Spironolactone Lowers Portal Hypertension by Inhibiting Liver Fibrosis, ROCK-2 Activity and Activating NO/PKG Pathway in the Bile-Duct-Ligated Rat

OBJECTIVE: Aldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS), has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension. METHODS: Liver cirrhosis was induced by bile duct ligation (BDL). Spironolactone was administered orally (20 mg/kg/d) after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA) expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR). Portal pressure and intrahepatic resistance were examined in vivo. RESULTS: Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6). Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and the activity of NO effector-protein kinase G (PKG) in the liver. CONCLUSION: Spironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and portal hypertension

Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with (“lesional”) and without (“non-lesional”) radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68–75%) compared to models to lateralize the side of TLE (56–73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67–75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68–76%) than models that stratified non-lesional patients (53–62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care

Millisecond-Timescale Local Network Coding in the Rat Primary Somatosensory Cortex

Correlation among neocortical neurons is thought to play an indispensable role in mediating sensory processing of external stimuli. The role of temporal precision in this correlation has been hypothesized to enhance information flow along sensory pathways. Its role in mediating the integration of information at the output of these pathways, however, remains poorly understood. Here, we examined spike timing correlation between simultaneously recorded layer V neurons within and across columns of the primary somatosensory cortex of anesthetized rats during unilateral whisker stimulation. We used Bayesian statistics and information theory to quantify the causal influence between the recorded cells with millisecond precision. For each stimulated whisker, we inferred stable, whisker-specific, dynamic Bayesian networks over many repeated trials, with network similarity of 83.3±6% within whisker, compared to only 50.3±18% across whiskers. These networks further provided information about whisker identity that was approximately 6 times higher than what was provided by the latency to first spike and 13 times higher than what was provided by the spike count of individual neurons examined separately. Furthermore, prediction of individual neurons' precise firing conditioned on knowledge of putative pre-synaptic cell firing was 3 times higher than predictions conditioned on stimulus onset alone. Taken together, these results suggest the presence of a temporally precise network coding mechanism that integrates information across neighboring columns within layer V about vibrissa position and whisking kinetics to mediate whisker movement by motor areas innervated by layer V

Benefit of chemotherapy as part of treatment for HPV DNA-positive but p16-negative squamous cell carcinoma of the oropharynx

BACKGROUND: To determine (a) the cause of an improvement in survival from oropharyngeal squamous cell carcinoma (OSCC) in South East Scotland and (b) whether this improvement was human papillomavirus (HPV) and p16 subtype-dependent. METHODS: Clinicopathological characteristics and outcome data for patients referred with OSCC from 1999 to 2001 (Cohort-1) and 2003 to 2005 (Cohort-2) were obtained. Molecular HPV detection and immunohistochemistry for p16 were performed from paraffin blocks. RESULTS: Cohort-1 and Cohort-2 contained 118 and 136 patients, respectively. Kaplan–Meier analysis revealed significantly improved survival in Cohort-2 (P<0.0001). Sub-classification according to HPV and p16 status revealed no improvement in survival in Class-I (HPV−ve/p16−ve; 47 patients) or Class-III (HPV+ve/p16+ve; 77 patients). However in Class-II (HPV+ve/p16−ve; 56 patients) an increase in 5-year cause-specific survival from 36% in Cohort-1 to 73% in Cohort-2 was detected (P=0.0001). Proportional hazards analysis of 217 patients treated radically demonstrated that significant variables were p16 (P<0.0001), N stage (P=0.0006) and cohort (P=0.0024). Removing cohort from the variables offered to the model showed that, whereas p16 (P<0.0001) and N stage (P=0.0016) remain significant, chemotherapy (P=0.0163) and T stage (P=0.0139) are now significant. This suggests that much of the cohort effect is due to the higher use of chemotherapy in the second cohort. CONCLUSION: These data suggest that HPV+ve/p16−ve patients constitute a separate subclass of OSCC who may particularly benefit from chemotherapy. They imply that p16 status cannot be considered a surrogate for HPV status, and those trials to de-escalate treatment in HPV+ve OSCC should take p16 status into account