HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis

OBJECTIVE: To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial. METHODS: Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression. RESULTS: At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope. CONCLUSION: HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.     

Reduction of neuropeptide Y binding sites in the rat hippocampus after electroconvulsive stimulations

The role of vasoactive intestinal peptide (VIP) was investigated when mucosal stroking and 5-hydroxytryptamine (5-HT) were used to activate neural reflexes that stimulate chloride secretion in the guinea pig colon. Muscle-stripped segments of colon containing intact submucosal ganglia without myenteric ganglia were set up in modified flux chambers in order to record short-circuit current (Isc). Mucosal stroking with a brush for 1 s or a pulse of 5-HT (injection of 15 microliters of 100 microM 5-HT into 1.5 ml of mucosal solution) caused an increase in Isc that was reduced by the VIP antagonist, neurotensin6-11-VIP7-28, in a concentration-dependent manner. The Isc responses to mucosal stroking and a 5-HT pulse were reduced by 53% and 58%, respectively, by 2 microM neurotensin6-11-VIP7-28. The residual Isc response in the presence of neurotensin6-11-VIP7-28 was abolished by atropine. Blockade of 5-HT1P receptors on submucosal afferent neurons decreased Isc responses to stroking or a 5-HT pulse. The residual Isc response after 5-HT1P receptors were blocked was reduced by only 11-14% by neurotensin6-11-VIP7-28. In the presence of blockade of both 5-HT1P and VIP receptors, atropine abolished the Isc response to both stimuli. The observations suggest that the neural circuitry activated by stroking includes at least two independent pathways. One pathway contains VIP neurons which receive inputs directly or indirectly from 5-HT1P receptor-containing afferents. A second pathway involves muscarinic cholinergic transmission that is independent of 5-HT1P and VIP receptor activation.     

Experimental evaluation of fishway modifications on the passage behaviour of adult Chinook salmon and steelhead at Lower Granite Dam,Snake River,USA

Previous studies of Pacific salmonid passage over Snake River dams indicated slowed passage at transition pools, the transition area between the fishway entrance and the fish ladder. In 2001 and 2002, we conducted an experiment to determine if modified weirs affected adult salmon and steelhead passage times and route selection through the Lower Granite Dam transition pool. Fish attraction flows through the lower ladder weirs were experimentally increased using removable panels. During the experiment we monitored radio‐tagged adult Chinook salmon and steelhead to determine passage routes and times through the transition pool. The weir treatment increased the number of spring–summer Chinook salmon passing straight through the transition pool compared to those exiting the transition pool to the collection channel or tailrace. Mean passage times through the transition pool differed among routes and were significantly lower during treatment periods for the exit‐to‐collection channel route in spring‐summer Chinook salmon, but not for other routes. Passage times among routes differed in steelhead, but there was no evidence of treatment effects on route use or passage time. Fall Chinook exhibited similar trends in route use and passage time to spring–summer Chinook, but differences were not significant, perhaps because of relatively small sample size. Total dam passage times did not differ by treatment or route for any run. Fish depth during passage of the transition pool suggested that most fish passed through submerged orifices and supported the hypothesis that increased water velocity through these orifices caused the increase in straight‐through passage in spring–summer Chinook. Collectively, the results suggested the weir modifications provided improvement to passage through the transition pool for spring–summer Chinook and no evidence of negative effects on other runs. The results from this study were used to develop new design criteria and modifications of the Lower Granite Dam fishway. Copyright © 2006 John Wiley & Sons, Ltd.     

