Increased levels of inflammatory markers in the subscapularis tendon and joint capsule in patients with subacromial impingement.

PURPOSE: To analyze biopsy samples from the subscapularis tendon and from the joint capsule from male patients with subacromial impingement syndrome and compare them with samples from male patients with post-traumatic recurrent shoulder instability, to detect increased inflammatory activity that might be present inside the humeroscapular joint. METHODS: Twenty male patients scheduled for surgery for either subacromial decompression or Bankart reconstruction were included. Four biopsies from each patient were obtained during surgery from the capsule and the subscapularis tendon. Each specimen was analyzed for TNF-α, IL-6, CD-3 and CD-72. Multiplex fluorescence immunohistochemistry was performed on histological samples from the capsule and tendon to demonstrate the level of inflammatory markers. Fluorescence microscope images were acquired using an automated scanning system. On each slide, the number of pixels was registered and used in the analyses. RESULTS: The subacromial impingement syndrome group comprised eight patients, median age 53 (45-74) years, while the instability group 12, median age 27 (22-48) years (p < 0.00001). The amount of IL-6 and TNF-α was significantly higher in the subscapularis tendon of the patients with subacromial impingement syndrome compared with instability patients (p = 0.0015 and p = 0.0008 respectively). In the capsular samples, significantly higher amount of TNF-α and CD-72 was found in patients with subacromial impingement syndrome compared with instability patients (p < 0.0001 for both). On the other hand, the amount of CD-3 was significantly higher in the instability group (p = 0.0013). CONCLUSIONS: This study provides evidence that an extended inflammatory process is present, not only in the subacromial bursa but also in the glenohumeral joint in patients with subacromial impingement syndrome. LEVEL OF EVIDENCE: Level III. CLINICAL RELEVANCE: To develop a treatment targeted towards intra-articular inflammatory cytokines appears appealing.

ENDOCRINE REGULATION OF ERYTHROID LINEAGE OF HEMATOPOIESIS IN CHILDREN LIVING UNDER A LOW-DOSE RADIATION EXPOSURE AFTER THE CHORNOBYL NPP ACCIDENT. / ENDOKRYNNA REGULIaTsIIa ERYTROTsYTARNOÏ LANKY GEMOPOEZU V DITEI, IaKI ZhYVUT' NA RADIOAKTYVNO ZABRUDNENYKh TERYTORIIaKh PISLIa AVARIÏ NA ChAES.

OBJECTIVE: Elucidation of relationship between the levels of thyroid-stimulating hormone (TSH), free serum thyroxine, serum and urine cortisol and parameters of erythroid lineage of hematopoiesis to estimate the thyroid functionin children of prepubertal, pubertal, and postpubertal age permanently residing under a low-dose radiation exposureto determine the premorbid state of thyroid function. MATERIALS AND METHODS: Children aged 3 to 18 years old (n = 203) living in the most intensively radionuclide-contaminated regions of Kyiv, Zhytomyr and Chornihiv oblasts of Ukraine after the Chornobyl NPP accident wereenrolled. Complaints of ossalgia, arthralgia, fatigue, bone fractures in the history, bone dysembryogenetic stigmata,hypermobility syndrome degree, and types of somatic diseases were taken into account. Peripheral blood countparameters, biochemical indices of blood serum were studied, namely the levels of total protein, cholesterol, creatinine and alkaline phosphatase activity. Levels of the free thyroxine, pituitary TSH, serum and daily urine cortisol, anddoses of radiation exposure were determined. RESULTS: The radiation dose values in children ranged from (0.35 ± 0.09) mSv to (0.54 ± 0.12) mSv. There was nodifference between the parameters of erythroid lineage of hematopoiesis depending on radiation dose. At the levels of serum TSH up to 1.0 µIU/ml no correlation was found with cortisol levels; at TSH levels of 1.0-3.0 µIU/ml thecorrelation coefficient was r = 0.31; at TSH levels higher than 3.0 µIU/ml the correlation coefficient was r = 0.61probably indicating a compensatory role of adrenal cortex in children at risk of thyroid disease development. In children with joint hypermobility grade II there was a higher incidence of dentofacial anomalies (χ2 = 6.9), deformitiesof lower extremities (χ2 = 6.9), and dental caries (χ2 = 4.3) (p < 0.05). There was a direct correlation between theserum TSH level (over 3 µIU/ml) and micrognathia (brachygnathia) (r = 0.62) indicating the impact of thyroid disease on dentofacial development. The TSH at a level of upper limit of the reference range values may contribute toa decreased RBC count in peripheral blood, increased average volume and hemoglobin content in erythrocyte beingassociated with the initial manifestations of thyroid dysfunction. CONCLUSIONS: Abnormal endocrine regulation of hematopoiesis affects the connective tissue, stromal microenvironment of bone marrow, and accordingly the erythroid branch of hematopoiesis in children, which may be relevant inthe development and course of oncohematological diseases.

