Serum neurofilament light chain in patients with epilepsy and cognitive impairment.

BACKGROUND: The neurofilament light chain (NfL) is receiving increased attention as a biomarker of neurological diseases, as NfL concentration elevated in the blood and cerebrospinal fluid after neuronal damage. However, few studies have addressed NfL in epilepsy. We aimed to investigate the alteration of serum NfL in adult patients with epilepsy, and the association between this biomarker and cognitive impairment. METHODS: A total of 38 consecutive patients with epilepsy and 24 controls underwent cross-sectional measurement of serum NfL levels and cognitive testing using the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), the Frontal Assessment Battery (FAB), the Trail-Making Test, and the Stroop Color-Word Test. Statistical analysis was performed with Student's t-test to compare serum NfL levels between the epilepsy group and the control group, and with Spearman's correlation and age-corrected partial correlation analyses to evaluate the association between serum NfL level and cognitive impairment in epilepst patients. RESULTS: There was no difference in serum NfL levels between the epilepsy and control groups (epilepsy [mean ± SD]: 17.3 ± 13.9 pg/mL; control: 17.7 ± 11.5 pg/mL; p = .92); however, the MoCA-J scores were lower in the epilepsy group (26.6 ± 3.1 vs. 28.1 ± 1.6; p = .03). The age-corrected partial correlation analysis showed a correlation between serum NfL level and cognitive test scores in the epilepsy group (MMSE: rs = -.63, p < .01; MoCA-J: rs = -.54, p < .01; FAB: rs = -.68, p < .01), whereas serum NfL levels were correlated exclusively with MMSE scores in the control group (rs = .44, p = .04). SIGNIFICANCE: In adult epilepsy patients, the serum NfL level was not significantly elevated, but was correlated with cognitive test scores. Our findings suggest that serum NfL concentration could be an indicator of cognitive function in epilepsy patients.

Wearable sensor device-based detection of decreased heart rate variability in Parkinson's disease.

The evidence that heart rate variability (HRV) decreases during early Parkinson's disease (PD) largely depends on electrocardiogram data. In this study, we examined HRV in PD using wearable sensors and assessed various evaluation methods for detecting disease-related alterations. We evaluated 27 patients with PD and 23 disease controls. The wearable sensors POLAR V800 HR and POLAR H10 were used for the HRV measurements. The participants wore the two sensors for approximately 24 h, and long-term HRV data were acquired. We analyzed the standard deviation of normal R-R intervals (SDNN) and coefficient of variation of R-R intervals (CVRR) for every 100 consecutive beats. Focusing on the fluctuation of SDNN and CVRR, we extracted the minimum, first decile, first quartile, and median values of SDNN and CVRR. The area under the receiver operating characteristic curve (AUC) for each HRV parameter was calculated to differentiate PD from the disease controls. The minimum values of SDNN and CVRR had the highest AUC (SDNN: AUC 0.90, 95% confidence interval [CI] 0.78-0.96; CVRR: AUC 0.90, CI 0.76-0.96) among the evaluation methods tested. The minimum values of SDNN and CVRR were significantly decreased in PD (SDNN: 9.5 ± 4.0 ms vs. 4.4 ± 2.0 ms, p < 0.0001; CVRR: 1.15 ± 0.33% vs. 0.65 ± 0.24%, p < 0.0001). We detected decreased HRV in PD using wearable sensors. Analyzing the minimum values of the HRV parameter in long-term recordings appears to be appropriate for detecting the decrease in HRV in PD.

NOD2 Mutation-Associated Case with Blau Syndrome Triggered by BCG Vaccination.

We describe a patient who developed multiple granulomatous skin lesions after Bacille de Calmette et Guérin (BCG) vaccination without significant effect by topical corticosteroid, followed by painless cystic tumors on the bilateral knees and hands and inflammatory changes on ophthalmologic examination. A functional mutation in NOD2 was detected by a genetic analysis, and he was diagnosed as sporadic Blau syndrome. Since NOD2 acts as a sensor for the BCG component, it is possible that BCG vaccination may trigger granuloma formation in Blau syndrome patients with such genetic background.

