bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory back pain in ankylosing spondylitis: A reassessment of the clinical history for application as classification and diagnostic criteria
Authors: Rudwaleit Martin , Metter Anke , Listing Joachim , Sieper Joachim , Braun Jürgen
Published: January 2006

Objective

Back pain associated with ankylosing spondylitis (AS) is referred to as inflammatory back pain (IBP). The value of the clinical history in differentiating IBP from mechanical low back pain (MLBP) has been investigated in only a few studies. In this exploratory study, we sought to evaluate the individual features of IBP and to compose and compare various combinations of features for use as classification and diagnostic criteria.

Methods

We assessed the clinical history of 213 patients (101 with AS and 112 with MLBP) younger than 50 years who had chronic back pain. Single clinical parameters and combinations of parameters were compared between the AS and MLBP patient groups.

Results

Morning stiffness of >30 minutes' duration, age at onset of back pain, no improvement in back pain with rest, awakening because of back pain during the second half of the night only, alternating buttock pain, and time period of the onset of back pain were identified as independent contributors to IBP. Importantly, none of the single parameters sufficiently differentiated AS from MLBP. In contrast, several sets of combined parameters proved to be well balanced between sensitivity and specificity. Among these, a new candidate set of criteria for IBP, which consisted of morning stiffness of >30 minutes' duration, improvement in back pain with exercise but not with rest, awakening because of back pain during the second half of the night only, and alternating buttock pain, yielded a sensitivity of 70.3% and a specificity of 81.2% if at least 2 of these 4 parameters were fulfilled (positive likelihood ratio 3.7). If at least 3 of the 4 parameters were fulfilled, the positive likelihood ratio increased to 12.4.

Conclusion

A new set of criteria for IBP performed better than previous criteria in AS patients with established disease. A prospective study is needed to validate the diagnostic properties of the new candidate criteria set in patients with early disease.
Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling
Authors: Spector Tim D. , Reneland Richard H. , Mah Steven , Valdes Ana M. , Hart Deborah J. , Kammerer Stefan , Langdown Maria , Hoyal Carolyn R. , Atienza Josephine , Doherty Michael , Rahman Proton , Nelson Matthew R. , Braun Andreas
Published: January 2006

Objective

To perform a large‐scale association analysis of single‐nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee.

Methods

We examined >25,000 SNPs located within ∼14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case–control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression.

Results

The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as‐yet‐unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case–control groups. Additional subanalyses in case–control samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine‐mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up‐regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role.

Conclusion

A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.
Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction
Authors: Zwerina Jochen , Hayer Silvia , Redlich Kurt , Bobacz Klaus , Kollias Giorgos , Smolen Josef S. , Schett Georg
Published: January 2006

Objective

To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed.

Methods

Human TNF‐transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed.

Results

Both p38 MAPK inhibitors significantly reduced clinical signs of TNF‐mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin‐1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK‐activated protein kinase 2 (MAPKAP‐2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP‐2 as well as differentiation markers in cultured osteoclast precursors.

Conclusion

These results suggest the major importance of p38 MAPK for TNF‐mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.
Platelet C4d is highly specific for systemic lupus erythematosus
Authors: Navratil Jeannine S. , Manzi Susan , Kao Amy H. , Krishnaswami Shanthi , Liu Chau‐Ching , Ruffing Margie J. , Shaw Penny S. , Nilson Abbey C. , Dryden Emily R. , Johnson Jeffrey J. , Ahearn Joseph M.
Published: January 2006

Objective

Complement‐activation product C4d is deposited on normal erythrocytes, while abnormal levels have been observed on the surface of erythrocytes of patients with systemic lupus erythematosus (SLE). This study examines whether C4d also deposits on human platelet surfaces, and whether platelet‐bound C4d may provide a biomarker for SLE.

Methods

We conducted a cross‐sectional study of 105 patients with SLE, 115 patients with other diseases, and 100 healthy controls. Levels of C4d on the surface of platelets were examined by flow cytometry and scanning confocal microscopy. Statistical analyses were performed to determine the clinical variables associated with platelet C4d.

Results

Abnormal levels of platelet C4d were found to be highly specific for SLE. Platelet C4d was detected in 18% of patients with SLE, being 100% specific for a diagnosis of SLE compared with healthy controls and 98% specific for SLE compared with patients with other diseases (P < 0.0001). In addition, platelet C4d was significantly associated with positivity for lupus anticoagulant (P < 0.0001) and anticardiolipin antibodies of the IgG (P = 0.035) or the IgM (P = 0.016) isotype. Platelet C4d was also significantly associated with SLE disease activity according to the SLE Disease Activity Index (P = 0.039), low serum C4 (P = 0.046), an elevated erythrocyte sedimentation rate (P = 0.006), and abnormal levels of C4d on erythrocytes (P < 0.0001).

