bluuebunny/crossref_metadata_2025 huggingface dataset:
Third- and fourth-order perturbation corrections to excitation energies from configuration interaction singles
Authors: Hirata So
Published: February 2005

Complete third-order and partial fourth-order Rayleigh–Schrödinger perturbation corrections to excitation energies from configuration interaction singles (CIS) have been derived and termed CIS(3) and CIS(4)P. They have been implemented by the automated system TENSOR CONTRACTION ENGINE into parallel-execution programs taking advantage of spin, spatial, and index permutation symmetries and applicable to closed- and open-shell molecules. The consistent use of factorization, first introduced by Head-Gordon et al. in the second-order correction to CIS denoted CIS(D), has reduced the computational cost of CIS(3) and CIS(4)P from O(n8) and O(n6) to O(n6) and O(n5), respectively, with n being the number of orbitals. It has also guaranteed the size extensivity of excited-state energies of these methods, which are in turn the sum of size-intensive excitation energies and the ground-state energies from the standard Møller–Plesset perturbation theory at the respective orders. The series CIS(D), CIS(3), and CIS(4)P are usually monotonically convergent at values close to the accurate results predicted by coupled-cluster singles and doubles (CCSD) with a small fraction of computational costs of CCSD for predominantly singly excited states characterized by a 90%–100% overlap between the CIS and CCSD wave functions. When the overlap is smaller, the perturbation theory is incapable of adequately accounting for the mixing of the CIS states through higher-than-singles sectors of the Hamiltonian matrix, resulting in wildly oscillating series with often very large errors in CIS(4)P. Hence, CIS(3) and CIS(4)P have a rather small radius of convergence and a limited range of applicability, but within that range they can be an inexpensive alternative to CCSD.
Detailed characterization of (3×3) iodine adlayer on Pt(111) by unequal-sphere packing model
Authors: Tkatchenko Alexandre , Batina Nikola
Published: February 2005

A simple unequal-sphere packing model is applied to study the iodine (3×3) adlayer on the Pt(111) surface. By using a newly introduced parameter, defined as the average adsorbate height, three characteristic adlattices, (3×3)-sym, (3×3)-asym, and (3×3)-lin, have been selected and characterized in great detail, including the exact adatom registry. The (3×3)-sym iodine adlattice, observed in many experimental studies, appears to be, on average, the closest one to the substrate surface. A special contour plot of average adsorbate height vs X and Y positions of the (3×3) iodine unit cell indicates the existence of two local minima, which are related to preferential formation of (3×3)-sym and (3×3)-asym iodine adlattices. Our model gives good agreement with experimental findings, and explains the mechanism of preferential appearance of (3×3)-sym and (3×3)-asym structures.
Theoretical study of intramolecular interaction energies during dynamics simulations of oligopeptides by the fragment molecular orbital-Hamiltonian algorithm method
Authors: Ishimoto Takayoshi , Tokiwa Hiroaki , Teramae Hiroyuki , Nagashima Umpei
Published: February 2005

We analyzed the interaction energies between residues (fragments) in an oligopeptide occurring during dynamic simulations by using the fragment molecular orbital-Hamiltonian algorithm (FMO-HA) method, an ab initio MO-molecular dynamics technique. The FMO method enables not only calculation of large molecules based on ab initio MO but also easy evaluation of interfragment interaction energies. The glycine pentamer [(Gly)5] and decamer [(Gly)10] were divided into five and ten fragments, respectively. α-helix structures of (Gly)5 and (Gly)10 were stabilized by attractive interaction energies owing to intramolecular hydrogen bonds between fragments n and n+3 (and n+4), and β-strand structures were characterized by repulsive interaction energies between fragments n and n+2. We analyzed interfragment interaction energies during dynamics simulations as the peptides’ geometries changed from α helix to β strand. Intramolecular hydrogen bonds between fragments 2-4 and 2-5 control the geometrical preference of (Gly)5 for the β-strand structure. The pitch of one turn of the α helix of (Gly)10 elongated and thus weakened during dynamics due to a shifting of the intramolecular hydrogen bonds, and enabled the β-strand structure to form. Changes in interaction energies due to the intramolecular hydrogen bonds controlled the tendency toward α-helix or β-strand structure of (Gly)5 and (Gly)10. Evaluation of interfragment interaction energies during dynamics simulations thus enabled detailed analysis of the process of the geometrical changes occurring in oligopeptides.
Flow curves of dense colloidal dispersions: Schematic model analysis of the shear-dependent viscosity near the colloidal glass transition
Authors: Fuchs Matthias , Ballauff Matthias
Published: February 2005

A recently proposed schematic model for the nonlinear rheology of dense colloidal dispersions is compared to flow curves measured in suspensions that consist of thermosensitive particles. The volume fraction of this purely repulsive model system can be adjusted by changing temperature. Hence, high volume fractions (ϕ⩽0.63) can be achieved in a reproducible manner. The quantitative analysis of the flow curves suggests that the theoretical approach captures the increase of the low shear viscosity with increasing density, the shear thinning for increasing shear rate, and the yielding of a soft glassy solid. Variations of the high shear viscosity can be traced back to hydrodynamic interactions which are not contained in the present approach but can be incorporated into the data analysis by an appropriate rescaling.
Triplet exciton diffusion in fac-tris(2-phenylpyridine) iridium(III)-cored electroluminescent dendrimers
Authors: Namdas Ebinazar B. , Ruseckas Arvydas , Samuel Ifor D. W. , Lo Shih-Chun , Burn Paul L.
Published: February 2005

