Magnetic resonance imaging of amyloid plaques using hollow manganese oxide nanoparticles conjugated with antibody a&bgr;1–40 in a transgenic mouse model

Kim, Jae-Hun,Ha, Tae Lin,Im, Geun Ho,Yang, Jehoon,Seo, Sang Won,Lee, In Su,Lee, Jung Hee Lippincott Williams Wilkins, Inc. 2013 NEUROREPORT - Vol.24 No.1

<P>In this study, we have shown the feasibility of hollow manganese oxide nanoparticles (HMON) conjugated with an antibody of A beta 1-40 peptide (abA beta 40) (HMON-abA beta 40) for MRI of amyloid plaques in APP/PS1 transgenic mice. MR brain images in APP/PS1 transgenic mice and their nontransgenic littermates were acquired using a 7.0 T MRI system before, and 24 and 72 h after an injection of HMON-abA beta 40. After the injection of HMON-abA beta 40, we found hyperenhanced spots in the frontal cortex area on T1-weighted MR images for transgenic mice, which corresponded qualitatively to amyloid plaques detected by thioflavin-S staining. For quantitative analysis, percent MR signal changes in six brain regions (olfactory cortex, frontal cortex, cerebral cortex, thalamus, hippocampus, and cerebellar cortex) were compared between transgenic and wild-type mice. We found significant increases in the percent MR signal changes in the olfactory cortex, frontal cortex, cerebral cortex, and hippocampus, but there were no significant differences in the thalamus and cerebellar cortex for transgenic mice compared with wild-type mice. This unique strategy allowed us to detect brain regions subjected to amyloid plaque deposition in Alzheimer's disease transgenic mouse models and has a potential to be developed for human applications, which has a current utility in preclinical research, particularly in monitoring therapeutic response for drug development in Alzheimer's disease. NeuroReport 24:16-21 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. NeuroReport 2013, 24:16-21</P>

Changes in neurocognitive function in patients with schizophrenia after starting or switching to amisulpride in comparison with the normal controls.

Ahn, Yong Min,Lee, Kyu Young,Kim, Chul-Eung,Kim, Jae-Jin,Kang, Dae-Yeob,Jun, Tae-Youn,Choi, Jin Sook,Chung, In-Won,Kim, Se Hyun,Hwang, Samuel S-H,Kim, Yong Sik Williams Wilkins ; Lippincott Williams Wilkins 2009 JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Vol.29 No.2

<P>We examined short- and long-term changes in neurocognitive functions in patients with schizophrenia who were either started or switched to amisulpride in comparison with the normal controls. Fifty-seven patients treated with amisulpride and 60 normal controls completed a comprehensive neurocognitive function test battery at the baseline, the 8-week, and the 1-year follow-up. We conducted and compared the results of both intention-to-treat (ITT) and per-protocol (PP) analyses to account for the follow-up loss. Three general results obtained were as follows: (1) the degree of the improvements in neurocognitive function was comparable to those of other second-generation antipsychotics in both ITT and PP analysis; (2) in light of the relative effect size, the composite effect size and the effect size in most measures in both ITT and PP analyses were smaller for the patient group than those of the control group, signifying that improvement in performance may be largely attributable to practice effects; and (3) nonetheless, there were evidences of both short- and long-term improvements in some cognitive tasks, such as in the Korean-Wechsler Adult Intelligence Scale vocabulary subtest and the Trail Making Test, that may not be accounted by practice effect. These results suggest the need to include a healthy control group to validate the medication effect of cognitive improvements in patients with schizophrenia and to consider practice effect in interpreting the results of repeated administration of neurocognitive function tests.</P>

Comments on 'Short-term testosterone augmentation in male schizophrenics: a randomized, double-blind, placebo-controlled trial' by Dr Ko and colleagues.

Williams Wilkins ; Lippincott Williams Wilkins 2009 JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Vol.29 No.2

Glutamine suppresses airway neutrophilia by blocking cytosolic phospholipase A(2) via an induction of MAPK phosphatase-1.