Conclusion

This observation suggests that platelet‐bound C4d may be a useful biomarker for SLE and may be a clue to the pathogenic mechanisms responsible for the myriad thrombotic and vascular complications of lupus associated with antiphospholipid antibodies.
Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations
Authors: Liang Kimberly P. , Liang Kelly V. , Matteson Eric L. , McClelland Robyn L. , Christianson Teresa J. H. , Turesson Carl
Published: January 2006

Objective

To investigate the incidence of noncardiac vascular disease in patients with rheumatoid arthritis (RA) and its relationship to systemic extraarticular disease in a community‐based cohort.

Methods

A retrospective medical record review of 609 patients with incident RA diagnosed during 1955–1994 was carried out in Olmsted County, Minnesota. Patients were followed up from 1955 to 2000 (median followup 11.8 years). Incident noncardiac vascular disease and severe extraarticular RA manifestations (including pericarditis, pleuritis, and vasculitis) were recorded according to predefined criteria, and incidence rates were estimated. Using Cox proportional hazards models, the risk (hazard ratio [HR]) of developing vascular events was assessed in patients with and without severe extraarticular RA.

Results

Cerebrovascular and peripheral arterial events occurred in 139 patients (22.8%). The 30‐year cumulative incidence rates of peripheral arterial events, cerebrovascular events, and venous thromboembolic events were estimated to be 19.6%, 21.6%, and 7.2%, respectively. The presence of severe extraarticular RA manifestations was found to be associated with all subgroups of noncardiac vascular disease except cerebrovascular disease alone (HR 2.3, 95% confidence interval [95% CI] 1.2–4.3 for peripheral arterial events; HR 3.7, 95% CI 1.3–10.3 for venous thromboembolic events; HR 1.5, 95% CI 0.7–3.2 for cerebrovascular events) after adjusting for age, sex, body mass index, smoking, and rheumatoid factor status.

Conclusion

This is the first study to assess the incidence of noncardiac vascular disease in RA. Severe extraarticular RA was associated with all forms of noncardiac vascular disease except cerebrovascular disease alone. Similar to cardiac disease, the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with the extraarticular manifestations of RA.
A new classification of HLA–DRB1 alleles differentiates predisposing and protective alleles for rheumatoid arthritis structural severity
Authors: Gourraud Pierre‐Antoine , Boyer Jean‐Frédéric , Barnetche Thomas , Abbal Michel , Cambon‐Thomsen Anne , Cantagrel Alain , Constantin Arnaud
Published: January 2006

Objective

A new classification of HLA–DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA.

Methods

The study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA–DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence‐specific oligonucleotide probes. HLA–DRB1 alleles were classified according to the above‐mentioned new system. The association between the HLA–DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests.

Results

The presence of S2 alleles (HLA–DRB1*0401 and HLA–DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA–DRB1*11001, HLA–DRB1*1104, HLA–DRB1*12, and HLA–DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01).

Conclusion

The studied classification of HLA–DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70–74 of the third hypervariable region of the HLA–DRβ chain.
Early cytokine profiles in the joint define pathogen clearance and severity of arthritis in Chlamydia‐induced arthritis in rats
Authors: Inman Robert D. , Chiu Basil
Published: January 2006

Objective

Although Chlamydia trachomatis–induced arthritis is among the most common rheumatic diseases having an identified infectious trigger, the pathogenesis of this arthritis is not well defined. We sought to investigate the host–microbe interactions that contribute to the severity of arthritis initiated by chlamydial infection.

Methods

We established an experimental rat model of C trachomatis–induced arthritis that recapitulates many pathologic features of the clinical disease. The severity of the arthritis was defined using an established histopathologic scoring system. Host clearance of the pathogen and local cytokine production were examined by enzyme‐linked immunosorbent assays.

Results

Lewis rats were susceptible to C trachomatis–induced arthritis, whereas BN rats were relatively resistant to this disease. Significant differences in the histopathologic severity of arthritis were originally observed on day 21, and this prompted an examination of the acute phase of the arthritis. As early as day 5 after the onset of the arthritis, pathologic changes in Lewis rats were more severe than those in BN rats. An evaluation of the role of complement using cobra venom factor treatment excluded complement as being the key to differential sensitivity, because decomplementation did not eliminate the differences in arthritis severity between Lewis and BN rats. Host clearance, in contrast, was significantly different between the rat strains, with BN rats showing more prompt and effective clearance of the pathogen from both synovial tissues and spleen compared with Lewis rats. Local cytokine profiles demonstrated that host resistance was characterized by enhanced synovial expression of tumor necrosis factor α, interferon‐γ (IFNγ), and interleukin‐4.

