Secular trends of hip fractures in Québec, Canada.

UNLABELLED: This study examined the secular trends of hip fracture incidence among individuals 50 years and older in Québec between 1993 and 2004. Age-standardized rates decreased at both the provincial and regional levels. The largest relative decrease was observed among younger females, and rates declined more slowly in the elderly. INTRODUCTION: The population of the province of Québec is among the oldest in North America. Before the trend rupture reported in the late 1990s in several countries, hip fracture (HF) incidence rates did not show a secular trend (between 1981 and 1992). This study examined the secular trends of HF incidence at the provincial level and in two of the most important urban areas of the province, Montréal and Québec City, between 1993 and 2004. METHODS: All hospitalisations of individuals 50 years and older living in the province of Québec between 1993 and 2004 with a main diagnosis of HF were included. Standardized rates of HF incidence were calculated for females and males, 50-74 years and 75 years and older. RESULTS: The Québec City area showed a strong decreasing trend in HF rates for younger females, but the other groups did not show an obvious trend. Although our models did not support the existence of significant differences in trends between both areas, the rates of HF of younger males and, to a lesser extent, of older women in the Montréal area were significantly higher than in the Québec City area. CONCLUSIONS: Differences observed in hip fracture rates as well as in secular trends between age groups and gender emphasise the need for decision makers to rely on results based on age-specific and sex-specific analyses.

Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

OBJECTIVES: To assess the comparative clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis (AS). DATA SOURCES: Major electronic databases were searched up to November 2005. Unpublished evidence such as conference abstracts, reviews of published economic evaluations, and company submissions to the National Institute for Health and Clinical Excellence (NICE) were also reviewed. REVIEW METHODS: The assessment was conducted according to accepted procedures for conducting and reporting systematic reviews and economic evaluations. Full economic evaluations that compared two or more options for treatment and considered both costs and consequences were eligible for inclusion in the economic literature review. RESULTS: Nine placebo controlled randomised controlled trials (RCTs) were included in the review of clinical effects. These included two studies of adalimumab, five of etanercept and two of infliximab in comparison with placebo (along with conventional management). No RCTs directly comparing anti-tumour necrosis factor-alpha (TNF-alpha) agents were identified. Meta-analyses were conducted for data on Assessment in Ankylosing Spondylitis (ASAS) (20, 50 and 70% improvement), mean change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and mean change in Bath Ankylosing Spondylitis Functional Index (BASFI) at 12 weeks following initiation of anti-TNF-alpha therapy or placebo for all three drugs. Meta-analyses were also conducted at 24 weeks for etanercept and infliximab. Each meta-analysis of anti-TNF-alpha therapy demonstrated statistically significant advantages over placebo, although there was no significant difference between individual anti-TNF-alpha agents. At 12 weeks, ASAS 50% responses were 3.6-fold more likely with anti-TNF-alpha treatment than placebo. Compared with baseline, BASDAI scores were reduced by close to 2 points at 12 weeks. Functional scores (BASFI) were reduced at 12 weeks. Six full economic evaluations (two peer-reviewed published papers, four abstracts) were included in the review. The conclusions among economic evaluations were mixed, although the balance of evidence indicates that over short time-frames anti-TNF-alpha therapies are unlikely to be considered cost-effective. The limitations of the clinical outcome data impose restrictions on the economic assessment of cost-effectiveness. Direct unbiased RCT evidence is only available in the short term. Current assessment tools are limited and at present BASDAI and BASFI are the best available, although not designed for, or ideal for, use in economic evaluations. The review of the three models submitted to NICE identified a number of inherent flaws and errors. The incremental cost-effectiveness ratios (ICERs) of etanercept and adalimumab were roughly similar, falling below an assumed willingness-to-pay threshold of 30,000 pounds. The ICER for infliximab was in the range of 40,000-50,000 pounds per quality-adjusted life-year (QALY). The short-term (12-month) model developed by this report's authors confirmed the large front-loading of costs with a result that none of the three anti-TNF-alpha agents appears cost-effective at the current acceptable threshold, with infliximab yielding much poorer economic results (57,000-120,000 pounds per QALY). The assumptions of the short-term model were used to explore the cost-effectiveness of the use of anti-TNF-alpha agents in the long term. This model is far more speculative than the first since trends and parameter values must be projected far beyond the available evidence. Sensitivity analyses reveal wide variations in estimates of cost over the long term although it is considered unlikely that costs will decrease over time. CONCLUSIONS: The review of clinical data related to the three drugs (including conventional treatment) compared with conventional treatment plus placebo indicates that in the short term (12-24 weeks), the three treatments are clinically effective in relation to assessment of ASAS, BASDAI and BASFI. Indirect comparisons of treatments were limited and did not show a significant difference in effectiveness between the three agents. The short-term economic assessment indicates that none of the three anti-TNF-alpha agents is likely to be considered cost-effective at current acceptability thresholds, with infliximab consistently the least favourable option. There is an absence of evidence concerning a number of limiting factors related to patients suffering from AS, the disease itself and its treatment. In order to obtain robust estimates of the longer term clinical effectiveness and cost-effectiveness of anti-TNF-alpha agents for AS, clinical trials that aim to address these limiting factors need to be conducted.

