bluuebunny/crossref_metadata_2025 huggingface dataset:
Distress in Older Patients With Cancer
Authors: Hurria Arti , Li Daneng , Hansen Kurt , Patil Sujata , Gupta Ravi , Nelson Christian , Lichtman Stuart M. , Tew William P. , Hamlin Paul , Zuckerman Enid , Gardes Jonathan , Limaye Sewanti , Lachs Mark , Kelly Eva
Published: August 2009

Purpose

To determine the predictors of distress in older patients with cancer.

Patients and Methods

Patients age ≥ 65 years with a solid tumor or lymphoma completed a questionnaire that addressed these geriatric assessment domains: functional status, comorbidity, psychological state, nutritional status, and social support. Patients self-rated their level of distress on a scale of zero to 10 using a validated screening tool called the Distress Thermometer. The relationship between distress and geriatric assessment scores was examined.

Results

The geriatric assessment questionnaire was completed by 245 patients (mean age, 76 years; standard deviation [SD], 7 years; range, 65 to 95 years) with cancer (36% stage IV; 71% female). Of these, 87% also completed the Distress Thermometer, with 41% (n = 87) reporting a distress score of ≥ 4 on a scale of zero to 10 (mean score, 3; SD, 3; range, zero to 10). Bivariate analyses demonstrated an association between higher distress (≥ 4) and poorer physical function, increased comorbid medical conditions, poor eyesight, inability to complete the questionnaire alone, and requiring more time to complete the questionnaire. In a multivariate regression model based on the significant bivariate findings, poorer physical function (increased need for assistance with instrumental activities of daily living [P = .015] and lower physical function score on the Medical Outcomes Survey [P = .018]) correlated significantly with a higher distress score.

Conclusion

Significant distress was identified in 41% of older patients with cancer. Poorer physical function was the best predictor of distress. Further studies are needed to determine whether interventions that improve or assist with physical functioning can help to decrease distress in older adults with cancer.
Cancer-Related Direct-to-Consumer Advertising: Awareness, Perceptions, and Reported Impact Among Patients Undergoing Active Cancer Treatment
Authors: Abel Gregory A. , Burstein Harold J. , Hevelone Nathanael D. , Weeks Jane C.
Published: August 2009

Purpose

Although cancer-related direct-to-consumer advertising (CR-DTCA) is prevalent, little is known about cancer patients' experiences with this controversial medium of medical communication.

Methods

We administered a 41-item, mailed questionnaire to consecutive patients with breast and hematologic malignancies who were undergoing active treatment at our institution. We assessed awareness of CR-DTCA within the prior year, perceptions of CR-DTCA, and CR-DTCA–prompted patient and provider behaviors.

Results

We received 348 completed questionnaires (response rate, 75.0%). Overall, 86.2% reported being aware of CR-DTCA, most frequently from television (77.7%). Awareness did not vary with clinical or sociodemographic factors except that patients were more likely to be aware of CR-DTCA for products specific to their cancer types (P < .0001). A majority of those aware reported that CR-DTCA made them “aware of treatments they did not know about” (62.2%), provided information in “a balanced manner” (65.2%), and helped them to have “better discussions” with their provider (56.8%). These perceptions were significantly more favorable among those who had not graduated from college (P < .05 for each). Overall, 11.2% reported that CR-DTCA made them “less confident” in their providers' judgment. Of those aware, 17.3% reported talking to their provider about an advertised medication, although less than one fifth of those reported receiving a prescription for the advertised medication.

Conclusion

The patients in our cohort were highly aware of CR-DTCA. CR-DTCA was found to be accessible and useful; however, it decreased some patients' confidence in their providers' judgment. CR-DTCA prompted a modest amount of patient-provider discussion but infrequent patient-reported changes in therapy.
Reduced Intensity Conditioning Compared With Myeloablative Conditioning Using Unrelated Donor Transplants in Patients With Acute Myeloid Leukemia
Authors: Ringdén Olle , Labopin Myriam , Ehninger Gerhard , Niederwieser Dietger , Olsson Richard , Basara Nadezda , Finke Juergen , Schwerdtfeger Rainer , Eder Matthias , Bunjes Donald , Gorin Norbert-Claude , Mohty Mohamad , Rocha Vanderson
Published: August 2009

Purpose

Reduced intensity conditioning regimen (RIC) is increasingly used in hematopoietic stem cell transplantation (HSCT). Unrelated donor (UD) transplants have more complications. We wanted to examine if RIC is a valid treatment option using UD in acute myeloblastic leukemia (AML).

Patients and Methods

Between 1999 and 2005, 401 patients with AML were treated with RIC and 1,154 received myeloablative conditioning (MAC), using UD and reported to the European Group for Blood and Marrow Transplantation Registry. Patients < and ≥ 50 years of age were analyzed separately.

