bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuning of defects in ZnO nanorod arrays used in bulk heterojunction solar cells
Authors: Iza Diana C , Muñoz-Rojas David , Jia Quanxi , Swartzentruber Brian , MacManus-Driscoll Judith L
Published: November 2012

With particular focus on bulk heterojunction solar cells incorporating ZnO nanorods, we study how different annealing environments (air or Zn environment) and temperatures impact on the photoluminescence response. Our work gives new insight into the complex defect landscape in ZnO, and it also shows how the different defect types can be manipulated. We have determined the emission wavelengths for the two main defects which make up the visible band, the oxygen vacancy emission wavelength at approximately 530 nm and the zinc vacancy emission wavelength at approximately 630 nm. The precise nature of the defect landscape in the bulk of the nanorods is found to be unimportant to photovoltaic cell performance although the surface structure is more critical. Annealing of the nanorods is optimum at 300°C as this is a sufficiently high temperature to decompose Zn(OH)2 formed at the surface of the nanorods during electrodeposition and sufficiently low to prevent ITO degradation.
The gamma chain subunit of Fc receptors is required for alpha-synuclein-induced pro-inflammatory signaling in microglia
Authors: Cao Shuwen , Standaert David G , Harms Ashley S
Published: November 2012

Background

The protein alpha-synuclein (α-SYN), which is found in the Lewy bodies of dopamine-producing (DA) neurons in the substantia nigra (SN), has an important role in the pathogenesis of Parkinson’s disease (PD). Previous studies have shown that neuroinflammation plays a key role in PD pathogenesis. In an AAV-synuclein mouse model of PD, we have found that over-abundance of α-SYN triggers the expression of NF-κB p65, and leads to microglial activation and DA neurodegeneration. We also have observed that Fcγ receptors (FcγR), proteins present on the surface of microglia that bind immunoglobulin G (IgG) and other ligands, are key modulators of α-SYN-induced neurodegeneration.

Methods

In order to study the role of FcγRs in the interactions of α-SYN and microglia, we treated the primary microglial cultures from wild-type (WT) and FcγR−/−mice with aggregated human α-SYNin vitro.

Results

Using immunocytochemistry, we found that α-SYN was taken up by both WT and FcγR−/−microglia, however, their patterns of internalization were different, with aggregation in autophagosomes in WT cells and more diffuse localization in FcγR−/−microglia. In WT microglia, α-SYN induced the nuclear accumulation of NF-κB p65 protein and downstream chemokine expression while in FcγR−/−mouse microglia, α-SYN failed to trigger the enhancement of nuclear NF-κB p65, and the pro-inflammatory signaling was reduced.

Conclusions

Our results suggest that α-SYN can interact directly with microglia and can be internalized and trafficked to autophagosomes. FcγRs mediate this interaction, and in the absence of the gamma chain, there is altered intracellular trafficking and attenuation of pro-inflammatory NF-κB signaling. Therefore, blocking either FcγR signaling or downstream NF-κB activation may be viable therapeutic strategies in PD.
Development of a SYBR green real-time PCR method for rapid detection of sheep pox virus
Authors: Tian Hong , Wu Jingyan , Chen Yan , Zhang Keshan , Shang Youjun , Liu Xiangtao
Published: November 2012

Background

In this study, we developed a SYBR Green-based real-time PCR assay for the detection of sheep pox virus using a plasmid construct carrying one of the highly conserved genes encoding the virion envelope protein (P32) as a template.

Results

The method was demonstrated to be highly sensitive, allowing a precise SPV DNA quantitation over a range of nine orders of magnitude (from 101 to 109 copies of standard DNA). Then, specimens from SPV suspected sheep were analyzed by conventional gel-based PCR, real-time PCR and sequence analysis.

Conclusion

Comparison between these different techniques revealed that real-time PCR is more sensitive than conventional gel-based PCR, allowing detection low viral titers of SPV in infected sheep.
Guanylate-binding protein 1 participates in cellular antiviral response to dengue virus
Authors: Pan Wen , Zuo Xiangyang , Feng Tingting , Shi Xiaohong , Dai Jianfeng
Published: November 2012

Background

Dengue virus (DENV), the causative agent of human Dengue hemorrhagic fever, is a mosquito-borne virus found in tropical and sub-tropical regions around the world. Vaccines against DENV are currently unavailable. Guanylate-binding protein 1 (GBP1) is one of the Interferon (IFN) stimulated genes (ISGs) and has been shown important for host immune defense against various pathogens. However, the role of GBP1 during DENV infection remains unclarified. In this study, we evaluated the relevance of GBP1 to DENV infection in in vitro model.