We have studied triplet-triplet annihilation in neat films of electrophosphorescent fac-tris(2-phenylpyridine) iridium(III) [Ir(ppy)3]-cored dendrimers containing phenylene- and carbazole-based dendrons with 2-ethylhexyloxy surface groups using time-resolved photoluminescence. From measured annihilation rates, the limiting current densities above which annihilation would dominate in dendrimer light-emitting devices are found to be >1A∕cm2. The triplet exciton diffusion length varies in the range of 2–10 nm depending on the dendron size. The distance dependence of the nearest-neighbor hopping rate shows that energy transfer is dominated by the exchange mechanism.
Continuous configuration time-dependent self-consistent field method for polyatomic quantum dynamical problems
Authors: Zhang Dong H. , Bao Weizhu , Yang Minghui , Lee Soo-Y.
Published: February 2005

A new continuous configuration time-dependent self-consistent field method has been developed to study polyatomic dynamical problems by using the discrete variable representation for the reaction system, and applied to a reaction system coupled to a bath. The method is very efficient because the equations involved are as simple as those in the traditional single configuration approach, and can account for the correlations between the reaction system and bath modes rather well.
Yellowish-white luminescence in codoped zinc oxide
Authors: Ohashi Naoki , Ebisawa Naoki , Sekiguchi Takashi , Sakaguchi Isao , Wada Yoshiki , Takenaka Tadashi , Haneda Hajime
Published: February 2005

The broad-band visible emission of codoped ZnO was studied. The codoped ZnO specimens were intentionally and simultaneously doped with IIIa elements (donors) and Li (acceptor). Broad-band emission covering nearly the whole visible range was achieved. The emission was found to be yellowish white to the naked eye. The visible band was composed of two components, i.e., a green emission having a peak at 2.2 eV and a yellow emission having a peak at 2.0 eV. The peak at 2.2 eV was distinct from the nonstructured green emission at 2.45 eV. The 2.2 and 2.0 eV peaks were attributed to donor-acceptor pair transitions involving the zinc vacancy and lithium, respectively.
Ti gate compatible with atomic-layer-deposited HfO2 for n-type metal-oxide-semiconductor devices
Authors: Yang Hyundoek , Son Yunik , Baek Sungkwon , Hwang Hyunsang , Lim Hajin , Jung Hyung-Seok
Published: February 2005

The electrical characteristics were evaluated for the metal-oxide-semiconductor (MOS) devices with Ti and Pt gates on the atomic-layer-deposited (ALD) HfO2. The equivalent oxide thickness (EOT) of the Ti gate is shown to be nearly the same as that of the Pt gate, which means that a negligible chemical reaction occurs between the gate and dielectric. The values of the effective metal work function (Φm,eff), extracted from the conventional relations of flatband voltage versus EOT, were ∼4.2eV for Ti and ∼5.4eV for Pt, respectively. However, somewhat higher values of Φm,eff were extracted by considering the existence of an interfacial layer and the high negative charge at an interface between HfO2 and interfacial layer. The exact values of Φm,eff were ∼4.37eV for Ti and ∼5.51eV for Pt, respectively. Therefore, the Ti gate is compatible with ALD-HfO2 and can be a candidate for n-type MOS devices.
Ductile titanium-based glassy alloy ingots
Authors: Guo Faqiang , Wang Hsiang-Jen , Poon S. Joseph , Shiflet Gary J.
Published: February 2005

We report that ductile and strong amorphous titanium metallic alloys (∼ twice the strength of high-strength titanium alloys) have been discovered that are in the form of glassy ingots. It is found that the suppression of a competing stable quasicrystalline phase upon solidification is particularly important in forming the current glassy ingots. While there is significant technological potential for these titanium alloys, the present findings have important implications on the design of highly processable bulk metallic glasses.
TerraByte flash memory with carbon nanotubes
Authors: Kish Laszlo B. , Ajayan Pulickel M.
Published: February 2005

Using the large maximal current density and the small diameter of carbon nanotubes, a flash memory arrangement is proposed. It makes use of the spin sensitive transport through hybrid conductor junctions. This memory contains no moving mechanical part and a single layer’s theoretical information density can reach beyond 40Gbit∕cm2. It is easy to build a three-dimensional memory structure. Then, the theoretical capacity can reach beyond 1015bit∕cm3 (1000Terrabit∕cm3), which means that a memory with 1cm area and 1mm thickness could have about 10TerraByte capacity.
The Role of Ylides in the Chlorination of Unsymmetrical Sulfides: An Ab Initio Molecular Orbital Study
Authors: Potvin Michael , Mothana Belquis , Albrecht Laura , Darvesh Katherine Valenta , Langler Richard F.
Published: February 2005