Results

Patients receiving RIC were older, received transplants more recently, received peripheral blood stem cells more frequently, and were treated with total-body irradiation less often. In multivariable analysis, in patients younger than 50 years of age, nonrelapse mortality (NRM) was similar using RIC (hazard ratio [HR], 0.85; P = .41), relapse was increased (HR, 1.46; P = .02) and leukemia-free survival (LFS) was the same (HR, 0.88; P = .28), as compared with MAC. In patients ≥ 50 years of age, NRM was decreased in the RIC group (HR, 0.64; P = .04), relapse probability was not significantly different (HR, 1.34; P = .16) and LFS was similar (HR, 1.04; P = .79) compared with MAC.

Conclusion

RIC-UD transplants are associated with higher relapse in AML patients younger than 50 years of age and decreased NRM in those ≥ 50 years compared with MAC-UD. LFS was similar after both conditioning regimens, regardless of age. Therefore, RIC-UD extend the use of allotransplants for elderly patients and strategies that decrease relapse should be considered mainly in younger patients with AML.
Phase II Study of Axitinib in Sorafenib-Refractory Metastatic Renal Cell Carcinoma
Authors: Rini Brian I. , Wilding George , Hudes Gary , Stadler Walter M. , Kim Sinil , Tarazi Jamal , Rosbrook Brad , Trask Peter C. , Wood Laura , Dutcher Janice P.
Published: August 2009

Purpose

To investigate the efficacy and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 in patients with metastatic renal cell carcinoma (mRCC) refractory to prior therapies that included, but were not limited to, sorafenib.

Patients and Methods

In this multicenter, open-label, phase II study, patients with sorafenib-refractory mRCC received a starting dose of axitinib 5 mg orally twice daily. A one-arm, single-stage design was used to estimate the primary end point of objective response rate (ORR), defined by RECIST (Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival (PFS), overall survival (OS), and patient-reported outcomes.

Results

Of 62 patients recruited, 100% had received prior sorafenib, and 74.2% had received two or more prior systemic treatments. The axitinib dose was titrated to greater than 5 mg twice daily in 53.2% of patients, and 35.5% of patients had the dose modified to less than 5 mg twice daily. In 62 patients evaluable for response, the ORR was 22.6%, and the median duration of response was 17.5 months. Median PFS and OS times were 7.4 months (95% CI, 6.7 to 11.0 months) and 13.6 months (95% CI, 8.4 to 18.8 months), respectively. All-causality grade 3 to 4 adverse events included hand-foot syndrome (16.1%), fatigue (16.1%), hypertension (16.1%), dyspnea (14.5%), diarrhea (14.5%), dehydration (8.1%), and hypotension (6.5%).

Conclusion

Axitinib has antitumor activity in patients with mRCC refractory to prior VEGF-targeted therapy, including sorafenib. Toxicities were mild to moderate and were manageable. A randomized, phase III trial to compare axitinib with sorafenib in patients who have mRCC refractory to one prior first-line therapy regimen is underway.
Phase I/II Trial of AEG35156 X-Linked Inhibitor of Apoptosis Protein Antisense Oligonucleotide Combined With Idarubicin and Cytarabine in Patients With Relapsed or Primary Refractory Acute Myeloid Leukemia
Authors: Schimmer Aaron D. , Estey Elihu H. , Borthakur Gautam , Carter Bing Z. , Schiller Gary J. , Tallman Martin S. , Altman Jessica K. , Karp Judith E. , Kassis Jeannine , Hedley David W. , Brandwein Joseph , Xu Wei , Mak Duncan H. , LaCasse Eric , Jacob Christine , Morris Stephen J. , Jolivet Jacques , Andreeff Michael
Published: August 2009

Purpose

X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy.

Patients and Methods

Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m2) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m2 in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA.

Results

Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m2 of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m2 AEG35156. Among the patients receiving 350 mg/m2 of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156.

Conclusion

At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen.
Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase
Authors: Hughes Timothy , Saglio Giuseppe , Branford Susan , Soverini Simona , Kim Dong-Wook , Müller Martin C. , Martinelli Giovanni , Cortes Jorge , Beppu Lan , Gottardi Enrico , Kim Dongho , Erben Philipp , Shou Yaping , Haque Ariful , Gallagher Neil , Radich Jerald , Hochhaus Andreas
Published: August 2009

Purpose

Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed.

Patients and Methods

Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial.

Results

Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR.

Conclusion

For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.
Phase II Study of Sorafenib in Patients With Sunitinib-Refractory Metastatic Renal Cell Cancer
Authors: Di Lorenzo Giuseppe , Cartenì Giacomo , Autorino Riccardo , Bruni Gianni , Tudini Marianna , Rizzo Mimma , Aieta Michele , Gonnella Antonio , Rescigno Pasquale , Perdonà Sisto , Giannarini Gianluca , Pignata Sandro , Longo Nicola , Palmieri Giovannella , Imbimbo Ciro , De Laurentiis Michele , Mirone Vincenzo , Ficorella Corrado , De Placido Sabino
Published: August 2009

Purpose

No previous prospective trials have been reported with sorafenib in patients with sunitinib-refractory metastatic renal cell cancer (MRCC). We conducted a multicenter study to determine the activity and tolerability of sorafenib as second-line therapy after sunitinib progression in MRCC.