Dysarthric sentence intelligibility: contribution of iconic gestures and message predictiveness.

This study examined changes in the sentence intelligibility scores of speakers with dysarthria in association with different signal-independent factors (contextual influences). This investigation focused on the presence or absence of iconic gestures while speaking sentences with low or high semantic predictiveness. The speakers were 4 individuals with dysarthria, who varied from one another in terms of their level of speech intelligibility impairment, gestural abilities, and overall level of motor functioning. Ninety-six inexperienced listeners (24 assigned to each speaker) orthographically transcribed 16 test sentences presented in an audio + video or audio-only format. The sentences had either low or high semantic predictiveness and were spoken by each speaker with and without the corresponding gestures. The effects of signal-independent factors (presence or absence of iconic gestures, low or high semantic predictiveness, and audio + video or audio-only presentation formats) were analyzed for individual speakers. Not all signal-independent information benefited speakers similarly. Results indicated that use of gestures and high semantic predictiveness improved sentence intelligibility for 2 speakers. The other 2 speakers benefited from high predictive messages. The audio + video presentation mode enhanced listener understanding for all speakers, although there were interactions related to specific speaking situations. Overall, the contributions of relevant signal-independent information were greater for the speakers with more severely impaired intelligibility. The results are discussed in terms of understanding the contribution of signal-independent factors to the communicative process.

The low molecular weight heparin, enoxaparin, limits infarct size at reperfusion in the dog.

OBJECTIVE: Heparin (HEP) is used in the post-thrombolytic state to prevent vessel reocclusion, thereby aiding myocardial salvage. Side effects limit its benefits, but besides anticoagulant activity HEP has diffuse actions that may be potentially beneficial to jeopardized reperfused myocardium. This study compares the effect of therapeutic doses of HEP and enoxaparin (ENOX), a low molecular weight heparin, and to streptokinase (SK), on infarct size. METHODS: The left anterior descending coronary artery was occluded in dogs for 90 min, followed by 6 h of reperfusion with a residual critical stenosis in place. Five min before reperfusion, HEP (2800 IU) was injected i.v., and perfused at 500 IU/h until sacrifice in group 2, while groups 3 and 4 received ENOX (2128 anti-Xa IU i.v.) followed by 380 anti-Xa IU/h. Group 4 was also given 500,000 IU SK over 30 min before reperfusion beginning at 55 min of occlusion (ENOX + SK), while group 5 received only SK. Controls (CON, group 1) received saline. P-selectin mediated platelet-neutrophil rosettes formation was also tested in vitro in the presence of HEP and ENOX. RESULTS: The area at risk delimited by dye perfusion was statistically similar among groups. Covariance analysis between infarct size (% of area at risk) delimited with triphenyltetrazolium and collateral flow measured with radioactive microspheres confirmed that groups given ENOX (21.6 +/- 5.5%) and ENOX + SK (24.9 +/- 3.9%) developed smaller infarcts (P < 0.05) than CON (48.1 +/- 4.5%), as opposed to HEP (32.2 +/- 3.6%) and SK (46.8 +/- 3.4%) groups. 111In-platelet counts in the infarct were reduced significantly by 64% in the ENOX group as compared to CON, and to a lesser extent (42%, n.s.) in the ENOX + SK group, but were not reduced by HEP and SK treatments. Neutrophil accumulation in the infarcts was decreased significantly and by more than 75% in the ENOX and ENOX + SK groups versus CON, but not in the HEP and SK groups. Also, only ENOX (10-100 micrograms/ml) significantly inhibited platelet-neutrophil rosettes formation in a plasmatic milieu. CONCLUSIONS: The ENOX treatment, as opposed to that of HEP, reduces myocardial platelet and neutrophil accumulations, and limits infarct size when given just before and during reperfusion. The benefits of ENOX on infarct size were not modified by SK, and may be related, at least in part, to an interaction with P-selectin-mediated cell adhesion.

