In vitro effects of macrophages on orthopaedic implant alloys and local release of metallic alloy components.

AIMS: This study aimed to determine if macrophages can attach and directly affect the oxide layers of 316L stainless steel, titanium alloy (Ti6Al4V), and cobalt-chromium-molybdenum alloy (CoCrMo) by releasing components of these alloys. METHODS: Murine peritoneal macrophages were cultured and placed on stainless steel, CoCrMo, and Ti6Al4V discs into a 96-well plate. Cells were activated with interferon gamma and lipopolysaccharide. Macrophages on stainless steel discs produced significantly more nitric oxide (NO) compared to their control counterparts after eight to ten days and remained elevated for the duration of the experiment. RESULTS: On stainless steel, both nonactivated and activated cell groups were shown to have a significant increase in metal ion release for Cr, Fe, and Ni (p < 0.001, p = 0.002, and p = 0.020 respectively) compared with medium only and showed macrophage-sized corrosive pits on the stainless steel surface. On titanium alloy discs there was a significant increase in aluminum (p < 0.001) among all groups compared with medium only. CONCLUSION: These results indicated that macrophages were able to attach to and affect the oxide surface of stainless steel and titanium alloy discs. Cite this article: Bone Joint J 2020;102-B(7 Supple B):116-121.

Small Talk: Identifying communication problems in maltreated children.

Development of speech and language is rapid in early years, yet if developmental problems in speech and language are not addressed they are likely to continue and impact negatively on a child's overall development and their life trajectory. Children who have experienced abuse and or neglect are particularly vulnerable. The aim of this study was to develop a tool to assist in identifying a child's need for assessment by a speech pathologist so that there could be early identification of problems. A culturally sensitive tool was developed to be completed by the child's carer included questions on language, speech and hearing, voice, fluency, understanding sentences, vocabulary and expression. Sixty-five children aged between 4 and 8 years, who had experienced abuse and/or neglect participated in the study. Fourteen percent were Aboriginal. A speech pathologist undertook an assessment for each child and the results were compared with the information on the Small Talk tool. The Tool was found to be high in sensitivity but low in specificity, requiring further refinement. However, it has the potential to assist non speech pathologists to identify a child's need for speech and language assessment with the findings identifying the Tool as promising practice.

A randomized trial comparing balloon kyphoplasty and vertebroplasty for vertebral compression fractures due to osteoporosis.

BACKGROUND AND PURPOSE: Several trials have compared vertebral augmentation with nonsurgical treatment for vertebral compression fractures. This trial compares the efficacy and safety of balloon kyphoplasty and vertebroplasty. MATERIALS AND METHODS: Patients with osteoporosis with 1-3 acute fractures (T5-L5) were randomized and treated with kyphoplasty (n = 191) or vertebroplasty (n = 190) and were not blinded to the treatment assignment. Twelve- and 24-month subsequent radiographic fracture incidence was the primary end point. Due to low enrollment and early withdrawals, the study was terminated with 404/1234 (32.7%) patients enrolled. RESULTS: The average age of patients was 75.6 years (77.4% female). Mean procedure duration was longer for kyphoplasty (40.0 versus 31.8 minutes, P < .001). At 12 months, 7.8% fewer patients with kyphoplasty (50/140 versus 57/131) had subsequent radiographic fracture, and there were 8.6% fewer at 24 months (54/110 versus 64/111). The results were not statistically significant (P > .21). When we used time to event for new clinical fractures, kyphoplasty approached statistical significance in longer fracture-free survival (Wilcoxon, P = .0596). Similar pain and function improvements were observed. CT demonstrated lower cement extravasation for kyphoplasty (157/214 versus 164/201 levels treated, P = .047). For kyphoplasty versus vertebroplasty, common adverse events within 30 postoperative days were procedural pain (12/191, 9/190), back pain (14/191, 28/190), and new vertebral fractures (9/191, 17/190); similar 2-year occurrence of device-related cement embolism (1/191, 1/190), procedural pain (3/191, 3/190), back pain (2/191, 3/190), and new vertebral fracture (2/191, 2/190) was observed. CONCLUSIONS: Kyphoplasty and vertebroplasty had similar long-term improvement in pain and disability with similar safety profiles and few device-related complications. Procedure duration was shorter with vertebroplasty. Kyphoplasty had fewer cement leakages and a trend toward longer fracture-free survival.

A tidally distorted dwarf galaxy near NGC 4449.