Patients and Methods

Between January 2006 and September 2008, 52 patients were enrolled onto this single-arm phase II study. All patients received sorafenib 400 mg orally twice a day until disease progression or intolerable toxicity. The primary end point was objective response rate (complete or partial response) evaluated every 8 weeks by use of the Response Evaluation Criteria in Solid Tumors; secondary end points were toxicity, time to progression (TTP), and overall survival (OS).

Results

All patients were included in response and safety analyses. Partial responses were observed in 9.6% of patients (five of 52 patients; 95% CI, 5% to 17%) after two cycles. Grade 1 to 2 fatigue, diarrhea, nausea/vomiting, rash, and neutropenia were the most common side effects, noted in 16 (30.8%), 19 (36.5%), 20 (38.5%), 19 (36.5%), and 20 patients (38.5%), respectively. The most common grade 3 toxicity was diarrhea, noted in six patients (11.5%). Median TTP was 16 weeks (range, 8 to 40 weeks), and median OS was 32 weeks (range, 16 to 64 weeks).

Conclusion

Although well tolerated, sorafenib shows limited efficacy in sunitinib-refractory MRCC. Further randomized trials comparing sorafenib with other drugs that target different biologic pathways are needed to define the best second-line treatment option in these patients.
Hell-Fire Jane: Austen and the Dashwoods of West Wycombe
Authors: Barchas Janine
Published: August 2009

Modern readers of Jane Austen have been reluctant to acknowledge that Sense and Sensibility (1811) rewards, and perhaps even demands, detailed knowledge of one of England's most notorious families in Austen's time, namely the Dashwoods of West Wycombe Park. The best-known member of the Dashwood clan was Sir Francis Dashwood (1708-81), second Baronet and Lord Le Despencer, leader of a group of high-profile libertines whose decades of bacchanals earned it the label Hell-Fire Club. At West Wycombe, Sir Francis also designed an emblematic garden, infamous for the ribald features that mimicked the female form. Although Francis Dashwood died in 1781, throughout Austen's lifetime stories about his garden and Hell-Fire shenanigans proliferated in print, while his heirs (the next two baronets were both named John Dashwood) perpetuated his rakish legacy with high-profile domestic conflicts. In short, a lively print market for gossip at the turn of the century insured that the infamous name of Dashwood remained synonymous with diabolism, sexual lewdness, and the dubious privileges of wealth. This essay outlines some of the interpretive implications of this ignored historical context for the Dashwood-centered story of Sense and Sensibility.
Decision Support for Retirement Portfolio Management: Overcoming Myopic Loss Aversion via Technology Design
Authors: Looney Clayton Arlen , Hardin Andrew M.
Published: August 2009

As firms continue to abandon pensions in favor of employee-managed retirement plans, tremendous demands are being placed on the decision-making proficiency of future retirees. As reflected in the equity premium puzzle, individual investors tend to hold overly conservative portfolios that provide meager payoffs over time. Consequently, there is growing concern that the vast majority of retirement accounts might be insufficiently funded when employees reach retirement. Given that most retirement plans can now be managed online, a potential solution lies in designing a Web-based decision support system (DSS) that helps future retirees make more-profitable portfolio management decisions. This paper reports the results of a study in which 159 retirement plan participants were asked to use an experimental website to manage a portfolio of retirement investments over a simulated 30-year period. Using a psychological approach toward designing the DSS, myopic loss aversion is put forth as a theoretical explanation for the psychological mechanisms that encourage investors to hold overly conservative portfolios. Armed with this knowledge, three design features—information horizon, system restrictiveness, and decisional guidance—are implemented as part of an overarching design strategy targeted at increasing investors' willingness to take calculated risks. The results indicate that investor conservatism diminishes when the DSS presents prospective probabilities and payoffs over long time horizons. In contrast, short-term information horizons constitute a major stumbling block for investors. However, when confronted with short-term information horizons, risk aversion can be successfully counteracted by configuring a DSS to either restrict the frequency of decisions or to suggest a relatively aggressive portfolio allocation. These findings carry important implications for theory and practice.
Density functional theory study of the Jahn-Teller effect in cobaltocene
Authors: Zlatar Matija , Schläpfer Carl-Wilhelm , Penka Fowe Emmanuel , Daul Claude A.
Published: August 2009

A detailed discussion of the potential energy surface of bis(cyclopentadienyl)cobalt(II), cobaltocene, is given. Vibronic coupling coefficients are calculated using density functional theory (DFT). Results are in good agreement with experimental findings. On the basis of our calculation there is no second-order Jahn–Teller (JT) effect as predicted by group theory. The JT distortion can be expressed as a linear combination of all totally symmetric normal modes of the low-symmetry, minimum-energy conformation. The out-of-plane ring deformation is the most important mode. The JT distortion is analyzed by seeking the path of minimal energy of the adiabatic potential energy surface.
Dispersion of antimony from oxidizing ore deposits
Authors: Diemar Glen A. , Filella Montserrat , Leverett Peter , Williams Peter A.
Published: August 2009

