bluuebunny/crossref_metadata_2025 huggingface dataset:
Simplified molecular detection of Leishmania parasites in various clinical samples from patients with leishmaniasis
Authors: Mugasa Claire M , Laurent Thierry , Schoone Gerard J , Basiye Frank L , Saad Alfarazdeg A , el Safi Sayda , Kager Piet A , Schallig Henk DFH
Published: March 2010

Background

Molecular methods to detect Leishmania parasites are considered specific and sensitive, but often not applied in endemic areas of developing countries due to technical complexity. In the present study isothermal, nucleic acid sequence based amplification (NASBA) was coupled to oligochromatography (OC) to develop a simplified detection method for the diagnosis of leishmaniasis. NASBA-OC, detecting Leishmania RNA, was evaluated using clinical samples from visceral leishmaniasis patients from East Africa (n = 30) and cutaneous leishmaniasis from South America (n = 70) and appropriate control samples.

Results

Analytical sensitivity was 10 parasites/ml of spiked blood, and 1 parasite/ml of culture. Diagnostic sensitivity of NASBA-OC was 93.3% (95% CI: 76.5%-98.8%) and specificity was 100% (95% CI: 91.1%-100%) on blood samples, while sensitivity and specificity on skin biopsy samples was 98.6% (95% CI: 91.2%-99.9%) and 100% (95% CI: 46.3%-100%), respectively.

Conclusion

The NASBA-OC format brings implementation of molecular diagnosis of leishmaniasis in resource poor countries one step closer.
Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis
Authors: Jin Fei , Qu Li-Shuai , Shen Xi-Zhong
Published: March 2010

Background

Hereditary hemochromatosis (HH) is an autosomal recessive disorder mainly associated with homozygosity for the C282Y and H63D mutations in the hemochromatosis (HFE) gene. The reports about the C282Y and H63D mutations and hepatocellular carninoma (HCC) were controversial. To clarify the relationship between C282Y and H63D mutations and HCC, a meta-analysis including nine studies (1102 HCC cases and 3766 controls, mainly came from European populations) was performed.

Methods

The association was measured using random-effect (RE) or fixed-effect (FE) odds ratios (ORs) combined with 95% confidence intervals (CIs) according to the studies' heterogeneity.

Results

Meta-analysis of nine studies showed that Y allele of C282Y was associated with HCC risk: RE OR reached 1.50 (95%CI: 1.05-2.14, p for heterogeneity = 0.02, I2 = 0.57). Subgroup analysis of seven studies also showed Y allele was associated with HCC risk in healthy populations: RE OR reached 1.61 (95%CI: 1.08-2.39, p for heterogeneity = 0.04, I2 = 0.55). We further did subgroup analysis in alcoholic liver cirrhosis (LC) patients of four studies (224 cases and 380 controls) and found that both the dominant model and Y allele of C282Y were associated with HCC risk (FE OR reached 4.06, 95%CI: 2.08-7.92 and 3.41, 95%CI: 1.81-6.41, respectively). There was no distinct heterogeneity among the studies (I2 = 0). Sensitivity analyses showed the results were robust in the subgroup analysis of alcoholic LC patients.

Conclusions

C282Y mutation was associated with HCC in European alcoholic LC patients.
microRNA as a new immune-regulatory agent in breast milk
Authors: Kosaka Nobuyoshi , Izumi Hirohisa , Sekine Kazunori , Ochiya Takahiro
Published: March 2010

Background

Breast milk is a complex liquid that provides nutrition to the infant and facilitates the maturation of the infant's immune system. Recent studies indicated that microRNA (miRNA) exists in human body fluid. Because miRNAs are known to regulate various immune systems, we hypothesized that human breast milk contains miRNAs that may be important for the development of the infant's immune system.

Findings

We profiled miRNA expression in human breast milk and detected high expression levels of immune-related miRNAs in the first 6 months of lactation. Furthermore, these miRNA molecules are stable even in very acidic conditions, indicating that breast milk allows dietary intake of miRNAs by infants.

Conclusions

Our findings provide new insight into how breast milk can modulate the development of the infant's immune system. This study suggests the transfer of genetic material as miRNA from human to human occurs by means other than through sexual reproduction.
Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study
Authors: Cronin-Fenton Deirdre P , Pedersen Lars , Lash Timothy L , Friis Søren , Baron John A , Sørensen Henrik T
Published: March 2010

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting.

