bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Cardiac Resynchronization Therapy With or Without a Defibrillator on Survival and Hospitalizations in Patients With New York Heart Association Class IV Heart Failure
Authors: Lindenfeld JoAnn , Feldman Arthur M. , Saxon Leslie , Boehmer John , Carson Peter , Ghali Jalal K. , Anand Inder , Singh Steve , Steinberg Jonathan S. , Jaski Brian , DeMarco Teresa , Mann David , Yong Patrick , Galle Elizabeth , Ecklund Fred , Bristow Michael
Published: December 2006

Background—

Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III and IV HF. There is concern that the device procedure may destabilize these very ill class IV patients. We sought to examine the outcomes of NYHA class IV patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial to assess the potential benefits of CRT and CRT-D.

Methods and Results—

The COMPANION trial randomized 1520 patients with NYHA class III and IV HF to optimal medical therapy, CRT, or CRT-D. In the class IV patients (n=217), the primary end point of time to death or hospitalization for any cause was significantly improved by both CRT (hazard ratio [HR], 0.64; 95% CI, 0.43 to 0.94;
P
=0.02) and CRT-D (HR, 0.62; 95% CI, 0.42 to 0.90;
P
=0.01). Time to all-cause death and HF hospitalization was also significantly improved in both CRT (HR, 0.57; 95% CI, 0.37 to 0.87;
P
=0.01) and CRT-D (HR, 0.49; 95% CI, 0.32 to 0.75;
P
=0.001) Time to all-cause death trended to an improvement in both CRT (HR, 0.67; 95% CI, 0.41 to 1.10;
P
=0.11) and CRT-D (HR, 0.63; 95% CI, 0.39 to 1.03;
P
=0.06). Time to sudden death appeared to be significantly reduced in the CRT-D group (HR, 0.27; 95% CI, 0.08 to 0.90;
P
=0.03). There was a nonsignificant reduction in time to HF deaths for both CRT (HR, 0.68; 95% CI, 0.34 to 1.37;
P
=0.28) and CRT-D (HR, 0.79; 95% CI, 0.41 to 1.52;
P
=0.48).

Conclusions—

CRT and CRT-D significantly improve time to all-cause mortality and hospitalizations in NYHA class IV patients, with a trend for improved mortality. These devices should be considered in ambulatory NYHA class IV HF patients similar to those enrolled in COMPANION.
Subclinical Coronary and Aortic Atherosclerosis Detected by Magnetic Resonance Imaging in Type 1 Diabetes With and Without Diabetic Nephropathy
Authors: Kim Won Yong , Astrup Anne Sofie , Stuber Matthias , Tarnow Lise , Falk Erling , Botnar René M. , Simonsen Cheryl , Pietraszek Lotte , Hansen Peter R. , Manning Warren J. , Andersen Niels T. , Parving Hans-Henrik
Published: December 2006

Background—

Patients with type 1 diabetes and nephropathy maintain an excess cardiovascular mortality compared with diabetic patients with normoalbuminuria. We sought to evaluate coronary and aortic atherosclerosis in a cohort of asymptomatic type 1 diabetic patients with and without diabetic nephropathy using cardiovascular magnetic resonance imaging.

Methods and Results—

In a cross-sectional study, 136 subjects with long-standing type 1 diabetes without symptoms or history of cardiovascular disease, including 63 patients (46%) with nephropathy and 73 patients with normoalbuminuria, underwent cardiovascular magnetic resonance imaging. All subjects underwent cardiac exercise testing and noninvasive tests for peripheral artery disease and autonomic neuropathy. Coronary artery stenoses were identified in 10% of subjects with nephropathy (versus 0% with normoalbuminuria;
P
=0.007). Coronary plaque burden, expressed as right coronary artery mean wall thickness (1.7±0.3 versus 1.3±0.2 mm;
P
<0.001) and maximum right coronary artery wall thickness (2.2±0.5 versus 1.6±0.3 mm;
P
<0.001), was greater in subjects with nephropathy. The prevalence of thoracic (3% versus 0%;
P
=0.28) and abdominal aortic plaque (22% versus 16%;
P
=0.7) was similar in both groups. Subjects with and without abdominal aortic plaques had similar coronary plaque burden.

Conclusions—

In asymptomatic type 1 diabetes, cardiovascular magnetic resonance imaging reveals greater coronary plaque burden in subjects with nephropathy compared with those with normoalbuminuria.
Triglycerides and the Risk of Coronary Heart Disease
Authors: Sarwar Nadeem , Danesh John , Eiriksdottir Gudny , Sigurdsson Gunnar , Wareham Nick , Bingham Sheila , Boekholdt S. Matthijs , Khaw Kay-Tee , Gudnason Vilmundur
Published: December 2006

Background—

Many epidemiological studies have reported on associations between serum triglyceride concentrations and the risk of coronary heart disease, but this association has not been reliably quantified. In the present study, we report 2 separate nested case-control comparisons in 2 different prospective, population-based cohorts, plus an updated meta-analysis of 27 additional prospective studies in general Western populations.

