MRI Features May Predict Molecular Features of Glioblastoma in Isocitrate Dehydrogenase Wild-Type Lower-Grade Gliomas.

BACKGROUND AND PURPOSE: Isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas (histologic grades II and III) with epidermal growth factor receptor (EGFR) amplification or telomerase reverse transcriptase (TERT) promoter mutation are reported to behave similar to glioblastoma. We aimed to evaluate whether MR imaging features could identify a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma. MATERIALS AND METHODS: In this multi-institutional retrospective study, pathologically confirmed IDH wild-type lower-grade gliomas from 2 tertiary institutions and The Cancer Genome Atlas constituted the training set (institution 1 and The Cancer Genome Atlas, 64 patients) and the independent test set (institution 2, 57 patients). Preoperative MRIs were analyzed using the Visually AcceSAble Rembrandt Images and radiomics. The molecular glioblastoma status was determined on the basis of the presence of EGFR amplification and TERT promoter mutation. Molecular glioblastoma was present in 73.4% and 56.1% in the training and test sets, respectively. Models using clinical, Visually AcceSAble Rembrandt Images, and radiomic features were built to predict the molecular glioblastoma status in the training set; then they were validated in the test set. RESULTS: In the test set, a model using both Visually AcceSAble Rembrandt Images and radiomic features showed superior predictive performance (area under the curve = 0.854) than that with only clinical features or Visually AcceSAble Rembrandt Images (areas under the curve = 0.514 and 0.648, respectively; P < . 001, both). When both Visually AcceSAble Rembrandt Images and radiomics were added to clinical features, the predictive performance significantly increased (areas under the curve = 0.514 versus 0.863, P < .001). CONCLUSIONS: MR imaging features integrated with machine learning classifiers may predict a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma.

Suspected Frequent Relapsing IgG4-related Lung Disease in Kidney Transplant Patient: A Case Report.

Besides the initial description of IgG4-related pancreatic disease, other sites are now commonly involved. However, occurrence of IgG4-related disease is rare in organ transplanted patients. A 57-year-old man who received a kidney transplantation presented with recurrent dyspnea on exertion. A computed tomography scan of the chest revealed bilateral interlobular septal thickening and multiple tubular and branching small nodular lesions in the right upper lobe, and mass-like consolidation of the left middle lobe. Despite no elevation of serum IgG4 level, a percutaneous core needle biopsy on consolidative mass showed interstitial fibrosis and infiltration of IgG4-positive plasma cells to be more than > 20 per high power field. After treatment with glucocorticoids and rituximab, the consolidative mass of the left middle lobe disappeared.

Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas.

BACKGROUND AND PURPOSE: Prediction of the isocitrate dehydrogenase 1 (IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. MATERIALS AND METHODS: Ninety-three patients with World Health Organization grade II gliomas with known IDH1-mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1-mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1-mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1-mutant subgroups were evaluated using the least absolute shrinkage and selection operator. RESULTS: Various histogram and texture parameters differed significantly according to IDH1-mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1-mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. CONCLUSIONS: Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas.

Prediction of IDH1-Mutation and 1p/19q-Codeletion Status Using Preoperative MR Imaging Phenotypes in Lower Grade Gliomas.

BACKGROUND AND PURPOSE: WHO grade II gliomas are divided into three classes: isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant and no 1p/19q codeletion, and IDH-mutant and 1p/19q-codeleted. Different molecular subtypes have been reported to have prognostic differences and different chemosensitivity. Our aim was to evaluate the predictive value of imaging phenotypes assessed with the Visually AcceSAble Rembrandt Images lexicon for molecular classification of lower grade gliomas. MATERIALS AND METHODS: MR imaging scans of 175 patients with lower grade gliomas with known IDH1 mutation and 1p/19q-codeletion status were included (78 grade II and 97 grade III) in the discovery set. MR imaging features were reviewed by using Visually AcceSAble Rembrandt Images (VASARI); their associations with molecular markers were assessed. The predictive power of imaging features for IDH1-wild type tumors was evaluated using the Least Absolute Shrinkage and Selection Operator. We tested the model in a validation set (40 subjects). RESULTS: Various imaging features were significantly different according to IDH1 mutation. Nonlobar location, larger proportion of enhancing tumors, multifocal/multicentric distribution, and poor definition of nonenhancing margins were independent predictors of an IDH1 wild type according to the Least Absolute Shrinkage and Selection Operator. The areas under the curve for the prediction model were 0.859 and 0.778 in the discovery and validation sets, respectively. The IDH1-mutant, 1p/19q-codeleted group frequently had mixed/restricted diffusion characteristics and showed more pial invasion compared with the IDH1-mutant, no codeletion group. CONCLUSIONS: Preoperative MR imaging phenotypes are different according to the molecular markers of lower grade gliomas, and they may be helpful in predicting the IDH1-mutation status.

