Flyways and migratory behaviour of the Vega gull (Larus vegae), a little-known Arctic endemic.

Large gulls are generalist predators that play an important role in Arctic food webs. Describing the migratory patterns and phenology of these predators is essential to understanding how Arctic ecosystems function. However, from all six large Arctic gull taxa, including three long-distance migrants, to date seasonal movements have been studied only in three and with small sample sizes. To document the flyways and migratory behaviour of the Vega gull, a widespread but little-studied Siberian migrant, we monitored 28 individuals with GPS loggers over a mean period of 383 days. Birds used similar routes in spring and autumn, preferring coastal to inland or offshore routes, and travelled 4000-5500 km between their breeding (Siberia) and wintering grounds (mainly the Republic of Korea and Japan). Spring migration mainly occurred in May, and was twice as fast and more synchronized among individuals than autumn migration. Migration bouts mainly occurred during the day and twilight, but rates of travel were always higher during the few night flights. Flight altitudes were nearly always higher during migration bouts than during other bouts, and lower during twilight than during night or day. Altitudes above 2000m were recorded during migrations, when birds made non-stop inland flights over mountain ranges and vast stretches of the boreal forest. Individuals showed high inter-annual consistency in their movements in winter and summer, indicating strong site fidelity to their breeding and wintering sites. Within-individual variation was similar in spring and autumn, but between individual variation was higher in autumn than in spring. Compared to previous studies, our results suggest that the timing of spring migration in large Arctic gulls is likely constrained by snowmelt at breeding grounds, while the duration of migration windows could be related to the proportion of inland versus coastal habitats found along their flyways ('fly-and-forage' strategy). Ongoing environmental changes are hence likely in short term to alter the timing of their migration, and in long term possibly affect the duration if e.g. the resource availability along the route changes in the future.

Tetralogy of Fallot associated with a rare type partially anomalous pulmonary venous connection and levoatrial cardinal vein.

Tetralogy of Fallot is rarely associated with partially anomalous pulmonary venous connection. Unidentified partially anomalous pulmonary venous connection, however, might increase the risk of pulmonary valve replacement in repaired tetralogy of Fallot patients. Here, we present a case of a 19-year-old male who received a correction of tetralogy of Fallot 18 years ago and a rare type of partially anomalous pulmonary venous connection with levoatrial cardinal vein was identified during the follow-up period. The anomalous pulmonary veins were connected to the left hepatic vein and the right superior caval vein. Performing a pulmonary valve replacement, partially anomalous pulmonary venous connection was also corrected with a new approach using the venous plexus between the hepatic veins.

REV1 Inhibition Enhances Radioresistance and Autophagy.

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1's important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens.

Arterial stiffness and progression of cerebral white matter hyperintensities in patients with type 2 diabetes and matched controls: a 5-year cohort study.

BACKGROUND: Stroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls. METHODS: In a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59 ± 10 years and patients had a median (range) diabetes duration of 1.8 (0.8-3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method). RESULTS: Patients with T2DM had a higher PWV than controls (8.8 ± 2.2 vs. 7.9 ± 1.4 m/s, p < 0.01). WMH progression were similar in the two groups (p = 0.5). One m/s increase in baseline PWV was associated with a 16% [95% CI 1-32%], p < 0.05) increase in cWMH volume at 5 years follow-up after adjustment for age, sex, diabetes, pulse pressure and smoking. High PWV was associated with cWMH progression in the combined cohort (p < 0.05). We found no interaction between diabetes and PWV on cWMH progression. CONCLUSIONS: PWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.

Association between body mass index and the risk of falls: a nationwide population-based study.