Ab initio molecular orbital theory has been used to investigate a series of possible chlorosulfonium ylides to assess the potential for ylide intermediacy in the chlorination of organic sulfides. The majority of optimized structures are best viewed as thionium salts. Only ylide structures in which the putative carbanionic centre bears a powerful anion stabilizer (e.g. cyano or carbomethoxy) survive optimization.
A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness
Authors: Potash Mary Jane , Chao Wei , Bentsman Galina , Paris Nicolae , Saini Manisha , Nitkiewicz Jadwiga , Belem Paula , Sharer Leroy , Brooks Andrew I. , Volsky David J.
Published: February 2005

We created a model of HIV-1 infection of conventional mice for investigation of viral replication, control, and pathogenesis. To target HIV-1 to mice, the coding region of gp120 in HIV-1/NL4-3 was replaced with that of gp80 from ecotropic murine leukemia virus, a retrovirus that infects only rodents. The resulting chimeric virus construct, EcoHIV, productively infected murine lymphocytes, but not human lymphocytes, in culture. Adult, immunocompetent mice were readily susceptible to infection by a single inoculation of EcoHIV as shown by detection of virus in splenic lymphocytes, peritoneal macrophages, and the brain. The virus produced in animals was infectious, as shown by passage in culture, and immunogenic, as shown by induction of antibodies to HIV-1 Gag and Tat. A second chimeric virus based on clade D HIV-1/NDK was also highly infectious in mice; it was detected in both spleen and brain 3 wk after tail vein inoculation, and it induced expression of infection response genes, MCP-1, STAT1, IL-1β, and complement component C3, in brain tissue as determined by quantitative real-time PCR. EcoHIV infection of mice forms a useful model of HIV-1 infection of human beings for convenient and safe investigation of HIV-1 therapy, vaccines, and potentially pathogenesis.
A Mutation indVps28Reveals a Link between a Subunit of the Endosomal Sorting Complex Required for Transport-I Complex and the Actin Cytoskeleton inDrosophila
Authors: Sevrioukov Evgueni A. , Moghrabi Nabil , Kuhn Mary , Krämer Helmut
Published: February 2005

Proteins that constitute the endosomal sorting complex required for transport (ESCRT) are necessary for the sorting of proteins into multivesicular bodies (MVBs) and the budding of several enveloped viruses, including HIV-1. The first of these complexes, ESCRT-I, consists of three proteins: Vps28p, Vps37p, and Vps23p or Tsg101 in mammals. Here, we characterize a mutation in the Drosophila homolog of vps28. The dVps28 gene is essential: homozygous mutants die at the transition from the first to second instar. Removal of maternally contributed dVps28 causes early embryonic lethality. In such embryos lacking dVps28, several processes that require the actin cytoskeleton are perturbed, including axial migration of nuclei, formation of transient furrows during cortical divisions in syncytial embryos, and the subsequent cellularization. Defects in actin cytoskeleton organization also become apparent during sperm individualization in dVps28 mutant testis. Because dVps28 mutant cells contained MVBs, these defects are unlikely to be a secondary consequence of disrupted MVB formation and suggest an interaction between the actin cytoskeleton and endosomal membranes in Drosophila embryos earlier than previously appreciated.
The Clinical Features of Facioscapulohumeral Muscular Dystrophy Associated With Borderline (≥35 kb) 4q35 EcoRI Fragments
Authors: Felice Kevin J , Whitaker Charles H
Published: February 2005

Objectives:

The objectives of this study were to characterize the clinical features of facioscapulohumeral muscular dystrophy (FSHD) in patients with borderline (≥35 kb) EcoRI fragments and to compare patients with borderline EcoRI fragments with FSHD patients harboring fragments of <35 kb.

Background:

Most patients with FSHD harbor 4q35 EcoRI fragments of less than 35 kb. The clinical findings in patients with borderline fragments are not well known.

Methods:

The authors conducted a retrospective review of patients with FSHD followed at a regional neuromuscular center over a 12-year period.

Results:

Eleven patients with DNA-positive FSHD, found to harbor borderline (≥35 kb) EcoRI fragments (group 1), were compared with 30 patients with fragments of <35 kb (group 2). Group 1 patients were less likely (18%) to present with the classic FSHD phenotype as compared with group 2 patients (63%). Statistically significant differences in clinical disease severity and manual muscle testing scores were noted between the 2 groups, with group 1 patients showing less severe weakness and disability at presentation.

Conclusions:

Patients with borderline fragments are more likely to have a partial or less severe form of FSHD, probably resulting from a less disruptive DNA alteration at the 4q35 locus.
Characteristics of Human Calicivirus Enteritis in Intestinal Transplant Recipients
Authors: Kaufman Stuart S , Chatterjee Nando K , Fuschino Meghan E , Morse Dale L , Morotti Raffaella A , Magid Margret S , Gondolesi Gabriel E , Florman Sander S , Fishbein Thomas M
Published: February 2005

Objectives:

The human caliciviruses, which include Norwalk‐like viruses (or Noroviruses) and Sapporo viruses, commonly cause epidemic and endemic viral gastroenteritis of short duration in healthy individuals. However, the impact of human calicivirus in immunosuppressed populations has not been established. The authors report five pediatric patients who developed human calicivirus enteritis after intestinal transplantation.

Methods:

Infection was documented with repetitive reverse transcription polymerase chain reaction testing with nucleotide sequencing of tissue and lumen fluid specimens.

