COUP-TFII plays a role in cAMP-induced Schwann cell differentiation and in vitro myelination by up-regulating Krox20.

Schwann cells (SCs) are known to produce myelin for saltatory nerve conduction in the peripheral nervous system (PNS). Schwann cell differentiation and myelination processes are controlled by several transcription factors including Sox10, Oct6/Pou3f1, and Krox20/Egr2. Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan receptor that plays a role in the development and differentiation. However, the role of COUP-TFII in the transcriptional regulatory network of SC differentiation has not been fully identified yet. Thus, the objective of this study was to investigate the role and molecular hierarchy of COUP-TFII during cAMP-induced SC differentiation. Our results showed that dibutyryl-cAMP (db-cAMP) increased expression levels of COUP-TFII along with the expressions of Oct6, Krox20, and myelin-related genes known to be related to SC differentiation. Our mechanistic studies showed that COUP-TFII acted downstream of Hsp90/ErbB2/Gab1/ERK-AKT pathway during db-cAMP-induced SC differentiation. In addition, we found that COUP-TFII induced Krox20 expression by directly binding to Krox20-MSE8 as revealed by chromatin immunoprecipitation assay and promoter activity assay. In line with this, the expression of COUP-TFII was increased before up-regulation of Oct6, Krox20, and myelin-related genes in the sciatic nerves during early postnatal myelination period. Finally, COUP-TFII knockdown by COUP-TFII siRNA or via AAV-COUP-TFII shRNA in SCs inhibited db-cAMP-induced SC differentiation and in vitro myelination of sensory axons, respectively. Taken together, these findings indicate that COUP-TFII might be involved in postnatal myelination through induction of Krox20 in SCs. Our results present a new insight into the transcriptional regulatory mechanism in SC differentiation and myelination.

Neutrophil-to-lymphocyte ratio is an independent predictor for neurological disability in patients with idiopathic transverse myelitis.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) has been found to be useful in the prognostication of immune-mediated neurological disorders because it roughly reflects the systemic innate immune response compared to the adaptive immune response. However, studies on the validity of NLR in demyelinating disorders of the central nervous system have shown conflicting results. Therefore, we aimed to investigate NLR in the idiopathic transverse myelitis (ITM) cohort. METHODS: We retrospectively analyzed the cohort data of patients with ITM between January 2006 and February 2020. The medical data of all patients with myelitis were reviewed to exclude patients with disease-associated myelopathy according to predefined exclusion criteria. The relationship between the natural log-transformed NLR (lnNLR) and the clinical, paraclinical, and imaging data was evaluated. Factors associated with neurological disability were analyzed using a linear mixed-effects model. Predictive factors for moderate-to-severe neurological disability (Expanded Disability Status Scale [EDSS] score ≥ 4) were investigated. RESULTS: A total of 124 participants were included in the analysis. The lnNLR correlated with EDSS and lesion length. Linear mixed-effects analysis showed that age, lesion length, and lnNLR were independently associated with neurological disabilities. Multivariable logistic regression revealed that lnNLR (odds ratio [OR] = 4.266, 95% confidence interval [CI] = 1.220-14.912, p = 0.023) and lesion length (OR = 1.848, 95% CI = 1.249-2.734, p = 0.002) were independent predictive factors of the worst neurological disability. CONCLUSION: NLR may be used as an independent prognostic factor for predicting poor neurological outcomes in patients with ITM.

Are second primary head and neck cancers with previous hematological malignancy more aggressive than de novo head and neck cancers?

