bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: Results of a twelve‐week randomized, double‐blind, placebo‐controlled trial followed by an open‐label extension up to week fifty‐two
Authors: Haibel Hildrun , Rudwaleit Martin , Listing Joachim , Heldmann Frank , Wong Robert L. , Kupper Hartmut , Braun Jürgen , Sieper Joachim
Published: June 2008

Objective

To evaluate the efficacy and safety of the tumor necrosis factor (TNF) antagonist adalimumab in patients with axial spondylarthritis (SpA) without radiographically defined sacroiliitis refractory to conventional treatment.

Methods

Patients with active axial SpA (n = 46) were randomized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks, followed by an open‐label extension that continued up to week 52. The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria, including 2 of the following 3 criteria: inflammatory back pain, HLA–B27 positivity, or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging, in the absence of radiographic evidence of sacroiliitis. The primary end point was a 40% response according to the improvement criteria of the Assessment of SpondyloArthritis international Society (ASAS40).

Results

All 46 patients (22 receiving adalimumab and 24 receiving placebo) completed the 12‐week trial; 38 patients completed the extension period to week 52. At week 12, an ASAS40 response was achieved by 54.5% of the adalimumab‐treated patients, as compared with 12.5% of the placebo‐treated patients (P = 0.004). After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo. Efficacy was maintained in all patients until week 52. Young age at study entry and an elevated C‐reactive protein concentration were the best predictors of achieving an ASAS40 response. Serious adverse events occurred in 5 patients, none of which was related to the study drug.

Conclusion

Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis.
Inhibition of β‐catenin signaling in articular chondrocytes results in articular cartilage destruction
Authors: Zhu Mei , Chen Mo , Zuscik Michael , Wu Qiuqian , Wang Yong‐Jun , Rosier Randy N. , O'Keefe Regis J. , Chen Di
Published: June 2008

Objective

Osteoarthritis is a degenerative joint disease whose molecular mechanism is currently unknown. Wnt/β‐catenin signaling has been demonstrated to play a critical role in the development and function of articular chondrocytes. To determine the role of β‐catenin signaling in articular chondrocyte function, we generated Col2a1‐ICAT–transgenic mice to inhibit β‐catenin signaling in chondrocytes.

Methods

The expression of the ICAT transgene was determined by immunostaining and Western blot analysis. Histologic analyses were performed to determine changes in articular cartilage structure and morphology. Cell apoptosis was determined by TUNEL staining and the immunostaining of cleaved caspase 3 and poly(ADP‐ribose) polymerase (PARP) proteins. Expression of Bcl‐2, Bcl‐xL, and Bax proteins and caspase 9 and caspase 3/7 activities were examined in primary sternal chondrocytes isolated from 3‐day‐old neonatal Col2a1‐ICAT–transgenic mice and their wild‐type littermates and in primary chicken and porcine articular chondrocytes.

Results

Expression of the ICAT transgene was detected in articular chondrocytes of the transgenic mice. Associated with this, age‐dependent articular cartilage destruction was observed in Col2a1‐ICAT–transgenic mice. A significant increase in cell apoptosis in articular chondrocytes was identified by TUNEL staining and the immunostaining of cleaved caspase 3 and PARP proteins in these transgenic mice. Consistent with this, Bcl‐2 and Bcl‐xL expression were decreased and caspase 9 and caspase 3/7 activity were increased, suggesting that increased cell apoptosis may contribute significantly to the articular cartilage destruction observed in Col2a1‐ICAT–transgenic mice.

Conclusion

Inhibition of β‐catenin signaling in articular chondrocytes causes increased cell apoptosis and articular cartilage destruction in Col2a1‐ICAT– transgenic mice.
Patient preference disability questionnaire in systemic sclerosis: A cross‐sectional survey
Authors: Mouthon Luc , Rannou François , Bérezné Alice , Pagnoux Christian , Guilpain Philippe , Goldwasser François , Revel Michel , Guillevin Loïc , Fermanian Jacques , Poiraudeau Serge
Published: June 2008

Objective

To assess patient priorities concerning disability in systemic sclerosis (SSc).

Methods

A total of 150 SSc patients (22 men) fulfilling the American College of Rheumatology and/or LeRoy and Medsger criteria for SSc were evaluated by the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR), Karnofsky performance status (KPS), Cochin Hand Function Scale, Health Assessment Questionnaire (HAQ), Hospital Anxiety and Depression Scale, Mouth Handicap in SSc (MHISS) scale, and global perception regarding their health status. Correlations between scores were analyzed using Spearman's coefficient. Logistic regression analysis was used to determine factors associated with patients' global perception of their health.

Results

Of the patients investigated, 81 (54%) had limited cutaneous SSc, 65 (43.3%) diffuse SSc, and 4 (2.7%) limited SSc. The 3 disability domains most often cited were walking (82 patients [54.6%]), housekeeping (67 patients [44.6%]), and sport activities (59 patients [39.3%]). The MACTAR score correlated moderately with KPS (r = 0.58) but only weakly with the HAQ score (r = 0.38). In multivariate analysis, 2 factors were associated with patients' negative global perception of their health status: KPS (odds ratio [OR] 1.07, 95% confidence interval [95% CI] 1.00–1.15) and MHISS score (OR 0.93, 95% CI 0.88–0.99).