NGC 4449 is a nearby Magellanic irregular starburst galaxy with a B-band absolute magnitude of -18 and a prominent, massive, intermediate-age nucleus at a distance from Earth of 3.8 megaparsecs (ref. 3). It is wreathed in an extraordinary neutral hydrogen (H I) complex, which includes rings, shells and a counter-rotating core, spanning ∼90 kiloparsecs (kpc; refs 1, 4). NGC 4449 is relatively isolated, although an interaction with its nearest known companion--the galaxy DDO 125, some 40 kpc to the south--has been proposed as being responsible for the complexity of its H I structure. Here we report the presence of a dwarf galaxy companion to NGC 4449, namely NGC 4449B. This companion has a V-band absolute magnitude of -13.4 and a half-light radius of 2.7 kpc, with a full extent of around 8 kpc. It is in a transient stage of tidal disruption, similar to that of the Sagittarius dwarf near the Milky Way. NGC 4449B exhibits a striking S-shaped morphology that has been predicted for disrupting galaxies but has hitherto been seen only in a dissolving globular cluster. We also detect an additional arc or disk ripple embedded in a two-component stellar halo, including a component extending twice as far as previously known, to about 20 kpc from the galaxy's centre.

Increased epithelial permeability in pulmonary fibrosis in relation to disease progression.

Epithelial injury contributes to pathogenesis in idiopathic pulmonary fibrosis (IPF) but its role in the interstitial lung disease (ILD) of systemic sclerosis (SSc) is uncertain. We quantified the prognostic significance of inhaled technetium-99m ((99m)Tc)-labelled diethylene triamine pentacetate (DTPA) pulmonary clearance, a marker of the extent of epithelial injury, in both diseases. Baseline (99m)Tc-DTPA pulmonary clearance was evaluated retrospectively in patients with SSc-ILD (n = 168) and IPF (n = 97) against mortality and disease progression. In SSc-ILD, the rapidity of total clearance (hazard ratio (HR) 1.02, 95% CI 1.01-1.03; p = 0.001) and the presence of abnormally rapid clearance (HR 2.10; 95% CI 1.25-3.53; p = 0.005) predicted a shorter time to forced vital capcity (FVC) decline, independent of disease severity. These associations were robust in both mild and severe disease. By contrast, in IPF, delayed clearance of the slow component, an expected consequence of honeycomb change, was an independent predictor of a shorter time to FVC decline (HR 1.01, 95% CI 1.00-1.02; p<0.01). Epithelial injury should be incorporated in pathogenetic models in SSc-ILD. By contrast, outcome is not linked to the overall extent of epithelial injury in IPF, apart from abnormalities ascribable to honeycombing, suggesting that core pathogenetic events may be more spatially focal in that disease.

Induction of immune memory by a multisubunit chlamydial vaccine.

We tested the hypothesis that intramuscular immunization with a multisubunit chlamydial vaccine candidate will induce long lasting immune responses in mice. Accordingly, groups of female C57BL/6 mice were immunized intramuscularly with Vibrio cholerae ghosts (VCG) expressing the Poring B and polymorphic membrane protein-D proteins of Chlamydia trachomatis or a control antigen. Humoral and cell-mediated immune responses were evaluated following immunization and after live chlamydial infection. Immunization induced an anamnestic response characterized by chlamydial-specific IgG2a and IgA antibodies in sera and vaginal lavage as well as specific genital and splenic T cell responses. The results also revealed that the local mucosal and systemic cellular and humoral immune effectors induced in mice following immunization with the vaccine candidate are long lasting. Vaccinated mice cleared intravaginal challenge with 10(5) chlamydial inclusion forming units within 12 days compared to control mice, which shed up to 2 × 10(3) IFUs at this time point. Moreover, rechallenge of mice 98 days after resolution of the primary infection resulted in the recall and retention of a relatively high frequency of chlamydial-specific Th1 cells and IgG2a in the genital mucosa. These results provide the first evidence that a VCG-based multisubunit chlamydial vaccine is capable of effectively stimulating anamnestic systemic and mucosal immune responses in mice. The data support further vaccine evaluation and testing for induction of long-term protective immunity.

Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis.

OBJECTIVE: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). METHOD: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. RESULTS: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). CONCLUSION: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study.