The solubilities of brandholzite, [Mg(H2O)6][Sb(OH)6]2, and bottinoite, [Ni(H2O)6][Sb(OH)6]2, at 25 °C in water have been measured. Solubilities are 1.95(4) × 10-3 and 3.42(11) × 10-4 mol dm-3, respectively. The incongruent dissolution of romeite, Ca2Sb2O7, and bindheimite, Pb2Sb2O7, at 25 °C in 0.100 mol dm-3 aqueous HNO3 was also investigated. Equilibrium dissolved Sb concentrations were 3.3 ± 1.0 × 10-7 and 7.7 ± 2.1 × 10-8 mol dm-3, respectively. These values have been used to re-evaluate the geochemical mobility of Sb in the supergene environment. It is concluded that the element is geochemically immobile in solution and in soils. This was in part validated by an orientation soil geochemical survey over the Bayley Park prospect near Armidale, New South Wales, Australia. Anomalous soil Sb levels are confined to within 100 m of known stibnite mineralization.
Imputation of 10-year osteoporotic fracture rates from hip fractures: A clinical validation study
Authors: Leslie William D , Lix Lisa M
Published: August 2009

The World Health Organization (WHO) fracture risk assessment system (FRAX) allows for calibration from country-specific fracture data. The objective of this study was to evaluate the method for imputation of osteoporotic fracture rates from hip fractures alone. A total of 38,784 women aged 47.5 years or older at the time of baseline femoral neck bone mineral density (BMD) measurement were identified in a database containing all clinical dual energy X-ray absorptiometry (DXA) results for the Province of Manitoba, Canada. Health service records were assessed for the presence of nontrauma osteoporotic fracture codes after BMD testing (431 hip, 787 forearm, 336 clinical vertebral, and 431 humerus fractures). Ten-year hip and osteoporotic fracture rates were estimated by the Kaplan-Meier method. The population was stratified by age (50 to 90 years, 5-year width strata) and again by femoral neck T-scores (−4.0 to 0.0, 0.5 SD width strata). Within each stratum, the ratio of hip to osteoporotic fractures was calculated and compared with the predicted ratio from FRAX. Increasing age was associated with greater predicted hip-to-osteoporotic ratios (youngest 0.07 versua oldest 0.41) and observed ratios (youngest 0.10 versus oldest 0.48). Lower T-scores were associated with greater predicted (highest 0.04 versus lowest 0.71) and observed ratios (highest 0.06 versus lowest 0.44). There was a strong positive correlation between predicted and observed ratios (Spearman r = 0.90–0.97, p < .001). For 14 of the 18 strata, the predicted ratio was within the observed 95% confidence interval (CI). Since collection of population-based hip fracture data is considerably easier than collection of non–hip fracture data, this study supports the current emphasis on using hip fractures as the preferred site for FRAX model calibration. © 2010 American Society for Bone and Mineral Research
Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice
Authors: Zhang Heng-Wei , Ding Jiong , Jin Jian-Liang , Guo Jian , Liu Jing-Ning , Karaplis Andrew , Goltzman David , Miao Dengshun
Published: August 2009

In parathyroid hormone–related protein 1-84 [PTHrP(1-84)] knockin mice, expression of the polycomb protein Bmi-1 is reduced and potentially can mediate the phenotypic alterations observed. We have therefore now examined the skeletal phenotype of Bmi-1−/− mice in vivo and also assessed the function of bone marrow mesenchymal stem cells (BM-MSCs) from Bmi-1−/− mice ex vivo in culture. Neonatal Bmi-1−/− mice exhibited skeletal growth retardation, with reduced chondrocyte proliferation and increased apoptosis. Osteoblast numbers; gene expression of alkaline phosphatase, type I collagen, and osteocalcin; the mineral apposition rate; trabecular bone volume; and bone mineral density all were reduced significantly; however, the number of bone marrow adipocytes and Ppar-γ expression were increased. These changes were consistent with the skeletal phenotype observed in the PTHrP(1-84) knockin mouse. The efficiency of colony-forming unit fibroblast (CFU-F) formation in bone marrow cultures was decreased, and the percentage of alkaline phosphatase–positive CFU-F and Runx2 expression were reduced. In contrast, adipocyte formation and Ppar-γ expression in cultures were increased, and expression of the polycomb protein sirtuin (Sirt1) was reduced. Reduced proliferation and increased apoptosis of BM-MSCs were associated with upregulation of senescence-associated tumor-suppressor genes, including p16, p19, and p27. Analysis of the skeletal phenotype in Bmi-1−/− mice suggests that Bmi-1 functions downstream of PTHrP. Furthermore, our studies indicate that Bmi-1 maintains self-renewal of BM-MSCs by inhibiting the expression of p27, p16, and p19 and alters the cell fate of BM-MSCs by enhancing osteoblast differentiation and inhibiting adipocyte differentiation at least in part by stimulating Sirt1 expression. Bmi-1 therefore plays a critical role in promoting osteogenesis. © 2010 American Society for Bone and Mineral Research
Short-term exposure to low-carbohydrate, high-fat diets induces low bone mineral density and reduces bone formation in rats
Authors: Bielohuby Maximilian , Matsuura Maiko , Herbach Nadja , Kienzle Ellen , Slawik Marc , Hoeflich Andreas , Bidlingmaier Martin
Published: August 2009