Results:

A single strain, type Miami Beach, affected all patients in the hospital with an apparent index case. A potential mode of transmission was not defined. Severe osmotic or secretory diarrhea necessitated intravenous fluid therapy for 40 days or more in three of the five infants. Concurrent or recent subclinical allograft infection with adenovirus in two patients was associated with more severe symptoms. Virus excretion exceeded 80 days in two patients. Differentiation of human calicivirus enteritis from allograft rejection was difficult, as both disorders were associated with increased enterocyte apoptosis and inflammation. Intensification of immunosuppressive therapy because of suspected rejection appeared to prolong symptoms.

Conclusion:

These findings demonstrate that human calicivirus can be a significant pathogen in intestinal transplant recipients and potentially in other immunocompromised patients.
Ipsilateral and Contralateral MRI Volumetric Abnormalities in Chronic Unilateral Temporal Lobe Epilepsy and their Clinical Correlates
Authors: Seidenberg Michael , Kelly Kiesa Getz , Parrish Joy , Geary Elizabeth , Dow Christian , Rutecki Paul , Hermann Bruce
Published: February 2005

Summary:  Purpose: To assess the presence, extent, and clinical correlates of quantitative MR volumetric abnormalities in ipsilateral and contralateral hippocampus, and temporal and extratemporal lobe regions in unilateral temporal lobe epilepsy (TLE).

Methods: In total, 34 subjects with unilateral left (n = 15) or right (n = 19) TLE were compared with 65 healthy controls. Regions of interest included the ipsilateral and contralateral hippocampus as well as temporal, frontal, parietal, and occipital lobe gray and white matter. Clinical markers of neurodevelopmental insult (initial precipitating insult, early age of recurrent seizures) and chronicity of epilepsy (epilepsy duration, estimated number of lifetime generalized seizures) were related to magnetic resonance (MR) volume abnormalities.

Results: Quantitative MR abnormalities extend beyond the ipsilateral hippocampus and temporal lobe with extratemporal (frontal and parietal lobe) reductions in cerebral white matter, especially ipsilateral but also contralateral to the side of seizure onset. Volumetric abnormalities in ipsilateral hippocampus and bilateral cerebral white matter are associated with factors related to both the onset and the chronicity of the patients' epilepsy.

Conclusions: These cross‐sectional findings support the view that volumetric abnormalities in chronic TLE are associated with a combination of neurodevelopmental and progressive effects, characterized by a prominent disruption in ipsilateral hippocampus and neural connectivity (i.e., white matter volume loss) that extends beyond the temporal lobe, affecting both ipsilateral and contralateral hemispheres.
Changes in Baroreflex Responses of Kindled Rats
Authors: Kaya Çiğdem Apaydin , Özkaynakçi Aydan Ergün , Gören M. Zafer , Onat Filiz Yilmaz
Published: February 2005

Summary:  Purpose: This study was planned to investigate the baroreflex responses (BRs) in kindled rats during seizure‐free period to put forward new data on cardiac autonomic changes in epilepsy.

Methods: Male Wistar rats were randomized into sham‐operated (SO) and kindled groups where stimulation and recording electrodes were implanted stereotaxically into the basolateral amygdala and the cortex, respectively. For kindling process, rats were stimulated twice daily at their afterdischarge threshold current and accepted as being kindled after 10 grade 5 seizures. Six to 8 weeks after the establishment of the kindled state, mean arterial pressure (MAP) and heart rate (HR) were evaluated. BR was defined as the ratio of HR response to changes in MAP induced by i.v. nitroprusside (10, 25 μg/kg) or i.v. phenylephrine (10, 25 μg/kg). The sympathetic or parasympathetic component of the BR was evaluated in rats pretreated with atropine or atenolol where phenylephrine or nitroprusside was administered at 25 μg/kg.

Results: Basal MAP and HR values were found to be similar in SO and kindled rats. Phenylephrine increased MAP more in the kindled group (p < 0.05), but the HR decreased similarly in both groups. Nitroprusside decreased MAP at similar rates, but the increase in HR was higher in the kindled rats (p < 0.05). BRs to phenylephrine and nitroprusside were abolished after pretreatment with atenolol and atropine, whereas phenylephrine‐ and nitroprusside‐induced changes in MAP remained unchanged in both groups.

Conclusions: These results may indicate that amygdaloid kindling affects BRs in long‐term seizure‐free periods.
Memoirs of a Peace Historian
Authors: Abrams Irwin
Published: February 2005

This article will tell the personal story of how I came to write about the peace movement and then something about my work on this subject during my year in Europe 1936–37 as a Harvard Sheldon Traveling Fellow. Due to time and space restrictions, I will concentrate mainly on my time in Geneva at the International Peace Bureau and the Library of the League of Nations.

