Differentiation and Migration of Bone Marrow Mesenchymal Stem Cells Transplanted through the Spleen in Rats with Portal Hypertension

Aims

The goals of this paper were to evaluate the differentiation of bone marrow mesenchymal stem cells (BMSCs) into hepatocyte-like cells in vitro, and to determine whether stem cells can migrate and plant into the liver with portal hypertension accompanied by the end-stage of liver disease.

Methods

BMSCs were isolated from rats and amplified with hepatocyte growth factor (HGF) and fibroblast growth factor-4 (FGF-4). The expression of alpha-fetoprotein (AFP), cytokeratin 18 (CK-18), and albumin (ALB) was detected by immunofluorescence in induced cells. Rats were randomly divided into experimental (with common bile duct ligation) and control groups. After injection of fluorescence labeled cells, cell distribution was observed under a fluorescence microscope. The integrated optical density (IOD) and cell distribution scores were evaluated using Image-Pro Plus 6.0 software. The portal pressure was measured before the rats were killed.

Results

After being induced with HGF and FGF-4, the Golgi apparatus, endoplasmic reticulum, ribosomes, and mitochondria all significantly increased in the fifth generation cells. Immunofluorescent analysis showed that the induced cells expressed AFP, CK-18, and ALB. BMSCs were stained by CM-Dil, and the labeling rate was as high as 95.5%. The portal pressure in experimental group was much higher than that of the control group (18.04±2.35 vs. 9.75±1.40cm H₂O p<0.01). The IOD of transplanted cells in the experimental group was also significantly higher than that of the control group (11.30±2.09×10⁵ vs. 2.93±0.88×10⁵, p<0.01). In addition, the cell distribution score in the experimental group was lower than that of the control group (1.99±0.36 vs. 2.36±0.27, P<0.05).

Conclusions

The combination of HGF and FGF-4 induces the differentiation of BMSCs into hepatocyte-like cells, which express AFP, CK-18, and ALB. In addition, the recruitment of BMSCs (after transplantation in the spleen) was improved in rats with portal hypertension.     

Relationship of CHA2DS2-VASc and CHADS2 Score to Left Atrial Remodeling Detected by Velocity Vector Imaging in Patients with Atrial Fibrillation

Background

The CHADS₂/CHA₂DS₂-VASc scores are used to predict thrombo-embolic/stroke in patients with nonvalvular atrial fibrillation (AF). Nevertheless, limited data are available regarding the association between these risk stratification for stroke and left atrial (LA) remodeling status of AF patients. The purpose of this study was to explore the association between these scores and LA remodeling status assessed quantificationally by echocardiography in AF patients.

Methods

One hundred AF patients were divided into 3 groups based on the CHA₂DS₂-VASc/CHADS₂ score: the score of 0 (low stroke risk), the score of 1 (moderate stroke risk) and the score of ≥2 (high stroke risk). All patients were performed through conventional and velocity vector imaging echocardiography. Echocardiographic parameters: maximum LA volume index (LAVImax), LA total emptying fraction (LAEFt) and LA mean strain were obtained to assess quantificationally LA remodeling status.

Results

On categorizing with CHA₂DS₂-VASc, the score of 1 group showed augment in LAVImax and attenuation in LA mean strain derived from VVI, compared with the score of 0 group (LAVImax: 40.27±21.91 vs. 26.79±7.87, p=0.002; LA mean strain: 15.18±6.36 vs. 22±8.54, p=0.001). On categorizing with the CHADS₂ score, similar trends were seen between the score of ≥2 and 1 groups (LAVImax: 43.72±13.77 vs. 31.41±9.50, p<0.001; LA mean strain: 11.01±5.31 vs. 18.63±7.00, p<0.001). With multivariate logistic regression, LAVImax (odds ratio: 0.92 , 95% C=I: 0.85 to 0.98, p= 0.01) and LA mean strain reflecting LA remodeling (odds ratio: 1.10, 95% CI: 1.02 to 1.19, p=0.01) were strongly predictive of the CHA₂DS₂-VASc score of 0.

Conclusions

The superiority of the CHADS₂ score may lay in identifying LA remodeling of AF patients with high stroke risk. Whereas, the CHA₂DS₂-VASc score was better than the CHADS₂ score at identifying LA remodeling of AF patients presenting low stroke risk.     

BRAFV600E Mutation Analysis in Patients with Metastatic Colorectal Cancer (mCRC) in Daily Clinical Practice: Correlations with Clinical Characteristics,and Its Impact on Patients’ Outcome

Background

To prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice in patients with metastatic Colorectal Cancer (mCRC).