OBJECTIVES: Secondary solid tumors can occur after the treatment of hematological malignancies and are associated with a poor prognosis. We evaluated the survival outcomes of patients with second primary head and neck cancers according to the site of cancer origin, type of hematological malignancy, and age. MATERIALS AND METHODS: We enrolled all patients who underwent surgery for second primary head and neck cancer and were previously treated for hematological malignancy between 1997 and 2020. We analyzed the survival outcomes of patients with second primary head and neck cancer, and compared them with 3126 de novo head and neck cancer patients diagnosed during the same period at our hospital. RESULTS: The 5-year overall survival (OS) rate was significantly worse for second primary head and neck cancer patients than de novo cancer patients (52.0 % and 77.9 %, respectively; p = 0.04) and those results were similarly observed in second primary oral cavity cancer (33.3 % and 75.7 %, respectively; p < 0.01). Patients with myelodysplastic syndrome and acute myeloid leukemia showed significantly worse 5-year OS rate than those with other types of hematological malignancies (p = 0.036). Multivariate analysis showed that bone marrow transplantation (BMT) was a risk factor for the recurrence of head and neck cancers (odds ratio = 6.635, p = 0.042). CONCLUSION: Patients with second primary head and neck cancer, particularly of the oral cavity, had a worse prognosis than patients with de novo head and neck cancer. BMT predicts recurrence in second primary head and neck cancer patients.

Center Deviation Measurement of Color Contact Lenses Based on a Deep Learning Model and Hough Circle Transform.

Ensuring the quality of color contact lenses is vital, particularly in detecting defects during their production since they are directly worn on the eyes. One significant defect is the "center deviation (CD) defect", where the colored area (CA) deviates from the center point. Measuring the extent of deviation of the CA from the center point is necessary to detect these CD defects. In this study, we propose a method that utilizes image processing and analysis techniques for detecting such defects. Our approach involves employing semantic segmentation to simplify the image and reduce noise interference and utilizing the Hough circle transform algorithm to measure the deviation of the center point of the CA in color contact lenses. Experimental results demonstrated that our proposed method achieved a 71.2% reduction in error compared with existing research methods.

Subgrouping of Peripheral Neuropathic Pain Patients According to Sensory Symptom Profile Using the Korean Version of the PainDETECT Questionnaire.

BACKGROUND: A culturally validated Korean version of the PainDETECT Questionnaire (PD-Q) was used to identify neuropathic pain components (NeP) in patients suffering from chronic pain. The purpose of this study was to determine if the Korean PD-Q can be used to subgroup patients with peripheral NeP according to sensory symptom profiles. METHODS: This study included 400 Korean patients with peripheral neuropathic pain diagnosed as probable or definite NeP. The total scores and subscores for each item in PD-Q were transformed into a Z-score for standardization. Hierarchical cluster analysis was performed to identify clusters of subjects by PD-Q scores. RESULTS: The mean total PD-Q score of the study participants was 14.57 ± 6.46. A hierarchical cluster analysis identified 5 clusters with distinct pain characteristic profiles. Cluster 1 had relatively severe burning and tingling sensations. The mean total PD-Q score for cluster 2 was the lowest of the 5 clusters. Cluster 3 tended to be vulnerable to pain in response to cold/heat stimulation. Cluster 4 showed relatively severe pain induced by physical stimuli, such as light touch or slight pressure. Cluster 5 had high scores for all NeP symptoms. CONCLUSION: This study demonstrates the ability of patients to cluster by symptoms using the Korean PD-Q. Subgrouping of peripheral neuropathic pain by sensory symptom profile may be useful in making effective drug treatment decisions.

p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence.

Cellular senescence acts as an important barrier to tumorigenesis by eliminating precancerous cells. Previous studies have shown an essential role of the tumor suppressor p53 in cellular senescence, but how p53 induces cellular senescence is not fully understood. We found that p53 promoted the formation of highly interconnected and elongated mitochondria prior to the onset of cellular senescence. The inhibition of mitochondrial elongation upon p53 expression suppressed cellular senescence, suggesting that mitochondrial elongation is required for the induction of p53-dependent senescence. p53-induced mitochondrial elongation resulted in mitochondrial dysfunction and subsequent increases in intracellular reactive oxygen species (ROS) levels, an important mediator of cellular senescence. Mechanistically, the inhibitory phosphorylation of Drp1 Ser637 increased upon p53 expression, suppressing the translocation of Drp1 into mitochondria. The transcriptional function of p53 was crucial for controlling the inhibitory phosphorylation of Drp1, whereas p21 was nonessential. Protein kinase A (PKA) activity was responsible for p53-mediated Drp1 Ser637 phosphorylation and mitochondrial dysfunction. Taken together, these results suggest that p53 regulates mitochondrial dynamics through the PKA-Drp1 pathway to induce cellular senescence.

