Loss of Brain Angiogenesis Inhibitor-3 (BAI3) G-Protein Coupled Receptor in Mice Regulates Adaptive Thermogenesis by Enhancing Energy Expenditure.

Effective energy expenditure is critical for maintaining body weight (BW). However, underlying mechanisms contributing to increased BW remain unknown. We characterized the role of brain angiogenesis inhibitor-3 (BAI3/ADGRB3), an adhesion G-protein coupled receptor (aGPCR), in regulating BW. A CRISPR/Cas9 gene editing approach was utilized to generate a whole-body deletion of the BAI3 gene (BAI3-/-). In both BAI3-/- male and female mice, a significant reduction in BW was observed compared to BAI3+/+ control mice. Quantitative magnetic imaging analysis showed that lean and fat masses were reduced in male and female mice with BAI3 deficiency. Total activity, food intake, energy expenditure (EE), and respiratory exchange ratio (RER) were assessed in mice housed at room temperature using a Comprehensive Lab Animal Monitoring System (CLAMS). While no differences were observed in the activity between the two genotypes in male or female mice, energy expenditure was increased in both sexes with BAI3 deficiency. However, at thermoneutrality (30 °C), no differences in energy expenditure were observed between the two genotypes for either sex, suggesting a role for BAI3 in adaptive thermogenesis. Notably, in male BAI3-/- mice, food intake was reduced, and RER was increased, but these attributes remained unchanged in the female mice upon BAI3 loss. Gene expression analysis showed increased mRNA abundance of thermogenic genes Ucp1, Pgc1α, Prdm16, and Elov3 in brown adipose tissue (BAT). These outcomes suggest that adaptive thermogenesis due to enhanced BAT activity contributes to increased energy expenditure and reduced BW with BAI3 deficiency. Additionally, sex-dependent differences were observed in food intake and RER. These studies identify BAI3 as a novel regulator of BW that can be potentially targeted to improve whole-body energy expenditure.

Ablation of Sam68 in adult mice increases thermogenesis and energy expenditure.

Genetic deletion of Src associated in mitosis of 68kDa (Sam68), a pleiotropic adaptor protein prevents high-fat diet-induced weight gain and insulin resistance. To clarify the role of Sam68 in energy metabolism in the adult stage, we generated an inducible Sam68 knockout mice. Knockout of Sam68 was induced at the age of 7-10 weeks, and then we examined the metabolic profiles of the mice. Sam68 knockout mice gained less body weight over time and at 34 or 36 weeks old, had smaller fat mass without changes in food intake and absorption efficiency. Deletion of Sam68 in mice elevated thermogenesis, increased energy expenditure, and attenuated core-temperature drop during acute cold exposure. Furthermore, we examined younger Sam68 knockout mice at 11 weeks old before their body weights deviate, and confirmed increased energy expenditure and thermogenic gene program. Thus, Sam68 is essential for the control of adipose thermogenesis and energy homeostasis in the adult.

Ischemic burden assessment of myocardial perfusion CT, compared with SPECT using semi-quantitative and quantitative approaches.

BACKGROUND: We aimed to compare the myocardial ischemic burden assessed using semi-quantitative and quantitative analysis of computed tomography-myocardial perfusion imaging (CT-MPI) with that of single-photon emission computed tomography (SPECT). METHODS: From 2011 to 2013, 97 patients who underwent CT-MPI and SPECT were evaluated. The extent and severity of perfusion defects were assessed on a 5-point scale using a standard 16-segment model, and were expressed as summed stress score (SSS) and summed difference score (SDS). Receiver operating characteristic (ROC) curves for quantitative parameters were generated for the diagnosis of abnormal perfusion defect (SSS ≥ 4) and presence of ischemia (SDS ≥ 2) on SPECT. RESULTS: On CT-MPI, 298 (19.2%) of the 1552 segments showed perfusion abnormalities during stress, whereas perfusion abnormalities were shown in 179 (11.5%) segments on SPECT-MPI. On a per-person basis, there was good agreement, with intraclass correlation coefficients of 0.78 for SSS and 0.72 for SDS. A significant reduction of attenuation in stress and myocardial perfusion reserve index, along with an increase in % defect volume of CT-MPI, were demonstrated as the degree of perfusion defect or ischemia on SPECT increased. On the ROC curves, % defect volume on CT-MPI demonstrated the highest area under the curve: 0.91 for abnormal perfusion defect and 0.89 (all p < 0.001) for the presence of ischemia on SPECT. CONCLUSIONS: Semi-quantitative analysis of CT-MPI showed good accordance with SPECT. A quantitative approach for CT-MPI, especially % defect volume, may provide additional value in the identification of myocardial perfusion abnormalities. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01696006.