Methods and Results—

Measurements were made in a total of 3582 incident cases of fatal and nonfatal coronary heart disease and 6175 controls selected from among the 44 237 men and women screened in the Reykjavik and the European Prospective Investigation of Cancer (EPIC)-Norfolk studies. Repeat measurements were obtained an average of 4 years apart in 1933 participants in the EPIC-Norfolk Study and an average of 12 years apart in 379 participants in the Reykjavik study. The long-term stability of log-triglyceride values (within-person correlation coefficients of 0.64 [95% CI, 0.60 to 0.68] over 4 years and 0.63 [95% CI, 0.57 to 0.70] over 12 years) was similar to those of blood pressure and total serum cholesterol. After adjustment for baseline values of several established risk factors, the strength of the association was substantially attenuated, and the adjusted odds ratio for coronary heart disease was 1.76 (95% CI, 1.39 to 2.21) in the Reykjavik study and 1.57 (95% CI, 1.10 to 2.24) in the EPIC-Norfolk study in a comparison of individuals in the top third with those in the bottom third of usual log-triglyceride values. Similar overall findings (adjusted odds ratio, 1.72; 95% CI, 1.56 to 1.90) were observed in an updated meta-analysis involving a total of 10 158 incident coronary heart disease cases from 262 525 participants in 29 studies.

Conclusions—

Available prospective studies in Western populations consistently indicate moderate and highly significant associations between triglyceride values and coronary heart disease risk. Because these associations depend considerably on levels of established risk factors, however, further studies are needed to help assess the nature of any independent associations.
Regional Differences in Process of Care and Outcomes for Older Acute Myocardial Infarction Patients in the United States and Ontario, Canada
Authors: Ko Dennis T. , Krumholz Harlan M. , Wang Yongfei , Foody JoAnne M. , Masoudi Fredrick A. , Havranek Edward P. , You John J. , Alter David A. , Stukel Therese A. , Newman Alice M. , Tu Jack V.
Published: December 2006

Background—

Previous comparisons of acute myocardial infarction (AMI) treatment between the United States and Canada are limited because they compared selected patients from randomized trials, used administrative data that lacked clinical detail, or did not consider regional differences in AMI treatment.

Methods and Results—

We compared medication use, invasive cardiac procedure use, and 30-day risk-standardized mortality rates of 38 886 fee-for-service Medicare beneficiaries hospitalized with AMI in the United States and 5634 similarly aged patients in Ontario, Canada, from 1998 and 2001. Baseline characteristics and illness severity across the US regions and Ontario were not substantially different. Cardiac catheterization use in AMI patients was significantly higher in the United States compared with Ontario (38.7% versus 16.8%,
P
<0.001), but significant regional variations existed, in which the northeastern United States had significantly lower utilization rates (25.6%) compared with other US regions. β-Blocker use among ideal candidates was highest in the northeastern United States (77.6% versus 69.7% in the United States as a whole,
P
<0.001) and angiotensin-converting enzyme inhibitor use was highest in Ontario (69.1% versus 58.2% in the United States,
P
<0.001). Risk-standardized mortality rates at 30 days were not substantially different across the regions.

Conclusions—

Previous studies have suggested a clear divergence in invasive cardiac therapy for AMI patients between the United States and Canada on the basis of health care financing and structural differences. Our findings of similar treatment patterns in the northeastern United States and Ontario suggest that regional practices may have a greater impact on treatment patterns than the respective health care delivery systems.
Persistence of Functional Atrioventricular Accessory Pathways in Postseptated Embryonic Avian Hearts
Authors: Kolditz Denise P. , Wijffels Maurits C.E.F. , Blom Nico A. , van der Laarse Arnoud , Markwald Roger R. , Schalij Martin J. , Gittenberger-de Groot Adriana C.
Published: December 2006

Background—

During heart development, the ventricular activation sequence changes from a base-to-apex to an apex-to-base pattern. We investigated the possibility of impulse propagation through remnants of atrioventricular (AV) connections in quail hearts.

Methods and Results—

In 86 hearts (group A, HH30–34, n=15; group B, HH35–44, n=65; group C, 5 to 6 months, n=6) electrodes were positioned at the left atrium, right ventricular base, left ventricular (LV) base, and LV apex. In group A, LV base activation preceded LV apex activation in the majority of cases (60%; 9 of 15), whereas hearts in group B primarily demonstrated an LV apex-to-base activation pattern (72%; 47 of 65). Interestingly, in group B, the right ventricular base (17%; 11 of 65) or LV base (8%; 5 of 65) exhibited premature activation in 25% (16 of 65) of cases, whereas in 26% (17 of 65), the right ventricular base or LV base was activated simultaneously with the LV apex. Morphological analysis confirmed functional data by showing persistent muscular AV connections in embryonic hearts. Interestingly, all myocardial AV connections stained positive for periostin, a nonmyocardial marker. Longitudinal analysis (HH35–44) demonstrated a decrease in both the number of hearts that exhibited premature base activation (
P
=0.015) and the number (
P
=0.004) and width (
P
=0.179) of accessory AV pathways with developmental stage in a similar time course. In the adult quail hearts, accessory myocardial AV pathways were functionally and morphologically absent.

