Circulatory Levels of RANKL, OPG, and Oxidative Stress Markers in Postmenopausal Women With Normal or Low Bone Mineral Density.

INTRODUCTION: Receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and oxidative stress markers are suggested to contribute to bone loss in osteoporosis that occurs in menopause. However, the association between these markers and bone mineral density (BMD) is controversial. The aim of this study was to measure circulatory levels of these parameters in postmenopausal women with normal or low BMD. METHODS: The study population included 71 postmenopausal women, of whom 25 had normal BMD, 31 had osteopenia, and 15 had osteoporosis. Serum levels of RANKL, OPG, and 5 oxidative stress markers (catalase, peroxiredoxin 2 [PRX2], superoxide dismutase 1 [SOD1], superoxide dismutase 2 [SOD2], and thioredoxin [TRx1]) were measured using the Multiplex system. RESULTS: As compared with subjects having normal BMD, subjects with low BMD had significantly lower median serum levels of OPG, catalase, SOD2, and PRX2 (P = .004, .031, .044, and .041 respectively). Although levels of RANKL were not different between the 2 groups, the RANKL/OPG ratio was higher in women with low BMD (P = .027). CONCLUSIONS: These data provide insights into the possible roles of OPG, RANKL, and oxidative stress in the pathogenesis of postmenopausal osteoporosis. However, the lack of association between these markers and BMD indicates that osteoporosis is complex and multivariate.

Circulatory pattern of cytokines, adipokines and bone markers in postmenopausal women with low BMD.

Objective: In addition to some well-characterized bone turnover markers (BTMs), cytokines and adipokines have also been suggested to be linked to osteoporosis seen in menopause. However, there is much controversy on the possible association between these markers and bone mineral density (BMD). This study was aimed at measuring circulatory levels of selected cytokines, adipokines and BTMs in postmenopausal women with normal and low BMD. Methods: The study population included 71 post-menopausal women, of whom 25 had normal BMD, 31 had osteopenia and 13 had osteoporosis. Circulatory levels of selected pro-resorptive (TNF-α, IL-1ß, IL-6, IL-8, IL-12, IL-17), anti-resorptive (IFN-γ, IL-4, IL-10, IL-13, TGF-ß) and five adipokine markers (adiponectin, adipsin, lipocalin-2/NGAL, PAI-1 and resistin) were measured using the Multiplex system and read on the Magpix ELISA platform. Further, two bone turnover markers (PINP, CTX) as well as estradiol levels were assayed from the same samples. Results: While circulatory levels of cytokines were comparable between groups, women with low BMD had statistically significantly higher median circulatory levels of adipokines as compared to those with normal BMD. Further, while levels of CTX were not different between the two groups; PINP, PINP/CTX ratio and estradiol levels were significantly lower in women with low BMD. Levels of adiponectin, PINP, PINP/CTX ratio and estradiol correlated significantly with BMD of the hip and spine. Conclusion: The associations between various markers and BMD are complex and multivariate. Our data provide insights into the possible use of circulatory levels of cytokines, adipokines and bone turnover markers on the pathogenesis of postmenopausal osteoporosis because of the well-documented effects of these molecules on bone tissue and their relevance to osteoporosis.

Soft Tissue Pathology Detected By Ultrasound Seem To Be Risk Factors for Painful Flare in Osteoarthritic Knee.

BACKGROUND: To our knowledge, the importance of US findings, pain (brief pain inventory (BPI)) and disability in osteoarthritic knee (OA) pain patients remain uncertain. AIM: The objectives are to evaluate the correlation of US findings, pain (brief pain inventory (BPI)) and disability in OA pain patients. MATERIALS AND METHODS: Eighty - three patients with OA knee were divided into two groups. The first group was OA as symptomatic knee group and the second group was an asymptomatic control group. The maximum sagittal height of synovial fluid in 12 scans at 0, 30, 60 and 90 degrees flexion knee in 3 major recesses were measured. RESULTS: There were a significant positive correlation between BPI Pain severity index, or BPI function interference index and a maximum height of effusion at 30-degree flexion angle in a supra-patellar recess in painful symptomatic knees. But, there was a significant negative correlation between BPI Pain severity index, and BPI function interference index and cartilage thickness in painful symptomatic knees. CONCLUSION: The increase of maximum height of synovial effusion at different angles of knee and decrease of cartilage thickness associated with pain and disability in OA pain patients and are being predictors for pain severity and disability in OA pain patients.