Patients and Methods

504 mCRC patients treated with systemic chemotherapy ± biologics were analyzed.

Results

A statistically significant higher incidence of the BRAF mutation was observed in patients with ECOG-PS 2 (p=0.001), multiple metastatic sites (p=0.002),> 65 years old (p=0.004), primary tumors located in the colon (p<0.001), high-grade tumors (p=0.001) and in those with mucinous features (p=0.037). Patients with BRAFV600E mutated tumors had a statistically significantly reduced progression-free survival (PFS) compared to wild-type (wt) ones (4.1 and 11.6 months, respectively; p<0.001) and overall survival (OS) (14.0 vs. 34.6 months, respectively; p<0.001). In the multivariate analysis the BRAFV600E mutation emerged as an independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7–6.2; p<0.001) and OS (HR: 5.9, 95% CI 3.7–9.5; p<0.001). Among the 273 patients treated with salvage cetuximab or panitumumab, the BRAFV600E mutation was correlated with reduced PFS (2.2 vs. 6.0 months; p<0.0001) and OS (4.3 vs. 17.4 months; p<0.0001).

Conclusions

The presence of BRAFV600E-mutation in mCRC characterizes a subgroup of patients with distinct biologic, clinical and pathological features and is associated with very poor patients’ prognosis.     

Relation of Leptin,Ghrelin and Inflammatory Cytokines with Body Mass Index in Pulmonary Tuberculosis Patients with and without Type 2 Diabetes Mellitus

Background

Pulmonary tuberculosis (TB) patients often suffer from anorexia and poor nutrition, causing weight loss. The peptide hormones leptin and its counterpart ghrelin, acting in the regulation of food intake and fat utilization, play an important role in nutritional balance. This study aimed to investigate the association of blood concentrations of leptin, ghrelin and inflammatory cytokines with body mass index (BMI) in TB patients with and without type 2 diabetes mellitus (T2DM).

Methods

BMI, biochemical parameters and plasma levels of leptin, ghrelin and inflammatory cytokines were measured before the start of treatment in 27 incident TB patients with T2DM, 21 TB patients and 23 healthy subjects enrolled in this study.

Results

The levels of leptin were significantly higher in TB patients (35.2±19.1 ng/ml) than TB+T2DM (12.6±6.1 ng/ml) and control (16.1±11.1 ng/ml) groups. The level of ghrelin was significantly lower in TB (119.9±46.1 pg/ml) and non-significantly lower in TB+T2DM (127.7±38.6 pg/ml) groups than control (191.6±86.5 pg/ml) group. The levels of TNF-α were higher, while IFN-γ and IL-6 levels were lower in patients than in the control group. Leptin showed a negative correlation with BMI in TB (r=-0.622, p<0.05) and TB+T2DM (r= -0.654, p<0.05) groups, but a positive correlation with BMI in the control group (r=0.521, p<0.05). Contrary ghrelin showed a positive correlation with BMI in TB (r=0.695, p<0.05) and TB+T2DM (r= 0.199, p>0.05) groups, but negative correlation with BMI in the control (r=-0.693, p<0.05) group. Inflammatory cytokines were poorly correlated with BMI in this study. Only IFN-γ showed a significant negative correlation with BMI in the control group (r=-0.545, p<0.05).

Conclusions

This study may suggest that possible abnormalities in ghrelin and leptin regulation (high levels of leptin and low levels of ghrelin) may be associated with low BMI and may account for the poor nutrition associated with TB and TB+T2DM.     

Imaging of Treatment Response to the Combination of Carboplatin and Paclitaxel in Human Ovarian Cancer Xenograft Tumors in Mice Using FDG and FLT PET

Introduction

A combination of carboplatin and paclitaxel is often used as first line chemotherapy for treatment of ovarian cancer. Therefore the use of imaging biomarkers early after initiation of treatment to determine treatment sensitivity would be valuable in order to identify responders from non-responders. In this study we describe the non-invasive PET imaging of glucose uptake and cell proliferation using 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) and 3’-deoxy-3’-[¹⁸F]fluorothymidine (FLT) for early assessment of treatment response in a pre-clinical mouse model of human ovarian cancer treated with carboplatin and paclitaxel.