Conclusion—

Thus, impulse propagation through persistent accessory AV connections remains possible at near-hatching stages (HH44) of development, which may provide a substrate for AV reentrant arrhythmias in perinatal life. Periostin positivity and absence of AV pathways in the adult heart suggest that these connections eventually lose their myocardial phenotype, which implicates ongoing AV ring isolation perinatally and postnatally.
Oral Antidiabetic Drugs: Bioavailability Assessment of Fixed‐Dose Combination Tablets of Pioglitazone and Metformin. Effect of Body Weight, Gender, and Race on Systemic Exposures of Each Drug
Authors: Karim Aziz , Slater Margaret , Bradford Dawn , Schwartz Lisa , Zhao Zhen , Cao Charlie , Laurent Aziz
Published: December 2006

Bioavailability of pioglitazone and metformin, in 2 dose strengths, given either as a fixed‐dose combination tablet or as coadministration of commercial tablets (coad), was studied in young healthy subjects in 2 separate studies. In study I (n = 63), single oral doses of 15‐mg pioglitazone/500‐mg metformin fixed‐dose combination tablets or equivalent doses of commercial tablets were administered, in a fasting state, in an open‐label, randomized, crossover study with a 7‐day washout period between treatments. Study II (n = 61) was similar in design to study I, except the 15/850‐mg fixed‐dose combination tablet and coad treatments were evaluated. Least squares mean (fixed‐dose combination/coad) ratios and 90% confidence intervals of the ratios for the 15/500‐mg dose strength for the maximum observed serum concentration (Cmax) and area under the serum concentration‐time curve from time 0 to infinity (AUC∞) were 0.95 (0.86–1.05) and 1.02 (0.98–1.08), respectively, for pioglitazone and 0.99 (0.95–1.03) and 1.03 (0.98–1.08), respectively, for metformin. Bioequivalency for pioglitazone and metformin between fixed‐dose combination tablets and coad treatments was met for both strengths of fixed‐dose combination tablets. In a post hoc meta‐analysis of combined data from the 2 studies (n = 124), there was considerable overlapping in AUC∞ values between gender and race (Caucasians, Blacks, and Hispanics), making neither gender‐ nor racial‐based dosing of pioglitazone or metformin necessary.
Oral Antidiabetic Drugs: Effect of Food on Absorption of Pioglitazone and Metformin From a Fixed‐Dose Combination Tablet
Authors: Karim Aziz , Slater Margaret , Bradford Dawn , Schwartz Lisa , Laurent Aziz
Published: December 2006

An open‐label, randomized, crossover study involving 28 healthy subjects was conducted to compare the peak (Cmax) and total (AUClqc, AUC) exposures to pioglitazone and metformin after single‐dose administration of a fixed‐dose combination tablet containing 15 mg of pioglitazone plus 850 mg metformin when given under fasted versus fed states, with a washout period of 7 days between treatments. Two different fixed‐dose combination formulations (bilayer and pioglitazone‐micronized fixed‐dose combination tablets) were tested. The pioglitazone‐micronized fixed‐dose combination formulation was selected for clinical development and regulatory approval; the present study describes food effect results with this formulation. For pioglitazone, least squares mean ratios (fed/fasted) and the 90% confidence intervals of these ratios were 1.05 (0.93–1.18) for Cmax, 1.13 (1.02–1.25) for AUClqc, and 1.11 (1.01–1.22) for AUC∞. For metformin, these values were 0.72 (0.65–0.79) for Cmax, 0.87 (0.81–0.94) for AUClqc, and 0.87 (0.81–0.94) for AUC∞. Dosing with food resulted in median prolongation of tmax values by 1.5 hours for metformin and 2.0 hours for pioglitazone. Because bioequivalency criteria were met (fed/fasted 90% confidence interval between 0.80 and 1.25) for both pioglitazone and metformin AUC, fixed‐dose combination tablets can be taken with or without food, but to minimize gastrointestinal adverse effects of metformin, the fixed‐dose combination tablets are recommended to be taken with food.
Dose‐Proportional Pharmacokinetics of d‐threo‐Methylphenidate After a Repeated‐Action Release Dosage Form
Authors: Tuerck Dietrich , Appel‐Dingemanse Silke , Maboudian Mojdeh , Pommier Francoise , Wang Yibin , Sedek Greg
Published: December 2006