In the journal I started on January 18, 1936, I wrote, “I do not know how long I can keep this up, but if I am able to, how much pleasure I shall have when I, as a bearded and bent octogenarian, can read over this record.” I did keep it up through those years, and though I am not bearded and not too bent, but still an octogenarian for another month, I have indeed been reading with much enjoyment my pages about how this rather naive twenty‐two‐year‐old encountered Europe for the first time.
Exploring Robust Design Capabilities, Their Role in Creating Global Products, and Their Relationship to Firm Performance*
Authors: Swan K. Scott , Kotabe Masaaki , Allred Brent B.
Published: February 2005

With the increasing desire for products suitable for widely varying markets worldwide, this study offers insight into capabilities associated with successful robust design in global product markets. These robust design capabilities (i.e., the possibility for success under varying circumstances or scenarios) are a potential organizational response to rapid change and uncertainty, which also improve the likelihood of product acceptance on a global basis. From literature, executive interviews, and anecdotal evidence, four capabilities associated with robust product design are derived: (1) functional; (2) aesthetic; (3) technological; and (4) quality based. A model is proposed and an empirical test conducted that considers the moderating influence of environmental uncertainty on the relationship between these robust capabilities and firm performance. The findings suggest that the use of robust design capabilities are affected by uncertainty and have an important influence on firm performance and speed to market. Specifically, the product development process tends to be characterized by aesthetic and technological robust design capabilities in more certain environments and functional robust design capabilities in more uncertain environments when seeking to improve firm performance. Alternatively, technological design capabilities in more certain environments and functional design capabilities in more uncertain environments are associated with improved speed to market.
Design of Robust New Products under Variability: Marketing Meets Design*
Authors: Luo Lan , Kannan P. K. , Besharati Babak , Azarm Shapour
Published: February 2005

In designing consumer durables such as appliances and power tools, it is important to account for variations in product performance across different usage situations and conditions. Since the specific usage of the product and the usage conditions can vary, the resultant variations in product performance also can impact consumer preferences for the product. Therefore, any new product that is designed should be robust to these variations—both in product performances and consumer preferences. This article refers to a robust product design as a design that has (1) the best possible (engineering and market) performance under the worst‐case variations and (2) the least possible sensitivity in its performance under the variations. Achieving these robustness criteria, however, implies consideration of a large number of design factors across multiple functions. This article's objectives are (1) to provide a tutorial on how variations in product performance and consumer preferences can be incorporated in the generation and comparison of design alternatives and (2) to apply a multi‐objective genetic algorithm (MOGA) that incorporates multifunction criteria in order to identify better designs while incorporating the robustness criteria in the selection process. Since the robustness criteria is based on variations in engineering performance as well as consumer preferences, the identified designs are robust and optimal from different functional perspectives, a significant advantage over extant approaches that do not consider robustness issues from multifunction perspectives. This study's approach is particularly useful for product managers and product development teams, who are charged with developing prototypes. They may find the approach helpful for obtaining customers' buy‐in as well as internal buy‐in early on in the product development cycle and thereby for reducing the cost and time involved in developing prototypes. This study's approach and its usefulness are illustrated using a case‐study application of prototype development for a handheld power tool.
Retrospective analyses of pooled data from CREST I and CREST II trials for treatment of cocaine dependence
Authors: Elkashef Ahmed , Holmes Tyson H. , Bloch Daniel A. , Shoptaw Steve , Kampman Kyle , Reid Malcolm S. , Somoza Eugene , Ciraulo Domenic , Rotrosen John , Leiderman Deborah , Montgomery Ann , Vocci Frank
Published: February 2005

Aim  To analyze pooled data from the Cocaine Rapid Evaluation Screening Trial (CREST). Pooling data from these small pilot trials into four major drug classes permitted data exploration for treatment and covariate effects with increased sample size.

Design  Small pilot trials were conducted to screen fifteen medications as prospective treatments for cocaine dependence. Studies included a flexible 2‐week to 4‐week screening/baseline period followed by an 8‐week randomized treatment condition. Participants were randomized equally to one of up to three active medications or placebo.

Setting  Five Medications Development Research Units at the five academic centers of University of Cincinnati, New York University, University of Pennsylvania, University of California Los Angeles and Boston University.

Participants  The pooled data set consisted of 357 total subjects. Standardized inclusion and exclusion criteria were employed in subject selection to enhance consistency of cocaine‐dependent study participants across all sites (see reports on individual trials in this supplement for details). All participants provided at least two urine samples that were positive for cocaine metabolite during a two‐week period prior to being randomized.

Intervention  All subjects in these trials, those randomized to placebo and active medications, received active treatment in the form of evidence‐based cognitive behavioral therapy.

Measures  Quantitative urine benzoylecgonine (BE), self‐report of cocaine use, and total Brief Substance Craving Scale (BSCS) scores were compared between each class of medication and its matched‐placebo group.

Findings  Regression analysis of pooled data did not identify any statistically significant differences between treatment and matched‐placebo for any of the four classes. Exploration of the effects of baseline covariates indicated that gender and African American status were associated significantly with outcome. Female gender was consistently associated with poorer outcomes for medication and placebo groups, while the direction of association between African American status and outcome differed by treatment groups. Retention was also examined: dropout rates may have been somewhat higher for placebo than treatment groups during the early active‐treatment period. Classification trees were used to identify characteristics of subjects who were abstinent for at least two weeks during the eight‐week trial; only 4.0% of females while 17.9% of males achieved this criterion.