Inhibition effect of Caragana sinica root extracts on Osteoarthritis through MAPKs, NF-κB signaling pathway.

Osteoarthritis (OA) is a common joint disease characterized by degradation and inflammation of cartilage extracellular matrix. We aimed to evaluate the protective effect of Caragana sinica root (CSR) on interleukin (IL)-1ß-stimulated rat chondrocytes and a monosodium iodoacetate (MIA)-induced model of OA. In vitro, cell viability of CSR-treated chondrocytes was measured by MTT assay. The mRNA expression of Matrix metallopeptidases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) and extracellular matrix (ECM) were analyzed by quantitative real-time PCR (qRT-PCR). Moreover, the protein expression of MAPK (phosphorylation of EKR, JNK, p38), inhibitory kappa B (IκBα) and nuclear factor-kappa B (NF-κB p65) was detected by western blot analysis. In vivo, the production of nitric oxide (NO) was detected by Griess reagent, while those of inflammatory mediators, MMPs and ECM were detected by ELISA. The degree of OA was evaluated by histopathological analyses, Osteoarthritis Research Society International (OARSI) score and micro-CT analysis. CSR significantly inhibited the expression of MMPs, ADAMTSs and the degradation of ECM in IL-1ß-stimulated chondrocytes. Furthermore, CSR significantly suppressed IL-1ß-stimulated of MAPKs, NF-κB signaling pathway. In vivo, CSR and Indomethacin inhibited the production of inflammatory mediators, MMPs and degradation of ECM in MIA-induced model of OA. In addition, CSR improved the severity of OA. Taken together, these results suggest CSR is a potential therapeutic active agent in the treatment of OA.

Evaluation of neutrophil extracellular traps as the circulating marker for patients with acute coronary syndrome and acute ischemic stroke.

INTRODUCTION: Neutrophil extracellular traps (NETs) are known to be induced by various factors. In this study, we tried to identify circulating levels of NETs in patients with acute coronary syndrome (ACS) and acute ischemic stroke (AIS) and to confirm its suitability as a new circulating marker in their detection. METHODS: We prospectively enrolled 95 patients with a diagnosis of ACS (N = 37) or AIS (N = 58) in Dong-A University Hospital, Busan, Korea. The control group was selected from healthy adults (N = 25) who visited the hospital for health screening. Circulating levels of NETs were evaluated by measuring plasma concentrations of double-stranded DNA (dsDNA) and DNA-histone complex. RESULTS: The concentrations of dsDNA were statistically higher in patients with ACS or AIS than those in the control group (both P < .001). In the univariable and multivariable analyses, statistically significant risk factors were troponin I (TnI) level and dsDNA concentration in the ACS group (P = .046 and P = .015, respectively) and only dsDNA concentration in the AIS group (P = .002). In the receiver operating characteristic curve analyses, the area under the curve values for TnI level and dsDNA concentration in the ACS group were 0.878 and 0.968, respectively, and the value for dsDNA concentration in the AIS group was 0.859. CONCLUSIONS: In this study, it was confirmed that the circulating level of NETs was increased in patients with ACS and AIS at initial presentation. Findings in this study show that NETs could be used as a new circulating marker for the initial diagnosis of ACS or AIS.

The stress response neuropeptide CRF increases amyloid-ß production by regulating γ-secretase activity.

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-ß (Aß) production. In cells, CRF treatment increases Aß production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by ß-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aß. These data collectively link CRF to increased Aß through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aß and in some cases preferentially increase Aß42 via complex effects on γ-secretase.

Heat Shock Protein 90 is Required for cAMP-Induced Differentiation in Rat Primary Schwann Cells.

