RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1.

RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of γ-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors.

Vitamin D and vitamin K status in postmenopausal women with normal and low bone mineral density.

OBJECTIVES: Vitamin D and K are believed to promote bone health, but existing evidence is controversial. This study aimed to measure several metabolites of both vitamins by liquid chromatography tandem mass spectrometry (LC-MS/MS) in a cohort of postmenopausal women with low and normal bone mineral density (BMD). METHODS: Vitamin metabolites (25-hydroxyvitamin D (25[OH]D), 24,25-dihydroxyvitamin D (24,25(OH)2D), phylloquinone (K1), menaquinone-4 (MK-4) and MK-7) were measured in 131 serum samples by LC-MS/MS. The vitamin D metabolite ratio (VMR) was calculated. Parathyroid hormone (PTH), type I procollagen-N-terminal-peptide (PINP) and C-terminal telopeptides of type I collagen (CTX-I) were measured by immunoassay. Dual X-ray absorptiometry was performed to identify participants with normal (T-score>-1) and low (T-score<-1) BMD. RESULTS: Mean age was 58.2±8.5 years. BMD was normal in 68 and low in 63 women. Median (interquartile range) for 25(OH)D and total vitamin K concentrations were 53.5 (39.6-65.9) nmol/L and 1.33 (0.99-2.39) nmol/L. All vitamin metabolites were comparable in individuals with normal and low BMD. Furthermore, BMD and trabecular bone score were comparable in participants with adequate and inadequate vitamin status (at least one criterion was met: 25(OH)D <50 nmol/L, 24,25(OH)2D <3 nmol/L, VMR <4 %, total vitamin K <0.91 nmol/L). PTH, but not PINP or CTX-I, was inversely correlated with 25(OH)D, 24,25(OH)2D and VMR. Synergistic effects between vitamin D and K were not observed. CONCLUSIONS: Vitamin D and K status is not related to BMD and trabecular bone quality in postmenopausal women. Inverse associations were only seen between vitamin D metabolites and PTH.

Shoulder Dysfunction in Parkinson Disease: Review of Clinical, Imaging Findings and Contributing Factors.

This study aimed to review shoulder clinical and imaging findings in Parkinson's disease (PD), focusing on the significance of timely diagnosis and management of shoulder dysfunction in PD for the prevention of shoulder-related complications. A bibliographical search was employed, using "Parkinson's" and "Shoulder Dysfunction" as keywords. A Magnetic Resonance Imaging, twenty clinical and three US studies were selected as relevant to shoulder dysfunction in PD. Shoulder pain, frozen shoulder and arm swing asymmetry are the most prevalent clinical findings that may antedate cardinal PD symptoms. Supraspinatus tendon thickening or tearing, adhesive capsulitis, acromioclavicular changes, bursa and joint effusion are common shoulder MRI or US-detected abnormalities in mild or severe PD stages. Fractures due to falls or osteoporosis are secondary shoulder pathologies. Higher ipsilateral Unified Parkinson's Disease Rated Scale (UPDRS) scores, rigidity, tremor, and bradykinesia are associated with frozen shoulder. Disease duration, rigidity, and falls are contributing factors for tendon tears, adhesive capsulitis, and fractures respectively. When common symptoms, such as pain and frozen shoulder are unaccounted for by orthopedic or other local primary pathology, they might indicate underlying early PD. Timely diagnosis and appropriate early management of PD may, in turn, help delay or prevent shoulder-related complications.

Suggestion of a Novel Classification Based on the Anatomical Region and Type of Bilateral Fatigue Femoral Fractures.