Methods

We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls.

Results

Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk.

Conclusions

Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.
90Y-Edotreotide for Metastatic Carcinoid Refractory to Octreotide
Authors: Bushnell David L. , O'Dorisio Thomas M. , O'Dorisio M. Sue , Menda Yusuf , Hicks Rodney J. , Van Cutsem Eric , Baulieu Jean-Louis , Borson-Chazot Francoise , Anthony Lowell , Benson Al B. , Oberg Kjell , Grossman Ashley B. , Connolly Mary , Bouterfa Hakim , Li Yong , Kacena Katherine A. , LaFrance Norman , Pauwels Stanislas A.
Published: March 2010

Purpose

Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using 90Y-edotreotide to treat symptomatic patients with carcinoid tumors.

Patients and Methods

Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) 90Y-edotreotide each, once every 6 weeks.

Results

Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days.

Conclusion

90Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.
Breast Cancer Subtypes and the Risk of Local and Regional Relapse
Authors: Voduc K. David , Cheang Maggie C.U. , Tyldesley Scott , Gelmon Karen , Nielsen Torsten O. , Kennecke Hagen
Published: March 2010

Purpose

The risk of local and regional relapse associated with each breast cancer molecular subtype was determined in a large cohort of patients with breast cancer. Subtype assignment was accomplished using a validated six-marker immunohistochemical panel applied to tissue microarrays.

Patients and Methods

Semiquantitative analysis of estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin (CK) 5/6 was performed on tissue microarrays constructed from 2,985 patients with early invasive breast cancer. Patients were classified into the following categories: luminal A, luminal B, luminal-HER2, HER2 enriched, basal-like, or triple-negative phenotype–nonbasal. Multivariable Cox analysis was used to determine the risk of local or regional relapse associated the intrinsic subtypes, adjusting for standard clinicopathologic factors.

Results

The intrinsic molecular subtype was successfully determined in 2,985 tumors. The median follow-up time was 12 years, and there have been a total of 325 local recurrences and 227 regional lymph node recurrences. Luminal A tumors (ER or PR positive, HER2 negative, Ki-67 < 1%) had the best prognosis and the lowest rate of local or regional relapse. For patients undergoing breast conservation, HER2-enriched and basal subtypes demonstrated an increased risk of regional recurrence, and this was statistically significant on multivariable analysis. After mastectomy, luminal B, luminal-HER2, HER2-enriched, and basal subtypes were all associated with an increased risk of local and regional relapse on multivariable analysis.

Conclusion

Luminal A tumors are associated with a low risk of local or regional recurrence. Molecular subtyping of breast tumors using a six-marker immunohistochemical panel can identify patients at increased risk of local and regional recurrence.
Ofatumumab As Single-Agent CD20 Immunotherapy in Fludarabine-Refractory Chronic Lymphocytic Leukemia
Authors: Wierda William G. , Kipps Thomas J. , Mayer Jiří , Stilgenbauer Stephan , Williams Cathy D. , Hellmann Andrzej , Robak Tadeusz , Furman Richard R. , Hillmen Peter , Trneny Marek , Dyer Martin J.S. , Padmanabhan Swami , Piotrowska Magdalena , Kozak Tomas , Chan Geoffrey , Davis Randy , Losic Nedjad , Wilms Joris , Russell Charlotte A. , Österborg Anders
Published: March 2010

Purpose

New treatments are needed for patients with fludarabine- and alemtuzumab-refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment; these groups have poor outcomes with available salvage regimens. Ofatumumab (HuMax-CD20) is a human monoclonal antibody targeting a distinct small-loop epitope on the CD20 molecule. We conducted an international clinical study to evaluate the efficacy and safety of ofatumumab in patients with FA-ref and BF-ref CLL.

Patients and Methods

Patients received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg); response by an independent review committee (1996 National Cancer Institute Working Group criteria) was assessed every 4 weeks until week 24 and then every 3 months until month 24.

Results

This planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. Median progression-free survival and overall survival times were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the BF-ref group, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia.