Conclusion

These studies demonstrated that cytokines thought to be proinflammatory in nature can play an important role in host defense in infection‐triggered arthritis and serve to highlight the dynamic cytokine relationships that constitute effective host–pathogen interactions.
Interfacing Pichia pastoris cultivation with expanded bed adsorption
Authors: Jahic Mehmedalija , Knoblechner Josef , Charoenrat Theppanya , Enfors Sven‐Olof , Veide Andres
Published: January 2006

For improved interfacing of the Pichia pastoris fed‐batch cultivation process with expanded bed adsorption (EBA) technique, a modified cultivation technique was developed. The modification included the reduction of the medium salt concentration, which was then kept constant by regulating the medium conductivity at low value (about 8 mS/cm) by salt feeding. Before loading, the low conductivity culture broth was diluted only to reduce viscosity, caused by high cell density. The concept was applied to a one‐step recovery and purification procedure for a fusion protein composed of a cellulose‐binding module (CBM) from Neocallimastix patriciarum cellulase 6A fused to lipase B from Candida antarctica (CALB). The modified cultivation technique resulted in lower cell death and consequently lower concentration of proteases and other contaminating proteins in the culture broth. Flow cytometry analysis showed 1% dead (propidium‐stained) cells compared to 3.5% in the reference process. During the whole process of cultivation and recovery, no proteolysis was detected and in the end of the cultivation, the product constituted 87% of the total supernatant protein. The lipase activity in the culture supernatant increased at an almost constant rate up to a value corresponding to 2.2 g/L of CBM–CALB. In the EBA process, no cell‐adsorbent interaction was detected but the cell density had to be reduced by a two‐times dilution to keep a proper bed expansion. At flow velocity of 400 cm/h, the breakthrough capacity was 12.4 g/L, the product yield 98%, the concentration factor 3.6 times, the purity about 90%, and the productivity 2.1 g/L · h. © 2006 Wiley Periodicals, Inc.
Captopril protects mice bone marrow cells against genotoxicity induced by gamma irradiation
Authors: Hosseinimehr Seyed Jalal , Mahmoudzadeh Aziz , Akhlagpour Shahram
Published: January 2006

The radioprotective effects of captopril were investigated by using the micronucleus test for anticlastogenic and cell proliferation activity. A single intraperitoneal administration of captopril at doses of 10, 25 and 50 mg/kg 1 h prior to gamma irradiation (2 Gy) reduced the frequencies of micronuleated polychromatic erythrocytes (MnPCEs). All three doses of captopril significantly reduced the frequencies of MnPCEs and increased polychromatic erythrocytes (PCE)/PCE+NCE (normochromatic erythrocyte) ratio in mice bone marrow compared to the non‐drug‐treated irradiated control (p < 0.001). The optimum dose for protection in mouse was 10 mg/kg to protect mice bone marrow 2.18‐fold against the clastogenic effects of γ‐irradiation with respect to the non‐drug‐treated irradiated control. There was a drug dose‐response effect of captopril in increasing the PCE/PCE+NCE ratio in bone marrow cells. The maximum protective effect of captopril was at a dose of 25 mg/kg for increasing the PCE/PCE + NCE ratio. Captopril exhibited concentration‐dependent antioxidant activity, scavenging > 96% of the 1,1‐diphenyl‐2‐picryl hydrazyl free radicals when used at a concentration of 0.2 mM. In this study captopril reduced lipid peroxidation induced by hydrogen peroxide in mice liver. It appears that captopril, due to its free radical scavenging properties, protects mice bone marrow cells from radiation‐induced DNA damage and genotoxicity. Copyright © 2006 John Wiley & Sons, Ltd.
Lipid peroxidation in liver tissue of ovariectomized and pinealectomized rats: effect of estradiol and progesterone supplementation
Authors: Oztekin Esma , Tiftik Ali Muhtar , Baltaci Abdulkerim Kasim , Mogulkoc Rasim
Published: January 2006

The present study aimed to determine the effect of estradiol‐progesterone supplementation and pinealectomy on lipid peroxidation of liver tissue in ovariectomized rats.

The study was carried out on 36 adult Sprague‐Dawley female rats, which weighed 200–250 g. The rats were divided into 6 groups: Group 1: Sham Ovariectomy (Sham‐Ovx), Group 2: Ovariectomy (Ovx), Group 3: Ovx + Estradiol‐Progesterone supplementation (Ovx + H), Group 4: Sham Pinealectomy and Ovx (Sham Pnx ‐Ovx), Group 5: Ovx ‐Pnx, Group 6: Ovx ‐Pnx + H. Malondialdehyde (MDA), reduced form of glutathione (GSH) and glutathione peroxidase (GSH‐Px) levels were determined in liver tissue of rats.

The highest MDA levels and the lowest GSH‐Px levels were determined in the ovariectomized‐pinealectomized group, whereas the lowest MDA was in the Sham‐Ovx group, and the highest GSH‐Px levels were found in the Sham‐Ovx and Ovx + Hormone supplemented group. Furthermore, the highest GSH levels were in group 1 and lowest levels were in group 5.

