bluuebunny/crossref_metadata_2025 huggingface dataset:
Germline Genetic Variation in an Organic Anion Transporter Polypeptide Associated With Methotrexate Pharmacokinetics and Clinical Effects
Authors: Treviño Lisa R. , Shimasaki Noriko , Yang Wenjian , Panetta John C. , Cheng Cheng , Pei Deqing , Chan Diana , Sparreboom Alex , Giacomini Kathleen M. , Pui Ching-Hon , Evans William E. , Relling Mary V.
Published: November 2009

Purpose

Methotrexate plasma concentration is related to its clinical effects. Our aim was to identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL).

Patients and Methods

We performed a genome-wide analysis of 500,568 germline single-nucleotide polymorphisms (SNPs) to identify how inheritance affects methotrexate plasma disposition among 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients.

Results

Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1. Two SNPs in SLCO1B1, rs11045879 (P = 1.7 × 10−10) and rs4149081 (P = 1.7 × 10−9), were in linkage disequilibrium (LD) with each other (r2= 1) and with a functional polymorphism in SLCO1B1, T521C (rs4149056; r2> 0.84). rs11045879 and rs4149081 were validated in an independent cohort of 206 patients (P = .018 and P = .017), as were other SLCO1B1 SNPs residing in different LD blocks. SNPs in SLCO1B1 were also associated with GI toxicity (odds ratio, 15.3 to 16.4; P = .03 to .004).

Conclusion

A genome-wide interrogation identified inherited variations in a plausible, yet heretofore low-priority candidate gene, SLCO1B1, as important determinants of methotrexate's pharmacokinetics and clinical effects.
Cyclophosphamide, Epirubicin, and Fluorouracil Versus Dose-Dense Epirubicin and Cyclophosphamide Followed by Paclitaxel Versus Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Node-Positive or High-Risk Node-Negative Breast Cancer
Authors: Burnell Margot , Levine Mark N. , Chapman Judith-Anne W. , Bramwell Vivien , Gelmon Karen , Walley Barbara , Vandenberg Ted , Chalchal Haji , Albain Kathy S. , Perez Edith A. , Rugo Hope , Pritchard Kathleen , O'Brien Patti , Shepherd Lois E.
Published: November 2009

Purpose

Cyclophosphamide, epirubicin, and fluorouracil (CEF) and doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) are commonly used adjuvant regimens in women with early breast cancer. In a previous trial in women with locally advanced breast cancer, 3 months of high-dose epirubicin and cyclophosphamide (EC) administered every 2 weeks (dose-dense) was equivalent to 6 months of CEF. We hypothesized that 3 months of paclitaxel after dose-dense EC (EC/T) would be superior to CEF or AC/T.

Methods

After lumpectomy or mastectomy, women 60 years of age or younger with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive CEF, EC/T, or AC/T for 6 months. This article reports the interim analysis for recurrence-free survival (RFS), which was planned after 227 recurrences.

Results

A total of 2,104 patients were enrolled. The median follow-up is 30.4 months. Hazard ratios for recurrence are as follows: AC/T versus CEF, 1.49 (95% CI, 1.12 to 1.99), P = .005; AC/T versus EC/T, 1.68 (95% CI, 1.25 to 2.27), P = .0006; and EC/T versus CEF, 0.89 (95% CI, 0.64 to 1.22), P = .46. Three-year RFS rates for CEF, EC/T, and AC/T are 90.1%, 89.5%, and 85.0%, respectively. There was more febrile neutropenia with CEF (22.3%) and EC/T (16.4%) compared with AC/T (4.8%), but more neuropathy with the last two regimens.

Conclusion

Three-weekly AC/T is significantly inferior to CEF or EC/T in terms of RFS. It is too early to detect any difference between CEF and dose-dense EC/T.
Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer
Authors: Makhija Sharmila , Amler Lukas C. , Glenn Dana , Ueland Frederick R. , Gold Michael A. , Dizon Don S. , Paton Virginia , Lin Chin-Yu , Januario Thomas , Ng Kimmie , Strauss Andreas , Kelsey Stephen , Sliwkowski Mark X. , Matulonis Ursula
Published: November 2009

Purpose

Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor receptor 2 (HER2) heterodimerization and has single-agent activity in recurrent epithelial ovarian cancer. The primary objective of this phase II study was to characterize the safety and estimate progression-free survival (PFS) of pertuzumab with gemcitabine in patients with platinum-resistant ovarian cancer.

Patients and Methods

Patients with advanced, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received a maximum of one prior treatment for recurrent cancer were randomly assigned to gemcitabine plus either pertuzumab or placebo. Collection of archival tissue was mandatory to permit exploration of biomarkers that would predict benefit from pertuzumab in this setting.

Results

One hundred thirty patients (65 per arm) were treated. Baseline characteristics were similar between arms. The adjusted hazard ratio (HR) for PFS was 0.66 (95% CI, 0.43 to 1.03; P = .07) in favor of gemcitabine + pertuzumab. The objective response rate was 13.8% in patients who received gemcitabine + pertuzumab compared with 4.6% in patients who received gemcitabine + placebo. In patients whose tumors had low HER3 mRNA expression (< median, n = 61), an increased treatment benefit was observed in the gemcitabine + pertuzumab arm compared with the gemcitabine alone arm (PFS HR = 0.32; 95% CI, 0.17 to 0.59; P = .0002). Grade 3 to 4 neutropenia, diarrhea, and back pain were increased in patients treated with gemcitabine + pertuzumab. Symptomatic congestive heart failure was reported in one patient in the gemcitabine + pertuzumab arm.