Purpose: Bilateral fatigue femoral fractures (BFFF) represent an extremely rare clinical entity. The present study introduces a novel classification, in order to categorize the BFFFs and provide a thorough review of all these, so far in the literature, reported cases. Methods: The BFFF were classified taking into account the anatomical region of the femoral fracture; (fh): femoral head, (sc): sub-capital, (pt): peri-trochanteric, (st): sub-trochanteric, (s): shaft, (d): distal femur and the fracture type (complete or incomplete); type I: bilateral incomplete fractures, type II: unilateral incomplete fracture, and type III: bilateral complete fractures. Type III was further subdivided into type IIIA: bilateral non-displaced fractures, type IIIB: unilateral displaced fracture, and type IIIC: bilateral displaced fractures. Furthermore, a meticulous review of the PubMed and MEDLINE databases was conducted to locate all articles reporting these injuries. Results: A total of 38 patients (86.8% males), with a mean age of 25.3 years, suffering BFFFs were identified from the literature search. The mean time interval from symptoms' onset to diagnosis was 54 days. According to the proposed classification, 2.6% of the fractures were categorized as type I (h), 36.8% as type I (sc), 2.6% as type I(st/s), 7.9% as type I (s), 2.6% as type I (d), 5.4% as type II (fh), 26.3% as type II (sc), 2.6% as type IIIA (st), 2.6% as type IIIA (d), 5.4% as type IIIB (sc), 2.6% as type IIIB (d) and 2.6% as type IIIC (sc). Surgery was performed in 52.6%, while non-operative treatment was followed in 47.4% of the population. Regarding the fracture type, 75% of type I fractures were conservatively treated, while 91.7% and 66.6% of type II and III fractures were surgically treated. For patients treated conservatively, the mean time from diagnosis to return to previous status was 260 days, while for patients treated surgically, 343 days. Conclusions: BFFFs, although rare, may pose a diagnostic and therapeutic challenge. The present classification offers valuable information and may act as a guide for the management of these patients.

Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism.

The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community's attention towards designing an FGF23-inhibitor as a potential specific therapy. The monoclonal antibody burosumab was approved for the treatment of children and adult patients with X-linked hypophosphatemia and recently for tumor-induced osteomalacia patients, demonstrating benefits regarding their symptoms, biochemical profile and bone mineralization status. Asfotase alfa is a hydroxyapatite-targeted recombinant alkaline phosphatase, an enzymatic replacement therapy, substituting the defective activity of tissue non-specific alkaline phosphatase, in patients suffering from hypophosphatasia. Promising data regarding its favorable effect on survival rate, bone quality, fracture healing, muscle strength, mobility, respiratory function, and general quality of life have led to the approval of the drug for the treatment of childhood-onset hypophosphatasia. Given the high costs of treatment for both agents and their limited clinical use until now, more data are needed to define patients' characteristics that make them ideal candidates for therapy. Long-term safety issues also need to be clarified.

The effect of table olive wastewater extract administration on the adult ovariectomised rat model of osteoporosis.

Recent efforts for alternative non-pharmaceutical treatments for postmenopausal osteoporosis are focused on nutritional measures. The aim of this study was to investigate the effect of table olive wastewater extract (OE) administration on bone mineral density (BMD) and biomechanical strength in ovariectomised rats. Thirty mature 9-month-old female Wistar rats were separated into three groups of ten: Control, Ovariectomised (OVX) and OVX + OE. BMD was measured before ovariectomy, 3 and 6 months afterwards. At the end of the study, blood, both femurs and tibias, internal organs and abdominal fat were collected. After 3 months, the percentage changes from baseline of the total and proximal tibial BMD of the OVX + OE group were both higher compared with the OVX group (P < 0·005). Similar results were found after 6 months, when the percentage changes from baseline of the total and proximal tibial BMD of the OVX + OE group were both higher compared with the OVX group (P < 0·005). Biomechanical testing of the femurs did not reveal any statistically significant difference between the groups. Body weights throughout the study, organs' and abdominal fat ratios to final body weight and blood results (alanine aminotransferase (ALT), gamma-glutamyltransferase (γ-GT), total cholesterol, HDL-cholesterol, LDL-cholesterol, Ca and P) were within normal limits and did not show any significant difference between the treated and untreated groups. As a conclusion, the administration of OE for 6 months protected tibial BMD loss in comparison with the untreated OVX group without causing adverse effects.

Association of vitamin D, BMD and knee osteoarthritis in postmenopausal women.

OBJECTIVES: The aim of this study was to analyze the association of knee OA with bone mineral density (BMD) and vitamin D serum levels in postmenopausal women. METHODS: A cross-sectional study including 240 postmenopausal women with knee OA was conducted. Demographic data were recorded along with balance and functionality scores. Knee OA severity was assessed by the radiological Kellgren & Lawrence scale. BMD and T-scores were calculated in hips and lumbar spine. Serum levels of vitamin D were also measured. RESULTS: High BMI (p<0.005), high number of children (p=0.022) and family history of hip fracture (p=0.011) are significantly associated with knee OA severity. Lumbar spine OP is negatively associated with knee OA (p<0.005). A significant difference was detected between vitamin D deficiency and severe knee OA, adjusted for BMD [OR (95%CI); 3.1 (1.6-6.1), p=0.001]. BMD does not affect the relationship of vitamin D levels in relation to OA and vitamin D levels do not affect the relationship of BMD with OA. CONCLUSIONS: Low BMD has a protective role against knee OA while vitamin D deficiency contributes significantly to knee OA severity. However, the association between OA and OP is not affected by vitamin D deficiency and the association of OA and vitamin D serum levels is not affected by BMD.