The Initial Area Under the Curve Derived from Dynamic Contrast-Enhanced MRI Improves Prognosis Prediction in Glioblastoma with Unmethylated MGMT Promoter.

BACKGROUND AND PURPOSE: Although perfusion and permeability MR parameters have known to have prognostic value, they have reproducibility issues. Our aim was to evaluate whether the initial area under the time-to-signal intensity curve (IAUC) derived from dynamic contrast-enhanced MR imaging can improve prognosis prediction in patients with glioblastoma with known MGMT status. MATERIALS AND METHODS: We retrospectively examined 88 patients with glioblastoma who underwent preoperative dynamic contrast-enhanced MR imaging. The means of IAUC values at 30 and 60 seconds (IAUC30mean and IAUC60mean) were extracted from enhancing tumors. The prognostic values of IAUC parameters for overall survival and progression-free survival were assessed with log-rank tests, according to the MGMT status. Multivariate overall survival and progression-free survival models before and after adding the IAUC parameters as covariates were explored by net reclassification improvement after receiver operating characteristic analysis for 1.5-year overall survival and 1-year progression-free survival and by random survival forest. RESULTS: High IAUC parameters were associated with worse overall survival and progression-free survival in the unmethylated MGMT group, but not in the methylated group. In the unmethylated MGMT group, 1.5-year overall survival and 1-year progression-free survival prediction improved significantly after adding IAUC parameters (overall survival area under the receiver operating characteristic curve, 0.86; progression-free survival area under the receiver operating characteristic curve, 0.74-0.76) to the model with other prognostic factors (overall survival area under the receiver operating characteristic curve, 0.81; progression-free survival area under the receiver operating characteristic curve, 0.69; P < .05 for all) except in the case of IAUC60mean for 1-year progression-free survival prediction (P = .059). Random survival forest models indicated that the IAUC parameters were the second or most important predictors in the unmethylated MGMT group, except in the case of the IAUC60mean for progression-free survival. CONCLUSIONS: IAUC can be a useful prognostic imaging biomarker in patients with glioblastoma with known MGMT status, improving prediction of glioblastoma prognosis with the unmethylated MGMT promoter status.

Stereotactic Ablative Body Radiotherapy for the Treatment of Spinal Oligometastases.

AIMS: To report multicentre outcomes of patients with spinal oligometastases treated with stereotactic ablative body radiotherapy (SABR). The primary objective was to estimate the widespread failure-free survival (WFFS) at 2 years - defined as freedom from metastases not amenable to local salvage therapy and death. MATERIALS AND METHODS: Patients with one to three metastases treated with spinal SABR between January 2010 and July 2014 at four academic institutions were included in this retrospective review. The median dose/fractionation was 24 Gy (range 16-52.5 Gy) in two fractions (range one to three) and the median biologically effective dose (α/ß=10) was 52.5 Gy (range 40-144.4 Gy). The WFFS, overall survival, freedom from local progression and toxicity rates were described using Kaplan-Meier statistics. RESULTS: In total, 60 patients with 72 spinal metastases were analysed. The median follow-up was 21 months. Patients had a median age of 66 years, Eastern Cooperative Oncology Group performance 0-1 in 97% and metachronous oligometastases in 85%. The 1 and 2 year WFFS rates were 67% (95% confidence interval 55-80) and 59% (95% confidence interval 47-75), respectively. The 1 and 2 year overall survival rates were 90% (95% confidence interval 83-98) and 76% (95% confidence interval 64-91), respectively. The 1 and 2 year freedom from local progression were 92% (95% confidence interval 85-99) and 86% (95% confidence interval 75-99), respectively. There were four cases (6.7%) of vertebral compression fracture and no cases of radiation myelopathy. CONCLUSION: Despite the use of relatively low biological doses respecting spinal cord constraints, SABR results in excellent 2 year local control rates with low morbidity. Through careful selection of patients with oligometastases, most patients are alive and free from widespread metastases at 2 years. This cohort warrants further investigation in clinical trials of SABR.