Conclusion

Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer. Low HER3 mRNA expression may predict pertuzumab clinical benefit and be a valuable prognostic marker.
Survival Effect of Venous Thromboembolism in Patients With Multiple Myeloma Treated With Lenalidomide and High-Dose Dexamethasone
Authors: Zangari Maurizio , Tricot Guido , Polavaram Latha , Zhan Fenghuang , Finlayson Ashlie , Knight Robert , Fu Tommy , Weber Donna , Dimopoulos Meletios A. , Niesvizky Ruben , Fink Louis
Published: November 2009

Purpose

We conducted a retrospective analysis of the survival effect of venous thromboembolism (VTE) development in patients with multiple myeloma (MM).

Methods

Two identically designed, multicenter, double-blind, phase III clinical trials (MM-009 and MM-010) were conducted in Europe and the United States to assess the effect of lenalidomide in combination with dexamethasone versus dexamethasone plus placebo in patients with relapsed or refractory MM, after failing at least one prior line of treatment. In this retrospective analysis, we evaluated incidence and survival effect of thromboembolism in 353 patients randomly assigned to receive 25 mg of lenalidomide on days 1 through 21 of a 28-day cycle, plus 40 mg of oral dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 for the first four cycles; after the fourth cycle, 40 mg of dexamethasone was administered on days 1 through 4 only.

Results

Seventeen percent of patients experienced a thromboembolic episode. The development of VTE did not significantly affect overall survival (P = .90) or time to progression (P = .34). No significant survival impact was observed in a subgroup of patients who received prophylactic anticoagulation (overall survival P = .7, time to progression P = .1).

Conclusion

Patients with MM treated with lenalidomide and high-dose dexamethasone who developed a VTE did not experience shorter overall survival or time to progression.
Neoadjuvant Chemotherapy Shows Similar Response in Patients With Inflammatory or Locally Advanced Breast Cancer When Compared With Operable Breast Cancer: A Secondary Analysis of the GeparTrio Trial Data
Authors: Costa Serban Dan , Loibl Sibylle , Kaufmann Manfred , Zahm Dirk-Michael , Hilfrich Jörn , Huober Jens , Eidtmann Holger , du Bois Andreas , Blohmer Jens-Uwe , Ataseven Beyhan , Weiss Erich , Tesch Hans , Gerber Bernd , Baumann Klaus H. , Thomssen Christoph , Breitbach Georg Peter , Ibishi Shaip , Jackisch Christian , Mehta Keyur , von Minckwitz Gunter
Published: November 2009

Purpose

Neoadjuvant chemotherapy followed by mastectomy is the treatment of choice in patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC), but it is considered less effective in these diseases than in operable breast cancer (OBC). We report a prospective comparison of the GeparTrio trial of patients with IBC (cT4 days) or LABC (cT4a-c or cN3; stage IIIB or IIIC) and patients with OBC (cT2-3).

Patients and Methods

Participants were stratified by stage and were randomly assigned to six or eight cycles of docetaxel/doxorubicin/cyclophosphamide (TAC) or to two cycles of TAC followed by four cycles of vinorelbine/capecitabine. We present results of a secondary aim of the study, which was to compare pathologic complete response (pCR; ie, no remaining invasive/noninvasive tumor in breast and lymph nodes) in different stage groups.

Results

A total of 287 patients with IBC (n = 93) or LABC (n = 194) and 1,777 patients with OBC were entered onto the trial. At baseline, parameters were as follows for the three types of cancer, respectively: median tumor sizes: 8.0 cm, 7.0 cm, and 4.0 cm (P < .001); multiple lesions: 31.2%, 27.3%, and 19.6% (P < .001); nodal involvement: 86.6%, 71.2%, and 51.6% (P < .001); grade 3: 44.4%, 30.4%, and 39.9% (P = .178); lobular-invasive type: 7.5%, 17.5%, and 13.3% (P = .673); negative hormone receptor status: 38.0%, 20.0%, and 36.4% (P = .008); and positive human growth factor receptor 2 status: 45.1%, 38.9%, and 35.7% (P = .158). Response rates for IBC, LABC, and OBC, respectively, were 8.6%, 11.3%, and 17.7% for pCR (P = .002); 71.0%, 69.6%, and 83.4% for overall response by physical or sonographic examination (P < .001); and 12.9%, 33.0%, and 69.9% for breast conservation (P < .001). All P values were for IBC and LABC versus OBC. However, tumor stage itself was not an independent predictor for pCR in multivariable analysis (odds ratio, 1.51; 95% CI, 0.88 to 2.59; P = .13).

