Do-Young Kang

Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats

The effect of peroxisome proliferator-activated receptor (PPAR)-alpha activators on the liver is well established, but the other effects on muscle and adipose tissue about lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation affects adiposity of skeletal muscle as well as adipose tissue and improves insulin sensitivity in spontaneous type 2 diabetes model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Thirty-three weeks of aged, 20 male OLETF rats were divided into two groups. Control group (n=10) was fed with chow and treatment group (n=10) with chow contained fenofibrate for 7 weeks. At the age of 40 weeks, all rats were examined with MRI, intravenous glucose tolerance test, and then sacrificed for measurement of fat mass and RNA analyses. The total fat (the sum of subcutaneous, mesenteric, epididymal, and retroperitoneal fat pads) measured by dissection was significantly reduced in treatment group. The signal intensity of muscular adiposity was significantly decreased in treatment group. The mRNA levels of FAT/CD36 and mitochondrial carnitine palmitoyltransferase I (M-CPT I) in liver were remarkably increased. Fasting plasma insulin and leptin levels, insulin response after intravenous glucose loading and homeostasis model assessment insulin resistance (HOMA(IR)) index were lowered in treatment group. Fenofibrate increase mitochondrial fatty acid beta-oxidation in liver but not in skeletal muscle and lower the plasma levels of triglyceride and free fatty acid. It might result in reduction of adiposity of truncal adipose tissue and skeletal muscle. We suggest that reduction of adiposity in trunk and skeletal muscle might improve insulin sensitivity.

Lymphatic Mapping and Sentinel Node Biopsy Using 99mTc tin Colloid in Gastric Cancer

Objective:The aim of this study was to determine the feasibility of sentinel lymph node (SLN) biopsy in patients with gastric cancer for the assessment of regional lymph node status. Summary Background Data:SLN is the first draining node from the primary lesion, and it is the first site of lymph node metastasis in malignancy. SLN mapping and biopsy are of great significance in the determination of the extent of lymphadenectomy, allowing patients with gastric cancer to have a better quality of life without jeopardizing survival. Methods:The SLN biopsy was performed in 46 consecutive patients having gastric cancer with a preoperative imaging stage of T1/T2, N0, or M0. Three hours prior to each operation, 99mTc tin colloid (2.0 mL, 1.0 mCi) was endoscopically injected into the gastric submucosa around the primary tumor. Subsequently, serial lymphoscintigraphy was performed using a dual-head gamma camera. After the SLN biopsy had been performed using a gamma probe, all patients underwent radical gastrectomy (D2 or D2+α). The SLN was cut and immediately frozen-sectioned. A paraffin block was then produced for permanent hematoxylin-eosin staining and immunohistochemistry (IHC). Results:SLNs were successfully identified in 43 of 46 patients (success rate, 93.5%). On average, 2 (range, 1–8) SLNs were identified per patient. The positive predictive value, negative predictive value, sensitivity, and specificity of SLN biopsy were 100% (11 of 11), 93.8% (30 of 32), 84.6% (11 of 13), and 100% (30 of 30), respectively. SLNs were located at the level I lymph nodes in 38 (88.4%), the level I+II nodes in 2 (4.7%), and the level II nodes in 3 (7.0%). No micrometastases of SLNs was found on IHC for cytokeratin. Conclusions:SLN biopsy using a radioisotope in patients with gastric cancer is a technically feasible and accurate technique, and it is a minimally invasive approach in the assessment of patient nodal status.

Mutant p53 (G199V) Gains Antiapoptotic Function through Signal Transducer and Activator of Transcription 3 in Anaplastic Thyroid Cancer Cells

In the present study, we identified a missense mutation (G199V) in KAT-18 cell line established from primary cultures of anaplastic thyroid cancer (ATC). Notably, knockdown of this mutant (mt) p53 reduced cell viability and exerted antitumor activity equivalent to high doses of several chemotherapeutic agents. We showed that p53 knockdown had an antitumor effect via the induction of apoptosis. We further examined the underlying mechanism by which mt p53 (G199V) gains antiapoptotic function in KAT-18 cells. Microarray analysis revealed that p53 knockdown modified the expression of numerous apoptosis-related genes. Importantly, p53 knockdown led to downregulation of signal transducer and activator of transcription-3 (STAT3) gene expression. We further observed that p53 knockdown induced the downregulation of STAT3 protein. We also observed that a STAT3 inhibitor augmented the reduction of cell viability induced by p53 knockdown, whereas interleukin-6 treatment alleviated this effect. In addition, overexpression of STAT3 protected ATC cells against cell death induced by p53 knockdown. Taken together, these data show that mt p53 (G199V) gains antiapoptotic function mediated by STAT3 in ATC cells. Inhibition of the function of mt p53 (G199V) could be a novel and useful therapeutic strategy for decreasing the extent and severity of toxicity due to chemotherapeutic agents. (Mol Cancer Res 2009;7(10):1645–54)

Regional cerebral blood flow differences in patients with mild cognitive impairment between those who did and did not develop Alzheimer's disease