Modelling of fatigue damage progression and life of CFRP laminates

A progressive fatigue damage model has been developed for predicting damage accumulation and life of carbon fibre‐reinforced plastics (CFRP) laminates with arbitrary geometry and stacking sequence subjected to constant amplitude cyclic loading. The model comprises the components of stress analysis, fatigue failure analysis and fatigue material property degradation. Stress analysis of the composite laminate was performed by creating a three‐dimensional finite element model in the ANSYS FE code. Fatigue failure analysis was performed by using a set of Hashin‐type failure criteria and the Ye‐delamination criterion. Two types of material property degradations on the basis of element stiffness and strength were applied: a sudden degradation because of sudden failure detected by the fatigue failure criteria and a gradual degradation because of the nature of cyclic loading, which is driven by the increased number of cycles. The gradual degradation of the composite material was modelled by using functions relating the residual stiffness and residual strength of the laminate to the number of cycles. All model components have been programmed in the ANSYS FE code in order to create a user‐friendly macro‐routine. The model has been applied in two different quasi‐isotropic CFRP laminates subjected to tension–compression (T–C) fatigue and the predictions of fatigue life and damage accumulation as a function of the number of cycles were compared with experimental data available in the literature. A very good agreement was obtained.     

Distinct stability of recombinant L and H subunits of human ferritin: calorimetric and ANS binding studies

Thermodynamic and pH stability of recombinant human L- and H-ferritins wereprobed by differential scanning calorimetry and 8-anilino-1-naphthalenesulfonate (ANS) binding in the pH range 2-7. At pH 2.0-2.8 theywere dissociated into subunit monomers and in this pH interval theH-subunit displayed a single calorimetrically-revealed domain withproperties of a molten globule-like state: low enthalpy (6.3-8.0 J/g or169-172 kJ/mol) and Tm of thermal unfolding (approximately 50 degrees C), awide transition range (approximately 20 degrees C) and high ANS binding. Incontrast, at pH 2 the L-ferritin subunit showed two calorimetric domainswith Tm of 35 and 40 degrees C with similar unfolding enthalpies and withmoderate extent of interactions, as indicated by the ratio of calorimetricenthalpy (293.9 kJ/mol) and van't Hoff enthalpy (174.2 kJ/mol) for thethermal transition. A pH increase from 2.0 to 2.8 determined the couplingof the two domains into a single cooperative folding unit and drasticincrease of the transition temperature (from 37 to 80 degrees C). Thecontacts between the two domains in the L-subunit appeared to contribute toabout 30% of the total stabilization free energy. The unfolding enthalpies,heat capacity changes and pronounced ANS binding of the L-subunit at pH2.0- 2.8 indicated that part of the structure lacked 'meltable' tertiaryinteractions. The results indicate that H- and L-subunits are stabilized bylargely different intra-chain interactions with a critical contribution toL-subunit stability of embedded salt bridge(s) absent in the H-subunit.     

With regard to "The role of air plethysmography in monitoring results of venous surgery"

By homology to the mgt gene (encoding a macrolide glycosyltransferase) from Streptomyces lividans, a 3.3-kb DNA fragment from the oleandomycin producer, Streptomyces antibioticus, was cloned and sequenced. Analysis of the sequence revealed the presence of the 3' end of a gene (ORF1) and two complete ORFs (ORF2 and oleD), all of them translationally coupled. The deduced product of the sequenced region of ORF1 contained the typical signature of integral membrane proteins responsible for the translocation of substrates across the membrane. The ORF2 product did not show significant similarity with proteins in databases, but contains an N-terminus leader peptide region characteristic of secreted proteins, and a lipid attachment site motif characteristic of membrane lipoproteins synthesized with a precursor signal peptide. The oleD product showed clear similarity with several UDP-glucuronosyl- and UDP-glycosyl-transferases from different origins and particularly with the mgt gene from S. lividans, and might encode a glycosyltransferase activity capable of inactivating macrolides. It is proposed that these three genes could participate in the intracellular glycosylation of oleandomycin and its secretion during antibiotic production.     