Lee, Chang-Hoon,Kim, Hae-Kyoung,Kim, June-Mo,Ayush, Otgonzaya,Im, Suhn-Young,Oh, Dae-Kyu,Lee, Hern-Ku Williams Wilkins 2012 JOURNAL OF IMMUNOLOGY Vol.189 No.11

<P>Neutrophils are inflammatory cells that may contribute in a crucial way to the pathophysiology of steroid-resistant severe asthma. We previously reported that the nonessential amino acid l-glutamine (Gln) suppressed the recruitment of neutrophils into the airway in a murine model of asthma. In this study, we investigated the mechanisms by which Gln exerts beneficial effects in airway neutrophilia. We used the model we previously developed, which is suitable for examining sequential early asthmatic events, including neutrophil infiltration. Gln suppressed airway neutrophilia in a CXC chemokine-independent way. Airway neutrophilia was associated with cytosolic phospholipase A(2) (cPLA(2)) and 5-lipoxygenase (5-LO) activities. p38 MAPK, the upstream pathway of cPLA(2) and 5-LO, played a key role in inducing airway neutrophilia. Gln inhibited not only the phosphorylation of cPLA(2) and p38 MAPK but also leukotriene B(4) levels in the airways. Gln induced the early induction of MAPK phosphatase-1 (MKP-1) protein, a negative regulator of p38. MKP-1 small interfering RNA abrogated all the effects of Gln. Our results suggest that pathways involving p38/cPLA(2)/5-LO have a major role in airway neutrophilia. Gln suppresses airway neutrophilia via inhibiting p38 MAPK and its downstream pathways in an MKP-1-dependent way, which may provide a novel therapeutic strategy for pulmonary neutrophilic inflammatory diseases.</P>

Autophagy Negatively Regulates Keratinocyte Inflammatory Responses via Scaffolding Protein p62/SQSTM1.

Lee, Hye-Mi,Shin, Dong-Min,Yuk, Jae-Min,Shi, Ge,Choi, Dae-Kyoung,Lee, Sang-Hee,Huang, Song Mei,Kim, Jin-Man,Kim, Chang Deok,Lee, Jeung-Hoon,Jo, Eun-Kyeong Williams Wilkins 2011 JOURNAL OF IMMUNOLOGY Vol.186 No.2

<P>The scaffolding adaptor protein p62/SQSTM1 (p62) has been shown to be an autophagy receptor that acts as a link between the ubiquitination and autophagy machineries. However, the roles of autophagy and p62 in human keratinocytes are not well understood. In this study, we show that keratinocyte autophagy negatively regulates p62 expression, which is essential for the prevention of excessive inflammation and the induction of cathelicidin in human keratinocytes. Stimulation of TLR2/6 or TLR4 in primary human keratinocytes robustly activated autophagy pathways and up-regulated p62 expression through induction of NADPH oxidases 2 and 4 and the generation of reactive oxygen species. MyD88 and TNFR-associated factor 6, key signaling molecules that mediate TLR activation, played an essential role in the induction of autophagy and p62 expression. Additionally, blockade of autophagy significantly increased the generation of inflammatory cytokines and expression of p62 in primary human keratinocytes. Notably, silencing hp62 through RNA interference resulted in a significant decrease in NF-관B activation, inflammatory cytokine production, cathelicidin expression, and cell proliferation (as well as cyclin D1 expression) in keratinocytes. Epidermal expression of p62 was further found to be significantly higher in psoriatic skin than in skin affected by atopic dermatitis or from healthy controls. Collectively, our data provide new insights into the roles of autophagy and p62 in controlling cutaneous inflammation.</P>

Overestimated Oncologic Significance of Lymph Node Metastasis in G1 Nonfunctioning Neuroendocrine Tumor in the Left Side of the Pancreas