Patterns of circulatory and peripheral blood mononuclear cytokines in rheumatoid arthritis.

An imbalance in pro- and anti-inflammatory cytokines is suggested to contribute to tissue damage in rheumatoid arthritis (RA). This study was aimed at investigating profiles of cytokines in circulation and cytokines produced by mitogen-stimulated peripheral blood mononuclear cells (PBMC) in RA patients and healthy controls, and to explore correlations of cytokines with disease activity. Our aim was to identify patterns of cytokine expression as possible indicators of disease activity. Levels of plasma cytokines and PBMC-secreted cytokines were estimated in 26 female RA patients and 28 controls. Five pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-17, IL-12) and three anti-inflammatory cytokines (IL-4, IL-10, IL-13) were assayed in a multiplex ELISA. RA patients had significantly higher plasma levels of TNF-α, IL-12, and IL-4 compared to healthy controls. On the other hand, mitogen-activated PBMC secreted significantly higher levels of the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-12, but lower levels of the anti-inflammatory cytokine IL-10 in RA compared to healthy subjects. The ratios TNF-α/IL-10, IFN-γ/IL-10, IL-17/IL-10, IL-12/IL-10, and IFN-γ/IL-13 were significantly higher in RA patients compared to healthy controls. The range and expression of cytokines were higher in PBMC than in the plasma in all the groups studied. Multivariate pattern analysis of eight cytokines revealed a prediction accuracy of 69% in differentiating RA patients from healthy controls, and of 73% in classifying patients as in remission or active RA. Our data suggest that it is worthwhile to explore ratios of pro- to anti-inflammatory cytokines produced by mitogen-stimulated PBMC in RA, and the use of multivariate cytokine pattern and algorithms for better delineation of this condition.

Cytokine profiles in osteoporosis suggest a proresorptive bias.

OBJECTIVE: As the immune system is suggested to contribute to the pathophysiology of osteoporosis in menopause, we compared the levels of proresorptive and antiresorptive cytokines produced by peripheral blood mononuclear cells (PBMCs) from postmenopausal women with normal and low bone mineral density (BMD). METHODS: Seventy-one postmenopausal women were studied; 25 had normal BMD and 46 had low BMD. Participants were categorized as normal (n = 25), osteopenic (n = 31), and osteoporotic (n = 15) based on T-scores. Levels of 10 cytokines produced by mitogen-stimulated PBMCs were measured by Multiplex ELISA. RESULTS: PBMCs from women with low BMD produced higher levels of the proresorptive cytokines tumor necrosis factor-alpha, interleukin (IL)-6, IL-12, and IL-17 (P = 0.014, 0.012, 0.011, and 0.049), and lower levels of the antiresorptive cytokines IL-4, IL-10, and IL-23 (P = 0.003, 0.018, and 0.025) compared with women with normal BMD. Proresorptive cytokines were similar in osteopenic and osteoporotic women, but both had higher levels than women with normal BMD. Osteoporotic women produced lower levels of the antiresorptive cytokines IL-4, IL-10, IL-13, and IL-23 compared with the normal BMD group (P = 0.001, 0.05, 0.05, and 0.026), and lower levels of IL-4 as compared with osteopenic women (P = 0.05). Osteopenic women produced lower levels of IL-4 and IL-10 compared with the normal BMD group (P = 0.025 and 0.038). Ratios of proresorptive to antiresorptive cytokines suggest a stronger proresorptive cytokine bias in women with low BMD. Most of the ratios are lowest in the normal BMD group, modest in osteopenic women, and highest in the osteoporotic group. CONCLUSIONS: Women with low BMD have a proresorptive cytokine bias.

