Functional Outcome and Complications in Management of Proximal Humerus Fractures Operated with Proximal Humerus Locking Plate.

INTRODUCTION: Controversies exist in treatment of proximal humerus fractures as treatment options vary greatly from conservative management, closed pinning, stacked intramedullary nails, plating and hemi-arthroplasty. The purpose of this study is to study the fracture patterns of each case and document the functional outcome and complications post-operative in the management of proximal humerus fractures operated with proximal humerus plate. MATERIAL AND METHODS: Thirty five patients with closed proximal humerus fractures, above 18 years old, admitted in our tertiary care hospital during the study period were enrolled. Patients underwent open reduction internal fixation with proximal humerus locking plate under general anaesthesia. Post-operative patients were assessed using Constant and DASH scores. Complications were recorded. RESULTS: In our study the absolute Constant score of the study population increases at three months and six months and was found to be significant. Mean Constant score for 4-part fractures was 45.6 which were inferior as compared to 2-part and 3-part fractures (43.1 and 44.6, respectively). The mean Constant score at six months was 51.80 +/- 6.71. All three types of proximal humerus fractures showed significant improvement in the mean DASH score over our study period of six months and was found to be significant. Mean DASH score at six months was 27.97+/-12.84. Out of the 35 cases in the study two had complications. One had implant failure (Neer's type 3, 60-year-old female) and one had varus collapse (Neer's type 3, 45-year-old male). CONCLUSION: Due to angular stability and effective maintenance of the intraoperative fracture reduction during follow-up period, early post-operative mobilisation is possible which helps the patient to attain better shoulder range of motion and return to activity faster.

The association of pain and stiffness with fatigue in incident polymyalgia rheumatica: baseline results from the polymyalgia rheumatica cohort study.

We aimed to examine the association between pain, stiffness and fatigue in newly diagnosed polymyalgia rheumatica (PMR) patients using baseline data from a prospective cohort study. Fatigue is a known, but often ignored symptom of PMR. Newly diagnosed PMR patients were recruited from general practice and mailed a baseline questionnaire. This included a numerical rating scale for pain and stiffness severity, manikins identifying locations of pain and stiffness and the FACIT-Fatigue questionnaire. A total of 652 PMR patients responded (88.5%). The mean age of responders was 72.6 years (SD 9.0) and the majority were female (62.0%). Manikin data demonstrated that bilateral shoulder and hip pain and stiffness were common. The mean fatigue score (FACIT) was 33.9 (SD 12.4). Adjusted regression analysis demonstrated that a higher number of pain sites (23-44 sites) and higher pain and stiffness severity were associated with greater levels of fatigue. In newly diagnosed PMR patients, fatigue was associated with PMR symptom severity.

A serological marker of the N-terminal neoepitope generated during LOXL2 maturation is elevated in patients with cancer or idiopathic pulmonary fibrosis.

OBJECTIVES: Lysyl oxidase like 2 (LOXL2) is associated with poor prognosis in idiopathic pulmonary disease (IPF) and cancer. We developed an Enzyme-linked immunosorbent assay (ELISA) targeting the LOXL2 neo-epitope generated through the release of the signal peptide during LOXL2 maturation. DESIGN AND METHODS: An ELISA targeting the N-terminal site of the human LOXL2 was developed including technical optimization and validation steps. Serum LOXL2 was measured in patients with breast, colorectal, lung, ovarian, pancreatic and prostate cancer, melanoma, IPF and in healthy controls (n = 16). RESULTS: A technically robust and specific assay was developed. LOXL2 was detectable in serum from healthy controls and showed reactivity towards recombinant LOXL2. Compared to controls, LOXL2 levels were significantly (p < 0.001-0.05) elevated in serum from patients with breast, colerectal, lung, ovarian and pancreatic cancer (mean range: 49-84 ng/mL), but not in prostate cancer (mean: 36 ng/mL) and malignant melanoma patients (41 ng/mL). Serum LOXL2 was elevated in IPF patients compared to healthy controls (mean: 76.5 vs 46.8 ng/mL; p > 0.001). CONCLUSIONS: A specific ELISA towards the N-terminal neo-epitope site in LOXL2 was developed which detected significantly elevated serum levels from patients with above-mentioned cancer types or IPF compared to healthy controls.