Yoo, Young Jin,Yang, Seok Jeong,Hwang, Ho Kyoung,Kang, Chang Moo,Kim, Hogeun,Lee, Woo Jung Williams & Wilkins Co 2015 Medicine Vol.94 No.36

<P><B>Abstract</B></P><P>Recent studies have expounded on the oncologic significance of lymph node metastasis in nonfunctioning (NF) neuroendocrine tumors (NETs) of the pancreas and suggest regional lymph node dissection for treating pancreatic NET. We tested this recommendation in NF pancreatic NET-G1, as these tumors are generally small and suitable for function-preserving minimally invasive pancreatectomy.</P><P>From January 2005 to December 2014, medical records of patients who underwent pancreatectomy for pathologically confirmed NF NET-G1 of the left side of the pancreas were retrospectively reviewed. Oncologic outcomes were compared between limited pancreatectomy and distal pancreatosplenectomy.</P><P>Thirty-five patients (14 males and 21 females) with a mean age of 55.9 ± 11.4 years were enrolled in this study. Six patients (17.1%) underwent distal pancreatosplenectomy. Limited pancreatectomies comprised 15 spleen-preserving distal pancreatectomies (42.8%), 10 enucleations (28.6%), and 4 central pancreatectomies (11.4%). Lymph node metastasis was not found in 6 patients who underwent distal pancreatectomy with a splenectomy; meanwhile, the others were regarded as pNx since no lymph node retrieval was attempted during the limited pancreatectomy. Overall disease-free survival was 36.5 months (95% confidence interval [CI]: 25.9–47.1) and no tumor-related mortality was noted. Minimally invasive pancreatectomy (<I>P</I> = 0.557) and limited pancreatectomy (<I>P</I> = 0.758) showed no adverse impact in treating NF NET-G1 of the left side of the pancreas.</P><P>The oncologic significance of lymph node metastasis is overestimated in NF NET-G1 of the left side of the pancreas. Routine conventional distal pancreatosplenectomy to retrieve regional lymph nodes may be too excessive in treating NF NET-G1 of the distal pancreas.</P>

Astrocytes, but not microglia, rapidly sense H2O2via STAT6 phosphorylation, resulting in cyclooxygenase-2 expression and prostaglandin release.

Park, Soo Jung,Lee, Jee Hoon,Kim, Hee Young,Choi, Youn Hee,Park, Jung Sup,Suh, Young Ho,Park, Sang Myun,Joe, Eun-hye,Jou, Ilo Williams Wilkins 2012 JOURNAL OF IMMUNOLOGY Vol.188 No.10

<P>Emerging evidence has established that astrocytes, once considered passive supporting cells that maintained extracellular ion levels and served as a component of the blood-brain barrier, play active regulatory roles during neurogenesis and in brain pathology. In the current study, we demonstrated that astrocytes sense H(2)O(2) by rapidly phosphorylating the transcription factor STAT6, a response not observed in microglia. STAT6 phosphorylation was induced by generators of other reactive oxygen species (ROS) and reactive nitrogen species, as well as in the reoxygenation phase of hypoxia/reoxygenation, during which ROS are generated. Src-JAK pathways mediated STAT6 phosphorylation upstream. Experiments using lipid raft disruptors and analyses of detergent-fractionated cells demonstrated that H(2)O(2)-induced STAT6 phosphorylation occurred in lipid rafts. Under experimental conditions in which H(2)O(2) did not affect astrocyte viability, H(2)O(2)-induced STAT6 phosphorylation resulted in STAT6-dependent cyclooxygenase-2 expression and subsequent release of PGE(2) and prostacyclin, an effect also observed in hypoxia/reoxygenation. Finally, PGs released from H(2)O(2)-stimulated astrocytes inhibited microglial TNF-α expression. Accordingly, our results indicate that ROS-induced STAT6 phosphorylation in astrocytes can modulate the functions of neighboring cells, including microglia, through cyclooxygenase-2 induction and subsequent release of PGs. Differences in the sensitivity of STAT6 in astrocytes (highly sensitive) and microglia (insensitive) to phosphorylation following brief exposure to H(2)O(2) suggest that astrocytes can act as sentinels for certain stimuli, including H(2)O(2) and ROS, refining the canonical notion that microglia are the first line of defense against external stimuli.</P>

<i>RAS</i> Mutations in AUS/FLUS Cytology: Does it Have an Additional Role in BRAF ^V600E Mutation-Negative Nodules?