Early assessment of response to induction therapy in acute myeloid leukemia using 18F-FLT PET/CT.

BACKGROUND: We evaluated the suitability of 18F-fluorodeoxythymidine (18F-FLT) positron emission tomography (PET)/computed tomography (CT) for assessment of the early response to induction therapy and its value for predicting clinical outcome in patients with acute myeloid leukemia (AML). Adult patients who had histologically confirmed AML and received induction therapy were enrolled. All patients underwent 18F-FLT PET/CT after completion of induction. PET/CT images were visually and quantitatively assessed. Cases with intensely increased bone marrow uptake in more than one third of the long bones and throughout the central skeleton were interpreted as PET-positive for resistant disease (RD). PET results were compared to the clinical response and outcome. RESULTS: In visual PET analysis of 10 eligible patients (7 male, 3 female; median age 58 years), 5 patients were interpreted as being PET-positive and 5 as PET-negative. Standardized uptake values were significantly different between PET-positive and PET-negative groups. Eight of 10 patients achieved clinical complete remission (CR)/CR with incomplete blood count recovery (CRi). Five CR/CRi patients had PET-negative findings, but 3 CR patients had PET-positive findings. Both of the RD patients had PET-positive findings. During follow-up, 2 CR patients with PET-positive findings relapsed, or were strongly suspected of relapse, 4 months after consolidation. CONCLUSION: 18F-FLT PET/CT after induction therapy showed good sensitivity and negative-predictive value for evaluating RD in patients with AML. This preliminary study suggests that 18F-FLT PET/CT may be valuable as a noninvasive tool for early assessment of the response to treatment and may provide prognostic value for survival in patients with AML.

Coronary artery vasculitis: assessment with cardiac multi-detector computed tomography.

Coronary artery vasculitis is rare and comprises an array of inflammatory diseases. It often results in severe and life-threatening complications, including coronary artery aneurysm, coronary artery stenosis, intraluminal thrombosis, and microcirculation abnormalities. These may occur at a young age and are often silent in the early phases. Invasive coronary angiography is the gold standard for diagnosing coronary artery disease (CAD); however, multi-detector computed tomography (MDCT) is now widely regarded as a powerful non-invasive tool for the detection of CAD. It is important for clinicians to recognize the various CT findings associated with coronary artery vasculitis in order to promote accurate diagnosis and proper patient management. The purpose of this article is to present an overview of the conditions associated with coronary artery vasculitis, with an emphasis on etiology and cardiac MDCT diagnosis of CAD. Cardiac MDCT is clinically useful and can provide information for the accurate diagnosis and treatment of coronary vasculitis.

Grade-response relationship between blood pressure and severity of coronary atherosclerosis in asymptomatic adults: assessment with coronary CT angiography.

Hypertension is known to be a strong risk factor for coronary atherosclerosis. We aimed to investigate the prevalence, severity, and plaque characteristics of coronary atherosclerosis according to grade of blood pressure (BP) using coronary CT angiography (CCTA) in asymptomatic adults. We enrolled 8,238 asymptomatic subjects who underwent coronary artery calcium scoring (CACS) and CCTA for health screening purposes. Subjects were classified according to JNC 7 guidelines (normal, systolic BP/diastolic BP < 120/80; pre-hypertension [PH], 120-139/80-89; hypertension stage 1 [H1], 140-159/90-99; hypertension stage 2 [H2], >160/100). Isolated systolic hypertension (ISH; systolic BP > 140, diastolic BP < 80) was additionally categorized. With CCTA, the presence of plaques, severity of stenosis, and plaque types were assessed. Using multiple logistic regression analysis, the adjusted odds ratios (AORs) for plaque, obstructive coronary artery disease (CAD) (luminal stenosis ≥50 %), non-calcified plaque (NCP), and CACS > 100 were assessed according to BP grade. After adjustment for clinical risk factors, the risk of subclinical atherosclerosis, NCP, and CACS > 100 gradually increased from PH stage (all P values for trend <0.05), while the risk of obstructive CAD increased from the H1 stage (AORs of H1 and H2: 1.70 and 2.33, respectively). In the ISH group, the AOR of subclinical atherosclerosis (1.64) was higher than in the H1 group (1.55), while the AOR of obstructive CAD (2.58) was higher than in the H2 group (2.33). Therefore, our study strongly suggests that coronary atherosclerosis in asymptomatic adults shows a grade-response relationship according to hypertension grade.