Vocal reaction times of children with CAPD, age-matched peers, and young adults to printed words.

The purpose of this study was to determine if there were differences between children identified in a clinical setting as having Central Auditory Processing Disorder (CAPD), an age-matched peer group, and young adults when tested using a vocal reaction time (VRT) format. The children with CAPD were matched by gender and age to peers between the ages of 8 and 10 years. All speakers were presented visually with printed third-grade-level one- and two-syllable words (e.g., boy, mother) as well as the syllable "uh". Participants spoke each word according to the criteria of seven separate conditions, which included immediate naming tasks (0 s delay), a short delay before speaking (M = 1.5 s), and a longer delay before speaking (M = 4.0 s). Speakers VRTs were measured, and production errors were recorded. All speakers took longer to respond in the immediate-response conditions than the delayed-response conditions. Statistically significant differences were found for the immediate-response conditions, with means for the children with CAPD reflecting slower performance than that of their peers. The peer group was slower than the adults. For the delayed conditions, both groups of children responded with significantly longer VRTs than the adults. The two groups of children did not differ for these tasks. The children with CAPD produced a significantly greater number of errors than their peers, specifically for the long-delay conditions. The adults showed no performance differences across the immediate response conditions nor across the delayed conditions. These results suggested that children with CAPD may have processing difficulties with visual stimuli.

Augmented expression of platelet-activating factor receptor gene by TNF-alpha through transcriptional activation in human monocytes.

Tumor necrosis factor alpha (TNF-alpha) is a cytokine produced by activated monocytes and often associated with platelet-activating factor (PAF) during the pathogenesis of many inflammatory and infectious diseases. PAFR is a G-protein-coupled receptor constitutively expressed on monocytes. TNF-alpha (100-400 U/mL) significantly increased PAFR mRNA expression in human monocytes. This increase was seen after 1 h of stimulation and persisted up to 24 h. Actinomycin D pretreatment studies revealed a transcriptional increase in PAFR gene expression without effect on mRNA half-life. [3H]WEB 2086 binding studies showed a significant (43%) increase in specific binding sites in 24-h-treated cells without change in receptor affinity. Increased interleukin-6 production in response to PAF was also found in 24-h TNF-alpha-pretreated monocytes. These observations provide new evidence for TNF-alpha and PAF interactions in human monocytes during inflammatory processes through up-regulation of PAFR expression by TNF-alpha.

Electropalatography in the treatment of articulation/phonological disorders.

Treatment using electropalatography (EPG) is described. Speech learners wear a custom-made appliance called a pseudopalate in order to view their tongue-to-palate (lingual palatal) contacts on a computer monitor. The results from studies with children who have either articulation or phonology-based problems are discussed. Assessments of contact patterns used by articulation-impaired children suggests that they may produce more atypical articulatory contacts than are noted perceptually. Remediation, using electropalatography, showed that the children benefited from learning new articulatory gestures rather than learning to correct isolated errors. Studies with phonologically-impaired children have shown that perceptually neutralized (or non-contrasted) sounds may actually be produced with consistent articulatory contrasts. This knowledge could assist in identifying sounds that might soon emerge and be more responsive to therapy. Training studies with phonologically-impaired children have shown that a motor approach using sound contrasts to teach a phonetic inventory is an effective way to assist these children. Considerations for candidacy for EPG training are also discussed.

Inferential abilities of normal and right hemisphere damaged adults.

There were two aims of this study. The first was to compare indirect inferencing abilities by nine right hemisphere brain-damaged (RHD) adults with 18 matched normal controls. The second purpose was to determine the best condition in which to present information to the RHD individuals for the purpose of forming these inferences. Three conditions were evaluated: (1) Auditory-Only, (2) Orthographic-Only, and (3) Combined Auditory/Orthographic. It was hypothesized that right hemisphere damaged persons would perform most successfully when the materials (narrative paragraphs) were presented using the combined condition. Both groups performed significantly better in the combined Auditory/Orthographic condition. There were no significant differences in the performances of the RHD group as compared to the normal controls. This suggested that the RHD group did not exhibit an inference impairment on this type of linguistic task.

