Assessment of the economic relevance of the use of single-use digital flexible ureteroscopes A systematic review.

Introduction: Breakages and repairs related to flexible digital reusable ureteroscopes (flURS) are expensive. Thus, we aimed to assess the cost-effectiveness of single-use flexible digital ureteroscopes ureteroscopes (SUFDU).

Methods: We conducted a literature review on MEDLINE and EMBASE until September 19, 2018.

Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections.

Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead , we describe efforts to identify an improved compound with a lower human dose projection, minimal P-glycoprotein (P-gp) efflux, and acceptable pregnane X receptor (PXR) profile through fluorine substitution.

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs).

Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.

Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS).

A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy.

Mutations in the lysosomal enzyme glucocerebrosidase (GCase, GBA1 gene) are the most common genetic risk factor for developing Parkinson's disease (PD). GCase metabolizes the glycosphingolipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Mutations in GBA1 reduce enzyme activity and the resulting accumulation of glycosphingolipids may contribute to the underlying pathology of PD, possibly via altering lysosomal function.

Decreased glucocerebrosidase activity and substrate accumulation of glycosphingolipids in a novel GBA1 D409V knock-in mouse model.

Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher's disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson's disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiopathic PD.

LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson's disease.

LRRK2 has been implicated in endolysosomal function and likely plays a central role in idiopathic Parkinson's disease (iPD). In iPD, dopaminergic neurons within the substantia nigra are characterized by increased LRRK2 kinase activity, endolysosomal deficits, and accumulation of autophagic vesicles with incompletely degraded substrates, including α-synuclein. Although LRRK2 has been implicated in endolysosomal and autophagic function, it remains unclear whether inhibition of LRRK2 kinase activity can prevent endolysosomal deficits or reduce dopaminergic neurodegeneration.

Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease.

Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.

Improving flow in the OR.

Purpose The purpose of this paper is to increase efficiency in ORs without affecting quality of care by improving the workflow processes. Administrative processes independent of the surgical act can be challenging and may lead to clinical impacts such as increasing delays. The authors hypothesized that a Lean project could improve efficiency of surgical processes by reducing the length of stays in the recovery ward.

Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity.

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis.

TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation.

Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease.

Potent, selective and orally bioavailable leucine-rich repeat kinase 2 (LRRK2) inhibitors.

Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection.

Pathology of ear hematomas in swine.

The objectives of our study were to describe the pathology of ear hematomas in swine and to add to the comprehension of the pathogenesis of this condition. The pathogenesis of aural hematomas has been studied mainly in dogs; however, disagreements exist about the precise anatomic location of the hemorrhage. Sixteen pigs with ear hematoma at various stages of development were included in this study.

Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells.

Unlabelled: Neuronal inclusions of hyperphosphorylated and aggregated tau protein are a pathological hallmark of several neurodegenerative tauopathies, including Alzheimer's disease (AD). The hypothesis of tau transmission in AD has emerged from histopathological studies of the spatial and temporal progression of tau pathology in postmortem patient brains. Increasing evidence in cellular and animal models supports the phenomenon of intercellular spreading of tau.

Core competencies for shared decision making training programs: insights from an international, interdisciplinary working group.

Shared decision making is now making inroads in health care professionals' continuing education curriculum, but there is no consensus on what core competencies are required by clinicians for effectively involving patients in health-related decisions. Ready-made programs for training clinicians in shared decision making are in high demand, but existing programs vary widely in their theoretical foundations, length, and content. An international, interdisciplinary group of 25 individuals met in 2012 to discuss theoretical approaches to making health-related decisions, compare notes on existing programs, take stock of stakeholders concerns, and deliberate on core competencies.

Proportional mortality: A study of 152 goats submitted for necropsy from 13 goat herds in Quebec, with a special focus on caseous lymphadenitis.

The objectives of this study were to determine the main causes of mortality, with a special focus on caseous lymphadenits as a cause of death or wasting in caprine herds from Quebec. Goats (n = 152) from 13 herds were submitted for necropsy; the cause of mortality, and the presence, location, and cause of abscesses (if present) were recorded. Proportional mortalities were distributed as: Clostridium perfringens type D enterotoxemia (17.

Non-motor parkinsonian pathology in aging A53T α-synuclein mice is associated with progressive synucleinopathy and altered enzymatic function.

Aging, the main risk factor for Parkinson's disease (PD), is associated with increased α-synuclein levels in substantia nigra pars compacta (SNc). Excess α-synuclein spurs Lewy-like pathology and dysregulates the activity of protein phosphatase 2A (PP2A). PP2A dephosphorylates many neuroproteins, including the catecholamine rate-limiting enzyme, tyrosine hydroxylase (TH).

Congenital cutaneous histiocytosis in a piglet.

A 2-week-old crossbred male piglet with numerous congenital, variably sized macules, plaques, and papules distributed all over the body was submitted for necropsy. Significant gross and histological lesions were restricted to the skin. On light microscopic examination, these cutaneous lesions corresponded to dermal and/or subcutaneous masses composed of spindle-shaped to round cells that multifocally contained hemosiderin; epidermotropism was not observed.

Alopecia areata and humpy-back syndrome in suckling piglets.

This report describes an uncommon variant of humpy-back syndrome associated with multiple rib fractures and multisystemic vasculitis in several nursing piglets and, for the first time, a skin disease in swine consistent with alopecia areata. Both conditions were observed concurrently on the farm and occasionally in the same piglets.

Androgens in the maternal and fetal circulation: association with insulin resistance.

Objective: To examine maternal insulin resistance in relationship with maternal and fetal androgen levels as well as with term placenta mRNA and protein abundance of steroidogenic enzymes implicated in androgen dynamics.

Methods: The study included 20 women with gestational diabetes mellitus and 27 controls tested using a 120 min., 75 g oral glucose tolerance test.

Training health professionals in shared decision-making: an international environmental scan.

Objective: To identify and analyze training programs in shared decision-making (SDM) for health professionals.

Methods: We conducted an environmental scan looking for programs that train health professionals in SDM. Pairs of reviewers independently analyzed the programs identified using a standardized data extraction sheet.

Costochondral junction osteomyelitis in 3 septic foals.

The costochondral junction constitutes a potential site of infection in septic foals and it could be favored by thoracic trauma. Standard radiographs and ultrasonography are useful tools for diagnosis of this condition and ultrasound-guided needle aspiration could permit the definitive confirmation of infection.