Findings

Quantitative RT-PCR (qRT-PCR) and Western blot showed that the expression of mouse Gbp1 was dramatically upregulated in DENV-infected RAW264.7 cells. The intracellular DENV loads were significantly higher in Gbp1 silenced cells compared with controls. The expression levels of selective anti-viral cytokines were decreased in Gbp1 siRNA treated cells, while the transcription factor activity of NF-κB was impaired upon GBP1 silencing during infection.

Conclusions

Our data suggested that GBP1 plays an antiviral role during DENV infection.
Successful treatment of gallbladder mixed adenoneuroendocrine carcinoma with neo-adjuvant chemotherapy
Authors: Song Wu , Chen Wenfang , Zhang Sheng , Peng Jianjun , He Yulong
Published: November 2012

Mixed adenoneuroendocrine carcinoma (MANEC) carcinomas rarely occur in the gallbladder. Here we reported a case of giant gallbladder unresectable mass with local liver invasion and omentum metastasis, which proved to be neuroendocrine carcinoma (NEC) by biopsy, received successful radical operation after neo-adjuvant chemotherapy plus somatostatin treatment. The patient showed good response as the neoplasm diminished dramatically and showed clear margin after 6 courses of treatment. A radical operation including cholecystectomy, hepatic wedge resection of the gallbladder fossa segment and lymph node of group 8a and 8p resection was performed successfully. Postoperative histopathological examination revealed neuroendocrine carcinoma mixed with adenocarcinoma in the gallbladder wall. Followed up showed no evidence of recurrence after 7 months of the operation. We suggest that neo-adjuvant chemotherapy may be beneficial to gallbladder mixed neuroendocrine carcinomas in an advanced stage which could also be advantageous to NEC of other organs.

Virtual slides

http://www.diagnosticpathology.diagnomx.eu/vs/2731892837743787
Three-dimensional conformal radiation for esophageal squamous cell carcinoma with involved-field irradiation may deliver considerable doses of incidental nodal irradiation
Authors: Ji Kai , Zhao Lujun , Yang Chengwen , Meng Maobin , Wang Ping
Published: November 2012

Background

To quantify the incidental irradiation dose to esophageal lymph node stations when irradiating T1-4N0M0 thoracic esophageal squamous cell carcinoma (ESCC) patients with a dose of 60 Gy/30f.

Methods

Thirty-nine patients with medically inoperable T1–4N0M0 thoracic ESCC were treated with three-dimensional conformal radiation (3DCRT) with involved-field radiation (IFI). The conformal clinical target volume (CTV) was re-created using a 3-cm margin in the proximal and distal direction beyond the barium esophagogram, endoscopic examination and CT scan defined the gross tumor volume (GTV) and a 0.5-cm margin in the lateral and anteroposterior directions of the CT scan-defined GTV. The PTV encompassed 1-cm proximal and distal margins and 0.5-cm radial margin based on the CTV. Nodal regions were delineated using the Japanese Society for Esophageal Diseases (JSED) guidelines and an EORTC-ROG expert opinion. The equivalent uniform dose (EUD) and other dosimetric parameters were calculated for each nodal station. Nodal regions with a metastasis rate greater than 5% were considered a high-risk lymph node subgroup.

Results

Under a 60 Gy dosage, the median Dmean and EUD was greater than 40 Gy in most high-risk nodal regions except for regions of 104, 106tb-R in upper-thoracic ESCC and 101, 104-R, 105, 106rec-L, 2, 3&7 in middle-thoracic ESCC and 107, 3&7 in lower-thoracic ESCC. In the regions with an EUD less than 40Gy, most incidental irradiation doses were significantly associated with esophageal tumor length and location.

Conclusions

Lymph node stations near ESCC receive considerable incidental irradiation doses with involved-field irradiation that may contribute to the elimination of subclinical lesions.
Pulling chromatin apart: Unstacking or Unwrapping?
Authors: Victor Jean Marc , Zlatanova Jordanka , Barbi Maria , Mozziconacci Julien
Published: November 2012

Background

Understanding the mechanical properties of chromatin is an essential step towards deciphering the physical rules of gene regulation. In the past ten years, many single molecule experiments have been carried out, and high resolution measurements of the chromatin fiber stiffness are now available. Simulations have been used in order to link those measurements with structural cues, but so far no clear agreement among different groups has been reached.

Results

We revisit here some of the most precise experimental results obtained with carefully reconstituted fibers.

Conclusions

We show that the mechanical properties of the chromatin fiber can be quantitatively accounted for by the stiffness of the DNA molecule and the 3D structure of the chromatin fiber.
Alcohol and breast cancer risk among Asian-American women in Los Angeles County
Authors: Wu Anna H , Vigen Cheryl , Razavi Pedram , Tseng Chiu-Chen , Stancyzk Frank Z
Published: November 2012

Introduction

The role of alcohol and breast cancer risk in Asians has not been well studied. Recent studies suggest that even moderate alcohol intake may be associated with an increase in breast cancer risk, and this may be particularly relevant as alcohol intake is traditionally low among Asians.