Prevalence of joint hypermobility in Kuwait.

AIM: To determine the prevalence of joint hypermobility (JH) among young Kuwaiti adults. METHODS: This was a cross-sectional study of 390 randomly selected healthy undergraduate university students, aged 18-29 years from the Health Sciences Centre, Kuwait University, Safat, Kuwait. Beighton score at four peripheral sites bilaterally (knees, elbows, thumbs and fifth fingers) and forward flexion of the trunk were used to evaluate joint hypermobility. Any student who met four out of the nine criteria was considered hypermobile. Joint pain was documented in all subjects through personal interview. RESULTS: A total of 390 subjects (male : female ratio 1.0 : 0.9) were assessed. Of those, 87 (22.3%) were found to have JH: 60 (29.4%) males and 27 (14.5%) females, showing a significantly higher male predominance (P < 0.001). Beighton score was inversely correlated with age (ρ = -0.15, P = 0.003). A higher incidence of finger signs was noted in comparison to elbow-knee hyperextension and hands-to-floor. Knee joint, back, neck and shoulder pains, in descending order, were the commonest type of joint complaints, although not statistically significant (P > 0.05) in subjects with and without joint hypermobility. It was also observed that the left side, at all the sites, was slightly more hypermobile in comparison to the right side in hypermobile subjects. CONCLUSIONS: The prevalence of joint hypermobility is not uncommon among young Kuwaiti adults, and was comparable to the data published in other Asian-Pacific regions. General practitioners should therefore be familiar with the condition and its clinical associations, while assessing musculoskeletal complaints.

Knee Osteoarthritis in Type 2 Diabetes Mellitus: Does Insulin Therapy Retard Osteophyte Formation?

OBJECTIVE: The aim of this study was to investigate whether or not radiographic changes observed in knee osteoarthritis (OA) in type 2 diabetes mellitus (T2DM) patients on insulin therapy differed from those not on insulin. MATERIAL AND METHODS: A cross-sectional study was performed in 311 subjects: 211 T2DM patients and 100 without diabetes (controls) in Mubarak Hospital, Kuwait. Patients were categorized into 3 groups: T2DM patients not on insulin (G1, n = 99), T2DM patients on insulin (G2, n = 112) and a nondiabetic control group (G3, n = 100). Plain X-ray of both knees was used to assess the changes of knee OA and graded using the Kellegren-Lawrence scale (0-4) and the Osteoarthritis Research Society International Atlas grading scale (0-3). A total of 622 knee X-rays were evaluated. SPSS version 21.0 was used for data analysis. RESULTS: A highly significant association (p < 0.0001) was observed for joint space narrowing (JSN) as well as for osteophyte formation between the three groups. Comparing G2 and G3, a highly significant association (p < 0.0001) was retained for JSN [201 (89.7%) vs. 199 (99.5%)] and for osteophyte formation [26 (11.7%) vs. 72 (36.0%)]. Comparing G1 and G2, significantly less osteophyte formation was noted in G2 patients compared to G1 patients [26 (11.7%) vs. 39 (19.7%), p = 0.02]. Multivariate logistic regression analysis showed that the G2 group had less chance of osteophyte formation than either the G1 group or G3 control group (OR = 0.294, p = 0.008 and OR = 0.098, p < 0.001, respectively). CONCLUSION: Our findings show that T2DM patients with OA knees on insulin therapy have less radiographic osteophytes compared to T2DM patients not on insulin.

Rheumatic complications of inflammatory bowel disease among Arabs: a hospital-based study in Kuwait.