Schwann cells (SCs) play an important role in producing myelin for rapid neurotransmission in the peripheral nervous system. Activation of the differentiation and myelination processes in SCs requires the expression of a series of transcriptional factors including Sox10, Oct6/Pou3f1, and Egr2/Krox20. However, functional interactions among several transcription factors are poorly defined and the important components of the regulatory network are still unknown. Until now, available evidence suggests that SCs require cAMP signaling to initiate the myelination program. Heat shock protein 90 (Hsp90) is known as a chaperone required to stabilize ErbB2 receptor. In recent years, it was reported that cAMP transactivated the ErbB2/ErbB3 signaling in SCs. However, the relationship between Hsp90 and cAMP-induced differentiation in SCs is undefined. Here we investigated the role of Hsp90 during cAMP-induced differentiation of SCs using Hsp90 inhibitor, geldanamycin and Hsp90 siRNA transfection. Our results showed that dibutyryl-cAMP (db-cAMP) treatment upregulated Hsp90 expression and led to nuclear translocation of Gab1/ERK, the downstream signaling pathway of the ErbB2 signaling mechanism in myelination. The expression of myelin-related genes and nuclear translocation of Gab1/ERK following db-cAMP treatment was inhibited by geldanamycin pretreatment and Hsp90 knockdown. These findings suggest that Hsp90 might play a role in cAMP-induced differentiation via stabilization of ErbB2 and nuclear translocation of Gab1/ERK in SCs.

Holotoxin A1 Induces Apoptosis by Activating Acid Sphingomyelinase and Neutral Sphingomyelinase in K562 and Human Primary Leukemia Cells.

Marine triterpene glycosides are attractive candidates for the development of anticancer agents. Holotoxin A1 is a triterpene glycoside found in the edible sea cucumber, Apostichopus (Stichopus) japonicus. We previously showed that cladoloside C2, the 25(26)-dihydro derivative of holotoxin A1 induced apoptosis in human leukemia cells by activating ceramide synthase 6. Thus, we hypothesized that holotoxin A1, which is structurally similar to cladoloside C2, might induce apoptosis in human leukemia cells through the same molecular mechanism. In this paper, we compared holotoxin A1 and cladoloside C2 for killing potency and mechanism of action. We found that holotoxin A1 induced apoptosis more potently than cladoloside C2. Moreover, holotoxin A1-induced apoptosis in K562 cells by activating caspase-8 and caspase-3, but not by activating caspase-9. During holotoxin A1-induced apoptosis, acid sphingomyelinase (SMase) and neutral SMase were activated in both K562 cells and human primary leukemia cells. Specifically inhibiting acid SMase and neutral SMаse with chemical inhibitors or siRNAs significantly inhibited holotoxin A1-induced apoptosis. These results indicated that holotoxin A1 might induce apoptosis by activating acid SMase and neutral SMase. In conclusion, holotoxin A1 represents a potential anticancer agent for treating leukemia. Moreover, the aglycone structure of marine triterpene glycosides might affect the mechanism involved in inducing apoptosis.

Peroxisome proliferator-activated receptor γ coactivator-1α is a predictor of lymph node metastasis and poor prognosis in human colorectal cancer.

Peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) expression levels are correlated with clinical outcome in breast cancer. However, the potential biological and clinical significance of PPARγ and PGC-1α in colorectal cancer remains unknown. Here we investigated PPARγ and PGC-1α expression in colorectal cancer, and the associations of these expression levels with clinicopathological features. We also evaluated the roles of PPARγ and PGC-1α as prognostic factors in colorectal cancer. We performed immunohistochemical analysis to investigate PPARγ and PGC-1α expression in human colorectal cancer tissues and adjacent normal tissues from 108 primary colorectal cancer patients. We then examined how these expression levels correlated with clinicopathological features. Using the Kaplan-Meier method, we evaluated 3-year disease-free survival (DFS) and overall survival (OS) in patients with tumors expressing different levels of PPARγ and PGC-1α. Our results revealed that PPARγ expression was not significantly correlated with age at surgery, gender, differentiation, depth of infiltration, relapse, or TNM stage. Additionally, PGC-1α expression was not significantly correlated with age at surgery, differentiation, depth of infiltration, relapse, or TNM stage. However, PGC-1α expression was significantly correlated with nodal metastasis (p=0.020). Survival analysis demonstrated reduced OS in the PGC-1α-positive group compared to the PGC-1α-negative group (p=0.03). Our present findings suggest that PGC-1α may be useful for predicting nodal metastasis, and may represent a biomarker for poor prognosis in colorectal cancer.