FEATURES OF CLINICAL SYMPTOMS AND SIGNS, HEMATOLOGICAL AND BIOCHEMICAL PARAMETERS IN CHILDREN WITH JOINT HYPERMOBILITY IN A LATE PERIOD UPON THE CHORNOBYL NPP ACCIDENT. / OSOBLYVOSTI KLINIChNOÏ SYMPTOMATYKY, GEMATOLOGIChNYKh TA BIOKhIMIChNYKh POKAZNYKIV U DITEY̆ Z GIPERMOBIL'NISTIu SUGLOBIV U VIDDALENYY̆ PERIOD PISLIa AVARIÏ NA ChORNOBYL'S'KIY̆ AES.

OBJECTIVE: establishing the types and frequency of disembriogenetic stigma in children with joint hypermobility given the clinical and laboratory features, genetic component and endocrine regulation of these disorders in a late period upon the accident. MATERIALS AND METHODS: Children (n = 109) inhabiting the radiologically contaminated territories and having the connective tissue dysplasia (CTD) signs were involved in the study. Diseases in family history, ossalgia complaints, fractures in a personal history, bone disembriogenetic stigma, joint hypermobility, type of somatic diseases, blood serum biochemical parameters (namely calcium, alkaline phosphatase, total protein, cholesterol, creatinine, iron, ferritin content), serum cortisol, free thyroxine, pituitary thyroid-stimulating hormone (TSH) levels, free amino acid composition in urine and radiation dose were considered. RESULTS: Radiation doses in children having the CTD ranged from (0.37 ± 0.11) mSv to (0.56 ± 0.10) mSv with no difference from that in those without CTD. Joint hypermobility (JHM) correlated with cancer in family history (rs = 0.53) and lower extremity varicose vein disease (rs = 0.40) (p < 0.05). Incidence of ossalgia, easy fatigability, and bone fractures was higher in children with CTD. Anomalies of the dentofacial system were first in line (38.5 %) in these children. Proportion of children with grade II JHM and platypodia was lower (rs = 0.42), but with lower extremity deformations was higher (rs = 0.68) (p < 0.05) vs. in the control group. Iron and ferritin deficiencies both with lymphocytosis were more common in children with CTD than in the comparison group (p < 0.05). The increased content of oxyproline, lysine, proline both with glycine deficiency were detected in children having the CTD, i.e. an imbalance of amino acids from the collagen content was observed featuring a predominance of catabolic processes over anabolic ones. There was a direct correlation between the TSH level and the JHM grade (rs = 0.49), although the values of hormone concentration in these children did not exceed the reference range (maximum values were 3.3 µIU/ml). CONCLUSIONS: The revealed abnormalities in amino acid content, ferrokinetics, and thyroid function indices can affect the collagen formation, organic matrix structure of bone tissue and significantly deregulate the hemato- poiesis. The later can underlie the pathways of haematologic malignancy development.

Adhesive capsulitis of the shoulder: protocol for the adhesive capsulitis biomarker (AdCaB) study.

