Cevimeline enhances the excitability of rat superior salivatory neurons

Cevimeline, a therapeutic drug for xerostomia, is an agonist of muscarinic acetylcholine receptors (mAChRs), and directly stimulates the peripheral mAChRs of the salivary glands. Since cevimeline is distributed in the brain after its oral administration, it is possible that it affects the central nervous system. However, it is unknown how cevimeline affects the superior salivatory (SS) neurons, which control submandibular salivation. In the present study, we examined the effects of cevimeline on the SS neurons using the whole-cell patch-clamp technique in brain slices. In Wistar rats (6-10 days), the SS neurons were retrogradely labeled by Texas Red applied to the chorda-lingual nerve. Two days after injection, whole-cell recordings were obtained from the labeled cells, and miniature excitatory postsynaptic currents (mEPSCs) were examined. Cevimeline induced the inward currents dose-dependently and increased the frequency of mEPSCs. Therefore, it is suggested that cevimeline enhances the excitability via post- and presynaptic muscarinic receptors in the rat SS neurons. In conclusion, cevimeline may enhance the excitability of the SS neurons

Phaseâ amplitude coupling between interictal highâ frequency activity and slow waves in epilepsy surgery

ObjectiveWe hypothesized that the modulation index (MI), a summary measure of the strength of phaseâ amplitude coupling between highâ frequency activity (>150 Hz) and the phase of slow waves (3â 4 Hz), would serve as a useful interictal biomarker for epilepsy presurgical evaluation.MethodsWe investigated 123 patients who underwent focal cortical resection following extraoperative electrocorticography recording and had at least 1 year of postoperative followâ up. We examined whether consideration of MI would improve the prediction of postoperative seizure outcome. MI was measured at each intracranial electrode site during interictal slowâ wave sleep. We compared the accuracy of prediction of patients achieving International League Against Epilepsy class 1 outcome between the full multivariate logistic regression model incorporating MI in addition to conventional clinical, seizure onset zone (SOZ), and neuroimaging variables, and the reduced logistic regression model incorporating all variables other than MI.ResultsNinety patients had class 1 outcome at the time of most recent followâ up (mean followâ up = 5.7 years). The full model had a noteworthy outcome predictive ability, as reflected by regression model fit R2 of 0.409 and area under the curve (AUC) of receiver operating characteristic plot of 0.838. Incomplete resection of SOZ (P < 0.001), larger number of antiepileptic drugs at the time of surgery (P = 0.007), and larger MI in nonresected tissues relative to that in resected tissue (P = 0.020) were independently associated with a reduced probability of class 1 outcome. The reduced model had a lower predictive ability as reflected by R2 of 0.266 and AUC of 0.767. Anatomical variability in MI existed among nonepileptic electrode sites, defined as those unaffected by magnetic resonance imaging lesion, SOZ, or interictal spike discharges. With MI adjusted for anatomical variability, the full model yielded the outcome predictive ability of R2 of 0.422, AUC of 0.844, and sensitivity/specificity of 0.86/0.76.SignificanceMI during interictal recording may provide useful information for the prediction of postoperative seizure outcome.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146440/1/epi14544_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146440/2/epi14544.pd

Decreases in the Serum VLDL-TG/Non-VLDL-TG Ratio from Early Stages of Chronic Hepatitis C: Alterations in TG-Rich Lipoprotein Levels

BACKGROUND: The liver secretes very-low-density lipoproteins (VLDLs) and plays a key role in lipid metabolism. Plasma total triglyceride (TG) level variations have been studied in patients with hepatitis C virus (HCV)-related chronic hepatitis (CH-C). However, the results of these studies are variable. A homogenous assay protocol was recently proposed to directly measure the TG content in VLDL (VLDL-TG) and VLDL remnants. METHODOLOGY/PRINCIPAL FINDINGS: Using the assay protocol, we determined serum VLDL-TG levels in 69 fasting patients with biopsy-proven HCV-related chronic liver disease and 50 healthy subjects. Patients were classified into stages F0-F4 using the 5-point Desmet scale. Serum total TG levels in patients with non-cirrhotic (F1-F3) CH-C did not demonstrate significant differences compared with healthy subjects, but serum VLDL-TG levels did demonstrate significant differences. Mean serum VLDL-TG levels tended to decrease with disease progression from F1 to F4 (cirrhosis). Compared with healthy subjects, serum non-VLDL-TG levels significantly increased in patients with stages F2 and F3 CH-C; however, we observed no significant difference in patients with liver cirrhosis. Furthermore, the serum VLDL-TG/non-VLDL-TG ratio, when taken, demonstrated a significant decrease in patients with CH-C from the mildest stage F1 onward. CONCLUSIONS/SIGNIFICANCE: The decrease in serum VLDL-TG levels was attenuated by increase in non-VLDL-TG levels in patients with non-cirrhotic CH-C, resulting in comparable total TG levels. Results of previous studies though variable, were confirmed to have a logical basis. The decrease in the serum VLDL-TG/non-VLDL-TG ratio as early as stage F1 demonstrated TG metabolic alterations in early stages of CH-C for the first time. The involvement of TG metabolism in CH-C pathogenesis has been established in experimental animals, while conventional TG measurements are generally considered as poor indicators of CH-C progression in clinical practice. The serum VLDL-TG/non-VLDL-TG ratio, which focuses on TG metabolic alterations, may be an early indicator of CH-C