Impaired pain processing and its association with attention disturbance in patients with amyotrophic lateral sclerosis.

BACKGROUND: Cognitive dysfunction characterized by executive dysfunction and persistent attention function has been reported in patients with amyotrophic lateral sclerosis (ALS); however, it is unclear if this contributes to the pain processing deficits associated with the disease. OBJECTIVE: We clarified the relationship between pain processing and both cognitive function and sensory symptoms in patients with ALS. METHODS: We enrolled 23 patients with ALS and 14 healthy control subjects. We examined pain-related somatosensory evoked potentials (SEPs) using an intra-epidermal needle electrode. We evaluated cognitive function and the clinical characteristics of sensation and analyzed their relationships with pain-related SEPs. RESULTS: Pain-related SEP amplitudes were significantly lower, while the rate of amplitude attenuation due to habituation or change in attention was significantly greater in patients with ALS than in control subjects. There were no significant differences in pain-related SEP parameters between patients with or without sensory symptoms. Instead, pain-related SEP amplitude and its rate of attenuation were correlated with cognitive dysfunction, particularly with attention domains. CONCLUSIONS: Our results suggest that attention deficit, but not sensory nerve involvement, is a major cause of the alterations in pain-related SEP in patients with ALS.

Difference in cardiovascular response during orthostatic stress in Parkinson's disease and multiple system atrophy.

Although orthostatic hypotension is more prominent in multiple system atrophy (MSA) than in Parkinson's disease (PD), there is no study comparing the degree of decrease in total peripheral resistance and cardiac response during orthostatic stress between both diseases. In this study, we examined whether there is a difference in cardiovascular response between MSA and PD. We examined the results of the head-up tilt test in 68 patients with MSA, 28 patients with cardiac non-denervated PD, and 70 patients with cardiac denervated PD whose total peripheral resistance after 60° tilting was lower than the value at 0°. Differences in cardiac output and blood pressure changes were compared against the decrease in total peripheral resistance. There was no difference in the degree of decrease in total peripheral resistance among the three groups. However, the slope of the regression line revealed that the increase in cardiac output against the change in total peripheral resistance was significantly lower in the MSA group than in the cardiac non-denervated and denervated PD groups, and that the decrease in systolic blood pressure against the change in total peripheral resistance was significantly greater in the MSA group than in the cardiac non-denervated and denervated PD groups. In MSA, the cardiac response during orthostatic stress is lower than that in PD, possibly underlying the fact that orthostatic hypotension is more prominent in MSA than in PD.

Impact of orthostatic hypotension on wheelchair use in patients with Parkinson's disease.

Wheelchair use is an important indicator of disease progression in Parkinson's disease (PD). Here, we investigated whether orthostatic hypotension (OH) affects the time to wheelchair use. We examined 33 PD patients with OH and 95 without OH. Median time to start using a wheelchair calculated from the time of disease onset was significantly shorter in patients with OH than in those without OH (12.0 vs 19.0 years; p < 0.001). Thus, appropriate management of OH and motor function is necessary.

Change in allodynia of patients with post-lingual nerve repair iatrogenic lingual nerve disorder.

PURPOSE: Mandibular third molar extractions are common treatment in oral maxillofacial surgery, but risk disturbance of the lingual nerves causing anesthesia, eating difficulty and allodynia, which can seriously reduce patient quality of life. This study investigates the change in allodynia before and after repair in patients with lingual nerve disorder. SUBJECTS AND METHODS: This retrospective cohort study comprises the 52 patients with affected lingual nerve after third molar extraction at our hospital over a 7-year period. Pre- and postoperative (6 months and 12 months) neurosensory records were analyzed. RESULTS: Fifty-two patients underwent lingual nerve repair and returned for at least 1 year of follow-up. Mean age was 36.8 ± 11.9. Median interval between injury and surgery was 5 (4, 8) months. In 92.9% of those with pain before surgery, allodynia disappeared postoperatively. CONCLUSIONS: This study shows that microsurgical lingual reconstructions are effective in patients with preoperative allodynia, but a small number of patients may have remaining allodynia after surgery. Large-scale, more detailed analysis of such cases is required.

