bluuebunny/crossref_metadata_2025 huggingface dataset:
Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA–DRB1 shared epitope for antibodies to citrullinated proteins
Authors: Huizinga Tom W. J. , Amos Christopher I. , van der Helm‐van Mil Annette H. M. , Chen Wei , van Gaalen Floris A. , Jawaheer Damini , Schreuder Geziena M. T. , Wener Mark , Breedveld Ferdinand C. , Ahmad Naila , Lum Raymond F. , de Vries Rene R. P. , Gregersen Peter K. , Toes Rene E. M. , Criswell Lindsey A.
Published: October 2005

Objective

The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA–DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti‐CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti‐CCP antibodies.

Methods

HLA–DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population‐based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well‐established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti‐CCP antibodies was determined by enzyme‐linked immunosorbent assay.

Results

For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti‐CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti‐CCP–negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti‐CCP–positive disease and not with anti‐CCP–negative disease. Stratified analyses indicated that anti‐CCP antibodies primarily mediated association of the SE with joint damage or disease persistence.

Conclusion

HLA–DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.
Patterns of clinical remission in select categories of juvenile idiopathic arthritis
Authors: Wallace Carol A. , Huang Bin , Bandeira Marcia , Ravelli Angelo , Giannini Edward H.
Published: October 2005

Objective

To characterize disease activity patterns in a large cohort of children with juvenile idiopathic arthritis (JIA), by applying newly developed preliminary definitions of inactive disease, clinical remission on medication, and clinical remission off medication.

Methods

Children with persistent or extended oligoarthritis, polyarthritis (either rheumatoid factor [RF] positive or RF negative), or systemic JIA who had been followed up for a period of at least 4 years were evaluated for episodes of inactive disease, clinical remission on medication, and clinical remission off medication. Descriptive statistics, correlation analyses, and survival analyses were performed.

Results

Four hundred thirty‐seven children met the criteria for review. Three hundred ninety‐one patients (89%) experienced a total of 878 episodes of inactive disease, with a median episode length of 12.7 months. Two hundred twenty‐eight episodes of inactive disease (26%) resulted in clinical remission off medication; it was equally as likely that episodes of inactive disease would or would not follow a period of clinical remission on medication. Thirty‐six percent of episodes of clinical remission off medication persisted for at least 2 years, and only 6% of such episodes persisted for 5 years. RF‐positive patients were the least likely to achieve clinical remission off medication (5%), and patients with persistent oligoarticular JIA were the most likely (68%). Among patients with persistent oligoarticular JIA, most of the disease course was characterized by inactive disease; in most other patients the majority of the disease course involved active disease.

Conclusion

Using newly developed preliminary criteria for inactive disease, clinical remission on medication, and clinical remission off medication, we observed that only one‐fourth of 878 episodes of inactive disease resulted in clinical remission off medication during followup of at least 4 years. Only a small proportion of episodes of clinical remission off medication were sustained for >5 years. These results highlight the critical need for therapies that have the ability to induce sustained remission of JIA.
Evidence for common genetic control in pathways of inflammation for Crohn's disease and psoriatic arthritis
Authors: Ho Pauline , Bruce Ian N. , Silman Alan , Symmons Deborah , Newman Bill , Young Helen , Griffiths Christopher E. M. , John Sally , Worthington Jane , Barton Anne
Published: October 2005

Objective

Clinical, pharmacologic, and epidemiologic evidence supports the hypothesis that common genetic pathways may underlie inflammatory diseases. In a previous study, a Crohn's disease gene, CARD15, was demonstrated to be associated with psoriatic arthritis (PsA). Recently, a functional haplotype of 2 single‐nucleotide polymorphisms (SNPs) mapping to the organic cation transporter (OCTN) genes, SLC22A4 and SLC22A5, was identified as a second Crohn's disease susceptibility locus. The SLC22A4 gene has also been associated with rheumatoid arthritis. This study was undertaken to further elucidate associations of PsA with Crohn's disease susceptibility genes.

Methods

Association with CARD15 and OCTN was investigated in UK Caucasian patients with PsA (n = 472) and population controls (n = 594), using 5′ allelic discrimination assays (TaqMan). Two SNPs in OCTN, forming a haplotype previously associated with Crohn's disease, were also tested in patients with psoriasis (n = 218) and patients with early undifferentiated inflammatory arthritis (n = 386). Allele and estimated haplotype frequencies were compared between patients and controls.

Results

No association of PsA with CARD15 was detected. In contrast, a functional SNP mapping to the promoter region of SLC22A5 (rs2631367) was associated with PsA (for CC versus GG, odds ratio 1.65, 95% confidence interval 1.13–2.41, uncorrected P = 0.005). In addition, the haplotype associated with Crohn's disease was also associated with PsA (P = 0.001). No association was detected in the cohort with psoriasis alone or in the cohort with undifferentiated inflammatory arthritis.

Conclusion

The OCTN haplotype previously associated with Crohn's disease is also associated with PsA, suggesting that these 2 diseases may share some common genetic control in pathways of inflammation.
Obesity is an independent contributor to functional capacity and inflammation in systemic lupus erythematosus
Authors: Oeser Annette , Chung Cecilia P. , Asanuma Yu , Avalos Ingrid , Stein C. Michael
Published: October 2005

Objective

Obesity induces a proinflammatory state and is a major cause of morbidity in the general population. However, little is known about the effects of obesity in patients with chronic inflammatory illnesses such as systemic lupus erythematosus (SLE).