Conclusion

No evidence of a difference in response to neoadjuvant chemotherapy was found by tumor stage when analysis was adjusted for baseline characteristics.
NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma With Procarbazine, Lomustine, and Vincristine or Temozolomide
Authors: Wick Wolfgang , Hartmann Christian , Engel Corinna , Stoffels Mandy , Felsberg Jörg , Stockhammer Florian , Sabel Michael C. , Koeppen Susanne , Ketter Ralf , Meyermann Richard , Rapp Marion , Meisner Christof , Kortmann Rolf D. , Pietsch Torsten , Wiestler Otmar D. , Ernemann Ulrike , Bamberg Michael , Reifenberger Guido , von Deimling Andreas , Weller Michael
Published: November 2009

Purpose

The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas.

Patients and Methods

Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence.

Results

Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O6-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm.

Conclusion

Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation.
Phase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1
Authors: Loprinzi Charles L. , Qin Rui , Baclueva Ernie P. , Flynn Kathleen A. , Rowland Kendrith M. , Graham David L. , Erwin Nancy K. , Dakhil Shaker R. , Jurgens Donald J. , Burger Kelli N.
Published: November 2009

Purpose

Hot flashes are a common problem for which effective and safe treatments are needed. The current trial was conducted on the basis of preliminary promising data that pregabalin decreased hot flashes.

Patients and Methods

A double-blind, placebo-controlled, randomized trial design was used to compare pregabalin at target doses of 75 mg twice daily and 150 mg twice daily with a placebo. Hot flash frequencies and scores (frequency times mean severity) were recorded daily during a baseline week and for six treatment weeks. The primary end point for this study was the change-from-baseline hot flash score during treatment week 6 between the 150 mg twice daily target pregabalin treatment and placebo. Nonparametric Wilcoxon rank sum tests, two-sample t tests, and χ2 tests were used to compare the primary and secondary hot flash efficacy end points between pregabalin treatments and placebo.

Results

Hot flash score changes available for 163 patients during the sixth treatment week compared with a baseline week decreased by 50%, 65%, and 71% in the placebo, and target 75 mg twice daily and 150 mg twice daily pregabalin arms, respectively (P = .009 and P = .007, comparing respective pregabalin arms to the placebo arm). While some toxicities were significantly more common in the pregabalin arms, being more evident with the higher dose, pregabalin was generally well tolerated by most patients.

Conclusion

Pregabalin decreases hot flashes and is reasonably well tolerated. A target dose of 75 mg twice daily is recommended. Its effects appear to be roughly comparable to what has been reported with gabapentin and with some newer antidepressants.
Boundary element method analysis of cracked anisotropic bodies
Authors: Nourine L , Sahli A , Abdelkader M Riyad , Rahmani O
Published: November 2009

This paper presents a two-dimensional (2D) parametric study of the behaviour of uniformly cooled homogeneous linear elastic anisotropic bodies containing cracks using the boundary element method (BEM). The present work investigates the effects of varying material properties, and varying the orientation of these material properties, on the magnitude of the stress intensity factors (SIFs) of the cracked bodies. Five cracked plate geometries are considered in this study, namely: (i) a plate with an edge crack; (ii) a plate with a central crack; (iii) a plate with a double-edge crack; (iv) a plate with an edge crack emanating from a circular notch; and (v) a plate with symmetric cracks emanating from a central hole. The results of this study show that, for all crack geometries, the mode I SIF.
A review of optical near-fields in particle/tip-assisted laser nanofabrication
Authors: Wang Z B , Joseph N , Li L , Luk'yanchuk B S
Published: November 2009

Nanofabrication by using lasers with a spatial resolution beyond the optical diffraction limit is a challenging task. One of the solutions is to use near-field techniques, in which evanescent waves dominate over free waves in the vicinity of scattering objects and sub-diffraction-limited focus (as small as ∼10 nm) can be achieved. Theoretical modelling of near-field phenomena is extremely important for the understanding of these near-field techniques, especially for some cases where it is not possible to directly measure the near-fields. In this article, a brief review of the existing near-field laser nanofabrication techniques is given. Different theoretical methods for the computation of optical near-fields, including both analytical and numerical methods, are then presented. The optical near-field distributions of different micro/nano-systems (isolated particles, aggregated particles, particles on the substrate, particles in liquid, and the tip-sample system) are then reviewed in detail within the framework of laser nanofabrication.
Force tracking control for an electro-hydraulic actuator based on an intelligent feed forward compensator
Authors: Pan J , Shi G L , Zhu X M
Published: November 2009

This article presents a scheme for the control of an electro-hydraulic passive force tracking system using the compound controller with an intelligent feed forward compensator (IFFC), which is designed as a test equipment to reproduce on-ground aerodynamics load for reverse thrust system on a certain kind of plain. Through detailed analysis, the mathematical and simulation models are established. Since the conventional proportion integration (PI) method is unsatisfactory due to its bad adaptability to the parametric uncertainties, an IFFC with an off-line self-tuning mechanism is proposed. The related simulations are made and the results show that the compound controller will have good performance after training even though the parameters of the PI part are not optimal. To validate the feasibility of the proposed control strategy, the experiments are carried out on an electro-hydraulic test platform and the experimental results demonstrate the effectiveness of the proposed controller with IFFC for different tracking tasks.
The effect of the neutral point position on the natural frequencies of lateral vibrations of a hanging beam
Authors: Kazemi R , Jafari A , Faraji Mahyari M
Published: November 2009