AIM: To investigate the rheumatic complications of inflammatory bowel disease (IBD) Arab patients in relation to the clinical manifestations of IBD using the Montréal classification system in a hospital-based population in Kuwait. METHOD: A cohort of 130 consecutive patients with IBD, either ulcerative colitis (UC) or Crohn's disease (CD) attending gastroenterology and rheumatology clinics of Kuwait University hospital from January to December 2010 were recruited. IBD diagnosis, classification, and the rheumatologic characteristics of patients were assessed and noted on a pro forma. RESULTS: In the 130 IBD patients (mean age 32.6 ± 12.3 years), 45 (34.6%) had UC and 85 (65.4%) had CD. Forty-five (34.6%) IBD patients developed rheumatic manifestations; the difference in proportion was not significant among UC and CD patients (18 [40.0%] vs. 27 [31.7%], P = 0.215). Peripheral arthritis was seen in 41 (31.5%) IBD patients. Axial skeletal involvement presenting as a combination of spondyloarthritis with sacroiliitis was seen in 11 (8.5%) out of 130 IBD patients. Isolated sacroiliitis was seen in four (3.1%) IBD patients. Enthesopathy was seen in seven (5.4%) and dactylitis in two (1.5%) IBD patients. No statistically significant difference (P > 0.05) was detected between the frequency of the rheumatic manifestations and the IBD clinical subtypes. CONCLUSION: This study delineates the rheumatic complications in relation to clinical manifestations (phenotypes) of IBD using the Montréal classification, in a hospital-based cohort of an Arab population. The rheumatic manifestations of IBD in our study were comparable to previously published data from other parts of the world.

Musculoskeletal pain: should physicians test for vitamin D level?

AIM: The aim of this study was to evaluate vitamin D levels using a reliable method in patients with regional and generalized musculoskeletal (MSK) pain in comparison to healthy controls. METHODS: A consecutive prospective case control cohort was recruited. Patients with generalized MSK pain, for example, fibromyalgia (FM), and regional MSK pain, for example, nonspecific low back pain (LBP) and knee osteoarthritis (OA) were screened for 25 hydroxy-vitamin D [25(OH)D3 ] levels over a period of 9 months in a hospital-based setting. RESULTS: One hundred and twenty-four patients and 82 age-sex matched controls were evaluated. The mean age for patients was 41.71 ± 13.86 years. Of the 124 patients, 118 (95%) were female, 77 (62.6%) had FM, 18 (14.6%) had LBP and 28 (22.8%) had knee OA. All patients had normal muscle power; 83.7% of females wore long garments, 11.4% wore veils, 95.5% had sun exposure < 10 min/day and 58.5% were multiparaous; 7.3% were strict vegetarians, 45.5% took inadequate dairy products. The mean calcium, parathyroid hormone, alkaline phosphatase and albumin levels were within normal limits for all study subjects. The vitamin D level was deficient in all patients. There was no statistical difference between the mean vitamin D values of the patients and controls, 27.61 ± 13.06 and 25.82 ± 15.06 nmol/L respectively, (P = 0.368). CONCLUSION: Our findings suggest that it is unlikely that measuring vitamin D will be of diagnostic value in the routine assessment of regional and generalized MSK pain.

Ossification of ligamentum flavum in Middle East Arabs: a hospital-based study.

OBJECTIVE: To investigate the frequency of ossification of the ligamentum flavum (OLF) in the spine among the Arab population in Kuwait using magnetic resonance imaging (MRI) surveillance of the whole spine. SUBJECTS AND METHODS: A consecutive series of 102 patients with low back pain were recruited from the outpatient clinic of Mubarak Al-Kabeer Hospital, Kuwait. MRI of the whole spine in the sagittal plane was obtained in at least two sequences (T(1) and T(2)). The OLF was defined as low signal intensity thickening of the ligament in both T(1) and T(2) sequences on the posterior margin of the spinal canal, causing indentation of the theca with or without cord compression. RESULTS: Of the 102 cases, 19 (18.6%) patients had OLF. Of the 19 positive cases, 12 (63.2%) were present at a single level, and 7 (36.8%) at multiple levels. A total of 26 OLF segments were identified in the following anatomical distribution: cervical: 15 (57.7%); upper thoracic (T1-T4): 1 (3.8%); mid thoracic (T5-T8): 4 (15.4%); lower thoracic (T9-T12): 4 (15.4%), and lumbar region: 2 (7.7%). Of the 19 OLF patients, 2 (10.5%) had tandem ossification of the posterior longitudinal ligament in the cervical spine and were symptomatic. CONCLUSIONS: The frequency of OLF appears to be high among this hospital-based cohort of the Arab population. OLF should be kept in mind if a patient presents with radiculopathy, particularly in the cervical region, for which surgical intervention is contemplated.