Detection of anti-neutrophil cytoplasmic antibodies by immunoprecipitation.

Immunoprecipitation (IP) of radiolabeled PMN extracts was used as the gold standard for anti-proteinase 3 (PR-3) autoantibody detection to validate immunofluorescence (IF) and alpha granule (alpha) ELISA. A myeloperoxidase (MPO) ELISA was also used in parallel. We studied 48 patients with strictly defined vasculitic syndromes in the initial active phase of their disease. The 3 methods confirmed the high (> 90%) sensitivity and specificity of anti-PR-3 for patients with Wegener's granulomatosis (WG). Similarly, a high (86%) sensitivity of MPO-ELISA was found in microscopic polyarteritis as defined. Using alpha-ELISA, we could not improve the detection rate of anti-PR-3 obtained by IF-cANCA-pattern reading. Moreover, a small proportion (< 15%) of biopsy-proven WG patients had anti-MPO antibodies detected by IF, usually as pANCA but also, even if rarely, as bona fide cANCA (< 5%). Thus, IF would seem to be the most reliable screening method and alpha-ELISA should be used for confirmation. On the other hand, because MPO-ELISA detected twice as many anti-MPO positive sera as did pANCA pattern reading by IF, we suggest that in the clinical context of a vasculitis, MPO-ELISA should also be used as a screening test. Although IP is not designed for routine clinical use, it should be required when reporting the presence of anti-PR-3 in vasculitis-like diseases that are fertile grounds for false positive reactions.

Direct covalent attachment of small peptide antigens to enzyme-linked immunosorbent assay plates using radiation and carbodiimide activation.

Direct adsorption of small peptide antigens to unaltered, commercially available polystyrene surfaces may be too weak to permit suitable assay by ELISA. We therefore developed a simple method for the covalent attachment of small, potentially single epitope antigens to polystyrene surfaces. Chemical activation of polystyrene plates with carbodiimide considerably improves the total and covalent attachment of radioactive octapeptides. The covalent attachment was demonstrated by washing with hot detergent. A 3.5 Mrad gamma-irradiation of plates also increases total binding, particularly in combination with chemical activation. The covalent attachment presumably occurs through formation and chemical activation of carboxylate functions on the polystyrene surface which form amide bonds with peptides. ELISA test was performed with CGRP and successive smaller CGRP fragments. Covalent attachment of C-terminal peptide fragments as detection antigens allows optimal recognition and sensitivity even for hexapeptides, while decapeptide antigens were already poorly recognized using a conventional antigen plating technique. Repetitive detergent washes and/or prolonged storage of plates with covalently bound antigens did not reduce their ELISA sensitivity. The method with storage and reutilization capacities that we present here will be useful for the development of preplated antibody screening test.

Comparing abilities of children with profound hearing impairments to learn consonants using electropalatography or traditional aural-oral techniques.

Two groups of nine children with profound hearing impairments and low intelligibility were taught to produce the consonants /t,d,k,g,s,z,S/ using either electropalatographic (palatometry) or traditional aural-oral techniques. Testing was completed pre-, immediately post-, and 6 months post-treatment by examining productions of CV syllables (V = /i,a/) using electropalatography-determined linguapalatal contacts and listener identifications. Intelligibility was also measured using the CID Picture Speech Intelligibility Evaluation (SPINE) test. Both groups improved their consonant productions as a result of 26 50-minute sessions. Sessions were given twice daily over 3- to 4-week training periods. Immediately post-treatment, the electropalatography-trained subjects produced better consonants as measured by linguapalatal contact patterns and listener identifications. The linguapalatal-contact patterns learned by the electropalatography-trained group better matched normal speaker productions than did those of the traditionally trained group. Both groups showed equal improvement for both post-treatment conditions when tested with the CID SPINE test. Although further research is needed, the results of this study suggest that electropalatographic techniques are, at least, equal alternatives to traditional aural-oral speech training techniques for speakers with profound hearing impairments.

Methotrexate in systemic lupus erythematosus.

OBJECTIVE: Methotrexate (MTX) has been used successfully in the treatment of rheumatoid arthritis, psoriatic arthritis, polymyositis, and Reiter's syndrome. Our objective was to determine the effectiveness of MTX in the treatment of systemic lupus erythematosus (SLE). METHODS: We reviewed retrospectively MTX therapy in 5 patients with SLE, 3 with renal disease and 2 with arthritis. RESULTS: MTX therapy was well tolerated and effective in all 5 patients. CONCLUSION: MTX appears to be both effective and well tolerated in patients with SLE.

