Scn1a missense mutation causes limbic hyperexcitability and vulnerability to experimental febrile seizures

Mutations of the voltage-gated sodium (Na_v) channel subunit SCN1A have been implicated in the pathogenesis of human febrile seizures including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI). Hyperthermia-induced seizure-susceptible (Hiss) rats are the novel rat model carrying a missense mutation (N1417H) of Scn1a, which is located in the third pore-forming region of the Na_v1.1 channel. Here, we conducted behavioral and neurochemical studies to clarify the functional relevance of the Scn1a mutation in vivo and the mechanism underlying the vulnerability to hyperthermic seizures. Hiss rats showed markedly high susceptibility to hyperthermic seizures (mainly generalized clonic seizures) which were synchronously associated with paroxysmal epileptiform discharges. Immunohistochemical analysis of brain Fos expression revealed that hyperthermic seizures induced a widespread elevation of Fos-immunoreactivity in the cerebral cortices including the motor area, piriform, and insular cortex. In the subcortical regions, hyperthermic seizures enhanced Fos expression region—specifically in the limbic and paralimbic regions (e.g., hippocampus, amygdala, and perirhinal–entorhinal cortex) without affecting other brain regions (e.g., basal ganglia, diencephalon, and lower brainstem), suggesting a primary involvement of limbic system in the induction of hyperthermic seizures. In addition, Hiss rats showed a significantly lower threshold than the control animals in inducing epileptiform discharges in response to local stimulation of the hippocampus (hippocampal afterdischarges). Furthermore, hyperthermic seizures in Hiss rats were significantly alleviated by the antiepileptic drugs, diazepam and sodium valproate, while phenytoin or ethosuximide were ineffective. The present findings support the notion that Hiss rats are useful as a novel rat model of febrile seizures and suggest that hyperexcitability of limbic neurons associated with Scn1a missense mutation plays a crucial role in the pathogenesis of febrile seizures.     

Evaluation of hypervascular hepatocellular carcinoma in cirrhotic liver: comparison of different concentrations of contrast material with multi-detector row helical CT--a prospective randomized study

Purpose

To evaluate two different iodine concentrations of contrast material for detecting hypervascular hepatocellular carcinomas (HCCs) in cirrhotic liver by multi-detector row helical CT (MDCT) when a fixed contrast material volume and injection rate is used.

Materials and methods

Institutional Review Board approval was obtained, and informed consent was obtained from all patients. In this prospective study, 105 patients were randomly assigned a group A (an iodine concentration of 300 mg I/mL), and a group B (an iodine concentration of 370 mg I/mL). In both groups the volume of contrast material was 100 mL and the injection rate was 4 mL/s. Fifty-two patients had 122 hypervascular HCCs. The diagnosis of HCCs was established histopathologically (n = 24) and by imaging findings (n = 98). Three readers independently analyzed four image sets: an arterial phase (AP), a portal phase (PP), an equilibrium phase (EP), and combined all three phase images set. Sensitivity, specificity, and diagnostic accuracy were calculated by receiver operating characteristic (ROC) analysis.

Results

The mean sensitivity for detecting hypervascular HCCs of the AP set, EP set, and combination set in group B (0.94, 0.81, and 0.93) was significantly higher than in group A (0.84, 0.69, and 0.80). Area under the ROC curve of the AP set and the combination set in group B (0.974 and 0.981) was significantly higher than in group A (0.939 and 0.958).

Conclusion

At the same contrast material volume and injection rate, higher iodine concentration of contrast material was effective for detecting hypervascular HCCs by MDCT.     

Gd-EOB-DTPA-enhanced 3.0?T MR imaging: quantitative and qualitative comparison of hepatocyte-phase images obtained 10?min and 20?min after injection for the detection of liver metastases from colorectal carcinoma

Objective

To compare quantitatively and qualitatively hepatocyte-phase images obtained 10 and 20?min (Images-10, and Images-20) after injection of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) to detect liver metastases from colorectal carcinoma on 3.0?T MR imaging.

Methods

A total of 48 patients (26 men, 22 women; mean age, 64?years) with 88 histopathologically confirmed liver metastases underwent Gd-EOB-DTPA-enhanced MR imaging. Tumour-to-liver contrast-to-noise ratio (CNR), signal intensity gain (SIG) of liver parenchyma and overall image quality were analysed. Two radiologists independently reviewed two sets of MR images: set 1, unenhanced (T1- and T2-weighted), dynamic images and Images-10; set 2, unenhanced, dynamic and Images-20. Sensitivity and positive predictive value (PPV) to detect liver metastases, and diagnostic performance using the alternative free-response receiver operating characteristics (AFROC) method were calculated.

Results

The mean tumour-to-liver CNR, SIG of liver parenchyma and overall image quality on Images-20 were significantly higher than those on Images-10. The overall image quality of ??fair to excellent?? was achieved on both images in 93.8% of the patients. Sensitivity, PPV and area under the AFROC curve on set 1 were similar to set 2, including lesions <1?cm.

Conclusion

In detecting liver metastases from colorectal carcinoma, Images-10 could replace Images-20 in 3.0?T MR imaging.     

A case of infantile epileptic encephalopathy with frequent focal motor status convulsivus: successful treatment with zonisamide]

We reported a 41-day-old girl starting with partial status convulsivus. She had suffered from infantile epileptic encephalopathy manifesting with recurrent focal motor status convulsivus, eventually requiring general anesthesia for the treatment. She had had never myoclonic seizures nor tonic spasms. The examinations including brain MRI scan and metabolic screening tests were all negative. The ictal EEGs showed the onset of the seizures from the left frontal region. Interictal EEG demonstrated multifocal spike discharges as well as discontinuous abnormal EEG pattern resembling suppression-burst during sleep. The seizures were resistant to the multiple antiepileptic drugs, but zonisamide achieved full seizure control as well as improvement of the EEG. Her psychomotor development was severely retarded at 3 years of age.     

