Adipokine secretion and lipolysis following gender-affirming treatment in transgender individuals.

BACKGROUND: The organ-specific effects of gender-affirming sex hormone treatment (GAHT) in transgender women (TW) and transgender men (TM) are insufficiently explored. This study investigated the effects of GAHT on adipose tissue function. METHODS: In a single-center interventional prospective study, 32 adults undergoing GAHT, 15 TW and 17 TM, were examined with anthropometry and abdominal subcutaneous adipose tissue biopsies obtained before initiation of treatment, 1 month after endogenous sex hormone inhibition and three and 11 months after initiated GAHT. Fat cell size, basal/stimulated lipolysis and cytokine secretion in adipose tissue were analyzed. RESULTS: TW displayed an increase in complement component 3a and retinol-binding protein 4 (RBP4) secretion after sex hormone inhibition, which returned to baseline following estradiol treatment. No changes in lipolysis were seen in TW. TM showed downregulation of RBP4 after treatment, but no changes in basal lipolysis. In TM, the estrogen suppression led to higher noradrenaline stimulated (NA) lipolysis that was normalized following testosterone treatment. At 11 months, the ratio of NA/basal lipolysis was lower compared to baseline. There were no significant changes in fat cell size in either TW or TM. CONCLUSION: In TW, gonadal hormone suppression results in transient changes in cytokines and in TM there are some changes in NA-stimulated lipolysis following testosterone treatment. However, despite the known metabolic effects of sex hormones, the overall effects of GAHT on adipose tissue function are small and likely have limited clinical relevance, but larger studies with longer follow-up are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02518009, Retrospectively registered 7 August 2015.

Posterolateral corner injuries: Epidemiology, anatomy, biomechanics and diagnosis.

Increased internal and external rotational laxity of the knee may result from a wide range of pathologies in or around the knee. However, the principal cause of increased external rotational laxity is damage to the posterolateral corner (PLC). The aim of the review is to discuss the epidemiology, anatomy, biomechanics and diagnosis of PLC injuries.

Gait comparison of unicompartmental and total knee arthroplasties with healthy controls.

AIMS: To compare the gait of unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA) patients with healthy controls, using a machine-learning approach. PATIENTS AND METHODS: 145 participants (121 healthy controls, 12 patients with cruciate-retaining TKA, and 12 with mobile-bearing medial UKA) were recruited. The TKA and UKA patients were a minimum of 12 months post-operative, and matched for pattern and severity of arthrosis, age, and body mass index. Participants walked on an instrumented treadmill until their maximum walking speed was reached. Temporospatial gait parameters, and vertical ground reaction force data, were captured at each speed. Oxford knee scores (OKS) were also collected. An ensemble of trees algorithm was used to analyse the data: 27 gait variables were used to train classification trees for each speed, with a binary output prediction of whether these variables were derived from a UKA or TKA patient. Healthy control gait data was then tested by the decision trees at each speed and a final classification (UKA or TKA) reached for each subject in a majority voting manner over all gait cycles and speeds. Top walking speed was also recorded. RESULTS: 92% of the healthy controls were classified by the decision tree as a UKA, 5% as a TKA, and 3% were unclassified. There was no significant difference in OKS between the UKA and TKA patients (p = 0.077). Top walking speed in TKA patients (1.6 m/s; 1.3 to 2.1) was significantly lower than that of both the UKA group (2.2 m/s; 1.8 to 2.7) and healthy controls (2.2 m/s; 1.5 to 2.7; p < 0.001). CONCLUSION: UKA results in a more physiological gait compared with TKA, and a higher top walking speed. This difference in function was not detected by the OKS. Cite this article: Bone Joint J 2016;98-B(10 Suppl B):16-21.

Internal fixation of femoral neck stress fractures in young female athletes with a dynamic locking plate.