A bimodal extended‐release formulation of d‐methylphenidate (d‐MPH) has been developed to enable fast onset of action and once‐daily administration in patients with attention deficit hyperactivity disorder. The authors studied the dose proportionality of extended‐release d‐MPH pharmacokinetics. Twenty‐five healthy adult volunteers received 5, 10, 20, 30, and 40 mg d‐MPH in a crossover study with 7 days between doses. All doses were well tolerated. Dose proportionality was shown for all dose‐dependent pharmacokinetic parameters. Geometric means (%gCV) for the first Cmax peak, Cmax 0–4, were 3.25 (29.0%), 6.05 (27.1%), 12.6 (31.9%), 18.5 (31.9%), and 25.2 ng/mL (29.3%) for d‐MPH 5, 10, 20, 30, and 40 mg, respectively. Geometric means (%gCV) for Cmax4–10 were 3.18 (27.5%), 5.84 (27.7%), 12.5 (31.7%), 17.7 (31.6%), and 23.6 ng/mL (29.0%), respectively. Geometric means for AUC0‐∞ were 24.3 (30.7%), 45.9 (30.2%), 96.4 (35.5%), 144 (33.3%), and 195 ng • h/mL (30.9%), respectively. The pharmacokinetics of once‐daily extended‐release d‐MPH are proportional to the dose.
Systemic Availability of the Active Metabolite Hydroxy‐Fasudil After Administration of Fasudil to Different Sites of the Human Gastrointestinal Tract
Authors: Hinderling Peter H. , Karara Adel H. , Tao Ben , Pawula Maria , Wilding Ian , Lu Ming
Published: December 2006

This study evaluated the gastrointestinal absorption of fasudil, a novel Rho kinase inhibitor for the treatment of stable angina, at different sites using remote‐controlled capsules and assessed the feasibility of developing an extended‐release formulation. Ten healthy male volunteers were enrolled, and 8 subjects completed this single‐dose, open‐label, randomized, 5‐way crossover study. Forty milligrams of fasudil HCl was administered as solution to the distal ileum and ascending colon, as powder to the ascending colon, and orally as an immediate‐release tablet and solution. All treatments were well‐tolerated and no serious adverse events were observed. The mean systemic availabilities of M3 relative to the oral solution were 1.04 (distal ileum, solution), 1.14 (ascending colon, solution), 1.27 (ascending colon, powder) and 1.04 (oral tablet), indicating similar systemic availability of M3 after administration of fasudil HCl to different gastrointestinal sites. The results suggest that development of a once‐a‐day extended‐release formulation for fasudil HCl should be readily achievable.
Single‐Dose and Steady‐State Pharmacokinetics of Fentanyl Buccal Tablet in Healthy Volunteers
Authors: Darwish Mona , Kirby Mary , Robertson Philmore , Hellriegel Edward , Jiang John G.
Published: December 2006

This study evaluated the single‐dose and steady‐state pharmacokinetics of fentanyl buccal tablet 400 μg in healthy adult volunteers. After receiving naltrexone 50 mg to block opioid receptor–mediated effects of fentanyl, subjects received fentanyl buccal tablet 400 μg on day 1, then every 6 hours from day 4 to day 9 (21 doses). Naltrexone 50 mg was administered every 12 hours throughout the study. Plasma fentanyl concentrations were determined for 72 hours after administration of fentanyl buccal tablet 400 μg on day 1 and the last dose of fentanyl buccal tablet 400 μg on day 9. Following single‐ and multiple‐dose administration of fentanyl buccal tablet, the median time to maximum concentration (tmax) was 52.2 and 49.8 minutes, respectively. Peak plasma concentration of fentanyl (Cmax) was 0.88 ng/mL for the single‐dose regimen and 1.77 ng/mL for the multiple‐dose regimen. Steady state was reached within 5 days, consistent with the observed median half‐life of approximately 22 hours following multiple doses. Observed accumulation of fentanyl after multiple doses of fentanyl buccal tablet was slightly greater than would be expected based on the single‐dose data. This was attributed to the redistribution of fentanyl from a deep tissue compartment into the plasma. This study indicates that fentanyl buccal tablet has predictable pharmacokinetics following multiple‐dose administration.
Dose‐Proportional Intraindividual Single‐ and Repeated‐Dose Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor
Authors: Bethke Thomas D. , Böhmer Gabriele M. , Hermann Robert , Hauns Bernhard , Fux Richard , Mörike Klaus , David Michael , Knoerzer Dietrich , Wurst Wilhelm , Gleiter Christoph H.
Published: December 2006

The dose‐proportional, intraindividual, single‐ and repeated‐dose pharmacokinetics of roflumilast, an oral, once‐daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2‐period, 2‐sequence crossover study, 15 subjects received immediate‐release tablets of roflumilast 250 or 500 μg as single (day 1) and as repeated, once‐daily doses for 8 days (days 5–12). Dose‐adjusted point estimates and 90% confidence intervals of test (500 μg)/reference (250 μg) ratios for AUC and Cmaxof roflumilast and its pharmacologically active N‐oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N‐oxide. Repeated oral dosing with roflumilast 250 and 500 μg once daily was well tolerated.
Significant Pharmacokinetic and Pharmacodynamic Interaction of Warfarin With the NO‐Independent sGC Activator HMR1766
Authors: Oberwittler Heike , Hirschfeld‐Warneken Andreas , Wesch Roland , Willerich Hans , Teichert Lenore , Lehr Karl‐Heinz , Ding Reinhard , Haefeli Walter Emil , Mikus Gerd
Published: December 2006