BACKGROUND: Adhesive capsulitis (AC) is a disabling and poorly understood pathological condition of the shoulder joint. The current study aims to increase our understanding of the pathogenesis, diagnosis and clinical outcomes of people with AC by investigating: 1) transcriptome-wide alterations in gene expression of the glenohumeral joint capsule in people with AC compared to people with non-inflammatory shoulder instability (controls); 2) serum and urine biomarkers to better understand diagnosis and staging of AC; and 3) clinical outcomes in people with AC compared to controls 12-months following arthroscopic capsular release or labral repair respectively. METHODS: The study is a prospective multi-centre longitudinal study investigating people undergoing arthroscopic capsulotomy for AC compared to people undergoing arthroscopic stabilization for shoulder instability. Tissue samples collected from the anterior glenohumeral joint capsule during surgery will undergo RNA-seq to determine differences in gene expression between the study groups. Gene Set Enrichment Analysis will be used to further understand the pathogenesis of AC as well as guide serum and urine biomarker analysis. Clinical outcomes regarding pain, function and quality of life will be assessed using the Oxford Shoulder Score, Oxford Shoulder Instability Score, Quick DASH, American Shoulder and Elbow Society Score, EQ-5D-5 L and active shoulder range of movement. Clinical outcomes will be collected pre-operatively and 12-months post-operatively and study groups will be compared for statistically significant differences using linear regression, adjusting for baseline demographic variables. DISCUSSION: This study will provide much needed information regarding the pathogenesis, diagnosis and staging of AC. It will evaluate clinical outcomes for people undergoing arthroscopic release of AC by comparing this group to people undergoing arthroscopic surgery for shoulder instability. TRIAL REGISTRATION: ACTRN12618000431224 , retrospectively registered 26 March 2018.

17ß-Estradiol Induced Effects on Anterior Cruciate Ligament Laxness and Neuromuscular Activation Patterns in Female Runners.

BACKGROUND: We investigate the effects of 17ß-Estradiol across phases of menstrual cycle on the laxness of the anterior cruciate ligament (ACL) and the neuromuscular control patterns around the knee joint in female runners. METHODS: Twelve healthy female runners who reported normal menstrual cycles for the previous 6 months were tested twice across one complete menstrual cycle for serum levels of 17ß-estradiol, and knee joint laxity (KJL). Electromyographic (EMG) activity of the quadriceps and hamstrings muscles was also recorded during running on a treadmill. The changes in the EMG activity, KJL, and hormonal concentrations were recorded for each subject during the follicular and the ovulatory phases across the menstrual cycle. RESULTS: An observed increase in KJL in response to peak estradiol during the ovulatory phase was associated with increased preactivity of the hamstring muscle before foot impact (p<0.001). A consistent pattern was also observed in the firing of the quadriceps muscle recruitment pattern throughout the follicular phase associated with decreased hamstring recruitment pattern during weight acceptance phase of running (p=0.02). Additionally, a low ratio of medial to lateral quadriceps recruitment was associated with a significant reduction of the quadriceps to hamstring co-contraction ratio during the follicular phase. CONCLUSIONS: Changes in KJL during the menstrual cycle in response to 17ß-estradiol fluctuations changes the neuromuscular control around the knee during running. Female runners utilize different neuromuscular control strategies during different phases of the menstrual cycle, which may contribute to increased ACL injury risk.

Relationship of serum relaxin to generalized and trapezial-metacarpal joint laxity.