Can Kidney Transplantation Improve Arterial Stiffness in End-Stage Renal Patients?

BACKGROUND: Arterial stiffness is associated with cardiovascular disease in end-stage renal disease (ESRD) and after kidney transplantation. We examined how kidney transplantation influences brachial-ankle pulse-wave velocity (baPWV) in ESRD patients. METHODS: The prospective observational study enrolled 67 patients who underwent successful kidney transplantation. Serial baPWV and biochemical parameters were measured before surgery and 6 months, 1 year, and 2 years after transplantation. RESULTS: baPWV prior to kidney transplantation and 6 months, 1 year, and 2 years after transplantation was 1533 ± 261 cm/s, 1417 ± 254 cm/s, 1414 ± 285 cm/s, and 1384 ± 233 cm/s, respectively. baPWV and biochemical parameters including alkaline phosphatase, intact parathyroid hormone, and 1,25 hydroxyvitamin D improved significantly at 6 months (P < .05), but there were no changes between 6 months and 2 years after transplantation. The majority of patients (73%) improved, whereas the remainder showed progression of baPWV after transplantation. Sixty-three percent of all kidney transplantation patients displayed higher baPWV than the healthy control subjects at 6 months after transplant. CONCLUSIONS: In the majority of patients, baPWV improved soon after kidney transplantation but overall remained higher than in the generally healthy population.

Stereotactic Ablative Body Radiotherapy for Primary Renal Cell Carcinoma in Non-surgical Candidates: Initial Clinical Experience.

AIMS: To report the outcomes of a cohort of patients with renal cell carcinoma (RCC) treated using stereotactic ablative body radiotherapy (SABR). MATERIALS AND METHODS: Patients treated with SABR for primary RCC from 1 January 2012 to 1 April 2015 were retrospectively reviewed. Patients were non-surgical candidates treated with doses ranging from 30 to 40 Gy in five fractions. The tumour sizes and serum creatinine were compared between the pre-treatment assessment and subsequent follow-up assessments. The worst acute and late grade ≥2 toxicity rates were recorded. RESULTS: In total, 16 patients were included in this study. The median follow-up was 19 months (range 7-30). Eleven patients had stable disease, four had partial responses and none had progressive disease, indicating a local control rate of 100%. One patient had grade 2 acute nausea and two patients had grade 4 renal toxicities (two patients with pre-existing stage 4-5 chronic kidney disease required dialysis following SABR). Four of four patients with pre-SABR symptoms (pain and/or haematuria) had symptomatic relief after SABR. CONCLUSION: SABR for RCC is safe, the toxicities are minimal, and the local control is excellent at early follow-up. This technique should be further evaluated in prospective clinical trials.

The Added Prognostic Value of Preoperative Dynamic Contrast-Enhanced MRI Histogram Analysis in Patients with Glioblastoma: Analysis of Overall and Progression-Free Survival.