The findings of this study demonstrate that ovariectomy led to lipid peroxidation in liver tissues of rats. Pinealectomy in addition to ovariectomy, increases lipid peroxidation, but, estradiol and progesterone supplementations to the ovariectomized‐pinealectomized rats protect against lipid peroxidation to a significant extent. Copyright © 2006 John Wiley & Sons, Ltd.
Unexpected Oxidation of a Depsipeptide Substrate Analogue in Crystalline Isopenicillin N Synthase
Authors: Daruzzaman Adam , Clifton Ian J. , Adlington Robert M. , Baldwin Jack E. , Rutledge Peter J.
Published: January 2006

Isopenicillin N synthase (IPNS) is a non‐heme iron(ii)‐dependent oxidase that is central to penicillin biosynthesis. Herein, we report mechanistic studies of the IPNS reaction in the crystalline state, using the substrate analogue δ‐(L‐α‐aminoadipoyl)‐(3R)‐methyl‐L‐cysteine D‐α‐hydroxyisovaleryl ester (AmCOV) to probe the early stages of the catalytic cycle. The X‐ray crystal structure of the anaerobic IPNS:FeII:AmCOV complex was solved to 1.40 Å resolution, and it reveals several subtle differences in the active site relative to the complex of the enzyme with its natural substrate. The crystalline IPNS:FeII:AmCOV complex was then exposed to oxygen gas at high pressure; this brought about reaction to give what appears to be a hydroxymethyl/ene‐thiol product. A mechanism for this reaction is proposed. These results offer further insight into the delicate interplay of steric and electronic effects in the IPNS active site and the mechanistic intricacies of this remarkable enzyme.
C‐Terminal Modifications of a Protein by UAG‐Encoded Incorporation of Puromycin during in vitro Protein Synthesis in the Absence of Release Factor 1
Authors: Agafonov Dmitry E. , Rabe Kersten S. , Grote Michael , Voertler C. Stefan , Sprinzl Mathias
Published: January 2006

Deactivation of release factor 1 by polyclonal antibodies in an in vitro translation system, which was used to express the esterase gene, led to the reversible elimination of naturally occurring termination. This technique allowed the antibiotic puromycin to be used as an acceptor substrate for the peptidyl residue in the peptidyl‐transferase reaction. This resulted in more than 80 % yield of protein with C‐terminally incorporated puromycin. pCpPuromycin that was either conjugated with the Cy3 fluorophor or biotin by N4 alkylation of cytosine, also acted as an acceptor substrate for the peptidyl‐transferase reaction and was incorporated into the protein C terminus. The resulting conjugates possessed Cy3‐specific fluorescence and affinity to streptavidin‐coated surfaces, respectively. This left the enzymatic activity of the reporter protein unaffected. It was also shown that extension of puromycin on its 5′‐hydroxyl end by up to ten deoxyoligonucleotides also allowed conjugation with the C terminus of in vitro translated protein when RF1‐dependent termination was suppressed. However, the conjugation yield decreased upon addition of more than six nucleotides.
Cover Picture: Design, Synthesis, and Preliminary Biological Evaluation of a DNA Methyltransferase‐Directed Alkylating Agent (ChemBioChem 2/2006)
Authors: Weller Rachel L. , Rajski Scott R.
Published: January 2006

The cover picture shows the envisioned pathways for how the DNA methyltransferase, M.HhaI, can use either S‐adenosyl‐L‐methionine (SAM; left) or an unnatural aziridinium cofactor (right). The aziridinium ion is proposed to arise in situ from the appropriately functionalized 5′ N‐mustard precursor. By virtue of its structural similarity to SAM, this highly reactive alkylating agent is bound by a methyltransferase (MTase) and delivered to a specific DNA nucleobase (extrahelical cytosine colored by atom). The stick structures (center) depict the envisioned approach of SAM vs. the proposed aziridinium intermediate to an M.HhaI DNA substrate within the M.HhaI active site. We thank Peter Anderson for assistance in generating the modeling images. The DNA substrate and cofactor structures were adapted from coordinates for the ternary structure of M.HhaI in complex with duplex DNA and S‐adenosyl‐homocysteine (RCSB PDB). Detailed information regarding this new synthetic DNA alkylating agent and MTase‐driven DNA alkylation is reported by S. Rajski and R. Weller on p. 243 ff.
Prediction of Dextrose Nucleation Kinetics by the Growth Rate of Crystallites
Authors: Parisi M. , Rivallin M. , Chianese A.
Published: January 2006