Methods

We investigated the association between lifetime alcohol intake (including frequency, quantity, duration, timing, and beverage type) and breast cancer in a population-based case-control study of 2,229 Asian Americans diagnosed with incident breast cancer and 2,002 matched control women in Los Angeles County. Additionally, we examined the relation between current alcohol intake and serum concentrations of sex-hormones and growth factors in a subset of postmenopausal control women.

Results

Regular lifetime alcohol intake was significantly higher in US-born than non-US-born Asian Americans (P < 0.001) and almost twice as common in Japanese- than in Chinese- and Filipino-Americans (P < 0.001). Breast cancer risk increased with increasing alcohol intake among US-born Asian Americans; the odds ratios (ORs) per 5 grams per day and per 10 years of drinking were 1.21 (95% confidence interval (CI) 1.00 to 1.45) and 1.12 (95% CI, 0.98 to 1.28), respectively. Regular alcohol intake was a significant risk factor for Japanese-, but not for Chinese- and Filipino-Americans. Current consumers compared with nondrinkers showed lower concentrations of insulin-like growth factor binding protein 3 (P = 0.03) and nonsignificantly higher concentrations of estrone and androgens.

Conclusions

Regular lifetime alcohol intake is a significant breast cancer risk factor in US-born Asian Americans and Japanese Americans, emphasizing the importance of this modifiable lifestyle factor in traditionally low-risk populations.
Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients
Authors: Helbok Raimund , Kurtz Pedro , Schmidt Michael J , Stuart Morgan R , Fernandez Luis , Connolly Sander E , Lee Kiwon , Schmutzhard Erich , Mayer Stephan A , Claassen Jan , Badjatia Neeraj
Published: November 2012

Introduction

Daily interruption of sedation (IS) has been implemented in 30 to 40% of intensive care units worldwide and may improve outcome in medical intensive care patients. Little is known about the benefit of IS in acutely brain-injured patients.

Methods

This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2) during IS trials.

Results

Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics were not considered safe on 28 days (34%). An increase in the FOUR Score (Full Outline of UnResponsiveness score) was observed in 50% of IS-trials by a median of three (two to four) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one-third of IS-trials the trial had to be stopped due to an ICP-crisis (> 20 mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in PbtO2 (P < 0.05), including 67% with critical values of PbtO2 < 20 mmHg, a tendency to brain metabolic distress (P < 0.07) was observed.

Conclusions

Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome the clinical benefit.
Human genes with CpG island promoters have a distinct transcription-associated chromatin organization
Authors: Vavouri Tanya , Lehner Ben
Published: November 2012

Background

More than 50% of human genes initiate transcription from CpG dinucleotide-rich regions referred to as CpG islands. These genes show differences in their patterns of transcription initiation, and have been reported to have higher levels of some activation-associated chromatin modifications.

Results

Here we report that genes with CpG island promoters have a characteristic transcription-associated chromatin organization. This signature includes high levels of the transcription elongation-associated histone modifications H4K20me1, H2BK5me1 and H3K79me1/2/3 in the 5' end of the gene, depletion of the activation marks H2AK5ac, H3K14ac and H3K23ac immediately downstream of the transcription start site (TSS), and characteristic epigenetic asymmetries around the TSS. The chromosome organization factor CTCF may be bound upstream of RNA polymerase in most active CpG island promoters, and an unstable nucleosome at the TSS may be specifically marked by H4K20me3, the first example of such a modification. H3K36 monomethylation is only detected as enriched in the bodies of active genes that have CpG island promoters. Finally, as expression levels increase, peak modification levels of the histone methylations H3K9me1, H3K4me1, H3K4me2 and H3K27me1 shift further away from the TSS into the gene body.

Conclusions

These results suggest that active genes with CpG island promoters have a distinct step-like series of modified nucleosomes after the TSS. The identity, positioning, shape and relative ordering of transcription-associated histone modifications differ between genes with and without CpG island promoters. This supports a model where chromatin organization reflects not only transcription activity but also the type of promoter in which transcription initiates.
Gene Expression–Based Model Using Formalin-Fixed Paraffin-Embedded Biopsies Predicts Overall Survival in Advanced-Stage Classical Hodgkin Lymphoma
Authors: Scott David W. , Chan Fong Chun , Hong Fangxin , Rogic Sanja , Tan King L. , Meissner Barbara , Ben-Neriah Susana , Boyle Merrill , Kridel Robert , Telenius Adele , Woolcock Bruce W. , Farinha Pedro , Fisher Richard I. , Rimsza Lisa M. , Bartlett Nancy L. , Cheson Bruce D. , Shepherd Lois E. , Advani Ranjana H. , Connors Joseph M. , Kahl Brad S. , Gordon Leo I. , Horning Sandra J. , Steidl Christian , Gascoyne Randy D.
Published: November 2012

Purpose

Our aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET).