Change in kyphosis does not affect the risk of falling in postmenopausal osteopenic and osteoporotic women.

OBJECTIVES: To examine the influence of the annual change in kyphosis on the risk of falling in postmenopausal osteopenic and osteoporotic women. METHODS: This prospective observational study included 498 postmenopausal Greek women over the age of 50, suffering from either osteoporosis or osteopenia. Data on age, height, weight, and self-reported falls were collected. Additionally, we evaluated the degree of the kyphosis angle, the balance, the mobility, the functionality and the handgrip strength on both hands of each subject using the Debrunner kyphometer, the Berg Balance Scale, the Timed-Up-and-Go test, the 30 Seconds Sit-to-Stand test and the Jamar Hydraulic Hand Dynamometer, respectively. All the above data were recorded at the baseline visit and the 12-month follow-up visit for each participant. RESULTS: All examined variables presented a statistically significant change at the 12-month follow-up visit. Nevertheless, the annual change in kyphosis did not show any association with the risk of falling. CONCLUSION: No association was shown between the annual change in kyphosis and the risk of falling in postmenopausal osteopenic and osteoporotic women, nor bears any substantial prognostic value for future falls.

Mitchell's osteotomy augmented with bio-absorbable pins for the treatment of hallux valgus: A comparative finite element study.

BACKGROUND: There is an inadequacy of conventional means to assess the surgical outcomes of a bunion surgery. We used the Finite Element Analysis for evaluating the typical Mitchell's procedure outcomes with or without bio-absorbable pins. METHODS: We developed a 3D FE model based on the CT images of a female volunteer with hallux valgus. A typical procedure was simulated on the foot model and two pins were virtually inserted for enhancing the fixation. We validated our model by comparing the predicted pressure results with the plantar pressure measured by a specific platform. RESULTS: The comparison of the plantar pressure distribution revealed similar patterns. A greater displacement was observed on the medial side of the osteotomy, but it was decreased after using pins. The maximum average pressure under the 1st metatarsal head was decreased after the osteotomy. The respective pressure under the 3rd and 5th metatarsal head was decreased more after using pins, while, under the 2nd and 4th metatarsal head, an increase was developed. CONCLUSION: The use of pins had no significant influence on the healing process but gave additional stability inside the osteotomy and could be used in cases where enhancement is needed. The surgeon should be familiar with the expected stress rising to the other metatarsal, considering the concomitant pathology or the additional interventions that should be performed.

Long-term outcome of arthroscopic remplissage in addition to the classic Bankart repair for the management of recurrent anterior shoulder instability with engaging Hill-Sachs lesions.

PURPOSE: The evaluation of the long-term outcome of the arthroscopic remplissage performed in addition to the classic Bankart repair for the primary management of recurrent anterior shoulder instability with engaging Hill-Sachs lesion without inverted pear appearance of the glenoid during arthroscopy. METHODS: During a 6-year period, from 2007 to 2012, 65 patients whose average age was 30.1 ± 7.6 years were operated on in our department and satisfied the inclusion criteria of this study. They all had a positive apprehension sign preoperatively. Among them, 51 patients (82%) were available for long-term evaluation. The mean follow-up period was 8.1 ± 1.8 years (range 5.6-10.6). RESULTS: Three patients (5.6%) had suffered a new dislocation. The remaining patients (94.4%) were satisfied with the surgical result and returned to their previous daily activities, whereas 71% continued to participate in sports without restrictions. The ASES score increased from 72.5 (range 18-100) preoperatively to 100 (range 85-100) postoperatively (p < 0.01). The modified Rowe score increased from 40 (range 15-70) to 100 (range 70-100) (p < 0.001), and the Oxford Instability score from 29 (range 9-47) to 48 (range 36-48) (p < 0.001). No significant restriction in the shoulder range of motion was documented. CONCLUSIONS: The combination of the arthroscopic remplissage with the classic Bankart repair was proven to be a safe and effective procedure for the treatment of "engaging" Hill-Sachs lesions without inverted pear appearance of the glenoid. This combination has long-term outcomes in terms of the recurrence rate and does not significantly influence the range of motion of the shoulder. LEVEL OF EVIDENCE: Therapeutic Study-Case series with no comparison group, Level IV.

Jules Pean (1830-1898)-A Pioneer Surgeon: His Achievements and His Total Shoulder Arthroplasty.