Methods

One hundred consecutive patients with SLE were studied to determine the relationship between body mass index (BMI) and functional capacity, measures of fatigue, quality of life, and the inflammation markers C‐reactive protein (CRP), the erythrocyte sedimentation rate, and interleukin‐6 (IL‐6). The association between BMI and patient characteristics was determined, and multiple logistic regression models were used to adjust for age, sex, disease activity, and disease‐related damage.

Results

Thirty‐three patients had a normal BMI (<25 kg/m2), 28 were overweight (25–29.9 kg/m2), and 39 were obese (≥30 kg/m2). Obese patients had worse functional capacity, more fatigue, and higher concentrations of inflammation markers. The mean ± SD modified Health Assessment Questionnaire (M‐HAQ) score was 0.6 ± 0.4 in obese patients compared with 0.3 ± 0.4 and 0.2 ± 0.3 in overweight patients and those with a normal BMI, respectively (P = 0.001). The mean ± SD concentrations of CRP in obese patients (10.0 ± 8.6 mg/liter) were higher than those in patients who were overweight (4.7 ± 5.4 mg/liter) or had a normal BMI (6.2 ± 9.9 mg/liter) (P < 0.001). Similarly, concentrations of IL‐6 were higher in obese patients (P = 0.003). After adjusting for age, sex, disease activity, and damage indices, the associations between BMI and CRP (P < 0.001), M‐HAQ scores (P = 0.005), and IL‐6 concentrations (P = 0.01) remained significant.

Conclusion

Obesity is independently associated with impaired functional capacity and inflammation markers in patients with lupus. Thus, weight loss may improve functional capacity and decrease cardiovascular risk factors.
Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial
Authors: Goekoop‐Ruiterman Y. P. M. , De Vries‐Bouwstra J. K. , Allaart C. F. , Van Zeben D. , Kerstens P. J. S. M. , Hazes J. M. W. , Zwinderman A. H. , Ronday H. K. , Han K. H. , Westedt M. L. , Gerards A. H. , Van Groenendael J. H. L. M. , Lems W. F. , Van Krugten M. V. , Breedveld F. C. , Dijkmans B. A. C.
Published: October 2005

Objective

Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long‐term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients.

Methods

In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease‐modifying antirheumatic drug monotherapy (group 1), step‐up combination therapy (group 2), initial combination therapy with tapered high‐dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of ≤2.4).

Results

Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step‐up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D‐HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D‐HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1–4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups.

Conclusion

In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step‐up combination therapy.
Influence of mechanical stress and surface interaction on the aggregation of Aspergillus niger conidia
Authors: Grimm L.H. , Kelly S. , Völkerding I.I. , Krull R. , Hempel D.C.
Published: October 2005

Productivity of fungal cultures is closely linked with their morphologic development. Morphogenesis of coagulating filamentous fungi, like Aspergillus niger, starts with aggregation of conidia, also denominated as spores. Several parameters are presumed to control this event, but little is known about their mode of action. Rational process optimization requires models that mirror the underlying reaction mechanisms. An approach in this regard is suggested and supported by experimental data. Aggregation kinetics was examined for the first 15 h of cultivation under different cultivation conditions. Mechanical stress was considered as well as pH‐dependent surface interaction. Deliberations were based on a two‐step aggregation mechanism. The first aggregation step is only affected by the pH‐value, not by the fluid dynamic conditions in the bioreactor. The second aggregation step, in contrast, depends on the pH‐value as well as on agitation and aeration induced power input. For the given experimental set‐up, agitation had much more influence than aeration. In addition, hyphal growth rate was determined to be the driving force for the second aggregation step. © 2005 Wiley Periodicals, Inc.
Heterologous protein production capacity of mammalian cells cultivated as monolayers and microtissues
Authors: Sanchez‐Bustamante Carlota Diaz , Kelm Jens M. , Mitta Barbara , Fussenegger Martin
Published: October 2005

A precise understanding of processes managing heterologous protein production in vitro and in vivo is essential for the manufacture of sophisticated biopharmaceuticals as well as for future gene therapy and tissue engineering initiatives. Capitalizing on the gravity‐enforced self‐assembly of monodispersed cells into coherent (multicellular) microtissues we studied heterologous protein production of microtissues and monolayers derived from cell lines and primary cells engineered/transduced for (i) constitutive, (ii) proliferation‐controlled, (iii) macrolide‐, or (iv) gas‐inducible expression of the human placental secreted alkaline phosphatase (SEAP) and of the Bacillus stearothermophilus‐derived secreted α‐amylase (SAMY). Specific productivity of cells assembled in microtissues was up to 20‐fold higher than isogenic monolayer cultures. Diffusion across microtissues could be further increased by HUVEC‐mediated vascularization. As well as higher specific protein productivities, microtissues were also more efficient than monolayer cultures in assembling transgenic lentiviral particles. Our results showed that mammalian cells embedded in a tissue‐like three‐dimensional (3D) microenvironment exhibit increased production capacity. This observation should be considered for gene therapy and tissue engineering scenarios as well as for biopharmaceutical manufacturing. © 2005 Wiley Periodicals, Inc.
High‐level production and covalent immobilization of Providencia rettgeri penicillin G acylase (PAC) from recombinant Pichia pastoris for the development of a novel and stable biocatalyst of industrial applicability
Authors: Senerovic Lidija , Stankovic Nada , Spizzo Patrizia , Basso Alessandra , Gardossi Lucia , Vasiljevic Branka , Ljubijankic Goran , Tisminetzky Sergio , Degrassi Giuliano
Published: October 2005