Methods

In vivo uptake of FLT and FDG in human ovarian cancer xenografts in mice (A2780) was determined before treatment with carboplatin and paclitaxel (CaP) and repeatedday 1, 4 and 8 after treatment start. Tracer uptake was quantified using small animal PET/CT. Tracer uptake was compared with gene expression of Ki67, TK1, GLUT1, HK1 and HK2.

Results

Tumors in the CaP group was significantly smaller than in the control group (p=0.03) on day 8. On day 4 FDG SUVmax ratio was significantly lower in the CaP group compared to the control group (105±4% vs 138±9%; p=0.002) and on day 8 the FDG SUVmax ratio was lower in the CaP compared to the control group (125±13% vs 167±13%; p=0.05). On day 1 the uptake of FLT SUVmax ratio was 89±9% in the CaP group and 109±6% in the control group; however the difference was not statistically significant (p=0.08).

Conclusions

Our data suggest that both FDG and FLT PET may be used for the assessment of anti-tumor effects of a combination of carboplatin and paclitaxel in the treatment of ovarian cancer. FLT provides an early and transient signal and FDG a later and more prolonged response. This underscores the importance of optimal timing between treatment and FLT or FDG imaging since treatment response may otherwise be overlooked.     

Differences between Total Intravenous Anesthesia and Inhalation Anesthesia in Free Flap Surgery of Head and Neck Cancer

Background

Many studies have evaluated risk factors associated with complications after free flap surgery, but these studies did not evaluate the impact of anesthesia management. The goal of the current study was to evaluate the differences between patients who received inhalation and total intravenous anesthesia (TIVA) in free flap surgery.

Methods

One hundred and fifty-six patients who underwent free flap surgery for head and neck cancer were retrospectively divided into the TIVA (96 patients) and the inhalation group (87 patients). Perioperative hemodynamic data and postoperative medical complications were determined by documented medical records.

Results

Ninety-six patients in the TIVA group were compared with 87 patients who received inhalation anesthesia. There were no differences in gender, age, classification of physical status based on American Society for Anesthesiologists (ASA) score, and cormobidities between the two groups. Patients in the TIVA group required less perioperative crystalloid (4172.46 ± 1534.95 vs. 5183.91 ± 1416.40 ml, p < 0.0001) and colloid (572.46 ± 335.14 vs. 994.25 ± 434.65 ml, p < 0.0001) to maintain hemodynamic stability. Although the mean anesthesia duration was shorter in the TIVA group (11.02 ± 2.84 vs. 11.70± 1.96 hours, p = 0.017), the blood loss was similar between groups (p = 0.71). There was no difference in surgical complication rate, but patients in the TIVA group developed fewer pulmonary complications (18 vs. 47, p = 0.0008). After multivariate regression, patients in the TIVA group had a significantly reduced risk of pulmonary complication compared with the inhalation group (Odds ratio 0.41, 95% CI 0.18–0.92).

Conclusions

Total intravenous anesthesia was associated with significantly fewer pulmonary complications in patients who received free flap reconstruction.     

Adequately Adapted Insulin Secretion and Decreased Hepatic Insulin Extraction Cause Elevated Insulin Concentrations in Insulin Resistant Non-Diabetic Adrenal Incidentaloma Patients

Background

Insulin-resistance is commonly found in adrenal incidentaloma (AI) patients. However, little is known about beta-cell secretion in AI, because comparisons are difficult, since beta–cell-function varies with altered insulin-sensitivity.

Objectives

To retrospectively analyze beta–cell function in non-diabetic AI, compared to healthy controls (CON).

Methods

AI (n=217, 34%males, 57±1years, body-mass-index:27.7±0.3kg/m²) and CON [n=25, 32%males, 56±1years, 26.7±0.8kg/m²] with comparable anthropometry (p≥0.31) underwent oral-glucose-tolerance-tests (OGTTs) with glucose, insulin, and C–peptide measurements. 1mg-dexamethasone-suppression-tests were performed in AI. AI were divided according to post–dexamethasone-suppression–test cortisol-thresholds of 1.8 and 5µg/dL into 3subgroups: pDexa<1.8µg/dL, pDexa1.8-5µg/dL and pDexa>5µg/dL. Using mathematical modeling, whole-body insulin-sensitivity [Clamp-like-Index (CLIX)], insulinogenic Index, Disposition Index, Adaptation Index, and hepatic insulin extraction were calculated.