The association of BMI with falls differed between men and women in Korea. Obesity was associated with a greater risk of falls in women, whereas underweight seemed to increase the risk of falls compared with normal weight in men. PURPOSE: This study examined the sex-specific association between body mass index (BMI) and falls in Korean adults using data from a large population-based survey. METHODS: We analyzed 113,805 men and women (age ≥ 50 years) who participated in the Korean Community Health Survey in 2013. Logistic regression was used to assess the relationship between BMI and falls. RESULTS: The mean (± standard deviation) age and BMI of all participants were 63.8 ± 9.6 years and 23.2 ± 2.9 kg/m2, respectively. Among the 113,805 subjects, 19.1% and 6.7% had histories of falls and recurrent falls, respectively. The association of BMI with recurrent falls differed between men and women. The multivariable-adjusted odd ratios (ORs) for recurrent falls were 0.98 (95% confidence interval [CI] 0.86-1.12), 1.23 (1.14-1.32), and 1.51 (1.26-1.81) in women with BMIs of < 18.5, 25-29.9, and ≥ 30 kg/m2, respectively, relative to those with BMIs of 18.5-24.9 kg/m2. The corresponding ORs for men were 1.20 (95% CI 1.01-1.42), 1.05 (0.96-1.14), and 0.97 (0.69-1.38), respectively. Older age and low economic level were associated independently with higher ORs of recurrent falls in men and women, respectively. In addition, comorbidities, including diabetes, stroke, arthritis, osteoporosis, and asthma, correlated significantly with an increased risk of recurrent falls (all p < 0.001). CONCLUSIONS: Obesity was associated with a greater risk of recurrent falls in women, whereas underweight seemed to be associated with a greater risk of falls in men.

A mortality analysis of septic shock, vasoplegic shock and cryptic shock classified by the third international consensus definitions (Sepsis-3).

INTRODUCTION: This study aimed to compare the 28-day mortality of patients with septic shock, defined by Sepsis-3 criteria and patients with vasoplegic or cryptic shock who are excluded from this new definition. OBJECTIVES: This retrospective observational study was performed using a tertiary emergency department's septic shock registry and investigated the records of patients managed between January 2010 and December 2015. In 2,138 total patients, 1004 (47.0%) had septic shock, 476 (22.2%) had vasoplegic shock and 655 (30.6%) had cryptic shock. RESULTS: There was significant variation in 28-day mortality among the three groups: 23.4% for septic shock, 8.8% for vasoplegic shock and 12.2% for cryptic shock (P < .001). In subgroup analysis of cryptic shock or septic shock according to lactate levels (2-3, 3-4 and >4 mmol/L), the mortality rate increased as lactate increased (cryptic shock: 9.5%, 14.8% and 18.0%; septic shock: 18.6%, 22.6% and 27.0%, respectively; P < .001). Multivariable analysis revealed odds ratios for mortality of 0.31 (95% CI 0.22-0.44; P < .001) for vasoplegic shock and 0.46 (95% CI 0.35-0.61; P < .001) for cryptic shock relative to septic shock. Survival curve analysis showed significant differences among patients with septic shock, vasoplegic shock and cryptic shock (Log rank test: P < .0001). CONCLUSION: The new septic shock definition may be useful for identifying high-risk patients requiring intensive care. However, cryptic shock-associated mortality increased to 18.0% as serum lactate increased, which suggests that some cryptic shock patients may also require intensive management.

PD-L1 expression and infiltration by CD4+ and FoxP3+ T cells are increased in Xp11 translocation renal cell carcinoma and indicate poor prognosis.