HMR1766 is a new nitric oxide (NO)–independent activator of soluble guanylyl cyclase (sGC) in development for the treatment of cardiovascular diseases and chronic heart failure. A significant fraction of patients to be treated with HMR1766 is expected to be maintained on warfarin. Because HMR1766 is an inhibitor and warfarin a substrate of CYP2C9, the authors studied whether warfarin pharmacokinetics and pharmacodynamics are influenced by HMR1766. Eighteen healthy males were to receive a single oral dose of 20 mg warfarin each under steady‐state conditions of HMR1766 or placebo. Plasma concentrations of HMR1766, (R)‐ and (S)‐warfarin, and its 7‐hydroxy‐metabolites were determined using high‐performance liquid chromatography and prothrombin time, and the international standardized ratio was determined by the nephelometric method. (S)‐Warfarin AUCinf and t1/2 were 106 471 h·μg/L and 82.92 hours versus 33 148 h·μg/L under HMR1766 and 31.72 hours under placebo, and the maximum decrease in prothrombin time values after warfarin dosing was 58.75% versus 39.94%. These data demonstrate a CYP2C9‐mediated pharmacokinetic interaction with pharmacodynamic, clinically relevant consequences, which might require warfarin dose adjustment.
Pharmacokinetics and Safety of Ketorolac Following Single Intranasal and Intramuscular Administration in Healthy Volunteers
Authors: McAleer Sarah D. , Majid Oneeb , Venables Esther , Polack Torsten , Sheikh Muhammed S.
Published: December 2006

Ketorolac was administered to 15 healthy volunteers in a phase 1, single‐dose, crossover, randomized study. Subjects received open‐label randomized 15‐ and 30‐mg intramuscular (IM) ketorolac and blinded randomized 15‐ and 30‐mg intranasal (IN) ketorolac. The IN ketorolac was well tolerated; the only nasal symptoms were some instances of mild irritation. The IN ketorolac was rapidly and well absorbed (median tmax, 0.50–0.75 hours), and the half‐life was approximately 5 to 6 hours, values that were similar to those following IM administration. Relative bioavailability of IN compared to IM administration at the same doses was approximately 67% to 75%. Dose proportionality was noted between the 15‐ and 30‐mg IN and IM dose levels. Thus, IN ketorolac offers a therapeutic alternative to IM administration and may provide benefits in the clinical setting.
Effect of Polymorphic CYP3A5 Genotype on the Single‐Dose Simvastatin Pharmacokinetics in Healthy Subjects
Authors: Kim Kyoung‐Ah , Park Pil‐Whan , Lee Ock‐Je , Kang Dong‐Kyun , Park Ji‐Young
Published: December 2006

Simvastatin, a cholesterol‐lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty‐two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20‐mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (±SD) area under the plasma concentration‐time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 ± 2.25 ng • h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 ± 6.37 ng • h/mL; P = .013, Bonferroni test). The mean (±SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 ± 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 ± 0.61 L/h; P < .05, Dunn's test). However, other pharmacokinetic parameters including peak plasma concentrations and half‐life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition.
Highly Variable Mycophenolate Mofetil Bioavailability Following Nonmyeloablative Hematopoietic Cell Transplantation
Authors: Jacobson Pamala , Green Kathleen , Rogosheske John , Brunstein Claudio , Ebeling Breta , DeFor Todd , McGlave Philip , Weisdorf Daniel
Published: December 2006

This study determined the oral bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, in patients undergoing nonmyeloablative hematopoietic cell transplantation. Eighteen adults receiving a preparative regimen containing fludarabine, cyclophosphamide, and total body irradiation were studied. Immune suppression consisted of cyclosporine and mycophenolate 1 g twice daily. Pharmacokinetic variability was high after intravenous and oral dosing. Intravenous dosing resulted in a median area under the curve (AUC) of 28.3 μg•h/mL (range, 9.96–70.4) and an oral AUC of 16.7 μg•h/mL (range, 9.38–35.3). C max after intravenous and oral dosing was 12.18 and 5.29 μg/mL, respectively. The median oral bioavailability was 72.3% (20.5%–172%), with 8‐fold variability. Five patients (28%) had an oral bioavailability ≤50%. At time of oral pharmacokinetics, 15 patients (83%) had an AUC0–12 <30 μg•h/mL. The initial oral dose should be at least 25% greater than the intravenous dose with follow‐up assessment of plasma concentrations.
Population Pharmacokinetic–Based Dosing of Intravenous Busulfan in Pediatric Patients
Authors: Booth Brian P. , Rahman Atiqur , Dagher Ramzi , Griebel Donna , Lennon Shari , Fuller David , Sahajwalla Chandra , Mehta Mehul , Gobburu Jogarao V. S.
Published: December 2006

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty‐four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages ≤4 years or >4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1‐compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients ≤12 kg should be dosed at 1.1 mg/kg and those >12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.
Regional Occupational and Industrial Structure: Does One Imply the Other?
Authors: Barbour Elisa , Markusen Ann
Published: December 2006