Results

CLIX was lower in AI combined (4.9±0.2mg·kg^-1·min^-1), pDexa<1.8µg/dL (4.9±0.3) and pDexa1.8-5µg/dL (4.7±0.3, p<0.04 vs.CON:6.7±0.4). Insulinogenic and Disposition Indexes were 35%–97% higher in AI and each subgroup (p<0.008 vs.CON), whereas C–peptide–derived Adaptation Index, compensating for insulin-resistance, was comparable between AI, subgroups, and CON. Mathematical estimation of insulin–derived (insulinogenic and Disposition) Indexes from associations to insulin-sensitivity in CON revealed that AI-subgroups had ~19%-32% higher insulin-secretion than expectable. These insulin-secretion-index differences negatively (r=-0.45, p<0.001) correlated with hepatic insulin extraction, which was 13-16% lower in AI and subgroups (p<0.003 vs.CON).

Conclusions

AI-patients show insulin-resistance, but adequately adapted insulin secretion with higher insulin concentrations during an OGTT, because of decreased hepatic insulin extraction; this finding affects all AI-patients, regardless of dexamethasone-suppression-test outcome.     

Assessment of Clinical Signs of Liver Cirrhosis Using T1 Mapping on Gd-EOB-DTPA-Enhanced 3T MRI

Objectives

To assess the differences between normal and cirrhotic livers by means of T1 mapping of liver parenchyma on gadoxetic acid (Gd-EOB-DTPA)-enhanced 3 Tesla (3T) MR imaging (MRI).

Methods

162 patients with normal (n = 96) and cirrhotic livers (n = 66; Child-Pugh class A, n = 30; B, n = 28; C, n = 8) underwent Gd-EOB-DTPA-enhanced 3T MRI. To obtain T1 maps, two TurboFLASH sequences (TI = 400 ms and 1000 ms) before and 20 min after Gd-EOB-DTPA administration were acquired. T1 relaxation times of the liver and the reduction rate between pre- and post-contrast enhancement images were measured.

Results

The T1 relaxation times for Gd-EOB-DTPA-enhanced MRI showed significant differences between patients with normal liver function and patients with Child-Pugh class A, B, and C (p < 0.001). The T1 relaxation times showed a constant significant increase from Child-Pugh class A up to class C (Child-Pugh class A, 335 ms ± 80 ms; B, 431 ms ± 75 ms; C, 557 ms ± 99 ms; Child-Pugh A to B, p < 0.001; Child-Pugh A to C, p < 0.001; Child-Pugh B to C, p < 0.001) and a constant decrease of the reduction rate of T1 relaxation times (Child-Pugh class A, 57.1% ± 8.8%; B, 44.3% ± 10.2%, C, 29.9% ± 6.9%; Child-Pugh A to B, p < 0.001; Child-Pugh A to C,p < 0.001; Child-Pugh B to C, p < 0.001).

Conclusion

Gd-EOB-DTPA-enhanced T1 mapping of the liver parenchyma may present a useful method for determining severity of liver cirrhosis.     

Preterm Birth Has Sex-Specific Effects on Autonomic Modulation of Heart Rate Variability in Adult Sheep

Introduction

Globally, 11% of infants are born preterm. In adulthood, individuals born preterm are at increased risk of cardiovascular morbidity and mortality, but the mechanistic basis of this remains unknown. Clinically overt cardiovascular disease may be preceded by altered cardiac autonomic activity characterised by increased sympathetic activity and/or reduced parasympathetic activity. Thus, altered cardiac autonomic activity in survivors of preterm birth may underlie later cardiovascular risk.

Objective

To investigate the impact of gestational age on cardiac autonomic activity in juvenile and adult sheep.

Methods and Results

Singleton-bearing ewes were randomised antenatally to spontaneous term birth (TC; n=73) or corticosteroid induced preterm birth (PT; n=60). Cardiac autonomic modulation was assessed using heart rate variability analysis in juvenile and adult offspring. Preterm birth in adult males was associated with altered sympatho-vagal modulation (LFnu: PT 64±4 vs. TC 49±4, p<0.05; LogLF/HF: PT 1.8±0.1 vs. TC 1.5±0.1, p<0.05) and reduced parasympathetic modulation (LogRMSSD: PT 2.9±0.2 vs. TC 3.4±0.1, p<0.05; LogNN50: PT 0.3±0.4 vs. TC 1.6±0.4, p<0.05). Within the range of term birth, each one-day increment in gestational age was associated with a decrement in LFnu in juvenile females and with a decrement in LFnu and LF/HF ratio, but an increment in RMSSD and NN50 in adult females.