Conclusion

For assessing SSc patient priorities concerning disability, the MACTAR has acceptable construct validity. Its weak correlation with the HAQ suggests that it adds useful information on disability.
Does knee malalignment mediate the effects of quadriceps strengthening on knee adduction moment, pain, and function in medial knee osteoarthritis? A randomized controlled trial
Authors: Lim Boon‐Whatt , Hinman Rana S. , Wrigley Tim V. , Sharma Leena , Bennell Kim L.
Published: June 2008

Objective

To examine whether the effects of 12 weeks of quadriceps strengthening on the knee adduction moment, pain, and function in people with medial knee osteoarthritis (OA) differ in those with and without varus malalignment.

Methods

A single‐blind, randomized controlled trial of 107 community volunteers with medial knee OA was conducted. Participants were stratified according to knee malalignment (more varus or more neutral) and then randomized into either a 12‐week supervised home‐based quadriceps strengthening group or a control group with no intervention. The primary outcome was the knee adduction moment, measured using 3‐dimensional gait analysis. Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index scores (measuring pain and physical function), step test score, stair climb test score, and maximum quadriceps isometric strength. Analyses of covariance were carried out based on intent‐to‐treat principles.

Results

Quadriceps strengthening did not significantly alter the knee adduction moment in either the more malaligned or the more neutral group (unadjusted knee adduction moment 0.12 and 0.05% Nm/BW×HT, respectively). Function did not improve significantly following quadriceps strengthening in either alignment group, but there was a significant improvement in knee pain in the more neutrally aligned group (P < 0.001).

Conclusion

Quadriceps strengthening did not have any significant effect on the knee adduction moment in participants with either more varus or more neutral alignment. The benefits of quadriceps strengthening on pain were more evident in those with more neutral alignment. Knee alignment thus represents a local mechanical factor that can mediate symptomatic outcome from exercise interventions in knee OA.
A randomized, double‐blind, multicenter, controlled clinical trial of chicken type II collagen in patients with rheumatoid arthritis
Authors: Zhang Ling‐Ling , Wei Wei , Xiao Feng , Xu Jian‐Hua , Bao Chun‐De , Ni Li‐Qing , Li Xing‐Fu
Published: June 2008

Objective

To assess the efficacy and safety of chicken type II collagen (CCII) in rheumatoid arthritis (RA) compared with methotrexate (MTX).

Methods

We conducted a prospective, 24‐week, followup, multicenter, double‐blind, controlled study of CCII (0.1 mg/day) versus MTX (10 mg/week) in patients with active RA. Clinical assessments were performed at screening and at 12, 18, and 24 weeks of treatment.

Results

A total of 236 RA patients were included; 211 patients (89.4%) completed the 24‐week followup. In both groups there was a decrease in pain, morning stiffness, tender joint count, swollen joint count, Health Assessment Questionnaire score, and investigator and patient assessment of function; all differences were statistically significant. In the MTX group, erythrocyte sedimentation rate and C‐reactive protein level decreased. Rheumatoid factor did not change in either group. At 24 weeks, 68.57% of patients in the CCII group and 83.02% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR20), and 40.95% and 57.54%, respectively, met the ACR50 criteria. The ACR20 and ACR50 response rates in the CCII group were lower than those in the MTX group, and this difference was statistically significant (P < 0.05). Gastrointestinal symptoms were common in both groups. There were fewer and milder side effects in the CCII group than the MTX group. The difference in incidence of adverse events between the 2 groups was statistically significant (P < 0.05).

Conclusion

CCII is effective in the treatment of RA. CCII is well tolerated, and the incidence of adverse events of CCII is lower than that of MTX.
Sleep disturbances in fibromyalgia syndrome: Relationship to pain and depression
Authors: Bigatti Silvia M. , Hernandez Ann Marie , Cronan Terry A. , Rand Kevin L.
Published: June 2008

Objective

This study is an examination of sleep, pain, depression, and physical functioning at baseline and 1‐year followup among patients with fibromyalgia syndrome (FMS). Although it is clear that these symptoms are prevalent among FMS patients and that they are related, the direction of the relationship is unclear. We sought to identify and report sleep problems in this population and to examine their relationship to pain, depression, and physical functioning.

Methods

Patients diagnosed with fibromyalgia were recruited from a Southern California health maintenance organization and evaluated according to American College of Rheumatology criteria in the research laboratory. Six hundred patients completed the baseline assessment and 492 completed the 1‐year assessment. Measures included the Center for Epidemiologic Studies Depression Scale, the McGill Pain Questionnaire, the Pittsburgh Sleep Quality Index, and the Fibromyalgia Impact Questionnaire.

Results

The majority of the sample (96% at baseline and 94.7% at 1 year) scored within the range of problem sleepers. Path analyses examined the impact of baseline values on 1‐year values for each of the 4 variables. No variable of interest predicted sleep, sleep predicted pain (β = 0.13), pain predicted physical functioning (β = −0.13), and physical functioning predicted depression (β = −0.10).