Yoon, Jung Hyun,Kwon, Hyeong Ju,Lee, Hye Sun,Kim, Eun-Kyung,Moon, Hee Jung,Kwak, Jin Young Williams & Wilkins Co 2015 Medicine Vol.94 No.27

<P><B>Abstract</B></P><P>The object of this study is to evaluate the additional role of <I>RAS</I> mutation in detecting thyroid malignancy among BRAF<SUP>V600E</SUP> mutation-negative nodules diagnosed as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) on cytology.</P><P>From December 2009 to December 2011, 202 BRAF<SUP>V600E</SUP> mutation-negative thyroid nodules diagnosed as AUS/FLUS cytology in 201 patients were included in this study. <I>RAS</I> mutation analysis was performed using residual material from ultrasonography-guided fine needle aspiration (US-FNA) cytology testing for <I>K-RAS</I>, <I>N-RAS</I>, and <I>H-RAS</I> codons 12/13 and 61 point mutations. The authors evaluated the association between <I>RAS</I> mutation status and cytopathologic characteristics.</P><P>Of the 202 BRAF<SUP>V600E</SUP> mutation-negative thyroid nodules with AUS/FLUS cytology, 4 were considered insufficient for mutation analysis. Of the 198 thyroid nodules, 148 (74.7%) were confirmed as benign and 50 (25.3%) as malignant. Thirty-one (15.7%) of the 198 thyroid nodules were positive for any <I>RAS</I> mutation, 4 positive for <I>K-RAS</I> 12/13, 26 for <I>N-RAS</I> 61, and 1 positive for <I>H-RAS</I> 61. Seven (22.6%) of the <I>RAS</I> mutation positive nodules were malignant, 1 with <I>K-RAS</I> 12/13, 6 with <I>N-RAS</I> 61. Twenty-four (77.4%) of the 31 nodules positive for <I>K-RAS</I> 12/13 (N = 3), <I>N-RAS</I> 61 (N = 20), or <I>H-RAS</I> 61 (N = 1) mutations were proven benign. None of the 198 thyroid nodules were positive for <I>K-RAS</I> 61, <I>N-RAS</I> 12/13, or <I>H-RAS</I> 12/13 mutations.</P><P><I>N-RAS</I> 61 mutation is the most common mutation detected among BRAF<SUP>V600E</SUP> mutation-negative nodules with AUS/FLUS cytology. <I>RAS</I> mutation has limited value in predicting malignancy among BRAF<SUP>V600E</SUP> mutation-negative thyroid nodules with AUS/FLUS cytology and further, investigation is anticipated to evaluate the true role of <I>RAS</I> mutation in thyroid malignancy.</P>

Serum Bone Morphogenic Protein-4 Contributes to Discriminating Coronary Artery Disease Severity

Park, Chul Soo,Hong, Oak-Kee,Kim, Mee Kyoung,Chung, Woo Baek,Choi, Yun Seok,Baek, Ki-Hyun,Song, Ki-Ho,Lee, Man Young,Kwon, Hyuk-Sang Williams & Wilkins Co 2015 Medicine Vol.94 No.39