Value of three-dimensional T2-weighted turbo spin-echo imaging with tissue-specific variable refocusing flip angle for 3-T magnetic resonance imaging of prostate cancer: comparison with conventional two- and three-dimensional T2-weighted turbo spin-echo imaging

Purpose

To investigate the impact of three-dimensional (3D) T2-weighted turbo spin-echo imaging (TSE-T2WI) with tissue-specific variable refocusing flip angle (TS-VRFA) on image quality and prostate cancer (PCa) detection and extraprostatic extension (EPE) evaluation compared to 2D TSE-T2WI and conventional 3D TSE-T2WI with volume isotropic TSE acquisition (VISTA).

Materials and methods

Image data sets of 40 patients who underwent 3-T MRI before prostatectomy, including multiplane 2D T2WI, 3D T2WI with TS-VRFA and VISTA, and diffusion-weighted images were independently evaluated by two radiologists. The detectability of PCa and EPE of each sequence was assessed using areas by the receiver operating characteristic curve (AUC) analysis. Image quality measures and contrast ratios (CR) between cancerous lesions and non-cancerous regions for each T2WI were also evaluated.

Results

Overall image quality of TS-VRFA was better than that of VISTA and equivalent to 2D. The highest CR was obtained with TS-VRFA (P < 0.05). For both readers, no significances were observed in detectability for PCa detection between three sequences (P > 0.05). For both readers, there were no significant differences in AUC for EPE evaluation between three sequences (P > 0.05).

Conclusion

3D T2 WI using TS-VRFA could potentially replace multiplane 2D T2 WI for prostate cancer diagnosis with better image quality than VISTA.

     

Kidney Outcomes Associated With SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs in Real-world Clinical Practice: The Japan Chronic Kidney Disease Database

OBJECTIVERandomized controlled trials have shown kidney-protective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy, as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitor initiation modify treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients, is unknown.RESEARCH DESIGN AND METHODSUsing the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease.RESULTSAt baseline, mean age at initiation of the SGLT2 inhibitor (n = 1,033) or other glucose-lowering drug (n = 1,033) was 64.4 years, mean eGFR was 68.1 mL/min per 1.73 m², and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs. other drugs 0.75 mL/min/1.73 m² per year [0.51 to 1.00]). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26–0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiation of SGLT2 inhibitors (P_{heterogeneity} ≥ 0.35).CONCLUSIONSThe benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.     

Modified interventional obliteration for variceal hemorrhage from elevated jejunum after pylorus-preserving pancreatoduodenectomy

Ectopic variceal hemorrhage caused by sinistral portal hypertension after splenic vein ligation during a pyloric-preserving pancreatoduodenectomy is a rare entity. We report the case of a 58-year-old man with symptoms of refractory melena. The varices could not be treated endoscopically and surgery was considered unsuitable due to severe adhesions and altered anatomy. Following clinical failure of partial splenic embolization, an alternative obliteration method by a retrograde trans-portal-venous approach was successfully performed and resolved the problem. It seems to be an effective method for ectopic variceal bleeding, especially when other interventions are unavailable or highly risky.     

In vivo evaluation of percutaneous carbon dioxide treatment for improving intratumoral hypoxia using 18F-fluoromisonidazole PET-CT

Carbon dioxide (CO₂) treatment is reported to have an antitumor effect owing to the improvement in intratumoral hypoxia. Previous studies were based on histological analysis alone. In the present study, the improvement in intratumoral hypoxia by percutaneous CO₂ treatment in vivo was determined using ¹⁸F-fluoromisonidazole positron emission tomography-computed tomography (¹⁸F-FMISO PET-CT) images. Twelve Japanese nude mice underwent implantation of LM8 tumor cells in the dorsal subcutaneous area 2 weeks before percutaneous CO₂ treatment and ¹⁸F-FMISO PET-CT scans. Immediately after intravenous injection of ¹⁸F-FMISO, CO₂ and room air were administered transcutaneously in the CO₂-treated group (n=6) and a control group (n=6), respectively; each treatment was performed for 10 minutes. PET-CT was performed 2 h after administration of ¹⁸F-FMISO. ¹⁸F-FMISO tumor uptake was quantitatively evaluated using the maximum standardized uptake value (SUV_max), tumor-to-liver ratio (TLR), tumor-to-muscle ratio (TMR), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Mean ± standard error of the mean (SEM) of the tumor volume was not significantly different between the two groups (CO₂-treated group, 1.178±0.450 cm³; control group, 1.368±0.295 cm3; P=0.485). Mean ± SEM of SUV_max, TLR, MTV (cm3) and TLG were significantly lower in the CO₂-treated group compared with the control group (0.880±0.095 vs. 1.253±0.071, P=0.015; 1.063±0.147361 vs. 1.455±0.078, P=0.041; 0.353±0.139 vs. 1.569±0.438, P=0.015; 0.182±0.070 vs. 1.028±0.338, P=0.015), respectively. TMR was not significantly different between the two groups (4.520±0.503 vs. 5.504±0.310; P=0.240). In conclusion, ¹⁸F-FMISO PET revealed that percutaneous CO₂ treatment improved intratumoral hypoxia in vivo. This technique enables assessment of the therapeutic effect in CO₂ treatment by imaging, and may contribute to its clinical application.