The purpose of this study is to summarize the life and work of the French surgeon Jules Pean (1830-1898). Pean made an impact in the history of surgery through his work and especially with his innovative surgical techniques in abdominal surgery and in orthopedics as well as with the invention of numerous surgical instruments. He also made an impact with his pioneering total shoulder arthroplasty.

Abulcasis (936-1013): his work and contribution to orthopaedics.

AIM OF THE STUDY: The purpose of this historic review is to summarize the life and work of Abulcasis (936-1013) and his contribution to surgery and orthopaedics. METHOD: We conducted an extensive search in libraries as well as online in PubMed and Google Scholar. RESULTS: Abulcasis in his work combines the knowledge of ancient Greek and Roman physicians and surgeons with the extensive knowledge of Arabic medicine and pharmacology. He also pioneered surgical technique with the invention of numerous surgical instruments and with several revolutionary surgical techniques. CONCLUSION: Abulcasis made an impact with his medical writings in which he summarized the works of ancient Greek and Roman physicians like Hippocrates and Galen with the influence of medieval authors and the knowledge of the Arabic medicine and pharmacology. His descriptions and innovations in his work remained a work of reference in the West and East for many centuries to come.

Clinical manifestations of osteoarthritis in osteoporotic and osteopenic postmenopausal women.

OBJECTIVE: We investigated the frequency of clinical manifestations of osteoarthritis in women with low BMD. METHODS: This prospective epidemiological study investigated the degree of osteoarthritic pain and functional disability in symptomatic joints of a randomly selected population of postmenopausal Greek women aged >45 years with osteoporosis or osteopenia. Degree of osteoarthritic impairment (none, mild, moderate or severe) was classified at the knee, hip, neck or hand using a site-specific internationally validated osteoarthritis questionnaire. RESULTS: 3000 women were included with mean age of 66.7 years. Osteoporosis was more common than osteopenia. Mild osteoarthritic impairment was most prevalent. An inverse relationship between severity of osteoarthritic impairment and mean femoral neck T-score was observed, regardless of site. There was a significant difference in mean femoral neck T-score between patients with severe osteoarthritic impairment and those with no, mild, or moderate impairment. This was also observed when lumbar spine BMD results were pooled. CONCLUSIONS: Most postmenopausal women with low BMD suffer from osteoarthritic impairment, with an inverse association between severity of osteoarthritic impairment and mean femoral neck T-score. Mean lumbar spine or femoral neck T-scores of patients with severe osteoarthritic impairment were significantly lower than those of patients with less impairment.

Association between abductor muscle strength and functional outcomes in hip-fractured patients: a cross-sectional study.

OBJECTIVES: To explore associations between abductor strength and functionality in hip-fracture patients. METHODS: Ninety-six participants (70-84 years) followed a 12-week physiotherapy programme emphasizing hip abductor strengthening. The abductor's isometric strength, the hip strength asymmetry (HSA), expressing the ratio of abductor strength in the fractured versus the contralateral hip, and the patients' functional level were recorded 3 months post-intervention. Functionality was assessed using the Timed Up & Go (TUG) test and the Lower Extremity Functional Scale (LEFS-Greek). RESULTS: Abductor isometric strength and HSA were correlated negatively with TUG test (Pearson's r: -0.881 and -0.810, respectively; p⟨0.001) and positively with LEFS-Greek (Spearman's ρ: 0.668 and 0.404, respectively; p⟨0.001). Of all independent variables examined, abductor isometric strength was the main predictor of functional capacity, being strongly and directly associated with a faster TUG test time (p⟨0.001) and a better LEFS-Greek score (p⟨0.001). Abductor's isometric strength and age explained 79.0% and 49.5%, whereas HSA and age explained 69.7% and 41.9% of TUG and LEFS-Greek variance, respectively. CONCLUSIONS: Abductor isometric strength was the main predictor of hip-fracture patients' functionality, strongly enhancing the measured functional outcomes. Hip abductor strengthening appears to be of major clinical importance and may contribute significantly to the functional rehabilitation of hip-fractured patients.

Effects of mechanical loading on the expression of pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in a rat spinal deformity model.

