Osteoporosis identification among previously undiagnosed individuals with vertebral fractures.

Because osteoporosis is under-recognized in patients with vertebral fractures, we evaluated characteristics associated with osteoporosis identification. Most patients with vertebral fractures did not receive evaluation or treatment for osteoporosis. Black, younger, and male participants were particularly unlikely to have had recognized osteoporosis, which could increase their risk of negative outcomes. INTRODUCTION: Vertebral fractures may be identified on imaging but fail to prompt evaluation for osteoporosis. Our objective was to evaluate characteristics associated with clinical osteoporosis recognition in patients who had vertebral fractures detected on their thoracolumbar spine imaging reports. METHODS: We prospectively identified individuals who received imaging of the lower spine at primary care clinics in 4 large healthcare systems who were eligible for osteoporosis screening and lacked indications of osteoporosis diagnoses or treatments in the prior year. We evaluated characteristics of participants with identified vertebral fractures that were associated with recognition of osteoporosis (diagnosis code in the health record; receipt of bone mineral density scans; and/or prescriptions for anti-osteoporotic medications). We used mixed models to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: A total of 114,005 participants (47% female; mean age 65 (interquartile range: 57-72) years) were evaluated. Of the 8579 (7%) participants with vertebral fractures identified, 3784 (44%) had recognition of osteoporosis within the subsequent year. In adjusted regressions, Black participants (OR (95% CI): 0.74 (0.57, 0.97)), younger participants (age 50-60: 0.48 (0.42, 0.54); age 61-64: 0.70 (0.60, 0.81)), and males (0.39 (0.35, 0.43)) were less likely to have recognized osteoporosis compared to white participants, adults aged 65 + years, or females. CONCLUSION: Individuals with identified vertebral fractures commonly did not have recognition of osteoporosis within a year, particularly those who were younger, Black, or male. Providers and healthcare systems should consider efforts to improve evaluation of osteoporosis in patients with vertebral fractures.

Long-term effectiveness of epidural steroid injections after new episodes of low back pain in older adults.

BACKGROUND: There is limited research on the long-term effectiveness of epidural steroid injections (ESI) in older adults despite the high prevalence of back and leg pain in this age group. We tested the hypotheses that older adults undergoing ESI, compared to patients not receiving ESI: (1) have worse pain, disability and quality of life ('outcomes') pre-ESI, (2) have improved outcomes after ESI and (3) have improved outcomes due to a specific ESI effect. METHODS: We prospectively studied patients ≥65 years old presenting to primary care with new episodes of back pain in three US healthcare systems (BOLD registry). Outcomes were leg and back pain intensity, disability and quality of life, assessed at baseline and 3-, 6-, 12- and 24-month follow-ups. We categorized participants as: (1) ESI within 6 months from the index visit (n = 295); (2) no ESI within 6 months (n = 4809); (3) no ESI within 6 months, propensity-score matched to group 1 (n = 483). We analysed the data using linear regression and Generalized Estimating Equations. RESULTS: Pain intensity, disability and quality of life at baseline were significantly worse at baseline in ESI patients (group 1) than in group 2. The improvement from baseline to 24 months in all outcomes was statistically significant for group 1. However, no statistically significant differences were observed between outcome trajectories for the propensity-score matched groups 1 and 3. CONCLUSIONS: Older adults treated with ESI have long-term improvement. However, the improvement is unlikely the result of a specific ESI effect. SIGNIFICANCE: In this large, two-year, prospective study in older adults with a new episode of low back pain, back pain, leg pain, disability and quality of life improved after epidural steroid injections; however, propensity-score matching revealed that the improvement was unlikely the result of a specific effect of the injections, indicating that epidural steroids are unlikely to provide long-term benefits in older adults with new episodes of back and leg pain.