PURPOSE: Displaced stress fractures of the femoral neck in young female athletes are a rare but a difficult injury to treat with a favourable outcome, as there is a reported high incidence of avascular necrosis. Traditionally they are internally fixed with either cannulated screws or a sliding hip screw. Our study aims to highlight the Targon Femoral Neck (FN, B-Braun, Aesculap Inc, Germany) implant as a safe alternative for fixation of these injuries. METHODS: Three consecutive young female recreational athletes were reviewed from our institution with a displaced stress fracture of the femoral neck treated with the dynamic locking plate. RESULTS: Two patients achieved good results with full union and no complications. One patient had a poor result as she developed avascular necrosis 5 months post-operatively requiring revision to a total hip arthroplasty. CONCLUSION: Our study highlights the Targon FN implant is a safe alternative for internal fixation of displaced stress fractures of the femoral neck in young female recreational athletes.

Progressive retinal atrophy in Shetland sheepdog is associated with a mutation in the CNGA1 gene.

Progressive retinal atrophy (PRA) is the collective name of a class of hereditary retinal dystrophies in the dog and is often described as the equivalent of retinitis pigmentosa in humans. PRA is characterized by visual impairment due to degeneration of the photoreceptors in the retina, usually leading to blindness. PRA has been reported in dogs from more than 100 breeds and can be genetically heterogeneous both between and within breeds. The disease can be subdivided by age at onset and rate of progression. Using genome-wide association with 15 Shetland Sheepdog (Sheltie) cases and 14 controls, we identified a novel PRA locus on CFA13 (Praw  = 8.55 × 10(-7) , Pgenome  = 1.7 × 10(-4) ). CNGA1, which is known to be involved in human cases of retinitis pigmentosa, was located within the associated region and was considered a likely candidate gene. Sequencing of this gene identified a 4-bp deletion in exon 9 (c.1752_1755delAACT), leading to a frameshift and a premature stop codon. The study indicated genetic heterogeneity as the mutation was present in all PRA-affected individuals in one large family of Shelties, whereas some other cases in the studied Sheltie population were not associated with this CNGA1 mutation. To our knowledge, this is the first report of a mutation in CNGA1 causing PRA in dogs.

Gait asymmetry detection in older adults using a light ear-worn sensor.

Measuring gait asymmetry is an important feature when characterizing functional imbalance between limbs. This could be due to pathologies, such as osteoarthritis, stroke, or associated with the effects of surgeries such as hip arthroplasty. Generally, the study of asymmetry or imbalance has required the use of a gait lab or force plates, which could be expensive and difficult to use in home settings. This work validates the use of a light weight ear sensor (7.4 g) with an instrumented treadmill for 64 subjects (age (60.04 (15.36)) including healthy subjects (14) as well as subjects who had been treated for hip (17), knee-replacement surgery (21) and knee osteoarthritis (12). Subjects performed treadmill walking at several speeds on flat surfaces, inclines and declines. Accelerometer data from the ear sensor were segmented into consecutive steps and temporal features were extracted. The measures of gait cycle time and step-period asymmetry obtained from the ear sensor matched well those of the treadmill for flat surfaces, inclines and declines. The key implication of the study is that the proposed method could replace expensive equipment for monitoring temporal gait features in clinics as well as free-living environments, which is important for monitoring rehabilitation after surgery and the progress of diseases affecting limb imbalance.

Changes in proteinase 3 anti-neutrophil cytoplasm autoantibody levels in early systemic granulomatosis with polyangiitis (Wegener's) may reflect treatment rather than disease activity.

OBJECTIVES: To investigate the nature of the relationship between proteinase 3 anti-neutrophil cytoplasm autoantibody (PR3-ANCA) and relapse in patients with early systemic granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: Clinical data from 16 relapsing and 12 non-relapsing patients with early systemic GPA from a randomised clinical trial were correlated to monthly PR3-ANCA values over 18 months. Each sample was examined using 9 different enzyme-linked immunosorbent assays (ELISAs) to ensure reliability of ANCA results. PR3-ANCA peaks were identified by the highest sum of logarithmic transformation values from all assays in samples after remission. RESULTS: A PR3-ANCA peak was identified in all relapsing and non-relapsing patients and coincided with relapse in all 14 evaluable relapsing patients. The monthly increment before the peak, however, was similar in relapsing and non-relapsing patients in all assays. Increments from remission to peak were higher in relapsing patients in 2/9 assays. PR3-ANCA values at entry and peak PR3-ANCA values were higher in relapsing patients in 3/9 and 2/9 assays, respectively. However, large overlaps of PR3-ANCA values prevented a distinction between relapsing and non-relapsing patients. The median time to reach peak values was 14 months in relapsing and 12 months in non-relapsing patients with scheduled termination of treatment at 12 months. CONCLUSIONS: The predictive value for relapses of PR3-ANCA determinations confirm and extend previous reports. Although all relapses were related to PR3-ANCA increases, reduction or withdrawal of immunosuppression without relapse was also related to increases and may explain the lack of predictive value of sequential PR3-ANCA determinations.

Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients.

OBJECTIVE: To determine whether the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin M (RF IgM) is associated with endothelial dysfunction in patients with rheumatoid arthritis (RA). METHODS: We studied the presence of anti-CCP antibodies and RF IgM and endothelial function in terms of the reactive hyperaemic index (RHI) in 53 consecutive RA patients. Endothelial function was measured by using a finger plethysmograph. RESULTS: RHI was significantly lower in anti-CCP-positive RA patients (n = 33, RHI = 1.78, SD = 0.30) than in anti-CCP-negative RA patients (n = 20, RHI = 2.19, SD = 0.59; p = 0.008). A similar result was found in RF IgM-positive patients (n = 34, RHI = 1.77, SD = 0.30) vs. RF IgM-negative patients (n = 19, RHI = 2.23, SD = 0.58; p = 0.003). There were no significant differences between the groups regarding age, gender, traditional cardiovascular risk markers, Disease Activity Score using 28 joint counts (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), extra-articular manifestations (EAMs), use of glucocorticosteroids, statins, angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSION: The presence of anti-CCP antibodies and RF IgM was related to impaired endothelial function independent of other cardiovascular risk factors in RA patients. Thus, these autoantibodies might reflect an early reversible stage of the atherosclerotic process, and may indicate increased risk of cardiovascular disease (CVD). Further studies are needed to explore whether anti-CCP antibodies and RF IgM may act directly or indirectly to cause endothelial dysfunction, or merely reflect endothelial dysfunction in RA patients.

An approach to the diagnosis and management of systemic vasculitis.

The systemic vasculitides are a complex and often serious group of disorders which, while uncommon, require careful management in order to ensure optimal outcome. In most cases there is no known cause. Multi-system disease is likely to be fatal without judicious use of immunosuppression. A prompt diagnosis is necessary to preserve organ function. Comprehensive and repeated disease assessment is a necessary basis for planning therapy and modification of treatment protocols according to response. Therapies typically include glucocorticoids and, especially for small and medium vessel vasculitis, an effective immunosuppressive agent. Cyclophosphamide is currently the standard therapy for small vessel multi-system vasculitis, but other agents are now being evaluated in large randomized trials. Comorbidity is common in patients with vasculitis, including the cumulative effects of potentially toxic therapy. Long-term evaluation of patients is important in order to detect and manage relapses.

A population study of a mutation allele associated with cone-rod dystrophy in the standard wire-haired dachshund.

Cone-rod dystrophy in the standard wire-haired dachshund (SWHD) is inherited as a simple autosomal recessive trait and the recently discovered mutation is widespread within the SWHD population in Norway and other Scandinavian countries. The gene frequency was estimated to be 4.8%. On the basis of the assumption that the size of the ancestral haplotype around a mutation is inversely correlated with the number of generations since the mutation arose, we have found that the mutation is of a relatively recent origin. The conserved haplotype was found to be 8 Mb in size and therefore we estimate that the mutation arose roughly eight generations (approximately 37 years) ago. This indicates that the mutation arose after breed separation.

Activation of estrogen response elements is mediated both via estrogen and muscle contractions in rat skeletal muscle myotubes.