Conclusions  Results presented here may prove useful for planning future clinical trials for therapies targeting cocaine dependence.
Cocaine Rapid Efficacy Screening Trial (CREST): a paradigm for the controlled evaluation of candidate medications for cocaine dependence
Authors: Leiderman Deborah B. , Shoptaw Steve , Montgomery Ann , Bloch Daniel A. , Elkashef Ahmed , LoCastro Joseph , Vocci Frank
Published: February 2005

Aim  Development of effective medications for the treatment of cocaine dependence remains a major priority for the National Institute on Drug Abuse (NIDA) at the National Institutes of Health. The Cocaine Rapid Efficacy Screening Trial (CREST) paradigm was developed by the Division of Treatment Research and Development (DT R&D) at NIDA with the goal of enhancing pilot clinical trial validity when systematically assessing a range of medications and drug classes for potential utility in treatment of cocaine dependence.

Design  CREST utilizes a randomized, controlled, parallel group, blinded methodology for comparing one or more marketed medications against a standard, pharmaceutical grade placebo. The trial design is comprised of a flexible 2–4‐week screening/baseline period followed by randomization to an 8‐week treatment period.

Measures  Standard measures of outcomes for the CREST included urinary benzoylecgonine (primary metabolite of cocaine), retention, cocaine craving, depression, clinical global impression and HIV‐risk behaviors. In order to facilitate comparisons of data from the CREST studies across sites, drug classes and time, standardized procedures, measures and psychosocial counseling were used.

Results  A total of 19 medications were evaluated in out‐patient treatment research clinics in Boston, Cincinnati, Los Angeles, New York and Philadelphia.

Conclusions  Findings supported decisions to move forward three medications (cabergoline, reserpine, tiagabine) using full‐scale, adequately powered, randomized placebo‐controlled trial designs. Lessons learned from the CREST experience continue to shape cocaine pharmacotherapy trial design and execution.
A placebo‐controlled screening trial of celecoxib for the treatment of cocaine dependence
Authors: Reid Malcolm S. , Angrist Burt , Baker Sherryl , Woo Caroline , Schwartz Marion , Montgomery Ann , Majewska Dorota , Robinson James , Rotrosen John
Published: February 2005

Aims  To conduct a medication screening trial study on the efficacy of celecoxib versus placebo for the treatment of cocaine dependence.

Design  A modified blinded, parallel group study in an outpatient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design.

Setting  The study was performed at the New York Medications Development Research Unit (MDRU).

Participants  All participants met Diagnostic and Statistical Manual version IV (DSM‐IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2‐week screening period. Twenty‐three participants were enrolled in the treatment phase of the study.

Intervention  After a 2‐week screening period, subjects were assigned randomly to receive either celebrex (200 mg/day) or placebo for an 8‐week treatment period. All subjects also received individual cognitive behavioral counseling during treatment.

Measurements  Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self‐report of drug use and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs and extrapyramidal side‐effects tests.

Results  Study retention was similar across both treatment groups and safety measures indicated that celecoxib was moderately tolerated. Cocaine use, as measured by self‐report and urine BE levels at end of treatment, indicated weaker improvement in the celecoxib group. Reductions in the intensity of cocaine craving were also weaker in the celecoxib group. Cocaine abstinence rates, global impression scores and all other related psychometric measures did not differ significantly between treatment groups.

Conclusion  This study does not support the effectiveness of celecoxib for the treatment of cocaine dependence.
A placebo‐controlled screening trial of olanzapine, valproate, and coenzyme Q10/L‐carnitine for the treatment of cocaine dependence
Authors: Reid Malcolm S. , Casadonte Paul , Baker Sherryl , Sanfilipo Michael , Braunstein Dania , Hitzemann Robert , Montgomery Ann , Majewska Dorota , Robinson James , Rotrosen John
Published: February 2005

Aims  To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L‐carnitine combination versus placebo for the treatment of cocaine dependence.

Design  A four‐arm, modified blinded, parallel group study in an out‐patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design.

Setting  The study was performed at the New York Medications Development Research Unit (MDRU).

Participants  All participants met Diagnostic and Statistical Manual version IV (DSM‐IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2‐week screening period. Sixty‐eight participants were enrolled with 39 completing the study.

Intervention  After a 2‐week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L‐carnitine (500 mg/day) combination or placebo for an 8‐week treatment period. All subjects also received individual cognitive behavioral counseling during treatment.

Measurements  Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self‐report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side‐effects tests.

Results  Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self‐report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed.

Conclusion  This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/ L‐carnitine combination for the treatment of cocaine dependence.
Prospective screening for coeliac disease in patients with Graves’ hyperthyroidism using anti‐gliadin and tissue transglutaminase antibodies
Authors: Ch’ng Chin Lye , Biswas Moushmi , Benton Ann , Jones M. Keston , Kingham Jeremy G. C.
Published: February 2005

Introduction  Coeliac disease (CD) is associated with autoimmune thyroid disease (AITD) although its prevalence among those with Graves’ hyperthyroidism in the UK is unknown. We determined the prevalence and evaluated the role of screening for CD prospectively in a consecutive cohort of patients with Graves’ hyperthyroidism using IgA class antibodies to gliadin (AGA) and tissue transglutaminase (anti‐tTG).

Methods  All patients with Graves’ hyperthyroidism attending the thyroid clinic over a 9‐month period were offered screening for CD using AGA (normal < 3 mg/l) and anti‐tTG (normal < 15 µ/ml). Comparison was made with an age‐ and sex‐matched healthy control group from the local population whose sera were tested for anti‐tTG. In patients with borderline or raised anti‐tTG (> 7 µ/ml) endomysial antibody (EmA) was measured. Serum IgA was also measured to exclude IgA deficiency. Patients with raised AGA, raised or borderline anti‐tTG, positive EmA, IgA deficiency or haematinic deficiencies were offered endoscopic duodenal biopsy.