An investigation on the dextrose nucleation carried out in the presence of seeds is reported. Induction time and nucleation point were measured in seeded solutions by eye and by using a nephelometer. The nucleation point was interpreted as the instant when crystallites, generated by seeds, grow up to crystals of detectable size. By applying the approach proposed by Kashchiev [1], the induction time values obtained were satisfactorily predicted when a birth and spread growth rate model was assumed. Moreover, by extending the same approach to the prediction of the nucleation point, obtained by linear cooling, a nucleation curve in good agreement with the experimental points was determined.
Effect of Fluid Dynamics on Particle Size Distribution in Particulate Processes
Authors: Marchisio D. L. , Soos M. , Sefcik J. , Morbidelli M. , Barresi A. A. , Baldi G.
Published: January 2006

The final product quality of crystallization and precipitation processes is often determined by the interplay between mixing and relevant phenomena such as, nucleation, molecular growth, aggregation and breakage. In this work the attention is focused on the aggregation and breakage processes and on the level of details needed to accurately describe them. Different modeling approaches are tested and compared for two different shear devices: a Taylor‐Couette cell and a stirred tank. Results show that when aggregation and breakage processes are much slower than mixing a simplified homogeneous model can be used whereas when aggregation and breakage occur on a time‐scale comparable with that of mixing then a detailed approach based on computational fluid dynamics (CFD) is needed. The very common lumped model, used to derive kinetic expressions for aggregation and breakage rates, can eventually lead to serious errors.
Pharmaceutical Compound Crystallization: Growth Mechanism of Needle‐Like Crystals
Authors: Taulelle P. , Astier J. P. , Hoff C. , Pèpe G. , Veesler S.
Published: January 2006

In this paper, crystallization of needle‐like crystals is investigated using both experimental and numerical approaches. The structure, morphology, habit, and growth behavior of Irbesatan phase A grown from 2‐propanol solution are studied. In this case, molecular modeling shows an unusually high anisotropy of the internal crystal structure, leading to the prediction of an acicular habit which is in good agreement with the experimental habit. Irbesartan phase A is an example of crystals for which the properties are governed by internal properties rather than external properties. The influence of the growth conditions is investigated by in situ and ex situ monitoring, namely optical microscopy and AFM. These investigations show that crystals are agglomerated with the same crystallographic orientation as the individual constituent; this was explained by regular over‐ and intergrowths as in the case of twinning.
Influence of Crystallization Conditions on Rheology and Microstructure of Dense Suspensions of Crystals of Eflucimibe
Authors: Teychene S. , Autret J. M. , Biscans B.
Published: January 2006

The crystallization process of eflucimibe, a new ACAT inhibitor, was carried out in a mixture of two solvents, ethanol and n‐heptane, by cooling. During the process, as the volume fraction of crystals was raised, the suspension went towards a very structured gel‐like network. This phenomenon acts as a brake to the extrapolation of the process. Experiments were carried out in a glass double‐jacketed 750 mL reactor in a LABMAX controlled system. At the end of the crystallization, rheological flow characteristics at constant ambient temperature were determined. The samples behave like a plastic fluid. The evolution of the elastic and viscous moduli as a function of the applied strain for a given oscillation frequency was measured. The results showed that the variation of the elastic modulus with particle concentration follows a power law. It was shown that for particle concentration higher than 2 % (volume fraction) needle‐like growing crystals form a network in which solvent is trapped.
Thermodynamic Predictions of Physical Properties – Prediction of Solid Solutions in Molecular Solutes Exhibiting Polymorphism
Authors: Coquerel G.
Published: January 2006

Polymorphism is a widespread phenomenon among molecular components, and usually the lattice energies of the different varieties are rather close. It is shown that solid solutions, by means of insertion (e.g., due to solvent) or by means of substitution (e.g., due to derivatives of the components), can substantially modify the energy landscape between polymorphs. Fluctuations in the transition temperatures lead to the prediction of the existence of solid solutions.
Polymorphism of Active Pharmaceutical Ingredients
Authors: Karpinski P. H.
Published: January 2006

Different polymorphs of the same active pharmaceutical ingredient (API) display distinct physical properties, such as melting point, solubility, dissolution rate, hygroscopicity, or stability. The ability to successfully produce and reproduce specific stable polymorphs is intricately correlated with the efficiency and speed of drug development, the robustness of manufacturing process, and – ultimately – the stability and quality of APIs. This paper focuses on eight case study examples of interesting polymorphic transformations observed in the course of the regular API development process. Through extensive physicochemical characterization, using multiple analytical techniques, the phenomena observed could be elucidated and proper measures recommended to reduce the risk of unexpected polymorphic transformations.
Prins‐Type Synthesis and SAR Study of Cytotoxic Alkyl Chloro Dihydropyrans
Authors: Miranda Pedro O. , Padrón José M. , Padrón Juan I. , Villar Jesús , Martín Víctor S.
Published: January 2006