Conclusion

Ofatumumab is an active, well-tolerated treatment providing clear clinical improvements for fludarabine-refractory patients with very poor-prognosis CLL.
Potential Role of Lymphadenectomy in Advanced Ovarian Cancer: A Combined Exploratory Analysis of Three Prospectively Randomized Phase III Multicenter Trials
Authors: du Bois Andreas , Reuss Alexander , Harter Philipp , Pujade-Lauraine Eric , Ray-Coquard Isabelle , Pfisterer Jacobus
Published: March 2010

Purpose

Primary surgery followed by platinum/taxane-based chemotherapy is the standard therapy in advanced ovarian cancer. The prognostic role of complete debulking has been well described; however, the impact of systematic pelvic and para-aortic lymphadenectomy and its interaction with biologic factors are still not fully defined.

Methods

This was an exploratory analysis of three prospective randomized trials (Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom trials 3, 5, and 7) investigating platinum/taxane-based chemotherapy regimens in advanced ovarian cancer conducted between 1995 and 2002.

Results

One thousand nine hundred twenty-four patients were analyzed. Lymphadenectomy was associated with superior survival in patients without gross residual disease. In patients with and without lymphadenectomy, the median survival time was 103 and 84 months, respectively, and 5-year survival rates were 67.% and 59.2%, respectively (P = .0166); multivariate analysis confirmed a significant impact of lymphadenectomy on overall survival (OS; hazard ratio [HR] = 0.74; 95% CI, 0.59 to 0.94; P = .0123). In patients with small residual tumors up to 1 cm, the effect of lymphadenectomy on OS barely reached significance (HR = 0.85; 95% CI, 0.72 to 1.00; P = .0497). For patients with small residual tumors and clinically suspect nodes, lymphadenectomy resulted in a 16% gain in 5-year OS (log-rank test, P = .0038).

Conclusion

Lymphadenectomy in advanced ovarian cancer might offer benefit mainly to patients with complete intraperitoneal debulking. However, this hypothesis should be confirmed in the context of a prospectively randomized trial.
Randomized Phase III Trial of Gemcitabine Plus Cisplatin Compared With Single-Agent Gemcitabine As First-Line Treatment of Patients With Advanced Pancreatic Cancer: The GIP-1 Study
Authors: Colucci Giuseppe , Labianca Roberto , Di Costanzo Francesco , Gebbia Vittorio , Cartenì Giacomo , Massidda Bruno , Dapretto Elisa , Manzione Luigi , Piazza Elena , Sannicolò Mirella , Ciaparrone Marco , Cavanna Luigi , Giuliani Francesco , Maiello Evaristo , Testa Antonio , Pederzoli Paolo , Falconi Massimo , Gallo Ciro , Di Maio Massimo , Perrone Francesco
Published: March 2010

Purpose

Single-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696).

Patients and Methods

Patients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) ≥ 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m2weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m2added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral α .05, 355 events were needed and 400 patients planned.

Results

Four hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS ≥ 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity.

Conclusion

The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer.
Large Randomized Study of Thymosin α 1, Interferon Alfa, or Both in Combination With Dacarbazine in Patients With Metastatic Melanoma
Authors: Maio Michele , Mackiewicz Andrzej , Testori Alessandro , Trefzer Uwe , Ferraresi Virginia , Jassem Jacek , Garbe Claus , Lesimple Thierry , Guillot Bernard , Gascon Pere , Gilde Katalin , Camerini Roberto , Cognetti Francesco
Published: March 2010

Purpose

Thymosin α 1 (Tα1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Tα1 with dacarbazine (DTIC) and interferon alfa (IFN-α) in patients with metastatic melanoma.

Patients and Methods

Four hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-α+Tα1 (1.6 mg); DTIC+IFN-α+Tα1 (3.2 mg); DTIC+IFN-α+Tα1 (6.4 mg); DTIC+Tα1 (3.2 mg); DTIC+IFN-α (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months.

Results

Ten and 12 tumor responses were observed in the DTIC+IFN-α+Tα1 (3.2 mg) and DTIC+Tα1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P0 ≤ .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Tα1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Tα1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Tα1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Tα1 to DTIC and IFN-α did not lead to any additional toxicity.

