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2.  New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy 
Journal of Biomedical Research  2016;30(5):393-410.
Abstract
Endocrine therapy using estrogen receptor-α (ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O6-methylguanine DNA methyltransferase (MGMT), a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines (MCF-7, T47D) and ER- negative cell lines (MDAMB-468, MDAMB-231), and established inhibitors of ER-α and MGMT, namely, ICI-182,780 (Faslodex) and O6-benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements (EREs) and two antioxidant-responsive elements (AREs). MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 (nuclear factor-erythroid 2-related factor-2) increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this drug-resistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-α and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-α proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents, namely, temozolomide and BCNU by 3 to 4-fold in ER-α positive cells, but not in ER–negative cells. We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation. The findings offer a clear rationale for combining alkylating agents with endocrine therapy.
doi:10.7555/JBR.30.20160040
PMCID: PMC5044712  PMID: 27845303
estrogen signaling; MGMT DNA repair; ubiquitin-proteasome pathway; breast cancer; anti-estrogens
3.  Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development 
Journal of neurochemistry  2015;133(5):730-738.
The development of drugs to inhibit glioblastoma (GBM) growth requires reliable preclinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2 and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four TCGA subtypes: 8 classical, 8 mesenchymal, and 4 proneural; none neural. Amplification of EGFR gene was observed in 9 out of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n=5) and low (n=15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent preclinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR.
doi:10.1111/jnc.13032
PMCID: PMC4514443  PMID: 25598002
Glioblastoma; Xenografts; RPPA; EGFR; signaling
4.  Apelin Levels in Patients with Coronary Artery Ectasia 
Korean Circulation Journal  2016;46(3):431.
doi:10.4070/kcj.2016.46.3.431
PMCID: PMC4891612  PMID: 27275184
5.  History of chickenpox in glioma risk: a report from the glioma international case–control study (GICC) 
Cancer Medicine  2016;5(6):1352-1358.
Abstract
Varicella zoster virus (VZV) is a neurotropic α‐herpesvirus that causes chickenpox and establishes life‐long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case‐Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two‐stage random‐effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65–0.96). Furthermore, the protective effect of chickenpox was stronger for high‐grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta‐analyses of the literature and investigations of the potential biological mechanism, are warranted.
doi:10.1002/cam4.682
PMCID: PMC4924393  PMID: 26972449
Brain tumor; chickenpox; glioma; shingles
6.  Red Cell Distribution Width and Coronary Artery Calcification 
Korean Circulation Journal  2016;46(2):270-272.
doi:10.4070/kcj.2016.46.2.270
PMCID: PMC4805575  PMID: 27014361
7.  Assessment of expressions of Bcl-XL, b-FGF, Bmp-2, Caspase-3, PDGFR-α, Smad1 and TGF-β1 genes in a rat model of lung ischemia/reperfusion 
Objective(s):
Ischemia is described as organs and tissues are destitute of oxygen due to decreased arterial or venous blood flow. Many mechanisms play role in cell death happened as a consequence of a new blood flow is needed for both cell regeneration and to clean toxic metabolites during ischemia and later. Lung damage induced by ischemia/reperfusion (I/R) is a frequent problem in lung transplantation. Apoptosis (programmed cell death) is known as cell suicide, and plays a key role in embryonic developmental and in maintain adult tissue’s life.
Materials and Methods:
It is investigated expressions of Smad1, Bmp-2, Bcl-XL, b-FGF, Caspase-3, TGF-β1, PDGFR-α genes for molecular changes in lung tissues, after I/R is formed, in this study. For this, we included 40 Wistar albino rats to this study and divided 4 groups (n=10). The Groups were determined as Control (C), Group 1= 1 hr ischemia (I), Group 2= 1 hr ischemia+2 hr reperfusion (I+2R), Group 3= 1 hr ischemia+4 hr reperfusion (I+4R). Besides, molecular analysis and histopathologic examinations of tissues were performed, and the results were evaluated by normalization and statistics analysis.
Results:
We have found a significant increase in expression of Bcl-XL (P=0.046) and Caspase-3 (P=0.026) genes of group 1, and it was not monitored any significant difference in Group 2 and Group 3. In all groups, the changes in b-FGF (P=0.087), Bmp-2 (P=0.457), TGF-β1 (P=0.201) and PDGFR-α (P=0.116) were not significant compared to control group. We did not see any mRNA expression of Smad1 gene in all groups include control.