A complete, integrated process for the production of an innovative formulation of penicillin G acylase from Providencia rettgeri(rPACP.rett)of industrial applicability is reported. In order to improve the yield of rPAC, the clone LN5.5, carrying four copies of pac gene integrated into the genome of Pichia pastoris, was constructed. The proteinase activity of the recombinant strain was reduced by knockout of the PEP4 gene encoding for proteinase A, resulting in an increased rPACP.rett activity of approximately 40% (3.8 U/mL vs. 2.7U/mL produced by LN5.5 in flask). A high cell density fermentation process was established with a 5‐day methanol induction phase and a final PAC activity of up to 27 U/mL. A single step rPACP.rett purification was also developed with an enzyme activity yield of approximately 95%. The novel features of the rPAC
P.rett expressed in P.pastoris were fully exploited and emphasized through the covalent immobilization of rPACP.rett. The enzyme wasimmobilized on a series of structurally correlated methacrylic polymers, specifically designed and produced for optimizing rPACP.rett performances in both hydrolytic and synthetic processes. Polymers presenting aminic functionalities were the most efficient, leading to formulations with higher activity and stability (half time stability >3 years and specific activity ranging from 237 to 477 U/g dry based on benzylpenicillin hydrolysis). The efficiency of the immobilized rPACP.rett was finally evaluated by studying the kinetically controlled synthesis of β‐lactam antibiotics (cephalexin) and estimating the synthesis/hydrolysis ratio (S/H), which is a crucial parameter for the feasibility of the process. © 2005 Wiley Periodicals, Inc.
Optimal in‐vitro expansion of chondroprogenitor cells in monolayer culture
Authors: Melero‐Martin Juan M , Dowling Mary‐Ann , Smith Mark , Al‐Rubeai Mohamed
Published: October 2005

A continuous production of large quantities of chondroprogenitor cells for the manufacture of engineered cartilage tissue products is required. Expansion of the cell population in vitro has become an essential step in the process of tissue engineering of articular cartilage and the optimization of the culture conditions is a fundamental problem that needs to be addressed. The analysis of both seeding density and passage length was considered crucial in the optimization of expansion processes, and their correct selection should be taken as a requisite to establish culture conditions for monolayer systems. The determination of the optimal seeding density and the corresponding passage length for cell expansion in a serial passaging operation was found to be a compromise between growth kinetics and process time. This optimal determination was carried out using a mathematical approach that led to values of 104 cell/cm2 for seeding density and 73 h for passage length. Additional considerations concerning the running cost of the process were introduced. Although the optimal passage length gave the desired expansion factor in a minimum process time, the selection of an alternative value of 120 h was shown to reduce the cost of the expansion process in more than 60%. The optimization approach presented will contribute to the development of feasible large scale expansion operations of chondroprogenitor cells required by the cartilage tissue engineering industry. © 2005 Wiley Periodicals, Inc.
Satellite cells from dystrophic (Mdx) mice display accelerated differentiation in primary cultures and in isolated myofibers
Authors: Yablonka‐Reuveni Zipora , Anderson Judy E.
Published: October 2005

In the dystrophic (mdx) mouse, skeletal muscle undergoes cycles of degeneration and regeneration, and myogenic progenitors (satellite cells) show ongoing proliferation and differentiation at a time when counterpart cells in normal healthy muscle enter quiescence. However, it remains unclear whether this enhanced satellite cell activity is triggered solely by the muscle environment or is also governed by factors inherent in satellite cells. To obtain a better picture of myogenesis in dystrophic muscle, a direct cell‐by‐cell analysis was performed to compare satellite cell dynamics from mdx and normal (C57Bl/10) mice in two cell culture models. In one model, the kinetics of satellite cell differentiation was quantified in primary cell cultures from diaphragm and limb muscles by immunodetection of MyoD, myogenin, and MEF2. In mdx cell cultures, myogenin protein was expressed earlier than normal and was followed more rapidly by dual myogenin/MEF2A expression and myotube formation. In the second model, the dynamics of satellite cell myogenesis were investigated in cultured myofibers isolated from flexor digitorum brevis (FDB) muscle, which retain satellite cells in the native position. Consistent with primary cultures, satellite cells in mdx myofibers displayed earlier myogenin expression, as well as an enhanced number of myogenin‐expressing satellite cells per myofiber compared to normal. The addition of fibroblast growth factor 2 (FGF2) led to an increase in the number of satellite cells expressing myogenin in normal and mdx myofibers. However, the extent of the FGF effect was more robust in mdx myofibers. Notably, many myonuclei in mdx myofibers were centralized, evidence of segmental regeneration; all central nuclei and many peripheral nuclei in mdx myofibers were positive for MEF2A. Results indicated that myogenic cells in dystrophic muscle display accelerated differentiation. Furthermore, the study demonstrated that FDB myofibers are an excellent model of the in vivo state of muscle, as they accurately represented the dystrophic phenotype. Developmental Dynamics 235:203–212, 2006. © 2005 Wiley‐Liss, Inc.
cadherin‐6 Message expression in the nervous system of developing zebrafish
Authors: Liu Qin , Liu Bei , Wilson Amy L. , Rostedt Jason
Published: October 2005