Morphological changes and cellular proliferation in mouse colon during fetal and postnatal development.

To document regional structural and cellular proliferation changes in the developing mouse colon, tissues from fetal, suckling, and weanling mice were analyzed by light microscopy (LM), transmission electron microscopy (TEM), scanning electron microscopy (SEM), [3H]-thymidine incorporation studies, and radioautography. The proximal and distal colon were studied independently at all ages. At 17-18 days of gestation, the mouse proximal colonic mucosa was projected into high and low longitudinal folds disposed in a V-shaped pattern. From birth up to 9 days, the mucosal folds observed by SEM can easily be misinterpreted as being a succession of high and low villus-like structures at LM level. TEM study confirmed the presence of highly specialized absorptive cells in the upper halves of the mucosal folds during this period. No recognizable crypts were noted at birth. Instead, LM and radioautography showed the presence of cell aggregates developing at the base of the epithelium at all levels of the mucosal folds. These cell aggregates evolved into rudimentary crypts giving fully differentiated crypts by day 16 with radiolabeled cells located in the midcrypt portion. As opposed to the proximal segment, a flat mucosa interspersed with well defined short crypts at birth was observed in the distal colon. During the following days, crypts further developed and by 16 days, the radiolabeled epithelial cells were still exclusively located at the base of the crypt. TEM observations illustrated that specialized cells as those found in the proximal segment did not differentiate in this segment.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification and functional characterization of platelet-activating factor receptors in human leukocyte populations using polyclonal anti-peptide antibody.

Recently, the successful cloning of a receptor for platelet-activating factor (PAF), a lipid mediator of inflammation, was reported. Here we investigated the distribution and potential diversity of human PAF receptors (hPAF-Rs) among individual leukocyte populations by (i) hPAF-R mRNA transcription studies and (ii) analysis of cell surface expression of hPAF-R protein using a polyclonal anti-peptide antibody (anti-hPAF-R164-173). Northern blot analysis, flow cytometry, and immunoblotting with anti-hPAF-R antibody indicated that monocytic, neutrophilic, and B-lymphocytic cell lines all shared a similar hPAF-R species, whereas resting T-cell and natural killer cell lines failed to express detectable levels of either hPAF-R protein or mRNA. Peripheral blood leukocyte populations showed a distribution of hPAF-R cell surface expression similar to that of the corresponding cell lines. Furthermore, binding of anti-hPAF-R164-173 antiserum, purified IgG, or Fab and F(ab')2 fragments to the receptor of all investigated PAF-R-positive cell lines induced an increase in intracellular free calcium concentration. The characterization of the expression of a lipid ligand receptor using antibodies against an intrinsic portion of the receptor protein has, to our knowledge, never been reported previously.

Anti-angiotensin antibodies cross-reactive with nonpeptide angiotensin antagonists as angiotensin receptor model.

Anti-angiotensin II (Ang) antibodies could become important receptor mimicking tools if an antibody with binding properties identical to a particular Ang receptor could be generated. For this purpose, anti-Ang sera from mice were screened for antibodies with structure-affinity relationships similar or identical to a particular Ang receptor. Mice were immunized with BSA-coupled [Sar1]Ang and the sera were screened in ELISA for crossreactivity with the Ang analogues saralasin, L158,809, EXP 3147, DuP 753, DuP 532, PD 123177, PD 123319 and the non-related compounds ACTH, naloxone, and CP 96,345. All sera had at least some cross-reactivity with saralasin and some also with L158,809, a potent non-peptide Ang antagonist, selective for the AT1 site. One serum out of eight recognized most Ang analogues except the AT2 selective PD 123177 and PD 123319. ELISA detection antigens were prepared by two different BSA conjugations: [Sar1]Ang was N-terminally attached and [Sar1,Lys8]Ang was C-terminally attached. Against both detection antigens, the peptide antagonists saralasin and [Sar1,Phe(Br5)8]Ang displaced in a sigmoidal manner the antibodies with an IC50-value of 0.4 mM. L158,809 and EXP 3147 displaced also in a parallel manner, suggesting an apparently homogenous population of binding sites. The selectivity profile of the serum has some resemblance to the AT1 selectivity profile but the observed affinities are too low to suggest AT1 receptor mimicry.