AIMS: Interaction between programmed death-1 ligand (PD-L1) and its receptor programmed death 1 (PD-1) on T cells inactivates antitumour immune responses. PD-L1 expression has been associated with poor prognosis in renal cell carcinoma (RCC) and predicts adverse outcome. This study was designed to evaluate the impact of PD-L1 expression and the immune microenvironment on the clinical outcome in Xp11 translocation renal cell carcinoma (TRCC) and, therefore, their potential relevance as prognostic biomarkers. METHODS AND RESULTS: The present retrospective analysis investigated expression of PD-L1 and immune cells CD8, CD4, CD3, forkhead box protein 3 (FoxP3) and PD-1 in TRCC compared to other types of RCC. FFPE specimens were collected between 2011 and 2017 from 311 patients who underwent nephrectomy at our institution for RCC. Specimens were immunostained for PD-L1, CD8, CD4, CD3, FoxP3 and PD-1, and an outcome analysis was conducted. PD-L1 expression rate was highest in TRCC (68%, 16 of 25), followed by mucinous tubular and spindle cell RCC and collecting duct carcinoma (33%, one of three), papillary RCC (27%, seven of 26), clear cell RCC (16%, 29 of 233), chromophobe RCC (11%, two of 18) and multilocular cystic RCC (0%, none of three). In TRCC, PD-L1 expression was associated with poor recurrence-free survival (RFS) (P = 0.041). The CD4high and FoxP3high groups showed a significantly shorter RFS (P = 0.05 and P = 0.031, respectively) compared to CD4low and FOXPlow groups. CONCLUSION: PD-L1 expression was higher in TRCC than in other types of RCC. High PD-L1 tumour cell expression and tumour infiltration by CD4+ and FoxP3+ immune cells were associated with poor RFS in TRCC.

Complete sequence analysis of human norovirus GII.17 detected in South Korea.

Norovirus, a major cause of gastroenteritis in people of all ages worldwide, was first reported in South Korea in 1999. The most common causal agents of pediatric acute gastroenteritis are norovirus and rotavirus. While vaccination has reduced the pediatric rotavirus infection rate, norovirus vaccines have not been developed. Therefore, prediction and prevention of norovirus are very important. Norovirus is divided into genogroups GI-GVII, with GII.4 being the most prevalent. However, in 2012-2013, GII.17 showed a higher incidence than GII.4 and a novel variant, GII.P17-GII.17, appeared. In this study, 204 stool samples collected in 2013-2014 were screened by reverse transcriptase-polymerase chain reaction; 11 GI (5.39%) and 45 GII (22.06%) noroviruses were identified. GI.4, GI.5, GII.4, GII.6 and GII.17 were detected. The whole genomes of the three norovirus GII.17 were sequenced. The whole genome of GII.17 consists of three open reading frames of 5109, 1623 and 780 bp. Compared with 20 GII.17 strains isolated in other countries, we observed numerous changes in the protruding P2 domain of VP1 in the Korean GII.17 viruses. Our study provided genome information that might aid in epidemic prevention, epidemiology studies and vaccine development.

Low normal fasting glucose and risk of accidental death in Korean adults: A prospective cohort study.

AIM: This study aimed to prospectively examine whether low normal glucose levels and hypoglycaemia are associated with increased mortality due to external causes, especially unintentional accidents. METHODS: A total of 345,318 normoglycaemic Korean adults who had undergone health examinations during 2002-2003 were followed-up to 2013. To avoid potential biases related to glucose-lowering medication use, those with known diabetes or hyperglycaemia were excluded. RESULTS: During 3.6 million person-years of follow-up, 1293 participants died because of unintentional accidents. Hazard ratios (HRs) for these accidental deaths were 1.26 (95% CI: 1.11-1.42), 1.60 (1.21-2.11) and 3.07 (1.37-6.85) for fasting serum glucose (FSG) levels of 70-79, 55-69 and <55mg/dL (3.9-4.4, 3.05-3.83 and <3.05mmol/L), respectively, compared with 80-99mg/dL (4.44-5.5mmol/L). FSG levels<80mg/dL were associated with an approximately 30% higher mortality due to accidents: specifically, 40% were non-fall-related injury; 50% were automobile-related; and 80% were motorcycle-related. The associations were weak (approximately 10% higher mortality, with P>0.05 for each cause) for deaths due to traffic accidents (pedestrians, pedal cyclists), falls, intentional self-harm and physical assault. The population attributable risks for FSG levels <80mg/dL were 10% (95% CI: 2-18%) for non-fall-related injury, 11% (6-17%) for car accidents and 17% (6-27%) for motorcycle accidents. CONCLUSION: FSG levels of 70-79mg/dL (3.9-4.4mmol/L) as well as <70mg/dL are risk factors for accidental death. Appropriate management of the impact of FSG levels <80mg/dL might reduce unintended deaths due to non-fall-related injury, and automobile and motorcycle accidents, by ≥10%.