Comparison of Subjective and Objective Assessments of Neurosensory Function after Lingual Nerve Repair.

OBJECTIVE: Mandibular third molar extractions are important in oral maxillofacial surgery. Damage to the lingual nerves, although rare, is a possible complication. There are reports of postoperative recovery after lingual nerve repair, but few reports have compared subjective and objective assessments of neurosensory function. Therefore, this study aims to compare subjective and objective assessments of neurosensory function after lingual nerve repair. SUBJECTS AND METHODS: This retrospective cohort study comprised 52 patients with lingual nerve anesthesia after third molar extraction at the Department of Oral and Maxillofacial Surgery, Wakayama Medical University Hospital, Wakayama, Japan, between December 2008 and December 2015. We recorded pre- and postoperative (6 months and 12 months) neurosensory examinations. RESULTS: Patient's subjective assessments of neurosensory function suggested improvement between the preoperative period and 12 months postoperation, although this difference was not significant. Objective assessment based on examination and testing, on the other hand, showed a significant difference in improvement (p < 0.05). CONCLUSIONS: There was no evidence that improvement of subjective preoperative and postoperative assessments was significantly associated with improvement of objective neurosensory assessments after lingual nerve repair. Overall physical condition and background were thought to affect subjective evaluation. Subjective assessment is important in conjunction with objective evaluation because it may reveal dysesthesia that would otherwise be missed. In the future, we will examine those cases in whom subjective assessments showed no improvement although objective assessments showed improvement.

An Autopsy Case of Intimal Sarcoma of the Abdominal Aorta with Bone Metastasis and Lymph Node Metastasis: A Case Report and Review of the Japanese Literature.

A 73-year-old man complained of sternoclavicular joint pain; blood tests revealed elevated C-reactive protein. The patient developed delirium; magnetic resonance imaging showed metastatic bone tumors. He died two weeks after admission. Autopsy revealed abdominal aortic intimal sarcoma with metastasis to the peritracheal lymph nodes and sternum. Peripheral arterial embolism and bone metastasis are common symptoms of aortic intimal sarcoma, which implies a place for aortic intimal sarcoma in differential diagnoses of embolism or bone tumors of unknown origin.

Efficacy and Safety Results From a Phase II, Placebo-Controlled Study of Onartuzumab Plus First-Line Platinum-Doublet Chemotherapy for Advanced Squamous Cell Non-Small-Cell Lung Cancer.

INTRODUCTION: The treatment options for squamous cell non-small-cell lung cancer (NSCLC) are limited. We assessed the efficacy and safety of onartuzumab plus platinum-doublet chemotherapy in previously untreated advanced squamous cell NSCLC. PATIENTS AND METHODS: The patients were randomized to receive onartuzumab plus paclitaxel plus carboplatin/cisplatin (n = 55) or placebo plus paclitaxel plus carboplatin/cisplatin (n = 54). Randomization was stratified by MET diagnostic status: MET immunohistochemistry (IHC)-positive (MET IHC 3+/2+) or MET IHC-negative (MET IHC 1+/0). The co-primary endpoints were investigator-assessed progression-free survival in the intent-to-treat and the MET IHC+ populations. RESULTS: The risk of disease progression or death was similar between the 2 treatment arms in both the intent-to-treat (stratified hazard ratio, 0.95; 95% confidence interval, 0.63-1.43) and MET IHC+ populations (unstratified hazard ratio, 1.27; 95% confidence interval, 0.69-2.32). Comparable results were obtained for overall survival and the objective response rate. In all safety-evaluable patients, the grade 3 to 5 adverse events occurring at a > 5% greater incidence in the onartuzumab-containing versus the placebo-containing arm were neutropenia (14.8% vs. 5.8%) and pulmonary embolism (5.6% vs. 0%). Eight patients died as a result of adverse events: 1 case each of pneumonitis, pneumonia, cardiac failure, and unexplained death in the onartuzumab arm and 1 case each of hemorrhage, cardiac arrest, hemoptysis, and febrile neutropenia in the placebo arm. CONCLUSION: Studies using alternative assays of MET activation might help to clarify the role of onartuzumab. However, with the lack of clinical activity seen in the present study, the development of onartuzumab for squamous cell NSCLC will not be pursued further.