The aim of the present study was to investigate the activation of estrogen response elements (EREs) by estrogen and muscle contractions in rat myotubes in culture and to assess whether the activation is dependent on the estrogen receptors (ERs). In addition, the effect of estrogen and contraction on the mRNA levels of ERalpha and ERbeta was studied to determine the functional consequence of the transactivation. Myoblasts were isolated from rat skeletal muscle and transfected with a vector consisting of sequences of EREs coupled to the gene for luciferase. The transfected myoblasts were then differentiated into myotubes and subjected to either estrogen or electrical stimulation. Activation of the ERE sequence was determined by measurement of luciferase activity. The results show that both ERalpha and ERbeta are expressed in myotubes from rats. Both estrogen stimulation and muscle contraction increased (P < 0.05) transactivation of the ERE sequence and enhanced ERbeta mRNA, whereas ERalpha was unaffected by estrogen and attenuated (P < 0.05) by muscle contraction. Use of ER antagonists showed that, whereas the estrogen-induced transactivation is mediated via ERs, the effect of muscle contraction is ER independent. The muscle contraction-induced transactivation of ERE and increase in ERbeta mRNA were instead found to be MAP kinase (MAPK) dependent. This study demonstrates for the first time that muscle contractions have a similar functional effect as estrogen in skeletal muscle myotubes, causing ERE activation and an enhancement in ERbeta mRNA. However, in contrast to estrogen, the effect is independent of ERs and dependent on MAPK, suggesting activation via the estrogen related receptor (ERR).

Expression of both oestrogen receptor alpha and beta in human skeletal muscle tissue.

There are two oestrogen receptors (ERs), ERalpha and ERbeta. ERbeta protein is expressed in human skeletal muscle in the nuclei of both myofibres and endothelial cells, whether ERalpha protein is present in this tissue is unknown. We studied the expression of ERalpha protein in human skeletal muscle biopsies taken from vastus lateralis from four men, four women, two children and two postmenopausal women. Immunohistochemistry was used to determine the proportions of nuclei that were positively stained for ERalpha, the proportion of ERalpha-positive nuclei located in the muscle fibres and in capillaries and to test for possible co-expression of ERalpha and ERbeta. Both ERs were expressed in all subjects. Of all nuclei, 63% stained for ERalpha with no sex difference. ERalpha was localised both in myofibres and in endothelial cells of the capillaries, 25% of the ERalpha-positive nuclei were located in the capillaries. ERalpha and ERbeta were generally expressed in the same nuclei. The present study shows for the first time the expression of ERalpha protein in human skeletal muscle independently of age and sex. These results might improve understanding of the physiological role of oestrogen in human skeletal muscle and raise new questions about activation of ERs in skeletal muscle.

Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case-control study nested in a cohort of Norwegian blood donors.

OBJECTIVE: To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA). METHODS: Case-control study nested in a prospective cohort of 31 330 blood donors in Oslo, Norway. Forty-nine donors developed RA up to 23 years after their most recent blood donation. Stored sera from these donors (case sera) and a sex- and age-matched sample of 245 healthy donors (control sera), and postdiagnostic sera from 33 of the 49 RA cases, were analysed for a panel of cytokines and cytokine-related markers, autoantibodies and antibodies against Epstein-Barr virus and parvovirus B19. RESULTS: Cytokines and cytokine-related markers were generally negative in case sera from >5 years before the diagnosis of RA. In the 5-year interval immediately before the diagnosis of RA, more case than control sera were positive (odds ratios >2) for interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-alpha and soluble tumour necrosis factor receptor I. In postdiagnostic sera, however, 11 of 16 examined cytokines and cytokine-related markers were statistically significantly elevated compared with control sera. Seropositivity for IgG antibodies against cyclic citrullinated peptides and for IgM and IgA rheumatoid factors were seen in case sera from up to 18 years before the diagnosis of RA. IgG antibodies against Epstein-Barr virus and parvovirus B19 did not differ significantly between case and control sera. CONCLUSIONS: Cytokines and cytokine-related markers appear to be upregulated rather late in RA pathogenesis. In contrast, IgM rheumatoid factor and IgG anti-cyclic citrullinated peptide autoantibodies may precede the diagnosis of RA by up to two decades.