A series of functionalized tetrahydropyran and dihydropyran derivatives was synthesized by means of a Prins‐type cyclization between unsaturated alcohols and several aldehydes. An unprecedented dimer bearing two 4‐chloro‐5,6‐dihydro‐2H‐pyran scaffolds was obtained in high yield. A panel of three representative human solid tumor cells from diverse origin was used to assess the cytotoxicity of the compounds. Overall, the results show the relevance of the chlorovinyl group in the biological activity, and 2‐alkyl‐4‐chloro‐5,6‐dihydro‐2H‐pyrans represent interesting leads for further chemical modifications and biological studies.
Glucokinase mutations in young children with hyperglycemia
Authors: Codner Ethel , Deng Liyong , Pérez‐Bravo Francisco , Román Rossana , Lanzano Patricia , Cassorla Fernando , Chung Wendy K.
Published: January 2006

Background

The etiology of mild hyperglycemia without ketoacidosis in young children is often unknown. Maturity onset diabetes of youth (MODY) is a form of diabetes mellitus (DM) characterized by fasting hyperglycemia without evidence for autoimmune destruction of β‐cells.

Methods

We genetically analyzed four families of young children with fasting hyperglycemia with family histories of diabetes for mutations in the genes for hepatocyte nuclear factor 4 alpha (HNF4α), glucokinase (GCK), and hepatocyte nuclear factor 1 alpha (HNF1α), the genes responsible for MODY1, MODY2, and MODY3, respectively.

Results

We identified mutations in GCK (Gly258Asp, Arg303Trp, and Arg191Gln) in three of the four families. Molecular genetic characterization in these children clarified the etiology and prognosis of the hyperglycemia and allowed discontinuation of insulin therapy in one family.

Conclusions

We conclude that molecular evaluation for MODY in children with mild fasting hyperglycemia without ketosis with family histories of diabetes can provide important prognostic information to guide therapy and exclude preclinical type 1 diabetes mellitus. Copyright © 2006 John Wiley & Sons, Ltd.
Kinetic and Theoretical Studies of a Facile, One‐Pot Preparation of a Spirocyclohexylindolinone Derivative
Authors: Sánta‐Csutor Andrea , Mucsi Zoltán , Finta Zoltán , Gönczi Csaba , Halász Judit , Csikós Éva , Hermecz István
Published: January 2006

Spirocyclohexylindolinone is used as a moiety in drug substances. A number of synthetic methods have been suggested to introduce the cyclohexyl ring into the C(3) position of N‐protected indolinones, which complicates their preparation. A previously developed, consecutive, one‐pot, multicomponent method is studied from a mechanistic aspect. We set out to clarify the details of this mechanism and the role of the acryl ester as a reagent and a protecting group in the same flask, by using theoretical and analytical methods, in order to optimise the preparative conditions. A mechanistic energy profile of the reaction is computed at the DFT level of theory. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
How does spatial extent of fMRI datasets affect independent component analysis decomposition?
Authors: Aragri Adriana , Scarabino Tommaso , Seifritz Erich , Comani Silvia , Cirillo Sossio , Tedeschi Gioacchino , Esposito Fabrizio , Di Salle Francesco
Published: January 2006

Spatial independent component analysis (sICA) of functional magnetic resonance imaging (fMRI) time series can generate meaningful activation maps and associated descriptive signals, which are useful to evaluate datasets of the entire brain or selected portions of it. Besides computational implications, variations in the input dataset combined with the multivariate nature of ICA may lead to different spatial or temporal readouts of brain activation phenomena. By reducing and increasing a volume of interest (VOI), we applied sICA to different datasets from real activation experiments with multislice acquisition and single or multiple sensory‐motor task‐induced blood oxygenation level‐dependent (BOLD) signal sources with different spatial and temporal structure. Using receiver operating characteristics (ROC) methodology for accuracy evaluation and multiple regression analysis as benchmark, we compared sICA decompositions of reduced and increased VOI fMRI time‐series containing auditory, motor and hemifield visual activation occurring separately or simultaneously in time. Both approaches yielded valid results; however, the results of the increased VOI approach were spatially more accurate compared to the results of the decreased VOI approach. This is consistent with the capability of sICA to take advantage of extended samples of statistical observations and suggests that sICA is more powerful with extended rather than reduced VOI datasets to delineate brain activity. Hum Brain Mapp, 2005. © 2006 Wiley‐Liss, Inc.
Simple and efficient synthesis of new chiral N,N′‐sulfonyl bis‐oxazolidin‐2‐ones
Authors: Berredjem Malika , Regainia Zine , Dewynter Georges , Montero Jean Louis , Aouf Nour‐Eddine
Published: January 2006

A series of new chiral N,N′‐sulfonyl bis‐oxazolidin‐2‐ones were synthesized starting from 2‐aminoalcohols, sulfuryl chloride, and diethyl carbonate. This method utilizes natural amino acids as a source of chirality for the preparation of oxazolidinones. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:61–65, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20183
The reactions of hexachlorocyclotriphosphazatriene with pyridine derivatives
Authors: Begeç Saliha , Alataş Sümeyya , Kılıç Adem
Published: January 2006

