Usefulness of contrast enhanced FLAIR imaging for predicting the severity of meningitis

The aim of this study was to evaluate whether contrast enhanced fluid attenuated inversion recovery (CE-FLAIR) imaging can be used to predict the severity of meningitis based on leptomeningeal enhancement (LE) score and cerebrospinal fluid signal intensity (CSF-SI) on CE-FLAIR. We retrospectively analyzed data collected from 43 consecutive patients admitted to our hospital due to meningitis. Clinical factors including initial Glasgow Coma Scale (GCS) score, CSF glucose ratio, log CSF protein, log CSF WBC, and prognosis were evaluated. The LE score was semi-quantitatively scored, and we evaluated CSF-SI ratio at the interpeduncular or quadrigerminal cisterns on CE-FLAIR. We evaluated the differences in clinical variables, LE scores and CSF-SI ratios between the recovery and the complication group. We assessed the correlation between clinical variables, LE scores and CSF-SI ratios. The values of log CSF protein, CSF-SI ratio, and LE score were significantly higher in the complication group (p value <0.05). GCS score and CSF glucose ratio were significantly lower in the complication group (p value <0.01). The LE scores had significant negative correlation with GCS scores and CSF glucose ratios (p value <0.001). The LE score was significantly positively correlated with the value of log CSF protein and CSF-SI ratio (p value <0.01). The CSF-SI ratio was negatively correlated with GCS score and CSF glucose ratio (p value <0.01). The CSF-SI ratio was positively correlated with the value of log CSF protein (p value <0.05). Our results suggest that LE score and CSF-SI ratio are well correlated with clinical prognostic factors. We may predict the clinical severity of meningitis by using LE scores and CSF-SI ration on CE-FLAIR imaging.     

Large liver cell dysplasia in hepatitis B virus x transgenic mouse liver and human chronic hepatitis B virus-infected liver

OBJECTIVES: Large liver cell dysplasia (LCD) is frequently associated with hepatitis B virus (HBV), but it remains uncertain whether it is reactive, senescent or preneoplastic. METHODS: The HBX transgenic mice and normal control mice were sacrificed at 1, 3, 5, 7, 9, 11, 13 and 15 months after birth. Twenty-three cases of human B viral chronic hepatitis/cirrhosis with prominent LCD were selected. The immunohistochemical stain of proliferating cell nuclear antigen (PCNA), transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and senescence-associated beta-galactosidase (SA-beta-Gal) were evaluated. RESULTS: In HBX transgenic mice, LCD was developed since 3 months and formed small nodules of hepatocellular adenoma, which progressed to hepatocellular carcinoma. The hepatocytes with LCD in HBX transgenic mice showed significantly higher PCNA-labeling index (LI) and lower TUNEL-LI than normal hepatocytes of control mice (p < 0.05). In the majority of human B viral chronic hepatitis/cirrhosis, the hepatocytes with LCD revealed higher PCNA-LI and lower TUNEL-LI than those without, when compared in each case using the same tissue block. SA-beta-Gal staining showed no difference between hepatocytes with and without LCD. CONCLUSION: It is suggested that LCD, related to HBV, might not be just an innocent bystander, but closely related to hepatocarcinogenesis.     

Axonal dysfunction,dysmyelination, and conduction failure in hereditary neuropathy with liability to pressure palsies

Introduction: Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. Methods: Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. Results: In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current–threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. Conclusions: Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a major predisposing factor for development of conduction block with mechanical stresses. Muscle Nerve 49 : 858–865, 2014     

Immunohistochemical analysis of cyclooxygenase‐2 and brain fatty acid binding protein expression in grades I‐II meningiomas: Correlation with tumor grade and clinical outcome after radiotherapy

This study was done to evaluate the association of cyclooxygenase 2 (COX‐2) and brain fatty acid binding protein (BFABP) with tumor grade and outcome of grades I‐II meningiomas treated with radiotherapy. From 1996 to 2008, 40 patients with intracranial grades I‐II meningiomas were treated with radiotherapy. Immunohistochemical staining for COX‐2 and BFABP were performed on formalin‐fixed paraffin‐embedded tissues. COX‐2 expression was significantly associated with BFABP status and both COX‐2 (P < 0.01) and BFABP (P = 0.01) expression were stronger in the grade II meningiomas than in grade I tumors. Among the clinicopathologic factors, age and COX‐2 status were prognostic in progression‐free survival. Patients with moderate or strong COX‐2 expression had worse outcome than those with negative or weak COX‐2 expression (P = 0.03) after controlling for potential confounders. Our results suggest that the molecular biomarker COX‐2 has prognostic significance in intracranial grades I‐II meningiomas following radiotherapy.     

Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4–Mediated Drug Efflux in the Kidney

Na⁺/H⁺ exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3^−/−) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3^−/− mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules.Assembly of protein complexes by adaptor proteins with PSD-95/discs large/ZO-1 (PDZ) domains plays an important role in the regulation of many membrane proteins, especially in epithelial and neuronal tissues.^1,2 For example, PDZ-based adapter proteins in epithelia, such as Shank2, synaptic scaffolding molecule (S-SCAM), and Na⁺/H⁺ exchanger regulatory factors (NHERFs), are known to be involved in the regulation of cell surface expression and the activity of many membrane transporters and receptors in the respiratory, digestive, urinary, and reproductive organs.^3–6 The four members of the NHERF proteins (NHERF1 to 4) contain either two or four PDZ domains and were the first family of PDZ-containing proteins shown to be involved in epithelial transport. NHERF3, also known as PDZK1 or CAP70, has four PDZ domains and is normally localized to the apical microdomains of gastrointestinal and kidney epithelia. Each PDZ domain of NHERF3 has been proposed to bind independently to the PDZ binding motif of various membrane proteins, such as the cystic fibrosis transmembrane conductance regulator (CFTR), the Na⁺/H⁺ exchanger 3, the urate transporter, and the organic anion transporter 4.^7–10 However, Nherf3 knockout (Nherf3^−/−) mice do not have a discernible phenotype except mild hypercholesterolemia,¹¹ and, consequently, the in vivo role of NHERF3 in transepithelial transport remains poorly understood.Transporters belonging to either the ATP binding cassette (ABC) or the solute-linked carrier superfamilies of membrane proteins play diverse roles in the pharmacokinetic and pharmacodynamic pathways of drugs and their metabolites.¹² Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the C subfamily of ABC transporters and mediates the efflux of a group of organic molecules using energy generated from the binding and hydrolysis of ATP.¹³ Cumulative evidence suggests that MRP4 pumps out purine compounds and plays an important role in the renal elimination of purine-based antiviral and antineoplastic agents.^14,15 However, the regulatory mechanisms for MRP4 expression and function have not been extensively studied.The COOH terminus of MRP4 contains a class 1 PDZ interaction motif (-S/T-X-Ф, where Ф is a hydrophobic amino acid),¹⁶ indicating that MRP4 may interact with PDZ-based adaptors in epithelia. In preliminary studies using a yeast two-hybrid assay, MRP4 was found to strongly interact with NHERF3 among several PDZ adaptor proteins expressed in epithelial tissues. The aim of the present study was to identify the physiologic and pharmacologic roles of the interaction of NHERF3 with MRP4 using a variety of in vitro and in vivo experimental approaches. The results obtained provide strong evidence that NHERF3 is a key regulator of organic transport in the kidney, particularly the MRP4-mediated clearance of purine-based drug molecules.