In this article, the effect of axial force variation by position, on the natural frequencies of lateral vibration of a hanging beam, is analysed for different boundary conditions. To this aim, the equations of motion are derived by writing the potential and kinetic energies of the beam, considering the non-linear coupling between the axial and lateral vibrations. These energy equations are discreted by the mode summation method. The effect of the neutral point position on the natural frequencies and the mode shapes of the linearized system are investigated. By increasing the end axial force, the beam's natural frequencies are reduced and, for a critical position of neutral point, the first natural frequency of the beam vanishes and the beam buckles.
Investigating the needle dynamic response during insertion into soft tissue
Authors: Alja'afreh T
Published: November 2009

This paper investigates the effect of the needle velocity on soft-tissue motion ex vivo and in vivo. In many needle-based intervention procedures, which are common minimally invasive surgical techniques, the needle can be assumed to be rigid and the tissue deforms and displaces considerably as the needle moves forwards to its target. This paper presents an energy-based fracture mechanics approach to show that the increasing needle velocity can reduce tissue motion during the insertion process. The main feature of this paper is that it extends the proposed approach to model the insertion dynamics, whereas most of the literature treats needle insertion as a quasi-static process. Ex-vivo test results on lamb heart samples show that the force required to initiate penetration decreases with increasing needle velocity up to a critical velocity, above which the rate-independent penetration force of the underlying tissue becomes the limiting factor. In-vivo tests show that increased needle velocity results in reduced force and displacement for needle insertion into the heart. Results indicate that automated insertion could substantially improve performance in some applications.
Tribological property of the cobalt—chromium femoral head with different regions of wear in total hip arthroplasty
Authors: Duong C-T , Nam J-S , Seo E-M , Patro B P , Chang J-D , Park S , Lee S-S
Published: November 2009

The tribological properties of engineering and biological materials have been investigated at microscale levels through the calculation of the surface roughness and frictional coefficient using atomic force microscopy (AFM). Although a number of previous studies have reported the frictional coefficients of diverse bearing materials in total hip arthroplasty (THA), the relationship between the surface roughness and frictional coefficient of bearing materials of THA have not been reported, and furthermore, the tribological properties for different wear regions of a cobalt-chromium (Co—Cr) femoral head have not been well identified. Therefore, the objective of this study is to investigate the relationships between the surface roughness, frictional coefficient, and hardness for both the main-wear and the least-wear regions of a Co—Cr femoral head 10 years after THA. The average Vickers hardness of the Co—Cr femoral head was 380.7 ± 11.3 HV. With the scanned area of 25 μm×25 μm through AFM, the frictional coefficients of the main-wear and the least-wear regions were 0.229 ± 0.054 and 0.243 ± 0.059, respectively, and showed no statistical differences between these two regions ( p = 0.449). However, differences in the surface roughness ( Rq) between the main-wear region ( Rq = 96.5 ± 26.2 nm) and the least-wear region ( Rq = 17.7 ± 4.2 nm) were statistically significant ( p<0.0001). The results of the current study suggest that the frictional property of the Co—Cr femoral head is not significantly correlated with its surface roughness, and also provide guidelines for improving the surface characteristics of metallic implant materials.
Photoinduced Hydrogen-Evolution System with an Antibody–Porphyrin Complex as a Photosensitizer
Authors: Yamaguchi Hiroyasu , Onji Takeshi , Ohara Hidetaka , Ikeda Noriaki , Harada Akira
Published: November 2009

A complex between a monoclonal antibody for porphyrin and zinc–porphyrin was utilized to construct an energy conversion system. Monoclonal antibody 2B6 bound meso-tetrakis(4-carboxyphenyl)porphyrin zinc complex (ZnTCPP) with a dissociation constant of 2.1 × 10−8 M. Upon binding the antibody, the lifetime of the excited triplet state of ZnTCPP increased from 0.5 to 1.2 ms. A stable cationic radical of viologen was obtained by irradiating the solution containing the complex of 2B6 with ZnTCPP, methyl viologen (MV2+), and ethylenediaminetetraacetic acid tetrasodium salt (EDTA-4Na) with light. When colloidal platinum was added as a catalyst, photoinduced hydrogen production was observed upon continuous irradiation of visible light. The estimated turnover number of photoinduced hydrogen evolution was 5.0 × 10−3 s−1. The catalytic activity of the 2B6–ZnTCPP complex on the hydrogen evolution was compared with that of ZnTCPP alone and the complexes of ZnTCPP with fragments of antibody 2B6 (2B6-H and 2B6-L). The heavy chain of antibody 2B6 mainly contributed to the complex formation with ZnTCPP and the resultant hydrogen production, and the whole antibody–ZnTCPP complex led to the efficient hydrogen production.
Predictable ventricular shift after focal cerebral ischaemia in rats: practical considerations for intraventricular therapeutic interventions
Authors: Lourbopoulos A , Grigoriadis N , Karacostas D , Spandou E , Artemis N , Milonas I , Tascos N , Simeonidou C
Published: November 2009