Results  A total of 115 patients (97 female and 18 male) with Graves’ hyperthyroidism were offered screening tests and 111 accepted. AGA was raised in 15 patients, anti‐tTG was raised in two (both positive for EmA) and equivocal in six (one positive for EmA). IgA deficiency was present in three. Four patients were known to have haematinic deficiencies. Twenty‐five patients were invited and 19 agreed to have endoscopic duodenal biopsy. Three new patients were found to have CD while two patients were already known to have CD, thus five of 111 patients with Graves’ hyperthyroidism had CD. One of 115 healthy controls had a strong positive anti‐tTG (> 200 µ/ml) and EmA indicating probable CD.

Conclusions  Screening 111 consecutive patients with Graves’ hyperthyroidism revealed AGA in 14%, anti‐tTG in 2% and IgA deficiency in 3%. Two patients were known to have CD. Screening detected three new cases. The prevalence of CD in patients with Graves’ hyperthyroidism was 4·5% as compared with 0·9% in matched healthy controls. Routine screening for CD should be considered.
An update on the biochemical diagnosis of congenital ACTH insufficiency
Authors: Mehta Ameeta , Hindmarsh Peter C. , Dattani Mehul T.
Published: February 2005

Objective  Congenital ACTH insufficiency due to disorders of the hypothalamo–pituitary axis is life threatening. However, the optimal method for establishing the diagnosis remains controversial. The standard Synacthen test (SST) is safe and easy to perform in infancy, but its performance has not been well evaluated in infants and children with ACTH insufficiency.

Design, Patients and Measurements  We aimed to determine the value of the SST by comparing the 30‐min SST cortisol concentration with physiological (spontaneous) cortisol secretion (2‐hourly measurements for 24 h) in 28 patients (13 male; age range 0–5·1 years) with one or a combination of optic nerve (25) midline forebrain (17) and other pituitary hormone (17) abnormalities. Spontaneous cortisol secretion (mean < 145 nmol/l) was arbitrarily used as the ‘gold‐standard’ in the diagnosis of ACTH insufficiency as it offered a reflection of endogenous cortisol mileu. A normal SST was defined as a 30‐min serum cortisol > 540 nmol/l.

Results  The SST basal, 30‐min and 60‐min serum cortisol concentrations were significantly (P < 0·001) lower in patients with ACTH insufficiency (mean spontaneous cortisol < 145 nmol/l). 3/13 patients without and 12/15 patients with ACTH insufficiency failed the SST (specificity 76·9%; sensitivity 80%). Two out of three patients with ACTH insufficiency who passed the test were symptomatic with fatigue, poor growth and hypoglycaemia that resolved with hydrocortisone treatment. An 08:00 h serum cortisol cut‐off of 175 nmol/l provided a sensitivity of 93·3% and a specificity of 92·3% as compared with spontaneous cortisol secretion. The 30‐min increment and the 60‐min SST cortisol concentrations although highly specific (100%) had reduced sensitivity (40% and 60%, respectively).

Conclusions  A normal SST does not rule out ACTH insufficiency and measurement of physiological cortisol secretion may be required to confirm the diagnosis. A combination of 08:00 h serum cortisol > 175 nmol/l and a 30‐min SST serum cortisol > 540 nmol/l to exclude ACTH insufficiency (sensitivity 69%, specificity 100%) would ensure that no child with ACTH insufficiency would be missed and hence would prevent serious consequences, although it may lead to over‐diagnosis in some cases.
Gender differences in growth hormone response to exercise before and after rhGH administration and the effect of rhGH on the hormone profile of fit normal adults
Authors: Giannoulis M. G. , Boroujerdi M. A. , Powrie J. , Dall R. , Napoli R. , Ehrnborg C. , Pentecost C. , Cittadini A. , Jørgensen J. O. L. , Sonksen P. H.
Published: February 2005

Objectives  Exercise is a potent physiological stimulus of GH secretion. We hypothesized that exogenous recombinant human growth hormone (rhGH) administration through an increase in GH and IGF‐I levels would blunt the GH response to exercise. The aim of the study was to examine and compare the impact of rhGH on the exercise‐induced GH response in healthy normal men and women.

Design and Measurements  Sixty‐nine subjects (36 men, 33 women) were randomized to receive low‐dose rhGH (0·1 U/kg/day), high dose rhGH (0·2 U/kg/day), or placebo. Subjects were matched for age (24 ± 3·1), and body mass index (BMI). rhGH was given as a single subcutaneous (s.c.) injection for the first 28 days. All subjects exercised to exhaustion (maximal oxygen consumption – VO2max) before rhGH treatment (Test 1), and on day 28 (Test 2). GH was measured before exercise (time 0), immediately after exercise (time 0′) and at 15, 30, 60, 90 and 120 min postexercise. Baseline IGF‐I levels were measured before exercise on days 0 and 28.

