handling large tau aggregates. Importantly, residual tau aggregates left after the clearance phase leads to a rapid reinstatement of robust tau pathology once soluble tau expression is turned on again. Moreover, we succeeded in generating monoclonal cells persistently carrying tau aggregates without obvious cytotoxicity. Live imaging of GFP-tagged tau aggregates showed that tau inclusions are dynamic structures constantly undergoing "fission" and "fusion," which facilitate stable propagation of tau pathology in dividing cells. These findings provide a greater understanding of cell-to-cell transmission of tau aggregates in dividing cells and possibly neurons.