Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia.

Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology.

TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed ten patients with C9orf72-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.

Mediation effects of clinical practice stress between clinical education environment and satisfaction with clinical practice.

PURPOSE: The purpose of this study was to identify the possible correlations of 'satisfaction with clinical practice (SA)' with 'clinical learning environment (EN)' and 'clinical practice stress (ST).' We searched for the mediating effect of 'clinical practice stress' on 'satisfaction with clinical practice' when the clinical learning environment influences 'satisfaction with clinical practice.' METHODS: This research investigated 208 medical and nursing students attending the school of medicine and nursing in Korea. The total number of nursing students was 135 (64.9%); 73 medical students participated (35.1%). We used the Korean-Undergraduate Clinical Education Environment in 24 questions for EN, ST scale in 24 questions, and SA scale in 10 questions. We performed measurement structural equation model analysis to identify a path of the model. RESULTS: Medical students had significantly higher levels of ST. EN had a significant negative correlation with ST and a significant positive correlation with SA. The ST had a significant negative correlation with SA. The results of the goodness of fit index have fulfilled the criteria of goodness of fit. There was a significant mediating effect of ST on SA when EN influences SA. CONCLUSION: The clinical learning environment affected satisfaction with the clinical practice directly or indirectly mediated by clinical practice stress. Therefore, educational institutes should try to increase satisfaction with clinical practice by continuously monitoring and improving the clinical learning environment in addition to taking measures for decreasing the clinical practice stress.

Optical switching of near infrared light transmission in metamaterial-liquid crystal cell structure.

A metamaterial-liquid crystal cell structure is fabricated with the metamaterial as one of the liquid crystal alignment layers. Nano-sized double-split ring resonator in the metamaterial accommodates two distinct resonances in the near infrared regime. By adopting an azo-nematic liquid crystal in a twisted nematic liquid crystal cell structure, a photo-isomerization process is utilized to achieve an optical switching of light transmissions between two resonances. A single device of the metamaterial-liquid crystal cell structure has a potential application in the photonic switching in optical fiber telecommunications.

The Association between the Consumption of Fish/Shellfish and the Risk of Osteoporosis in Men and Postmenopausal Women Aged 50 Years or Older.

Fish rich in n-3 polyunsaturated fatty acids have been suggested to have a favorable effect on bone health, but previous epidemiologic studies have shown inconsistent results. The purpose of the present study was to investigate the hypothesis that the consumption of fish and shellfish is positively associated with bone mass and negatively associated with the risk of osteoporosis in Koreans and Americans. Men and postmenopausal women ≥ 50 years old from the Korean National Health and Nutrition Examination Survey 2008-2011 (n = 7154) and the National Health and Nutrition Examination Survey 2007-2010 (n = 2658) were included. There was a positive correlation between the consumption of fish and shellfish and bone mineral density (BMD) of the total femur, femoral neck, and lumbar spine in Koreans. Consistently, multivariate logistic regression analysis showed a significant association between intake of fish and shellfish and the risk of osteoporosis in Koreans but not in Americans. Consumption of fish and shellfish was 4-5 times higher in Koreans than Americans in the present study. In conclusion, intake of fish and shellfish was associated with BMD and the risk of osteoporosis in Koreans but not in Americans, suggesting that a minimum intake level of fish and shellfish might be recommended to protect against bone loss and osteoporosis.

Sorting of the human folate receptor in MDCK cells.

The human folate receptor (hFR) is a glycosylphosphatidy-linositol (GPI) linked plasma membrane protein that mediates delivery of folates into cells. We studied the sorting of the hFR using transfection of the hFR cDNA into MDCK cells. MDCK cells are polarized epithelial cells that preferentially sort GPI-linked proteins to their apical membrane. Unlike other GPI-tailed proteins, we found that in MDCK cells, hFR is functional on both the apical and basolateral surfaces. We verified that the same hFR cDNA that transfected into CHO cells produces the hFR protein that is GPI-linked. We also measured the hFR expression on the plasma membrane of type III paroxysmal nocturnal hemoglobinuria (PNH) human erythrocytes. PNH is a disease that is characterized by the inability of cells to express membrane proteins requiring a GPI anchor. Despite this defect, and different from other GPI-tailed proteins, we found similar levels of hFR in normal and type III PNH human erythrocytes. The results suggest the hypothesis that there may be multiple mechanisms for targeting hFR to the plasma membrane.

Sorting and function of the human folate receptor is independent of the caveolin expression in Fisher rat thyroid epithelial cells.

Caveolae are small, flask-shaped, non-clathrin coated invaginations of the plasma membrane of many mammalian cells. Caveolae have a coat that includes caveolin. They have been implicated in numerous cellular processes, including potocytosis. Since the human folate receptor (hFR) and other glycosyl-phosphatidylinositol GPI)-tailed proteins have been co-localized to caveolae, we studied the caveolin role in the hFR function by transfecting hFR and/or caveolin cDNA into Fisher rat thyroid epithelial (FRT) cells that normally do not express detectable levels of either protein. We isolated and characterized stable clones as follows: they express (1) high levels of caveolin alone, (2) hFR and caveolin, or (3) hFR alone. We discovered that hFR is correctly processed, sorted, and anchored by a GPI tail to the plasma membrane in FRT cells. No difference in the total folic acid binding or cell surface folic acid binding activity were found between the FRT cells that were transfected with hFR, or cells that were transfected with hFR and caveolin. The hFR that was expressed on the cell surface of clones that were transfected with hFR was also sensitive to phosphatidylinositol-specific phospholipase C (PI-PLC) release, and incorporated radiolabeled ethanolamine that supports the attachment of a GPI-tail on hFR. We conclude that the processing, sorting, and function of hFR is independent on the caveolin expression in FRT cells.

The effect of high dose simvastatin on, platelet size in patients with, type 2 diabetes mellitus.

Statins reduce coronary heart disease risk by altering blood lipids and other mechanisms. One of the possible other mechanisms is through an effect on thrombosis. We assessed the effect of simvastatin 80 mg daily versus placebo given in a single blind crossover fashion on platelet size in response to standard ex vivo stimuli, a surrogate for platelet activation, in 12 subjects with type 2 diabetes and mixed dyslipidemia. Exposure to collagen, cold, and heat caused the expected changes in platelet volume. Contrary to our expectations, ex vivo platelet size during collagen and cold exposure increased by 2.6 and 1.7%, respectively (P < 0.05), during simvastatin treatment as opposed to the placebo period. We conclude that some of the effects of high dose simvastatin therapy on platelets may not necessarily be anti-atherogenic.