Conclusions

Cardiac autonomic function in adult sheep is affected in a sex-specific manner by gestational age at birth, even within the term range. Altered cardiac autonomic function may contribute to increased later cardiovascular morbidity in those born preterm.     

Squamous Tissue Lymphocytes in the Esophagus of Controls and Patients with Reflux Esophagitis and Barrett’s Esophagus Are Characterized by a Non-Inflammatory Phenotype

Background and Objective

Reflux esophagitis (RE) is characterized by inflammation of the squamous epithelium (SQ) of the esophagus and may progress to Barrett’s esophagus (BE) characterized by intestinal metaplasia. The role of inflammation in this transition has been postulated but lacks experimental evidence. Here, the inflammatory responses in the esophagus of these patients were investigated.

Patients and Methods

Fifty-one esophageal biopsies from with patients BE (n = 19), RE (n = 8) and controls (n = 23) were analyzed. T-cells were analyzed before and after ex vivo expansion (14 days) by multicolor flow cytometric analysis. The following markers were studied: CD3, CD4, CD8 (T-cell markers), Granzyme B (marker of cytotoxicity), CD103 (αE/epithelial integrin) and NKg2a (inhibitory receptor on T-cells and NK-cells).

Results

Analysis of ex vivo cultures from normal looking SQ from controls, RE patients, and BE patients revealed no significant differences in the number and phenotypes of T-cells. In contrast, tissue from RE was different to normal SQ in four aspects: 1) higher percentages of CD3⁺CD4⁺-cells (72±7% vs 48±6%, p = 0.01) and 2) CD8⁺GranzymeB⁺ -cells (53±11% vs 26±4%, p<0.05), while 3) lower percentages of CD4⁺CD103⁺-cells (45±19% vs 80±3%, p = 0.02) and 4) CD8⁺NKg2a⁺- cells (31±12% vs 44±5%).

Conclusion

Despite the fact that both tissues are exposed to the same reflux associated inflammatory triggers, the immune response observed in RE is clearly distinct from that in SQ of BE. The differences in immune responses in BE tissue might contribute to its susceptibility for transformation into intestinal metaplasia.     

Gender Differences in In-Hospital Clinical Outcomes after Percutaneous Coronary Interventions: An Insight from a Japanese Multicenter Registry

Background

Gender differences in clinical outcomes after percutaneous coronary intervention (PCI) among different age groups are controversial in the era of drug-eluting stents, especially among the Asian population who are at higher risk for bleeding complications.

Methods and Results

We analyzed data from 10,220 patients who underwent PCI procedures performed at 14 Japanese hospitals from September 2008 to April 2013. A total of 2,106 (20.6%) patients were women. Women were older (72.7±9.7 vs 66.6±10.8 years, p<0.001), and had a lower body mass index (23.4±4.0 vs 24.3±3.5, p<0.001), with a higher prevalence of hypertension (p<0.001), hyperlipidemia (p<0.001), insulin-dependent diabetes (p<0.001), renal failure (p<0.001), and heart failure (p<0.001) compared with men. Men tended to have more bifurcation lesions (p = 0.003) and chronic totally occluded lesions (p<0.001) than women. Crude overall complications (14.8% vs 9.5%, p<0.001) and the rate of bleeding complications (5.3% vs 2.8%, p<0.001) were significantly higher in women than in men. On multivariate analysis in the total cohort, female sex was an independent predictor of overall complications (OR, 1.47; 95% CI, 1.26–1.71; p<0.001) and bleeding complications (OR, 1.74; 95% CI, 1.36–2.24; p<0.001) after adjustment for confounding variables. A similar trend was observed across the middle-aged group (≥55 and <75 years) and old age group (≥75 years).

Conclusions

Women are at higher risk than men for post-procedural complications after PCI, regardless of age.     

Assessment of Dynamic Cerebral Autoregulation in Patients with Basilar Artery Stenosis

Background and Aims

Previous studies have shown impaired cerebral autoregulation (CA) in carotid and middle cerebral artery (MCA) stenosis/occlusion. Little is known about CA in patients with basilar artery (BA) stenosis. We therefore investigated dynamic CA patterns in BA stenosis using transfer function analysis (TFA).

Methods

We measured spontaneous oscillations of blood flow velocity (CBFV) in the right posterior cerebral artery (PCA), and left MCA and mean arterial pressure (ABP) continuously in 25 patients with BA stenosis (moderate n=16 with 50-69% occlusion and severe n=9 with ≥70% occlusion) and 22 healthy volunteers in supine position during 6 circles per minute deep breath. Analysis was based on the ‘black-box’ model of transfer function deriving phase and gain in both PCA and MCA.