Are 25(OH)D levels related to the severity of knee osteoarthritis and function?

OBJECTIVE: To investigate the effect of 25-hydroxyvitamin D [25(OH)D] in Kuwaiti patients with primary knee osteoarthritis (OA) and to assess its relation with radiological grading and functional status. SUBJECTS AND METHODS: In this cross-sectional study, 25(OH)D was measured using radioimmunoassay in 99 patients [90 women and 9 men; mean age 56.5 ± 9.1 years (range: 36-80)] with clinical and radiological findings of primary knee OA. X-ray grading using the Kellgren-Lawrence grading scale and the Osteoarthritis Research Society International (OARSI) Atlas grading scale and functional assessments using Lequesne's indices were evaluated in relation to the 25(OH)D level. Other variables studied were age at onset of symptoms, body mass index and duration of disease. RESULTS: The age of the patients at the onset and the duration of disease were 51.58 ± 7.14 and 3.88 ± 2.51 years, respectively. Mean scoring for functional assessment was 10.31 ± 4.35 and mean Kellgren-Lawrence radiological grading was 2.43 ± 0.85. Radiological finding according to the OARSI Atlas revealed joint space narrowing of grades 2-3 in 87 (87.9%) patients and the presence of osteophytes in 55 (55.6%) patients. The mean value of 25(OH)D level was 11.4 ± 6.07 ng/ml. Of the 99 patients, 92 (92.9%) were vitamin D deficient. Comparison of 25(OH)D levels to radiological findings and different functional classes showed no significant association. CONCLUSION: Most of our patients had vitamin D deficiency, but the level of 25(OH)D was not related to the severity of the knee X-ray grading or to the functional assessment in our patients with primary knee OA.

Antibodies to mutated citrullinated vimentin and anti-cyclic citrullinated peptide antibodies in inflammatory bowel disease and related arthritis.

BACKGROUND: Antibodies that react with citrullinated proteins (anti-mutated citrullinated vimentin [anti-MCV] and second-generation anti-cyclic citrullinated peptide antibodies [anti-CCP2]) are markers for rheumatoid arthritis. Recent studies have demonstrated that these antibodies are present in other arthropathies including the spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Arthritis associated with inflammatory bowel disease (IBD) takes various forms, with some shared similarities with classic spondylarthropathies. Our objective was to investigate the role of anti-MCV and anti-CCP2 as potential biomarkers in IBD and related arthritis. METHODS: In all, 125 IBD patients (71 males, 54 females) were compared to 81 age- and sex-matched healthy controls. Anti-MCV and Anti-CCP2 IgG were measured using an enzyme linked immunosorbent assay. RESULTS: In the 125 IBD patients (mean age 32.6 ± 12.3 years), 44 (35.2%) had ulcerative colitis and 81 (64.8%) had Crohn's disease. Forty-four (35.2%) IBD patients developed arthritic manifestations. Antibody positivity was observed in 24/125 (19.2%) IBD patients and in 18/81 (22.2%) healthy subjects. The proportion of anti-MCV positivity among IBD patients and healthy individuals were similar: 16.8% vs. 16.0%, P = 0.887. Anti-CCP2 positivity among IBD patients and healthy individuals was also comparable: 6.4% vs. 6.2%, P = 0.948. Similarly, the presence of anti-MCV and anti-CCP2 antibodies was not different among IBD patients with and without arthritis. The mean titers of antibodies were low: anti-MCV (29.6 ± 7.5 U/mL) and anti-CCP2 (27.6 ± 4.0 U/mL) in IBD patients with arthritis. CONCLUSIONS: Autoantibodies to citrullinated proteins were low in IBD-related arthritis. These findings suggest that these antibodies are not useful biomarkers in IBD to predict who may develop IBD-related arthropathy.