Methods

Expression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.

Results

A 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.

Conclusion

A gene expression–based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.
Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496)
Authors: Gordon Leo I. , Hong Fangxin , Fisher Richard I. , Bartlett Nancy L. , Connors Joseph M. , Gascoyne Randy D. , Wagner Henry , Stiff Patrick J. , Cheson Bruce D. , Gospodarowicz Mary , Advani Ranjana , Kahl Brad S. , Friedberg Jonathan W. , Blum Kristie A. , Habermann Thomas M. , Tuscano Joseph M. , Hoppe Richard T. , Horning Sandra J.
Published: November 2012

Purpose

Although ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD.

Patients and Methods

The Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level.

Results

There was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32).

Conclusion

ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.
Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer
Authors: Forastiere Arlene A. , Zhang Qiang , Weber Randal S. , Maor Moshe H. , Goepfert Helmuth , Pajak Thomas F. , Morrison William , Glisson Bonnie , Trotti Andy , Ridge John A. , Thorstad Wade , Wagner Henry , Ensley John F. , Cooper Jay S.
Published: November 2012

Purpose

To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation.

Patients and Methods

Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point.

Results

Five hundred twenty patients were analyzed. Median follow-up for surviving patients is 10.8 years. Both chemotherapy regimens significantly improved LFS compared with RT alone (induction chemotherapy v RT alone: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone).

Conclusion

These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.
Fibroblast Growth Factor Receptor 1 Gene Amplification Is Associated With Poor Survival and Cigarette Smoking Dosage in Patients With Resected Squamous Cell Lung Cancer
Authors: Kim Hye Ryun , Kim Dae Joon , Kang Dae Ryong , Lee Jin Gu , Lim Sun Min , Lee Chang Young , Rha Sun Young , Bae Mi Kyung , Lee Young Joo , Kim Se Hoon , Ha Sang-Jun , Soo Ross Andrew , Chung Kyung Young , Kim Joo Hang , Lee Ji Hyun , Shim Hyo Sup , Cho Byoung Chul
Published: November 2012

Purpose

To investigate the frequency and the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected squamous cell carcinoma of the lung (SCCL) and the association between smoking and FGFR1 amplification.

Patients and Methods

Gene copy number of FGFR1 was investigated in microarrayed tumors from 262 patients with SCCL who had tumor tissue as well as smoking and survival data available. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1-amplified tumor (FGFR1 amp+) was prespecified as a tumor with nine or more copies of FGFR1.

Results

Among 262 patients, the frequency of FGFR1 amp+ was 13.0%. Patients with FGFR1 amp+ had significantly shorter disease-free survival (DFS; 26.9 v 94.6 months; P < .001) as well as shorter overall survival (OS; 51.2 v 115.0 months; P = .002) than those without FGFR1 amp+. Multivariate modeling confirmed that patients with FGFR1 amp+ had a significantly greater risk of recurrence and death than those without FGFR1 amp+ after adjusting for sex, smoking status, pathologic stage, and adjuvant chemotherapy (DFS: adjusted hazard ratio [AHR], 2.24; 95% CI, 1.45 to 3.45; P < .001; OS: AHR, 1.83; 95% CI, 1.15 to 2.89; P = .01). The frequency of FGFR1 amp+ was significantly higher in current smokers than in former smokers and never-smokers (28.9% v 2.5% v 0%; Ptrend < .001). As the smoking dosage increased, so did the incidence of FGFR1 amp+ (Ptrend = .002).

Conclusion

FGFR1 amplification is an independent negative prognostic factor in surgically resected SCCL and is associated with cigarette smoking in a dose-dependent manner. FGFR1 amplification is a relevant therapeutic target in Asian patients with SCCL.
Changes in Histone Modification and DNA Methylation of the StAR and Cyp19a1 Promoter Regions in Granulosa Cells Undergoing Luteinization during Ovulation In Rats
Authors: Lee Lifa , Asada Hiromi , Kizuka Fumie , Tamura Isao , Maekawa Ryo , Taketani Toshiaki , Sato Shun , Yamagata Yoshiaki , Tamura Hiroshi , Sugino Norihiro
Published: November 2012