Identification of a bipartite nuclear localization signal in the silkworm Masc protein.

The silkworm Masculinizer (Masc) gene encodes a CCCH-tandem zinc finger protein that controls both masculinization and dosage compensation. Masc protein is a nuclear protein, but the mechanism underlying the transport of this protein into the nucleus has not yet been elucidated. Here, we identified a functional bipartite nuclear localization signal (NLS) located between residues 274 and 290 of the Masc protein. Sequence comparison revealed that this bipartite NLS is evolutionarily conserved in Masc proteins from other lepidopteran insects. Furthermore, we showed that the degree of nuclear localization is not associated with the masculinizing activity of the Masc protein.

Salt stress induces internalization of plasma membrane aquaporin into the vacuole in Arabidopsis thaliana.

Salt stress is a major environmental stress for plants, causing hyperosmotic, ionic and drought-like stresses. Plasma membrane intrinsic protein 2;1 (PIP2;1), which forms a water channel that regulates water flux thorough the plasma membrane (PM), is constitutively trafficked between the PM and the trans-Golgi network (TGN) in Arabidopsis thaliana. Salt stress is known to relocalize PIP2;1 to intracellular compartments, probably to decrease the water permeability of the root. However, the destination of internalized PIP2;1 and the mechanism by which PIP2;1 is internalized remain unclear. Here, we examined the effects of salt stress and inhibitors of endocytosis on the intracellular localization of green fluorescent protein-fused PIP2;1 (GFP-PIP2;1) in Arabidopsis thaliana root epidermal cells. Salt stress decreased the fluorescence of GFP-PIP2;1 at the PM and increased it in the vacuolar lumen as shown by staining of the vacuolar membrane. The internalization of PIP2;1 was suppressed by an inhibitor of clathrin-mediated endocytosis and by inhibitors of two kinases that appear to have roles in salt stress, phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol 4-kinase (PI4K). Inhibiting PI4K suppressed the salt-induced endocytosis of GFP-PIP2;1 at the PM, whereas inhibiting PI3K suppressed the trafficking of GFP-PIP2;1 after its internalization. These results suggest that salt stress induces the internalization of PIP2;1 from the PM to the vacuolar lumen, and that these processes are dependent on clathrin, PI3K and PI4K.

[A case of dural arteriovenous fistula at the craniocervical junction, which spinal MRI findings reveals increased intensity signal in Th3-medullary cone].

A 60-year-old woman had transient weakness of the legs and urinary retention for six weeks. She presented with a gait disorder and was admitted to the hospital. She showed symptoms of paraplegia, tingling in the lower extremities, dysuria. She underwent an MRI, and T2-weighted images showed an enlargement of the thoracolumbar spinal cord and high intensity signal from Th3 to the medullary cone, and a contrast-enhanced T1-weighted image showed abnormal vessels anterior to the spine cord. Cervical and spinal angiography documented a dural arteriovenous fistula at the craniocervical junction that was fed by the right vertebral artery and the right ascending pharyngeal arteries and drained into the perimedullary veins. Surgical therapy improved her symptoms and MRI images. Craniocervical junction DAVF with thoracic-medullary cones lesion is rare.

[A case of myelitis with eosinophilia of the cerebrospinal fluid].