BACKGROUND AND PURPOSE: The prognostic value of dynamic contrast-enhanced MR imaging in patients with glioblastoma is controversial. We investigated the added prognostic value of dynamic contrast-enhanced MR imaging to clinical parameters and molecular biomarkers in patients with glioblastoma by using histogram analysis. MATERIALS AND METHODS: This retrospective study consisted of 61 patients who underwent preoperative dynamic contrast-enhanced MR imaging for glioblastoma. The histogram parameters of dynamic contrast-enhanced MR imaging, including volume transfer constant, extravascular extracellular volume fraction, and plasma volume fraction, were calculated from entire enhancing tumors. Univariate analyses for overall survival and progression-free survival were performed with preoperative clinical and dynamic contrast-enhanced MR imaging parameters and postoperative molecular biomarkers. Multivariate Cox regression was performed to build pre- and postoperative models for overall survival and progression-free survival. The performance of models was assessed by calculating the Harrell concordance index. RESULTS: In univariate analysis, patients with higher volume transfer constant and extravascular extracellular volume fraction values showed worse overall survival and progression-free survival, whereas plasma volume fraction showed no significant correlation. In multivariate analyses for overall survival, the fifth percentile value of volume transfer constant and kurtosis of extravascular extracellular volume fraction were independently prognostic in the preoperative model, and kurtosis of volume transfer constant and extravascular extracellular volume fraction were independently prognostic in the postoperative model. For progression-free survival, independent prognostic factors were minimum and fifth percentile values of volume transfer constant and kurtosis of extravascular extracellular volume fraction in the preoperative model and kurtosis of extravascular extracellular volume fraction in the postoperative model. The performance of preoperative models for progression-free survival was significantly improved when minimum or fifth percentile values of volume transfer constant and kurtosis of extravascular extracellular volume fraction were added. CONCLUSIONS: Higher volume transfer constant and extravascular extracellular volume fraction values are associated with worse prognosis, and dynamic contrast-enhanced MR imaging may have added prognostic value in combination with preoperative clinical parameters, especially in predicting progression-free survival.

UV Light and Gas Sensing Properties of Hybrid Sensor Based on Indium-Tin-Oxide Nanocrystals.

We proposed a hybrid sensor which is able to detect both UV light and gas species. The sensor was fabricated by screen printing using indium-tin-oxide (ITO) nanocrystals. To improve the UV sensitivity, high temperature annealing (600 degrees C) under an external pressure (0.2 MPa) was applied. We could observe room temperature operation of the sensor under the simultaneous stimulation of UV light and CH4 gas. This is indicating that an improved fire warning is possible by using the proposed hybrid sensor.

Pilot study on interfractional and intrafractional movements using surface infrared markers and EPID for patients with rectal cancer treated in the prone position.

OBJECTIVE: To evaluate interfractional and intrafractional movement of patients with rectal cancer during radiotherapy with electronic portal imaging device (EPID) and surface infrared (IR) markers. METHODS: 20 patients undergoing radiotherapy for rectal cancer with body mass index ranging from 18.5 to 30 were enrolled. Patients were placed in the prone position on a couch with a leg pillow. Three IR markers were put on the surface of each patient and traced by two stereo cameras during radiotherapy on a twice-weekly basis. Interfractional isocentre movement was obtained with EPID images on a weekly basis. Movement of the IR markers was analysed in correlation with the isocentre movement obtained from the EPID images. RESULTS: The maximum right-to-left (R-L) movement of the laterally located markers in the horizontal isocentre plane was correlated with isocentre translocation with statistical significance (p = 0.018 and 0.015, respectively). Movement of the surface markers was cyclical. For centrally located markers, the 95% confidence intervals for the average amplitude in the R-L, cranial-to-caudal (C-C) and anterior-to-posterior (A-P) directions were 0.86, 2.25 and 3.48 mm, respectively. In 10 patients, intrafractional movement exceeding 5 mm in at least one direction was observed. Time-dependent systematic movement of surface markers during treatment, which consisted of continuous movement towards the cranial direction and a sail back motion in the A-P direction, was also observed. CONCLUSION: Intrafractional movement of surface markers has both cyclic components and time-dependent systematic components. Marker deviations exceeding 5 mm were mainly seen in the A-P direction. Pre- or post-treatment EPID images may not provide adequate information regarding intrafractional movement because of systematic movement in the A-P direction during radiotherapy. ADVANCES IN KNOWLEDGE: This work uncovered a sail back motion of patients in the A-P direction during radiotherapy. Pre- or post-treatment EPID images may not provide accurate positioning of patients in the A-P direction because of this time-dependent intrafractional motion.