Efectividad a largo plazo de las inyecciones epidurales de esteroides tras nuevos episodios de dolor lumbar en adultos mayores / Long-term effectiveness of epidural steroid injections after new episodes of low back pain in older adults

Antecedentes: Hay pocos estudios sobre la eficacia a largo plazo de las inyecciones epidurales de esteroides (IEE) en las personas mayores a pesar de la elevada prevalencia del dolor de espalda y de miembros inferiores en este grupo de edad. Probamos las hipótesis de que los adultos mayores que reciben IEE, frente a los que no: (1) tienen más dolor y discapacidad y peor calidad de vida (‘resultados’) antes de las IEE, (2) presentan mejores resultados después de las IEE y (3) tienen resultados mejores debido a un efecto específico de las IEE.Métodos: Estudiamos prospectivamente a pacientes de ≥ 65 años de edad que acudieron a la atención primaria con nuevos episodios de dolor de espalda en tres sistemas sanitarios estadounidenses (registro BOLD). Los resultados a evaluar fueron la intensidad del dolor de miembros inferiores y de espalda, la discapacidad y la calidad de vida, valorados en el momento basal y a los 3, 6, 12 y 24 meses de seguimiento. Clasificamos a los participantes en: (1) IEE en los 6 meses siguientes a la visita inicial (n = 295); (2) sin IEE en el plazo de 6 meses (n = 4809); (3) sin IEE en el plazo de 6 meses, puntuación de propensión equiparada a la del grupo 1 (n = 483). Analizamos los datos mediante regresión lineal y ecuaciones de estimación generalizadas.Resultados: La intensidad del dolor, la discapacidad y la calidad de vida basales fueron significativamente peores en los pacientes con IEE (grupo 1) que en los del grupo 2. La mejoría de todos los resultados evaluables desde el momento basal hasta los 24 meses fue estadísticamente significativa para el grupo 1. Sin embargo, no se observaron diferencias estadísticamente significativas entre las evoluciones de los resultados en los grupos con puntuaciones de propensión equiparadas, 1 y 3.Conclusiones: Los adultos mayores tratados con IEE presentan mejorías a largo plazo. Sin embargo, es improbable que dicha mejoría se deba a un efecto específico de la IEE.(AU)

Background: There is limited research on the longterm effectiveness of epidural steroid injections (ESI) in older adults despite the high prevalence of back and leg pain in this age group. We tested the hypotheses that older adults undergoing ESI, compared to patients not receiving ESI: (1) have worse pain, disability and quality of life (‘outcomes’) pre-ESI, (2) have improved outcomes after ESI and (3) have improved outcomes due to a specific ESI effect.Methods: We prospectively studied patients ≥ 65 years old presenting to primary care with new episodes of back pain in three US healthcare systems (BOLD reg- istry). Outcomes were leg and back pain intensity, disability and quality of life, assessed at baseline and 3-, 6-, 12- and 24-month follow-ups. We categorized participants as: (1) ESI within 6 months from the index visit (n = 295); (2) no ESI within 6 months (n = 4809); (3) no ESI within 6 months, propensity-score matched to group 1 (n = 483). We analysed the data using linear regression and Generalized Estimating Equations.Results: Pain intensity, disability and quality of life at baseline were significantly worse at baseline in ESI patients (group 1) than in group 2. The improvement from baseline to 24 months in all outcomes was statistically significant for group 1. However, no statistically significant differences were observed between out- come trajectories for the propensity-score matched groups 1 and 3.Conclusions: Older adults treated with ESI have longterm improvement. However, the improvement is unlikely the result of a specific ESI effect.(AU)

Presence and extent of severe facet joint osteoarthritis are associated with back pain in older adults.

OBJECTIVE: To determine whether the presence and extent of severe lumbar facet joint osteoarthritis (OA) are associated with back pain in older adults, accounting for disc height narrowing and other covariates. DESIGN: Two hundred and fifty-two older adults from the Framingham Offspring Cohort (mean age 67 years) were studied. Participants received standardized computed tomography (CT) assessments of lumbar facet joint OA and disc height narrowing at the L2-S1 interspaces using four-grade semi-quantitative scales. Severe facet joint OA was defined according to the presence and/or degree of joint space narrowing, osteophytosis, articular process hypertrophy, articular erosions, subchondral cysts, and intraarticular vacuum phenomenon. Severe disc height narrowing was defined as marked narrowing with endplates almost in contact. Back pain was defined as participant report of pain on most days or all days in the past 12 months. We used multivariable logistic regression to examine associations between severe facet joint OA and back pain, adjusting for key covariates including disc height narrowing, sociodemographics, anthropometrics, and health factors. RESULTS: Severe facet joint OA was more common in participants with back pain than those without (63.2% vs 46.7%; P = 0.03). In multivariable analyses, presence of any severe facet joint OA remained significantly associated with back pain (odds ratio (OR) 2.15 [95% confidence interval (CI) 1.13-4.08]). Each additional joint with severe OA conferred greater odds of back pain [OR per joint 1.20 (95% CI 1.02-1.41)]. CONCLUSIONS: The presence and extent of severe facet joint OA on CT imaging are associated with back pain in community-based older adults, independent of sociodemographics, health factors, and disc height narrowing.