Intracerebroventricular (ICV) route of administration is a useful experimental method to study the effects of chemicals or cellular grafts in the ventricular compartment of the brain after focal ischaemia. However, the induced oedema may cause structural dislocating phenomena and render a stereotaxic ICV invasion difficult and practically unavailable especially during the acute post-ischaemia phase. The aim of this study was to measure these structural ventricular dislocations and set new stereotaxic coordinates for successful and cost-effective ICV invasion 6–18 h after focal cerebral ischaemia. Wistar rats were subjected to 2 h middle cerebral artery occlussion (t-MCAO), were neurologically evaluated (modified Neurological Stroke Scale [mNSS], modified Bederson's Scale [mBS] and grid-walking test [GWT]) and brain slides were studied at 6 and 18 h post-occlusion for infarction volume, hemispheric oedema, middle line dislocation and stereotaxia of the lateral ventricles. Our data indicated that stereotaxic coordinates of the lateral ventricles in the infarcted and contralateral hemispheres significantly ( P < 0.05) changed at both time-points and were linearly correlated with the mNSS, mBS and some GWT scores ( P < 0.001). This correlation allowed for the calculation of simple (linear) mathematical equations (stereotaxic coordinate = b0 + b1*mNSS, where ‘ b0’ and ‘b1’ are fixed number and factor, respectively, calculated by regression analysis) that determined individually new coordinates for each animal. Verification experiments revealed that the new coordinates render ICV invasion feasible in up to 80% of infarcted rats (number needed to treat 1.65), compared with only 19.4% using the classical coordinates for normal rats. Therefore, we propose a new, time- and cost-effective methodology for practically feasible ICV invasion in rats 6–18 h after t-MCAO.
Developmental changes in the electroencephalogram and responses to a noxious stimulus in anaesthetized tammar wallaby joeys (Macropus eugenii eugenii)
Authors: Diesch T J , Mellor D J , Johnson C B , Lentle R G
Published: November 2009

The tammar wallaby joey is born extremely immature and most of its neurological development occurs in the maternal pouch. It is not known at what in-pouch age functions such as conscious sensory perception commence. We determined the electroencephalographic (EEG) responses to noxious stimulation in lightly anaesthetized tammar wallaby joeys. Baseline median (F50) and spectral edge (F95) frequencies, total power (Ptot) and frequency spectra between 1 and 30 Hz of the EEG power spectrum were determined. Joeys aged less than 127 days showed little or no EEG activity. Prolonged periods of spontaneous EEG activity were present by 142 days. This activity increased, as did the power in all frequencies, while the duration of any intervening isoelectric periods decreased with increasing in-pouch age. EEG responses to a noxious stimulus (toe clamping) changed with increasing in-pouch age as there was no response from joeys aged 94–127 days (no EEG), a minimal decrease in the F50 in those aged between 142 and 181 days ( P = 0.052) and a greater decrease in the F50 in those aged between 187 and 261 days ( P < 0.001). The pattern of these changes, which presumably reflects anatomical and functional maturation of the cerebral cortex, is similar to, but develops more slowly than, that reported in the rat. The opening of the eyes and development of the pelage are discussed as markers of when brain development may be sufficient for joeys to consciously perceive noxious sensations including pain.
Editorial: The Eighth Rothkopf Rankings of Universities' Contributions to the INFORMS Practice Literature
Authors: Fricker Ronald D.
Published: November 2009

Continuing and expanding on the original work that Michael H. Rothkopf established in 1996, this paper presents the eighth ranking of universities according to their contributions to the INFORMS practice literature. Fittingly, we have named them the “Rothkopf Rankings” in honor of their originator, a scholar and practitioner with a passion for applied, effective, and influential operations research. The rankings assigned are based on two metrics: one measures visibility (the number of times a university is listed as the primary academic affiliation in the INFORMS practice literature), and the second measures yield (the equivalent number of INFORMS practice papers attributable to each university based on author primary academic affiliation). For US universities, the Naval Postgraduate School earns the top ranking for visibility and the second for yield, and the Colorado School of Mines earns the top ranking for yield and the second for visibility. For non-US universities, the University of Chile earns the top ranking for both visibility and yield.
ASP, The Art and Science of Practice: Tales from the Front: Case Studies Indicate the Potential Pitfalls of Misapplication of Lean Improvement Programs
Authors: Gorman Michael F. , Hoff Jayden , Kinion Robert
Published: November 2009

In recent years, lean manufacturing concepts have become more popular as an ever-growing number of companies have implemented lean programs. Some companies tout huge savings and benefits; those that do not are evaluated on the factors that led to their failed attempts. We suggest that the failure to implement lean is often because of an excessive and errant focus on inventory reduction as the primary, or sole, form of waste reduction. We describe the academic and popular literature on this topic and explain some sources of confusion and consternation surrounding lean initiatives. We then discuss four case studies in which a company's primary focus was on inventory reduction, but it attained true economic performance enhancements through inventory increases. We provide insights on how managers can identify similar situations in which they can productively implement well-defined and planned business-improvement programs to eliminate other kinds of wastes.
Active HIF-1 in the Normal Human Retina
Authors: Hughes John M. , Groot Arjan J. , van der Groep Petra , Sersansie René , Vooijs Marc , van Diest Paul J. , Van Noorden Cornelis J.F. , Schlingemann Reinier O. , Klaassen Ingeborg
Published: November 2009