Cadherins are cell surface adhesion molecules that play important roles in development of a variety of tissues including the nervous system. In this study, we analyzed expression pattern of cadherin‐6, a member of the type II cadherin subfamily, in the embryonic zebrafish nervous system using in situ hybridization methods. cadherin‐6 message is first expressed by the neural keel, then by restricted regions in the brain and spinal cord. cadherin‐6 expression in the brain transiently delineates specific brain regions. In the peripheral nervous system, cadherin‐6 message is expressed by the neurogenic placodes and the dorsal root ganglia. As development proceeds, cadherin‐6 expression domain and/or expression levels increased in the embryonic nervous system. Our results show that cadherin‐6 expression in the zebrafish developing nervous system is both spatially and temporally regulated, implicating a role for cadherin‐6 in the formation of these nervous structures. Developmental Dynamics 235:272–278, 2006. © 2005 Wiley‐Liss, Inc.
Expression of avian C‐terminal binding proteins (Ctbp1 and Ctbp2) during embryonic development
Authors: Van Hateren Nick , Shenton Tom , Borycki Anne‐Gaëlle
Published: October 2005

C‐terminal binding proteins (CtBPs) are transcriptional corepressors of mediators of Notch, Wnt, and other signalling pathways. Thus, they are potential players in the control of several developmentally important processes, including segmentation, somitogenesis, and neural tube and limb patterning. We have cloned the avian orthologues of Ctbp1 and Ctbp2 and examined their expression pattern by whole‐mount in situ hybridization between Hamburger and Hamilton (HH) stages 3 and 24. Both Ctbp genes show similar expression patterns during embryonic development, and both are detected from HH stage 3 in the developing central nervous system, by HH stage 7 in the paraxial mesoderm and later in the limb bud. In most places, Ctbp1 and Ctbp2 are expressed in overlapping domains. However, there are interesting domains and/or temporal expression patterns that are specific to each Ctbp gene. For instance, Ctbp1 is predominantly expressed in the epiblast, whereas Ctbp2 is in the primitive streak at HH stage 3. However, by HH stage 4, both genes are found in the primitive streak and in the ectoderm. Similarly, although both genes display similar expression patterns in early somitogenesis, in mature somites, Ctbp1 transcripts are located in myotomal cells, whereas Ctbp2 transcripts are observed in dermomyotomal cells. Finally, we found that emigrating neural crest cells express Ctbp2, whereas dorsal root ganglia express Ctbp1. These data suggest that Ctbp1 and Ctbp2 may be functionally redundant in some tissues and have unique functions in other tissues. Developmental Dynamics 235:490–495, 2005. © 2005 Wiley‐Liss, Inc.
Regulation of early Xenopus development by ErbB signaling
Authors: Nie Shuyi , Chang Chenbei
Published: October 2005

ErbB signaling has long been implicated in cancer formation and progression and is shown to regulate cell division, migration, and death during tumorigenesis. The functions of the ErbB pathway during early vertebrate embryogenesis, however, are not well understood. Here we report characterization of ErbB activities during early frog development. Gain‐of‐function analyses show that EGFR, ErbB2, and ErbB4 induce ectopic tumor‐like cell mass that contains increased numbers of mitotic cells. Both the muscle and the neural markers are expressed in these ectopic protrusions. ErbBs also induce mesodermal markers in ectodermal explants. Loss‐of‐function studies using carboxyl terminal‐truncated dominant‐negative ErbB receptors demonstrate that blocking ErbB signals leads to defective gastrulation movements and malformation of the embryonic axis with a reduction in the head structures in early frog embryos. These data, together with the observation that ErbBs are expressed early during frog embryogenesis, suggest that ErbBs regulate cell proliferation, movements, and embryonic patterning during early Xenopus development. Developmental Dynamics 235:301–314, 2006. © 2005 Wiley‐Liss, Inc.
Robust Synthesis and Crystal‐Structure Analysis of 7‐Cyano‐7‐deazaguanine (PreQ0 Base) and 7‐(Aminomethyl)‐7‐deazaguanine (PreQ1 Base)
Authors: Klepper Florian , Polborn Kurt , Carell Thomas
Published: October 2005

We describe robust and efficient synthetic methods for the synthesis of the preQ0 and preQ1 bases, which are the biosynthetic precursors of the hypermodified RNA nucleoside queuosine. The X‐ray crystal‐structure analysis of preQ1 is also described.
Mechanistic Studies on the Oxidation of Nitrite by a μ‐Oxodiiron(III,III) Complex in Aqueous Acidic Media
Authors: Bhattacharyya Jhimli , Mukhopadhyay Subrata
Published: October 2005