Comparison of gynecologic cancer risk factors, incidence and mortality trends between South Korea and Israel, 1999-2013.

OBJECTIVE: To discuss possible causes of disparities in incidence and mortality rates of ovarian cancer, uterine cancer and cervical cancer between two diverse populations from east and west Asia. METHODS: Incidence and mortality data from 1999 to 2013 were extracted from Korean and Israeli cancer registries. Age-standardized rates and annual percent changes were calculated. Trends were analyzed using Joinpoint analysis and discussed with respect to risk factor exposure. RESULTS: Age-standardized rate of ovarian cancer significantly increased in Korea (annual percent change 1.7%) but decreased among Jews (annual percent change -2.15%). Age-standardized rate of uterine cancer increased among both Koreans and Israeli Jews (annual percent changes 5.8 and 1.17%, respectively). Incidence of cervical cancer significantly decreased in Korea (annual percent change -3.8%) while remained stable on Israel. Mortality trends paralleled incidence trends with a significant increase in ovarian cancer and uterine cancer mortality in Korea (annual percent changes 1.2 and 4.6%, respectively) and a drop in cervical cancer mortality from 2002 (annual percent change -5.8%). Among Israeli Jews, uterine cancer mortality increased (annual percent change 1.01%), while ovarian cancer mortality decreased (annual percent change -0.58%). Uterine cancer mortality among Arabs declined (annual percent change -0.5%), while cervical cancer mortality remained unchanged. CONCLUSIONS: Gynecologic malignancies show different incidence trends in Korea and Israel. Uterine cancer is rising in both countries and is correlated to changing trends in obesity and dietary habits. Ovarian cancer is rising in Korea but declining among Israeli Jews along with changes in parity, childbearing age, contraceptive use and increasing awareness to BRCA gene carriers and risk reduction salpingo-oophorectomy. Cervical cancer is declining in Korea along with an effective screening program implemented. Mortality trends follow incidence trends in both countries.

Automatic calculation of myocardial external efficiency using a single 11C-acetate PET scan.

BACKGROUND: Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed (MVO2) by the left ventricular mass (LVM). We developed a fully automated method for estimating MEE based on a single 11C-acetate PET scan without ECG-gating. METHODS AND RESULTS: Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO2 was calculated using washout of 11C -acetate activity. FCO and LVM were calculated automatically using dynamic PET and parametric image formation. FCO and LVM were also obtained using cardiac magnetic resonance (CMR) in all subjects. The correlation between MEEPET-CMR and MEEPET was high (r = 0.85, P < 0.001) without significant bias. MEEPET was 23.6 ± 4.2% for controls and was lowered in AVS (17.2 ± 4.3%, P < 0.001) and in MVR (18.0 ± 5.2%, P = 0.004). MEEPET was strongly associated with both NYHA class (P < 0.001) and the magnitude of valvular dysfunction (mean aortic gradient: P < 0.001, regurgitant fraction: P = 0.009). CONCLUSION: A single 11C-acetate PET yields accurate and automated MEE results on different scanners. MEE might provide an unbiased measurement of the phenotypic response to valvular disease.

Whole-genome sequencing analysis of human bocavirus detected in South Korea.