<P><B>Abstract</B></P><P>Bone morphogenic protein 4 (BMP-4) is a known pro-inflammatory and pro-atherogenic cytokine. Here, we investigated whether the serum BMP-4 level predicts coronary artery disease (CAD) severity in humans.</P><P>We measured serum BMP-4 concentrations in 1044 consecutive patients who underwent elective coronary angiography and percutaneous coronary intervention. CAD severity was estimated by the number of diseased vessels showing ≥50% diameter stenosis.</P><P>Among males, the serum BMP-4 level was significantly lower in patients with multivessel disease (MVD) compared with those with single-vessel disease (SVD) (16.3 ± 22.6 vs. 22.0 ± 28.4 pg/mL, <I>P</I> < 0.01). After adjustment for other cardiovascular risk factors, a high serum BMP-4 level was an independent predictor for a decreased risk of MVD (odds ratio, 0.992; 95% confidence interval [CI], 0.985–0.998; <I>P</I> = 0.01) and patients in the lower tertile were 1.55-fold more likely to have MVD compared with upper tertile patients. Receiver-operating characteristic curve analysis demonstrated that the serum BMP-4 level had a 54% sensitivity and 54% specificity for predicting MVD (area under the curve [AUC], 56.5%; 95% CI, 51.9–61.0%; <I>P</I> < 0.01). Serum BMP-4 improved the predictive capability of risk factors for MVD (AUC with and without BMP-4: 64.9 and 63.6%, respectively). Considering the likelihood ratio and number of parameters, adding the serum BMP-4 level provided a better-fit model for predicting MVD compared with the model consisting of conventional risk factors (likelihood ratio <I>χ</I><SUP>2</SUP> = 6.20, <I>P</I> = 0.01). However, an association between serum BMP-4 and CAD was not observed in females.</P><P>Serum BMP-4 levels are independently associated with CAD severity and contribute to discriminating CAD severity in males.</P>

Molecular and Functional Characterization of ORAI and STIM in Human Corporeal Smooth Muscle Cells and Effects of the Transfer of Their Dominant-Negative Mutant Genes into Diabetic Rats

Sung, H.H.,Kam, S.C.,Lee, J.H.,Chae, M.R.,Hong, C.,Ko, M.,Han, D.H.,So, I.,Lee, S.W. Williams and Wilkins Co 2012 The Journal of urology Vol.187 No.5

Purpose: We investigated the molecular identity and functional activity of STIM1 and ORAI in human cavernous smooth muscle. We also determined whether transferring dominant negative mutants of the STIM1 or ORAI gene would correct diabetes related erectile dysfunction in a rat model. Materials and Methods: Reverse transcriptase-polymerase chain reaction was done to identify ORAI and STIM in human cavernous smooth muscle. For the in vivo study intracavernous pressure, blood pressure and their ratio were assessed after cavernous nerve stimulation to diabetic rats transfected with pcDNA encoding the ORAI1<SUP>DN</SUP> or the STIM1<SUP>DN</SUP> gene. Results: ORAI (1, 2 and 3) and STIM (1 and 2) were identified in human cavernous smooth muscle cells. After [Ca<SUP>2+</SUP>] depletion by thapsigargin and cyclopiazonic acid we recorded store operated Ca<SUP>2+</SUP> entry in human cavernous smooth muscle cells. Entry was decreased by the store operated Ca<SUP>2+</SUP> channel blockers La<SUP>3+</SUP> and SKF96365. Mean +/- SE intracavernous pressure/blood pressure in rats with ORAI1<SUP>DN</SUP> or STIM1<SUP>DN</SUP> gene transfer was 78.8% +/- 2.2% and 77.1% +/- 1.2% in 11 and 10, respectively. This result was significantly higher than that in 10 diabetic controls (51.0% +/- 3.7%) and similar to that in 9 normal controls (85.8% +/- 2.6%). Using reverse transcriptase-polymerase chain reaction we confirmed transgene expression in rat cavernous tissue. Conclusions: Transfer of ORAI<SUP>DN</SUP> or STIM1<SUP>DN</SUP> genes restored erectile function in diabetic rats. It might be applicable to develop new therapy for erectile dysfunction.