PURPOSE: The reproductive hormone relaxin acts to loosen pelvic ligaments in preparation for childbirth and is thought to be a mediator of joint laxity. The purpose of this study was to evaluate the correlation of serum relaxin with radiographic laxity at the trapezial-metacarpal joint and with generalized joint laxity. METHODS: We enrolled 289 healthy subjects prospectively. Participants completed a demographic questionnaire and were examined for generalized joint hypermobility using the Beighton-Horan scale. Stress radiographs of the trapezial-metacarpal joint were obtained in 163 subjects (56%). Blood samples were collected, and serum relaxin was measured for 287 subjects using enzyme-linked immunosorbent assay for human relaxin-2. RESULTS: The mean serum relaxin level among all subjects was 1.84 pg/mL (range, 0-45.25 pg/mL). Relaxin was not detectable in 166 of 287 samples, whereas the mean serum relaxin level among the 121 subjects with a detectable relaxin level (of 287 total relaxin samples) was 4.37 pg/mL (range, 0.46-45.25 pg/mL). Mean trapezial-metacarpal subluxation ratio scores were higher among those with a detectable relaxin level compared to those without a detectable relaxin level (0.34 vs 0.30 pg/mL). The average Beighton-Horan laxity score was 1.8 (range, 0-9). There was no correlation between generalized joint laxity measures and serum relaxin levels. CONCLUSIONS: In a large volunteer population, we demonstrated a relationship between circulating relaxin and trapezial-metacarpal joint laxity. However, we were unable to show a direct link between serum relaxin and generalized joint laxity. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

In vivo serum titanium ion levels following modular neck total hip arthroplasty--10 year results in 67 patients.

The objective of the present cross-sectional study was to determine in vivo titanium ion levels following cementless total hip arthroplasty (THA) using a modular stem system with different shapes for femoral canal fit and multiple neck options. A consecutive series of 173 patients (190 hips) who underwent cementless modular neck THA and a ceramic on polyethylene bearing with a median follow-up of 9 (7-13) years was evaluated retrospectively. According to a standardized protocol, titanium ion measurements were performed on 67 patients using high-resolution inductively coupled plasma-mass spectrometry. Ion levels were compared to a control group comprising patients with non-modular titanium implants (n=11) and to individuals without implants (n=23). Modular neck THA did not result in elevated titanium ion levels compared to non-modular THA. Compared to individuals without implants, both modular THA and non-modular THA showed elevated titanium ion levels. Absolute titanium ion levels, however, were comparatively low for both implants. The data suggest that the present modular stem system does not result in elevated systemic titanium ion levels in the medium term when compared to non-modular stems. Further longitudinal studies are needed to evaluate the use of systemic titanium ion levels as an objective diagnostic tool to identify THA failure and to monitor patients following revision surgery.

Alterations in knee joint laxity during the menstrual cycle in healthy women leads to increases in joint loads during selected athletic movements.

BACKGROUND: It has been speculated that the hormonal cycle may be correlated with higher incidence of ACL injury in female athletes, but results have been very contradictory. HYPOTHESIS: Knee joint loads are influenced by knee joint laxity (KJL) during the menstrual cycle. STUDY DESIGN: Controlled laboratory study. METHODS: Serum samples and KJL were assessed at the follicular, ovulation, and luteal phases in 26 women. Knee joint mechanics (angle, moment, and impulse) were measured and compared at the same intervals. Each of the 26 subjects had a value for knee laxity at each of the 3 phases of their cycle, and these were ordered and designated low, medium, and high for that subject. Knee joint mechanics were then compared between low, medium, and high laxity. RESULTS: No significant differences in knee joint mechanics were found across the menstrual cycle (no phase effect). However, an increase in KJL was associated with higher knee joint loads during movement (laxity effect). A 1.3-mm increase in KJL resulted in an increase of approximately 30% in adduction impulse in a cutting maneuver, an increase of approximately 20% in knee adduction moment, and a 20% to 45% increase in external rotation loads during a jumping and stopping task (P < .05). CONCLUSION: Changes in KJL during the menstrual cycle do change knee joint loading during movements. Clinical Relevance Our findings will be beneficial for researchers in the development of more effective ACL injury prevention programs.

Changing hormone levels during the menstrual cycle affect knee laxity and stiffness in healthy female subjects.