Conclusion:
These findings suggest that I/R injury may trigger apoptotic mechanism in lung.
PMCID: PMC4818370  PMID: 27081467
Apoptosis; Growth factors; Ischemia/reperfusion; Lung
9.  Germline Mutations in Shelterin Complex Genes Are Associated With Familial Glioma 
Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.
doi:10.1093/jnci/dju384
PMCID: PMC4296199  PMID: 25482530
10.  The Effect of Intravitreal Azithromycin on the Albino Newborn Rabbit Retina 
Purpose:
To evaluate the effect of intravitreal azithromycin on the retina in a newborn rabbit model.
Methods:
Twelve, two-week old New Zealand albino rabbits were divided into two groups (six in each). The right eyes of six rabbits received 0.75 mg (0.05 mL) azithromycin and the right eyes of the remaining six rabbits 1.5 mg (0.1 mL) azithromycin intravitreally. Left eyes were served as the control and received the same volume of saline. All eyes were enucleated at the third postinjection week. Retinal histology was examined by light microscopy. Apoptosis of the retinal cells was further evaluated by immunohistochemical staining for caspase-3 and in situ terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling (TUNEL) of DNA fragments.
Results:
Light microscopy demonstrated no retinal abnormalities in all eyes. However, retinal nuclear DNA fragmentation was evident in both study groups (33.6% with 1.5 mg and 21.4% with 0.75 mg azithromycin) with the TUNEL method. TUNEL staining ratio was statistically higher only in the second group treated with 1.5 mg azithromycin when compared to the control group (p=0.01 Mann Whitney U test). The ratio of caspase-3 positive cells in the two study groups was 21.5% and 20.2%, respectively. Caspase-3 staining ratio was statistically higher in both study groups when compared to the control eyes (p=0.00, p=0.00 respectively). The difference of TUNEL staining ratio between the two study groups was statistically significant (p=0.028), but there were no statistically significant differences in the two study groups by caspase-3 staining (p=0.247).
Conclusion:
In newborn rabbits, intravitreal azithromycin injection resulted in an apoptotic activity in the photoreceptor, bipolar and ganglion cells. Immunohistochemical analysis suggested that doses of 0.75 mg and 1.5 mg azithromycin, administered intravitreally might be toxic to the newborn rabbit retina.
doi:10.2174/1874364101610010012
PMCID: PMC4780483  PMID: 27014381
Azithromycin; apoptic cell death; bacteriostatic agent; retina
11.  Simultaneous Single Dexamethasone Implant and Ranibizumab Injection in a Case with Active Serpiginous Choroiditis and Choroidal Neovascular Membrane 
Case Reports in Ophthalmology  2015;6(3):408-414.
Intravitreal anti-vascular endothelial growth factor (VEGF) agents seem to be effective in choroidal neovascular membranes (CNV) in association with various entities of posterior uveitis. We herein report a 46-year-old woman who was treated with a simultaneous single intravitreal dexamethasone implant and ranibizumab administration for the treatment of unilateral extrafoveal CNV associated with an active serpiginous choroiditis. Simultaneously with the intravitreal therapy, oral mycophenolic acid (2 × 720 mg) was started, and oral cyclosporine (3 × 100 mg) was then added 2 months later. On the other hand, the fellow eye had been treated for subfoveal CNV but with an inactive disease 4 years previously and ended up with a final visual acuity of counting fingers despite treatment with a single session of photodynamic therapy and 3 subsequent intravitreal ranibizumab injections. Simultaneous administration of anti-VEGF agents and a dexamethasone implant can be a viable approach in eyes with CNV and active serpiginous choroiditis.
doi:10.1159/000442346
PMCID: PMC4777959  PMID: 26955341
Choroidal neovascular membrane; Dexamethasone implant; Ozurdex; Ranibizumab; Serpiginous choroiditis
12.  Grossesse sur utérus cloisonné menée à terme: à propos d'un cas avec revue de la literature 
L'utérus cloisonné est la malformation utérine la plus fréquente, comptant pour 30 à 50% des cas, suivie par les malformations utérines de type utérus bicorne et utérus unicorne. Nous rapportons un cas d'utérus cloisonné total suspecté lors de l'examen obstétrical d'une parturiente en travail, et confirmé à l'exploration au cours d'une césarienne réalisé pour le même motif. L'intérêt de ce cas est de montrer le pronostic obstétrical chez les femmes fertiles porteuses de cette malformation utérine.