BACKGROUND: Systemic sclerosis (SSc) has high mortality and morbidity. Current management focuses on early detection and treatment of organ-based manifestations. AIM: To determine whether the ascertainment of major organ complications of SSc has changed over time and if this is associated with better survival. DESIGN: Retrospective cohort analysis. METHODS: A total of 520 SSc patients, 234 with disease onset between 1990 and 1993 (historical cohort) and 286 with disease onset between 2000 and 2003 (contemporary cohort), were included. Survival and frequency of internal organ complications were compared between the two cohorts. RESULTS: Five-year survival among diffuse cutaneous SSc (dcSSc) patients has improved from 69% in the 1990-93 cohort to 84% in the 2000-03 cohort (P = 0.018), whereas 5-year survival among the limited cutaneous SSc (lcSSc) patients has remained unchanged-93 and 91%, respectively. Sixteen per cent of the lcSSc subjects and 38% of the dcSSc subjects from the contemporary cohort were diagnosed for the clinically significant pulmonary fibrosis compared with 3 and 7%, respectively, of the historical cohort (P < 0.001). Similarly, the diagnosis of pulmonary arterial hypertension was more frequent in the patients from the contemporary cohort (8 and 7% for lcSSc and dcSSc, respectively) compared with [ < 1% (P = 0.002) and 1% (P = 0.148), respectively] the historical cohort. There was no significant difference between the two cohorts in terms of scleroderma renal crisis and cardiac involvement. CONCLUSION: Survival has substantially improved for the diffuse cutaneous subset of SSc with better and more complete ascertainment of lung complications as a result of systematic annual screening.

Identification of candidate genes using the murine model of female genital tract infection with Chlamydia trachomatis.

The integrated approach to the study of female genital tract infection (GTI) with Chlamydia trachomatis is a conceptual framework through which a consistent and comprehensive evidence-based understanding of C. trachomatis GTI could evolve. One application of this approach has been to identify candidate genes that may play a role in the course and severity of C. trachomatis GTI in women, using human clinical and genetic data together with results obtained in the female mouse model to guide the selection process This model has been proven robust enough: i) to identify stable phenotypic differences in the course and outcome of GTI among commonly used immunocompetent inbred mouse stains that are used in the construction of gene knockout (KO) and transgenic mice; as well as ii) to serve as a platform in which to assess the influence of genetic differences among human genital tract isolates of C. trachomatis as well as between this biovar and the mouse biovar, Chlamydia muridarum. This review presents a summary of published and unpublished results from 25 years of studies in immunodeficient and gene-deficient KO mice that both inform our present understanding of the immunogenetics of C. trachomatis GTI and serve to guide candidate gene selection.

Does long term therapy with lansoprazole slow progression of oesophageal involvement in systemic sclerosis?

OBJECTIVES: Oesophageal scintigraphy is an effective, non-invasive screening test to detect oesophageal dysmotility and reflux. Our objective was to assess the long term effect of lansoprazole therapy on gastroesophageal dysmotility in systemic sclerosis (SSc). METHODS: 24 SSc patients were randomised to receive either lansoprazole 30 mg or placebo for 12 months. Gastroesophageal motility was assessed by scintigraphy at baseline, after 6 months and after 12 months. Symptoms were evaluated by self-reported gastrointestinal questionnaire. RESULTS: Of 21 patients starting treatment, 17 (81%) completed the first 6 months and 13 (62%) completed the study. 3 patients from each group were withdrawn due to adverse events. As expected, lansoprazole appeared to decrease frequency of gastroesophageal symptoms in the first 6 months of treatment, but long term benefit was not evident. Scintigraphy showed worsening oesophageal dysmotility in SSc patients irrespective of lansoprazole treatment. In addition, early signs of dysmotility were found in asymptomatic patients. We found no correlation of scintigraphy findings with symptoms of gastroesophageal dysmotility. CONCLUSION: Although lansoprazole 30 mg daily appears to suppress SSc-related gastroesophageal symptoms in the short term, benefit was not sustained at 12 months, and there was no evidence that progression of gastroesophageal motility was prevented. Scintigraphy findings did not correlate with symptoms of dysphagia.

An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis.