Low pulmonary function is related with a high risk of sarcopenia in community-dwelling older adults: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2011.

UNLABELLED: Sarcopenia is the age-related reduction of skeletal muscle mass in older individuals. Respiratory muscle strength may be related to skeletal muscle mass and, thus, the present study attempted to estimate the risk of sarcopenia relative to decreased pulmonary function. The present findings demonstrated that low pulmonary function was associated with low muscle mass in community-dwelling older adults. INTRODUCTION: Lean body mass is related to pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, the relationship between muscle mass and pulmonary function in healthy older adults has yet to be clarified. Thus, the present study investigated the association of pulmonary function with muscle mass in an older community-dwelling Korean population. METHODS: This study included 463 disease-free subjects over 65 years of age who underwent anthropometric measurements, laboratory tests, spirometry, and the estimation of appendicular skeletal muscle (ASM) mass in the 2008-2011 Korea National Health and Nutrition Examination Survey (KNHANES). Low muscle mass was defined as the value of ASM divided by height squared (ASM/height(2)) that was less than two standard deviations (SD) below the sex-specific mean of the young reference group. RESULTS: Forced expiratory volume in 1 s (FEV1[L]) and forced vital capacity (FVC[L]) were positively correlated with ASM/height(2) in males (p < 0.001 and p = 0.001, respectively) but not in females (p = 0.360 and p = 0.779, respectively). A univariate logistic regression analysis revealed that males with low FEV1 or FVC were more likely to have low muscle mass (odds ratio [OR] = 3.11, 95% confidence interval [CI] 1.62-5.99 for FEV1; OR = 1.99, 95% CI 1.13-3.53 for FVC); similar results were found for females, but the significance was lower (OR = 11.37, 95% CI 0.97-132.91 for FEV1; OR = 7.31, 95% CI 1.25-42.74 for FVC). After adjusting for age, smoking, and moderate physical activity, a low FEV1 value was associated with low muscle mass in both males (OR = 2.90, 95% CI 1.50-5.63) and females (OR = 9.15, 95% CI 1.53-54.77). CONCLUSIONS: Using nationally representative data from the 2008-2011 KNHANES, low pulmonary function was found to be associated with low muscle mass in community-dwelling older Korean adults.

Determinants of Perceived Physical Environment Barriers among Community-Dwelling Elderly in Taiwan.

OBJECTIVES: To test the hypothesis that mobility, activities of daily living, and the interaction between them can play a key role in determining perceived physical environment barriers among community-dwelling elderly. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: One hundred and ninety-seven community-dwelling elderly with more than 7 points on the Short Portable Mental State Questionnaire and less than 7 points on the Geriatric Depression Scale (15 items). INTERVENTION: None. MEASUREMENTS: Time Get-up and Go test (TUG), the subscales of basic activity of daily living (BADL)/instrumental activities of daily living (IADL) of the Hierarchy of Care Required (HCR), and the physical/structural subscale of the Craig Hospital Inventory of Environmental Factors in Community-dwelling Elderly in Taiwan were used to measure mobility, activities of daily living and perceived physical environment barriers, respectively. Hierarchical linear regression analyses were used to test the study hypothesis. RESULTS: Significant and positive relations were found to exist between perceived physical environment barriers and (1) the TUG time (ß=.300, p<.05), and (2) the IADL score for the HCR (ß=.322, p<.05), respectively. A significant and negative relation existed between perceived physical environment barriers and the interaction term (the TUG time and the IADL score for the HCR) (ß=-.211, p<.05). CONCLUSION: Mobility, IADL and the interaction between them are found to be significant determinants of perceived physical environment barriers in the community-dwelling elderly under consideration. Strategies targeting the enhancement of mobility among community-dwelling elderly are suggested to lead to improvements in the degree to which physical environment barriers are perceived. This beneficial effect could be greater in the case of elderly individuals with better IADL function.

Bicycle and motorcycle wheel spoke injury in children.