Conclusion

These results suggest Tα1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.
Overall Survival and Post-Progression Survival in Advanced Breast Cancer: A Review of Recent Randomized Clinical Trials
Authors: Saad Everardo D. , Katz Artur , Buyse Marc
Published: March 2010

With the availability of several lines of therapy, overall survival (OS) has been progressively substituted by progression-free survival (PFS) and other tumor-based assessments as the primary efficacy end point in advanced breast cancer trials. We investigated the frequency and determinants of OS gain in the recent literature and the duration of post-progression survival (PPS) according to treatment type and line. We used PubMed to search for phase III trials on systemic antineoplastic therapies published between January 1998 and December 2007 in 11 leading journals. The primary end point was the one stated explicitly, used for N calculation, or listed first. Significant gain was considered as reported P < .05 for superiority trials or proven non-inferiority or equivalence otherwise. We retrieved 76 trials, and gain in OS was reported in 15 cases (19.7%). The median gain in OS was 4.7 months, and such gain was more frequent when there was significant gain in PFS and in second-line and third-line trials. The average median OS was 20.7 months in trials assessing first-line chemotherapy and 31.1 months with first-line hormone therapy. The median proportion of OS accounted for by PPS was significantly longer in hormone therapy trials than in chemotherapy trials, but varied little across treatment lines. A statistically significant gain in OS has been reported in about one in five recent phase III trials in advanced breast cancer, despite the fact that OS has seldom been used as the primary end point. PPS represents nearly two thirds of patient survival after on-trial disease progression.
Imatinib Mesylate in Advanced Dermatofibrosarcoma Protuberans: Pooled Analysis of Two Phase II Clinical Trials
Authors: Rutkowski Piotr , Van Glabbeke Martine , Rankin Cathryn J. , Ruka Wlodzimierz , Rubin Brian P. , Debiec-Rychter Maria , Lazar Alexander , Gelderblom Hans , Sciot Raf , Lopez-Terrada Dolores , Hohenberger Peter , van Oosterom Allan T. , Schuetze Scott M.
Published: March 2010

Purpose

Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB).

Patients and Methods

Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment.

Results

Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (4%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%.

Conclusion

Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day.
Androgen Receptor-Dependent Activation of Endothelial Nitric Oxide Synthase in Vascular Endothelial Cells: Role of Phosphatidylinositol 3-Kinase/Akt Pathway
Authors: Yu Jing , Akishita Masahiro , Eto Masato , Ogawa Sumito , Son Bo-Kyung , Kato Shigeaki , Ouchi Yasuyoshi , Okabe Tetsuro
Published: March 2010

The mechanisms of testosterone-induced vasodilatation are not fully understood. This study investigated the effect of testosterone on nitric oxide (NO) synthesis and its molecular mechanism using human aortic endothelial cells (HAEC). Testosterone at physiological concentrations (1–100 nm) induced a rapid (15–30 min) increase in NO production, which was associated with phosphorylation and activation of endothelial NO synthase (eNOS). Then, the involvement of the androgen receptor (AR), which is abundantly expressed in HAEC, was examined. The effect of testosterone on eNOS activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA. In contrast, testosterone-induced eNOS phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERα small interference RNA. 5α-Dihydrotestosterone, a nonaromatizable androgen, also stimulated eNOS phosphorylation. Next, the signaling cascade that leads to eNOS phosphorylation was explored. Testosterone stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner, with maximal response at 15–60 min. The rapid phosphorylation of eNOS or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85α subunit of PI3-kinase. In conclusion, testosterone rapidly induces NO production via AR-dependent activation of eNOS in HAEC. Activation of PI3-kinase/Akt signaling and the direct interaction of AR with p85α are involved, at least in part, in eNOS phosphorylation.
Aromatase Deficiency Inhibits the Permeability Transition in Mouse Liver Mitochondria
Authors: Moro Loredana , Arbini Arnaldo A. , Hsieh Jer-Tsong , Ford Jeffery , Simpson Evan R. , Hajibeigi Asghar , Öz Orhan K.
Published: March 2010