Genetic and environmental factors and serum hormones, and risk of estrogen receptor-positive breast cancer in pre- and postmenopausal Japanese women

Breast cancer incidence in Japanese women has more than tripled over the past two decades. We have previously shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive, HER2-negative subtype. We conducted a case-control study; ER-positive, HER2-negative breast cancer patients who were diagnosed since 2011 and women without disease were recruited. Environmental factors, serum levels of testosterone and 25-hydroxyvitamin D, and common genetic variants reported as predictors of ER-positive breast cancer or found in Asian women were evaluated between patients and controls in pre-and postmenopausal women. To identify important risk predictors, risk prediction models were created by logistic regression models. In premenopausal women, two environmental factors (history of breastfeeding, and history of benign breast disease) and four genetic variants (TOX3-rs3803662, ESR1-rs2046210, 8q24-rs13281615, and SLC4A7-rs4973768) were considered to be risk predictors, whereas three environmental factors (body mass index, history of breastfeeding, and hyperlipidemia), serum levels of testosterone and 25-hydroxyvitamin D, and two genetic variants (TOX3-rs3803662 and ESR1-rs2046210) were identified as risk predictors. Inclusion of common genetic variants and serum hormone measurements as well as environmental factors improved risk assessment models. The decline in the birthrate according to recent changes of lifestyle might be the main cause of the recent notable increase in the incidence of ER-positive breast cancer in Japanese women

Hemispherotomy in a patient with intractable epilepsy also on anticoagulant therapy for coronary artery aneurysms secondary to Kawasaki disease - Proposal of an ethical approach

Purpose: To describe the safe performance of epilepsy surgery in a patient on anticoagulant therapy. Patient and method: An 11-year-old girl developed Kawasaki disease, which caused coronary artery aneurysms. She had a left middle cerebral artery area infarction, manifesting as intractable epilepsy. However, other medical facilities hesitated to perform the surgery due to the risks of vascular events as a result of stopping anticoagulant therapy. Results: The patient was firm in their desire to have epilepsy surgery performed. We discontinued anticoagulants and performed left hemispherotomy. After the surgery, the patient was free of seizures without any complications

Objective interictal electrophysiology biomarkers optimize prediction of epilepsy surgery outcome.

Researchers have looked for rapidly- and objectively-measurable electrophysiology biomarkers that accurately localize the epileptogenic zone. Promising candidates include interictal high-frequency oscillation and phase-amplitude coupling. Investigators have independently created the toolboxes that compute the high-frequency oscillation rate and the severity of phase-amplitude coupling. This study of 135 patients determined what toolboxes and analytic approaches would optimally classify patients achieving post-operative seizure control. Four different detector toolboxes computed the rate of high-frequency oscillation at ≥80 Hz at intracranial EEG channels. Another toolbox calculated the modulation index reflecting the strength of phase-amplitude coupling between high-frequency oscillation and slow-wave at 3-4 Hz. We defined the completeness of resection of interictally-abnormal regions as the subtraction of high-frequency oscillation rate (or modulation index) averaged across all preserved sites from that averaged across all resected sites. We computed the outcome classification accuracy of the logistic regression-based standard model considering clinical, ictal intracranial EEG and neuroimaging variables alone. We then determined how well the incorporation of high-frequency oscillation/modulation index would improve the standard model mentioned above. To assess the anatomical variability across non-epileptic sites, we generated the normative atlas of detector-specific high-frequency oscillation and modulation index. Each atlas allowed us to compute the statistical deviation of high-frequency oscillation/modulation index from the non-epileptic mean. We determined whether the model accuracy would be improved by incorporating absolute or normalized high-frequency oscillation/modulation index as a biomarker assessing interictally-abnormal regions. We finally determined whether the model accuracy would be improved by selectively incorporating high-frequency oscillation verified to have high-frequency oscillatory components unattributable to a high-pass filtering effect. Ninety-five patients achieved successful seizure control, defined as International League against Epilepsy class 1 outcome. Multivariate logistic regression analysis demonstrated that complete resection of interictally-abnormal regions additively increased the chance of success. The model accuracy was further improved by incorporating z-score normalized high-frequency oscillation/modulation index or selective incorporation of verified high-frequency oscillation. The standard model had a classification accuracy of 0.75. Incorporation of normalized high-frequency oscillation/modulation index or verified high-frequency oscillation improved the classification accuracy up to 0.82. These outcome prediction models survived the cross-validation process and demonstrated an agreement between the model-based likelihood of success and the observed success on an individual basis. Interictal high-frequency oscillation and modulation index had a comparably additive utility in epilepsy presurgical evaluation. Our empirical data support the theoretical notion that the prediction of post-operative seizure outcomes can be optimized with the consideration of both interictal and ictal abnormalities