The ovulatory LH surge induces rapid up-regulation of steroidogenic acute regulatory (StAR) protein and rapid down-regulation of aromatase (Cyp19a1) in granulosa cells (GCs) undergoing luteinization during ovulation. This study investigated in vivo whether epigenetic mechanisms including histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression. GCs were obtained from rats treated with equine chorionic gonadotropin (CG) before (0 h) and after human (h)CG injection. StAR mRNA levels rapidly increased after hCG injection, reached a peak at 4 h, and then remained higher compared with 0 h until 12 h. Cyp19a1 mRNA levels gradually decreased after hCG injection and reached their lowest level at 12 h. A chromatin immunoprecipitation assay revealed that levels of histone-H4 acetylation (Ac-H4) and trimethylation of histone-H3 lysine-4 (H3K4me3) increased whereas H3K9me3 and H3K27me3 decreased in the StAR promoter after hCG injection. On the other hand, the levels of Ac-H3 and -H4 and H3K4me3 decreased, and H3K27me3 increased in the Cyp19a1 promoter after hCG injection. Chromatin condensation, which was analyzed using deoxyribonuclease I, decreased in the StAR promoter and increased in the Cyp19a1 promoter after hCG injection. A chromatin immunoprecipitation assay also showed that binding activities of CAATT/enhancer-binding protein β to the StAR promoter increased and binding activities of phosphorylated-cAMP response element binding protein to the Cyp19a1 promoter decreased after hCG injection. These results provide in vivo evidence that histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression by altering chromatin structure of the promoters in GCs undergoing luteinization during ovulation.
Glucose Intolerance and Lipid Metabolic Adaptations in Response to Intrauterine and Postnatal Calorie Restriction in Male Adult Rats
Authors: Garg Meena , Thamotharan Manikkavasagar , Dai Yun , Lagishetty Venu , Matveyenko Aleksey V. , Lee W. N. Paul , Devaskar Sherin U.
Published: November 2012

Enhanced de novo lipogenesis (DNL), an adult hepatic adaption, is seen with high carbohydrate or low-fat diets. We hypothesized that ad libitum intake after prenatal calorie restriction will result in adult-onset glucose intolerance and enhanced DNL with modified lipid metabolic gene expression profile. Stable isotopes were used in 15-month-old adult male rat offspring exposed to prenatal (IUGR), pre- and postnatal (IPGR), or postnatal (PNGR) caloric restriction vs. controls (CON). IUGR vs. CON were heavier with hepatomegaly but unchanged visceral white adipose tissue (WAT), glucose intolerant with reduced glucose-stimulated insulin secretion (GSIS), pancreatic β-cell mass, and total glucose clearance rate but unsuppressed hepatic glucose production. Liver glucose transporter (Glut) 1 and DNL increased with decreased hepatic acetyl-CoA carboxylase (ACC) and fatty acid synthase but increased WAT fatty acid transport protein-1 and peroxisomal proliferator-activated receptor-γ, resistin, and visfatin gene expression. In contrast, PNGR and IPGR were lighter, had reduced visceral WAT, and were glucose tolerant with unchanged hepatic glucose production but with increased GSIS, β-cell mass, glucose clearance rate, and WAT insulin receptor. Hepatic Glut1 and DNL were also increased in lean IPGR and PNGR with increased hepatic ACC, phosphorylated ACC, and pAMPK and reduced WAT fatty acid transport protein-1, peroxisomal proliferator-activated receptor-γ, and ACCα. We conclude the following: 1) the heavy, glucose-intolerant and insulin-resistant IUGR adult phenotype is ameliorated by postnatal caloric restriction; 2) increased DNL paralleling hepatic Glut1 is a biomarker of exposure to early caloric restriction rather than the adult metabolic status; 3) hepatic lipid enzyme expression reflects GSIS rather than DNL; and 4) WAT gene expression reflects an obesogenic vs. lean phenotype.
Hydrogen Sulfide Impairs Glucose Utilization and Increases Gluconeogenesis in Hepatocytes
Authors: Zhang Ling , Yang Guangdong , Untereiner Ashley , Ju Youngjun , Wu Lingyun , Wang Rui
Published: November 2012

Mounting evidence has established hydrogen sulfide (H2S) as an important gasotransmitter with multifaceted physiological functions. The aim of the present study was to investigate the role of H2S on glucose utilization, glycogen synthesis, as well as gluconeogenesis in both HepG2 cells and primary mouse hepatocytes. Incubation with NaHS (a H2S donor) impaired glucose uptake and glycogen storage in HepG2 cells via decreasing glucokinase activity. Adenovirus-mediated cystathionine γ-lyase (CSE) overexpression increased endogenous H2S production and lowered glycogen content in HepG2 cells. Glycogen content was significantly higher in liver tissues from CSE knockout (KO) mice compared to that from wild type (WT) mice in fed condition. Glucose consumption was less in primarily cultured hepatocytes isolated from WT mice than those from CSE KO mice, but more glucose was produced by hepatocytes via gluconeogenesis and glycogenolysis pathways in WT mice than in CSE KO mice. NaHS treatment reduced the phosphorylation of AMP-activated protein kinase, whereas stimulation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside reversed H2S-impaired glucose uptake. H2S-increased glucose production was likely through increased phosphoenolpyruvate carboxykinase activity. In addition, insulin at the physiological range inhibited CSE expression, and H2S decreased insulin-stimulated phosphorylation of Akt in HepG2 cells. CSE expression was increased, however, in insulin-resistant state induced by exposing cells to high levels of insulin (500 nm) and glucose (33 mm) for 24 h. Taken together, these data suggest that the interaction of H2S and insulin in liver plays a pivotal role in regulating insulin sensitivity and glucose metabolism.
Continuous Administration of a P450 Aromatase Inhibitor Induces Polycystic Ovary Syndrome with a Metabolic and Endocrine Phenotype in Female Rats at Adult Age
Authors: Maliqueo Manuel , Sun Miao , Johansson Julia , Benrick Anna , Labrie Fernand , Svensson Henrik , Lönn Malin , Duleba Antoni J. , Stener-Victorin Elisabet
Published: November 2012