Low-carbohydrate, high-fat (LC-HF) diets are popular for inducing weight loss in adults and are also used as part of a treatment for children with epilepsy. However, potential risks and side effects remain controversial. We investigated effects of LC-HF diets on growth, bone mineral density (BMD), and turnover in growing rats fed for 4 weeks either normal chow (CH, 9% fat, 33% protein, and 58% carbohydrates), LC-HF-1 (66% fat, 33% protein, and 1% carbohydrates), or LC-HF-2 (94.5% fat, 4.2% protein, and 1.3% carbohydrates). Rats fed LC-HF diets accumulated significantly more visceral and bone marrow fat and showed increased leptin but decreased insulin-like growth-factor 1 (IGF-1). Both LC-HF diets significantly decreased body length (nose to rump), but lengths of humerus, tibia, and femur were significantly reduced with LC-HF-2 only. Peripheral quantitative computed tomography (pQCT) and micro-CT (µCT) independently revealed significant reductions in BMD of tibiae in both LC-HF groups, and tibial maximum load was impaired. Bone-formation marker N-terminal propeptide of type I procollagen was reduced in sera of LC-HF groups, whereas bone resorption marker CrossLaps remained unchanged. Real-time PCR analysis revealed significant reductions by 70% to 80% of transcription factors influencing osteoblastogenesis (Runx2, osterix, and C/EBPβ) in bone marrow of rats fed LC-HF diets. In conclusion, both LC-HF diets impaired longitudinal growth, BMD, and mechanical properties, possibly mediated by reductions in circulating IGF-1. Serum bone-formation markers as well as expression of transcription factors influencing osteoblastogenesis were reduced. This might indicate a lower rate of mesenchymal stem cells differentiating into osteoblasts, thus explaining reduced bone formation with LC-HF diets. © 2010 American Society for Bone and Mineral Research
The Etiological Moderation of Aggressive and Nonaggressive Antisocial Behavior by Age
Authors: Burt S. Alexandra , Klump Kelly L.
Published: August 2009

A recent study has suggested that aggressive (AGG) and non-aggressive, rule-breaking (RB) antisocial behavior evidence differential and subtype-specific patterns of genetic expression during development. Namely, although genetic influences on RB increase dramatically during early- to mid-adolescence, genetic influences on AGG appear to remain stable. As no other study has examined age-related change in AGG versus RB, more research is clearly needed before any firm conclusions can be drawn. The current study thus examined whether and how age impacted genetic and environmental influences on AGG and RB in a sample of 252 10- to 15-year-old twin pairs assessed as part of the Michigan State University Twin Registry (MSUTR). Results constructively replicated and extended prior findings, indicating that while the magnitude of genetic and environmental influences on AGG remained stable across adolescence, genetic influences on RB increased dramatically with age. Such findings provide additional support for etiological distinctions within the broader construct of antisocial behavior based on the presence or absence of aggression, and offer insights into the expression of genetic influences during development.
Heritability of Testis Size
Authors: Estourgie-van Burk G. Frederiek , Bartels Meike , Delemarre-van de Waal Henriette A. , Boomsma Dorret I.
Published: August 2009

Testis size is an important feature of male pubertal development. The genetic and environmental contributions to variation in human testis size have hardly been studied. We estimated the heritability of human testicular size in a group of mono- and dizygotic twins and their non-twin brothers (145 twins and 20 brothers from 95 families). Participants were 18 years old on average and all had reached Tanner development stage 4 or higher. Dizygotic twins and their siblings had a larger mean testis volume than monozygotic twins and their siblings. There was significant familial resemblance, with higher correlations in monozygotic twin pairs (0.59) than in dizygotic twin and sibling pairs (0.34). Heritability was estimated at 59% (95% CI = 37–75%), but a model that excluded genetic influences and attributed all familial resemblance to shared environment, fitted the data only marginally worse. The finding of larger mean testis volume in dizygotic twins may be of interest for future research into the mechanisms underlying dizygotic twinning.
Assessing Individual Differences in Genome-Wide Gene Expression in Human Whole Blood: Reliability Over Four Hours and Stability Over 10 Months
Authors: Meaburn Emma L. , Fernandes Cathy , Craig Ian W. , Plomin Robert , Schalkwyk Leonard C.
Published: August 2009