Human bocaviruses (HBoVs) have been detected in human gastrointestinal infections worldwide. In 2005, HBoV was also discovered in infants and children with infections of the lower respiratory tract. Recently, several genotypes of this parvovirus, including HBoV genotype 2 (HBoV2), genotype 3 (HBoV3) and genotype 4 (HBoV4), were discovered and found to be closely related to HBoV. HBoV2 was first detected in stool samples from children in Pakistan, followed by detection in other countries. HBoV3 was detected in Australia and HBoV4 was identified in stool samples from Nigeria, Tunisia and the USA. Recently, HBoV infection has been on the rise throughout the world, particularly in countries neighbouring South Korea; however, there have been very few studies on Korean strains. In this study, we characterised the whole genome and determined the phylogenetic position of CUK-BC20, a new clinical HBoV strain isolated in South Korea. The CUK-BC20 genome of 5184 nucleotides (nt) contains three open-reading frames (ORFs). The genotype of CUK-BC20 is HBoV2, and 98.77% of its nt sequence is identical with those of other HBoVs, namely Rus-Nsc10-N386. Especially, the ORF3 amino acid sequences from positions 212-213 and 454 corresponding to a variable region (VR)1 and VR5, respectively, showed genotype-specific substitutions that distinguished the four HBoV genotypes. As the first whole-genome sequence analysis of HBoV in South Korea, this information will provide a valuable reference for the detection of recombination, tracking of epidemics and development of diagnosis methods for HBoV.

The relationship between clinical characteristics including presence of exposed lesions and health-related quality of life (HRQoL) in patients with psoriasis: analysis from the nationwide epidemiologic study for psoriasis in Korea (EPI-PSODE study).

BACKGROUND: Psychological aspect and quality of life should be considered in treating patients with psoriasis. OBJECTIVE: We sought to ascertain which clinical characteristics including presence of exposed lesions are associated with impairment of health-related quality of life (HRQoL) in patients with psoriasis. METHODS: The EPI-PSODE study was a nationwide, multicenter, cross-sectional study conducted in Korea that included 1260 adult patients with psoriasis. In addition to clinical characteristics including presence of exposed lesions, data were collected using the Psoriatic Arthritis (PsA) Screening and Evaluation (PASE), Dermatology Life Quality Index (DLQI), MOS 36-Item Short-Form Health Survey (SF-36), Work Productivity and Activity Impairment Questionnaire Psoriasis (WPAI: PSO) and Medication Satisfaction Questionnaire (MSQ). RESULTS: Patients with a DLQI score > 5 (n = 990) were younger, had an earlier onset of psoriasis, scored higher on the Psoriasis Area and Severity Index (PASI), had higher body surface area (BSA) and had higher PASE scores than patients with DLQI ≤ 5 (n = 266). The group of patients with exposed lesions (n = 871) were younger and male predominance, earlier onset of psoriasis, longer disease duration, higher PASI/BSA score and a higher proportion with drinking and smoking history each than the group of patients without exposed lesions (n = 389). Presence of exposed lesions negatively influenced DLQI, 36-Item Short-Form Health Survey (SF-36) (mental component), presenteeism, total work productivity impairment and total activity impairment in the WPAI: PSO. In multiple regression model, PASI score was the only variable which was significantly associated with all HRQoL measures. Presence of exposed lesions was a significant factor affecting DLQI and SF-36 (mental). CONCLUSION: The presence of exposed lesions has a negative impact on quality of life, mental health and work productivity. Therefore, effective treatments are particularly needed for psoriasis patients with exposed lesions.

A multicentre, open, investigator-initiated phase IV clinical trial to evaluate the efficacy and safety of ingenol mebutate gel, 0·015% on the face and scalp, and 0·05% on the trunk and extremities, in Korean patients with actinic keratosis (PERFECT).