doi:10.11604/pamj.2015.22.219.7790
PMCID: PMC4760728  PMID: 26955410
Utérus cloisonné; utérus bicorne; utérus unicorne; échographie 3D; hystérosonographie 3D; septate uterus; Bicornuate uterus; horned uterus; 3D ultrasound; 3D hysterosonography
13.  Genome sequence of Anoxybacillus ayderensis AB04T isolated from the Ayder hot spring in Turkey 
Species of Anoxybacillus are thermophiles and, therefore, their enzymes are suitable for many biotechnological applications. Anoxybacillus ayderensis AB04T (= NCIMB 13972T = NCCB 100050T) was isolated from the Ayder hot spring in Rize, Turkey, and is one of the earliest described Anoxybacillus type strains. The present work reports the cellular features of A. ayderensis AB04T, together with a high-quality draft genome sequence and its annotation. The genome is 2,832,347 bp long (74 contigs) and contains 2,895 protein-coding sequences and 103 RNA genes including 14 rRNAs, 88 tRNAs, and 1 tmRNA. Based on the genome annotation of strain AB04T, we identified genes encoding various glycoside hydrolases that are important for carbohydrate-related industries, which we compared with those of other, sequenced Anoxybacillus spp. Insights into under-explored industrially applicable enzymes and the possible applications of strain AB04T were also described.
doi:10.1186/s40793-015-0065-2
PMCID: PMC4584021  PMID: 26413199
Anoxybacillus; Bacillaceae; Bacillus; Geobacillus; Glycoside hydrolase; Thermophile
14.  Effects of Bowel Preparation and Fluid Restriction in Robot-Assisted Radical Prostatectomy Patients 
Objective
In Robot-assisted radical prostatectomy (RARP) patients, preoperative bowel preparation and intraoperative fluid restriction may cause dehydration and electrolyte imbalance. In these patients, laboratory results that are considered “normal” in the pre-anaesthesia clinic may be misleading, and cardiac arrhythmia due to hypokalaemia and hypocalcaemia, as well as problems, such as prolonged non-depolarising blockade and delayed recovery from anaesthesia, may be observed during anaesthesia practice. In this study, we aimed to determine these disturbances by comparing the preoperative (T1) laboratory values with those at the beginning of the operation (T2) and at the 6th hour of the operation (T3) and values at discharge.
Methods
This prospective study comprised 49 American Society of Anesthesiologists (ASA) I-II patients. Bowel preparation was made with a rectal enema (NaP) twice in 12 hours and with one single dose of oral laxative soda (NaP). During surgery, 1 mL kg−1 h−1 0.09% NaCl and 1 mL kg−1 h−1 6% HES 200/05 infusions were applied.
Results
The potassium level at T2 was significantly lower than at T1 and T3. The calcium levels at T2 and T3 were significantly lower than at T1, and the level at T3 was significantly lower than at T2. The creatinine level at T3 was significantly higher than at T1 and T2.
Conclusion
Although there were no severe increases or decreases in laboratory test values due to bowel preparation and fluid restriction in RARP operations, which reflected on the clinical outcome in this ASA I–II patient group, these changes may be important in critically ill or ASA III–IV patients.
doi:10.5152/TJAR.2014.57704
PMCID: PMC4917149  PMID: 27366475
Remote operations (robotic); dehydration; water-electrolyte imbalance; bowel preparation
15.  Intravitreal Aflibercept Injection and Photodynamic Treatment of a Patient with Unilateral Subretinal Neovascular Membrane Associated with Fundus Flavimaculatus 
We report the good outcome of combined intravitreal aflibercept injection and photodynamic treatment in a case with fundus flavimaculatus (FFM) and unilateral subretinal neovascular membrane (SRNM). A 57-year-old man with FFM and unilateral SRNM who was treated with two consecutive ranibizumab injections with no improvement at another institution was referred to us. He was treated successfully with three aflibercept injections three months apart and a single photodynamic treatment performed a week after the initial aflibercept injection. Six weeks after the last aflibercept injection visual acuity was improved and submacular exudation exhibited dramatic resolution with a moderate degree of residual scarring. SRNM formation is rarely observed in eyes with FFM and a satisfactory outcome can be achieved with a proper treatment.
doi:10.1155/2015/748420
PMCID: PMC4363630  PMID: 25821619
16.  Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage 
Carcinogenesis  2013;35(3):692-702.
