Electrical induction of spikes in the hippocampus impairs recognition capacity and spatial memory in rats

In clinical studies, interictal EEG spikes (IS) have been associated with numerous neuropsychological abnormalities, ranging from transitory cognitive impairment to epileptic encephalopathies. Understanding the pathophysiological mechanisms of IS has been hampered by the lack of validated animal models. To mimic IS, a stimulating microelectrode was implanted in the ventral hippocampal commissure and a recording microelectrode in the CA1 region of the hippocampus of normal male rats. Spike patterns were induced using a series of electrical pulses 10-30 ms in duration with a frequency of 0.5-2Hz and a current of 0.2mA. The commissural stimulation-evoked population discharges in the hippocampus resembled naturally occurring IS in epileptic rats and, in no cases, resulted in behavioral seizures. For behavioral testing, the Morris water maze, radial arm maze, and object recognition tasks were used. Spikes were induced during sleep between the two sets of water maze trials; during the trials in the radial arm maze task; and prior to the sample phase and during the delay periods in the object recognition task. We demonstrated that rats that received spikes took longer to reach the escape platform in the second set of water maze trials; had significantly more reference errors and required more trials to complete the radial arm maze task; and had lower investigation ratios in the object recognition task. The results indicate that induction of spikes in the hippocampus results in impairment of spatial reference and nonspatial object recognition memory.     

Docking Based Screening of Potent Flavonoids as CHK2 Inhibitors from Genus Miliusa

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Annonaceae plants play significant role in ethanopharmacology due to their medicinal properties and...     

Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA–mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.     

A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families

Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two‐thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity. Pathogenicity of the 18 novel missense variants was analyzed functionally by determining the ability of the mutant cDNA to improve the survival of a FANCA‐null cell line when treated with MMC. Overexpressed pathogenic missense variants were found to reside in the cytoplasm, and nonpathogenic in the nucleus. RNA analysis demonstrated that two variants (c.522G > C and c.1565A > G), predicted to encode missense variants, which were determined to be nonpathogenic by a functional assay, caused skipping of exons 5 and 16, respectively, and are most likely pathogenic. We report 48 novel FANCA sequence variants. Defining both variants in a large patient cohort is a major step toward cataloging all FANCA variants, and permitting studies of genotype–phenotype correlations.     

Shoulder Position During Magnetic Resonance Arthrogram Significantly Affects Capsular Measurements

PurposeTo determine whether change in shoulder position between internal rotation (IR) and external rotation (ER) during magnetic resonance arthrography (MRA) affects previously defined capsular measurements and to determine the utility of rotation in the diagnosis of instability.MethodsA retrospective study was conducted of patients who received a shoulder MRA with humeral IR and ER views. Patients with an arthroscopically confirmed diagnosis of instability and those with clinically stable shoulders, no history of instability, and no MRA findings of instability were identified and compared. Humeral rotation, glenoid retroversion, humeral head subluxation, capsular length, and capsular area using axial sequences of IR and ER views were recorded. Analysis compared IR, ER, and Δ capsular measurements between groups using independent t tests and univariate and multivariate regression.ResultsThirty-one subjects who were diagnosed with instability were included, along with 28 control subjects. Capsular length, capsular area, and humeral subluxations were significantly greater with ER compared with IR views (P < .001, P < .001, P < .001). Patients with instability displayed greater ER capsular length (P = .0006) and ER capsular area (P = .005) relative to controls. Multivariate logistic regression identified age, weight, sex, ER capsular length, and retroversion to be significant predictors of instability. ER capsular length independently predicts instability with 86% sensitivity and 84% specificity. Interobserver reliability using the intraclass correlation coefficient was rated good or excellent on all measurements.ConclusionVariance in humeral rotation during shoulder MRA significantly affects capsular measurements. Rotational views increase the utility of capsular measurements when assessing for instability, particularly capsular length and capsular area. The implementation of ER positioning enhances the ability to examine capsular changes of the shoulder joint and can assist in the diagnosis of instability.Level of EvidenceIII, retrospective comparative study     

Clinical findings associated with bladder trabeculations in women

Introduction and hypothesis

This study evaluated whether bladder trabeculations are associated with advanced prolapse, urinary urgency, or detrusor overactivity among women undergoing office cystoscopy. It is well established that bladder trabeculations are associated with bladder outlet obstruction (BOO) in men; however, the clinical significance of trabeculations in women is unclear. Whereas an analogous relationship has been proposed between prostatic obstruction in men and advanced pelvic organ prolapse (POP) in women, little data in the medical literature supports this theory.

Methods

A retrospective cohort study was conducted using Current Procedural Terminology (CPT) codes (52000, 52204) to identify all women who underwent office cystoscopy at our urogynecology center between January 2008 and May 2011. The 551 women identified were grouped by the presence or absence of bladder trabeculations. Multivariable logistic regression was used to estimate the association between trabeculations and the primary aim, increasing stage of prolapse, and the secondary aims: bladder outlet obstruction, detrusor overactivity, or urge urinary incontinence (UUI).

Results

Of the 551 women meeting inclusion criteria, 86 had trabeculations. Controlling for age, the odds of bladder trabeculations were eightfold greater for women with stage IV POP when compared with women with stage 0 prolapse [odds ratio (OR) 8.2, 95 % confidence interval (CI) 1.6–43.1]. The odds of bladder trabeculations were twofold greater for women with detrusor overactivity (OR 2.3, 95 % CI 1.3–4.0) found on urodynamic study and also as reflected subjectively by answers to Pelvic Floor Distress Inventory (PFDI) item number 16 (OR 4.2, 95 % CI 1.3–14.5).

Conclusion

In this study, bladder trabeculations were associated with stage IV prolapse in the anterior compartment as well as with detrusor overactivity and UUI.     

The Webcam system: a simple, automated, computer-based video system for quantitative measurement of movement in nonhuman primates

Investigations using models of neurologic disease frequently involve quantifying animal motor activity. We developed a simple method for measuring motor activity using a computer-based video system (the Webcam system) consisting of an inexpensive video camera connected to a personal computer running customized software. Images of the animals are captured at half-second intervals and movement is quantified as the number of pixel changes between consecutive images. The Webcam system allows measurement of motor activity of the animals in their home cages, without devices affixed to their bodies. Webcam quantification of movement was validated by correlation with measures simultaneously obtained by two other methods: measurement of locomotion by interruption of infrared beams; and measurement of general motor activity using portable accelerometers. In untreated squirrel monkeys, correlations of Webcam and locomotor activity exceeded 0.79, and correlations with general activity counts exceeded 0.65. Webcam activity decreased after the monkeys were rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but the correlations with the other measures of motor activity were maintained. Webcam activity also correlated with clinical ratings of parkinsonism. These results indicate that the Webcam system is reliable under both untreated and experimental conditions and is an excellent method for quantifying motor activity in animals.