BACKGROUND: Whether knee laxity varies throughout the menstrual cycle remains controversial. As increased laxity may be a risk factor for anterior cruciate ligament (ACL) injury, further research is warranted. HYPOTHESIS: Variation in estradiol and progesterone levels during the menstrual cycle influences knee laxity and stiffness. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: The serum estradiol and progesterone levels of 26 healthy female subjects were recorded in the follicular phase, ovulation, and the luteal phase. Knee joint laxity was assessed using a standard knee arthrometer at the same intervals. Stiffness changes in the load-displacement curve were determined. Hormone levels across the cycle were compared between responders and nonresponders, defined by whether changes in knee laxity at 89 N occurred. RESULTS: Greater laxity at 89 N during ovulation was observed (ovulation: 5.13 +/- 1.70 mm vs luteal: 4.55 +/- 1.54 mm, P = .012). In knee laxity testing at manual maximum load, greater laxity was noticed during ovulation (14.43 +/- 2.60 mm, P = .018), as compared with the follicular phase (13.35 +/- 2.53 mm). A reduction in knee stiffness of approximately 17% (ovulation: 12.48 +/- 5.46 N/mm vs luteal: 15.02 +/- 7.71 N/mm, P = .042) during ovulation was observed. However, there were no differences in hormone levels between responders and nonresponders at 89 N. CONCLUSION: Female hormone levels are related to increased knee joint laxity and decreased stiffness at ovulation. To understand subject variations in knee joint laxity during the menstrual cycle in female athletes, further investigation is warranted.

Titanium serum levels may remain elevated despite hip revision surgery for wear-through of an acetabular component.

A 62-year-old female patient showed radiographic signs of severe linear wear of the acetabular component six years after cementless total hip arthroplasty. This suggested wear-through of the acetabular liner with secondary wear of the titanium shell. At revision surgery wear-through of both the inlay and the acetabular shell were confirmed. Despite meticulous debridement serum titanium levels remained elevated for more than 12 months. Wear-through of a polyethylene acetabular liner with secondary wear of the titanium shell can lead to increased titanium serum levels. Titanium serum levels can remain highly elevated despite revision surgery.

Vascular endothelial growth factor concentrations in synovial fluids of patients with symptomatic internal derangement of the temporomandibular joint.

BACKGROUND: Vascular endothelial growth factor (VEGF) is an inducer of angiogenesis and permeability of small blood vessels. We determined the concentrations of VEGF in synovial fluid of patients with symptomatic internal derangement of the temporomandibular joint (TMJ). METHODS: Diluted synovial fluid was collected by a pumping procedure from 22 TMJs of patients with internal derangement and 10 control TMJs. VEGF concentration was determined by an enzyme-linked immunosorbent assay. RESULTS: The VEGF was detected in 14 of the 22 joints (64%) of patients with internal derangement, at a mean concentration of 67 pg/ml, but in only one control joint (12.5 pg/ml) (P = 0.004 for the difference in concentration). There was a significant correlation between VEGF concentration and total protein concentration in the synovial fluid (P = 0.002). CONCLUSIONS: The increased concentration of VEGF in patients with symptomatic internal derangement suggests that this growth factor may be involved in the pathogenesis of this condition.

Serum 17 beta-estradiol in newborn and neonatal hip instability.

This study evaluates the association between the level of 17 beta-estradiol in the umbilical cord blood and neonatal hip instability (NHI) in a population-based prospective case-control study comprising 2,185 consecutively newborns. beta-Estradiol levels were measured with a standard fluoroimmunoassay kit. Neonatal hip instability was determined by the anterior dynamic ultrasound method. An increased risk of NHI was found after breech malposition and in girls. Levels of beta-estradiol were higher in boys without NHI than in girls. A negative association between beta-estradiol level and parity was found. A significant association between beta-estradiol level and NHI was shown in boys with low serum concentrations. High levels of beta-estradiol tended to be associated with an increased risk of NHI in girls. An association was found between gender, parity, and beta-estradiol level in cord blood. No firm conclusion on the association between NHI and beta-estradiol level can be made; the possible association may be gender-dependent.

Growth hormone, insulin, and insulin-like growth factor-1 in hypermobility syndrome.