Audit of the aetiology and prevalence of pulmonary hypertension in a tertiary hospital setting.

Appropriate diagnosis and initiation of disease-specific treatment is an important therapeutic goal in idiopathic pulmonary arterial hypertension. We evaluated the prevalence and aetiology of moderate-to-severe pulmonary hypertension in a cohort of patients referred for inpatient echocardiography, with significant pulmonary hypertension documented in 4.6%. Pulmonary hypertension complicating left heart disease was the most common aetiology, with idiopathic pulmonary arterial hypertension less frequent.

Vascular disease is associated with facet joint osteoarthritis.

OBJECTIVE: Epidemiologic studies have demonstrated associations between vascular disease and spinal degeneration. We sought to examine whether vascular disease was associated with lumbar spine facet joint osteoarthritis (FJ OA) in a community-based population. DESIGN: 441 participants from the Framingham Heart Study multi-detector computed tomography (MDCT) Study were included in this ancillary study. We used a quantitative summary measure of abdominal aortic calcification (AAC) from the parent study as a marker for vascular disease. AAC was categorized into tertiles of 'no' (reference), 'low', and 'high' calcification. FJ OA was evaluated on computerised tomography (CT) scans using a four-grade scale. For analytic purposes, FJ OA was dichotomized as moderate FJ OA of at least one joint from L2-S1 vs no moderate FJ OA. We examined the association of AAC and FJ OA using logistic regression before and after adjusting for age, sex and body mass index (BMI). Furthermore, we examined the independent effect of AAC on FJ OA after including the known cardiovascular risk factors; diabetes, hypertension, hypercholesterolemia, and smoking. RESULTS: Low AAC (OR 3.84 [2.33-6.34]; P

Schistosoma mansoni gene GP22 encodes the tegumental antigen sm25: (1) antibodies to a predicted B-cell epitope of Sm25 cross-react with other candidate vaccine worm antigens; (2) characterization of a recombinant product containing tandem-repeats of this peptide as a vaccine.

Monospecific antibodies against two putative epitopes of schistosome protein encoded by gene GP22 (182 codons, no introns) were used to probe worm extracts fractionated by lentil-lectin affinity chromatography or by electrophoresis. Anti-peptide-alpha (codons 70-84) exclusively identifies the N-glycanase-sensitive, 25 kDa tegumental glycoprotein Sm25 in the lectin-bound fraction of detergent-solubilized adult worm extract S3. In contrast, antipeptide-delta (codons 151-162) does not react with Sm25 but cross-reacts with other schistosome proteins, including candidate vaccine antigens paramyosin (Sm97) and glutathione-S-transferases (Sm26, Sm28, Sj26). Recombinant protein r4 x 47, constructed to express multiple copies of codon sequence 117-163 (containing delta), reacts with anti-delta and is uniquely recognized by protective Fischer twice-infected (F-2x) rat antiserum. Immunization with r4 x 47 induces antibodies with cross reactivities similar to anti-delta, but which also recognize Sm25. Despite these cross-reactivities with protective antigens, rodents vaccinated with r4 x 47 were not protected against cercarial infection. On the basis of these data, two hypotheses are proposed: (1) antigenic epitopes other than delta are present within the r4 x 47 sequence which induce antibodies reactive with Sm25 and/or (2) peptide-delta assumes alternative antigenic conformations, dependent upon the context of neighbouring sequences, some of which mimic epitopes of proteins encoded by other schistosome genes. These mimotopes are not targets of protective antibodies.

Interleukin-12 as an adjuvant for an antischistosome vaccine consisting of adult worm antigens: protection of rats from cercarial challenge.