A unique feature of the retina is the presence of photoreceptors, which require an enormous amount of oxygen for the conversion of light to an electrical signal. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that is the master regulator of cellular adaptation to low oxygen tension. Only in hypoxic conditions is HIF-1α protein stabilized and translocated to the nucleus, where it induces transcription of target genes involved in oxygen delivery and energy metabolism. We hypothesized that HIF-1α is constitutively stabilized and active in the normal human retina. We investigated the cellular distribution of HIF-1α and the expression of its downstream targets, vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), and carbonic anhydrase IX (CAIX), by immunohistochemistry and immunoblotting in the retina of normal rats and human donor eyes. Both human and rat retinas displayed prominent staining of HIF-1α in nuclei of most cell types in inner and outer nuclear layers and the ganglion cell layer, a cellular distribution pattern which was confirmed in human retina by immunoblotting of nuclear extracts. A negative correlation was found between HIF-1α protein levels and postmortem times. In human retina, staining of VEGF, GLUT-1, and CAIX was found. Our observations indicate that active HIF-1 signaling occurs constitutively in the normal human and rat retina, suggesting that HIF-1 has a physiological role in the retina.
Cytoplasmic p53 and Activated Bax Regulate p53-dependent, Transcription-independent Neural Precursor Cell Apoptosis
Authors: Geng Ying , Walls K.C. , Ghosh Arindam P. , Akhtar Rizwan S. , Klocke Barbara J. , Roth Kevin A.
Published: November 2009

The prodeath effects of p53 are typically mediated via its transcriptional upregulation of proapoptotic Bcl-2 family members, including PUMA, Noxa, and/or Bax. We previously reported that staurosporine (STS), a broad-spectrum kinase inhibitor and prototypical apoptosis-inducing agent, produced p53-dependent, Bax-dependent, neural precursor cell (NPC) apoptosis, but that this effect occurred independently of new gene transcription and PUMA expression. To further characterize the mechanism by which p53 regulates NPC death, we used primary cerebellar NPCs derived from wild-type, p53-deficient, and Bax-deficient neonatal mice and the mouse cerebellar neural stem cell line, C17.2. We found that STS rapidly increased p53 cytoplasmic immunoreactivity in neuritic-like processes in C17.2 cells, which preceded Bax activation and caspase-3 cleavage. Confocal microscopy analysis of STS-treated cells revealed partial colocalization of p53 with the mitochondrial marker pyruvate dehydrogenase as well as with conformationally altered “activated” Bax, suggesting an interaction between these proapoptotic molecules in triggering apoptotic death. Nucleophosmin (NPM), a CRM1-dependent nuclear chaperone, also exhibited partial colocalization with both activated Bax and p53 following STS treatment. These observations suggest that cytoplasmic p53 can trigger transcription-independent NPC apoptosis through its potential interaction with NPM and activated Bax.
Crystal structure determination of N,N′-1,4-phenylene-bis(3-oxobutanamide) from laboratory powder diffraction data
Authors: Brüning Jürgen , Alig Edith , Bats Jan W. , van de Streek Jacco , Schmidt Martin U.
Published: November 2009

The compound N,N′-1,4-phenylene-bis(3-oxobutanamide) is an industrial intermediate used in the synthesis of azo pigments.

Crystallisation experiments only led to the dihydrate form; drying the dihydrate at 120 °C leads to an anhydrous form, but suitable single crystals of the anhydrous form could not be grown. Therefore, its crystal structure was determined from laboratory powder diffraction data. The structure was solved by real-space methods using the program DASH and refined by the Rietveld method using the program TOPAS. The anhydrous form crystallises in P21/c, Z = 2 with lattice parameters a = 16.9749(5) Å, b = 4.8648(1) Å, c = 8.5372(2) Å, β = 93.396(2)°. The crystal structure of the dihydrate was determined by single-crystal structure analysis. The dihydrate crystallises in P – 1, Z = 1 with a = 5.0116(1) Å, b = 5.2199(2) Å, c = 14.7803(5) Å, α = 88.396(1)°, β = 80.250(1)°, γ = 81.439(1)°. In both crystal structures the molecule, which has a centre of symmetry, is situated on an inversion centre. For the anhydrous form dispersion-corrected DFT calculations were used to confirm the structure.
Induced ovulation mimics the time-table of natural development in the stripe-faced dunnart, Sminthopsis macroura and results in the birth of fertile young
Authors: Au Phil Chi Khang , Nation Angela , Parrott Marissa , Selwood Lynne
Published: November 2009

Induced ovulation maximizes captive breeding success, increasing productivity and facilitating the contribution of otherwise infertile animals to the genetic pool. In marsupials, induced ovulation to produce fertile young is unknown. Here we present an induction protocol efficient in inducing non-cycling and non-reproductive females to cycle, mate, ovulate, and conceive. Ovulation was induced inSminthopsis macrourausing an initial injection of 0.06 IU equine serum gonadotropin (eSG)/g (time 0), followed on day 4 by 0.04 IU eSG/g. Using this induction regime, the timing of follicular and embryonic development mimics natural cycles and results in the birth of viable, fertile young. Response to induction is not significantly affected by animal age, making this protocol an effective conservation tool. We have established a time-table of development following induction, providing a source of precisely timed research material. This is the first induced ovulation protocol in any marsupial to result in demonstrated fertile offspring and to allow the reliable collection of known-age samples during both the follicular phase and the gestation period.
Natural History of Spinal Anomalies and Scoliosis Associated With Esophageal Atresia
Authors: Sistonen Saara J. , Helenius Ilkka , Peltonen Jari , Sarna Seppo , Rintala Risto J. , Pakarinen Mikko P.
Published: November 2009

OBJECTIVE: Clinical characteristics of spinal deformities that commonly occur in patients with esophageal atresia (EA) are unclear. The objective of this study was to assess the incidence and natural history of spinal anomalies and scoliosis in patients with EA.