Lack of estrogens affects male physiology in a number of ways, including severe changes in liver metabolism that result in lipid accumulation and massive hepatic steatosis. Here we investigated whether estrogen deficiency may alter the functionality and permeability properties of liver mitochondria using, as an experimental model, aromatase knockout (ArKO) male mice, which cannot synthesize endogenous estrogens due to a disruption of the Cyp19 gene. Liver mitochondria isolated from ArKO mice displayed increased activity of the mitochondrial respiratory complex IV compared with wild-type mice and were less prone to undergo cyclosporin A-sensitive mitochondrial permeability transition (MPT) induced by calcium loading. The altered permeability properties of the mitochondrial membranes were not due to changes in reactive oxygen species, ATP levels, or mitochondrial membrane potential but were associated with increased content of the phospholipid cardiolipin, structural component of the mitochondrial membranes and regulator of the MPT pore, and with increased mitochondrial protein levels of Bcl-2 and the adenine nucleotide translocator (ANT), regulator and component of the MPT pore, respectively. Real-time RT-PCR demonstrated increased mRNA levels for Bcl-2 and ANT2 but not for the ANT1 isoform in ArKO livers. Supplementation of 17β-estradiol retrieved ArKO mice from massive hepatic steatosis and restored mitochondrial permeability properties, cardiolipin, Bcl-2, and ANT2 levels. Overall, our findings demonstrate an important role of estrogens in the modulation of hepatic mitochondrial function and permeability properties in males and suggest that estrogen deficiency may represent a novel positive regulator of Bcl-2 and ANT2 proteins, two inhibitors of MPT occurrence and powerful antiapoptotic molecules.
Tracking of Bone Mass and Density during Childhood and Adolescence
Authors: Kalkwarf Heidi J. , Gilsanz Vicente , Lappe Joan M. , Oberfield Sharon , Shepherd John A. , Hangartner Thomas N. , Huang Xangke , Frederick Margaret M. , Winer Karen K. , Zemel Babette S.
Published: March 2010

Context: Whether a child with low bone mineral density (BMD) at one point in time will continue to have low BMD, despite continued growth and maturation, is important clinically. The stability of a characteristic during growth is referred to as “tracking.”

Objective: We examined the degree of tracking in bone mineral content (BMC) and BMD during childhood and adolescence and investigated whether tracking varied according to age, sexual maturation, and changes in growth status.

Design: We conducted a longitudinal study with measurements at baseline and annually for 3 yr.

Setting: The Bone Mineral Density in Childhood Study was conducted at five clinical centers in the United States.

Study Participants: A total of 1554 girls and boys, ages 6–16 yr at baseline, participated in the study.

Main Outcome Measures: Whole body, spine, hip, and forearm BMC and BMD were measured by dual-energy x-ray absorptiometry, and age-, sex-, and race-specific Z-scores were calculated. Deviation from tracking was calculated as the Z-score at yr 3 minus baseline.

Results: Correlations between Z-scores at baseline and yr 3 ranged from 0.76–0.88. Among children with a Z-score below −1.5 at baseline, 72–87% still had a Z-score below −1 after 3 yr. Age, sexual maturation, and deviations in growth status (P < 0.01) were associated with deviation from tracking; however, tracking was strongly evident even after adjusting for the effects of age, maturation, and growth.

Conclusions: Bone density showed a high degree of tracking over 3 yr in children and adolescents. Healthy children with low bone density will likely continue to have low bone density unless effective interventions are instituted.
Comparison of Competitive Radioimmunoassays and Two-Site Sandwich Assays for the Measurement and Interpretation of Plasma Ghrelin Levels
Authors: Prudom Catherine , Liu Jianhua , Patrie James , Gaylinn Bruce D. , Foster-Schubert Karen E. , Cummings David E. , Thorner Michael O. , Geysen H. Mario
Published: March 2010

Context: Ghrelin, an endogenous ligand for the GH secretagogue receptor, is an orexigenic peptide hormone produced primarily by the stomach. Recent studies suggest significant differences in the specificity of currently available ghrelin assays.

Objective: The aim of the study was to compare four ghrelin assays (two commercially available and two developed by our group) of differing specificity, each used on the same set of more than 800 plasma samples from a human study.

Design: Thirteen volunteers were sampled every 20 min for 6 h after consumption of one of three isocaloric drinks consisting of either 80% fat, 80% carbohydrate, or 80% protein. The samples were assayed by RIA for total and active ghrelin, as well as by sandwich assays for acyl and des-acyl ghrelin. The ghrelin profiles for each individual were smoothed using a statistical algorithm to lessen the effects of pulsatility and noise.

Results: The sandwich assays for acyl and des-acyl ghrelin yielded ghrelin values that were lower than those from the corresponding RIAs. The ghrelin profiles after nutrient ingestion were similar, yet key differences among the four assays were apparent; in particular, percentage changes were significantly greater in the sandwich assays.

Conclusions: The lower levels and greater relative changes in ghrelin values reported by the sandwich assays are consistent with greater assay specificity. When applied to the nutrient study, the sandwich assays were better able to distinguish the different responses to different nutrients than were the RIAs.
Association of Lipoprotein-Associated Phospholipase A2 with Coronary Artery Disease in African-Americans and Caucasians
Authors: Anuurad Erdembileg , Ozturk Zeynep , Enkhmaa Byambaa , Pearson Thomas A. , Berglund Lars
Published: March 2010

Context: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is bound predominately to low-density lipoprotein and has been implicated as a risk factor for coronary artery disease (CAD).