Studying the mechanisms for the complex pathogenesis of polycystic ovary syndrome (PCOS) requires animal models with endocrine, reproductive, and metabolic features of the syndrome. Hyperandrogenism seems to be a central factor in PCOS, leading to anovulation and insulin resistance. In female rats, continuous administration of letrozole, a nonsteroidal inhibitor of P450 aromatase, at 400 μg/d starting before puberty induces hyperandrogenemia and reproductive abnormalities similar to those in women with PCOS. However, despite high circulating testosterone levels, these rats do not develop metabolic abnormalities, perhaps because of their supraphysiological testosterone concentrations or because estrogen synthesis is completely blocked in insulin-sensitive tissues. To test the hypothesis that continuous administration of lower doses of letrozole starting before puberty would result in both metabolic and reproductive phenotypes of PCOS, we performed a 12-wk dose-response study. At 21 d of age, 46 female Wistar rats were divided into two letrozole groups (100 or 200 μg/d) and a control group (placebo). Both letrozole doses resulted in increased body weight, inguinal fat accumulation, anovulation, larger ovaries with follicular atresia and multiples cysts, endogenous hyperandrogemia, and lower estrogen levels. Moreover, rats that received 200 μg/d had insulin resistance and enlarged adipocytes in inguinal and mesenteric fat depots, increased circulating levels of LH, decreased levels of FSH, and increased ovarian expression of Cyp17a1 mRNA. Thus, continuous administration of letrozole, 200 μg/d, to female rats for 90 d starting before puberty results in a PCOS model with reproductive and metabolic features of the syndrome.
Trefoil Factor 2 Promotes Cell Proliferation in Pancreatic β-Cells through CXCR-4-Mediated ERK1/2 Phosphorylation
Authors: Orime Kazuki , Shirakawa Jun , Togashi Yu , Tajima Kazuki , Inoue Hideaki , Ito Yuzuru , Sato Koichiro , Nakamura Akinobu , Aoki Kazutaka , Goshima Yoshio , Terauchi Yasuo
Published: November 2012

Decreased β-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic β-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic β-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic β-cells, whereas the role of TFF2 in pancreatic β-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic β-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in β-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing β-cell proliferation.
The chromatin remodeling factor Chd1l is required in the preimplantation embryo
Authors: Snider Alyssa C. , Leong Denise , Wang Q. Tian , Wysocka Joanna , Yao Mylene W. M. , Scott Matthew P.
Published: November 2012

During preimplantation development, the embryo must establish totipotency and enact the earliest differentiation choices, processes that involve extensive chromatin modification. To identify novel developmental regulators, we screened for genes that are preferentially transcribed in the pluripotent inner cell mass (ICM) of the mouse blastocyst. Genes that encode chromatin remodeling factors were prominently represented in the ICM, including Chd1l, a member of the Snf2 gene family. Chd1l is developmentally regulated and expressed in embryonic stem (ES) cells, but its role in development has not been investigated. Here we show that inhibiting Chd1l protein production by microinjection of antisense morpholinos causes arrest prior to the blastocyst stage. Despite this important function in vivo, Chd1l is non-essential for cultured ES cell survival, pluripotency, or differentiation, suggesting that Chd1l is vital for events in embryos that are distinct from events in ES cells. Our data reveal a novel role for the chromatin remodeling factor Chd1l in the earliest cell divisions of mammalian development.
Duplication and maintenance of the Myb genes of vertebrate animals
Authors: Davidson Colin J. , Guthrie Erin E. , Lipsick Joseph S.
Published: November 2012