AIM: The safety and potential efficacy of a chimaeric anti-tumour necrosis factor alpha monoclonal antibody (infliximab) were examined in diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A 26-week open-label pilot study in which 16 cases of dcSSc received five infusions of infliximab (5 mg/kg). Clinical assessment included skin sclerosis score, scleroderma health assessment questionnaire, self-reported functional score and physician global visual analogue scale. Collagen turnover, skin biopsy analysis and full safety evaluation were performed. RESULTS: There was no significant change in skin score at 26 weeks but a trend for lower modified Rodnan skin score at 22 weeks (OR 17, 95% CI 6 to 46) compared with peak value (OR 29, 95% CI 11 to 44; p = 0.10). Serum aminoterminal propeptide of type III collagen level was significantly lower at week 26 compared with baseline (p = 0.03). Secretion of type I collagen by dermal fibroblasts was reduced at 26 weeks compared with baseline (p = 0.02). There were no deaths during the study and no suspected unexpected serious adverse reactions. 21 serious adverse events (AE) occurred in seven subjects, mostly attributable to dcSSc. 127 distinct AE occurred in 16 subjects. Of these, 19 AE (15%) were probably or definitely related to infliximab treatment. Eight (50%) patients prematurely discontinued infliximab. Anti-infliximab antibodies developed during the study in five subjects and were significantly associated with suspected infusion reactions (p = 0.025). CONCLUSION: In dcSSc infliximab did not show clear benefit at 26 weeks but was associated with clinical stabilisation and a fall in two laboratory markers of collagen synthesis. The frequency of suspected infusion reactions may warrant additional immunosuppression in any future studies in systemic sclerosis.

Chlamydia trachomatis OmpA genotyping as a tool for studying the natural history of genital chlamydial infection.

OBJECTIVE: To investigate the relationship of Chlamydia trachomatis (CT) outer membrane protein A (OmpA) type to the clearance of CT infection before treatment. METHODS: CT OmpA genotyping, with amplification and sequencing of ompA, was utilised to study the natural history of CT infection (spontaneous resolution vs persistence) in 102 individuals with chlamydia-positive screening tests returning for treatment. RESULTS: CT OmpA distribution was associated with spontaneous resolution of CT, most notably with CT OmpA genotype J/Ja detected more often from the initial screening CT test than other genotypes in those who then had spontaneous resolution of CT noted at the time of treatment. Five individuals with presumed persisting CT infection had discordant CT OmpA genotypes at the screening and treatment visits, suggesting possible new interval CT infection. CONCLUSIONS: Clearance of chlamydia by the host before treatment may be influenced by the CT OmpA genotype infecting the host. CT OmpA genotyping may be a valuable tool in understanding the natural history of chlamydial infections.

Nitric oxide synthase expression and activity in the tight-skin mouse model of fibrosis.

OBJECTIVES: Nitric oxide (*NO) is an important physiological signalling molecule and a potent vasodilator. We have previously demonstrated abnormal *NO metabolism in the plasma of patients with systemic sclerosis (SSc; scleroderma), a disease that features vascular dysfunction as well as collagen overproduction and fibrosis. The aim of the present study was to examine nitric oxide synthase (NOS) expression and activity and assess the potential role of antioxidants in the scleroderma-like syndrome of the tight-skin 1 (TSK-1/+) mouse, an experimental animal model for fibrosis. METHODS: Skin, lung or plasma was taken from TSK-1/+ (n = 15) and wild-type (WT; n = 12) littermate mice. Type 1 collagen, endothelial NOS (eNOS), haemoxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein and gene expression were determined by western blot and reverse transcriptase-polymerase chain reaction. eNOS expression was further determined by immunohistochemistry. NOS activity was evaluated by conversion of [14C] L-arginine to [14C] L-citrulline. Levels of circulating plasma nitrite/nitrate (NO(x)) were also measured. Total antioxidant activity was evaluated by ABTS+ production (ABTS = 2,2'-azino-bis-[3-ethylbenz-thiazoline-6-sulphonic acid). RESULTS: In the skin, eNOS was present in the epidermal layer, hair follicles and also in the endothelial cells lining the blood vessels. Expression of both the eNOS protein and gene was significantly reduced in TSK-1/+ skin tissue, while type 1 collagen protein was elevated compared with WT. Furthermore, there was decreased NOS activity in TSK-1/+ skin tissue; however, there was no measurable difference in plasma NO(x). Correspondingly, the protective antioxidant enzyme HO-1 and the associated transcription factor Nrf2 showed reduced protein and gene expression levels in TSK-1/+ skin, while there was also less total antioxidant activity. In TSK-1/+ lung tissue, however, we observed no difference in collagen protein expression, *NO metabolism or HO-1 expression and total antioxidant activity compared with WT. CONCLUSIONS: The findings suggest that there is also abnormal *NO metabolism in the TSK-1/+ mouse model of fibrosis, particularly in the skin, while expression and activity of protective antioxidants are reduced. The TSK-1/+ mouse may also be useful for testing treatments that target vascular endothelial cell function in patients with SSc.

Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis.

BACKGROUND: Vascular damage is a key pathological process in systemic sclerosis (SSc) and accounts for significant disease-related morbidity. To determine the clinical burden of severe digital vasculopathy (SDV), we have reviewed hospital-based treatment for this important complication of SSc in a large single centre cohort. METHODS: Cases were identified from a cohort of 1168 patients with a diagnosis of SSc who were reviewed during an 18-month period. Patients with recorded episodes of SDV-related complications (digital ulceration, critical digital ischaemia or digital gangrene), requiring surgical amputation, digital sympathectomy or admissions for intravenous prostacyclin or calcitonin gene related peptide (CGRP) and/or intravenous antibiotic treatment were identified. RESULTS: From this large SSc cohort, 17.4% had SDV-related complications. Contrary to expectation, their frequency was significantly higher among the patients with the diffuse cutaneous subset of SSc (27.5%) compared with 13% among the patients with limited cutaneous SSc (p<0.0001). 16.6% had at least one recorded episode of digital ulcers, and 12% required at least one hospitalisation during the 18 months for treatment with intravenous prostacyclin/CGRP. Overall, there were 242 admissions with a mean duration of 6 days. CONCLUSIONS: Digital vasculopathy is a serious complication of SSc contributing significant morbidity and often requiring hospital-based management.

Can CCL2 serum levels be used in risk stratification or to monitor treatment response in systemic sclerosis?

OBJECTIVE: The chemokine CCL2 has been consistently found to be up-regulated in systemic sclerosis. To explore the potential value of serum CCL2 measurement in disease assessment, we have compared CCL2 levels with clinical phenotype and investigated effect of therapy on circulating CCL2. METHODS: Serum samples from a well characterised cohort of 94 systemic sclerosis (SSc) patients, 16 patients with primary Raynaud phenomenon and 11 healthy controls were examined by ELISA. Our cohort of patients included 50 patients with limited cutaneous (lc)SSc (20 with lcSSc alone and 30 with pulmonary arterial hypertension-lcSSc), and 44 with diffuse cutaneous (dc)SSc, 30 of which had early-onset dcSSc. RESULTS: Serum levels of CCL2 were increased in both major SSc subsets. In early stage dcSSc 18/30 (60%) cases demonstrated markedly elevated CCL2, and this was associated with anti-topoisomerase or anti-RNA polymerase I/III antibody reactivity, and with greater frequency of major organ-based complications. Elevation of CCL2 serum levels in the lcSSc subset was not associated with pulmonary arterial hypertension, although there was a trend for reduction following treatment with prostacyclin analogues or bosentan. CONCLUSION: These findings suggest that the CCL2/CCR2 axis is a potential therapeutic target in SSc, particularly in the early dcSSc subset. CCL2 measurement may be useful for risk stratification in early stage disease, but its value in disease monitoring is questionable.

Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril.

OBJECTIVE: To evaluate the efficacy and tolerability of prolonged administration of quinapril, a long-acting angiotensin-converting enzyme inhibitor, in the management of the peripheral vascular manifestations of limited cutaneous systemic sclerosis (lcSSc) and in the prevention of the progression of visceral organ involvement in the disease. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study evaluating quinapril 80 mg/day, or the maximum tolerated dosage, in 210 patients with lcSSc or with Raynaud's phenomenon (RP) and the presence of SSc-specific antinuclear antibodies. Treatment was for 2-3 years. The primary outcome measure was the number of new ischemic ulcers appearing on the hands; secondary measures were the frequency and severity of RP attacks, skin score, treatments for ischemia, health status (measured by the Short Form 36 instrument), measures of kidney and lung function, and echocardiographic estimates of pulmonary artery pressure. An intent-to-treat analysis was used. RESULTS: Quinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. It did not alter the treatments that were prescribed for either infected ulcers or severe RP symptoms. There was no apparent effect on the estimated tricuspid gradient. Health status was not affected by quinapril, and one-half of the patients who believed they had benefited from the trial treatment were in the placebo arm. Quinapril was not tolerated by one-fifth of the patients, with dry cough being the most frequent side effect. CONCLUSION: Administration of quinapril for up to 3 years had no demonstrable effects on the occurrence of upper limb digital ulcers or on other vascular manifestations of lcSSc in this patient population.