The reactions of hexachlorocyclotripho‐sphazatriene, N3P3Cl6 (1), with 2‐hydroxypyridine (2), 2‐aminopyridine (3), 2‐amino‐6‐methyl‐pyridine (4), and 2‐hydroxy‐4‐methylquinoline (5) have been investigated. The products were identified by elemental analyses, IR, 1H, 13C, and 31P NMR spectroscopy. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:57–60, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20185
Hepatitis A Virus: From Discovery to Vaccines
Authors: Martin Annette , Lemon Stanley M.
Published: January 2006

Hepatitis A virus (HAV), the causative agent of type A viral hepatitis, is an ancient human virus that was first identified almost 35 years ago. It has several characteristics that make it unique among the

Picornaviridae

, particularly in terms of its mechanisms of polyprotein processing and virion morphogenesis, and which likely contribute to its pathobiology. Although efficacious vaccines containing formalin-inactivated virus produced in cell culture have been licensed in multiple countries, their use has been limited by cost considerations. Changes in public health sanitation and generally increasing standards of living are leading to a decreasing incidence of acute hepatitis A worldwide, with the result that the prevalence of preexisting immunity among adults is declining in many regions. These changes in the epidemiology of HAV may paradoxically enhance the disease burden, as greater numbers of individuals become infected at older ages when disease is more likely to be clinically evident, thus providing greater incentives for vaccine utilization.
Hepatitis C — Identifying Patients with Progressive Liver Injury
Authors: Feld Jordan J. , Liang Jake T.
Published: January 2006

Hepatitis C follows a variable course with some patients developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma, while others have minimal or no significant liver disease after decades of infection. Studies have identified both host and viral factors associated with disease progression. The importance of general factors such as age at infection, gender, immune status and alcohol consumption has long been recognized; however recently, polymorphisms in a wide array of genes have also been shown to be associated with progressive fibrosis. How specific viral proteins may contribute to disease progression has also been studied. This review highlights what is currently known about the factors associated with progressive liver injury in patients with hepatitis C. A greater understanding of the determinants of disease progression will hopefully lead to improved utilization of existing treatments and ultimately may aid in identification of new therapeutic targets.
Wear and fatigue behavior of nano‐structured dental resin composites
Authors: Turssi Cecilia P. , Ferracane Jack L. , Ferracane Lucas L.
Published: January 2006

Theoretically, nano‐structured dental resin composites are purported to have increased wear and fatigue resistance compared with microfill composites and may favor the achievement of restoratives with better long‐term performance. This study sought to assess the behavior of nano‐structured composites resulting from either abrasion and fatigue loading. Ten specimens (12 × 5 × 2.5 mm) were prepared from each of five composites: Ceram‐X mono, Filtek Supreme, Grandio, Premise, and Heliomolar (serving as the microfill control). A surface profile was recorded using a three‐dimensional profiling system, and the specimens were subjected to 105 cycles of three‐body abrasion in the new OHSU oral wear simulator. A second profile was generated and the before and after profiles were fit and analyzed. The volume loss and maximum depth of the wear facet on each specimen were calculated. Another 30 specimens (25 × 2 × 2 mm) were tested for flexural fatigue limit (FFL) in four‐point bending via the staircase method. The test was carried out until 104 cycles were completed or until fracturing the specimen. One‐way ANOVA and Tukey's test demonstrated greater volumetric loss for Grandio and Ceram‐X than that observed for the remaining composites. Kruskal‐Wallis and the least significant difference test ascertained that Heliomolar, Grandio, and Supreme showed significantly higher FFL than Ceram‐X and Premise. In terms of wear and fatigue resistance, nano‐structured composites may perform either similarly or comparatively worse than a microfilled composite. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Effect of irradiation mode on polymerization of dental composite resins
Authors: Kwon Yong Hoon , Kang Soon‐Il , Hur Bock , Park Jeong Kil , Kim Hyung‐Il
Published: January 2006

Many researchers have sought to reduce the polymerization shrinkage in composite resins. Controlling the irradiation light seems practical because the polymerization process initiates with light by activating the photoinitiators. The present study evaluated the effect of irradiation mode on microhardness and polymerization shrinkage of composite resins. Three different irradiation modes, STD, EXP, and MED, were taken under 40‐s exposure condition. As results, the irradiation mode significantly affected the microhardness difference. However, in all products, the microhardness difference between the STD and MED modes was less than 10%. In all irradiation modes, microhardness was linearly correlated with the filler content of the tested specimens. The effect of mode on the difference of the polymerization shrinkage was not uniform even though the shrinkage values decreased following the order of the STD > EXP > MED mode. An inverse correlation was found between filler content and polymerization shrinkage in all irradiation modes and specimen thicknesses. In spite of the statistical significance of the irradiation modes on the difference of the measured values, their numeric difference was not great. Especially, compared with the STD and MED mode, the exponentially increasing light (EXP mode) produced no noticeable difference except for a delayed shrinkage process. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Role of wnts in prostate cancer bone metastases
Authors: Hall Christopher L. , Kang Sona , MacDougald Ormond A. , Keller Evan T.
Published: January 2006