Summary
This study identified the MGMT direct reversal DNA repair protein as a target for disulfiram (an established drug for treatment of alcoholism) and support repurposing of disulfiram for enhancing the efficacy of anti-glioma alkylating agents.
The alcohol aversion drug disulfiram (DSF) reacts and conjugates with the protein-bound nucleophilic cysteines and is known to elicit anticancer effects alone or improve the efficacy of many cancer drugs. We investigated the effects of DSF on human O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein and chemotherapy target that removes the mutagenic O6-akyl groups from guanines, and thus confers resistance to alkylating agents in brain tumors. We used DSF, copper-chelated DSF or CuCl2–DSF combination and found that all treatments inhibited the MGMT activity in two brain tumor cell lines in a rapid and dose-dependent manner. The drug treatments resulted in the loss of MGMT protein from tumor cells through the ubiquitin-proteasome pathway. Evidence showed that Cys145, a reactive cysteine, critical for DNA repair was the sole site of DSF modification in the MGMT protein. DSF was a weaker inhibitor of MGMT, compared with the established O6-benzylguanine; nevertheless, the 24–36h suppression of MGMT activity in cell cultures vastly increased the alkylation-induced DNA interstrand cross-linking, G2/M cell cycle blockade, cytotoxicity and the levels of apoptotic markers. Normal mice treated with DSF showed significantly attenuated levels of MGMT activity and protein in the liver and brain tissues. In nude mice bearing T98 glioblastoma xenografts, there was a preferential inhibition of tumor MGMT. Our studies demonstrate a strong and direct inhibition of MGMT by DSF and support the repurposing of this brain penetrating drug for glioma therapy. The findings also imply an increased risk for alkylation damage in alcoholic patients taking DSF.
doi:10.1093/carcin/bgt366
PMCID: PMC3941740  PMID: 24193513
17.  Single Bilateral Dexamethasone Implant in Addition to Panretinal Photocoagulation and Oral Azathioprine Treatment in IRVAN Syndrome 
Case Reports in Ophthalmology  2015;6(1):56-62.
The idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN) syndrome is a disease characterized by multiple retinal macroaneurysms, neuroretinitis and peripheral capillary nonperfusion. Visual loss may result from either ischemia-related complications or macular involvement. Treatment is not always rewarding. We report a case with stage 2 IRVAN syndrome who was successfully treated with a single bilateral intravitreal dexamethasone implant in addition to panretinal photocoagulation and systemic azathioprine treatment.
doi:10.1159/000375481
PMCID: PMC4357687  PMID: 25802506
Azathioprine; Dexamethasone implant; IRVAN syndrome; Laser photocoagulation; Ozurdex
18.  Targeted Sequencing in Chromosome 17q Linkage Region Identifies Familial Glioma Candidates in the Gliogene Consortium 
Scientific Reports  2015;5:8278.
Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned.
doi:10.1038/srep08278
PMCID: PMC4317686  PMID: 25652157
19.  A large primary dumbbell hydatid cyst causing neural foraminal widening of the thoracic spine: A case report and literature review 
Introduction
Spinal hydatid cyst is a rare, but serious condition.
Presentation of the case
Herein, we present a 17-year-old male patient with back pain radiating to the legs and progressive weakness in the lower limbs. CT and MRI showed a spinal-paraspinal hydatid cyst with a dumbbell appearance that caused neural foraminal widening and spinal cord compression. The case was explored via right T3-T4 hemilaminectomy, and the hydatid cyst was completely removed.
Discussion
The clinical presentation, diagnosis, and surgical treatment of this rare case of spinal hydatid disease are discussed, and all published cases of primary dumbbell hydatid cyst are reviewed.
Conclusion
Even if serological test results are negative, hydatid cysts should be considered in the differential diagnosis of cystic lesions of the spine.
doi:10.1016/j.ijscr.2014.12.036
PMCID: PMC4353951  PMID: 25625491
Echinococcosis; Hydatid cyst; Surgical treatment; Thoracic spine
20.  Spectral Domain Optical Coherence Tomographic Findings of Bietti Crystalline Dystrophy 
Journal of Ophthalmology  2014;2014:739271.