Cooperative interaction of hepatocyte growth factor and neuregulin regulates Schwann cell migration and proliferation through Grb2-associated binder-2 in peripheral nerve repair.

The sequential reactive changes in Schwann cell phenotypes in transected peripheral nerves, including dedifferentiation, proliferation and migration, are essential for nerve repair. Even though the injury-induced migratory and proliferative behaviors of Schwann cells resemble epithelial and mesenchymal transition (EMT) in tumors, the molecular mechanisms underlying this phenotypic change of Schwann cells are still unclear. Here we show that the reactive Schwann cells exhibit migratory features dependent on the expression of a scaffolding oncoprotein Grb2-associated binder-2 (Gab2), which was transcriptionally induced by neuregulin 1-ErbB2 signaling following nerve injury. Injury-induced Gab2 expression was dependent on c-Jun, a transcription factor critical to a Schwann cell reprograming into a repair-type cell. Interestingly, the injury-induced activation (tyrosine phosphorylation) of Gab2 in Schwann cells was regulated by an EMT signal, the hepatocyte growth factor-c-Met signaling, but not by neuregulin 1. Gab2 knockout mice exhibited a deficit in nerve repair after nerve transection due to limited Schwann cell migration. Furthermore, Gab2 was required for the proliferation of Schwann cells following nerve injury and in vitro, and was over-expressed in human Schwann cell-derived tumors. In contrast, the tyrosine phosphorylation of Gab1 after nerve injury was principally regulated by the neuregulin 1-ErbB2 signaling and was indispensable for remyelination after crush injury, but not for the proliferation and migration of Schwann cells. Our findings indicate that Gab1 and Gab2 in Schwann cells are nonredundant and play a crucial role in peripheral nerve repair.

Schwann cell dedifferentiation-associated demyelination leads to exocytotic myelin clearance in inflammatory segmental demyelination.

Schwann cells (SCs), which form the peripheral myelin sheath, have the unique ability to dedifferentiate and to destroy the myelin sheath under various demyelination conditions. During SC dedifferentiation-associated demyelination (SAD) in Wallerian degeneration (WD) after axonal injury, SCs exhibit myelin and junctional instability, down-regulation of myelin gene expression and autophagic myelin breakdown. However, in inflammatory demyelinating neuropathy (IDN), it is still unclear how SCs react and contribute to segmental demyelination before myelin scavengers, macrophages, are activated for phagocytotic myelin digestion. Here, we compared the initial SC demyelination mechanism of IDN to that of WD using microarray and histochemical analyses and found that SCs in IDN exhibited several typical characteristics of SAD, including actin-associated E-cadherin destruction, without obvious axonal degeneration. However, autophagolysosome activation in SAD did not appear to be involved in direct myelin lipid digestion by SCs but was required for the separation of SC body from destabilized myelin sheath in IDN. Thus, lysosome inhibition in SCs suppressed segmental demyelination by preventing the exocytotic myelin clearance of SCs. In addition, we found that myelin rejection, which might also require the separation of SC cytoplasm from destabilized myelin sheath, was delayed in SC-specific Atg7 knockout mice in WD, suggesting that autophagolysosome-dependent exocytotic myelin clearance by SCs in IDN and WD is a shared mechanism. Finally, autophagolysosome activation in SAD was mechanistically dissociated with the junctional destruction in both IDN and WD. Thus, our findings indicate that SAD could be a common myelin clearance mechanism of SCs in various demyelinating conditions.

Clinical characteristics of late-onset neuromyelitis optica spectrum disorder: A multicenter retrospective study in Korea.