The product/profit cycle and new international division of labor theories hypothesize that establishments in a single industry may be undertaking different activities in different locations: innovative and developmental activities will be anchored in regions of origin, while more routine production and service functions will be dispersed to lower cost and downstream consuming regions. Disparities in occupational composition offer a test of these theories. In this article, we test whether a region’s occupational structure can be read off of its industrial structure. Using a data set created for eleven California metropolitan areas for 1997, we explore the extent to which the occupational mix within a specific metropolitan industry is dissimilar to the mix found for that same industry in other metros. We find that estimating a metro’s occupational mix by assuming that its industries mirror the national occupational structure for those industries often provides a reasonable approximation especially for aggregate occupational categories. However, this does not hold for a cluster of innovative industries and occupations that we tested, specifically in high-tech research and development and information technology activities. In such cases, pursuing industrial targeting will not achieve the same consequence as pursuing occupational targeting.
New Economic Geography: Real or Hype?
Authors: Koo Jun , Lall Somik
Published: December 2006

New economic geography has become a mantra for many economists, geographers, and regional scientists. Many recent studies have tested the importance of economic geography for production activities and found a significant association between them. Most of these studies, however, have not taken into account that productivity gains from economic geography, if any, are conditional on firm-location choice. This article illustrates a potential bias that can arise when firm-location choice is not considered in estimating the contribution of economic geography to firm performance. An analysis using microdata of Indian manufacturing firms shows that there is an upward bias in the contribution of economic geography to productivity when firm-location choice is not jointly taken into account as part of production decisions.
Assessing the Regional Economic Development Impacts of Universities: A Review of Current Approaches
Authors: Drucker Joshua , Goldstein Harvey
Published: December 2006

Research universities in the United States have increasingly become involved in economic development since the mid-1980s. There has been a corresponding growth of interest in measuring the impacts of higher education on regional economies. This article reviews the approaches used to examine the influence of research universities on regional economic development outcomes. Considerable attention is paid to the methodological advantages and shortcomings of four major research designs evidenced in the literature: single-university impact studies, surveys, knowledge production functions, and cross-sectional and quasiexperimental designs. University activities, particularly knowledge-based activities such as teaching and basic research, have been found to have substantial positive effects on a variety of measures of regional economic progress.
Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia
Authors: Picard Stephane , Titier Karine , Etienne Gabriel , Teilhet Emmanuelle , Ducint Dominique , Bernard Marie-Agnes , Lassalle Regis , Marit Gerald , Reiffers Josy , Begaud Bernard , Moore Nicholas , Molimard Mathieu , Mahon Francois-Xavier
Published: December 2006

Using high-performance liquid chromatography–tandem mass spectrometry, we assessed trough imatinib plasma levels in 68 patients with chronic myeloid leukemia (CML) who responded or not to standard-dose imatinib, after at least 12 months' treatment. Mean trough imatinib plasma levels were significantly higher in the group with complete cytogenetic response (56 patients) than in the group without (12 patients; P = .03) and higher in the group with major molecular response (MMR) than in the group without (34 patients [1452 ± 649 ng/mL] versus 34 patients [869 ± 427 ng/mL]; P < .001). Regarding trough imatinib plasma levels and their discrimination potential for MMR, the area under receiver operating characteristic curve was 0.775, with best sensitivity (77%) and specificity (71%) at a plasma threshold of 1002 ng/mL. Therefore, monitoring of imatinib plasma levels could be very useful for the management of patients with CML or should at least be checked in the case of treatment failure or suboptimal response.
Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia
Authors: dos Santos Nuno R. , Rickman David S. , de Reynies Aurélien , Cormier Françoise , Williame Maryvonne , Blanchard Camille , Stern Marc-Henri , Ghysdael Jacques
Published: December 2006

The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from EμSRα-TEL-JAK2 transgenic mice present an aberrant CD8+ differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4−CD8− double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3ϵ- and pTα-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR–deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCRαβ transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCRαβ expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs.
Conservation of noncoding microsatellites in plants: implication for gene regulation
Authors: Zhang Lida , Zuo Kaijing , Zhang Fei , Cao Youfang , Wang Jiang , Zhang Yidong , Sun Xiaofen , Tang Kexuan
Published: December 2006

Background

Microsatellites are extremely common in plant genomes, and in particular, they are significantly enriched in the 5' noncoding regions. Although some 5' noncoding microsatellites involved in gene regulation have been described, the general properties of microsatellites as regulatory elements are still unknown. To address the question of microsatellites associated with regulatory elements, we have analyzed the conserved noncoding microsatellite sequences (CNMSs) in the 5' noncoding regions by inter- and intragenomic phylogenetic footprinting in the Arabidopsis and Brassica genomes.

Results

We identified 247 Arabidopsis-Brassica orthologous and 122 Arabidopsis paralogous CNMSs, representing 491 CT/GA and CTT/GAA repeats, which accounted for 10.6% of these types located in the 500-bp regions upstream of coding sequences in the Arabidopsis genome. Among these identified CNMSs, 18 microsatellites show high conservation in the regulatory regions of both orthologous and paralogous genes, and some of them also appear in the corresponding positions of more distant homologs in Arabidopsis, as well as in other plants. A computational scan of CNMSs for known cis-regulatory elements showed that light responsive elements were clustered in the region of CT/GA repeats, as well as salicylic acid responsive elements in the (CTT)n/(GAA)n sequences. Patterns of gene expression revealed that 70–80% of CNMS (CTT)n/(GAA)n associated genes were regulated by salicylic acid, which was consistent with the prediction of regulatory elements in silico.

