Abstract Recessively inherited loss-of-function mutations in the PTEN-induced putative kinase 1(Pink1), DJ-1 (Park7) and Parkin (Park2) genes are linked to familial cases of early-onset Parkinson's ...disease (PD). As part of its strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded the generation of novel rat models with targeted disruption ofPink1, DJ-1 or Parkin genes and determined if the loss of these proteins would result in a progressive PD-like phenotype. Pathological, neurochemical and behavioral outcome measures were collected at 4, 6 and 8 months of age in homozygous KO rats and compared to wild-type (WT) rats. Both Pink1 and DJ-1 KO rats showed progressive nigral neurodegeneration with about 50% dopaminergic cell loss observed at 8 months of age. ThePink1 KO and DJ-1 KO rats also showed a two to three fold increase in striatal dopamine and serotonin content at 8 months of age. Both Pink1 KO and DJ-1 KO rats exhibited significant motor deficits starting at 4 months of age. However, Parkin KO rats displayed normal behaviors with no neurochemical or pathological changes. These results demonstrate that inactivation of the Pink1 or DJ-1 genes in the rat produces progressive neurodegeneration and early behavioral deficits, suggesting that these recessive genes may be essential for the survival of dopaminergic neurons in the substantia nigra (SN). These MJFF-generated novel rat models will assist the research community to elucidate the mechanisms by which these recessive genes produce PD pathology and potentially aid in therapeutic development.
Heterozygous mutations in the GBA1 gene - encoding lysosomal glucocerebrosidase (GCase) - are the most common genetic risk factors for Parkinson's disease (PD). Experimental evidence suggests a ...correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable a better understanding of the relationship between aSyn and GCase activity, we developed and characterized two mouse models that investigate aSyn pathology in the context of reduced GCase activity. The first model used constitutive overexpression of wild-type human aSyn in the context of the homozygous GCase activity-reducing D409V mutant form of GBA1. Although increased aSyn pathology and grip strength reductions were observed in this model, the nigrostriatal system remained largely intact. The second model involved injection of aSyn preformed fibrils (PFFs) into the striatum of the homozygous GBA1 D409V knock-in mouse model. The GBA1 D409V mutation did not exacerbate the pathology induced by aSyn PFF injection. This study sheds light on the relationship between aSyn and GCase in mouse models, highlighting the impact of model design on the ability to model a relationship between these proteins in PD-related pathology.
Herein, the authors present the case of a 54-year-old male diagnosed with coronavirus disease 2019 (COVID-19) during a screening test. The patient was asked to self-isolate at home and report with ...any exacerbations of symptoms. He presented later with pneumonia complicated by encephalopathy at days 14 and 15 from initial diagnosis, respectively. MRI of the brain showed bithalamic and gangliocapsular FLAIR signal abnormality with mild right-sided thalamic and periventricular diffusion restriction. A CT venogram was obtained given the distribution of edema and demonstrated deep venous thrombosis involving the bilateral internal cerebral veins and the vein of Galen. CSF workup was negative for encephalitis, as the COVID-19 polymerase chain reaction (PCR) test and bacterial cultures were negative. A complete hypercoagulable workup was negative, and the venous thrombosis was attributed to a hypercoagulable state induced by COVID-19. The mental decline was attributed to bithalamic and gangliocapsular venous infarction secondary to deep venous thrombosis. Unfortunately, the patient's condition continued to decline, and care was withdrawn.