Mild cognitive impairment (MCI) is a heterogeneous condition associated with increased risk of Alzheimers disease (AD) and other dementias. This study aimed to identify areas of initial hypoperfusion in MCI conversion to AD using technetium (Tc-99m) hexamethylpropyleneamine oxime (TC-99m HMPAO) single photon emission computed tomography (SPECT) to compare baseline cerebral hypoperfusion in converted MCI and non-converted MCI patients and normal controls. Forty-nine MCI patients were recruited for brain magnetic resonance imaging (MRI), detailed neuropsychological testing, Tc-99m HMPAO SPECT, and 1- to 2-year periodic follow-up to monitor progression to dementia status. We processed SPECT images with Statistical Parametric Mapping 8 (SPM8) software and performed voxel-based statistical parametric mapping analysis. Thirty-nine of 49 MCI patients were included in our analysis. Nine patients were diagnosed with conversion to AD, on average 19.0±6.6 months after initial assessment. Compared with normal controls, converted MCI patients demonstrated perfusion deficits in both parahippocampal gyri and right precuneus, and non-converted MCI patients demonstrated hypoperfusion in the left parahippocampal gyrus. Compared with non-converted MCI patients, converted MCI patients demonstrated significant hypoperfusion in both cingulate gyri and right precuneus. Our study suggests that using brain SPECT to identify initial hypoperfusion in patients with MCI may be helpful for predicting MCI patients likely to develop AD.

Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis

Background: Eosinophilic inflammation is a major pathologic feature of chronic rhinosinusitis (CRS) and is frequently associated with severe refractory disease. Prostaglandin (PG) D2 levels are increased in patients with CRS, and PGD2 is an important contributing factor to eosinophilic inflammation. Autophagy has a pleiotropic effect on immune responses and disease pathogenesis. Recent studies suggest the potential involvement of autophagy in patients with CRS and the PG pathway. Objective: We sought to investigate whether altered function of autophagy is associated with eosinophilic inflammation and dysregulated production of PGD2 in patients with CRS. Methods: We used myeloid cell–specific deletion of autophagy‐related gene 7 (Atg7), which is vital for autophagy, and investigated the effects of impaired autophagy on eosinophilic inflammation in a murine model of eosinophilic chronic rhinosinusitis (ECRS). The effect of autophagy on PGD2 production and gene expression profiles associated with allergy and the PG pathway were assessed. Results: We found that impaired autophagy in myeloid cells aggravated eosinophilia, epithelial hyperplasia, and mucosal thickening in mice with ECRS. This aggravation was associated with gene expression profiles that favor eosinophilic inflammation, TH2 response, mast cell infiltration, and PGD2 dysregulation. Supporting this, PGD2 production was also increased significantly by impaired autophagy. Among other myeloid cells, macrophages were associated with autophagy deficiency, leading to increased IL‐1&bgr; levels. Macrophage depletion or blockade of IL‐1 receptor led to alleviation of eosinophilic inflammation and sinonasal anatomic abnormalities associated with autophagy deficiency. Conclusion: Our results suggest that impaired autophagy in myeloid cells, particularly macrophages, has a causal role in eosinophilic inflammation and ECRS pathogenesis.

Visual and Quantitative Analysis Methods of Respiratory Patterns for Respiratory Gated PET/CT.

We integrated visual and quantitative methods for analyzing the stability of respiration using four methods: phase space diagrams, Fourier spectra, Poincaré maps, and Lyapunov exponents. Respiratory patterns of 139 patients were grouped based on the combination of the regularity of amplitude, period, and baseline positions. Visual grading was done by inspecting the shape of diagram and classified into two states: regular and irregular. Quantitation was done by measuring standard deviation of x and v coordinates of Poincaré map (SDx, SDv) or the height of the fundamental peak (A 1) in Fourier spectrum or calculating the difference between maximal upward and downward drift. Each group showed characteristic pattern on visual analysis. There was difference of quantitative parameters (SDx, SDv, A 1, and MUD-MDD) among four groups (one way ANOVA, p = 0.0001 for MUD-MDD, SDx, and SDv, p = 0.0002 for A 1). In ROC analysis, the cutoff values were 0.11 for SDx (AUC: 0.982, p < 0.0001), 0.062 for SDv (AUC: 0.847, p < 0.0001), 0.117 for A 1 (AUC: 0.876, p < 0.0001), and 0.349 for MUD-MDD (AUC: 0.948, p < 0.0001). This is the first study to analyze multiple aspects of respiration using various mathematical constructs and provides quantitative indices of respiratory stability and determining quantitative cutoff value for differentiating regular and irregular respiration.

Functional volumetric analysis of striatum using F-18 FP-CIT PET in patients with idiopathic Parkinson's disease and normal subjects.