Studying the causes and correlates of natural variation in gene expression in healthy populations assumes that individual differences in gene expression can be reliably and stably assessed across time. However, this is yet to be established. We examined 4-hour test–retest reliability and 10 month test–retest stability of individual differences in gene expression in ten 12-year-old children. Blood was collected on four occasions: 10 a.m. and 2 p.m. on Day 1 and 10 months later at 10 a.m. and 2 p.m. Total RNA was hybridized to Affymetrix-U133 plus 2.0 arrays. For each probeset, the correlation across individuals between 10 a.m. and 2 p.m. on Day 1 estimates test–retest reliability. We identified 3,414 variable and abundantly expressed probesets whose 4-hour test–retest reliability exceeded .70, a conventionally accepted level of reliability, which we had 80% power to detect. Of the 3,414 reliable probesets, 1,752 were also significantly reliable 10 months later. We assessed the long-term stability of individual differences in gene expression by correlating the average expression level for each probe-set across the two 4-hour assessments on Day 1 with the average level of each probe-set across the two 4-hour assessments 10 months later. 1,291 (73.7%) of the 1,752 probe-sets that reliably detected individual differences across 4 hours on two occasions, 10 months apart, also stably detected individual differences across 10 months. Heritability, as estimated from the MZ twin intraclass correlations, is twice as high for the 1,752 reliable probesets versus all present probesets on the array (0.68 vs 0.34), and is even higher (0.76) for the 1,291 reliable probesets that are also stable across 10 months. The 1,291 probesets that reliably detect individual differences from a single peripheral blood collection and stably detect individual differences over 10 months are promising targets for research on the causes (e.g., eQTLs) and correlates (e.g., psychopathology) of individual differences in gene expression.
A Comparative Evaluation of Various Additives Used in the Stabilization of Sulfate Bearing Lean Clay
Authors: Solanki Pranshoo , Khoury Naji , Zaman Musharraf M.
Published: August 2009

A laboratory study was conducted on both raw and stabilized clay specimens to evaluate short- and long-term performance of three different additives, namely, hydrated lime, class C fly ash (CFA), and cement kiln dust (CKD), for providing better treatment of sulfate rich lean clay. Short-term performance evaluation experiments included Atterberg limits, resilient modulus (Mr), modulus of elasticity (ME), and unconfined compressive strength (UCS), after 28 days of curing. Long-term performance was evaluated in terms of moisture susceptibility (tube suction test) and three-dimensional swell during 120 days of capillary soaking. At the end of 120 days, specimens were also tested for Mr, ME, and UCS, as additional indicators to long-term pavement performance. Short-term performance evaluation projected 15 % CKD with highest improvement, while long-term performance evaluation showed 15 % CFA providing maximum enhancements after 120 days of capillary soaking. The study further indicated swelling of specimens stabilized with lime and CKD; however, CFA helped in reducing the swelling. All the percentages of additives used in the study helped in reducing the moisture susceptibility of clay. Mineralogical studies such as scanning electron microscopy, energy-dispersive spectroscopy, and X-ray diffraction were also used to verify research findings observed from the macro test results.
Cis-regulatory Changes atFLOWERING LOCUS TMediate Natural Variation in Flowering Responses ofArabidopsis thaliana
Authors: Schwartz Christopher , Balasubramanian Sureshkumar , Warthmann Norman , Michael Todd P , Lempe Janne , Sureshkumar Sridevi , Kobayashi Yasushi , Maloof Julin N , Borevitz Justin O , Chory Joanne , Weigel Detlef
Published: August 2009

Flowering time, a critical adaptive trait, is modulated by several environmental cues. These external signals converge on a small set of genes that in turn mediate the flowering response. Mutant analysis and subsequent molecular studies have revealed that one of these integrator genes, FLOWERING LOCUS T (FT), responds to photoperiod and temperature cues, two environmental parameters that greatly influence flowering time. As the central player in the transition to flowering, the protein coding sequence of FT and its function are highly conserved across species. Using QTL mapping with a new advanced intercross-recombinant inbred line (AI-RIL) population, we show that a QTL tightly linked to FT contributes to natural variation in the flowering response to the combined effects of photoperiod and ambient temperature. Using heterogeneous inbred families (HIF) and introgression lines, we fine map the QTL to a 6.7 kb fragment in the FT promoter. We confirm by quantitative complementation that FT has differential activity in the two parental strains. Further support for FT underlying the QTL comes from a new approach, quantitative knockdown with artificial microRNAs (amiRNAs). Consistent with the causal sequence polymorphism being in the promoter, we find that the QTL affects FT expression. Taken together, these results indicate that allelic variation at pathway integrator genes such as FT can underlie phenotypic variability and that this may be achieved through cis-regulatory changes.
Worms With a Single Functional Sensory Cilium Generate Proper Neuron-Specific Behavioral Output
Authors: Senti Gabriele , Ezcurra Marina , Löbner Jana , Schafer William R , Swoboda Peter
Published: August 2009

Studying the development and mechanisms of sensory perception is challenging in organisms with complex neuronal networks. The worm Caenorhabditis elegans possesses a simple neuronal network of 302 neurons that includes 60 ciliated sensory neurons (CSNs) for detecting external sensory input. C. elegans is thus an excellent model in which to study sensory neuron development, function, and behavior. We have generated a genetic rescue system that allows in vivo analyses of isolated CSNs at both cellular and systemic levels. We used the RFX transcription factor DAF-19, a key regulator of ciliogenesis. Mutations in daf-19 result in the complete absence of all sensory cilia and thus of external sensory input. In daf-19 mutants, we used cell-specific rescue of DAF-19 function in selected neurons, thereby generating animals with single, fully functional CSNs. Otherwise and elsewhere these animals are completely devoid of any environmental input through cilia. We demonstrated the rescue of fully functional, single cilia using fluorescent markers, sensory behavioral assays, and calcium imaging. Our technique, functional rescue in single sensory cilia (FRISSC), can thus cell-autonomously and cell-specifically restore the function of single sensory neurons and their ability to respond to sensory input. FRISSC can be adapted to many different CSNs and thus constitutes an excellent tool for studying sensory behaviors, both in single animals and in populations of worms. FRISSC will be very useful for the molecular dissection of sensory perception in CSNs and for the analysis of the developmental aspects of ciliogenesis.
mec-15 Encodes an F-Box Protein Required for Touch Receptor Neuron Mechanosensation, Synapse Formation and Development
Authors: Bounoutas Alexander , Zheng Qun , Nonet Michael L , Chalfie Martin
Published: August 2009