Objective: We investigated the association between Lp-PLA2 and CAD in a biethnic African-American and Caucasian population.

Design: Lp-PLA2 mass, activity, and index, an integrated measure of mass and activity, and other cardiovascular risk factors were determined in 224 African-Americans and 336 Caucasians undergoing coronary angiography.

Main Outcome Measures: We assessed the distribution of Lp-PLA2 levels and determined the predictive role of Lp-PLA2 as a risk factor for CAD.

Results: Levels of Lp-PLA2 mass and activity were higher among Caucasians compared with African-Americans (293 ± 75 vs. 232 ± 76 ng/ml, P < 0.001 for mass and 173 ± 41 vs. 141 ± 39 nmol/min/ml, P < 0.001 for activity, respectively). However, Lp-PLA2 index was similar in the two groups (0.61 ± 0.17 vs. 0.64 ± 0.19, P = NS). In both ethnic groups, Lp-PLA2 activity and index was significantly higher among subjects with CAD. African-American subjects with CAD had significantly higher Lp-PLA2 index than corresponding Caucasian subjects (0.69 ± 0.20 vs. 0.63 ± 0.18, P = 0.028). In multivariate regression analyses, after adjusting for other risk factors, Lp-PLA2 index was independently (odds ratio 6.7, P = 0.047) associated with CAD in African-Americans but not Caucasians.

Conclusions: Lp-PLA2 activity and index was associated with presence of CAD among African-Americans and Caucasians undergoing coronary angiography. The findings suggest an independent impact of vascular inflammation among African-Americans as contributory to CAD risk and underscore the importance of Lp-PLA2 as a cardiovascular risk factor.
Resisting the Constraint: The Constraint as a Methodological Tool for a Performance-Oriented History of the Theater
Authors: Biet Christian , Vanhaesebrouck Karel
Published: March 2010

This article investigates the way the notion of constraint could be extended to theater studies and theater history, focusing on the case of French classical tragedy in the seventeenth century. Can classical poetics be regarded as a set of constraints? Rather than viewing the constraint as a literary technique, the authors argue that it is also relevant to other, nonliterary phenomena, for example, to the theater. There the idea of constraint can be put to use as a tool for theoretical reflection on and critical or historical analysis of performance practice. The article pays special attention to (1) the way Aristotelian poetics developed throughout the seventeenth century from a flexible set of tips to a hegemonic theoretical practice; (2) the increasing use of textual and performative constraints to resolve the disorder and friction typical of French (early) modern theater practice; (3) the divergence between theory and practice, between the intended and the actual performance; and (4) the relationship between the notion of constraint, on the one hand, and that of discipline, on the other.
Constrained Writing, Creative Writing: The Case of Handbooks for Writing Romances
Authors: de Geest Dirk , Goris An
Published: March 2010

This article broadens the concept of “constrained writing” by applying it to a less prestigious domain of literature, namely, popular romance novels. In order to find out how constraints play a role in writing and publishing such commercial texts, a corpus of handbooks for writing romances is carefully analyzed. Such handbooks meticulously guide aspiring writers through the entire process of writing romances, from the first ideas to the final act of having their texts published. This product- and process-orientated approach is ultimately based on a number of discursive strategies that enable the aspiring writer to conceive of romance writing as an accessible and feasible yet highly constrained activity. In this article, three such dominant strategies are carefully discussed. One is the handbooks' constant appeal to the reading experience of the romance. Another is their conceptualization of writing as a craft and a profession and their infrequent but functional use of explicitly normative language. Finally, the role of the genre's highly influential institutional context in the handbooks' formulation of generic norms and constraints is considered as well. This article ultimately demonstrates the broad applicability of the notion of constrained writing to many forms of literature.
Tailoring the switch from IRES-dependent to 5′-end-dependent translation with the RNase P ribozyme
Authors: Fernández Noemi , Martínez-Salas Encarnación
Published: March 2010