The prevalence and characteristics of coronary atherosclerosis in asymptomatic subjects classified as low risk based on traditional risk stratification algorithm: assessment with coronary CT angiography.

OBJECTIVE: To evaluate the prevalence and characteristics of coronary atherosclerosis in asymptomatic subjects classified as low risk by National Cholesterol Education Program (NCEP) guideline using coronary CT angiography (CCTA). DESIGN: An observational study. SETTING: A single tertiary referral centre. PATIENTS: 2133 (49.2%) subjects, who were classified as low risk by the NCEP guideline, of 4339 consecutive middle-aged asymptomatic subjects who underwent CCTA with 64-slice scanners as part of a general health evaluation. MAIN OUTCOME MEASURES: The incidence of atherosclerosis plaques, significant stenosis. RESULTS: In the subjects at low risk, 11.4% (243 of 2133) of subjects had atherosclerosis plaques, 1.3% (28 of 2133) of subjects had significant stenosis, and 0.8% (18 of 2133) of subjects had significant stenosis caused by non-calcified plaque (NCP). Especially, 75.0% (21 of 28) of subjects with significant stenosis and 94.4% (17 of 18) of subjects with significant stenosis caused by NCP were young adults. Mid-term follow-up (29.3 ± 14.9 months) revealed four subjects with cardiac events: three subjects with unstable angina requiring hospital stay and one subject with percutaneous coronary intervention. CONCLUSIONS: Although an asymptomatic population classified as low risk by the NCEP guideline has been regarded as a minimal risk group, the prevalence of atherosclerosis plaques and significant stenosis were not negligible. However, considering very low event rate for those patients, CCTA should not be performed in low-risk asymptomatic subjects, although CCTA might have the potential for identification of high-risk groups in the selected subjects regarded as a minimal-risk group by NCEP guideline.

Coronary vasospastic angina: assessment by multidetector CT coronary angiography.

OBJECTIVE: We aimed to describe the imaging findings of multidetector CT coronary angiography (MDCTA) in cases of vasospastic angina (VA) and to determine the accuracy of MDCTA in the identification of VA as compared with invasive coronary angiography with an ergonovine provocation test (CAG with an EG test). MATERIALS AND METHODS: Fifty-three patients with clinically suspected VA were enrolled in this study. Two radiologists analyzed the stenosis degree, presence or absence of plaque, plaque composition, and a remodeling index of the related-segment in CAG with an EG test, which were used as a gold standard. We evaluated the diagnostic performances of MDCTA by comparing the MDCTA findings with those of CAG with an EG test. RESULTS: Among the 25 patients with positive CAG with an EG test, all 12 patients with significant stenosis showed no definite plaque with the negative arterial remodeling. Of the six patients with insignificant stenosis, three (50%) had non-calcified plaque (NCP), two (33%) had mixed plaque, and one (17%) had calcified plaque. When the criteria for significant stenosis with negative remodeling but no definite evidence of plaque as a characteristic finding of MDCTA were used, results showed sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) of 48%, 100%, 100%, and 68%, respectively. CONCLUSION: Significant stenosis with negative remodeling, but no definite evidence of plaque, is the characteristic finding on MDCTA of VA. Cardiac MDCTA shows good diagnostic performance with high specificity and PPV as compared with CAG with an EG test.

Significance of noncalcified coronary plaque in asymptomatic subjects with low coronary artery calcium score: assessment with coronary computed tomography angiography.