Gene duplication is an important means of generating new genes. The major mechanisms by which duplicated genes are preserved in the face of purifying selection are thought to be neofunctionalization, subfunctionalization, and increased gene dosage. However, very few duplicated gene families in vertebrate species have been analyzed by functional tests in vivo. We have therefore examined the three vertebrate Myb genes (c-Myb, A-Myb, and B-Myb) by cytogenetic map analysis, by sequence analysis, and by ectopic expression in Drosophila. We provide evidence that the vertebrate Myb genes arose by two rounds of regional genomic duplication. We found that ubiquitous expression of c-Myb and A-Myb, but not of B-Myb or Drosophila Myb, was lethal in Drosophila. Expression of any of these genes during early larval eye development was well tolerated. However, expression of c-Myb and A-Myb, but not of B-Myb or Drosophila Myb, during late larval eye development caused drastic alterations in adult eye morphology. Mosaic analysis implied that this eye phenotype was cell-autonomous. Interestingly, some of the eye phenotypes caused by the retroviral v-Myb oncogene and the normal c-Myb proto-oncogene from which v-Myb arose were quite distinct. Finally, we found that post-translational modifications of c-Myb by the GSK-3 protein kinase and by the Ubc9 SUMO-conjugating enzyme that normally occur in vertebrate cells can modify the eye phenotype caused by c-Myb in Drosophila. These results support a model in which the three Myb genes of vertebrates arose by two sequential duplications. The first duplication was followed by a subfunctionalization of gene expression, then neofunctionalization of protein function to yield a c/A-Myb progenitor. The duplication of this progenitor was followed by subfunctionalization of gene expression to give rise to tissue-specific c-Myb and A-Myb genes.
Gastrointestinal defects of the Gas1 mutant involve dysregulated Hedgehog and Ret signaling
Authors: Biau Sandrine , Jin Shiying , Fan Chen-Ming
Published: November 2012

The gastrointestinal (GI) tract defines the digestive system and is composed of the stomach, intestine and colon. Among the major cell types lining radially along the GI tract are the epithelium, mucosa, smooth muscles and enteric neurons. The Hedgehog (Hh) pathway has been implicated in directing various aspects of the developing GI tract, notably the mucosa and smooth muscle growth, and enteric neuron patterning, while the Ret signaling pathway is selectively required for enteric neuron migration, proliferation, and differentiation. The growth arrest specific gene 1 (Gas1) encodes a GPI-anchored membrane protein known to bind to Sonic Hh (Shh), Indian Hh (Ihh), and Ret. However, its role in the GI tract has not been examined. Here we show that the Gas1 mutant GI tract, compared to the control, is shorter, has thinner smooth muscles, and contains more enteric progenitors that are abnormally distributed. These phenotypes are similar to those of the Shh mutant, supporting that Gas1 mediates most of the Shh activity in the GI tract. Because Gas1 has been shown to inhibit Ret signaling elicited by Glial cell line-derived neurotrophic factor (Gdnf), we explored whether Gas1 mutant enteric neurons displayed any alteration of Ret signaling levels. Indeed, isolated mutant enteric progenitors not only showed increased levels of phospho-Ret and its downstream effectors, phospho-Akt and phospho-Erk, but also displayed altered responses to Gdnf and Shh. We therefore conclude that phenotypes observed in the Gas1 mutant are due to a combination of reduced Hh signaling and increased Ret signaling.
Radiation dose reduction for chest CT with non-linear adaptive filters
Authors: Singh Sarabjeet , Digumarthy Subba R , Back Anni , Shepard Jo-Anne O , Kalra Mannudeep K
Published: November 2012

Background

CT radiation dose reduction results in increased noise or graininess of images which affects the diagnostic information. One of the approaches to lower radiation exposure to patients is to reduce image noise with the use of image processing software in low radiation dose images.

Purpose

To assess image quality and accuracy of non-linear adaptive filters (NLAF) at low dose chest CT.

Material and Methods

In an IRB approved prospective study, 24 patients (mean age, 63±7.3 years; M:F ratio, 11:13) gave informed consent for acquisition of four additional chest CT image series at 150, 110, 75, and 40 mAs (baseline image series) on a 64-slice MDCT over an identical 10-cm length. NLAF was used to process three low dose (110, 75, and 40 mAs) image series (postprocessed image series). Two radiologists reviewed baseline and postprocessed images in a blinded manner for image quality. Objective noise, CT attenuation values, patient weight, transverse diameters, CTDIvol, and DLP were recorded. Statistical analysis was performed using parametric and non-parametric tests for comparing postprocessed and baseline images.

Results

No lesions were missed on baseline or postprocessed CT images ( n = 80 lesions, 73 lesions <1 cm). At 40 mAs, subjective noise in mediastinal window settings were graded as unacceptable in baseline images and acceptable in postprocessed images. Visibility of smaller structures improved from suboptimal visibility in baseline images at 40 mAs to excellent in postprocessed images at 40 mAs. No major artifacts were seen due to NLAF postprocessing, except for minor beam hardening artifacts not affecting diagnostic decision-making (14/22) in both baseline and postprocessed image series. Diagnostic confidence for chest CT was improved to fully confident in postprocessed images at 40 mAs. Compared to baseline images, postprocessing reduced objective noise by 26% (14.2±4.7/19.2±6.4), 31.5% (15.2±4.7/22.2±5.7), and 41.5% (16.9±6/28.9±10.2) at 110 mAs, 75 mAs, and 40 mAs tube current-time product levels.