BACKGROUND: Ingenol mebutate gel is a novel, field-directed topical treatment for actinic keratosis (AK). Most pivotal studies have targeted Western populations. No clinical study has been conducted to investigate its efficacy and safety in Asian populations. OBJECTIVES: To evaluate the efficacy and safety of ingenol mebutate gel for treating AK of face/scalp and trunk/extremities in a large Asian (Korean) population. PATIENTS AND METHODS: In this multicentre, open-label, interventional, parallel-group, prospective phase IV study (PERFECT, trial registration no.: NCT02716714), the eligible patients were allocated into either the face/scalp or the trunk/extremities group, according to their selected treatment area location. After application of ingenol mebutate gel, the participants were followed up for 6 months. The primary efficacy endpoint was complete clearance (CC) of AK lesions in the selected treatment area at day 57. Quality of life was evaluated using Skindex-29. Safety endpoints included local skin responses, scar, pigmentation, pain and adverse events. RESULTS: In total, 78·1% [95% confidence interval (CI) 66·86-86·92%] of subjects had CC at day 57, with 76·6% (95% CI 64·31-86·25%) in the face/scalp group and 88·9% (95% CI 51·75-99·72%) in the trunk/extremities group. Among them, CC was sustained in 88·9% (48 of 54, 95% CI 77·37-95·81%) at month 6. The local skin responses significantly increased 1 day after the treatment compared with baseline, and decreased afterwards. Among the total subjects, 7·8% (6 of 77) had hyperpigmentation on the application area. Scars were not reported. CONCLUSIONS: Ingenol mebutate is effective for the treatment of AK in Asians, with tolerable safety profiles.

Microscale Liquid Transport in Polycrystalline Inverse Opals across Grain Boundaries.

Delivering liquid through the void spaces in porous metals is a daunting challenge for a variety of emerging interface technologies ranging from battery electrodes to evaporation surfaces. Hydraulic transport characteristics of well-ordered porous media are governed by the pore distribution, porosity, and morphology. Much like energy transport in polycrystalline solids, hydraulic transport in semi-ordered porous media is predominantly limited by defects and grain boundaries. Here, we report the wicking performances for porous copper inverse opals having pore diameters from 300 to 1000 nm by measuring the capillary-driven liquid rise. The capillary performance parameter within single crystal domain (K ij /R eff = 10-3 to 10-2 µm) is an order of magnitude greater than the collective polycrystal (K eff /R eff = ~10-5 to 10-3 µm) due to the hydraulic resistances (i.e. grain boundaries between individual grains). Inspired by the heterogeneity found in biological systems, we report that the capillary performance parameter of gradient porous copper (K eff /R eff = ~10-3 µm), comparable to that of single crystals, overcomes hydraulic resistances through providing additional hydraulic routes in three dimensions. The understanding of microscopic liquid transport physics through porous crystals and across grain boundaries will help to pave the way for the spatial design of next-generation heterogeneous porous media.

A novel flexible drill device enabling arthroscopic transosseous repair of Bankart lesions.

We have developed a flexible drill device that makes arthroscopic transosseous repair possible, and report preliminary results. Twelve patients with post-traumatic anterior inferior glenohumeral instability were selected. SURGICAL TECHNIQUE: the flexible drill device is inserted into the shoulder joint through the posterior portal and the guide pipe unit is placed 5mm posterior to the margin of the anterior glenoid rim. The flexible drill is driven through the glenoid with the power drill, creating a hole in the glenoid. A non-absorbable suture is passed through the hole and a sliding knot tying is performed over the capsule and labrum after completing stitches with the suture hook loaded. The same procedures are repeated in the 2, 3 and 4 o'clock positions of the glenoid. There was no recurrence of dislocation at the mean follow-up period of 52.3 months. The mean Rowe score was 89.5.

The IGF system in patients with type 2 diabetes: associations with markers of cardiovascular target organ damage.

OBJECTIVE: Perturbations in the insulin-like growth factor (IGF) system may contribute to the accelerated cardiovascular disease (CVD) that occurs in patients with type 2 diabetes (T2D). However, it remains unknown whether the IGF system is also involved in the development of early, subclinical CVD. We characterised the IGF system in T2D patients and matched controls and examined the associations with markers of subclinical target organ damage. METHODS: The study included 99 patients with recently diagnosed T2D and 99 age- and sex-matched controls. IGF-1 and IGFBP-1 to -4 were measured by immunoassays, as were pregnancy-associated plasma protein-A (PAPP-A) and the PAPP-A-generated N-terminal (NT) and C-terminal (CT) IGFBP-4 fragments, which are novel CVD risk markers. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV). Cerebral white matter lesions (WMLs) and carotid artery remodelling were determined by MRI. RESULTS: After multivariate adjustments, patients with T2D had lower concentrations of IGFBP-2, IGFBP-4, NT- and CT-IGFBP-4, when compared with controls. IGFBP-2 was inversely correlated to PWV in all subjects in multivariate analysis (P < 0.05), and IGFBP-3 was inversely associated with severity of WMLs (P < 0.05). The NT-IGFBP-4 fragment was associated with the degree of carotid artery remodelling among all subjects (regression coefficient (95% CI): 2.95 (0.70, 5.16), P = 0.011). Levels of NT- and CT-IGFBP-4 were reduced in T2D patients receiving metformin compared to those in controls and patients not receiving metformin. CONCLUSIONS: Even in recently diagnosed and well-controlled T2D patients, IGF protein levels are altered and associated with CVD risk factors.