Perspectives and unmet needs in polymyalgia rheumatica. Providing the fundamental framework for the development of new treatment regimes in polymyalgia rheumatica.

Polymyalgia rheumatica is effectively treated with glucocorticoids. However, glucocorticoid treatment can cause numerous and potentially serious side effects. Therefore, lowest effective dose and shortest duration to control disease is aimed for and glucocorticoid-sparing treatments are needed. Nevertheless, development of treatment regimens in PMR has been hampered by the lack of reliable classification criteria and evidence-based outcome measures. In this editorial, we discuss the need for valid classification criteria in PMR, the strengths and limitations of the ACR/EULAR 2012 provisional classification criteria for PMR and the need of validation and possible refining of the criteria.

Association between characteristics of pain and stiffness and the functional status of patients with incident polymyalgia rheumatica from primary care.

This paper aims to examine the relationship between different characteristics of pain and stiffness and the functional status of patients with newly diagnosed polymyalgia rheumatica (PMR). Baseline analysis of an inception cohort study was conducted. Patients aged ≥18 years, with a new diagnosis of PMR were recruited from 382 English general practices. Participants were mailed a baseline questionnaire, including separate pain and stiffness manikins and numerical rating scales (NRS), a question on their ability to raise their arms above their head and the modified Health Assessment Questionnaire (mHAQ) to examine participants' functional status. Linear regression analysis, reported as regression co-efficients (95% confidence intervals (95% CI)), was used to assess the association of pain and stiffness with function, initially unadjusted and then adjusted for age, gender, deprivation status, smoking status, BMI, anxiety and depression. Six hundred fifty two patients responded to the baseline survey (88.5%). The majority (88.2%) reported no, or mild impairment in their functional status. Adjusted linear regression analysis demonstrated that high (NRS ≥8) pain (0.20 (95% CI 0.10-0.28)) or stiffness (0.18 (0.09-0.26)) ratings, an increasing number of sites of pain (0.18 (0.06-0.29)) or stiffness (0.19 (0.08-0.31)) and shoulder pain (0.18 (0.05-0.31)), stiffness (0.10 (0.01-0.20)) and difficulty raising arms above one's head (0.19 (0.10-0.28)) were all associated with increased functional impairment. The majority of newly diagnosed PMR patients reported no or minimal functional difficulty. However, those who experience severe or widespread pain or stiffness often have significant functional limitation in performing their daily activities and may be a subset worthy of additional focus in primary care.

Cathepsin-S degraded decorin are elevated in fibrotic lung disorders - development and biological validation of a new serum biomarker.

BACKGROUND: Decorin is one of the most abundant proteoglycans of the extracellular matrix and is mainly secreted and deposited in the interstitial matrix by fibroblasts where it plays an important role in collagen turnover and tissue homeostasis. Degradation of decorin might disturb normal tissue homeostasis contributing to extracellular matrix remodeling diseases. Here, we present the development and validation of a competitive enzyme-linked immunosorbent assay (ELISA) quantifying a specific fragment of degraded decorin, which has potential as a novel non-invasive serum biomarker for fibrotic lung disorders. METHODS: A fragment of decorin cleaved in vitro using human articular cartilage was identified by mass-spectrometry (MS/MS). Monoclonal antibodies were raised against the neo-epitope of the cleaved decorin fragment and a competitive ELISA assay (DCN-CS) was developed. The assay was evaluated by determining the inter- and intra-assay precision, dilution recovery, accuracy, analyte stability and interference. Serum levels were assessed in lung cancer patients, patients with idiopathic pulmonary fibrosis (IPF), patients with chronic obstructive pulmonary disease (COPD) and healthy controls. RESULTS: The DCN-CS ELISA was technically robust and was specific for decorin cleaved by cathepsin-S. DCN-CS was elevated in lung cancer patients (p < 0.0001) and IPF patients (p < 0.001) when compared to healthy controls. The diagnostic power for differentiating lung cancer patients and IPF patients from healthy controls was 0.96 and 0.77, respectively. CONCLUSION: Cathepsin-S degraded decorin could be quantified in serum using the DCN-CS competitive ELISA. The clinical data indicated that degradation of decorin by cathepsin-S is an important part of the pathology of lung cancer and IPF.