Conclusion

Our analyses showed that some noncoding microsatellites were conserved in plants and appeared to be ancient. These CNMSs served as regulatory elements involved in light and salicylic acid responses. Our findings might have implications in the common features of the over-represented microsatellites for gene regulation in plant-specific pathways.
Amygdala size in amyotrophic lateral sclerosis without dementia: an in vivostudy using MRI volumetry
Authors: Pinkhardt Elmar H , van Elst Ludger Tebartz , Ludolph Albert C , Kassubek Jan
Published: December 2006

Background

Evidence for extra-motor involvement in non-demented patients with amyotrophic lateral sclerosis (ALS) has been provided by multiple studies, in particular neuropathological studies have demonstrated neuronal loss in the amygdala. The aim of this study was to investigate possible alterations of amygdala volumesin vivo.

Methods

Twenty-two moderately disabled patients with definite ALS without cognitive or behavioural deficits and 22 age-matched healthy controls were included. Amygdala and total brain volumes were measured by region-of-interest-based volumetry in 3-D MRI.

Results

A trend was observed with reduced amygdala size in the ALS group, since mean absolute and brain size-corrected amygdala volumes were 6.9% and 7.6% lower in the patient group compared to those in normal controls (P = 0.086 and P = 0.110), respectively.

Conclusion

Volumetrically identifiable alterations of the amygdala can be mappedin vivoand may be associated with psychopathological findings in later stages of ALS.
The use of a pre-operative scoring system for the prediction of phacoemulsification case difficulty and the selection of appropriate cases to be performed by trainees
Authors: Osborne Stuart A , Severn Phillip , Bunce Catey V , Fraser Scott G
Published: December 2006

Background

To establish whether a previously validated scoring system (Habib) for the prediction of risk or likelihood of posterior capsule rupture during phacoemulsification surgery could be used to: 1. Predict the difficulty of a phacoemulsification case, and 2. Select appropriate phacoemulsification cases for trainees.

Methods

The study sample was consecutive phacoemulsification cases undertaken by senior surgeons at a single ophthalmic unit over a three-week period (170 cases). Each case was scored using a potential difficulty scoring system. Immediately post-operatively, each case was given two scores by the operating surgeon (who was masked with regard to the potential complication score). The first score indicated the perceived difficulty of the case, and the second score, the degree of experience that they thought a trainee would require in order to have performed the same case without complication.

Results

Using Cuzick's non-parametric test for trend, there was evidence for a trend of increasing perceived difficulty with increasing potential difficulty score (p = 0.05), and of increasing experience required with increasing potential difficulty score (p < 0.001)

Conclusion

The authors advocate that Habib's potential difficulty scoring system can be used to inform the surgeon of the likely difficulty of a phacoemulsification case and to aid selection of appropriate cases for trainees prior to surgery.
Non-randomised patients in a cholecystectomy trial: characteristics, procedures, and outcomes
Authors: Ros Axel , Carlsson Per , Rahmqvist Mikael , Bäckman Karin , Nilsson Erik
Published: December 2006

Background

Laparoscopic cholecystectomy is now considered the first option for gallbladder surgery. However, 20% to 30% of cholecystectomies are completed as open operations often on elderly and fragile patients. The external validity of randomised trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy has not been studied. The aim of this study is to analyse characteristics, procedures, and outcomes for all patients who underwent cholecystectomy without being included in such a trial.

Methods

Characteristics (age, sex, co-morbidity, and ASA-score), operation time, hospital stay, and mortality were compared for patients who underwent cholecystectomy outside and within a randomised controlled trial comparing mini-laparotomy and laparoscopic cholecystectomy.

Results

During the inclusion period 1719 patients underwent cholecystectomy. 726 patients were randomised and 724 of them completed the trial; 993 patients underwent cholecystectomy outside the trial. The non-randomised patients were older – and had more complications from gallstone disease, higher co-morbidity, and higher ASA – score when compared with trial patients. They were also more likely to undergo acute surgery and they had a longer postoperative hospital stay, with a median 3 versus 2 days (p < 0.001 for all comparisons). Standardised mortality ratio within 90 days of operation was 3.42 (mean) (95% CI 2.17 to 5.13) for non-randomised patients and 1.61 (mean) (95%CI 0.02 to 3.46) for trial patients. For non-randomised patients, operation time did not differ significantly between mini-laparotomy and open cholecystectomy in multivariate analysis. However, the operation for laparoscopic cholecystectomy lasted 20 minutes longer than open cholecystectomy. Hospital stay was significantly shorter for both mini-laparotomy and laparoscopic cholecystectomy compared to open cholecystectomy.