Results  Baseline IGF‐I levels showed no gender differences (42·3 women vs. 38·8 nmol/l men) but basal GH values were higher in women (9·9 vs. 1·8 mU/l, P < 0·001). The areas under the GH response curve, for Test 1 were similar in men and women. Peak GH values were higher in women than men (37·9 vs. 23·5 mU/l, but this did not quite reach statistical significance (P = 0·055). In men, administration of rhGH resulted in a significant increase in IGF‐I levels over the basal state in both the LD and HD groups (P < 0·0001). In women, the increase in lGF‐I levels reached significance only in the HD group (P < 0·0001). On day 28, GH secretion in response to exercise was calculated from the areas under the GH response curve correcting for an exogenous rhGH component (ΔAUC). In men, the ΔAUC, for Test 2 were similar in all three groups. In women, the ΔAUC was higher in the placebo group, than in the HD group (P < 0·02). Free T4 levels decreased significantly in men, and free T3 increased in both men and women, in HD group after the rhGH administration. TSH levels were suppressed only in women. No changes in sex hormones were found in men or women in any of the treatment groups.

Conclusions  In terms of IGF‐I, men are more responsive to rhGH treatment than women. In addition, as men, but not women, were able to overcome the negative feedback control of the elevated IGF‐I levels, it seems that exercise may be a more robust stimulus to GH release in men compared to women.
Determination of large bowel length and loop complexity in patients with acromegaly undergoing screening colonoscopy
Authors: Renehan Andrew G. , Painter John E. , Bell G. Duncan , Rowland Roger S. , O'Dwyer Sarah T. , Shalet Stephen M.
Published: February 2005

Background  Patients with acromegaly are at moderately increased risk of developing colorectal cancer and may be considered for screening colonoscopy. In turn, large bowel dimensions may be increased in these patients, factors that predict for increased risk of serious complications such as perforation.

Objective  To evaluate this risk potential, we measured large bowel length and loop complexity using magnetic endoscopic imaging (MEI).

Design  Case–control study in 25 unselected patients with acromegaly (mean age 56 years) vs. 41 nonacromegalic controls (mean age 60 years) undergoing screening colonoscopy.

Measurements  MEI parameters were determined and age‐ and sex‐adjusted mean differences calculated. The dependency of total large bowel length on various demographic and disease‐related factors (e.g. GH exposure, IGF‐I and IGFBP‐3 concentrations) was assessed using regression techniques.

Results  Total large bowel length was increased by 20%[95% confidence interval (CI) 9–31%] in patients with acromegaly compared with controls (unadjusted and adjusted; P‐values < 0·001). Acromegaly was also associated with increased time taken to reach the caecum (P = 0·01) and increased pelvic loop complexities (5/25 vs. 1/41, Fisher's exact test: P = 0·03). Total large bowel length was predicted by age at colonoscopy (P = 0·003) and patient height (P = 0·03), but not by surrogate biochemical markers of disease activity.

Conclusions  Acromegaly is associated with increased large bowel length and loop complexity making colonoscopy technically challenging, and theoretically increasing the risk of serious complications. Patients need to be counselled accordingly, and appropriate resources with experienced staff allocated.
β‐Cell dysfunction and low insulin clearance in insulin‐resistant human immunodeficiency virus (HIV)‐infected patients with lipodystrophy
Authors: Haugaard Steen B. , Andersen Ove , Vølund Aage , Hansen Birgitte R. , Iversen Johan , Andersen Ulrik B. , Nielsen Jens Ole , Madsbad Sten
Published: February 2005

Objective  To obtain a better understanding of the physiological aspects of glucose homeostasis in human immunodeficiency virus (HIV)‐infected patients with lipodystrophy, we evaluated separately β‐cell function and insulin sensitivity after an oral glucose load.

Design   β‐Cell function was investigated during an oral glucose tolerance test (OGTT) (75 g, 180 min) in 16 lipodystrophic HIV‐infected patients and in 15 age‐ and weight‐matched nonlipodystrophic HIV‐infected patients. All participants were sedentary Caucasian males, who were on highly active antiretroviral therapy with no history of diabetes mellitus or impaired glucose tolerance. Prehepatic insulin secretion rates were estimated by deconvolution of C‐peptide concentrations. A composite measure of insulin sensitivity was derived from the OGTT.

Results  β‐Cell secretory capacity (i.e. the rate of change in insulin secretion per unit change in glucose concentration) was similar in lipodystrophic and nonlipodystrophic patients (6·2 ± 1·0 mU kg−1 min−1 mg−1 dl vs. 5·4 ± 0·4, P > 0·4), but insulin sensitivity was reduced by 61% in lipodystrophic patients (P < 0·004). The disposition index (insulin capacity multiplied with insulin sensitivity) and insulin clearance rate were reduced in lipodystrophic patients (−55%, P < 0·003 and −31%, P < 0·004). Insulin clearance rate correlated strongly with insulin sensitivity (r = 0·82, P < 0·001). More lipodystrophic than nonlipodystrophic patients exhibited impaired glucose tolerance and diabetes mellitus (63%vs. 20%, P < 0·05).

Conclusions  Our data support the concept that impaired glucose tolerance in lipodystrophic HIV‐infected patients relates to a failure of the β‐cells to fully compensate for decrements in insulin sensitivity despite simultaneous reduction in insulin clearance.