Results

Though changes of phase shift and gain between the patients and healthy controls were observed in MCA, the differences are however not significant. Phase shift in PCA was significantly decreased in severe stenosis when comparing with healthy controls and moderate stenosis (4.2±34.2° VS 41.1±40.4°, 4.2±34.2° VS 34.2±27.2°, both p<0.05), whilst the gain in PCA is increased for moderate BA stenosis and decreased for severe BA stenosis. Furthermore, we found that phase shift were almost abolished in patients with ischemic stroke who developed unfavorable clinical outcome (mRs>2) on the 90 days after stroke onset.

Conclusion

Dynamic CA in PCA reduces in patients with severe BA stenosis and those with ischemic stroke who present poor outcome in 90 days after stroke onset. Phase shift might be a sensitive index prompting impaired CA in posterior circulation.     

Prevalence of Overweight and Obesity and Their Associations with Socioeconomic Status in a Rural Han Chinese Adult Population

Background

The purpose of this study is to describe the prevalence of overweight, general obesity, and abdominal obesity and examine their associations with socioeconomic status in a rural Chinese adult population.

Methods

This cross-sectional study was performed on 15,236 participants ≥ 35 years of age (6,313 men [41.4%] and 8,923 women [58.6%]). Each participant’s weight, height, waist circumference (WC), and hipline circumference (HC) were measured, and demographic and socioeconomic data were collected using questionnaires.

Results

The mean body mass index (BMI) values were 23.31 ± 2.96 and 23.89 ± 3.23 kg m^-2 and the mean WC values were 79.13 ± 8.43 and 79.54 ± 8.27 cm for men and women, respectively. The age-standardized prevalence rates of overweight (BMI ≥ 24.0 kg m^-2), general obesity (BMI ≥ 28.0 kg m^-2), and abdominal obesity (WC ≥ 85 cm for men and ≥ 80 cm for women) were 32.0%, 6.7%, and 27.0% for men and 35.1%, 9.7%, and 48.3% for women, respectively. All gender differences were statistically significant (p < 0.001). In addition, the age-specific prevalence rates of general and abdominal obesity slowly decreased among men but sharply increased among women as age increased (p < 0.001). In subsequent logistic regression analysis, educational level was negatively associated with both general obesity and abdominal obesity among women but positively associated with abdominal obesity among men. No significant correlation was found between obesity and income.

Conclusions

These results suggest a high prevalence of obesity which might differ by gender and age, and an inverse association among women and a mixed association among men noted between education and obesity in our locality. Preventive and therapeutic programs are warranted to control this serious public health problem. The gender-specific characteristics of populations at high-risk of developing obesity should be taken into consideration when designing interventional programs.     

Obesity Is Associated with Lower Coronary Microvascular Density

Background

Obesity is associated with diastolic dysfunction, lower maximal myocardial blood flow, impaired myocardial metabolism and increased risk of heart failure. We examined the association between obesity, left ventricular filling pressure and myocardial structure.

Methods

We performed histological analysis of non-ischemic myocardium from 57 patients (46 men and 11 women) undergoing coronary artery bypass graft surgery who did not have previous cardiac surgery, myocardial infarction, heart failure, atrial fibrillation or loop diuretic therapy.

Results

Non-obese (body mass index, BMI, ≤30 kg/m², n=33) and obese patients (BMI >30 kg/m², n=24) did not differ with respect to myocardial total, interstitial or perivascular fibrosis, arteriolar dimensions, or cardiomyocyte width. Obese patients had lower capillary length density (1145±239, mean±SD, vs. 1371±333 mm/mm³, P=0.007) and higher diffusion radius (16.9±1.5 vs. 15.6±2.0 μm, P=0.012), in comparison with non-obese patients. However, the diffusion radius/cardiomyocyte width ratio of obese patients (0.73±0.11 μm/μm) was not significantly different from that of non-obese patients (0.71±0.11 μm/μm), suggesting that differences in cardiomyocyte width explained in part the differences in capillary length density and diffusion radius between non-obese and obese patients. Increased BMI was associated with increased pulmonary capillary wedge pressure (PCWP, P<0.0001), and lower capillary length density was associated with both increased BMI (P=0.043) and increased PCWP (P=0.016).