BACKGROUND: There are currently few studies regarding late-onset neuromyelitis optica spectrum disorder (LO-NMOSD). OBJECTIVE: We aimed to describe the characteristic features of patients with LO-NMOSD in Korea. METHODS: Anti-aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder (NMOSD) from nine tertiary hospitals were reviewed retrospectively. The patients were divided into two groups based on age of onset: LO-NMOSD (⩾50 years of age at onset) versus early-onset neuromyelitis optica spectrum disorder (EO-NMOSD) (<50 years of age at onset). Clinical, laboratory, and magnetic resonance imaging (MRI) parameters were investigated. RESULTS: Among a total of 147 patients (125 female; age of onset, 39.4 ± 15.2 years), 45 patients (30.6%) had an age of onset of more than 50 years. Compared to patients with EO-NMOSD, patients with LO-NMOSD had more frequent isolated spinal cord involvement at onset (64.4% vs 37.2%, p = 0.002), less frequent involvement of the optic nerve (40.0% vs 67.7%, p = 0.002), and less frequent brain MRI lesions (31.1% vs 50.0%, p = 0.034). Furthermore, there was a significant positive correlation between age of onset and Expanded Disability Status Scale (EDSS) score at last follow-up ( r = 0.246, p = 0.003). CONCLUSION: Age of onset could be an important predictor of lesion location and clinical course of patients with NMOSD.

Cigarette smoking is an independent risk factor for post-stroke delirium.

BACKGROUND: Post-stroke delirium is a common problem in the care of stroke patients, and is associated with longer hospitalization, high short-term mortality, and an increased need for long-term care. Although post-stroke delirium occurs in approximately 10 ~ 30% of patients, little is known about the risk factors for post-stroke delirium in patients who experience acute stroke. METHODS: A total of 576 consecutive patients who experienced ischemic stroke (mean age, 65.2 years; range, 23-93 years) were screened for delirium over a 2-year period in an acute stroke care unit of a tertiary referral hospital. We screened for delirium using the Confusion Assessment Method. Once delirium was suspected, we evaluated the symptoms using the Korean Version of the Delirium Rating Scale-Revised-98. Neurological deficits were assessed using the National Institutes of Health Stroke Scale at admission and discharge, and functional ability was assessed using the Barthel Index and modified Rankin Scale at discharge and 3 months after discharge. RESULTS: Thirty-eight (6.7%) patients with stroke developed delirium during admission to the acute stroke care unit. Patients with delirium were significantly older (70.6 vs. 64.9 years of age, P = .001) and smoked cigarettes more frequently (40% vs. 24%, P = .033) than patients without delirium. In terms of clinical features, the delirium group experienced a significantly higher rate of major hemispheric stroke (55% vs. 26%, P < .001), exhibited poorer functional performance at discharge and 3 months after discharge, and stayed in hospital significantly longer. Independent risk factors for delirium were older age, history of cigarette smoking, and major hemispheric stroke. CONCLUSION: Abrupt cessation of cigarette smoking may be a risk factor for post-stroke delirium in ischemic stroke patients. The development of delirium after stroke is associated with worse outcome and longer hospitalization.

Ceramide as a Target of Marine Triterpene Glycosides for Treatment of Human Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous myeloid clonal disorder exhibiting the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. Standard AML therapy requires intensive combination chemotherapy, which leads to significant treatment-related toxicity. The search for new, low toxic marine agents, inducing the generation of ceramide in leukemic cells is a new approach to improve the therapy of leukemia. This review focuses on the metabolism of sphingolipids, the role of ceramide in treating leukemia, and the antitumor activity, related to ceramide metabolism, of some marine metabolites, particularly stichoposides, triterpene glycosides extracted from sea cucumbers of the family Stichopodiidae.

γ-Secretase processing and effects of γ-secretase inhibitors and modulators on long Aß peptides in cells.