Levels of circulating MMP-7 degraded elastin are elevated in pulmonary disorders.

OBJECTIVES: Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. DESIGN AND METHODS: Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls. RESULTS: The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls. CONCLUSIONS: MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases.

Fast track pathway reduces sight loss in giant cell arteritis: results of a longitudinal observational cohort study.

OBJECTIVES: To investigate the effectiveness of a fast track pathway (FTP) on sight loss in patients with suspected giant cell arteritis (GCA). METHODS: A longitudinal observational cohort study was conducted in the secondary care rheumatology department. One hundred and thirty-five newly referred suspected GCA patients seen via the FTP (Jan. 2012-Dec. 2013) were compared to 81 patients seen through the conventional referral and review system (Jan. 2009-Dec. 2011). RESULTS: The FTP resulted in significant reduction in irreversible sight loss from 37.0% (as seen in the historical cohort 2009-2011) to 9.0 % (2012-2013, OR 0.17, p=0.001). Adjustment for clinical and demographic parameters including known risk factors for GCA associated blindness did not significantly change the primary result (OR 0.08, p=0.001). FTP resulted in a reduction of time from symptom onset to diagnosis, particularly by reduction of time from general practitioner's (GP) referral to the rheumatology review (79% of FTP patients were seen within one working day compared to 64.6 % in the conventional pathway, p=0.023). The FTP has seen a reduction in number of GP appointments. CONCLUSIONS: There was a significant reduction of permanent sight loss with a fast track GCA pathway. The effect may be due to multiple factors including better GP education and reduction in delayed diagnosis. These results need verification at other sites.

Use of the WOMAC questionnaire in Mumbai and the challenges of translation and cross cultural adaptation.

Patient-reported outcome measures (PROMs) are disease specific questionnaires that are being increasingly used in clinical practice and research. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), is a widely used PROM in patients with hip or knee osteoarthritis. A validated WOMAC was used by us, and significant challenges were faced in administering it as several questions did not have a cultural connect. Functionally equivalent items in the Indian context had then to be used to complete the score. With greater emphasis today on the use of patient-reported outcome measures, and with data from multi-centric studies being pooled, cross-cultural adaptation becomes very important if the pooled data are to be really relevant. In India, with several languages being spoken, and a significant proportion of the population being illiterate, the physician and/ or the impartial witness must provide considerable explanation without attempting to influence the response. The key to the effective and correct use of PROMs thus lies not just in translation, but also in a stepwise validation of the questionnaire, and modification in the context of the country where it is used. Scores like WOMAC are often primary efficacy endpoints in clinical trials; are gaining greater importance to support label claims; have ethical implications, and directly impact regulatory decision making and thus, eventually, evidence-based practice.

Efficacy and tolerability of leflunomide in difficult-to-treat polymyalgia rheumatica and giant cell arteritis: a case series.

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are related inflammatory rheumatic conditions affecting adults over the age of 50 years. Both conditions respond to initial glucocorticoid (GC) therapy. However, most patients require 12-36 months of a tapering steroid regime. Adverse events at 2 years are seen in up to 65% of patients with PMR and 86% of patients with GCA with over 50% developing serious events. There is also a high incidence of relapse in both diseases -40% within 2 years for GCA and 50% of patients with PMR at some point having a relapse. Effective steroid-sparing adjuvant therapies are urgently required especially in incomplete, poorly sustained or non-responders to glucocorticoids. In this case series, we found that Leflunomide is efficacious, with 22 out of our 23 patients exhibiting a complete or partial response. It was also steroid sparing and well tolerated. It may be a useful adjunctive agent in difficult-to-treat GCA and PMR. Prospective randomised controlled trials of Leflunomide in both GCA and PMR are now required.