Our group previously demonstrated that a detergent extract (fraction S3) prepared from immature (4-week) Schistosoma mansoni parasites can induce partial, serum-transferable immunity to challenge infection in rats when administered as an alum precipitate. In the present study, we examined whether S3 prepared from adult (7-week) worms could similarly induce protection and whether immunity could be positively influenced by treatment with interleukin-12 (IL-12). IL-12 coadministered to Fischer rats and C57BL/6 mice at the time of S3 vaccination altered the prechallenge kinetics of S3-specific antibody titers in both species, ultimately leading to a stable enhancement of titers (relative to those in animals vaccinated without IL-12) in mice but not rats. Immunoblot analysis of prechallenge immune sera demonstrated that IL-12 treatment was associated with changes in the S3 antigen recognition profile in each species. Isotyping of specific antibodies in S3- plus IL-12-vaccinated mice prior to challenge infection revealed a moderate elevation in immunoglobulin G1 (IgG1) responses, strongly enhanced IgG2a and IgG2b responses, as well as diminished total serum IgE responses compared to those in mice given S3 only. In vaccinated rats, IL-12 profoundly suppressed specific IgG1 and enhanced IgG2b responses but did not affect IgG2a responses. S3- plus IL-12-vaccinated rats also produced less total IgE upon challenge infection. Enumeration of worm burdens revealed that vaccination with S3 plus IL-12 conferred 50% protection from cercarial challenge to rats, whereas rats given S3 only were not protected; mice were not protected by S3 vaccination regardless of IL-12 coadministration. The protection observed in S3- plus IL-12-vaccinated rats could not be transferred with serum, suggesting participation of an activated cellular component in the expression of immunity.

Evaluation of recombinant protein r140, a polypeptide segment of tegumental glycoprotein Sm25, as a defined antigen vaccine against Schistosoma mansoni.

To investigate the role of tegumental glycoprotein Sm25 in protective immunity against schistosomiasis, codons 43-182 of its gene (GP22) were amplified by PCR and cloned in the pET 15b bacterial expression system. Recombinant protein r140 was inducibly expressed in the presence of rifampicin and purified by Ni-affinity chromatography. In different vaccination trials, Balb/c mice and Fischer rats repeatedly immunized with r140 in combination with one of several adjuvants (alum, cholera toxin or complexed into proteosomes) produced high titre anti-r140 responses. These antibodies detected an N-glycanase sensitive. 25 kDa antigen in a detergent solubilized worm fraction using Western immunoblotting. The choice of adjuvant affected the isotype distribution of the specific anti-r140 antibodies. Despite the presence of high antibody titres and isotypes which have been shown to correlate with protective immunity, protection against subsequent cercarial challenge was not observed. In addition, no appreciable effects on worm sex ratios or liver egg yields were detected in mice. Studies involving biotin labelling of membrane proteins in live worms showed that the majority of anti-r140 reactive molecules present in adult schistosomes are biotinylated after permeabilization of the parasite surface. Several possibilities to account for the lack of protective immunity are analysed.

Role of the cyclic AMP response element in rat fibronectin gene expression.

Fibronectin expression is of considerable importance in normal and fibrotic liver. Plasma fibronectin levels are correlated with good prognosis in liver failure, and cellular fibronectin plays a crucial role in fibrogenesis. In this study, we observed that the H4II rat hepatoma cell line does not express fibronectin. Furthermore, a recombinant vector (pFGH) containing the promoter elements of the fibronectin gene showed no promoter function when transfected into this cell line. However, pFGH was actively expressed in L-cells and rat skin fibroblasts, cell types that express large amounts of endogenous fibronectin. To study the mechanisms regulating fibronectin expression, we evaluated the transcriptional regulatory elements of the rat fibronectin gene by mutational analysis and DNA-protein binding studies. Deletional mutation analysis showed that the sequences between positions -164 and -90 are essential for promoter activity. This region contains the consensus binding sites for CCAAT and the cyclic AMP-responsive element. Gel retardation assays demonstrated that although the binding activity to the CCAAT site at -140 was essentially the same as that in extracts from L-cells, hepatoma cells and rat livers, substantially greater amounts and different patterns of binding to the adjacent cyclic AMP-responsive element were observed in the extracts from the expressing L-cells and rat livers compared with those in the nonexpressing hepatoma cell nuclear extracts. Furthermore, mutagenesis of the cyclic AMP-responsive element site dramatically reduced promoter activity in transient transfection assays. The cyclic AMP-responsive element at position -160 appears to play an important role in the constitutive expression of the rat fibronectin gene.

Modern approaches to development of vaccines against schistosomes.

Vaccination, as currently practiced, is a prophylactic procedure. A vaccine is given before exposure to the infectious agent, in order to induce a state of specific immunological memory within the recipient.