We analyzed the OCT features of 24 eyes of 12 patients with Bietti crystalline dystrophy (BCD) with the Heidelberg HRA2-OCT. Seventeen of 24 eyes were in intermediate stage of the disease and seven in advanced stage of the disease at the time of latest OCT examination performed in 2014. Outer retinal tubulations and retinal hyperreflective dots were present in 20 of 24 eyes. The remaining four eyes had advanced disease with very thin retina. Appearance of bright plaque on top of RPE-Bruch membrane was present in all eyes. Choroidal hyperreflective spots were noted in 19 of 24 eyes. The remaining five eyes had advanced disease stage with very thin choroid. Mean central macular thickness was 163.08 μm ± 62.52 for all eyes (170.35 μm ± 56.46 in eyes with intermediate disease and 145.42 μm ± 77.2 in eyes with advanced disease). Mean subfoveal choroidal thickness was 95.37 μm ± 55.93 for the study eyes (116.47 ± 46.92 μm in eyes with intermediate disease and 44.14 μm ± 42.43 in eyes with advanced disease). Choroidal hyperreflective spots were noted in 21 of 24 eyes (87.5%). SD-OCT shows the disease progression in retinal and choroidal layers delicately in eyes with BCD and expands our knowledge about the ongoing disease process.
doi:10.1155/2014/739271
PMCID: PMC4258374  PMID: 25505979
21.  Endothelial Colony Forming Cells (ECFCs) As a Model for Studying Effects of Low-Dose Ionizing Radiation: Growth Inhibition by a Single Dose 
Cancer investigation  2013;31(5):359-364.
Identification of measurable nontransient responses to low-dose radiation in human primary cell cultures remains a problem. To this end, circulating endothelial colony-forming (progenitor) cells (ECFCs) were examined as an experimental model. ECFCs were isolated from three cord blood donors. Cells were positive for endothelial cell markers and remained highly proliferative after long-term cryopreservation. A single dose of X-ray radiation (0.06–0.38 Gy) inhibited ECFC culture growth. This effect was evident at 48 hours and persisted up to 72 hr postirradiation. Such protracted cytostatic response of ECFCs to low-dose radiation suggests that ECFC primary cultures can be used to study low-dose radiation effects.
doi:10.3109/07357907.2013.789903
PMCID: PMC3754852  PMID: 23621632
Cancer biomarkers; Cancer prevention; Carcinogenesis
22.  Carbon monoxide poisoning increases Tpeak–Tend dispersion and QTc dispersion 
Cardiovascular Journal of Africa  2014;25(3):106-109.
Summary
Objective
Carbon monoxide (CO) poisoning leads to cardiac dysrhythmia. Increased heterogeneity in ventricular repolarisation on electrocardiogram (ECG) shows an increased risk of arrhythmia. A number of parameters are used to evaluate ventricular repolarisation heterogeneity on ECG. The aim of our study is to investigate the effect of acute CO poisoning on indirect parameters of ventricular repolarisation on ECG.
Methods
Sixty-seven patients were included in this case–control study. Thirty patients with acute CO poisoning were assigned to group 1 (19 females, mean age: 30.8 ± 11.3 years). A control group was formed with patients without known cardiac disease (group 2, n = 37; 25 females, mean age: 26.0 ± 5.2 years). Twelve-lead ECG and serum electrolyte levels were recorded in all patients. Also, carboxyhaemoglobin (COHb) levels were recorded in group 1. Tpeak–Tend (TpTe) interval, TpTe dispersion, TpTe/QT ratio, QT interval and QTd durations were measured as parameters of ventricular repolarisation. Corrected QT (QTc) and QTc dispersion (QTcd) intervals were determined with the Bazett’s formula.
Results
The mean COHb level in group 1 was 27.6 ± 7.4% and mean duration of CO exposure was 163.5 ± 110.9 min. No statistically significant difference was found in age, gender, serum electrolytes or blood pressure levels between the groups. QRS, QT, QTc, TpTe interval and TpTe/QT ratio were similar between the groups (p > 0.05). QTcd (65.7 ± 64.4 vs 42.1 ± 14.2 ms, p = 0.003) and TpTe dispersion (40.5 ± 14.8 vs 33.2 ± 4.9 ms, p = 0.006) were significantly longer in group 1 than group 2. COHb level was moderately correlated with TpTe dispersion (r = 0.29; p = 0.01).