PURPOSE: To review bicycle and motorcycle wheel spoke injuries around the foot and ankle in 24 children. METHODS: Medical records of 12 boys and 12 girls aged 2 to 11 (mean, 5.3) years who presented with an isolated posterior heel injury caused by wheel spokes of a motorcycle (n=9) or bicycle (n=15) were reviewed. RESULTS: All 9 motorcycle injury patients and 8 of 15 bicycle injury patients had lacerations. The remaining 7 bicycle injury patients had abrasions and developed skin necrosis and ulcerations, with 5 requiring debridement. The most common site of laceration was the posterolateral heel; 7 of these patients had deep soft tissue injury, and in 5 the Achilles tendon was partially cut or completely severed. The mean number of operations was 2.2 in the motorcycle group and 1.3 in the bicycle group. Seven patients with severe skin loss required skin grafting or flap surgery for wound coverage. The mean time from injury to definitive treatment was 8.2 days. The mean length of hospital stay was 18.4 days in the motorcycle group and 8.1 days in the bicycle group. Delayed definitive treatment was associated with more operations (r=0.499, p=0.013) and longer hospital stay (r=0.567, p=0.004). CONCLUSION: Wheel spoke injuries may result in severe soft tissue damage and bony trauma. Poor prognostic factors included high-energy injury, contamination and infection, and delayed treatment.

Role of second-look ultrasound examinations for MR-detected lesions in patients with breast cancer.

PURPOSE: To assess the clinical value of second-look ultrasound (US) examination for the evaluation of additional enhancing lesions detected on magnetic resonance (MR) imaging. MATERIALS AND METHODS: Between May 2008 and February 2011, 794 consecutive patients with histologically confirmed breast cancer underwent breast MR imaging. We included 101 patients with 132 additional enhancing breast lesions detected on MR imaging who underwent second-look US.  The imaging features and lesion category according to the Breast Imaging and Reporting and Data System (BI-RADS) were assessed with MR and US imaging, respectively. RESULTS: According to the BI-RADS system, 67 lesions (50.8 %) were classified as category 0, 33 lesions (25.0 %) as category 3, and 32 lesions (24.2 %) as category 4. Of the 67 indeterminate lesions on MR imaging, 34 (50.7 %) were demonstrated on second-look US. 11 of these 34 lesions showed suspicious sonographic features, including 1 lesion that showed malignancy (9.1 %, 1/11). Most of the suspicious lesions on MR imaging (26 of 32 BI-RADS category 4 lesions, 81.3 %) were demonstrated on second-look US, and 17 were malignant (65.4 %, 17/26). Of the 6 BI-RADS category 4 lesions without sonographic correlation, 1 was malignant (16.7 %, 1/6). CONCLUSION: Second-look US examination was useful for evaluating MR-detected lesions in patients with breast cancer.

Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells.

Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α(-/-)) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP(+)GSCs). We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP(+)GSCs. The hypoxic-AP(+)GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP(+)GSCs; and, the inhibition of IGF-IR by RNA interference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2α dramatically suppressed Oct-4 and IGF-IR protein levels in AP(+)GSC cells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP(+)GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.

Gender flip-flop association between genetic variations of NEDD4L and metabolic syndrome in the Kazakh general population.

Genetic variation is thought to contribute to etiology of metabolic syndrome (MS). Neural precursor cell expressed developmentally downregulated 4-like gene (NEDD4L) is a candidate gene for MS. This study investigated the relationship between variations of NEDD4L and MS in the Kazakh, which is an ideal population to study the genetic mechanisms of complex diseases such as MS. We screened the promoter and exons of NEDD4L in 48 Kazakh individuals with MS to identify representative variations. By genotyping the representative variations [271420T>C (rs2288774), 271454A>G (rs2288775), and 296921-296923delTTG] in the Kazakh general population, we conducted a case-control study. In female subjects, the distribution of genotypes and alleles of rs2288775 and 296921-296923delTTG differed significantly between the MS pacients and controls. In male subjects, the genotype distributions of 296921-296923delTTG were significantly different between the MS pacients and controls in the dominant model (P = 0.047). After adjustment for age, smoking, and drinking, multivariate logistic regression analysis showed that rs2288775 was significantly associated with MS [for the A/A genotype, odds ratio (OR) = 3.296, P = 0.011] in female subjects. For 296921-296923delTTG, the I/D+D/D genotype was the high-risk genotype for MS in female subjects (OR = 2.791, P = 0.035) and was a protective factor for MS in male subjects (OR = 0.580, P = 0.045). The 296921-296923delTTG variation of NEDD4L is a gender flip-flop associated with MS in Kazakh individuals. The A allele of rs2288775 may be an independent risk factor for MS in Kazakh women. The results suggest that the genetic variations of NEDD4L might be involved in the pathogenesis of MS.