A 25-year-old woman developed numbness of the right flank two weeks after a one-month stay in Thailand and Laos, which are known as areas of angiostrongylosis cantonensis infections. The signs were numbness, pain sense disorder, and vibration sense disorder on the region of the 6th to 12th dermatome. On a MRI T(2) weighted image (T(2)WI), signal hyperintensity in a longitudinal spinal lesion was seen. In the cerebrospinal fluid (CSF), eosinophils were detected. The patient was diagnosed with eosinophilic meningitis and myelitis, and then treated with intravenous methylprednisolone. This improved her signs, CSF and MRI findings. She took no drugs, did not have any allergies, any vasculitis, or neuromyelitis optica spectrum disorders. Although anti-parasite antibodies were not identified, she was probably infected by angiostrongylus cantonensis from her history and examinations.

Association between baseline pulmonary status and interstitial lung disease in patients with non-small-cell lung cancer treated with erlotinib--a cohort study.

INTRODUCTION: Although interstitial lung disease (ILD) is a known serious adverse effect of epidermal growth factor receptor tyrosine kinase inhibitors, the risk factors for its development are poorly defined. To determine the risk factors for the development of drug-induced ILD and poor-prognosis (fatal) drug-induced ILD after erlotinib treatment, we assessed the baseline pulmonary status in patients with non-small cell lung cancer enrolled in a postmarketing clinical study of erlotinib. PATIENTS AND METHODS: In the present prospective cohort study, the baseline pulmonary status of all patients was evaluated using conventional or high-resolution computed tomography. The patients were monitored for the development of drug-induced ILD for 120 days after the start of treatment. All diagnoses of drug-induced ILD were confirmed by an independent ILD safety review committee. The risk factors were determined using logistic regression analysis. RESULTS: A total of 645 patients were enrolled, of whom 627 were evaluable. The committee confirmed the diagnoses of drug-induced ILD in 19 patients, 6 of whom had fatal outcomes. Multivariate logistic regression analysis revealed that pre-existing ILD and limited residual normal lung were significant risk factors for the development of drug-induced ILD. An additional multivariate logistic regression analysis revealed that limited residual normal lung was a significant risk factor for the development of poor-prognosis (fatal) drug-induced ILD. CONCLUSION: Pre-existing ILD and the amount of residual normal lung (≤ 50%) were identified as risk factors for the development of drug-induced ILD. The amount of residual normal lung (≤ 50%) was identified as a risk factor for the development of poor-prognosis (fatal) drug-induced ILD.

Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study.

BACKGROUND: In recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus. METHODS: The efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n = 56) or tofogliflozin (10, 20, or 40 mg; n = 58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at week 24. RESULTS: Overall, 229 patients were included in the full analysis set (placebo: n = 56; tofogliflozin 10 mg: n = 57; tofogliflozin 20 and 40 mg: n = 58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA1c at week 24 was -0.028% (-0.192 to 0.137) in the placebo group, compared with -0.797% (-0.960 to -0.634) in the tofogliflozin 10 mg group, -1.017% (-1.178 to -0.856) in the tofogliflozin 20 mg group, and -0.870% (-1.031 to -0.709) in the tofogliflozin 40 mg group (p < 0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were classified as mild or moderate in severity. CONCLUSIONS: Tofogliflozin 10, 20, or 40 mg administered once daily as monotherapy significantly decreased HbA1c and body weight, and was generally well tolerated in Japanese patients with type 2 diabetes mellitus. Phase 3 studies were recently completed and support the findings of this combined Phase 2 and 3 study. TRIAL REGISTRATION: This study was registered in the JAPIC clinical trials registry (ID: Japic CTI-101349).

Nested case control study of proteomic biomarkers for interstitial lung disease in Japanese patients with non-small-cell lung cancer treated with erlotinib: a multicenter phase IV study (JO21661).