Mechanical loading of the spine is a major causative factor of degenerative changes and causes molecular and structural changes in the intervertebral disc (IVD) and the vertebrae end plate (EP). Pleiotrophin (PTN) is a growth factor with a putative role in bone remodeling through its receptor protein tyrosine phosphatase beta/zeta (RPTPß/ζ). The present study investigates the effects of strain on PTN and RPTPß/ζ protein expression in vivo. Tails of eight weeks old Sprague-Dawley rats were subjected to mechanical loading using a mini Ilizarov external apparatus. Rat tails untreated (control) or after 0 degrees of compression and 10°, 30° and 50° of angulation (groups 0, I, II and III respectively) were studied. PTN and RPTPß/ζ expression were evaluated using immunohistochemistry and Western blot analysis. In the control group, PTN was mostly expressed by the EP hypertrophic chondrocytes. In groups 0 to II, PTN expression was increased in the chondrocytes of hypertrophic and proliferating zones, as well as in osteocytes and osteoblast-like cells of the ossification zone. In group III, only limited PTN expression was observed in osteocytes. RPTPß/ζ expression was increased mainly in group 0, but also in group I, in all types of cells. Low intensity RPTPß/ζ immunostaining was observed in groups II and III. Collectively, PTN and RPTPß/ζ are expressed in spinal deformities caused by mechanical loading, and their expression depends on the type and severity of the applied strain.

Clinimetric properties of WOMAC Index in Greek knee osteoarthritis patients: comparisons with both self-reported and physical performance measures.

This observational study aimed to examine the clinimetric properties of the Greek for Greece translation of the Western Ontario and McMaster Osteoarthritis Index (WOMAC(®)). One hundred and twenty-three patients with knee osteoarthritis (mean age 69.5 years) participated in the study. An extensive reliability study was carried out to assess WOMAC's internal consistency and repeatability (8-day interval). In addition, we examined the construct (convergent, nomological and known-groups) and criterion-related (concurrent and predictive) validity of the index against both self-report [SF-36 and combined visual analog/faces pain scale-revised (VAS/FPS-R)] and physical performance measures [timed up and go test (TUG)]. The internal consistency of the WOMAC subscales ranged from high (0.804) to excellent (0.956). Intra-class correlation coefficients for test-retest reliability were excellent, ranging from 0.91 to 0.95. Partial correlation analysis, adjusted for age and use of an assistive device, showed that WOMAC scores were significantly associated with all validation criteria, presenting fair to strong (-0.33 to -0.86) correlation coefficients. WOMAC-function was strongly associated with SF36-function (-0.86) and TUG (0.71), WOMAC-pain to VAS/FPS-R (0.71) and SF36-pain (-0.67). Of all WOMAC outcomes, stiffness subscale had the lowest, though still significant, correlations with all validation criteria. Multiple linear regression analyses indicated that WOMAC-function was a significant factor for TUG, WOMAC-pain for VAS/FPS-R and both for SF36-function and SF36-pain. The WOMAC LK3.1 Greek for Greece Index is a reliable and valid assessment tool for the evaluation of individuals with knee osteoarthritis, showing excellent reliability and significant validity properties.

Macrophage-specific metalloelastase (MMP-12) immunoexpression in the osteochondral unit in osteoarthritis correlates with BMI and disease severity.

BACKGROUND: Metalloproteinase 12 (MMP-12) is induced in chondrocytes during fetal development and malignant transformation. OBJECTIVES: The aim of our study is to examine the expression of MMP-12 in the cartilage and the subchondral bone of patients with osteoarthritis (OA) and to correlate its expression with disease severity and anthropometric characteristics. METHODS: Overall, 60 sections from 20 patients with idiopathic OA, were examined for the immunolocalization of MMP-12. As controls, we used the femoral heads of 4 patients treated with seniarthroplasty after fracture. Demographic characteristics and Body Mass Index (BMI) were calculated for all subjects. RESULTS: Specimens were divided into four groups based on the Mankin histological severity score. The immunohistochemical study showed MMP-12 expression in the cartilage and subchonral bone of OA patients, while there was no expression in normal controls. At the moderate OA changes (Mankin score: 6-7), MMP-12 was detected mainly at the matrix of fibrocartilage tissue. During disease progression, MMP-12 was expressed at the sides of the cartilage and bone erosion and in the bone cysts. Furthermore, it was traced in the osteocytes of the subchondral bone. Osteoblast-like cells and bone lining cells express MMP-12 during the stage of severe OA (Mankin: ≥8). Osteoclasts expressing MMP-12 were also detected in the group of severe OA. Interestingly, MMP-12 expression was positively correlated with the age and the BMI of OA patients. CONCLUSION: The increased expression of MMP-12 in the bone-cartilage unit of OA patients suggests a possible role in OA pathogenesis and progression. LEVEL OF EVIDENCE: III, prospective comparative study.