Conclusions

Obesity and its accompanying increase in left ventricular filling pressure were associated with lower coronary microvascular density, which may contribute to the lower maximal myocardial blood flow, impaired myocardial metabolism, diastolic dysfunction and higher risk of heart failure in obese individuals.     

Increased Red Blood Cell Distribution Width Associates with Cancer Stage and Prognosis in Patients with Lung Cancer

Background

Red cell distribution width (RDW), one of many routinely examined parameters, shows the heterogeneity in erythrocyte size. We investigated the association of RDW levels with clinical parameters and prognosis of lung cancer patients.

Methods

Clinical and laboratory data from 332 patients with lung cancer in a single institution were retrospectively studied by univariate analysis. Kaplan-Meier survival analysis and Cox proportional hazard models were used to examine the effect of RDW on survival.

Results

The RDW levels were divided into two groups: high RDW (>=15%), n=73 vs. low RDW, n=259 (<15%). Univariate analysis showed that there were significant associations of high RDW values with cancer stage, performance status, presence of other disease, white blood cell count, hemoglobin, mean corpuscular volume, platelet count, albumin level, C-reactive protein level, and cytokeratin 19 fragment level. Kruskal-Wallis tests revealed an association of RDW values with cancer stage in patients irrespective of comorbidity (patient with/without comorbidity: p<0.0001, patient without comorbidity: p<0.0001). Stages I-IV lung cancer patients with higher RDW values had poorer prognoses than those with lower RDW values (Wilcoxon test: p=0.002). In particular, the survival rates of stage I and II patients (n=141) were lower in the high RDW group (n=19) than in the low RDW group (n=122) (Wilcoxon test: p<0.001). Moreover, multivariate analysis showed higher RDW is a significant prognostic factor (p=0.040).

Conclusion

RDW is associated with several factors that reflect inflammation and malnutrition in lung cancer patients. Moreover, high levels of RDW are associated with poor survival. RDW might be used as a new and convenient marker to determine a patient’s general condition and to predict the mortality risk of lung cancer patients.     

A Novel Electrocardiographic Index for the Diagnosis of Diastolic Dysfunction

Background

Although the assessment of diastolic dysfunction (DD) is an integral part of routine cardiologic examinations, little is known about associated electrocardiographic (ECG) changes. Our aim was to investigate a potential role of ECG indices for the recognition of patients with DD.

Methods and Results

ECG parameters correlating with echocardiographic findings of DD were retrospectively assessed in a derivation group of 172 individuals (83 controls with normal diastolic function, 89 patients with DD) and their diagnostic performance was tested in a validation group of 50 controls and 50 patients. The patient group with a DD Grade 1 and 2 showed longer QTc (422±24ms and 434±32ms vs. 409±25ms, p<0.0005) and shorter Tend–P and Tend–Q intervals, reflecting the electrical and mechanical diastole (240±78ms and 276±108ms vs. 373±110ms, p<0.0001; 409±85ms and 447±115ms vs. 526±119ms, p<0.0001). The PQ–interval was significantly longer in the patient group (169±28ms and 171±38ms vs. 153±22ms, p<0.005). After adjusting for possible confounders, a novel index (Tend–P/[PQxAge]) showed a high performance for the recognition of DD, stayed robust in the validation group (sensitivity 82%, specificity 93%, positive predictive value 93%, negative predictive value 82%, accuracy 88%) and proved a substantial added value when combined with the indexed left atrial volume (LAESVI, sensitivity 90%, specificity 92%, positive predictive value 95%, negative predictive value 86%, accuracy 91%).

Conclusions

A novel electrocardiographic index Tend–P/(PQxAge) demonstrates a high diagnostic accuracy for the diagnosis of DD and yields a substantial added value when combined with the LAESVI.     

Hypoglycemia and Medical Expenses in Patients with Type 2 Diabetes Mellitus: An Analysis Based on the Korea National Diabetes Program Cohort

Background and Aims

Hypoglycemia is one of the most important adverse events in individuals with type 2 diabetes mellitus (T2DM). However, hypoglycemia-related events are usually overlooked and have been documented less in clinical practice.

Materials and Methods

We evaluated the incidence, clinical characteristics, and medical expenses of hypoglycemia related events in T2DM patients based on the Korea National Diabetes Program (KNDP), which is the largest multi-center, prospective cohort in Korea (n = 4,350). For accurate outcomes, the KNDP data were merged with claims data from the Health Insurance Review and Assessment Service (HIRA) of Korea.