Translation initiation driven by internal ribosome entry site (IRES) elements is dependent on the structural organization of the IRES region. We have previously shown that a structural motif within the foot-and-mouth-disease virus IRES is recognized in vitro as substrate for the Synechocystis sp. RNase P ribozyme. Here we show that this structure-dependent endonuclease recognizes the IRES element in cultured cells, leading to inhibition of translation. Inhibition of IRES activity was dependent on the expression of the active ribozyme RNA subunit. Moreover, expression of the antisense sequence of the ribozyme did not inhibit IRES activity, demonstrating that stable RNA structures located upstream of the IRES element do not interfere with internal initiation. RNAs carrying defective IRES mutants that were substrates of the ribozyme in vivo revealed an increased translation of the reporter in response to the expression of the active ribozyme. In support of RNA cleavage, subsequent analysis of the translation initiation manner indicated a switch from IRES-dependent to 5′-end-dependent translation of RNase P target RNAs. We conclude that the IRES element is inactivated by expression in cis of RNase P in the cytoplasm of cultured cells, providing a promising antiviral tool to combat picornavirus infections. Furthermore, our results reinforce the essential role of the structural motif that serves as RNase P recognition motif for IRES activity.
The Debate on Net Neutrality: A Policy Perspective
Authors: Cheng Hsing Kenneth , Bandyopadhyay Subhajyoti , Guo Hong
Published: March 2010

The status quo of prohibiting broadband service providers from charging websites for preferential access to their customers—the bedrock principle of net neutrality (NN)—is under fierce debate. We develop a game-theoretic model to address two critical issues of NN: (1) Who are gainers and losers of abandoning NN? (2) Will broadband service providers have greater incentive to expand their capacity without NN? We find that if the principle of NN is abolished, the broadband service provider stands to gain from the arrangement, as a result of extracting the preferential access fees from content providers. Content providers are thus left worse off, mirroring the stances of the two sides in the debate. Depending on parameter values in our framework, consumer surplus either does not change or is higher in the short run. When compared to the baseline case under NN, social welfare in the short run increases if one content provider pays for preferential treatment but remains unchanged if both content providers pay. Finally, we find that the incentive to expand infrastructure capacity for the broadband service provider and its optimal capacity choice under NN are higher than those under the no-net-neutrality (NNN) regime, except in some specific cases. Under NN, the broadband service provider always invests in broadband infrastructure at the socially optimal level but either under- or overinvests in infrastructure capacity in the absence of NN.
Price Formats as a Source of Price Dispersion: A Study of Online and Offline Prices in the Domestic U.S. Airline Markets
Authors: Chellappa Ramnath K. , Sin Raymond G. , Siddarth S.
Published: March 2010

A large body of research in economics, information systems, and marketing has sought to understand sources of price dispersion. Previous empirical work has mainly offered consumer- and/or product-based explanations for this phenomenon. In contrast, our research explores the key role played by vendors' price-format adoption in explaining price dispersion. We empirically analyze over a half-million online and offline prices offered by major U.S. airlines in the top 500 domestic markets. Our study shows that a vendor's price format remains an important source of price dispersion in both channels even after accounting for other factors known to impact dispersion in airline ticket prices. Importantly, this finding is true for both transacted and posted tickets. We document several other interesting empirical findings. First, the lower variance in the prices of “everyday low price” (EDLP) firms serves to reduce the market-level dispersion in prices when such firms are present. Moreover, the price variance of non-EDLP firms in these markets is also lower than in those markets in which EDLP competitors are absent. Second, we also find that dispersion in offered prices increases closer to the departure date, which is consistent with theoretical assertion that price dispersion increases with reservation prices. Finally, we continue to observe dispersion of online prices even after accounting for vendor strategy and other known sources of dispersion, suggesting that the prices are unlikely to converge even in the presence of sophisticated online search mechanisms.
Notes and Letters in Orthopaedic Surgery Revisited: Can Surgeons Change?
Authors: Longworth A , Davies D , Amirfeyz R , Bannister G
Published: March 2010

Outpatient clinic letters are a widely used and effective means of communication between doctors and nurses. In the literature there was an absence of professional guidelines detailing how outpatient letters should be constructed. A previous study highlighted the importance of effective communication by identifying information deemed important by clinicians and recording it in a structured letter format. General practitioners (GPs) and orthopaedic surgeons perceived diagnosis, treatment, management plan, date of injury, current condition and findings on physical examination to be most important. Nursing staff favoured a clear management plan, particularly any requirement for investigations on arrival at clinic.
How to Find Patients Who are 'Lost to Follow-up'
Authors: Biant LC , Eswaramoorthy VK , Field RE
Published: March 2010