We aimed to investigate the prevalence and severity of noncalcified coronary plaques (NCP) using coronary CT angiography (CCTA) and analyze predictors of significant coronary stenosis by NCP in asymptomatic subjects with low coronary artery calcium score (CACS). The institutional review board approved this retrospective study and all patients gave written, informed consent. The presence of plaque, severity of stenosis, plaque characteristics, and CACS were assessed in 7,515 asymptomatic subjects. We evaluated the prevalence and severity of NCP in subjects having low CACS (707 subjects; men with CACS from 1 to 50 and women from 1 to 10) in comparison to those having 0 CACS (6,040 subjects) as the reference standard. Conventional risk factors were assessed for predictors of NCP and significant stenosis by NCP. We also investigated the cardiac events of the patients through medical records. Compared to subjects with 0 CACS, those with low CACS showed higher prevalence of NCP (6.9% vs. 31.5%, P < 0.001) and significant stenosis caused by NCP (0.8% vs. 7.5%, P < 0.001). In the low CACS group, independent predictors for significant NCP included diabetes mellitus (DM), hypertension, and elevated low-density lipoprotein (LDL)-cholesterol (all P < 0.05). However, 47.2% of subjects with significant NCP were classified into the low to intermediate risk according to Framingham Risk Score. At the median follow up of 42 months (range: 3-60 months), cardiac events were significantly higher in the low CACS group compared to the 0 CACS group (2.6% vs. 0.27%, P < 0.001). In asymptomatic subjects having low CACS, the prevalence and severity of NCP were higher as compared to subjects having zero CACS and predictors of significant stenosis by NCP were DM, hypertension and LDL-Cholesterol. Therefore, CCTA may be useful for risk stratification of coronary artery disease as added value over CACS in selected populations with low CACS who have predictors of significant NCP.

Reproducibility in the assessment of noncalcified coronary plaque with 256-slice multi-detector CT and automated plaque analysis software.

We aimed to assess intra- and inter-observer reproducibility in evaluating volume and characteristics of non-calcified coronary plaques (NCPs) using a 256-slice multi-detector computed tomography (MDCT) angiography and dedicated automated plaque analysis software in asymptomatic individuals. Forty-two NCPs from 39 patients with a vessel diameter >2 mm were evaluated using a 256-slice MDCT with dedicated automated plaque analysis software. Two independent observers analyzed the characteristics of NCPs, including plaque volume (vol), mean CT number of the NCPs in Hounsfield units (HU(mean)), and remodeling index (RI). One of the observers repeated the evaluation of all datasets after an interval of at least 4 weeks. Bland-Altman analysis and concordance correlation coefficients (CCCs) were used to determine intra- and inter-observer variability. For vol measurements, the 95% limits of agreement were -21.6 and 13.2 mm(3), and -24.6 and 20.3 mm(3) for intra- and inter-observer variability, respectively. For HU(mean) measurements, the 95% limits of agreement were -22.2 and 20.8 HU, and -21.1 and 21.0 HU for intra- and inter-observer variability, respectively. For RI measurements, the 95% limits of agreement were -0.38 and 0.39, and -0.51 and 0.36 for intra- and inter-observer variability, respectively. The CCCs was very high for all measurements, ranging from 0.90 to 0.98. Using 256-slice MDCT with dedicated automated plaque analysis software, intra- and inter-observer reproducibility were excellent in evaluating the volume and characteristics of NCP in asymptomatic individuals.

Reliability and validity of the Korean Cancer Pain Assessment Tool (KCPAT).

The Korean Cancer Pain Assessment Tool (KCPAT), which was developed in 2003, consists of questions concerning the location of pain, the nature of pain, the present pain intensity, the symptoms associated with the pain, and psychosocial/spiritual pain assessments. This study was carried out to evaluate the reliability and validity of the KCPAT. A stratified, proportional-quota, clustered, systematic sampling procedure was used. The study population (903 cancer patients) was 1% of the target population (90,252 cancer patients). A total of 314 (34.8%) questionnaires were collected. The results showed that the average pain score (5 point on Likert scale) according to the cancer type and the at-present average pain score (VAS, 0-10) were correlated (r=0.56, p<0.0001), and showed moderate agreement (kappa=0.364). The mean satisfaction score was 3.8 (1-5). The average time to complete the questionnaire was 8.9 min. In conclusion, the KCPAT is a reliable and valid instrument for assessing cancer pain in Koreans.