Introduction Extracorporeal membrane oxygenation (ECMO) is associated with a high rate of neurologic complications. Multimodal neurologic monitoring (MNM) has the potential for early detection and ...intervention. We examined the safety and feasibility of noninvasive MNM during ECMO. We hypothesized that survivors and non-survivors would have meaningful differences in transcranial Doppler (TCD) sonography and electroencephalographic (EEG) characteristics, which we aimed to identify. We also investigated adverse neurologic events and attempted to identify differences in EEG and TCD characteristics among patients based on the type of ECMO and the occurrence of these events. Material and methods We performed an observational study on all patients undergoing ECMO at Baylor St. Luke's Medical Center's critical care unit in Houston, Texas, United States, from January 2017 to February 2019. All patients underwent a noninvasive MNM protocol. Results NM was completed in 75% of patients; all patients received at least one component of the monitoring protocol. No adverse events were noted, showing the feasibility and safety of the protocol. The 60.4% of patients who did not survive tended to be older, had lower ejection fractions, and had lower median right middle cerebral artery (MCA) pulsatility and resistivity indexes. Patients undergoing venoarterial (VA)-ECMO had lower median left and right MCA velocities and lower right Lindegaard ratios than patients who underwent venovenous-ECMO. In VA-ECMO patients, EEG less often showed sleep architecture, while other findings were similar between groups. Adverse neurologic events occurred in 24.7% of patients, all undergoing VA-ECMO. Acute ischemic stroke occurred in 22% of patients, intraparenchymal hemorrhage in 4.9%, hypoxic-ischemic encephalopathy in 3.7%, subarachnoid hemorrhage in 2.5%, and subdural hematoma in 1.2%. Conclusion Our results suggest that MNM is safe and feasible for patients undergoing ECMO. Certain EEG and TCD findings could aid in the early detection of neurologic deterioration. MNM may not just be used in monitoring patients undergoing ECMO but also in prognostication and aiding clinical decision-making.
Background: Helicobacter pylori (H. pylori) infection is widely recognized for its association with gastric diseases. Prior studies on the relationship between H. pylori infection and biliary ...diseases have faced constraints, including inadequate control of confounding factors and small sample sizes. This study aims to explore the association between H. pylori infection and biliary diseases using a large, population-based sample with adequate control for various covariates.Methods: The National Inpatient Sample (NIS) from 2016 to 2020 was used to investigate the association between H. pylori infection and biliary diseases. We identified patients with H. pylori infection using the International Classification of Diseases, Tenth Revision (ICD-10) code (B96.81). Descriptive analysis and inferential statistics, including univariate and multivariate regression, were performed to explore the relationship between H. pylori and selected biliary diseases. Results: Overall, 32,966,720 patients were analyzed. Among them, 736,585 patients had biliary diseases (n=1,637 with H. pylori and n=734,948 without H. pylori). The baseline characteristics revealed notable differences in demographics and healthcare variables between both groups. Univariate regression analysis demonstrated significant associations between H. pylori infection and various biliary diseases such as gallbladder stones, gallbladder cancer, cholangitis, acute cholecystitis, and biliary pancreatitis, with the highest risk for chronic cholecystitis (odds ratio: 5.21; 95% confidence interval: 4.1-6.62; p<0.0001). Multivariate regression analysis, after adjusting for various covariates, confirmed these associations, providing insights into the potential causal relationship between H. pylori and biliary diseases.Conclusion: This study strengthens the evidence suggesting a potential association between H. pylori infection and biliary diseases. The findings need to be validated in prospective clinical studies.
Parkinson's disease is characterized by age-related atrophy and loss of dopaminergic neurons within the compact portion of the substantia nigra (SNpc) projecting to neostriatum. Despite numerous ...studies using rodent models to examine mechanisms underlying this disorder, the fundamental question of whether development- or age-related changes occur in the rodent SNpc remains unanswered. The present study used a three-level, optical fractionator approach to estimate the number and size of SNpc neurons immunoreactive for tyrosine hydroxylase (TH) in eight young (2-month) and eight older (7-month) Sprague–Dawley rats. Following standard protocols for animal care and tissue harvesting, every eighth 60-μm section from a gapless coronal series was treated immunohistochemically for TH along with a thionin counterstain. Neither the ventral tegmental area nor the lateral part of the SN was included in the analysis. The total bilateral number of SNpc TH+ neurons (∼8000) was equivalent between groups, whereas mean TH+ neuronal volume decreased significantly in the older group (∼18%). In contrast, volume of the SNpc increased with age by 17%, as did volume of the entire brain (24%). TH+ cells in the SNpc were also significantly larger on the left versus right side of the brain. These data are consistent with the hypothesis that age-related volumetric expansion of the SNpc is accounted for by an increase in the ratio between neuropil and average neuron somal size during intermediate postnatal development.
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