Long-term surveillance of patients is necessary to ascertain the outcome of medical interventions. The rate of 'loss to follow-up' is the largest controllable variable in long-term follow-up studies. Such surveillance programmes are of particular importance to surgical interventions as differences between techniques or implants may take years to become apparent.
Decision criteria for rational selection of homogeneous genotyping platforms for pharmacogenomics testing in clinical diagnostics
Authors: Di Francia Raffaele , Frigeri Ferdinando , Berretta Massimiliano , Cecchin Erika , Orlando Claudio , Pinto Antonio , Pinzani Pamela
Published: March 2010

Background: Genotyping is crucial for the identification of genetic markers underlying the development of neoplastic diseases and for determining individual variations in response to specific drugs. Technologies which can accurately identify genetic polymorphisms will dramatically affect routine diagnostic processes and future therapeutic developments in personalized medicine. However, such methods need to fulfill the principles of analytical validation to determine their suitability to assess nucleotide polymorphisms in target genes.

Approach: This article reviews recent developments in homogeneous technologies for the genotyping of single nucleotide polymorphisms. Here, homogeneous methods essentially refer to “single-tube” assays performed in a liquid phase. For the appropriate choice of any method, several criteria must be considered: 1) detection of known genetic variations; 2) analytical performance including specificity, sensitivity and robustness of the method; 3) availability of large platforms and required equipment; 4) suitability of platforms and tests for routine diagnostics; 5) suitability for high throughput implementation.

Content: This review is intended to provide the reader with an understanding of these various technologies for pharmacogenomic testing in the routine clinical laboratory. A brief overview is provided on the available technologies for the detection of known mutations, a specific description of the homogeneous platforms currently employed in genotyping analysis, and considerations regarding the proper assessment of the analytical performance of these methods. Based on the criteria proposed here, potential users may evaluate advantages and limitations of the various analytical platforms and identify the most appropriate platform according to their specific setting and diagnostic needs.

Clin Chem Lab Med 2010;48:447–59.
UGT2B17 and SULT1A1 gene copy number variation (CNV) detection by LabChip microfluidic technology
Authors: Gaedigk Andrea , Gaedigk Roger , Leeder J. Steven
Published: March 2010

Background: Gene copy number variations (CNVs) are increasingly recognized to play important roles in the expression of genes and hence on their respective enzymatic activities. This has been demonstrated for a number of drug metabolizing genes, such as UDP-glucuronosyltransferases 2B17 (UGT2B17) and sulfotransferase 1A1 (SULT1A1), which are subject to genetic heterogeneity, including CNV. Quantitative assays to assess gene copy number are therefore becoming an integral part of accurate genotype assessment and phenotype prediction.

Methods: In this study, we evaluated a microfluidics-based system, the Bio-Rad Experion system, to determine the power and utility of this platform to detect UGT2B17 and SULT1A1 CNV in DNA samples derived from blood and tissue. UGT2B17 is known to present with 0, 1 or 2 and SULT1A1 with up to 5 gene copies.

Results: Distinct clustering (p<0.001) into copy number groups was achieved for both genes. DNA samples derived from blood exhibited less inter-run variability compared to DNA samples obtained from liver tissue. This variability may be caused by tissue-specific PCR inhibitors as it could be overcome by using DNA from another tissue, or after the DNA had undergone whole genome amplification.

Conclusions: This method produced results comparable to those reported for other quantitative test platforms.

Clin Chem Lab Med 2010;48:627–33.
Somme 1916 und Normandie 1944. Zwei Erinnerungslandschaften der Weltkriegsepoche zwischen Geschichte, Politik und Tourismus
Authors: Mütter Bernd
Published: March 2010

Der Beitrag geht aus vom Eindruck des heutigen deutschen Besuchers der beiden Weltkriegsschlachtfelder (1). Nach einer vergleichenden analytischen Skizze der beiden Schlachten (2) wird die westalliierte Inszenierung der Erinnerung (Kriegsspuren, Soldatenfriedhöfe, Denkmäler, Museen) untersucht (3). Schließlich stellt sich die Frage, wie die Erinnerung vor Ort auf dem Hintergrund der europäischen Verständigung ehemaliger Weltkriegsgegner und des anstehenden Generationswechsels zukunftsfähig gestaltet werden kann (4).