Conclusion

These findings highlight the high prevalence of sleep problems in this population and suggest that they play a critical role in exacerbating FMS symptoms. Furthermore, they support limited existing findings that sleep predicts subsequent pain in this population, but also extend the literature, suggesting that sleep may be related to depression through pain and physical functioning.
Ability of epistatic interactions of cytokine single‐nucleotide polymorphisms to predict susceptibility to disease subsets in systemic sclerosis patients
Authors: Beretta Lorenzo , Cappiello Francesca , Moore Jason H. , Barili Morena , Greene Casey S. , Scorza Raffaella
Published: June 2008

Objective

Gene–gene interaction, or epistasis, is considered a ubiquitous component of complex human diseases such as systemic sclerosis (SSc). Epistasis is difficult to model by traditional parametric approaches; therefore, nonparametric computational algorithms, such as multifactor dimensionality reduction (MDR), have been developed.

Methods

A total of 242 consecutive unrelated Italian SSc patients and an equal number of well‐matched healthy controls were genotyped for 22 cytokine single‐nucleotide polymorphisms (SNPs; 13 cytokine genes). The distribution of the SNPs between controls and SSc patients, controls and limited cutaneous SSc (lcSSc) patients, and controls and diffuse cutaneous SSc (dcSSc) patients was tested by the MDR constructive induction algorithm and by focused interaction testing framework (FITF), a logistic regression–based approach.

Results

None of the studied SNPs had main independent effects on SSc or disease subset susceptibility, therefore no epistatic interaction was detectable by FITF. The MDR analysis showed a significant epistatic interaction among the interleukin‐2 (IL‐2) G‐330T, IL‐6 C‐174G, and interferon‐γ AUTR5644T SNPs and the IL‐1 receptor Cpst1970T, IL‐6 Ant565G, and IL‐10 C‐819T SNPs in lcSSc and dcSSc susceptibility, respectively. The relevance of the single multilocus attributes constructed by the MDR inductive algorithm was then confirmed by the parametric approach (P < 0.001 for both controls versus lcSSc patients and controls versus dcSSc patients).

Conclusion

We provide evidence for gene–gene interaction among cytokine SNPs in the context of SSc. The interaction among cytokine SNPs with a profibrotic or a regulatory function on profibrotic interleukins is relevant to the susceptibility to SSc subsets and it appears to be more important than the contribution of any single cytokine SNP.
Tartardiamide‐Functionalized Chiral Organosilicas with Highly Ordered Mesoporous Structure
Authors: Zhang Lei , Liu Jian , Yang Jie , Yang Qihua , Li Can
Published: June 2008

A novel chiral mesoporous organosilica with L‐tartardiamide moieties integrated in the backbone has been synthesized for the first time by a mild synthetic approach with block copolymer P123 as a template. The materials have highly ordered 2D hexagonal mesostructure and uniform pore size in the range of 7.6 to 5.5 nm. NMR, IR, and TG analyses confirm that the tartardiamide group was successfully incorporated into the framework. The intrinsic chirality of L‐tartardiamide endows the materials with unique optical activities and chiral‐recognition properties. By dissolving the materials into NaOH, the solutions show rotation of polarized light by +8.42° to +15.53°, depending on the amount of the chiral moieties in the materials. Owing to the chirality of L‐tartardiamide, the materials exhibited chiral‐induction ability in the epoxidation of allyl alcohol, thus further demonstrating the chirality of the materials.
Catalyzed Oxidative Corrosion of Porous Silicon Used as an Optical Transducer for Ligand–Receptor Interactions
Authors: Voelcker Nicolas H. , Alfonso Ignacio , Ghadiri M. Reza
Published: June 2008

Biosensors fabricated on the nanoscale offer exciting new avenues in the quest for better understanding and characterization of biological systems. Porous silicon is an ideal nanostructured material for the construction of optical transducer matrices because it is easily functionalized with biomolecular probes and displays strong optical interferences. Here, we show that certain transition metal complexes, including nickel(II)cyclam, are able to induce corrosion in porous silicon films rapidly, generating a strong optical interferometric signal that originates from the porous layer. We subsequently exploit this effect to design a transducer for ligand–receptor recognition. With a nickel(II)cyclam derivative as a catalytic label, DNA‐ and avidin‐binding events are detected by time‐lapse interferometric reflectance spectroscopy in a fast, simple, and inexpensive fashion.
The Influence of Densely Organized Maltose Shells on the Biological Properties of Poly(propylene imine) Dendrimers: New Effects Dependent on Hydrogen Bonding
Authors: Klajnert Barbara , Appelhans Dietmar , Komber Hartmut , Morgner Nina , Schwarz Simona , Richter Sven , Brutschy Bernhard , Ionov Maksim , Tonkikh Anatoly K. , Bryszewska Maria , Voit Brigitte
Published: June 2008