OBJECTIVE: To investigate growth factors in patients with hypermobility syndrome (HMS), namely insulin, insulin-like growth factor-1 (IGF-1), and growth hormone (GH). METHODS: Standard radioimmunoassay quantified serum levels of insulin, IGF-1, and GH in 24 women and 7 men with HMS, and in suitable age and sex matched controls. Several patients with other heritable connective disorders were also studied, including congenital hip dysplasia and severe kyphosis. RESULTS: Patients with HMS and with otherwise unexplained joint and muscle pain were found to have elevated levels of insulin, IGF-1, and GH. Patients with heritable connective tissue disorders had elevated GH levels, and several patients had elevated insulin and IGF-1 levels. CONCLUSION: In patients with HMS, elevation of serum growth factors helps establish the diagnosis. GH alone can induce muscle and joint pain.

Correlation of estradiol in pregnancy and anterior cruciate ligament laxity.

The purpose of this study was to determine whether a correlation existed between estradiol in pregnancy and laxity of the anterior cruciate ligament by measuring anterior tibial translation. All patients underwent measurement of anterior tibial translation using KT-1000 knee arthrometer testing and serum estradiol determination during the third trimester of pregnancy and postpartum. Forty knees were studied. The average serum estradiol levels decreased from 10,755.0 ng/L to 50.3 ng/L. There was an average decrease anterior tibial translation with a manual maximum displacement of 3.0 mm (range, 1 mm-5 mm) from the first to second examinations. Average measurement of anterior tibial translation in pregnant women showed a statistically significant increase in laxity in the third trimester of pregnancy compared with the postpartum laxity. The results of this study show that high serum estradiol levels during the third trimester of pregnancy correlate with increased anterior tibial translation and that this anterior tibial translation decreases with the return of serum estradiol to nonpregnant levels.

Serum relaxin in the newborn is not a marker of neonatal hip instability.

It has been suggested that intrauterine exposure to high levels of relaxin causes hip instability in newborns. The aim of this work was to evaluate whether the serum relaxin concentration in umbilical vein blood is associated with hip instability in the newborn. Blood was collected by cordocentesis from 2,185 newborns, and serum relaxin levels were obtained by using a standard sandwich enzyme-linked immunosorbent assay (ELISA). Movement of the femoral head in the hip joint was determined for all 2,185 children by the anterior-dynamic ultrasound method. Hereby their status on neonatal hip instability was determined. Fifteen cases (12 girls, three boys) were found, and 106 controls were selected. Only six newborns had unstable hips to a degree requiring treatment. Ten newborns had Ortolani-positive hips. Only three specimens of the 121 samples measured had serum relaxin concentrations above the detection limit of 10 pg/ml. None of these were cases. This study does not show an association of serum relaxin with neonatal hip instability. It is suggested that detectable serum relaxin levels are found in samples from the umbilical cord only when these are contaminated with maternal blood.

Pathogenetic relevance of the pregnancy hormone relaxin to inborn hip instability.

The etiology of inborn hip dysplasia is unknown. In general, a multifactorial genesis is assumed. The influence of hormones on the development of the fetal hip joint and its stability is discussed as well as mechanical influences. This study was carried out with the intention to examine the correlation between the concentration of the pregnancy hormone relaxin and the stability of the hip joint in newborns. Both hips of 90 newborn children were examined clinically and sonographically. In 25 hips (13.9%), pathological sonograms according to the classification of Graf were found. The relaxin concentration was measured in cord blood using a heterologous radioimmunoassay. Statistical evaluation revealed an insignificant decrease of relaxin concentration with increasing sonographic hip instability. The results indicate that hip instability frequently occurs with decreasing relaxin concentration. These facts contradict the earlier assumption that hip instability coincides with increased relaxin concentrations in newborns. We assume that there is a worse preparation of the pelvis and the birth canal during pregnancy due to the lower relaxin concentration and thus that there could be a higher pressure on the fetus in the perinatal phase. A decreased relaxin concentration seems to have no direct effect on the hip joint tissue, but indirectly there is consequent rigidity of the tissue in mother and child, which can further promote the development of hip instability.