Conclusion

Applications of NLAF can help reduce tube current down to 40 mAs for chest CT while maintaining lesion conspicuity and image quality.
Cemented polyethylene and cementless porous-coated acetabular components have similar outcomes at a mean of seven years after total hip replacement
Authors: Angadi D. S. , Brown S. , Crawfurd E. J. P.
Published: November 2012

The aim of this prospective randomised study was to compare the clinical and radiological results of a cemented all-polyethylene Ultima acetabular component with those of a cementless porous-coated acetabular component (PFC) following total hip replacement (THR). A total of 287 patients received either a polyethylene acetabular component (group A) or a cobalt–chromium porous-coated component (group B) with an identical cemented femoral component and 28 mm cobalt-chromium head, thus making it the largest study of its type. Patients were evaluated radiologically and clinically using the Harris hip score (HHS). Group A comprised 183 patients (73 male, 110 female) with a mean age of 71.3 years (55 to 89). Group B comprised 104 patients (48 male, 56 female) with a mean age of 69.8 years (56 to 89). A total of 16 patients (13 in Group A, three in Group B) did not have post-operative data for analysis. The mean follow-up in group A was 7.52 years (0.4 to 15.0) and in Group B 7.87 years (0.5 to 14.0).

At final follow-up the mean HHS was similar between groups A and B (74.5 (25 to 100) and 78.0 (37 to 100), respectively; p = 0.068). The total number of revisions for any cause was 28, 17 of which were in group A and 11 in group B. The ten-year survivorship was 86.8% (95% confidence interval (CI) 78.4 to 92.1) and 89.2% (95% CI 78.3 to 94.8) for groups A and B, respectively (log-rank p-value = 0.938). A total of 20 cemented and two cementless acetabular components had evidence of acetabular radiolucencies or acetabular component migration at last follow-up (p = 0.001).

These results indicate that patients with a cemented all-polyethylene and cementless porous-coated polyethylene lined acetabular component have similar long-term clinical outcomes.
The results of uncemented total hip replacement in children with juvenile idiopathic arthritis at ten years
Authors: Daurka J. S. , Malik A. K. , Robin D. A. , Witt J. D.
Published: November 2012

The inherent challenges of total hip replacement (THR) in children include the choice of implant for the often atypical anatomical morphology, its fixation to an immature growing skeleton and the bearing surface employed to achieve a successful long-term result. We report the medium-term results of 52 consecutive uncemented THRs undertaken in 35 paediatric patients with juvenile idiopathic arthritis. The mean age at the time of surgery was 14.4 years (10 to 16). The median follow-up was 10.5 years (6 to 15). During the study period 13 THRs underwent revision surgery. With revision as an endpoint, subgroup analysis revealed 100% survival of the 23 ceramic-on-ceramic THRs and 55% (16 of 29) of the metal- or ceramic-on-polyethylene. This resulted in 94% (95% CI 77.8 to 98.4) survivorship of the femoral component and 62% (95% CI 41.0 to 78.0) of the acetabular component. Revision of the acetabular component for wear and osteolysis were the most common reasons for failure accounting for 11 of the 13 revisions.

The success seen in patients with a ceramic-on-ceramic articulation seems to indicate that this implant strategy has the potential to make a major difference to the long-term outcome in this difficult group of patients.
The safety of peri-articular local anaesthetic injection for patients undergoing total knee replacement with autologous blood transfusion
Authors: Wallace D. F. , Emmett S. R. , Kang K. K. , Chahal G. S. , Hiskens R. , Balasubramanian S. , McGuinness K. , Parsons H. , Achten J. , Costa M. L.
Published: November 2012

Intra-operative, peri-articular injection of local anaesthesia is an increasingly popular way of controlling pain following total knee replacement. At the same time, the problems associated with allogenic blood transfusion have led to interest in alternative methods for managing blood loss after total knee replacement, including the use of auto-transfusion of fluid from the patient’s surgical drain. It is safe to combine peri-articular infiltration with auto-transfusion from the drain. We performed a randomised clinical trial to compare the concentration of local anaesthetic in the blood and in the fluid collected in the knee drain in patients having either a peri-articular injection or a femoral nerve block. Clinically relevant concentrations of local anaesthetic were found in the fluid from the drains of patients having peri-articular injections (4.92 μg/ml (sd 3.151)). However, none of the patients having femoral nerve blockade had detectable levels. None of the patients in either group had clinically relevant concentrations of local anaesthetic in their blood after re-transfusion.

The evidence from this study suggests that it is safe to use peri-articular injection in combination with auto-transfusion of blood from peri-articular drains during knee replacement surgery.