Maltose‐modified poly(propylene imine) (PPI) dendrimers were synthesized by reductive amination of unmodified second‐ to fifth‐generation PPI dendrimers in the presence of excess maltose. The dendrimers were characterized by using 1H NMR, 13C NMR, and IR spectroscopies; laser‐induced liquid beam ionization/desorption mass spectrometry; dynamic light scattering analyses; and polyelectrolyte titration. Their scaffolds have enhanced molecular rigidity and their outer spheres, at which two maltose units are bonded to the former primary amino groups on the surface, have hydrogen‐bond‐forming properties. Furthermore, the structural features reveal the presence of a dense shell. Experiments involving encapsulation (1‐anilinonaphthalene‐8‐sulfonic acid) and biological properties (hemolysis and interactions with human serum albumin (HSA) and prion peptide 185‐208) were performed to compare the modified with the unmodified dendrimers. These experiments gave the following results: 1) The modified dendrimers entrapped a low‐molecular‐weight fluorescent dye by means of a dendritic box effect, in contrast to the interfacial uptake characteristic of the unmodified PPI dendrimers. 2) Both low‐ and high‐generation dendrimers containing maltose units showed markedly reduced toxicity. 3) The desirable features of bio‐interactions depended on the generation of the dendrimer; they were retained after maltose substitution, but were now mainly governed by nonspecific hydrogen‐bonding interactions involving the maltose units. The modified dendrimers interacted with HSA as strongly as the parent compounds and appeared to have potential use as antiprion agents. These improvements will initiate the development of the next platform of glycodendrimers in which apparently contrary properties can be combined, and this will enable, for example, therapeutic products such as more efficient and less toxic antiamyloid agents to be synthesized.
Heterocycles as Key Substrates in Multicomponent Reactions: The Fast Lane towards Molecular Complexity
Authors: Isambert Nicolas , Lavilla Rodolfo
Published: June 2008

Heterocycles display an intrinsic reactivity which enables rich, versatile and productive transformations. Taking into account their ubiquitous presence in natural products and drugs, the development of new, fast and efficient preparative protocols for these structures remains an urgent task in Organic Synthesis. Multicomponent reactions using heterocyclic chemistry offer new possibilities to exploit this exclusive reactivity. Recent results show relevant examples of such transformations. Several approaches which allow the construction of complex heterocyclic compounds from simple starting materials using this principle have been analyzed.
The effects of differences in explanations, employee attributions, type of infraction, and discipline severity on perceived fairness of employee discipline
Authors: Cole Nina D.
Published: June 2008

Participants reported perceptions of fairness after reading 1 of 72 scenarios describing a disciplinary discussion between a manager and an employee (crossing four different disciplinary infractions, with three types of explanations for each infraction, three different levels of discipline severity, and two types of employee attributions for their behaviour). Results indicate that type of attribution, type of infraction, and level of discipline severity all have significant effects on perceptions of distributive, procedural, interpersonal, and informational justice. Type of explanation also has significant effects on perceptions of justice other than informational justice. It appears that managing disciplinary fairness may require a contingency approach. Copyright © 2008 ASAC. Published by John Wiley & Sons, Ltd.
The business of blacklisting
Authors: Spector Bert
Published: June 2008

The omission of ideology from managerial discourse leaves unacknowledged the dominant influences that shape patterns of thinking and acting. The Cold War offers one such framework for analyzing the intersection of management and ideology. Specifically, the anti‐Communist blacklist in the United States offers a rich opportunity to explore the actions of business leaders and to test the assumptions on which those actions were based. Businessmen played a key role in creating and supporting the blacklist. This study suggests that enforcers of the blacklist distorted the nature of public response. The evidence suggests that businessmen were responding from an ideological rather than a pragmatic position and that, from a pragmatic perspective, they might have been well advised to ignore the blacklisters. Copyright © 2008 ASAC. Published by John Wiley & Sons, Ltd.
Taking a positive approach to organizational downsizing
Authors: Armstrong‐Stassen Marjorie , Schlosser Francine
Published: June 2008

We drew from the literature on positive organizational behaviour (Luthans & Youssef, 2007) to test a process model relating generalized optimism (Carver & Scheier, 1999) to the cognitions, affect, and behaviour of 237 Canadian federal government managers during and following a major organizational downsizing. Our data supported a model in which generalized optimism measured 18 months prior to the downsizing (T1) associated positively with managers' cognitions, attitudes, job performance, and self‐reported coping effectiveness measured 12 months postdownsizing (T3). Analyses suggested that some of these associations were partially mediated by a positive thinking coping strategy and expectations for future career and job success reported during the downsizing (T2). We advocate for more research that draws from the positive organizational behaviour literature to study the effects of downsizing on survivors. Copyright © 2008 ASAC. Published by John Wiley & Sons, Ltd.
DFT and Experimental Studies of Perchlorate Ion Coordination incis/trans‐Copper(II) Complexes of Tetradentate Pyridyl Ligands
Authors: Pandiyan Thangarasu , Guadalupe Hernández J. , Cruz Julian , Bernès Sylvain , Ugalde‐Salvdivar Víctor M. , González Ignacio
Published: June 2008