[Diagnostic strategies for autoimmune rheumatic diseases]. / Diagnostische Strategien bei rheumatischen Autoimmunerkrankungen.

In order to help the clinical rheumatologist set an early and precise diagnosis and plan a rational follow-up, a close collaboration between all parties involved in the diagnostic work-up must be established. Autoimmune serology plays a key role in achieving this goal by choosing test methods that are ideal from a clinical standpoint and by presenting results obtained in such a fashion that even less experienced clinicians can correctly use the information. Simple algorithms for test ordering and for the interpretation of laboratory findings are of great benefit in daily practice, but such tools must be mutually agreed upon by the laboratory and clinical scientists. A precise diagnosis and estimation of prognosis is instrumental for optimal decision making in the clinic, but this is too complicated to be left to chance due to the inappropriate use of information. Late or wrong decisions during follow-up lead to unnecessary suffering and far higher lifetime costs for chronic diseases such as those found in rheumatology.

European attempts to set guidelines for improving diagnostics of autoimmune rheumatic disorders.

The rational way to set a diagnosis and estimate a prognosis in rheumatology is to start by setting a tentative diagnosis and then follow a fixed scheme for laboratory testing, eg, by using an agreed algorithm. The use of order algorithms can be extended to post-test algorithms that will assist clinicians in approaching the right diagnosis and prognosis. New methods used in autoimmune serology do not deliver results that can be directly compared to those of older methods, and thus the new methods need to be thoroughly tested with sera from differential diagnostically relevant disease controls to set a clinically meaningful cut-off for positivity. Borderline positive results need to be treated with special care to avoid misuse. Early diagnosis is of great importance, and serological results can be very useful if used the right way. European efforts to secure rational diagnostic work-up in autoimmune rheumatic disease have led to a better dialogue between clinicians and laboratory scientists in several countries.

Anti-nuclear autoantibodies: clinical utility for diagnosis, prognosis, monitoring, and planning of treatment strategy in systemic immunoinflammatory diseases.

The determination of serum autoantibodies to nuclear and cytoplasmic cell components is relevant to the diagnosis of chronic immunoinflammatory disorders. Detection is based on screening methods that allow antibody binding to intact cell structures, followed by use of assays to demonstrate their antigen target specificity. The results can be used to help clinicians set diagnosis and estimate prognosis, plan further diagnostic work-up, monitoring strategy and sometimes therapeutic approach. To obtain such accuracy of use clinicians need to be involved in revealing the differential diagnostic potential of the autoimmune serology test programme by furnishing detailed clinical data on patients from whom serum samples have been obtained. Borders between positive and negative values should aim at attaining a high diagnostic specificity towards clinically important disease controls.

High serum levels of YKL-40 in patients with systemic sclerosis are associated with pulmonary involvement.

OBJECTIVES: YKL-40, a growth factor of connective tissue cells, is elevated in sera from patients with diseases characterized by inflammation, tissue remodelling, or fibrosis. The aim of the study was to determine serum YKL-40 levels in patients with systemic sclerosis (SSc) and to explore any possible clinical and prognostic associations. METHODS: YKL-40 was measured in sera from 88 patients with SSc (26 with diffuse and 62 with limited skin involvement) and in sera from 88 matched healthy controls. Immunohistochemical staining for YKL-40 antigen was performed in a biopsy from a patient with pulmonary SSc. RESULTS: Serum YKL-40 levels of the SSc patients were significantly higher than those of the controls (p<0.00001). Patients with pulmonary fibrosis by chest X-ray, obstructive ventilatory pattern, reduced diffusing capacity (DLco), and digital joint deformity due to skin retraction had significantly higher serum YKL-40 compared with patients without these findings. Patients with elevated serum YKL-40 had shorter survival times than patients with normal serum YKL-40 (p = 0.0005), although this was not independent of age and pulmonary function. YKL-40 protein expression was found in inflammatory cells in fibrosing pulmonary tissue from a patient with SSc. CONCLUSIONS: Serum YKL-40 is elevated in patients with SSc with pulmonary involvement.