Scalp EEG interictal high frequency oscillations as an objective biomarker of infantile spasms

ObjectiveTo investigate the diagnostic utility of high frequency oscillations (HFOs) via scalp electroencephalogram (EEG) in infantile spasms.MethodsWe retrospectively analyzed interictal slow-wave sleep EEGs sampled at 2,000&nbsp;Hz recorded from 30 consecutive patients who were suspected of having infantile spasms. We measured the rate of HFOs (80-500&nbsp;Hz) and the strength of the cross-frequency coupling between HFOs and slow-wave activity (SWA) at 3-4&nbsp;Hz and 0.5-1&nbsp;Hz as quantified with modulation indices (MIs).ResultsTwenty-three patients (77%) exhibited active spasms during the overnight EEG recording. Although the HFOs were detected in all children, increased HFO rate and MIs correlated with the presence of active spasms (p&nbsp;&lt;&nbsp;0.001 by HFO rate; p&nbsp;&lt;&nbsp;0.01 by MIs at 3-4&nbsp;Hz; p&nbsp;=&nbsp;0.02 by MIs at 0.5-1&nbsp;Hz). The presence of active spasms was predicted by the logistic regression models incorporating HFO-related metrics (AUC: 0.80-0.98) better than that incorporating hypsarrhythmia (AUC: 0.61). The predictive performance of the best model remained favorable (87.5% accuracy) after a cross-validation procedure.ConclusionsIncreased rate of HFOs and coupling between HFOs and SWA are associated with active epileptic spasms.SignificanceScalp-recorded HFOs may serve as an objective EEG biomarker for active epileptic spasms

Reduced muscle strength of knee extensors is a risk factor for silent lacunar infarcts among Japanese elderly people: the Bunkyo Health Study

Abstract Background Silent lacunar infarcts (SLIs) are often incidentally diagnosed by brain magnetic resonance imaging in elderly people and are associated with the future onset of stroke, dementia, and frailty. While decreased muscle strength was reported as a risk factor for stroke, it is still unclear whether it also predisposes to SLI. In this study, we investigated the association between muscle strength and SLI in elderly subjects. Methods The subjects were 1536 elderly people aged 65–84 years without previous stroke events, living in an urban area of Tokyo, Japan, and recruited in the Bunkyo Health Study. Lacunar infarcts were defined by brain magnetic resonance imaging. Muscle strength of the knee extensors was measured using a dynamometer. After categorizing subjects by age and sex, we divided them into three groups based on muscle strength tertiles (High, Medium, and Low) and investigated the association between muscle strength and SLI. Results The mean subject age was 73.0 ± 5.4 years, and 58.9% were female. The prevalence of SLI was 16.4% and was inversely associated with muscle strength (High, 12.3%; Medium, 17.7%; and Low, 19.3%; P for trend 0.003). After multivariate adjustment, the odds ratio for SLI was increased in the Medium and Low groups compared with the High group (High, 1.00 [reference]; Medium, 1.42 [95% confidence interval: 0.98–2.04]; and Low: 1.48 [1.02–2.14]), and the linear trend across the three groups was significant (P for trend 0.043). Conclusions Reduced knee extensor muscle strength is associated with SLI among Japanese elderly, independently of other established risk factors

Patient and healthy subject characteristics.

<p>p-values, when shown in italics such as <i>p<0.01</i>, indicate that there are significant differences. Values are shown as mean ± SD (standard deviation). BMI; Body Mass Index, AST; Aspartate transaminase, ALT; Alanine transaminase, CHO; cholesterol, TG; triglyceride.</p

Scatter plots of serum total TG, VLDL-TG, non-VLDL-TG levels, and VLDL-TG/non-VLDL-TG ratios.

<p>P-values are indicated as the values between groups with bars. The mean value of each group is indicated at the bottom of each diagram. P-values, when indicated in bold with an asterisk (such as <b>0.025*)</b>, indicate significant differences. SD; standard deviation.</p