Spectral and structural studies ofN,N′‐dimethyl‐N,N′‐bis(pyridin‐2‐ylmethyl)‐1,2‐diaminoethane (L1),N,N′‐dimethyl‐N,N′‐bis(pyridin‐2‐ylmethyl)‐1,3‐diaminopropane (L2), and their copper(II) complexes were carried out by spectroscopic and DFT methods. The DFT results show that conventional and nonconventional H‐bonds present in L1and L2influence the NMR chemical shifts at different pH values, which thus suggests that the protonation sites at the pyridyl and tertiary nitrogen atoms of the ligands change the chemical environment of the adjacent carbon atoms; this observation is consistent with13C NMR spectra recorded at different pH values. Furthermore, for their copper complexes, two possible geometrical isomers (cisandtrans) are obtained; for example,cis‐[CuL1]2+, where both NCH3groups are oriented in the same plane, is in equilibrium with itstransisomer and, as a result, a small energy difference (0.9 kcal mol–1) appears. In contrast,trans‐[CuL2]2+does not equilibrate with thecisisomer, because there is a greater energy difference (ΔE= 3.9 kcal mol–1) between the two isomers. Indeed, when [CuL1]2+with two perchlorate ions was optimized, it was found that although onlycis‐[CuL1]2+was able to accommodate a perchlorate ion in the axial position of the square pyramidal geometry by stabilizing the structure with twocisNCH3groups through H‐bonds, thetransisomer was unable to retain the perchlorate ion in the coordination sphere, because the NCH3groups were in thetransposition; this disfavors the presence of the perchlorate ion in the sphere, because of the absence of H‐bonds. This is consistent with the X‐ray structure, in whichcis‐[CuL1(ClO4)]+is resolved, whereas thetransisomer is not. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Selective Cleavage by Acids of One Metal–Carbon σ‐Bond of a Bis(ortho‐platinated) Triarylphosphane: A 31P NMR trans‐Influence Series Based on the Unit Pt(κ2‐C6H3‐5‐Me‐2‐PPh2)(PPh2‐4‐tol)
Authors: Bennett Martin A. , Bhargava Suresh K. , Privér Steven H. , Willis Anthony C.
Published: June 2008

Treatment of the bis(chelate) complex cis‐[Pt(κ2‐C6H3‐5‐Me‐2‐PPh2)2] (1) with strong acids causes selective cleavage of one of the metal–aryl bonds to give cis‐[PtX(κ2‐C6H3‐5‐Me‐2‐PPh2)(PPh2‐4‐tol)] [X = Cl (2), Br (3), I (4), ONO2 (5) and OCOCF3 (6)], from which a series of neutral and cationic derivatives can be derived by metathetical reactions. The complexes 2 and 6 rearrange spontaneously to the corresponding trans isomers, this reaction being promoted by CO. The J(Pt‐P) values for the phosphorus atom of the four‐membered ring can be ordered to establish a trans‐influence series of anionic ligands X and neutral ligands L, which correlates well with, but is more extensive than, that based earlier on PtMe(dppe) complexes. Single‐crystal X‐ray structural analysis of trans‐[Pt(κ1‐OCOCF3)(κ2‐C6H3‐5‐Me‐2‐PPh2)(PPh2‐4‐tol)] (trans‐6), cis‐[PtX(κ2‐C6H3‐5‐Me‐2‐PPh2)(PPh2‐4‐tol)] [X = Cl (2), CN (11), Me (43) and C6F5 (45)], and [Pt(κ2‐C6H3‐5‐Me‐2‐PPh2)(PPh2‐4‐tol)2]BF4 (34) show these complexes to have distorted square‐planar geometry. The Pt–P distances to the phosphorus atom of the four‐membered ring in 2, 11, 43 and 45 broadly follow the trend of J(Pt–P) values, Cl– being placed near the bottom and Me– near the top of the trans‐influence series, but the corresponding Pt–P distance in 34 is out of line. The Pt–P distances to PPh2‐4‐tol cis to X or L tend to decrease with increasing trans‐influence of X or L, in agreement with previous indications of a ligand cis‐influence that runs opposite to the trans‐influence. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Quantitative confirmation of testosterone and epitestosterone in human urine by LC/Q‐ToF mass spectrometry for doping control
Authors: Danaceau Jonathan P. , Scott Morrison M. , Slawson Matthew H.
Published: June 2008

Testosterone (T) is the primary male sex hormone. In addition to the development of secondary sex characteristics, testosterone has anabolic effects including increases in muscle size and strength and increases in lean body mass, making it an attractive candidate to enhance athletic performance. In the case of exogenous administration of testosterone, the ratio of testosterone to its isomer, epitestosterone (E), is elevated. WADA has set a standard for T/E ratios of 4.0 as indicative of possible exogenous testosterone administration. Typically, a sample that screens for a T/E ratio above that threshold is then subjected to quantitative confirmation by GC/MS. This methodology, however, can limited due to sensitivity issues as well as a limited number of qualifying ions that can be used for unambiguous identification. We have developed a confirmation method which uses liquid/liquid extraction, followed by room temperature Girard P derivatization, and analysis using LC/MS‐ToF. We observe a number of advantages over conventional GC/MS analysis. Analysis time is decreased. Sensitivity is increased, resulting in limits of detection of 2 and 0.5 ng/ml for testosterone and epitestosterone, respectively. The number of diagnostic qualifier ions is also increased allowing more confident identification of the analytes. Finally, while this method has been developed on a QToF instrument, it should be easily transferable to any tandem LC/MS/MS system. Copyright © 2008 John Wiley & Sons, Ltd.
MALDI‐TOF MS Coupled with Collision‐Induced Dissociation (CID) Measurements of Poly(methyl methacrylate)
Authors: Baumgaertel Anja , Becer C. Remzi , Gottschaldt Michael , Schubert Ulrich S.
Published: June 2008

Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) was chosen for an in‐detail analysis of poly(methyl methacrylate) (PMMA) in order to determine the possible fragmentation mechanism with the help of collision‐induced dissociation (CID). All experiments were performed on a well‐defined PMMA standard and were optimized for sample preparation and measurement conditions of both MS and MS/MS. In order to investigate the fragmentation pathways, two parent peaks—both charged with sodium (m/z = 1 625.9 and 2 226.2 Da, respectively)—were selected, thus permitting the examination of possible cleavages, and reaction pathways. For both chosen peaks, the MALDI‐TOF MS/MS spectra revealed four fragmentation series that could be explained by single or multiple main chain scissions and secondary reactions of the PMMA side groups. According to the molar mass of the fragments, a loss or migration of the side group to the end of the free radical, followed by a β‐scission, was favored. These insights are the first steps toward the construction of a library with fragments and fragmentation pathways, complementary to proteomics libraries, in order to obtain fast and automated identification of substances.