Examined in this study is the kinetics of a net 2e− transfer between [Fe2(μ‐O)(phen)4(H2O)2]4+ (1) and its hydrolytic derivatives [Fe2(μ‐O)(phen)4(H2O)(OH)]3+ (2) and [Fe2(μ‐O)(phen)4(OH)2]2+ (3) with $\rm{{{NO}}_{{2}}^ - }$ in aqueous media and in presence of excess 1,10‐phenanthroline (phen). The reaction is quantitative with a 1 : 1 stoichiometry between the oxidant and reductant to produce ferroin ([Fe(phen)3]2+) and $\rm{{{NO}}_{{3}}^ - }$. The order of reactivity of the oxidant species is 1 > 2 > 3, in agreement with the progressive cationic charge reduction. The reactions appear to be inner‐sphere where the initial one‐electron proton‐coupled redox (1e−, 1H+; electroprotic) seems to be rate‐determining.
Three New Compounds from Securidaca inappendiculata
Authors: Kang Wen‐Yi , Wang Zhe‐Ming , Li Zheng‐Quan , Xu Xiao‐Jie
Published: October 2005

Three new compounds, 2‐methoxy‐3,4‐(methylenedioxy)benzophenone (1), 4‐hydroxy‐2,3‐dimethoxybenzophenone (2), and 3‐hydroxy‐4,6‐dimethoxy‐9H‐xanthen‐9‐one (3), besides three known compounds were isolated from the roots of Securidaca inappendiculata. Their structures were established by spectroscopic means and X‐ray crystallographic diffraction analysis. The biogenetic relationships among these six compounds are discussed.
Cardenolides and Cardiac Aglycone from the Stem Bark of Trewia nudiflora
Authors: Kang Qian‐Jin , Zhao Pei‐Ji , He Hong‐Ping , Shen Yue‐Mao
Published: October 2005

Five new cardenolides and one new cardiac aglycone, i.e., (5α)‐sarmentogenin 3‐(α‐L‐rhamnopyranoside) (1), (5α)‐sarmentogenin (2), 11‐oxouzarigenin 3‐(α‐L‐rhamnopyranoside) (3), (5α)‐gitoxigenin 3‐(α‐L‐rhamnopyranoside) (4), (5α)‐oleandrigenin 3‐(α‐L‐rhamnopyranoside) (5), and (5α)‐oleandrigenin 3‐[β‐D‐glucopyranosyl‐(1 → 4)‐α‐L‐rhamnopyranoside] (6), together with two known cardenolides, i.e., frugoside (= (3β,5α)‐3‐[(6‐deoxy‐β‐D‐allopyranosyl)oxy]‐14,19‐dihydroxycard‐20(22)‐enolide) and (17α)‐ascleposide (= (3β,5α,17α)‐3‐[(6‐deoxy‐α‐D‐allopyranosyl)oxy]‐14‐hydroxycard‐20(22)‐enolide), were isolated from the stem bark of Trewia nudiflora L. (Euphorbiaceae) collected in Xishuangbanna, Yunnan Province, China. Their structures were established by spectroscopic studies. Cardenolides were first found in the genus Trewia (Euphorbiaceae).
(1S,2S,3R,6R)‐6‐Aminocyclohex‐4‐ene‐1,2,3‐triol (= (−)‐Conduramine B‐1) Is a Selective Inhibitor of α‐Mannosidases. Its Inhibitory Activity Is Enhanced by N‐Benzylation
Authors: Łysek Robert , Schütz Catherine , Vogel Pierre
Published: October 2005

(−)‐ and (+)‐Conduramine B‐1 ((−)‐ and (+)‐5, resp.) have been derived from (+)‐ and (−)‐7‐oxabicyclo[2.2.1]hept‐5‐en‐2‐one (‘naked sugars’ of the first generation). Although (−)‐5 imitates the structure of β‐glucosides, it does not inhibit β‐glucosidases but inhibits α‐mannosidases selectively. N‐Benzylation of (−)‐5 improves the potency of conduramine B‐1 as α‐mannosidase inhibitor and also generates compounds inhibiting β‐glucosidases. For instance, (−)‐N‐benzyl‐conduramine B‐1 ((−)‐19a) is a competitive inhibitor of β‐glucosidase from almonds (IC50 = 32 μM, Ki = 10 μM) and a weak inhibitor of α‐mannosidases from jack bean (IC50 = 171 μM) and from almonds (IC50 = 225 μM) whereas (−)‐N‐(4‐phenylbenzyl)conduramine B‐1 ((−)‐19g) is a good inhibitor of α‐mannosidase from jack beans (IC50 = 29 μM, Ki = 4.8 μM) and a weaker inhibitor of β‐glucosidase from almonds (IC50 = 32 μM, Ki = 7.8 μM) (Table 1).
LC–ESI‐MS/MS analysis for the quantification of morphine, codeine, morphine‐3‐β‐D‐glucuronide, morphine‐6‐β‐D‐glucuronide, and codeine‐6‐β‐D‐glucuronide in human urine
Authors: Murphy Constance M. , Huestis Marilyn A.
Published: October 2005