Understanding how different species of Aß are generated by γ-secretase cleavage has broad therapeutic implications, because shifts in γ-secretase processing that increase the relative production of Aßx-42/43 can initiate a pathological cascade, resulting in Alzheimer disease. We have explored the sequential stepwise γ-secretase cleavage model in cells. Eighteen BRI2-Aß fusion protein expression constructs designed to generate peptides from Aß1-38 to Aß1-55 and C99 (CTFß) were transfected into cells, and Aß production was assessed. Secreted and cell-associated Aß were detected using ELISA and immunoprecipitation MALDI-TOF mass spectrometry. Aß peptides from 1-38 to 1-55 were readily detected in the cells and as soluble full-length Aß proteins in the media. Aß peptides longer than Aß1-48 were efficiently cleaved by γ-secretase and produced varying ratios of Aß1-40:Aß1-42. γ-Secretase cleavage of Aß1-51 resulted in much higher levels of Aß1-42 than any other long Aß peptides, but the processing of Aß1-51 was heterogeneous with significant amounts of shorter Aßs, including Aß1-40, produced. Two PSEN1 variants altered Aß1-42 production from Aß1-51 but not Aß1-49. Unexpectedly, long Aß peptide substrates such as Aß1-49 showed reduced sensitivity to inhibition by γ-secretase inhibitors. In contrast, long Aß substrates showed little differential sensitivity to multiple γ-secretase modulators. Although these studies further support the sequential γ-secretase cleavage model, they confirm that in cells the initial γ-secretase cleavage does not precisely define subsequent product lines. These studies also raise interesting issues about the solubility and detection of long Aß, as well as the use of truncated substrates for assessing relative potency of γ-secretase inhibitors.

Sonographic findings in the ulnar nerve according to the electrophysiologic stage of carpal tunnel syndrome.

OBJECTIVES: Involvement of the ulnar nerve in patients with carpal tunnel syndrome is controversial. The aim of our study was to evaluate sonographic findings in the ulnar nerve in patients with carpal tunnel syndrome. METHODS: We performed median and ulnar nerve conduction studies with sonography in 109 hands of 60 patients with clinically suspected carpal tunnel syndrome. Sonographic findings were analyzed with regard to electrophysiologic stages of carpal tunnel syndrome. RESULTS: We found that the sensory conduction velocity of the ulnar nerve decreased as the electrophysiologic stage of carpal tunnel syndrome increased (P = .038), but there was no change in the cross-sectional area of the ulnar nerve at the wrist. The median-to-ulnar nerve cross-sectional area ratio at the wrist showed a significant correlation with the electrophysiologic stage of carpal tunnel syndrome (Spearman r = 0.431; P < .0001), in addition to the median nerve cross-sectional area at the wrist and the wrist-to- forearm median nerve cross-sectional area ratio. CONCLUSIONS: In our study, ulnar nerve involvement in patients with carpal tunnel syndrome was shown electrophysiologically but not sonographically. These results suggest that morphologic changes in the ulnar nerve do not occur in carpal tunnel syndrome, although functional changes may occur.

Three gastroenteritis outbreaks in South Korea caused by the consumption of kimchi tainted by norovirus GI.4.

BACKGROUND: In April 2013, outbreaks of acute gastroenteritis were reported at three schools in Jeonju, South Korea. Epidemiological investigations were performed to characterize the outbreaks and implement appropriate control measures. MATERIALS AND METHODS: Retrospective cohort studies were performed at these schools. Stool and environmental samples were collected for bacterial and viral assessment. A food supplier of the schools, food company X, was inspected, and samples of cabbage kimchi and groundwater were tested for norovirus by real-time reverse-transcriptase polymerase chain reaction. The relatedness of the detected norovirus strains was evaluated by phylogenetic analysis. RESULTS: Of the 3347 questionnaires distributed, 631 (attack rate: 18.9%) met the case definition. Among the consumed food items, kimchi products (i.e., cabbage and fresh kimchi) were significantly associated with illness. The kimchi products were supplied by food company X. Among stool samples from 95 students and 34 food handlers at the 3 schools, 39 (41.1%) and 14 (41.2%) samples, respectively, were positive for norovirus. The samples of groundwater and cabbage kimchi at food company X were positive for norovirus. The predominant genotype of norovirus detected in the patient, groundwater, and cabbage kimchi samples, GI.4, shared high nucleotide identity. CONCLUSIONS: Kimchi products tainted with norovirus GI.4 from contaminated groundwater were linked to the acute gastroenteritis outbreaks. Therefore, kimchi manufacturers in South Korea should apply chlorine disinfection when using groundwater. Moreover, more stringent sanitation requirements and strict regulations for food companies are recommended.