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The Maximum Likelihood Ensemble Filter as a non‐differentiable minimization algorithm
Authors: Zupanski Milija , Navon I. Michael , Zupanski Dusanka
Published: June 2008

The Maximum Likelihood Ensemble Filter (MLEF) equations are derived without the differentiability requirement for the prediction model and for the observation operators. The derivation reveals that a new non‐differentiable minimization method can be defined as a generalization of the gradient‐based unconstrained methods, such as the preconditioned conjugate‐gradient and quasi‐Newton methods. In the new minimization algorithm the vector of first‐order increments of the cost function is defined as a generalized gradient, while the symmetric matrix of second‐order increments of the cost function is defined as a generalized Hessian matrix. In the case of differentiable observation operators, the minimization algorithm reduces to the standard gradient‐based form.

The non‐differentiable aspect of the MLEF algorithm is illustrated in an example with one‐dimensional Burgers model and simulated observations. The MLEF algorithm has a robust performance, producing satisfactory results for tested non‐differentiable observation operators. Copyright © 2008 Royal Meteorological Society
A wavelet‐coefficient score for comparison of two‐dimensional climatic‐data fields
Authors: Livina V. N. , Edwards N. R. , Goswami S. , Lenton T. M.
Published: June 2008

A single‐valued wavelet‐coefficient score is proposed for assessing the similarity of two‐dimensional climate‐data fields (matrices). It is based on the comparison of wavelet‐decomposition coefficients by means of a mean‐squared‐error skill score. Two applications of the score are illustrated: comparison of real and model maps; and comparison of two model maps. The issue of missing data is addressed, and the evaluation is performed both when data are available over continents or oceans only, and when they are available globally, over the whole domain.

The score is tested against the conventional two‐dimensional correlation coefficient, which is widely used in evaluating forecast performance. We show that the score eliminates random correlations, which the correlation coefficient incorrectly detects as similarity of fields that are actually dissimilar. The technique is first applied to the case of non‐square matrices (spatial fields) of the same dimensions (spatial grids), and then to the most general case of matrices of different dimensions, by applying some necessary interpolations. The technique is tested on data from several runs of different GENIE models. It is then applied to the comparison of climate data (global fields of temperature and specific humidity) from the NCEP and ECMWF reanalyses and from the HadCM3 and GENIE models. To study the time evolution of a given 2D field, we analyse a plot of the score values for consecutive time slices, thus visualizing the temporal dynamics. The technique is particularly useful for automated comparison of large sets of 2D data, where direct visualization is best avoided. The score may be generalized for comparison of data of higher dimensions, in particular 3D ocean fields. Copyright © 2008 Royal Meteorological Society
Turbulence energetics in stably stratified geophysical flows: Strong and weak mixing regimes
Authors: Zilitinkevich S. S. , Elperin T. , Kleeorin N. , Rogachevskii I. , Esau I. , Mauritsen T. , Miles M. W.
Published: June 2008

Traditionally, turbulence energetics is characterised by turbulent kinetic energy (TKE) and modelled using solely the TKE budget equation. In stable stratification, TKE is generated by the velocity shear and expended through viscous dissipation and work against buoyancy forces. The effect of stratification is characterised by the ratio of the buoyancy gradient to squared shear, called the Richardson number, Ri. It is widely believed that at Ri exceeding a critical value, Ric, local shear cannot maintain turbulence, and the flow becomes laminar. We revise this concept by extending the energy analysis to turbulent potential and total energies (TPE, and TTE = TKE + TPE), consider their budget equations, and conclude that TTE is a conservative parameter maintained by shear in any stratification. Hence there is no ‘energetics Ric’, in contrast to the hydrodynamic‐instability threshold, Ric−instability, whose typical values vary from 0.25 to 1. We demonstrate that this interval, 0.25 < Ri < 1, separates two different turbulent regimes: strong mixing and weak mixing rather than the turbulent and the laminar regimes, as the classical concept states. This explains persistent occurrence of turbulence in the free atmosphere and deep ocean at Ri ≫ 1, clarifies the principal difference between turbulent boundary layers and free flows, and provides the basis for improving operational turbulence closure models. Copyright © 2008 Royal Meteorological Society
Impact of observational error on the validation of ensemble prediction systems
Authors: Candille G. , Talagrand O.
Published: June 2008

Ensemble prediction systems (EPSs) are usually validated under the assumption that the verifying observations are exact. In this paper, two methods are considered for taking observation errors into account. In the ‘perturbed‐ensemble’ method, which has already been studied by other authors, the predicted ensemble elements are randomly perturbed in a way that is consistent with the assumed observation error. In the ‘observational‐probability’ method, which is new, a verifying observation is considered as defining, together with the assumed associated error, a probability distribution. All standard scores for evaluation of EPSs (reliability diagram, Brier score, ranked probability score (RPS), continuous RPS (CRPS), relative‐operating‐characteristics (ROC) curve area), with the exception of the rank histogram, remain defined in this second method. In particular, the classical reliability–resolution decomposition of the Brier score, and of its extension to the RPS and CRPS, remain defined.