Schistosoma mansoni: two-dimensional gel electrophoretic analysis of antigens uniquely immunoreactive with protective rat serum.

Candidate vaccine antigens are defined by their differential immunoreactivity with antisera which are distinguishable by their capacity to confer passive resistance to infection. This "contrasting antisera" immunoassay has been successfully used in previous analyses of 4-week-old worm biosynthetically radiolabeled Schistosoma mansoni proteins to identify potentially protective antigens. Twice-infected Fischer (F-2x) and Wistar-Furth (W-2x) rat sera were the sources of protective and non-protective antibody, respectively. We have extended our original analysis by applying two-dimensional gel electrophoresis to resolve total and immunoreactive soluble proteins of the 4-week worms. Total proteins were characterized by silver staining and autoradiography. Radiolabeled protein antigens immunoprecipitated by F-2x and W-2x antisera were compared, and several were shown to be uniquely reactive with the protective immune serum. In a companion molecular approach to clone the candidate vaccine antigens, screening of a lambda gt11 adult S. mansoni cDNA expression library by the contrasting antisera assay has identified a clone (lambda 40) producing a fusion protein with epitopes uniquely reactive with F-2x. A rabbit antiserum to the lambda 40 fusion protein (anti-FP40) reacted with radiolabeled worm proteins in the 20-kDa size range. By 2D gel electrophoretic analysis, we can now demonstrate that anti-FP40 specifically immunoprecipitates most of the members of a multicomponent protein antigen subset 18-22 kDa in Mr, focusing over a pI range of 5.3-5.8, and recognized uniquely by F-2x.

Immunoprecipitation analysis of radiolabelled protein antigens biosynthesized in vitro by S. mansoni. I. Identification of antigens uniquely recognized by protective antibodies.

Protein antigens from 4-wk worms were metabolically radiolabelled with [3H]leucine or [35S]methionine. Three freeze-thaw cycles released a large proportion (50% to 60%) of the TCA-precipitable radioactivity from the worms. Immune serum from twice-infected Fischer rats (F-2x), which was shown to confer resistance in a passive immunization assay, and immune serum from twice-infected Wistar Furth rats (W-2x), which does not confer resistance, were used for analyzing antigens in this worm fraction. Antibodies in these antisera differed in their titers to the freeze-thaw released antigens (W-2x greater than F-2x) and in their relative affinities for these antigens (F-2x greater than W-2x). Gradient slab gel electrophoresis of immunoprecipitates of radiolabelled antigens under denaturing conditions revealed many components, which could be categorized into two main types: unique antigens, recognized only by F-2x antibodies, and nonunique antigens, recognized by both F-2x and W-2x antibodies. The potential relevance of these antigens in resistance was further examined by antibody absorption experiments in which 4-wk worms were used as an immunoabsorbent to remove 90% to 95% of the immunoprecipitating activity and 65% to 70% (p less than 0.005) of the capacity to confer resistance in a passive immunization assay. It was concluded that loss of both anti-schistosome activities was specific since antigen released by worms during absorption could account for only 16% of the reduction in antigen-binding capacity and the titer of antibodies directed against beta-galactosidase did not significantly change during absorption. Antigens recognized uniquely by F-2x antibodies are therefore candidates for immunization studies examining induction of resistance against Schistosoma mansoni.

Efflux of radiolabeled polyethylene glycols and albumin from rat brain.

Experiments were carried out to evaluate the role of convection in the removal of large molecules from brain interstitial fluid. Radiolabeled test compounds were injected into the caudate nucleus of anesthetized rats through a guide cannula implanted 1 wk previously and the concentrations of isotope in brain and cerebrospinal fluid (CSF) determined at various times after injection. Control studies with 22Na indicate that the permeability of the blood-brain barrier is normal in tissue surrounding the intracerebral injection cannula. For 69,000 dalton serum albumin, 4,000 dalton polyethylene glycol, and 900 dalton polyethylene glycol, clearance from brain approximates a single exponential decay with half times of disappearance of 12.2, 12.6, and 14.4 h, respectively. Similarly in efflux rate, despite a fivefold difference in diffusion coefficient, is consistent with convective losses from brain, and the maximal rate of interstitial fluid removal estimated on the basis of these data is 0.11 microliter.g brain-1.min-1. Only 10-20% of total efflux is into bulk CSF withdrawn from the cisterna magna.