Elicitation of health state utilities associated with differing durations of morning stiffness in rheumatoid arthritis.

OBJECTIVE: Specific symptoms of rheumatoid arthritis (RA), including joint stiffness and functional disability, are most severe in the morning. 'Morning stiffness' has a negative impact on health-related quality-of-life (HRQoL); however, how HRQoL is correlated to morning stiffness duration is unknown. The objective of this study was to obtain population-based utility values associated with different durations of morning stiffness in RA. DESIGN AND METHODS: The time-trade-off (TTO) approach was used to elicit utility values for four different health states (HS), which differed in morning stiffness duration. One hundred and nine members of the UK general public rated each HS in individual face-to-face interviews with trained investigators. TTO scores were converted into utility values. Visual Analog Scale (VAS) scores were obtained to validate TTO scores. RESULTS: On a scale of 0 (death) to 1 (full health), a mean utility value of 0.45±0.29 was elicited for ∼3 h of morning stiffness (anchor HS), 0.50±0.28 for 2-3 h of morning stiffness (HS1), 0.61±0.25 for 1-2 h of morning stiffness (HS2) and 0.78±0.20 for <1 h of morning stiffness (HS3). The difference between each HS was statistically significant (p<0.01). Mean VAS utility scores followed the same trend. Utility incrementally increased with each HS associated with a shorter duration of morning stiffness. Limitations of this research include potential bias from the TTO method due to the discounting effect of time, scale compatibility, and loss aversion. CONCLUSIONS: The UK population-based utility values show a reduction in morning stiffness duration in RA is associated with improved HRQoL. Despite the impact of morning stiffness on HRQoL, it is rarely evaluated and little is known as to how it is affected by current treatments. The results of this study can be applied in future cost-utility analyses of healthcare interventions which target an improvement in morning stiffness duration for RA patients.

EULAR recommendations for the management of large vessel vasculitis.

OBJECTIVES: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. METHODS: An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. RESULTS: Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures. CONCLUSIONS: On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.

EULAR recommendations for the management of primary small and medium vessel vasculitis.

OBJECTIVES: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. METHODS: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. RESULTS: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. CONCLUSIONS: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

KINALYZER, a computer program for reconstructing sibling groups.

A software suite KINALYZER reconstructs full-sibling groups without parental information using data from codominant marker loci such as microsatellites. KINALYZER utilizes a new algorithm for sibling reconstruction in diploid organisms based on combinatorial optimization. KINALYZER makes use of a Minimum 2-Allele Set Cover approach based on Mendelian inheritance rules and finds the smallest number of sibling groups that contain all the individuals in the sample. Also available is a 'Greedy Consensus' approach that reconstructs sibgroups using subsets of loci and finds the consensus of the partial solutions. Unlike likelihood methods for sibling reconstruction, KINALYZER does not require information about population allele frequencies and it makes no assumptions regarding the mating system of the species. KINALYZER is freely available as a web-based service.

Modification and validation of the Birmingham Vasculitis Activity Score (version 3).

BACKGROUND: Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee. OBJECTIVE: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. METHODS: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. RESULTS: The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman's r(s) = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (r(s) = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (r(s) = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (r(s) = 0.43, 95% CI 0.31 to 0.54), physician's global assessment (r(s) = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (r(s) = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test). CONCLUSION: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

Protective properties of Leucas lavendulaefolia extracts against D-galactosamine induced hepatotoxicity in rat.

Different extracts of the leaves of Leucas lavendulaefolia were tested against D-galactosamine (D-GalN) induced liver toxicity in rats. The methanol extract (100 mg/kg, p.o.) which exhibited significant hepatoprotective activity seems to support the claim of folk medicine.