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor‐induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine‐rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP‐produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf‐1 (DKK‐1). It appears that DKK‐1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK‐1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK‐1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK‐1 activity fits a model of CaP‐induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone‐related protein (PTHRP) and DKK‐1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK‐1); and an osteoblastic phase, in which tumor growth‐associated hypoxia results in production of vascular endothelial growth factor and endothelin‐1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases. J. Cell. Biochem. 97: 661–672, 2006. © 2005 Wiley‐Liss, Inc.
Chromatin remodeling in DNA replication
Authors: Falbo Karina B. , Shen Xuetong
Published: January 2006

Chromatin remodeling complexes have evolved to solve a very basic problem for eukaryotic cells accomodation of the genome to fit the dimensions of the nucleus without loss of access to the DNA molecule. In the nucleus, DNA is wrapped around histones to form nucleosomes and other higher order compact chromatin structures. Chromatin remodeling complexes enable highly regulated access to DNA sequences in the context of chromatin, and it is well known that these complexes are involved in regulation of transcription. However, gene expression is not the only process that occurs in the nucleus. DNA has to be replicated, recombined, and repaired. In this regard, it is notable that the recent discoveries have linked ATP‐dependent remodeling complexes to DNA damage repair. These results have raised challenging questions about the possible versatility of chromatin remodeling complexes in other nuclear activities, particularly in DNA replication, since a number of recent studies have suggested a connection between this essential cellular process and chromatin remodeling. However, the chromatin remodeling events regulating DNA replication have not been extensively investigated. The aim of this prospect is to summarize recent studies that implicate chromatin remodeling in DNA replication and to address potential roles of chromatin remodeling at various stages of eukaryotic DNA replication. J. Cell. Biochem. 97: 684–689, 2006. © 2005 Wiley‐Liss, Inc.
Rad9, an evolutionarily conserved gene with multiple functions for preserving genomic Integrity
Authors: Lieberman Howard B.
Published: January 2006

The Rad9 gene is evolutionarily conserved. Analysis of the gene from yeast, mouse and human reveal roles in multiple, fundamental biological processes primarily but not exclusively important for regulating genomic integrity. The encoded mammalian proteins participate in promoting resistance to DNA damage, cell cycle checkpoint control, DNA repair, and apoptosis. Other functions include a role in embryogenesis, the transactivation of multiple target genes, co‐repression of androgen‐induced transcription activity of the androgen receptor, a 3′‐5′ exonuclease activity, and the regulation of ribonucleotide synthesis. Analyses of the functions of Rad9, and in particular its role in regulating and coordinating numerous fundamental biological activities, should not only provide information about the molecular mechanisms of several individual cellular processes, but might also lend insight into the more global control and coordination of what at least superficially present as independent pathways. J. Cell. Biochem. 97: 690–697, 2006. © 2005 Wiley‐Liss, Inc.
A computational study of the lowest singlet and triplet states of neutral and dianionic 1,2‐substituted icosahedral and octahedral o‐carboranes
Authors: Oliva Josep M. , Serrano–Andrés Luis
Published: January 2006

This work introduces a calibrated B3LYP/6‐31G(d) study on the electronic structure of singlet and triplet neutral species of 1,2‐substituted icosahedral 1,2‐R2‐1,2‐C2B10H10 and octahedral 1,2‐R2‐1,2‐C2B4H4 molecules with R = {H, OH, SH, NH2, PH2, CH3, SiH3} and their respective dianions formed by proton removal on each R group. A variety of small adiabatic singlet‐triplet gaps ΔEST are obtained from these systems ranging from 2.93 eV (R = NH2) ≤ ΔEST ≤ 3.98 eV (R = SiH3) for the icosahedral neutrals and 1.56 eV (R = NH2) ≤ ΔEST ≤ 4.13 eV (R = SiH3) for the octahedral neutrals, these gaps being globally smaller for the dianionic systems, ranging from 0.94 eV (R− = CH2−) ≤ ΔEST ≤ 2.01 (R− = e−) for the icosahedral dianions 1,2‐(R−)2‐C2B10H10 and 0.91 (R− = CH2−) ≤ ΔEST ≤ 2.41 (R = SiH2−) for the octahedral dianions 1,2‐(R−)2C2B4H4 (R− = e−, O−, S−, NH−, PH−, CH2−, PH2−). The different gaps lie within or in the neighborhood of the visible region of the electromagetic spectrum. The optimized geometries for the molecular cage remain similar in substituted icosahedral and octahedral singlet states, while a rich variety of different structures can be found for the optimized triplet states. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 524–535, 2006