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis.

BACKGROUND AND OBJECTIVES: Peroxisome proliferator-activated receptors (PPARs) play an important role in a number of cellular and metabolic functions. This study was carried out to determine the prevalence of a missense mutation (Pro12Ala) in the PPARG2 gene in Kuwaiti Arab patients with primary knee osteoarthritis (OA) and healthy controls with the aim of identifying a possible association. DESIGN AND SETTING: A prospective cross-sectional study carried out at three major teaching hospitals (referral centers) in the country over a one-year period. PATIENTS AND METHODS: The prevalence of PPARG2 gene Pro12Ala missense mutation was determined in 104 Kuwaiti Arab patients with primary knee OA and 111 ethnically matched healthy controls. The prevalence of this Pro12Ala missense mutation was also determined in clinical subgroups of OA patients divided on the basis of age at onset, function and radiologic grading. RESULTS: The Pro-Pro genotype of the PPARG2 gene Pro12Ala missense mutation was detected in 95/104 (91.3%) cases compared to 111/111 (100%) in the control subjects. The heterozygous Pro-Ala genotype was detected in 9/104 (8.7%) of the OA patients, while it was not detected in any of the controls. The Ala-Ala genotype was not detected in any of the OA patients or the controls. No significant differences were detected in the PPARG2 gene Pro12Ala genotypes in the subgroups of patients classified on the basis of age at onset, functional assessment using Lequesne's functional index, and radiological grading using Kellgren-Lawrence (K-L) grading. CONCLUSIONS: This study found no significant association between the PPARG2 gene Pro12Ala missense mutation and knee OA. However, the presence of the Pro-Pro genotype of the PPARG2 gene mutation has a protective effect against development of OA.

Frequency and confidence in performing clinical skills among medical interns in Kuwait.

BACKGROUND: Several investigations suggest inadequate emphasis of basic clinical procedures during internship training. Many trainees had reported lack of competence, while some expressed confidence to manage conditions although not sufficiently experienced. AIMS: This study aimed at ascertaining the perceptions of new medical graduates regarding the performance of core clinical skills during training and confidence of performing them later. It also aimed at determining any gender variability in the confidence in performing selected clinical skills in Obstetrics & Gynaecology. METHODS: Interns trained during 2005/06 responded anonymously to a questionnaire that listed 48 core clinical skills. The 124 subjects eligible for the study comprised graduates from Kuwait (64), other Gulf Cooperation Council countries (29), Ireland (27) and Egypt. They indicated whether they felt confident to perform the skills in future, and the number of times they had performed them during training. We received 91 completed questionnaires. RESULTS: The majority felt confident in performing routine skills (basic ECG and X-ray interpretations, insertion of intravenous line, inserting urethral catheter and nasogastric feeding). Approximately two thirds had performed generic skills related to emergency resuscitation, with a half of them confident in performing them in the future. A third felt confident in performing artificial ventilation and endotracheal intubation. The confidence to perform common skills in Obstetrics & Gynaecology varied, with no significant gender variation. Approximately a fifth was confident in performing lumbar puncture, needle aspiration of joints, insertion of thoracic drainage, insertion of central venous catheter, venous cut-down and indirect laryngoscopy. A small proportion reported confidence in performing different clinical procedures although they had not undertaken them during training. CONCLUSIONS: Substantial proportions of trainees lacked confidence in performing emergency resuscitative measures and some routine clinical skills. Training needs to be closely monitored and interns who are not competent identified early for taking remedial measures.