Integrated radiation hybrid and yeast artificial chromosome map of chromosome 9p

OBJECTIVES: To determine concentrations of chondroitin sulphate (CS) and keratan sulphate (KS) epitopes, glycosaminoglycans (GAGs) and hyaluronan (HA) in knee synovial fluid (SF) from normal subjects and patients with osteoarthritis (OA) or rheumatoid arthritis (RA), to test whether these variables may be used as markers of the OA process. METHODS: OA was subdivided into large joint OA (LJOA), nodal generalised OA (NGOA), and OA with calcium pyrophosphate crystal deposition (CPA). Clinical assessment of inflammation (0-6) was undertaken on OA and RA knees. Knee SF was examined by enzyme linked immunosorbent assay for: CS epitopes, using monoclonal antibodies 3-B-3 and 7-D-4; KS epitope using monoclonal antibody 5-D-4; and HA, using biotinylated HA binding region of cartilage proteoglycan. Total sulphated GAGs were measured by dye binding with 1:9 dimethylmethylene blue. RESULTS: Increased SF 3-B-3 concentrations and 3-B-3/GAG ratio were found in OA, compared with RA or normal knees, with higher 3-B-3 and 3-B-3/GAG in LJOA and NGOA than in CPA. SF 7-D-4 and 7-D-4/GAG were reduced in RA, compared with normal and OA; SF 5-D-4 was reduced in OA compared with normal. GAG and HA concentrations were decreased in both OA and RA. No correlations with radiographic scores were observed, but SF 7-D-4 was lower in 'inflamed' compared with 'non-inflamed' RA and OA knees. In patients with bilateral samples there were strong correlations between right and left knees for all SF variables. CONCLUSIONS: Changed concentrations of SF CS and KS can be detected in OA with a profile that differs from that seen in RA. Clinical subgrouping and local joint inflammation may influence these measures, supporting different pathogenesis within OA subgroups and requirement for careful patient characterisation in SF studies.     

Carcinogenic polycyclic aromatic hydrocarbons increase intracellular Ca2+ and cell proliferation in primary human mammary epithelial cells

A method was developed to determine in eggs 2 components [4,6-dimethyl-2-hydroxypyrimidine and 1,3-bis(4-nitrophenyl)urea] of the anticoccidial drug nicarbazin, used to treat poultry. Samples were extracted with acetonitrile, and the extracts were washed with hexane and evaporated to dryness before analysis by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization. By switching from positive to negative ion monitoring and using gradient elution, both components were measured within one run. The limit of quantitation of the assay was 10 ng/g for each component. The results of a preliminary feeding trial in which chickens were fed contamination levels of the drug are also reported.     

Adult psychological functioning of individuals born with craniofacial anomalies

This study represents an initial investigation into the adult psychological functioning of individuals born with craniofacial disfigurement. A total of 24 men and women born with a craniofacial anomaly completed paper and pencil measures of body image dissatisfaction, self-esteem, quality of life, and experiences of discrimination. An age- and gender-matched control group of 24 non-facially disfigured adults also completed the measures. As expected, craniofacially disfigured adults reported greater dissatisfaction with their facial appearance than did the control group. Craniofacially disfigured adults also reported significantly lower levels of self-esteem and quality of life. Dissatisfaction with facial appearance, self-esteem, and quality of life were related to self-ratings of physical attractiveness. More than one-third of craniofacially disfigured adults (38 percent) reported experiences of discrimination in employment or social settings. Among disfigured adults, psychological functioning was not related to number of surgeries, although the degree of residual facial deformity was related to increased dissatisfaction with facial appearance and greater experiences of discrimination. Results suggest that adults who were born with craniofacial disfigurement, as compared with non-facially disfigured adults, experience greater dissatisfaction with facial appearance and lower self-esteem and quality of life; however, these experiences do not seem to be universal.     

Combination antiretroviral therapy and recent declines in AIDS incidence and mortality

The reasons for recent declines in AIDS incidence and mortality may include advances in treatment, but these may be confounded by earlier declines in the incidence of human immunodeficiency virus (HIV) infection. To determine whether the declines in AIDS and mortality may, in part, stem from wider use of combination antiretroviral therapy, 622 HIV-positive men with well-characterized dates of seroconversion were followed. In this group, combination therapy came into widespread use in only 1996. In a Cox proportional hazards model, the 1996 calendar period was significantly associated with slower progression to AIDS (relative hazard [RH]=0. 19, 95% confidence interval [CI], 0.05-0.69, P=.01) and death (RH=0. 45, 95% CI, 0.21-0.95, P=.04). Declines in incidence of HIV infection, changes in HIV virulence, and end-point underreporting cannot fully explain the decline in AIDS and death in 1996. The introduction of combination antiretroviral therapy as the standard of care may already have had measurable effects.