METHODS: A population-based cohort of 100 adults who had an operation for EA in our hospital were examined clinically and radiographically for spinal deformities. The results were compared with data obtained from normal population-based controls.

RESULTS: Vertebral anomalies were observed in 45 patients, predominating in the cervical spine in 38 patients. Any additional anomaly was the most significant risk factor (odds ratio [OR]: 27 [95% confidence interval (CI): 8–100]) for the occurrence of vertebral anomalies. Scoliosis of >10° was observed in 56 patients, >20° in 11 patients, and >45° in 1 patient. The risk for scoliosis of >10° was 13-fold (OR: 13 [95% CI: 8.3–21]), and the risk for scoliosis of >20° was 38-fold (OR: 38 [95% CI: 14–106]) compared with those in the normal population. Thoracotomy-induced rib fusions (OR: 3.6 [95% CI: 0.7–19]) and other associated anomalies (OR: 2.1 [95% CI: 0.9–2.9]) were the strongest predictive factors for scoliosis. The general clinical course of spinal deformities was mild, and none of the patients had undergone spinal surgery.

CONCLUSIONS: The risk of scoliosis is 13-fold after repair of EA in relation to general population. Nearly half of the patients have vertebral anomalies predominating in the cervical spine. Most of these deformities were not diagnosed primarily or during growth. Spinal surgery is rarely indicated.
HIV Risk Reduction Among Detained Adolescents: A Randomized, Controlled Trial
Authors: Bryan Angela D. , Schmiege Sarah J. , Broaddus Michelle R.
Published: November 2009

OBJECTIVES: Criminally involved adolescents engage in high levels of alcohol-related risky sex. A theory-based sexual and alcohol risk-reduction intervention was designed, implemented, and evaluated in juvenile detention facilities.

Participants and Methods. In a randomized, controlled trial, 484 detained adolescents received 1 of 3 group-based interventions: combined sexual and alcohol risk reduction (group psychosocial intervention [GPI] + group motivational enhancement therapy [GMET]); sexual risk reduction only (GPI); or HIV/sexually transmitted disease prevention information only (group information-only intervention [GINFO]). Follow-up data were obtained 3, 6, 9, and 12 months after the intervention. Behavioral outcomes were condom-use behavior, frequency of intercourse while drinking, and alcohol-related problems.

RESULTS: Condom-use behavior measured as frequency of condom use during sex (ranging from never to always) decreased over time, although the GPI and GPI + GMET interventions mitigated this tendency at the 3-, 6-, and 9-month follow-up assessments. Although both active interventions were significantly more successful than the GINFO condition and the pattern of effects favored the GPI + GMET, there were no statistically significant differences between the GPI and GPI + GMET interventions.

CONCLUSIONS: Findings support the feasibility of integrating alcohol-specific sexual risk content into a theory-based sexual risk-reduction intervention and provide additional evidence that theory-based interventions are effective at reducing risky sex in this population. There was limited evidence of intervention effects on alcohol-use outcomes. Future research should focus on strengthening the GPI + GMET to most effectively target risky sexual behavior among at-risk adolescents.
Bone Regeneration and Periosteoplasty: A 250-Year-Long History
Authors: Lazzeri Davide , Gatti Gian Luca , Romeo Gianfranco , Balmelli Bruno , Massei Alessandro
Published: November 2009

Background:

Since antiquity, many attempts have been carried out and a number of theories proposed to explain the process that leads to bone regeneration. Through manifold experiments, several authors tried to understand and subsequently to control the physiological events that enable bone healing. Between the 18th and 19th centuries something changed. Although the scientific world was initially skeptical, a new idea emerged in the field of bone surgery. It principally concerned the necessity to perform amputations and resections leaving intact the periosteum to obtain new bone formation.

Materials and Methods:

With this article we emphasize the contribution of many authors in the development of knowledge about the osteogenic properties of the periosteum. In particular we focus on the experiences of unknown Italian authors Michele Troja and Bernardino Larghi, consider well-recognized scientific personalities such as Leopold Ollier and Bernhard von Langenbeck, and reach a milestone of plastic surgery with Tord Skoog and his description of periosteoplasty.