Results

During a median follow-up period of 3.23 years (95% CI: 3.14, 3.19), 88 subjects (2.02%) were newly diagnosed with hypoglycemia, and the incidence of hypoglycemia was 6.44 cases per 1,000 person-years (PY). Individuals with hypoglycemia were significantly older (59.7±10.7 vs. 53.3±10.4 years, p < 0.001), had more hospital visits (121.94±126.88 days/PY, p < 0.001), had a longer hospital stays (16.13±29.21 days/PY, p < 0.001), and incurred greater medical costs ($2,447.56±4,056.38 vs. $1,336.37±3,403.39 /PY, p < 0.001) than subjects without hypoglycemia.

Conclusion

Hypoglycemia-related events were infrequently identified among the medical records of T2DM subjects. However, they were associated significantly with poor clinical outcomes, and thus, hypoglycemia could have a substantial burden on the Korean national healthcare system.     

The Adverse Effect of Selective Cyclooxygenase-2 Inhibitor on Random Skin Flap Survival in Rats

Background

Cyclooxygenase-2(COX-2) inhibitors provide desired analgesic effects after injury or surgery, but evidences suggested they also attenuate wound healing. The study is to investigate the effect of COX-2 inhibitor on random skin flap survival.

Methods

The McFarlane flap model was established in 40 rats and evaluated within two groups, each group gave the same volume of Parecoxib and saline injection for 7 days. The necrotic area of the flap was measured, the specimens of the flap were stained with haematoxylin-eosin(HE) for histologic analysis. Immunohistochemical staining was performed to analyse the level of VEGF and COX-2 .

Results

7 days after operation, the flap necrotic area ratio in study group (66.65±2.81)% was significantly enlarged than that of the control group(48.81±2.33)%(P <0.01). Histological analysis demonstrated angiogenesis with mean vessel density per mm² being lower in study group (15.4±4.4) than in control group (27.2±4.1) (P <0.05). To evaluate the expression of COX-2 and VEGF protein in the intermediate area II in the two groups by immunohistochemistry test .The expression of COX-2 in study group was (1022.45±153.1), and in control group was (2638.05±132.2) (P <0.01). The expression of VEGF in the study and control groups were (2779.45±472.0) vs (4938.05±123.6)(P <0.01).In the COX-2 inhibitor group, the expressions of COX-2 and VEGF protein were remarkably down-regulated as compared with the control group.

Conclusion

Selective COX-2 inhibitor had adverse effect on random skin flap survival. Suppression of neovascularization induced by low level of VEGF was supposed to be the biological mechanism.     

Using Oxidized Low-Density Lipoprotein Autoantibodies to Predict Restenosis after Balloon Angioplasty in Patients with Acute Myocardial Infarction

Objectives

Oxidized low-density lipoproteins (oxLDL) and oxidized low-density lipoprotein autoantibodies (OLAB) have been detected in human plasma and atherosclerotic lesions. OLAB appear to play a role in the clearance of oxLDL from circulation. Higher levels of OLAB appear to be associated with a reduced risk of a wide range of cardiovascular diseases. We investigated the prognostic value of plasma oxLDL and OLAB in patients undergoing primary coronary balloon angioplasty for acute ST-elevation myocardial infarction (STEMI).

Methods

Plasma oxLDL and OLAB concentrations were measured in 56 patients with acute STEMI before primary angioplasty, and then 3 days, 7 days and 1 month after the acute event. Follow-up angiography was repeated 6 months later to detect the presence of restensosis (defined as >50% luminal diameter stenosis). The thrombolysis in myocardial infarction (TIMI) risk score was calculated to determine the relationship between OLAB/oxLDL ratio and TIMI risk scores.

Results

Of the 56 patients, 18 (31%) had angiographic evidence of restenosis. Plasma OLAB concentrations were significantly lower in the restenosis group before angioplasty (181±114 vs. 335±257 U/L, p = 0.003), and at day 3 (155±92 vs. 277±185 U/L, p<0.001) and day 7 (177±110 vs. 352±279 U/L, p<0.001) after the acute event. There was no difference in oxLDL concentration between the two groups. The ratio of OLAB/oxLDL positively correlated with TIMI risk scores before angioplasty (p for trend analysis, p = 0.004), at day 3 (p = 0.008) and day 7 (p<0.001) after STEMI.

Significance

A relative deficit of OLAB, and hence likely impaired clearance of oxLDL, is associated with the risk of arterial restenosis after primary angioplasty for acute STEMI.