Selective protein degradation is a key regulator of neuronal development and synaptogenesis. Complexes that target proteins for degradation often contain F-box proteins. Here we characterize MEC-15, an F-box protein with WD repeats, which is required for the development and function of Caenorhabditis elegans touch receptor neurons (TRNs). Mutations in mec-15 produce defects in TRN touch sensitivity, chemical synapse formation, and cell-body morphology. All mec-15 mutant phenotypes are enhanced by mutations in a MAP kinase pathway composed of the MAPKKK DLK-1, the MAPKK MKK-4, and the p38 MAPK PMK-3. A mutation of the rpm-1 gene, which encodes an E3 ubiquitin ligase that negatively regulates this pathway to promote synaptogenesis, suppresses only the mec-15 cell-body defect. Thus, MEC-15 acts in parallel with RPM-1, implicating a second protein degradation pathway in TRN development. In addition, all mec-15 phenotypes can be dominantly suppressed by mutations in mec-7, which encodes a β-tubulin, and dominantly enhanced by mutations in mec-12, which encodes an α-tubulin. Since mec-15 phenotypes depend on the relative levels of these tubulins, MEC-15 may target proteins whose function is affected by these levels.
Point Mutation Rate of Bacteriophage ΦX174
Authors: Cuevas José M , Duffy Siobain , Sanjuán Rafael
Published: August 2009

The point mutation rate of phage ΦX174 was determined using the fluctuation test. After identifying the genetic changes associated with the selected phenotype, we obtained an estimate of 1.0 × 10−6 substitutions per base per round of copying, which is consistent with Drake's rule (0.003 mutations per genome per round of copying in DNA-based microorganisms).
Alcohol Sensitivity in Drosophila: Translational Potential of Systems Genetics
Authors: Morozova Tatiana V , Ayroles Julien F , Jordan Katherine W , Duncan Laura H , Carbone Mary Anna , Lyman Richard F , Stone Eric A , Govindaraju Diddahally R , Ellison R Curtis , Mackay Trudy F C , Anholt Robert R H
Published: August 2009

Identification of risk alleles for human behavioral disorders through genomewide association studies (GWAS) has been hampered by a daunting multiple testing problem. This problem can be circumvented for some phenotypes by combining genomewide studies in model organisms with subsequent candidate gene association analyses in human populations. Here, we characterized genetic networks that underlie the response to ethanol exposure in Drosophila melanogaster by measuring ethanol knockdown time in 40 wild-derived inbred Drosophila lines. We associated phenotypic variation in ethanol responses with genomewide variation in gene expression and identified modules of correlated transcripts associated with a first and second exposure to ethanol vapors as well as the induction of tolerance. We validated the computational networks and assessed their robustness by transposon-mediated disruption of focal genes within modules in a laboratory inbred strain, followed by measurements of transcript abundance of connected genes within the module. Many genes within the modules have human orthologs, which provides a stepping stone for the identification of candidate genes associated with alcohol drinking behavior in human populations. We demonstrated the potential of this translational approach by identifying seven intronic single nucleotide polymorphisms of the Malic Enzyme 1 (ME1) gene that are associated with cocktail drinking in 1687 individuals of the Framingham Offspring cohort, implicating that variation in levels of cytoplasmic malic enzyme may contribute to variation in alcohol consumption.
Fine Mapping and Marker Development for the Crossability Gene SKr on Chromosome 5BS of Hexaploid Wheat (Triticum aestivum L.)
Authors: Alfares Walid , Bouguennec Annaig , Balfourier François , Gay Georges , Bergès Hélène , Vautrin Sonia , Sourdille Pierre , Bernard Michel , Feuillet Catherine
Published: August 2009

Most elite wheat varieties cannot be crossed with related species thereby restricting greatly the germplasm that can be used for alien introgression in breeding programs. Inhibition to crossability is controlled genetically and a number of QTL have been identified to date, including the major gene Kr1 on 5BL and SKr, a strong QTL affecting crossability between wheat and rye on chromosome 5BS. In this study, we used a recombinant SSD population originating from a cross between the poorly crossable cultivar Courtot (Ct) and the crossable line MP98 to characterize the major dominant effect of SKr and map the gene at the distal end of the chromosome near the 5B homeologous GSP locus. Colinearity with barley and rice was used to saturate the SKr region with new markers and establish orthologous relationships with a 54-kb region on rice chromosome 12. In total, five markers were mapped within a genetic interval of 0.3 cM and 400 kb of BAC contigs were established on both sides of the gene to lay the foundation for map-based cloning of SKr. Two SSR markers completely linked to SKr were used to evaluate a collection of crossable wheat progenies originating from primary triticale breeding programs. The results confirm the major effect of SKr on crossability and the usefulness of the two markers for the efficient introgression of crossability in elite wheat varieties.
Implications of 99mTc-DMSA Scintigraphy Performed During Urinary Tract Infection in Neonates
Authors: Siomou Ekaterini , Giapros Vasileios , Fotopoulos Andreas , Âasioti Maria , Papadopoulou Frederica , Serbis Anastasios , Siamopoulou Antigoni , Andronikou Styliani
Published: August 2009