Conclusion
To our knowledge, this is the first study to investigate TpTe interval and dispersion in CO poisoning. Our results showed that TpTe dispersion and QTc dispersion increased after CO poisoning.
doi:10.5830/CVJA-2014-012
PMCID: PMC4120128  PMID: 25000439
carbon monoxide; electrocardiogram; dysrhythmia; ventricular repolarisation
23.  Cystoid Macular Edema in Bietti's Crystalline Retinopathy 
A 27-year-old man with progressive bilateral visual decline was diagnosed to have Bietti's crystalline dystrophy (BCD). Fluorescein angiography revealed bilateral petaloid type late hyperfluorescence implicating concurrent cystoid macular edema (CME). Optical coherence tomography exhibited cystoid foveal lacunas OU. During the follow-up of six years, intraretinal crystals reduced in amount but CME persisted angiographically and tomographically. CME is among the rare macular features of BCD including subfoveal sensorial detachment, subretinal neovascular membrane, and macular hole.
doi:10.1155/2014/964892
PMCID: PMC4037624  PMID: 24949209
24.  Malrotation-associated cholecystoduodenal fistula 
Patient: Female, 16
Final Diagnosis: Malrotation and cholecystoduodenal fistula
Symptoms: Abdominal pain • anorexia • fever • nausea • vomiting
Medication: —
Clinical Procedure: —
Specialty: Gastroenterology and Hepatology
Objective:
Anatomical anomaly/variation
Background:
Cholecystoduodenal fistula (CDF) is the most common cholecystenteric fistula. It is a late complication of gallbladder disease with calculus and is mainly encountered in the elderly and females.
Case Report:
We report the case of a teenage patient with cholecystoduodenal fistula and malrotation. Direct plain abdominal x-ray demonstrated air in the biliary system. Computed tomography revealed CDF-associated with an anomaly of intestinal malrotation. She had gallstones (with a few stones in the gallbladder) and cholecystitis. CDF is caused by malrotation, and cholecystitis has not been reported before. In this regard our patient is the first and youngest reported case.
Conclusions:
We suggest that CDF is probably a consequence of malrotation. The patient’s clinical features and operative management are presented and discussed with current literature.
doi:10.12659/AJCR.889903
PMCID: PMC3894915  PMID: 24454977
cholecystoduodenal fistula; cholecystitis; malrotation
25.  Small ubiquitin-like modifier 1-3 is activated in human astrocytic brain tumors and is required for glioblastoma cell survival 
Cancer science  2012;104(1):70-77.
Small ubiquitin-like modifier (SUMO1, 2, 3) is a group of proteins that conjugate to lysine residues of target proteins thereby modifying their activity, stability, and subcellular localization. A large number of SUMO target proteins are transcription factors and other nuclear proteins involved in gene expression. Furthermore, SUMO conjugation plays key roles in genome stability, quality control of newly synthesized proteins, proteasomal degradation of proteins and DNA damage repair. Any marked increase in levels of SUMO-conjugated proteins is therefore expected to have a major impact on the fate of cells. We show here that SUMO conjugation is activated in human astrocytic brain tumors. Levels of both SUMO1- and SUMO2/3-conjugated proteins were markedly increased in tumor samples. The effect was least pronounced in low-grade astrocytoma (WHO Grade II) and most pronounced in glioblastoma multiforme (WHO Grade IV). We also found a marked rise in levels of Ubc9, the only SUMO conjugation enzyme identified so far. Blocking SUMO1-3 conjugation in glioblastoma cells by silencing their expression blocked DNA synthesis, cell growth and clonogenic survival of cells. It also resulted in DNA-PK-dependent phosphorylation of H2AX, indicative of DNA double-strand damage, and G2/M cell cycle arrest. Collectively, these findings highlight the pivotal role of SUMO conjugation in DNA damage repair processes and imply that the SUMO conjugation pathway could be a new target of therapeutic intervention aimed at increasing the sensitivity of glioblastomas to radio- and chemotherapy.
doi:10.1111/cas.12047
PMCID: PMC3608476  PMID: 23078246
astrocytic brain tumors; DNA damage repair; DNA-PK; G2/M checkpoint; gene silencing; glioblastoma; H2AX; human; miRNA; SUMO conjugation; Ubc9

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