A liquid chromatographic‐electrospray ionization‐tandem mass spectrometric method for the quantification of the opiates morphine, codeine, and their metabolites morphine‐3‐β‐D‐glucuronide (M‐3‐G), morphine‐6‐β‐D‐glucuronide (M‐6‐G) and codeine‐6‐β‐D‐glucuronide (C‐6‐G) in human urine has been developed and validated. Identification and quantification were based on the following transitions: 286 to 201 and 229 for morphine, 300 to 215 and 243 for codeine, 644 to 468 for M‐3‐G, 462 to 286 for M‐6‐G, and 476 to 300 for C‐6‐G. Calibration by linear regression analysis utilized deuterated internal standards and a weighting factor of 1/X. The method was accurate and precise across a linear dynamic range of 25.0 to 4000.0 ng/ml. Pretreatment of urine specimens using solid phase extraction was sufficient to limit matrix suppression to less than 40% for all five analytes. The method proved to be suitable for the quantification of morphine, codeine, and their metabolites in urine specimens collected from opioid‐dependent participants enrolled in a methadone maintenance program. Copyright © 2005 John Wiley & Sons, Ltd.
Specificity of receptor–ligand interactions and their effect on dimerisation as observed by electrospray mass spectrometry: bile acids form stable adducts to the RXRα
Authors: Lengqvist Johan , Mata de Urquiza Alexander , Perlmann Thomas , Sjövall Jan , Griffiths William J.
Published: October 2005

Electrospray (ES) mass spectrometry data is presented showing that agonist binding to the nuclear receptor (NR), retinoid X receptor α (RXRα), is competitive. The competitive nature of agonist binding can be used to discriminate between the specific and non‐specific binding of small lipophilic molecules to NRs. Further, data is presented which show that high‐affinity ligand binding to the RXRα ligand‐binding domain (LBD) stabilises the domain homodimer. The results indicate that homodimerisation, a functional property of the receptor associated with the binding of agonist ligands, could be used to discriminate between specific and non‐specific binding events. Additionally, we report on the remarkable stability of the gas‐phase complex between the RXRα LBD protein and endogenous bile acids. Protein–bile acid interactions in the gas phase were found to be surprisingly strong, withstanding ‘in‐source’ fragmentation in the ES interface, and, in the case of taurocholic acid (TCA) and lithocholic acid‐3‐sulphate (LCA‐3‐sulphate), collision‐induced dissociation within the collision cell of a tandem mass spectrometer. Bile acids were found to be inactive towards RXRα in transfection assays, and have not been reported to be ligands for the RXRα, although lithocholic acid (LCA) has been found to be a competitor in the photoaffinity labelling of RXRβ with 9‐cis‐retinoic acid (9‐cis‐RA). The observation of strong RXRα‐bile acid non‐covalent complexes in ES mass spectrometry highlight the danger of extrapolating gas‐phase binding data to the solution phase and further to a possible biological activity, particularly when surface‐active compounds such as bile acids are involved. The introduction of a competitive ligand‐binding experiment can alleviate this problem and allow the differentiation between specific and non‐specific binding. Copyright © 2005 John Wiley & Sons, Ltd.
Beat‐to‐beat blood pressure analysis after premature ventricular contraction indicates sensitive baroreceptor dysfunction in Parkinson's disease
Authors: Haensch Carl‐Albrecht , Jörg Johannes
Published: October 2005

Extrasystoles occur in normal subjects but are significant more frequently (16.25% vs. 55%; χ2= 19.3;P< 0.001) seen in Parkinson's disease (PD) patients. The extrasystolic decreases in stroke volume and systolic pressure activate sympathetic vasomotor innervation and lead to a blood pressure increase for a few heartbeats. The purpose of this study was to prove whether the short time analysis of this blood pressure regulation allows the assessment of sympathetic neurocirculatory function. Records of noninvasive blood pressure monitoring were reviewed from 40 PD patients and 80 controls. A battery of cardiovascular autonomic tests, including Valsalva maneuver, tilt‐table testing, echocardiography, and cardiac scintigraphy with [123I]meta‐iodobenzylguanidine were performed. Fifty‐five percent of the PD patients had at least one premature ventricular contraction (PVC) in 10 minutes lying supine at rest. After every PVC (13 PVCs) recorded from normal subjects, we found an increase in systolic blood pressure above base line with a maximum at the seventh heart beat. In all of the 22 PD patients, the systolic blood pressure was significantly decreased less than baseline in every PVC from the second to the ninth postextrasystolic beat (P< 0.001). In both groups, the extrasystolic fall in blood pressure was on average approximately 22%. The postextrasystolic potentiation did not differ (5.3% vs. 4.4%, not significant). If a PVC occurs, the analysis of short‐time blood pressure regulation is a sensitive tool for baroreceptor reflex function. The advantage of this method results from the independence of patients cooperation and the high sensitivity to prove a sympathetic neurocirculatory failure within 10 heart beats. © 2005 Movement Disorder Society
Relapsing sensorimotor neuropathy with ophthalmoplegia, antidisialosyl antibodies, and extramembranous glomerulonephritis
Authors: Delval Arnaud , Stojkovic Tanya , Vermersch Patrick
Published: October 2005

A 72‐year‐old man presented with oculomotor dysfunction, subacute relapsing sensorimotor neuropathy, elevated erythrocyte sedimentation rate, IgM monoclonal paraprotein, cold agglutinins, and antidisialosyl IgM antibodies, features previously described by the acronym CANOMAD (chronic ataxic neuropathy with ophthalmoplegia, M protein, agglutination, and disialosyl antibodies). The patient also had extramembranous glomerulopathy associated with this syndrome. Treatment with corticosteroids improved both the neuropathy and glomerulopathy. This case suggests that the spectrum of neuropathy associated with monoclonal gammopathy may be broader than originally believed. Muscle Nerve, 2006
Missed opportunities in reactive chemical hazard evaluations
Authors: Ogle R. A. , Morrison D. R. , Carpenter A. R. , Su Y. S.
Published: October 2005