BACKGROUND: Interstitial lung disease (ILD) is a serious adverse drug reaction associated with epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR TKIs). Its risk factors are yet to be fully elucidated. We sought to identify proteomic biomarkers associated with ILD development in erlotinib-treated Japanese patients with non-small-cell lung cancer (NSCLC) to build predictive models. PATIENTS AND METHODS: We conducted a nested case-control study. The participants were patients with NSCLC enrolled in a phase IV study of erlotinib in whom ILD developed within 120 days after erlotinib administration. The controls were randomly selected patients without ILD from the overall study cohort who were also treated with erlotinib. Serum samples were obtained before the first administration of erlotinib and were assayed by liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS). Logistic regression analysis was performed to identify the peptide and proteins associated with ILD. RESULTS: A total of 645 patients were enrolled in the cohort; 15 case patients and 64 controls were analyzed. When multiplicity was taken into account, we were unable to statistically verify any genuine association between individual markers and ILD. Investigation of the predictive power based on leave-one-out cross-validation (LOOCV) showed that the area under the receiver operating characteristic curve was 0.73 at a maximum. Additional analysis suggested that 3 proteins (C3, C4A/C4B, and APOA1) have a stronger association with ILD than do the other proteins tested. CONCLUSION: We were unable to demonstrate predictive serum protein markers for ILD development. However, C3, C4A/C4B, and APOA1 are worthy of further investigation.

Multiple NF-Y-binding CCAAT boxes are essential for transcriptional regulation of the human C7orf24 gene, a novel tumor-associated gene.

Human chromosome 7 ORF 24 (C7orf24) has been identified as a tumor-related protein, and shown to be a γ-glutamyl cyclotransferase. In the current study, we characterized the promoter region of the human C7orf24 gene to explore the transcriptional regulation of the gene. We revealed that the human C7orf24 promoter is a TATA-less promoter, containing five CCAAT boxes aligned in a forward orientation. By performing a luciferase reporter assay with 5'-deleted and site-directed mutated constructs in HeLa, MCF-7 and IMR-90 cells, we found that three proximal CCAAT boxes are important for basal transcription. Electrophoretic mobility gel shift assay and chromatin immunoprecipitation assay demonstrated that NF-Y specifically bound to all three CCAAT boxes. In addition, the mRNA and protein expression levels of C7orf24 were significantly reduced in HeLa cells depleted of NF-YB, a subunit of NF-Y. These results suggested that NF-Ys bound to the three proximal CCAAT boxes play a central role in the transcription of the gene. Furthermore, as in the case of other genes transcribed under the control of multiple NF-Ys, such as human E2f1 and cyclin b1, the C7orf24 gene expression profile oscillated during the cell cycle, implying that C7orf24 is a novel cell cycle-associated gene.

Monoamine oxidase A is highly expressed by the human corpus luteum of pregnancy.

To investigate the physiological characteristics of the corpus luteum (CL) of pregnancy, we raised a mAb, human corpus luteum (HCL)-4, against human luteal cells obtained from CL of pregnancy. The affinity-purified antigen from human CL of pregnancy or placenta using HCL-4 was a 61 kDa protein. The partial amino acid sequence of the antigenic protein was identical to that of human monoamine oxidase A (MAOA, EC1.4.3.4). MAOA has been shown to catabolize catecholamines that were reported to regulate luteal function in CL and vasoconstriction in various organs. Immunohistochemistry using HCL-4 mAb showed that MAOA was intensely expressed on large luteal cells and moderately expressed on small luteal cells in the CL of pregnancy. In the CL of menstrual cycle, MAOA was weakly detected on large luteal cells but not detected at all on small luteal cells. Western blotting analysis confirmed the high expression of MAOA in CL of pregnancy. Northern blot analysis also showed the expression of MAOA mRNA in human CL, and showed that its expression was higher in CL of pregnancy than in CL of menstrual cycle. The increased expression of MAOA in the CL of pregnancy suggests the contribution of MAOA to the function of the CL of pregnancy.