ObjectiveWe applied a simple isocontour volume-of-interest (VOI) method to analyze the whole striatum in an F-18 FP-CIT PET image and to investigate the usefulness of the method in differentiating healthy subjects from idiopathic Parkinson’s disease (IPD) patients and the correlation of the value of functional volume parameters with the motor symptoms in patients with IPD.MethodsForty-three IPD patients and 23 age-matched healthy controls underwent F-18 FP-CIT PET. Using a dedicated workstation, VOIs for the whole striatum were drawn automatically with the gradient delineation method. The SUVmax, SUVmean, functional volume (FV), striatal volume activity (SVA), striatal-specific binding (SSB), and volume-specific uptake ratio (VSUR) were compared between the IPD patients and the normal subjects. In the IPD patients, the correlation between the clinical factor and the functional parameters was assessed.ResultsThe SUVmax, SUVmean, FV, SVA, SSB, and VSUR were significantly lower in the IPD patients than in the normal subjects. In the receiver operating characteristic analysis, those parameters had significant and good-to-excellent accuracy. In the patients with IPD, a moderate negative correlation was revealed between the SUVmax and H&Y stage, the SUVmean and H&Y stage, SVA and H&Y stage, the VSUR and H&Y stage, the FV and bradykinesia, and the SVA and bradykinesia.ConclusionThe functional volumetric analysis of the striatum based on simple isocontour VOI was a useful method of analyzing the F-18 FP-CIT PET image. Not only can it be easily applied in daily clinical practice, but it can also be used as a clinical parameter to discriminate IPD and to correlate it with the disease severity.

Significant correlation between cerebral hypoperfusion and neuropsychological assessment scores of patients with mild cognitive impairment.

PurposeThe regions of significant correlation between cerebral hypoperfusion and neuropsychological assessment scores were evaluated using 99mTc-HMPAO SPECT in patients with mild cognitive impairment (MCI) on the basis of its three subtypes, namely, single-domain amnestic MCI (aMCI-s), multiple-domain amnestic MCI (aMCI-m), and nonamnestic MCI (naMCI), following which comparisons were made among the three subtypes of MCI. MethodsRegions of hypoperfusion were determined by comparing the three groups with the normal group. Neuropsychological assessment included tests to evaluate attention, language and related functions, visuospatial function, memory, frontal-executive function, and mini-mental state examination and depression scores. Regions of cerebral hypoperfusion were identified by comparing the three groups of MCI patients with the normal group (P<0.05, uncorrected). One-way analysis of variance was used to examine differences across groups, and post-hoc a-priori pairwise comparisons were used for between-group analyses. The regions of significant correlation, related to the neuropsychological assessment scores, were identified by simple regression of SPM8 within the masking image of the area of cerebral hypoperfusion (P<0.05, uncorrected). ResultsThe regions of cerebral hypoperfusion were identified by comparing members of the normal group with patients with aMCI-s, aMCI-m, and naMCI. The patients with aMCI-m showed significant correlation with all neuropsychological assessment scores, but the patients with aMCI-s correlated with four neuropsychological assessment scores of attention. The patients with naMCI revealed no significantly correlated regions (P<0.05, uncorrected). The regions that correlated with neuropsychological assessment scores in patients with aMCI-s were very small compared with those in patients with aMCI-m. The correlated regions in patients with aMCI-m were restricted to the left cerebrum and cerebellum. Brain areas showed significant correlation between neuropsychological assessment scores and hypoperfusion, which was evaluated by simple regression with the threshold being P less than 0.05, uncorrected. Rey complex figure test 20 min delayed, Korean-color word stroop test word reading, and Korean mini-mental state examination scores correlated more strongly with cerebral hypoperfusion compared with other assessment scores. ConclusionThe specific pattern of significant correlation of cerebral hypoperfusion with neuropsychological assessment scores was classified into three subtypes (aMCI-s, aMCI-m, and naMCI) according to the patients’ deficits in their cognitive domains.

Role of Positron Emission Tomography as a Biologic Marker in the Diagnosis of Primary Progressive Aphasia: Two Case Reports

Primary progressive aphasia (PPA) is a heterogenous neurodegenerative disorder characterized by declining language and speech ability. Various underlying neuropathologies can induce PPA, and the disorder is divided into three subtypes—progressive non-fluent aphasia, semantic variant aphasia, and logopenic aphasia—according to clinical features. Accurate disease classification and prediction of underlying diseases are necessary for appropriate treatment, but proper use of imaging tests is important because clinical information alone often makes it difficult to make accurate decisions. Because there is a characteristic metabolic pattern according to the subtypes, F-18 fluorodeoxyglucose positron emission tomography (PET) can indicate subtype classification. In addition, PET studies for imaging amyloid or dopamine transporters play an important role in demonstrating underlying disease. The present case showed that PET imaging studies are useful in diagnosis and could be used as a biomarker in PPA.

Pattern of cerebral hypoperfusion according to the clinical staging in dementia with Lewy bodies

ABSTRACT This study aimed to detect different patterns of cerebral hypoperfusion in DLB according to clinical staging. Thirty-three patients with DLB were recruited by clinical dementia rating (CDR) stage. Compared with control, cerebral hypoperfusion was mainly observed in the lingual gyrus, the cuneus, the occipital gyrus in CDR 0.5 group; the fusiform gyrus, the middle temporal gyrus, and the posterior cingulate in CDR 1; and the lingual gyrus, the cuneus, the hippocampus, the fusiform gyrus, and the inferior frontal gyrus in CDR 2. Our findings suggest that cerebral hypoperfusion spreads to the frontal cortex and temporal lobes as disease progresses.