Numerical simulations, partially supported by theoretical considerations, show that, with respect to the case when observation errors are ignored, the perturbed‐ensemble method improves reliability, as well as the ROC score, while it has no significant impact on resolution, as measured by the Brier score. The observational‐probability method, on the other hand, degrades reliability and the ROC score, but improves resolution.

With respect to the ‘real’ performance of the system (i.e. the one that would be diagnosed if no error were present), reliability is unchanged in the perturbed‐ensemble method, while resolution and the ROC score are degraded. The observational‐probability method degrades reliability and the ROC score. As for resolution, an optimum value of the observational error is found, below which resolution is improved.

Diagnostics performed on the operational EPS of the Canadian Meteorological Centre confirm the results of the simulations as to the consequences of ignoring observation errors, or on the contrary of taking them into account through either of the two methods. The significance of those various results is discussed. This article replaces a previously published version (Q. J. R. Meteorol. Soc. 134(631): 509–521, DOI: 10.1002/qj.221). Copyright © 2008 Royal Meteorological Society
Polymer‐Wrapped Peptide Nanotubes: Peptide‐Grafted Polymer Mass Impacts Length and Diameter
Authors: Couet Julien , Biesalski Markus
Published: June 2008

The external structure of polymer‐wrapped nanotubes resembles that of small nanorods with a core/shell morphology, where the core consists of a self‐assembled peptide nanotube surrounded by a soft polymeric coat. The length and the diameter of the nanorods are investigated as a function of the molar mass of the peptide‐grafted macromolecules by statistical atomic force microscopy cross‐section analysis of dry nanorods adsorbed to a solid substrate. With increasing molar mass of the grafted polymers, the height increases from less than 2 nm up to more than 10 nm, and the length of the objects decreases from about 120 nm to about 30 nm. Additional analysis suggests excluded volume interactions between the highly grafted polymer chains on the surface of the peptide nanotube to be the major driving force for the shortening of the nanotubes. The present findings may provide a base for fine tuning the dimensions of such novel bioinspired nanomaterials.
Leptin receptor deficiency is associated with upregulation of cannabinoid 1 receptors in limbic brain regions
Authors: Thanos Panayotis K. , Ramalhete Roberto C. , Michaelides Michael , Piyis Yianni K. , Wang Gene‐Jack , Volkow Nora D.
Published: June 2008

Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB1R) in overeating and the effects of food deprivation on CB1R in the brain. One‐month‐old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB1R (CB1R binding levels) were assessed using [3H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB1R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB1R binding levels than Le in most brain regions and food restriction was associated with higher CB1R levels in all brain regions in Ob, but not in Le rats. CB1R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB1R in Ob rats suggest that leptin's inhibition of food‐intake is in part mediated by downregulation of CB1R and that leptin interferes with CB1R upregulation under food‐deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin. Synapse 62:637–642, 2008. Published 2008 Wiley‐Liss, Inc.
Perineal striated muscles: Anatomy, spinal motoneurons, and participation on copulatory behavior in male rabbits (Oryctolagus cuniculus)
Authors: Zempoalteca R. , Lucio R.A. , Eguibar J.R.
Published: June 2008

Despite the importance of rabbits in reproductive studies, little information is available on the anatomy and participation of the striated‐perineal muscles in male copulatory behavior. In our study, we describe the gross anatomy of two striated‐perineal muscles: the ischiocavernosus (ICm) and the bulbospongiosus (BSm). Both muscles have their origin at the ischiadic arc, but the ICm is inserted into the penile crura and the BSm onto the ligamentum suspensorium of the penis. The motoneurons of both muscles were identified using retrograde labeling with horseradish peroxidase coupled to wheat‐germ agglutinin. Motoneurons were dispersed in the lower‐lumbar and upper‐sacral spinal‐cord segments, instead of being aggregated in the neuronal nucleus as in other species: the rat, mouse, gerbil, cat, and man. Bilateral dennervation of the ICm or BSm or both in sexually experienced male rabbits did not affect copulatory variables measured at 10, 20, and 30 days after surgery. However, muscular dennervation produced extravaginal ejaculations in 42% of copulatory tests and no ejaculation in 7% of tests, although male pelvic thrusting occurred. These results suggest the participation of the ICm and BSm perineal muscles in penile orientation during copulation but not in seminal emission as described in other mammalian species. Synapse 62:653–661, 2008. © 2008 Wiley‐Liss, Inc.
Acute cocaine administration increases NO efflux in the rat prefrontal cortex via a neuronal NOS‐dependent mechanism
Authors: Sammut Stephen , West Anthony R.
Published: June 2008