Reactive chemicals pose a significant hazard to the process industries arising from their inherent nature. This paper examines four reactive chemical accidents caused by self‐heating that led to thermal runaway reactions. Although none of these case studies resulted in serious injuries, the runaway reactions caused fires, explosions, or toxic gas releases that resulted in extensive damages and loss of production. This paper considers the causal factors of these accidents, identifies the thermal stability data available before the accidents, and presents simple hazard calculations indicating the predictability of the accidents. The paper concludes with a discussion of lessons learned from these accidents. © 2005 American Institute of Chemical Engineers Saf Prog, 2006
The antisite LuAl defect‐related trap in Lu3Al5O12:Ce single crystal
Authors: Nikl M. , Mihokova E. , Pejchal J. , Vedda A. , Zorenko Yu. , Nejezchleb K.
Published: October 2005

The cover picture of the current issue refers to the Rapid Research Letter by Martin Nikl et al. [1]. It depicts the structure of a Lu3Al5O12:Ce single crystal, a possible high performance scintillator material. Its scintillation performance is, however, degraded by the occurrence of antisite defects. Such defects arise in the material structure sketched in the figure due to the occurrence of Lu3+ ions at the Al3+ octahedral sites as seen in the middle left octahedron. This defect constitutes a shallow electron trap, which delays energy delivery to the Ce3+ emission centers, and thus slows down the scintillation response of the material. Thermoluminescence measurements appear as sensitive diagnostic tool to evidence these defects in the single crystals grown.

Martin Nikl is senior scientist and head of the Laboratory of Luminescence and Scintillation Materials at the Institute of Physics of the Czech Academy of Sciences. His main research activities include the characterization of the luminescence and scintillation properties of wide band‐gap materials and the influence of material defects on them.
Cover Picture: Nanometer‐Scale Modification and Welding of Silicon and Metallic Nanowires with a High‐Intensity Electron Beam (Small 12/2005)
Authors: Xu Shengyong , Tian Mingliang , Wang Jinguo , Xu Jian , Redwing Joan M. , Chan Moses H. W.
Published: October 2005

The cover picture shows an artificially colored transmission electron microscopy image of a 39‐nm‐diameter silicon nanowire, where the word “small” has been sculpted on the nanowire by a high‐intensity electron beam. We demonstrate that an intense electron beam can be applied to create holes, gaps, and other patterns of atomic and nanometer dimensions on a single nanowire. The electron beam can also be used to weld individual nanowires, forming metal–metal or metal–semiconductor junctions. For more information, please read the Full Paper “Nanometer‐Scale Modification and Welding of Silicon and Metallic Nanowires with a High‐Intensity Electron Beam” by S. Y. Xu and co‐workers on page 1221 ff.
Interactions Between Human Activity, Volcanic Eruptions and Vegetation During the Holocene at Garua and Numundo, West New Britain, PNG
Authors: Boyd W.E. , Lentfer C.J. , Parr J.
Published: October 2005

This paper reviews recent fossil phytolith analysis from wet tropical West New Britain (Papua New Guinea). The Holocene vegetation has been influenced by spatially and temporally diverse patterns of both prehistoric human settlement and catastrophic volcanic events. We have hypothesized different landscape responses and recovery pathways to events during the last six millennia. Phytolith sequences on the coastal lowlands, the Willaumez Peninsula, and nearby island of Garua provide details of vegetational change and human interactions at different landscape scales since c. 5900 cal yr B.P. During this period four major volcanic eruptions (c. 5900, 3600, 1700 and 1400 cal yr B.P.) have disrupted the landscape. The evidence provides detailed descriptions of temporal and spatial patterning in the impacts and changes in the vegetation. In particular, vegetation responded differently from one event to another, reflecting both forest recovery from seed bank and shooting, and the influence of prehistoric people on recovering vegetation. Furthermore, after some events landscape recovery was moderately uniform, while after others there was considerable landscape partitioning. Although these differences largely relate to airfall tephra type, distribution and magnitude, the partitioning is more strongly influenced by human activity.
Why Kant Could not Have Been a Utilitarian
Authors: TIMMERMANN JENS
Published: October 2005

In 1993, Richard Hare argued that, contrary to received opinion, Kant could have been a utilitarian. In this article, I argue that Hare was wrong. Kant's theory would not have been utilitarian or consequentialist even if his practical recommendations coincided with utilitarian commands: Kant's theory of value is essentially anti-utilitarian; there is no place for rational contradiction as the source of moral imperatives in utilitarianism; Kant would reject the move to separate levels of moral thinking: first-order moral judgement makes use of the principle of morality; and, relatedly, he would resist the common utilitarian distinction between actions and their motives because any correct description of an action must refer to motivation. The article concludes with the thought that any consequentialist theory based on pre-given ends (teleology) lacks the philosophical resources to distinguish between willing something as a means and as an end, leaving means only, and destroying transparency.
The Doctrine of Sufficiency: A Defence
Authors: BENBAJI YITZHAK
Published: October 2005