Conclusion:

Various surgical approaches have been proposed to provide optimal care for patients with cleft lip and palate disorders. Among several treatment options, periosteoplasty is one of the choices to correct maxillary clefts. Highlighting difficulties and successes of many authors in demonstrating osteogenic properties of periosteum, this paper describes how periosteoplasty performed in maxillary cleft restoration capitalizes on what has been discovered during a 250-year-long history.
Longitudinal Study of Growth of Children with Unilateral Cleft-Lip Palate from Birth to Two Years of Age
Authors: Marques Ilza L. , Nackashi John A. , Borgo Hilton C. , Martinelli Ângela P. M. C. , Pegoraro-Krook Maria I. , Williams William N. , Dutka Jeniffer C. R. , Seagle Michael B. , Souza Telma V. , Garla Luis A. , Neto José S. M. , Silva Marcos L. N. , Graciano Maria I. G. , Moorhead Jacquelyn , Piazentin-Penna Sílvia H. A. , Feniman Mariza R. , Zimmermann Maria C. , Bento-Gonçalves Cristina G. A. , Pimentel Maria C. M. , Boggs Steve , Jorge José C. , Antonelli Patrick J. , Shuster Jonathan
Published: November 2009

Objective:

To study the growth of children with complete unilateral cleft lip and palate (UCLP) from birth to 2 years of age and to construct specific UCLP growth curves.

Design:

Physical growth was a secondary outcome measure of a National Institutes of Health–sponsored longitudinal, prospective clinical trial involving the University of Florida (United States) and the University of São Paulo (Brazil).

Patients:

Six hundred twenty-seven children with UCLP, nonsyndromic, both genders.

Methods:

Length, weight, and head circumference were prospectively measured for a group of children enrolled in a clinical trial. Median growth curves for the three parameters (length, weight, head circumference) were performed and compared with the median for the National Center for Health Statistics (NCHS) curves. The median values for length, weight, and head circumference at birth and 6, 12, 18, and 24 months of age were plotted against NCHS median values and statistically compared at birth and 24 months.

Setting:

Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, Brazil (HRAC-USP).

Results:

At birth, children of both genders with UCLP presented with smaller body dimensions in relation to NCHS median values, but the results suggest a catch-up growth for length, weight, and head circumference for girls and for weight (to some degree) and head circumference for boys.

Conclusions:

Weight was the most compromised parameter for both genders, followed by length and then head circumference. There was no evidence of short stature. This study established growth curves for children with UCLP.
Secondary Alveolar Bone Grafting: Outcomes, Revisions, and New Applications
Authors: Goudy Steven , Lott David , Burton Richard , Wheeler Jim , Canady John
Published: November 2009

Introduction:

Cleft lip and palate deformities are one of the most common birth defects. The alveolar cleft requires bony repair to allow proper eruption of dentition. The purpose of this study is to evaluate success in the repair of alveolar clefts and examine whether the addition of allogenic materials improves outcomes.

Materials and Methods:

One hundred three patients with cleft lip and palate were identified retrospectively after institutional review board approval was obtained. The authors reviewed their medical records, surgical complication rate, need for revision surgery, and whether allogenic materials were used. The data were then compared using analysis of variance.

Results:

The average patient age was 16.6 years (range, 7 to 25 years). There were 59% unilateral clefts and 41% bilateral clefts identified. The average age at palate repair was 17.5 months. The average age at alveolar bone grafting (ABG) was 8.9 years (range, 5 to 15 years). Allogenic material was used in 22 primary ABGs and 10 revision ABGs. The revision rate of unilateral ABGs was 18%, which was statistically different from the 32% revision rate of bilateral ABGs. The use of allogenic material during ABG repair did not affect the revision rate.

Conclusion:

Secondary alveolar bone grafting is necessary for complete rehabilitation of the cleft alveolus. The patients undergoing ABG had an overall 23% revision rate, 18% for unilateral and 32% for bilateral clefts. The use of allogenic materials during ABG did not show a statistical benefit in this study, but future review including more patients may be useful.
Apples and Oranges—Midface Hypoplasia and the Le Fort I Osteotomy in Cleft Lip and Palate Patients: A Classification Scheme and Treatment Protocol
Authors: Felemovicius Jacobo , Taylor Jesse A.
Published: November 2009

Objective:

To present a classification and treatment protocol for cleft lip and palate patients with midface hypoplasia.

Design:

Retrospective case series.

Setting:

Craniofacial center.

Patients:

The study included 133 patients with cleft lip and palate and maxillary hypoplasia treated with Le Fort I osteotomy between January 2000 and July 2006.

Interventions:

Modified Le Fort I osteotomy. Patients were divided into three groups based on the number of free-standing bony maxillary segments, and treatment was tailored to their deformity.

Main Outcome Measures:

Complications and long-term relapse rates.

Results:

The 133 patients underwent 142 operations with mean follow-up of 27 months. Mean horizontal advancement was 7.1 ± 1.9 mm, 6.5 ± 1.3 mm, 6.4 ± 1.6 mm, and 6.5 ± 1.3 mm for groups I, II, IIIA, and IIIB, respectively. Complications consisted of nine bony relapses, three hematomas, and two transitory neurosensory losses. Analysis of variance using number of maxillary pieces as the independent variable and millimeters of advancement as the dependent variable demonstrated no difference in the amounts that the groups were advanced (p  =  .23). Relapse rates for groups I, II, IIIA, and IIIB were 2/62 (3.2%), 5/53 (9.4%), 2/14 (14.3%), and 0/4 (0.0%), respectively. Analysis of variance did not demonstrate a statistical difference in relapse rates based on number of maxillary pieces.

Conclusions:

Cleft lip and palate patients can be classified into three groups based on the number of maxillary segments. Our classification system defines the differences among this diverse group of patients and also facilitates unique treatment of each group.