Conclusion

Non-randomised patients were older and more sick than trial patients. The assignment of healthier patients to trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy limits the external validity of conclusions reached in such trials.
Illness-related behaviour and utilization of oral health services among adult city-dwellers in Burkina Faso: evidence from a household survey
Authors: Varenne Benoît , Petersen Poul Erik , Fournet Florence , Msellati Philippe , Gary Jean , Ouattara Seydou , Harang Maud , Salem Gérard
Published: December 2006

Background

In sub-Saharan Africa, the availability and accessibility of oral health services are seriously constrained and the provision of essential oral care is limited. Reports from the region show a very low utilization of oral health care services, and visits to dental-care facilities are mostly undertaken for symptomatic reasons. The objectives of the present study were to describe the prevalence of oral symptoms among adults in Ouagadougou, capital city of Burkina Faso and the use of oral health services and self-medication in response to these symptoms and to measure the associations between predisposing, enabling and needs factors and decisions to seek oral health care.

Methods

The conceptual design of the study was derived from both the Andersen-Newman model of health care utilization and the conceptual framework of the WHO International Collaborative Study of Oral Health Outcomes. Data were obtained by two-stage stratified sampling through four areas representative of different stages of urbanization of Ouagadougou. The final study population comprised 3030 adults aged 15 years or over and the response rate was 65%.

Results

Overall, 28% of the respondents had experienced an oral health problem during the past 12 months; a high proportion (62%) reported pain or acute discomfort affecting daily life. In response to symptoms, only 28% used oral health facilities, 48% used self-medication and 24% sought no treatment at all. Multivariate analyses revealed that several socio-economic and socio-cultural factors such as religious affiliation, material living conditions and participation in a social network were significantly associated with the use of oral health care services by adults who had experienced oral health problems during the previous year.

Conclusion

The proportion of people who have obtained oral health care is alarmingly low in Ouagadougou and self-medication appears to be an important alternative source of care for adult city-dwellers. Decision-makers in sub-Saharan countries must seek to ensure that access to essential oral health care is improved.
Proteomic alteration in gastic adenocarcinomas from Japanese patients
Authors: Yoshihara Takahiro , Kadota Yoshito , Yoshimura Yoshiyuki , Tatano Yutaka , Takeuchi Naohiro , Okitsu Hiroshi , Umemoto Atsushi , Yamauchi Takashi , Itoh Kohji
Published: December 2006

Background

Gastric adenocarcinomas comprise one of the common types of cancers in Asian countries including Japan. Comprehensive protein profiling of paired surgical specimens of primary gastric adenocarcinomas and nontumor mucosae derived from Japanese patients was carried out by means of two-dimensional gel electrophoresis (2D-EP) and liquid chromatography-electrospray ionic tandem mass spectrometry (LC-ESI-MS) to establish gastric cancer-specific proteins as putative clinical biomarkers and molecular targets for chemotherapy.

Results

Relatively common alterations in protein expression were revealed in the tumor tissues. Increases in manganese dismutase and nonhistone chromosomal protein HMG-1 (HMG-1) were observed, while decreases in carbonic anhydrases I and II, glutatione-S-transferase and foveolin precursor (gastrokine-1) (FOV), an 18-kDa stomach-specific protein with putative tumor suppressor activity, were detected. RT-PCR analysis also revealed significant down-regulation of FOV mRNA expression in tumor tissues.

Conclusion

A possible pathological role for down-regulation of FOV in gastric carcinogenesis was demonstrated. Evaluation of the specific decreases in gene and protein expression of FOV in patients may be utilized as clinical biomarkers for effective diagnosis and assessment of gastric cancer.
ICI 182,780 has agonistic effects and synergizes with estradiol-17 beta in fish liver, but not in testis
Authors: Pinto Patrícia IS , Singh Pratap B , Condeça João B , Teodósio Helena R , Power Deborah M , Canário Adelino VM
Published: December 2006

Background

ICI 182,780 (ICI) belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER) actions in several mammalian species. In the present study, the effects and mechanism of action of ICI were investigated in the teleost fish, sea bream (Sparus auratus).

Methods

Three independent in vivo experiments were performed in which mature male tilapia (Oreochromis mossambicus) or sea bream received intra-peritoneal implants containing estradiol-17 beta (E2), ICI or a combination of both compounds. The effects of E2 and ICI on plasma calcium levels were measured and hepatic and testicular gene expression of the three ER subtypes, ER alpha, ER beta a and ER beta b, and the estrogen-responsive genes, vitellogenin II and choriogenin L, were analyzed by semi-quantitative RT-PCR in sea bream.

Results

E2 treatment caused an increase in calcium levels in tilapia, while ICI alone had no noticeable effect, as expected. However, pretreatment with ICI synergistically potentiated the effect of E2 on plasma calcium in both species. ICI mimicked some E2 actions in gene expression in sea bream liver upregulating ER alpha, vitellogenin II and choriogenin L, although, unlike E2, it did not downregulate ER beta a and ER beta b. In contrast, no effects of E2 or ICI alone were detected in the expression of ERs in testis, while vitellogenin II and choriogenin L were upregulated by E2 but not ICI. Finally, pretreatment with ICI had a synergistic effect on the hepatic E2 down-regulation of ER beta b, but apparently blocked the ER alpha up-regulation by E2.

Conclusion

These results demonstrate that ICI has agonistic effects on several typical estrogenic responses in fish, but its actions are tissue-specific. The mechanisms for the ICI agonistic activity are still unknown; although the ICI induced up-regulation of ER alpha mRNA could be one of the factors contributing to the cellular response.