This article proposes an analysis of the doctrine of sufficiency. According to my reading, the doctrine's basic positive claim is ‘prioritarian’: benefiting x is of special moral importance where (and only where) x is badly off. Its negative claim is anti-egalitarian: most comparative facts expressed by statements of the type ‘x is worse off than y’ have no moral significance at all. This contradicts the ‘classical’ priority view according to which, although equality per se does not matter, whenever x is worse off than y, at least some priority should be assigned to helping x. Section I elaborates and defends this reconstruction of the doctrine of sufficiency, and section II shows that the privileged utility level presumed within the sufficiency framework exists.
Some properties of Alfvén waves: Observations in the tail lobes and the plasma sheet boundary layer
Authors: Keiling A. , Parks G. K. , Wygant J. R. , Dombeck J. , Mozer F. S. , Russell C. T. , Streltsov A. V. , Lotko W.
Published: October 2005

We report properties of substorm‐related, globally excited Alfvén waves on a temporal scale of 6 to 300 s (3.3 to 167 mHz) at geocentric distances between 5 and 6 RE. The waves were observed in the tail lobes and the plasma sheet boundary layer (PSBL) by the Polar satellite. In each region we made the following observations: (1) The tail lobe Alfvén waves started at substorm onset as determined from ground magnetometer data. Hence these ULF lobe waves can possibly be used as a new substorm indicator. Although on open field lines, they often showed local standing wave signatures with a large perpendicular scale size and a near‐zero net Poynting flux. We do not classify those waves as FLR but interpret them as the superposition of incident and reflected waves. The same oscillations were simultaneously recorded in ground magnetometer data. Immediately poleward of the PSBL, the lobe Alfvén waves traveled earthward (no reflection), suggesting their dissipation in the ionosphere. The lobe waves were superimposed on the signature of a field‐aligned current (FAC). The onset of this FAC was simultaneous to the onset of the magnetic substorm bay. (2) The substorm‐related PSBL Alfvén waves carried two to three orders of magnitude larger Poynting flux (∼1 erg cm−2 s−1) than the lobe Alfvén waves. These PSBL waves were a mixture of standing and traveling Alfvén waves for different frequency ranges. Most Poynting flux was carried in large‐scale earthward traveling waves (40–300 s). For one event, we also measured large standing wave components (>0.5 erg cm−2 s−1), but such events are rare. In the intermediate range (40–67 s), which overlaps with the Pi2 range, some waves showed clear standing wave signatures. At smaller periods (6–24 s), noninterfering earthward and tailward traveling waves were present with small Poynting fluxes (<0.05 erg cm−2 s−1). A trend for increasing E to B ratios with increasing wave frequency was observed. The PSBL waves were left‐hand elliptically polarized. The wave vector was within 35° of the background magnetic field direction, suggesting that the waves were phase‐mixed. The large‐amplitude, substorm‐related PSBL Alfvén wave events (∼1 erg cm−2 s−1) were found in regions of upward currents.
Stokes parameter analysis of a packet of turbulence‐generating gravity waves
Authors: Lu Chungu , Koch Steven E. , Wang Ning
Published: October 2005

Stokes parameter analysis for small‐scale gravity waves was carried out from a set of aircraft observational data. The goal is to understand the polarization properties associated with gravity waves when turbulence is generated so that enough physical knowledge can be gained about the interaction between the two. A wavelet cross‐spectrum technique is introduced into the traditional Stokes parameter analysis. From this analysis it is shown that small‐scale gravity waves possess distinctive polarization signatures. Further extension of the Stokes parameter analysis by a wave‐averaging method is also proposed. The analysis using this method indicates that the turbulence production is closely related to an enhanced level of polarization and coherency in the two components of the horizontal wind in the gravity waves and that the turbulence surge is accompanied by a tendency for an instantaneous reduction of polarization and abrupt shift of horizontal wave vector of the progenitor gravity waves. These findings may be useful in the prediction of the occurrence of turbulence in association with gravity wave activities in the atmosphere.
Coulomb stress changes in Hesperia Planum, Mars, reveal regional thrust fault reactivation
Authors: Goudy Cheryl L. , Schultz Richard A. , Gregg Tracy K. P.
Published: October 2005

The orthogonal pattern of NE and NW striking wrinkle ridges in Hesperia Planum makes this area unique and enigmatic. The wrinkle ridge morphologies revealed in Mars Orbiter Laser Altimeter topography across ridge structures in Hesperia Planum suggest that wrinkle ridges form above thrust faults. The timing relationship among wrinkle ridge sets is evident in the digital elevation models; thrust faults striking NE are older than the NW striking ridges. The NE striking wrinkle ridges show unequal development adjacent to the NW striking wrinkle ridges, and an echelon pattern throughout Hesperia Planum; therefore formation by two independent sequential sets is not likely. Reactivation of the older (NE) thrust faults from the younger (NW) wrinkle ridges, inferred from the observations, is tested by resolving Coulomb failure stress changes along the older thrust faults from slip along the younger thrust faults. We find fault reactivation is likely in Hesperia Planum, regardless of the deposit material (basalt or tuff). Previously, the NE striking wrinkle ridges were interpreted as forming prior to, or contemporaneous to, the Tyrrhena Patera flank flow unit. This observation and the continuation of many of these ridges into the Noachian highlands as thrust fault scarps suggest formation of NE striking thrust faults no later than the late Noachian/early Hesperian. The NW striking wrinkle ridges, forming after the emplacement of the late Hesperian/early Amazonian Tyrrhena Patera deposit, imply geologically recent thrust faulting. The combination of NE and NW structural events implies a stress state rotation in Hesperia Planum of about 90° between the late Noachian and early Amazonian.