OBJECTIVE: To evaluate prospectively whether normal scintigraphic results during urinary tract infections (UTIs) in neonates were predictive of the absence of dilating vesicoureteral reflux (VUR) (grade ≥III) and permanent renal damage (PRD).

METHODS: Term neonates with a first symptomatic, community-acquired UTI participated in the study. Urinary tract ultrasonography and technetium-99m-labeled dimercaptosuccinic acid (99mTc-DMSA) scintigraphy were performed within 72 hours after diagnosis and voiding cystourethrography within 1 to 2 months. DMSA scintigraphy, to determine the development of PRD, was repeated 6 months after UTI.

RESULTS: Seventy-two neonates (144 renal units) were enrolled. Acute pyelonephritis was diagnosed through early DMSA scintigraphy in 19% of renal units, VUR in 22%, and grade ≥III VUR in 13%. The majority (71%) of renal units with grade ≥III VUR had normal early DMSA scintigraphic results. The sensitivity and specificity of abnormal early DMSA scintigraphic results to predict grade ≥III VUR were 29% (95% confidence interval: 11%–55%) and 82% (95% confidence interval: 74%–88%), respectively. PRD was found in 7% of renal units, all of which had abnormal early DMSA scintigraphic results. PRD was significantly more frequent among renal units with grade ≥III VUR than among nonrefluxing renal units (P < .05).

CONCLUSIONS: Normal early DMSA scintigraphic results for neonates with symptomatic UTIs were helpful in ruling out later development of PRD but were not predictive of the absence of dilating VUR. To rule out dilating VUR, voiding cystourethrography may be required.
Reports of Repetitive Penile-Genital Penetration Often Have No Definitive Evidence of Penetration
Authors: Anderst Jim , Kellogg Nancy , Jung Inkyung
Published: August 2009

OBJECTIVES: The goals were to evaluate the association of definitive hymenal findings with the number of reported episodes of penile-genital penetration, pain, bleeding, dysuria, and time since assault for girls presenting for nonacute, sexual assault examinations.

METHODS: Charts of all girls 5 to 17 of age who provided a history of nonacute, penile-genital, penetrative abuse were reviewed. Interviews and examinations occurred over a 4-year period at a children's advocacy center. Characteristics of the histories provided by the subjects were examined for associations with definitive findings of penetrative trauma.

RESULTS: Five hundred six patients were included in the study. Of the 56 children with definitive examination results, 52 had no history of consensual penile-vaginal intercourse and all were ≥10 years of age. Analysis was unable to detect an association between the number of reported penile-genital penetrative events and definitive genital findings. Eighty-seven percent of victims who provided a history of >10 penetrative events had no definitive evidence of penetration. A history of bleeding with abuse was more than twice as likely for subjects with definitive findings. Children <10 years of age were twice as likely to report >10 penetrative events, although none had definitive findings on examination.

CONCLUSIONS: Most victims who reported repetitive penile-genital contact that involved some degree of perceived penetration had no definitive evidence of penetration on examination of the hymen. Similar results were seen for victims of repetitive assaults involving perceived penetration over long periods of time, as well as victims with a history of consensual sex.
Physical Education Class Injuries Treated in Emergency Departments in the US in 1997–2007
Authors: Nelson Nicolas G. , Alhajj Maya , Yard Ellen , Comstock Dawn , McKenzie Lara B.
Published: August 2009

OBJECTIVE: The goal was to describe the epidemiological features of physical education (PE)-related injuries treated in US emergency departments.

METHODS: A retrospective analysis was conducted with data for children and adolescents (5–18 years of age) from the National Electronic Injury Surveillance Study of the US Consumer Product Safety Commission, from 1997 through 2007. Sample weights provided by the National Electronic Injury Surveillance System were used to calculate national estimates of PE-related injuries. Trend significance of the number of PE-related injuries over time was analyzed by using linear regression analysis.

RESULTS: An estimated 405305 children and adolescents were treated in emergency departments for PE-related injuries. The annual number of cases increased 150% during the study period (P = .001). Nearly 70% of PE-related injuries occurred during 6 activities, that is, running, basketball, football, volleyball, soccer, and gymnastics. Boys' injuries were more likely to involve the head, to be diagnosed as a laceration or fracture, to be attributable to contact with a person or structure, and to occur during group activities. Girls' injuries were more likely to involve the lower extremities, to be strains and sprains, to be acute noncontact injuries, and to occur during individual activities.

CONCLUSION: More research is needed to identify the cause of the increase in PE-related injuries, to examine the gender difference in PE-related injuries, and to determine appropriate injury prevention solutions and policies.