An understanding of the neurochemical changes occurring following exposure to psychostimulants such as cocaine is critical for the development of novel pharmacotherapies aimed at disrupting the addictive cycle. It is well established that the acute effects of cocaine associated with drug‐induced blockade of dopamine (DA) reuptake processes occur in reward‐related areas of the brain including the medial prefrontal cortex (mPFC). Considerable evidence has accumulated indicating that the interaction between DA, glutamate, and nitric oxide (NO) is likely to play a critical role in the neuroplastic changes associated with psychostimulant exposure. However, the potential impact of cocaine on NO synthase (NOS) activity in the mPFC has not been examined. In this study, NO efflux was measured in the mPFC of anesthetized male rats using a NO‐selective electrochemical microsensor. Acute systemic administration of cocaine significantly increased NO efflux in the mPFC in a time‐dependent manner. Similar injections using vehicle did not affect NO efflux. The facilitatory effect of cocaine on NO efflux was transient and reproducible. The signal was derived from neuronal sources of NO, because it was attenuated by systemic administration of the neuronal NO synthase inhibitor 7‐nitroindazole. These studies support a role for prefrontal cortical NO signaling in cocaine‐induced changes in neurotransmission in reward‐related circuits involved in addiction. Synapse 62:710–713, 2008. © 2008 Wiley‐Liss, Inc.
Differential expression of synaptic vesicle proteins after repeated electroconvulsive seizures in rat frontal cortex and hippocampus
Authors: Elfving Betina , Bonefeld Birgit Egeskov , Rosenberg Raben , Wegener Gregers
Published: June 2008

Electroconvulsive therapy (ECT) remains the treatment of choice for patients with severe or drug‐resistant depressive disorders, yet the mechanism behind its efficacy and the effect on neurotransmission is essentially unknown. As synaptic vesicle proteins (SVPs) are required for vesicle fusion and neurotransmitter release, we have examined the effect of single and repeated electroconvulsive seizures (ECS), an animal model of ECT, on the expression of 14 SVPs in the rat frontal cortex and the hippocampus using quantitative real‐time polymerase chain reaction (real‐time qPCR). Only in the frontal cortex, the mRNA level of synapsin II was significantly upregulated after repeated ECS. In contrast, the mRNA levels of 6 of the 14 SVPs were significantly regulated in the hippocampus after ECS. We found that SNAP29 was upregulated and synaptotagmin III was downregulated after one single ECS in the hippocampus. Furthermore, SNAP29, synapsin I, synapsin III, VAMP2, and VAMP5 were significantly upregulated, whereas synaptotagmin III was significantly downregulated after repeated ECS in the hippocampus. We suggest that these genes are highly important in the long‐term therapeutic effect of ECS, and thus it can behypothesized that the SVPs are involved in the pathophysiology of depression. Synapse 62:662–670, 2008. © 2008 Wiley‐Liss, Inc.
Positron emission tomography analysis of [11C]KW‐6002 binding to human and rat adenosine A2Areceptors in the brain
Authors: Brooks D.J. , Doder M. , Osman S. , Luthra S.K. , Hirani E. , Hume S. , Kase H. , Kilborn J. , Martindill S. , Mori A.
Published: June 2008

Adenosine A2Areceptors are found on striatal neurones projecting to the external pallidum. KW‐6002 (istradefylline) is a potent and selective antagonist for the adenosine A2Areceptors in the CNS and acts to inhibit the excessive activity of this pathway in the MPTP marmoset model of PD, thus relieving parkinsonism. The objectives of this study were to investigate the regional binding of the novel positron emission tomography tracer [11C]KW‐6002 in the healthy human brain and the rat brain, along with receptor occupancy by cold KW‐6002 at varying doses in human. The highest [11C]KW‐6002 uptake in the rat brain was seen in striatum and lower levels in cortex and cerebellum. Brain [11C]KW‐6002 uptake was well characterized in humans by a two‐tissue compartmental model with a blood volume term, and the ED50of cold KW‐6002 was 0.5 mg in the striatum. Over 90% receptor occupancy was achieved with daily oral doses of greater than 5 mg. In humans, blockable binding was present in all gray matter structures including the cerebellum, which has not been reported to express A2Areceptors. MRS 1745, an A2Breceptor selective antagonist, had no effect on the cerebellar binding of [11C]KW‐6002 in rats, suggesting that this blockable signal is unlikely to result from an affinity for adenosine A2Breceptors. Synapse 62:671–681, 2008. © 2008 Wiley‐Liss, Inc.
Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal
Authors: Kitanaka Nobue , Kitanaka Junichi , Hall F. Scott , Tatsuta Tomohiro , Morita Yoshio , Takemura Motohiko , Wang Xiao‐Bing , Uhl George R.
Published: June 2008

Neuronal adaptations have been found to occur in multiple brain regions after chronic intake of abused drugs, and are therefore thought to underlie drug dependence, tolerance, and withdrawal. Pathophysiological changes in drug responsiveness as well as behavioral sequelae of chronic drug exposure are thought to depend largely upon the altered state of heterotrimeric GTP binding protein (G protein)‐coupled receptor (GPCR)‐G protein interactions. Responsiveness of GPCR‐related intracellular signaling systems to drugs of abuse is heterogeneous, depending on the types of intracellular effectors to which the specific Gα protein subtypes are coupled and GPCR‐G protein coupling efficiency, factors influenced by the class of drug, expression levels of G protein subunits, and drug treatment regimens. To enhance understanding of the molecular mechanisms that underlie the development of pathophysiological states resulting from chronic intake of abused drugs, this review focuses on alterations in the expression levels of G protein subunits induced by various drugs of abuse. Changes in these mechanisms appear to be specific to particular drugs of abuse, and specific conditions of drug treatment. Synapse 62:689‐699, 2008. © 2008 Wiley‐Liss, Inc.