FOXO3 is essential for CD44 expression in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer and the 5-year survival rate is only 5%. Several studies have suggested that cancer stem cells (CSCs) are thought to be involved in recurrence and metastasis and so it is essential to establish an approach targeting CSCs. Here we have demonstrated that cyclic guanosine monophosphate (cGMP) suppressed CD44 expression and the properties of CSCs in PDAC. Microarray analysis suggested that cGMP inhibited Forkhead box O3 (FOXO3), which is known as a tumor suppressor. Surprisingly, our data demonstrated that FOXO3 is essential for CD44 expression and the properties of CSCs. Our data also indicated that patients with high FOXO3 activation signatures had poor prognoses. This evidence suggested that cGMP induction and FOXO3 inhibition could be ideal candidates for pancreatic CSC.

Short-term modulation of the ventilatory response to exercise is preserved in obstructive sleep apnea.

BACKGROUND: The ventilatory response to exercise can be transiently adjusted in response to environmentally (e.g., breathing apparatus) or physiologically altered conditions (e.g., respiratory disease), maintaining constant relative arterial PCO2 regulation from rest to exercise (Mitchell and Babb, 2006); this augmentation is called short-term modulation (STM) of the exercise ventilatory response. Obesity and/or obstructive sleep apnea could affect the exercise ventilatory response and the capacity for STM due to chronically increased mechanical and/or ventilatory loads on the respiratory system, and/or recurrent (chronic) intermittent hypoxia experienced during sleep. We hypothesized that: (1) the exercise ventilatory response is augmented in obese OSA patients compared with obese non-OSA adults, and (2) the capacity for STM with added dead space is diminished in obese OSA patients. METHODS: Nine obese adults with OSA (age: 39±6 yr, BMI: 40±5kg/m2, AHI: 25±24 events/h [range 6-73], mean±SD) and 8 obese adults without OSA (age: 38±10 yr, BMI: 37±6kg/m2, AHI: 1±2) completed three, 20-min bouts of constant-load submaximal cycling exercise (8min rest, 6min at 10 and 30W) with or without added external dead space (200 or 400mL; 20min rest between bouts). Steady-state measurements were made of ventilation (V˙E), oxygen consumption V˙O2), carbon dioxide production (V˙CO2), and end-tidal PCO2 (PETCO2). The exercise ventilatory response was defined as the slope of the V˙E-V˙CO2 relationship (ΔV˙E/ΔV˙CO2). RESULTS: In control (i.e. no added dead space), the exercise ventilatory response was not significantly different between non-OSA and OSA groups (ΔV˙E/ΔV˙CO2 slope: 30.5±4.2 vs 30.5±3.8, p>0.05); PETCO2 regulation from rest to exercise did not differ between groups (p>0.05). In trials with added external dead space, ΔV˙E/ΔV˙CO2 increased with increased dead space (p < 0.05) and the PETCO2 change from rest to exercise remained small (<2mmHg) in both groups, demonstrating STM. There were no significant differences between groups. CONCLUSIONS: Contrary to our hypotheses: (1) the exercise ventilatory response is not increased in obese OSA patients compared with obese non-OSA adults, and (2) the capacity for STM with added dead space is preserved in obese OSA and non-OSA adults.