[Patient with type II membranoproliferative glomerulonephritis: intravitreal bevacizumab therapy for choroidal neovascularization]. / Patient mit membranoproliferativer Glomerulonephritis Typ II: Intravitreale Bevacizumab-Therapie der choroidalen Neovaskularisation.

Membranoproliferative glomerulonephritis (MPGN) type II is a rare disease characterized by electron dense deposits on the basement membrane in the glomeruli of the kidneys and also in Bruch's membrane of the eye. Although most patients have asymptomatic drusen of the retina choroidal neovascularization can sometimes develop, which can permanently affect visual acuity. We report an unusual case of choroidal neovascularization in a patient with MPGN type II that was successfully treated with a single intravitreal injection of bevacizumab. The 6 months follow-up showed no recurrence of choroidal neovascularization.

Factors associated with early onset post-traumatic syringomyelia.

STUDY DESIGN: Retrospective study. OBJECTIVES: To identify factors associated with the development of early onset post-traumatic syringomyelia within 5 years of spinal cord injury. SETTING: Department of Rehabilitation Medicine, Pusan National University School of Medicine, Korea. METHODS: We retrospectively examined the records of 502 patients with traumatic cervical or thoracic spinal cord injury who underwent follow-up magnetic resonance imaging (MRI) examinations more than once a year for at least 5 years. Patients were assessed in terms of the neurological level of injury, the severity of initial spinal cord injury, the use of surgery and the extent of spinal canal involvement. The latter was evaluated by calculating the shortest antero-posterior diameter of the injured vertebral canal and the spinal reserve capacity as shown on MRI at the time of trauma onset and at the time of diagnosis of syringomyelia. RESULTS: Syringomyelia developed within 5 years in 37 (7.3%) of the 502 patients. The mean age of these 37 patients was 44.6 years (range, 17-67 years) and the mean interval from spinal cord injury to onset of syringomyelia was 38.8 months (range, 2-54 months). The development of post-traumatic syringomyelia within 5 years was not significantly related to the severity or level of injury, the use of spinal surgery or the extent of spinal canal encroachment (P≥0.05 for each comparison). CONCLUSION: Early onset syringomyelia occurring within 5 years after spinal cord injury was not associated with neurological injury level, severity of injury, the use of spinal surgery or canal encroachment.

An immunohistochemical study of the pancreatic endocrine cells of the Korean golden frog, Rana plancyi chosenica.

The regional distribution and quantitative frequency of pancreatic endocrine cells were demonstrated in the Korean golden frog (Rana plancyi chosenica Okada), which is known as a Korean endemic species, for the first time, by immunohistochemical methods using specific mammalian antisera to insulin, glucagon, somatostatin and human pancreatic polypeptide (PP). In the pancreas of the Korean golden frog, all four endocrine cell types were demonstrated. Insulin- and glucagon-positive cells were located in the pancreas as single cells or islet-like clusters with frequencies of 85.90±18.28 and 54.30±8.77/1,000/1,000 cells, respectively. Somatostatin-containing cells were also dispersed in the pancreas as single cells or clusters but in the case of clusters, they are exclusively situated in the marginal regions of insulin- or glucagon-positive cell clusters. Cells stained for somatostatin cell frequency was 15.50±3.10/1000 cells. PP-containing cells were also distributed as single cells or clusters with frequency of 53.40±11.96/1,000 cells. Clusters consisted of PP-positive cells are distributed as a core type and a marginally distributed type. Overall, there were 40.84±3.81% insulin-, 26.02±1.71% glucagon-, 7.63±2.09% somatostatin- and 25.51±3.26% PP-IR cells.